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From: SKERRITT, John

To: Cook, Jane;


Subject: RE: Craig Kelly email [SEC=OFFICIAL]
Date: Thursday, 10 September 2020 9:17:52 AM

Ok will prepare a brief response

Sent with BlackBerry Work (www.blackberry.com)

From: "
Sent: 10 Sep 2020 9:15 am
To: "SKERRITT John" < >; "Cook, Jane"

Subject: RE: Craig Kelly email [SEC=OFFICIAL]

Hi John

My view is that you should prepare a factual response to Mr Kelly on the key matters and the
position of the TGA – to come from the TGA

Lets discuss further

From: SKERRITT, John < >


Sent: Wednesday, 9 September 2020 7:04 PM
To: Cook, Jane < >;

Subject: FW: Craig Kelly email [SEC=OFFICIAL]

I think that I should respond to Mr Kelly through the Ministers office rather than get
involved in a back and forwards with him.

Your views?

Incidentally I do not agree that the dosing in the recovery study was incorrect. I
think that Mr Kelly has misread the papers.

John Skerritt

Sent with BlackBerry Work (www.blackberry.com)

From: "Kelly, Craig (MP)" <Craig.Kelly.MP@aph.gov.au>


Sent: 9 Sep 2020 5:29 pm
To: "SKERRITT, John" < >
Cc: "Greg.Hunt.MP" <Greg.Hunt.MP@aph.gov.au>
Subject: <no subject>

Dear Professor Skerritt,

I am writing to you as I am greatly concerned about the TGA’s advice “that it


strongly discourages the use of hydroxychloroquine to treat COVID-19”.

From the statement on the TGA’s website, this advice appears to be based
upon the recommendations from the National COVID-19 Clinical Evidence
Taskforce. And the Taskforce’s recommendations appear to be based
substantially upon the findings of the RECOVERY trial.

However the evidence appears to show that the RECOVERY trial was fatally
flawed, as in this trial they administered the group of patients taking HCQ
with 2400mg of the drug within the first 24 hours. All evidence indicates
that this was an excessive and toxic dose – 4 to 5 times the maximum
recommended. Further media reports indicate that this excessive dose was
the result of medical negligence where those running the RECOVERY trial
confused the drugs hydroxychloroquine with hydroxyquinoline.

Therefore, I believe there is a very strong that any results of the


RECOVERY should be disregarded in TGA making any recommendation.

I would also like to draw to your attention two meta-analysis studies


released in preprint in the past 48 hours. The first is a study out of France by
the Institut Hospitalo-Universitaire (IHU) Méditerranée Infection, which will
be published in the journal ‘Expert Review of Clinical Immunology’. This
most comprehensive study concluded for Covid-19;

‘’Treatment with an oral combination of hydroxychloroquine,


azithromycin and zinc may REPRESENT THE BEST CURRENT
THERAPEUTIC OPTION in relation to its antiviral and
immunomodulatory effects’’.

The second is a study from the US by Chadwick C Prodromos MD and Tobias


Rumschlag MD in which they concluded;

This study has four important findings. The first is that HCQ appears
to be consistently effective for the treatment of COVID-19 when used
early in the course of disease in the outpatient setting, and is generally
more effective the earlier it is used. The second is that overall HCQ has
had efficacy against COVID-19 in a majority of studies. The third is
that there are no unbiased studies showing a negative effect of HCQ
treatment of COVID-19. The fourth is that HCQ appears to be safe for
the treatment of COVID-19 when used responsibly.

And the authors further noted;

SIGNIFICANCE: We believe our findings have substantial societal


global importance since there have been numerous edicts either
preventing HCQ use for COVID-19 or limiting it to the inpatient setting
which we believe have resulted in many unnecessary deaths.

Our findings showing efficacy and safety of HCQ against COVID-19


indicate that HCQ should be freely available to patients and physicians
who choose to use it. And it should especially be freely available to be
used on an outpatient basis before hospitalization where it appears to
be more effective and where early fears of fatal heart arrhythmias
have been shown to be unfounded[45].

This is particularly important because the only drug to show efficacy,


Remdesivir, has shown no significant benefit in a recent study [46].It is
also expensive and not widely available. Convalescent plasma has
shown benefit [47] but even this is not well validated and plasma is
not available in large numbers of doses.

Thus HCQ with proven efficacy and safety, a cost of 37 cents per pill
and thus a total treatment cost of under 20 dollars[48], versus 3,100
dollars for Remdesivir[49], as well as wide supply chain availability,
would appear to be the best COVID-19 treatment option available and
needs to be widely promoted as such.

Unfortunately the controversies surrounding HCQ have resulted in


physicians being afraid to prescribe it for reasons which have nothing
to do with medicine, and in patients being afraid to take it due to
spurious reports of danger, or fears that is not effective.
It is hoped that this study will disabuse the medical community of
these misapprehensions about efficacy and validate that it is both
efficacious and safe, and needs to be freely
prescribable. Thousands of lives may lie in the balance.

We also do not believe that randomized controlled studies are


necessary before HCQ is authorized for general use because the
efficacy seen in studies already done indicates that control patients in
such studies might die unnecessarily; and because the time delay to do
any such study would cause yet more deaths by preventing HCQ use
when it is most needed – which is immediately. Our study has shown
that good evidence of efficacy exists; and there is no safety, cost, or
supply reason to not treat now.

Unnecessary death from delayed treatment is too high a price to pay


for greater certainty of knowledge. Many may have already died
unnecessarily due to HCQ misinformation and it is imperative that we
do not further add to the toll.

I would also like to point out this meta-study concluded collecting data on
the 3rd August 2020, and therefore it did not include the results from 4 large
studies which all found treatment with HCQ was associated with sustainable
reducing in death

· Castelnuovo et al., European J. Internal Medicine,


doi:10.1016/j.ejim.2020.08.019 (Peer Reviewed) – study found the
use of hydroxychloroquine in hospitalised COVID-19 patients was
associated with reduced mortality: Retrospective 3,451
hospitalized patients, 30% reduction in mortality with HCQ
after propensity adjustment.

· Catteau et al., Int. J. Antimicrobial Agents,


doi:10.1016/j.ijantimicag.2020.106144 (Peer Reviewed) –
Retrospective study of 8,075 hospitalized patients, 4,542 received
low-dose HCQ, 3,533 control - found a 35% lower mortality for
HCQ (17.7% vs. 27.1%)

· Ip et al., medRxiv, doi:10.1101/2020.08.20.20178772


(Preprint) - Retrospective study of 1,274 outpatients, which found
a 47% reduction in hospitalization with HCQ
· Gonzalez et al., medRxiv, doi:10.1101/2020.08.18.20172874
(Preprint) - Retrospective study focused on eosinophil recovery
with 9,644 hospitalized patients in Spain, showing lower
mortality for HCQ (14.7% vs 29.2%, p<0.001), and AZ (15.3%
vs. 18.4%, p<0.001).

In light of this most recent evidence, I respectfully suggest that the TGA’s
current recommends the use of hydroxychloroquine to treat COVID-19 can
longer be sustained and should be urgently reviewed.

Regards,

Craig Kelly MP
Member for Hughes
From: SKERRITT, John
To: Kelly, Craig (MP)
Cc: Greg.Hunt.MP; Cook, Jane
Subject: RE: hydroxychloroquine [SEC=OFFICIAL]
Date: Sunday, 13 September 2020 8:48:09 PM
Attachments: 2020.07.15.20151852v1.full HCQ RECOVERY trial report.pdf

Dear Mr Kelly

Thank you for your email.

I stand by our Department’s advice that the use of hydroxychloroquine (HCQ) to treat COVID-19
is strongly discouraged outside of a clinical trial. You are correct that this advice concurs with the
recommendations from the National COVID-19 Clinical Evidence Taskforce. It is also based on the
overwhelming balance of evidence thus far, and the consensus view of major global medicines
regulators and health departments, with whom I am in very regular conduct around the progress
of clinical trials for potential therapeutics for COVID-19.

Our Department’s advice was not just based on the results of the RECOVERY trial, although I
believe that trial was an important and well-conducted one. I do not agree that the dose of HCQ
used in that trial was excessive – it was a 2000 mg loading dose split over the first 24 hours (see
the attached trial publication). Such loading doses are commonly used in treatment of infectious
diseases – for example for malaria, a 1200 mg loading dose of HCQ is given compared with the
400-600 mg daily dose usual for rheumatoid arthritis.

I also contend that it would be inconceivable that the investigators confused hydroxychloroquine
with another agent – the trial was conducted across 176 UK hospitals and the trial design,
including the doses used, were approved by the UK regulator (MHRA) prior to the patients being
treated.

I am aware that a couple of early studies were suggestive of positive benefits of HCQ in COVID
but since the time that many of those studies were carried out, a much larger number of
negative studies have been published in the top global refereed medical journals. For example
three studies in the New England Journal of Medicine, which is in the top 4 global medical
journals have shown the following:

https://www.nejm.org/doi/full/10.1056/NEJMoa2019014
Brazilian study of individuals hospitalised with mild to moderate COVID-19 – no effect of HCQ
(800 mg/day) with or without azithromycin on clinical outcomes

https://www.nejm.org/doi/full/10.1056/NEJMoa2016638
US and Canadian study on potential use of HCQ for post exposure prophylaxis (1400 mg on day 1
then 600 mg a day) - no impact on clinical outcomes

https://www.nejm.org/doi/full/10.1056/nejmoa2012410
Observational study in New York hospitals – 1220 mg HCQ on day 1 then 400 mg daily – no
increase or decrease in risk of intubation or death in COVID-19 infected patients

It is possible that a “sweet spot” – a disease stage or patient population for which HCQ could be
effective in prevention or treatment of COVID-19 infection may exist, and about 20 significant
clinical trials continue in about 8 countries, including at some major medical centres. In
collaboration with the US FDA, the European Medicines Agency and other major regulators, the
TGA is closely monitoring the results of these studies as they become available.

Yours sincerely

John Skerritt

Adjunct Prof John Skerritt FTSE FIPAA (Vic)


Deputy Secretary for Health Products Regulation
Department of Health
(The Health Products Regulation Group comprises the Therapeutic Goods Administration and the
Office of Drug Control)

From: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>


Sent: Wednesday, 9 September 2020 5:30 PM
To: SKERRITT, John
Cc: Greg.Hunt.MP <Greg.Hunt.MP@aph.gov.au>
Subject:

Dear Professor Skerritt,

I am writing to you as I am greatly concerned about the TGA’s advice “that it


strongly discourages the use of hydroxychloroquine to treat COVID-19”.

From the statement on the TGA’s website, this advice appears to be based
upon the recommendations from the National COVID-19 Clinical Evidence
Taskforce. And the Taskforce’s recommendations appear to be based
substantially upon the findings of the RECOVERY trial.

However the evidence appears to show that the RECOVERY trial was fatally
flawed, as in this trial they administered the group of patients taking HCQ
with 2400mg of the drug within the first 24 hours. All evidence indicates
that this was an excessive and toxic dose – 4 to 5 times the maximum
recommended. Further media reports indicate that this excessive dose was
the result of medical negligence where those running the RECOVERY trial
confused the drugs hydroxychloroquine with hydroxyquinoline.

Therefore, I believe there is a very strong argument that any results of the
RECOVERY should be disregarded in TGA making any recommendation.

I would also like to draw to your attention two meta-analysis studies


released in preprint in the past 48 hours. The first is a study out of France by
the Institut Hospitalo-Universitaire (IHU) Méditerranée Infection, which will
be published in the journal ‘Expert Review of Clinical Immunology’. This
most comprehensive study concluded for Covid-19;

‘’Treatment with an oral combination of hydroxychloroquine,


azithromycin and zinc may REPRESENT THE BEST CURRENT
THERAPEUTIC OPTION in relation to its antiviral and
immunomodulatory effects’’.

The second is a study from the US by Chadwick C Prodromos MD and Tobias


Rumschlag MD in which they concluded;

This study has four important findings. The first is that HCQ appears
to be consistently effective for the treatment of COVID-19 when used
early in the course of disease in the outpatient setting, and is generally
more effective the earlier it is used. The second is that overall HCQ has
had efficacy against COVID-19 in a majority of studies. The third is
that there are no unbiased studies showing a negative effect of HCQ
treatment of COVID-19. The fourth is that HCQ appears to be safe for
the treatment of COVID-19 when used responsibly.

And the authors further noted;

SIGNIFICANCE: We believe our findings have substantial societal


global importance since there have been numerous edicts either
preventing HCQ use for COVID-19 or limiting it to the inpatient setting
which we believe have resulted in many unnecessary deaths.

Our findings showing efficacy and safety of HCQ against COVID-19


indicate that HCQ should be freely available to patients and physicians
who choose to use it. And it should especially be freely available to be
used on an outpatient basis before hospitalization where it appears to
be more effective and where early fears of fatal heart arrhythmias
have been shown to be unfounded[45].

This is particularly important because the only drug to show efficacy,


Remdesivir, has shown no significant benefit in a recent study [46].It is
also expensive and not widely available. Convalescent plasma has
shown benefit [47] but even this is not well validated and plasma is
not available in large numbers of doses.

Thus HCQ with proven efficacy and safety, a cost of 37 cents per pill
and thus a total treatment cost of under 20 dollars[48], versus 3,100
dollars for Remdesivir[49], as well as wide supply chain availability,
would appear to be the best COVID-19 treatment option available and
needs to be widely promoted as such.

Unfortunately the controversies surrounding HCQ have resulted in


physicians being afraid to prescribe it for reasons which have nothing
to do with medicine, and in patients being afraid to take it due to
spurious reports of danger, or fears that is not effective.

It is hoped that this study will disabuse the medical community of


these misapprehensions about efficacy and validate that it is both
efficacious and safe, and needs to be freely
prescribable. Thousands of lives may lie in the balance.

We also do not believe that randomized controlled studies are


necessary before HCQ is authorized for general use because the
efficacy seen in studies already done indicates that control patients in
such studies might die unnecessarily; and because the time delay to do
any such study would cause yet more deaths by preventing HCQ use
when it is most needed – which is immediately. Our study has shown
that good evidence of efficacy exists; and there is no safety, cost, or
supply reason to not treat now.

Unnecessary death from delayed treatment is too high a price to pay


for greater certainty of knowledge. Many may have already died
unnecessarily due to HCQ misinformation and it is imperative that we
do not further add to the toll.
I would also like to point out this meta-study concluded collecting data on
the 3rd August 2020, and therefore it did not include the results from 4 large
studies which all found treatment with HCQ was associated with sustainable
reducing in death

· Castelnuovo et al., European J. Internal Medicine,


doi:10.1016/j.ejim.2020.08.019 (Peer Reviewed) – study found the
use of hydroxychloroquine in hospitalised COVID-19 patients was
associated with reduced mortality: Retrospective 3,451
hospitalized patients, 30% reduction in mortality with HCQ
after propensity adjustment.

· Catteau et al., Int. J. Antimicrobial Agents,


doi:10.1016/j.ijantimicag.2020.106144 (Peer Reviewed) –
Retrospective study of 8,075 hospitalized patients, 4,542 received
low-dose HCQ, 3,533 control - found a 35% lower mortality for
HCQ (17.7% vs. 27.1%)

· Ip et al., medRxiv, doi:10.1101/2020.08.20.20178772


(Preprint) - Retrospective study of 1,274 outpatients, which found
a 47% reduction in hospitalization with HCQ

· Gonzalez et al., medRxiv, doi:10.1101/2020.08.18.20172874


(Preprint) - Retrospective study focused on eosinophil recovery
with 9,644 hospitalized patients in Spain, showing lower
mortality for HCQ (14.7% vs 29.2%, p<0.001), and AZ (15.3%
vs. 18.4%, p<0.001).

In light of this most recent evidence, I respectfully suggest that the TGA’s
current recommends the use of hydroxychloroquine to treat COVID-19 can
longer be sustained and should be urgently reviewed.

Regards,

Craig Kelly MP
Member for Hughes
medRxiv preprint doi: https://doi.org/10.1101/2020.07.15.20151852.this version posted July 15, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

Hydroxychloroquine for COVID-19 – Preliminary Report

3 Effect of Hydroxychloroquine in Hospitalized Patients


4 with COVID-19: Preliminary results from a
5 multi-centre, randomized, controlled trial.
6 Running title: Hydroxychloroquine for COVID-19 – Preliminary Report

8 RECOVERY Collaborative Group*

9
10
11 *The writing committee and trial steering committee are listed at the end of this manuscript and
12 a complete list of collaborators in the Randomised Evaluation of COVID-19 Therapy
13 (RECOVERY) trial is provided in the Supplementary Appendix.
14

15 Correspondence to: Dr Peter W Horby and Dr Martin J Landray, RECOVERY Central


16 Coordinating Office, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3
17 7LF, United Kingdom.

18 Email: recoverytrial@ndph.ox.ac.uk

19

20 Word count:
21 Abstract – 235 words
22 Main text – 2997
23 References – 39
24 Tables & Figures – 2 + 3
25
26

1
medRxiv preprint doi: https://doi.org/10.1101/2020.07.15.20151852.this version posted July 15, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

Hydroxychloroquine for COVID-19 – Preliminary Report

27 ABSTRACT
28 Background: Hydroxychloroquine and chloroquine have been proposed as treatments for

29 coronavirus disease 2019 (COVID-19) on the basis of in vitro activity, uncontrolled data, and

30 small randomized studies.

31 Methods: The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a

32 randomized, controlled, open-label, platform trial comparing a range of possible treatments with

33 usual care in patients hospitalized with COVID-19. We report the preliminary results for the

34 comparison of hydroxychloroquine vs. usual care alone. The primary outcome was 28-day

35 mortality.

36 Results: 1561 patients randomly allocated to receive hydroxychloroquine were compared with

37 3155 patients concurrently allocated to usual care. Overall, 418 (26.8%) patients allocated

38 hydroxychloroquine and 788 (25.0%) patients allocated usual care died within 28 days (rate

39 ratio 1.09; 95% confidence interval [CI] 0.96 to 1.23; P=0.18). Consistent results were seen in

40 all pre-specified subgroups of patients. Patients allocated to hydroxychloroquine were less likely

41 to be discharged from hospital alive within 28 days (60.3% vs. 62.8%; rate ratio 0.92; 95% CI

42 0.85-0.99) and those not on invasive mechanical ventilation at baseline were more likely to

43 reach the composite endpoint of invasive mechanical ventilation or death (29.8% vs. 26.5%; risk

44 ratio 1.12; 95% CI 1.01-1.25). There was no excess of new major cardiac arrhythmia.

45 Conclusions: In patients hospitalized with COVID-19, hydroxychloroquine was not associated

46 with reductions in 28-day mortality but was associated with an increased length of hospital stay

47 and increased risk of progressing to invasive mechanical ventilation or death.

48 Funding: Medical Research Council and NIHR (Grant ref: MC_PC_19056).

49 Trial registrations: The trial is registered with ISRCTN (50189673) and clinicaltrials.gov

50 (NCT04381936).

2
medRxiv preprint doi: https://doi.org/10.1101/2020.07.15.20151852.this version posted July 15, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

Hydroxychloroquine for COVID-19 – Preliminary Report

51 Keywords: COVID-19, hydroxychloroquine, clinical trial.

52

3
medRxiv preprint doi: https://doi.org/10.1101/2020.07.15.20151852.this version posted July 15, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

Hydroxychloroquine for COVID-19 – Preliminary Report

53 INTRODUCTION
54 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus

55 disease 2019 (COVID-19), emerged in China in late 2019 from a zoonotic source.1 The majority

56 of COVID-19 infections are either asymptomatic or result in only mild disease. However, a

57 substantial proportion of infected individuals develop a respiratory illness requiring hospital

58 care,2 which can progress to critical illness with hypoxemic respiratory failure requiring

59 prolonged ventilatory support.3-6 Amongst COVID-19 patients admitted to UK hospitals, the case

60 fatality rate is around 26%, and is over 37% in patients requiring invasive mechanical

61 ventilation.7

62 Hydroxychloroquine and chloroquine, 4-aminoquinoline drugs developed over 70 years ago and

63 used to treat malaria and rheumatological conditions, have been proposed as treatments for

64 COVID-19. Chloroquine has in vitro activity against a variety of viruses, including SARS-CoV-2

65 and the related SARS-CoV-1.8-13 The exact mechanism of antiviral action is uncertain but these

66 drugs increase the pH of endosomes that the virus uses for cell entry and also interfere with the

67 glycosylation of the cellular receptor of SARS-CoV, angiotensin-converting enzyme 2 (ACE2),

68 and associated gangliosides.10,14 The 4-aminoquinoline concentrations required to inhibit SARS-

69 CoV-2 replication in vitro are relatively high by comparison with the free plasma concentrations

70 observed in the prevention and treatment of malaria.15 These drugs are generally well tolerated,

71 inexpensive and widely available. Following oral administration they are rapidly absorbed, even

72 in severely ill patients. If active, therapeutic hydroxychloroquine concentrations could be

73 expected in the human lung shortly after an initial loading dose.

74 Small pre-clinical studies have reported that hydroxychloroquine prophylaxis or treatment had

75 no beneficial effect of clinical disease or viral replication.16 Clinical benefit and antiviral effect

76 from the administration of these drugs alone or in combination with azithromycin to patients with
17-21
77 COVID-19 infections has been reported in some observational studies but not in others.22-24

4
medRxiv preprint doi: https://doi.org/10.1101/2020.07.15.20151852.this version posted July 15, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

Hydroxychloroquine for COVID-19 – Preliminary Report

78 A few small controlled trials of hydroxychloroquine and chloroquine for the treatment of COVID-

79 19 infection have been inconclusive.25-28 Here we report preliminary results of the effects of a

80 randomized controlled trial of hydroxychloroquine in patients hospitalized with COVID-19.

81

82 METHODS

83 Trial design and participants

84 The RECOVERY trial is an investigator-initiated, individually randomized, controlled, open-label,

85 platform trial to evaluate the effects of potential treatments in patients hospitalized with COVID-

86 19. The trial is conducted at 176 hospitals in the United Kingdom (see Supplementary

87 Appendix), supported by the National Institute for Health Research Clinical Research Network.

88 The trial is coordinated by the Nuffield Department of Population Health at University of Oxford,

89 the trial sponsor. Although the hydroxychloroquine, dexamethasone, and lopinavir-ritonavir arms

90 have now been stopped, the trial continues to study the effects of azithromycin, tocilizumab, and

91 convalescent plasma (and other treatments may be studied in the future).

92 Hospitalized patients were eligible for the study if they had clinically suspected or laboratory

93 confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the

94 attending clinician, put the patient at significant risk if they were to participate in the trial. Initially,

95 recruitment was limited to patients aged at least 18 years but from 9 May 2020, the age limit

96 was removed. Patients with known prolonged electrocardiograph QTc interval were ineligible for

97 the hydroxychloroquine arm. Co-administration with medications that prolong the QT interval

98 was not an absolute contraindication but attending clinicians were advised to check the QT

99 interval by performing an electrocardiogram.

100 Written informed consent was obtained from all patients or from a legal representative if they

101 were too unwell or unable to provide consent. The trial was conducted in accordance with the

5
medRxiv preprint doi: https://doi.org/10.1101/2020.07.15.20151852.this version posted July 15, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

Hydroxychloroquine for COVID-19 – Preliminary Report

102 principles of the International Conference on Harmonization–Good Clinical Practice guidelines

103 and approved by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) and

104 the Cambridge East Research Ethics Committee (ref: 20/EE/0101). The protocol and statistical

105 analysis plan are available in the Supplementary Appendix and on the study website

106 www.recoverytrial.net.

107 Randomization

108 Baseline data collected using a web-based case report form included demographics, level of

109 respiratory support, major comorbidities, the suitability of the study treatment for a particular

110 patient, and treatment availability at the study site. Eligible and consenting patients were

111 assigned in a ratio of 2:1 to either usual standard of care or usual standard of care plus

112 hydroxychloroquine or one of the other available treatment arms (see Supplementary Appendix)

113 using web-based simple (unstratified) randomization with allocation concealment. Patients

114 allocated to hydroxychloroquine sulfate (200mg tablet containing 155mg base equivalent)

115 received a loading dose of 4 tablets (800 mg) at zero and 6 hours, followed by 2 tablets (400

116 mg) starting at 12 hours after the initial dose and then every 12 hours for the next 9 days or until

117 discharge (whichever occurred earlier) (see Supplementary Appendix).15 Allocated treatment

118 was prescribed by the attending clinician. Participants and local study staff were not blinded to

119 the allocated treatment.

120 Procedures

121 A single online follow-up form was to be completed when participants were discharged, had

122 died or at 28 days after randomization (whichever occurred earlier). Information was recorded

123 on adherence to allocated study treatment, receipt of other study treatments, duration of

124 admission, receipt of respiratory support (with duration and type), receipt of renal dialysis or

125 hemofiltration, and vital status (including cause of death). From 12 May 2020, extra information

6
medRxiv preprint doi: https://doi.org/10.1101/2020.07.15.20151852.this version posted July 15, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

Hydroxychloroquine for COVID-19 – Preliminary Report

126 was recorded on the occurrence of new major cardiac arrhythmia. In addition, routine health

127 care and registry data were obtained including information on vital status (with date and cause

128 of death); discharge from hospital; respiratory and renal support therapy.

129 Outcome measures

130 Outcomes were assessed at 28 days after randomization, with further analyses specified at 6

131 months. The primary outcome was all-cause mortality. Secondary outcomes were time to

132 discharge from hospital and, among patients not on invasive mechanical ventilation at

133 randomization, invasive mechanical ventilation (including extra-corporal membrane

134 oxygenation) or death. Subsidiary clinical outcomes included cause-specific mortality, use of

135 hemodialysis or hemofiltration, major cardiac arrhythmia (recorded in a subset), and receipt and

136 duration of ventilation.

137 Statistical Analysis

138 For the primary outcome of 28-day mortality, the log-rank ‘observed minus expected’ statistic

139 and its variance were used to both test the null hypothesis of equal survival curves and to

140 calculate the one-step estimate of the average mortality rate ratio, comparing all patients

141 allocated hydroxychloroquine with all patients allocated usual care. The few patients (2.1%) who

142 had not been followed for 28 days by the time of the data cut (22 June 2020) were either

143 censored on 22 June 2020 or, if they had already been discharged alive, were right-censored

144 for mortality at day 29 (that is, in the absence of any information to the contrary they were

145 assumed to have survived 28 days). Kaplan-Meier survival curves were constructed to display

146 cumulative mortality over the 28-day period. The same methods were used to analyze time to

147 hospital discharge, with patients who died in hospital right-censored on day 29. Median time to

148 discharge was derived from the Kaplan-Meier estimates. For the pre-specified composite

149 secondary outcome of invasive mechanical ventilation or death within 28 days (among those not

7
medRxiv preprint doi: https://doi.org/10.1101/2020.07.15.20151852.this version posted July 15, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

Hydroxychloroquine for COVID-19 – Preliminary Report

150 receiving invasive mechanical ventilation at randomization), the precise date of starting invasive

151 mechanical ventilation was not available and so the risk ratio was estimated instead. Estimates

152 of absolute risk differences between patients allocated hydroxychloroquine and patients

153 allocated usual care were also calculated.

154 Pre-specified analyses of the primary outcome were performed in five subgroups defined by

155 characteristics at randomization: age, sex, level of respiratory support, days since symptom

156 onset, and predicted 28-day mortality risk (See Supplementary Appendix). One further pre-

157 specified subgroup analysis (ethnicity) will be conducted once data collection is completed.

158 Observed effects within subgroup categories were compared using a chi-square test for trend

159 (which is equivalent to a test for heterogeneity for subgroups that have only two levels).

160 Estimates of rate and risk ratios (both hereon denoted RR) are shown with 95% confidence

161 intervals. All p-values are 2-sided and are shown without adjustment for multiple testing. All

162 analyses were done according to the intention-to-treat principle. The full database is held by the

163 study team which collected the data from study sites and performed the analyses at the Nuffield

164 Department of Population Health, University of Oxford.

165 Sample size and decision to stop enrolment

166 As stated in the protocol, appropriate sample sizes could not be estimated when the trial was

167 being planned at the start of the COVID-19 pandemic. As the trial progressed, the Trial Steering

168 Committee, blinded to the results of the study treatment comparisons, formed the view that if

169 28-day mortality was 20% then a comparison of at least 2000 patients allocated to active drug

170 and 4000 to usual care alone would yield at least 90% power at two-sided P=0.01 to detect a

171 proportional reduction of one-fifth (a clinically relevant absolute difference of 4 percentage

172 points between the two arms).

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Hydroxychloroquine for COVID-19 – Preliminary Report

173 The independent Data Monitoring Committee reviewed unblinded analyses of the study data

174 and any other information considered relevant at intervals of around 2 weeks. The committee

175 was charged with determining if, in their view, the randomized comparisons in the study

176 provided evidence on mortality that is strong enough (with a range of uncertainty around the

177 results that is narrow enough) to affect national and global treatment strategies. In such a

178 circumstance, the Committee would inform the Trial Steering Committee who would make the

179 results available to the public and amend the trial arms accordingly. Unless that happened, the

180 Trial Steering Committee, investigators, and all others involved in the trial would remain blind to

181 the interim results until 28 days after the last patient had been randomized to a particular

182 intervention arm.

183 On 4 June, in response to a request from the MHRA, the independent Data Monitoring

184 Committee conducted a review of the data and recommended the chief investigators review the

185 unblinded data on the hydroxychloroquine arm of the trial. The Chief Investigators and Trial

186 Steering Committee concluded that the data showed no beneficial effect of hydroxychloroquine

187 in patients hospitalized with COVID-19. Therefore enrolment of participants to the

188 hydroxychloroquine arm was closed on 5 June and the preliminary result for the primary

189 outcome was made public. Investigators were advised that any patients currently taking

190 hydroxychloroquine as part of the study should discontinue the treatment.

191

192 RESULTS

193 Patients

194 Of the 11,197 patients randomized while the hydroxychloroquine arm was open (25 March to 5

195 June 2020), 7513 (67%) were eligible to be randomized to hydroxychloroquine (that is

196 hydroxychloroquine was available in the hospital at the time and the attending clinician was of

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Hydroxychloroquine for COVID-19 – Preliminary Report

197 the opinion that the patient had no known indication for or contraindication to

198 hydroxychloroquine) (Figure 1 and Table S1). Of these, 1561 were randomized to

199 hydroxychloroquine and 3155 were randomized to usual care with the remainder being

200 randomized to one of the other treatment arms. Mean age of study participants in this

201 comparison was 65.3 (SD 15.3) years (Table 1) and 38% patients were female. No children

202 were enrolled in the hydroxychloroquine comparison. A history of diabetes was present in 27%

203 of patients, heart disease in 26%, and chronic lung disease in 22%, with 57% having at least

204 one major comorbidity recorded. In this analysis, 90% of patients had laboratory confirmed

205 SARS-CoV-2 infection, with the result currently awaited for 1%. At randomization, 17% were

206 receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were

207 receiving oxygen only (with or without non-invasive ventilation), and 24% were receiving neither.

208 Follow-up information was complete for 4619 (98%) of the randomized patients. Among those

209 with a completed follow-up form, 1395 (92%) patients allocated to hydroxychloroquine received

210 at least 1 dose (Table S2) and the median number of days of treatment was 6 days (IQR 3 to 10

211 days). 13 (0.4%) of the usual care arm received hydroxychloroquine. Use of azithromycin or

212 other macrolide drug during the follow-up period was similar in both arms (17% vs. 19%) as was

213 use of dexamethasone (8% vs. 9%).

214 Primary outcome

215 There was no significant difference in the proportion of patients who met the primary outcome of

216 28-day mortality between the two randomized arms (418 [26.8%] patients in the

217 hydroxychloroquine arm vs. 788 [25.0%] patients in the usual care arm; rate ratio, 1.09; 95%

218 confidence interval [CI], 0.96 to 1.23; P=0.18) (Figure 2). Similar results were seen across all

219 five pre-specified subgroups (Figure 3). In post hoc exploratory analyses restricted to the 4234

220 (90%) patients with a positive SARS-CoV-2 test result, the result was similar (rate ratio, 1.09, 95%

221 CI 0.96 to 1.24).

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Hydroxychloroquine for COVID-19 – Preliminary Report

222 Secondary outcomes

223 Allocation to hydroxychloroquine was associated with a longer time until discharge alive from

224 hospital than usual care (median 16 days vs. 13 days) and a lower probability of discharge alive

225 within 28 days (rate ratio 0.92, 95% CI 0.85 to 0.99) (Table 2). Among those not on invasive

226 mechanical ventilation at baseline, the number of patients progressing to the pre-specified

227 composite secondary outcome of invasive mechanical ventilation or death was higher among

228 those allocated to hydroxychloroquine (risk ratio 1.12, 95% CI 1.01 to 1.25).

229 Subsidiary outcomes

230 Information on the occurrence of new major cardiac arrhythmia was collected for 698 (44.7%)

231 patients in the hydroxychloroquine arm and 1357 (43.0%) in the usual care arm since these

232 fields were added to the follow-up form on 12 May 2020. Among these patients, there were no

233 significant differences in the frequency of supraventricular tachycardia (6.9% vs. 5.9%),

234 ventricular tachycardia or fibrillation (0.9% vs. 0.7%) or atrioventricular block requiring

235 intervention (0.1% vs. 0.1%) (Table S3). Analyses of cause-specific mortality, receipt of renal

236 dialysis or hemofiltration, and duration of ventilation will be presented once all relevant

237 information (including certified cause of death) is available. There was one report of a serious

238 adverse reaction believed related to hydroxychloroquine; a case of torsades de pointes from

239 which the patient recovered without the need for intervention.

240

241 DISCUSSION

242 Although preliminary, these results indicate that hydroxychloroquine is not an effective treatment

243 for patients hospitalized with COVID-19. The lower bound of the confidence limit for the primary

244 outcome rules out any reasonable possibility of a meaningful mortality benefit. In addition,

245 allocation to hydroxychloroquine was associated with an increase in the duration of

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Hydroxychloroquine for COVID-19 – Preliminary Report

246 hospitalization and an increased risk of requiring invasive mechanical ventilation or dying for

247 those not on invasive mechanical ventilation at baseline. The results were consistent across

248 subgroups of age, sex, time since illness onset, level of respiratory support, and baseline-

249 predicted risk.

250 RECOVERY is a large, pragmatic, randomized, controlled platform trial designed to provide

251 rapid and robust assessment of the impact of readily available potential treatments for COVID-

252 19 on 28-day mortality. Around 15% of all patients hospitalized with COVID-19 in the UK over

253 the study period were enrolled in the trial and the fatality rate in the usual care arm is consistent

254 with the hospitalized case fatality rate in the UK and elsewhere.7,29,30 Only essential data were

255 collected at hospital sites with additional information (including long-term mortality) ascertained

256 through linkage with routine data sources. We did not collect information on physiological,

257 electrocardiographic, laboratory or virologic parameters.

258 Hydroxychloroquine has been proposed as a treatment for COVID-19 based largely on its in

259 vitro SARS-CoV-2 antiviral activity and on data from observational studies reporting effective

260 reduction in viral loads. However, the 4-aminoquinoline drugs are relatively weak antivirals.15

261 Demonstration of therapeutic efficacy of hydroxychloroquine in severe COVID-19 would require

262 rapid attainment of efficacious levels of free drug in the blood and respiratory epithelium.31 Thus,

263 to provide the greatest chance of providing benefit in life threatening COVID-19, the dose

264 regimen was designed to result in rapid attainment and maintenance of plasma concentrations

265 that were as high as safely possible.15 These concentrations were predicted to be at the upper

266 end of those observed during steady state treatment of rheumatoid arthritis with

267 hydroxychloroquine.32 Our dosing schedule was based on hydroxychloroquine pharmacokinetic

268 modelling referencing a SARS-CoV-2 half maximal effective concentration (EC50) of 0.72 μM

269 scaled to whole blood concentrations and an assumption that cytosolic concentrations in the

270 respiratory epithelium are in dynamic equilibrium with blood concentrations.8,15,33

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271 The primary concern with short-term high dose 4-aminoquinoline regimens is cardiovascular

272 toxicity. Hydroxychloroquine causes predictable prolongation of the electrocardiograph QT

273 interval that is exacerbated by co-administration with azithromycin, as widely prescribed in

274 COVID-19 treatment.16-18 Although torsade de pointes has been described, serious

275 cardiovascular toxicity has been reported very rarely despite the high prevalence of

276 cardiovascular disease in hospitalized patients, the common occurrence of myocarditis in

277 COVID-19, and the extensive use of hydroxychloroquine and azithromycin together. The

278 exception is a Brazilian study which was stopped early because of cardiotoxicity. However in

279 that study, chloroquine 600 mg base was given twice daily for ten days, a substantially higher

280 total dose than used in other trials, including RECOVERY.34,35 Pharmacokinetic modelling in

281 combination with blood concentration and mortality data from a case series of 302 chloroquine

282 overdose patients predicts that the base equivalent chloroquine regimen to the RECOVERY

283 hydroxychloroquine regimen is safe.35 Hydroxychloroquine is considered to be safer than

284 chloroquine.15 We did not observe excess mortality in the first 2 days of treatment with

285 hydroxychloroquine, the time when early effects of dose-dependent toxicity might be expected.

286 Furthermore, the preliminary data presented here did not show any excess in ventricular

287 tachycardia (including torsade de pointes) or ventricular fibrillation in the hydroxychloroquine

288 arm.

289 The findings indicate that hydroxychloroquine is not an effective treatment for hospitalized

290 patients with COVID-19 but do not address its use as prophylaxis or in patients with less severe

291 SARS-CoV-2 infection managed in the community. Treatment of COVID-19 with chloroquine or

292 hydroxychloroquine has been recommended in many treatment guidelines, including in Brazil,

293 China, France, Italy, Netherlands, South Korea, and the United States.36 In a retrospective

294 cohort study in the United States, 59% of 1376 COVID-19 patients received

295 hydroxychloroquine.22,37 Since our preliminary results were first made public on 5 June 2020,

13
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Hydroxychloroquine for COVID-19 – Preliminary Report

296 the U.S. Food and Drugs Administration has revoked the Emergency Use Authorization that

297 allowed hydroxychloroquine and chloroquine to be used for hospitalized patients with COVID-

298 19,38 and the World Health Organization (WHO) and the National Institutes for Health have

299 ceased trials of its use in this setting on the grounds of lack of benefit. The WHO has recently

300 released preliminary results from the SOLIDARITY trial on the effectiveness of

301 hydroxychloroquine in hospitalized COVID-19 patients that are consistent with the results from

302 the RECOVERY trial.39

303

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Hydroxychloroquine for COVID-19 – Preliminary Report

304 Authorship

305 This manuscript was initially drafted by the first and last author, developed by the Writing

306 Committee, and approved by all members of the Trial Steering Committee. The funders had no

307 role in the analysis of the data, preparation and approval of this manuscript, or the decision to

308 submit it for publication. The first and last members of the Writing Committee vouch for the data

309 and analyses, and for the fidelity of this report to the study protocol and data analysis plan.

310

311 Writing Committee (on behalf of the RECOVERY Collaborative Group):

312 Peter Horby FRCP,a,* Marion Mafham MD,b,* Louise Linsell DPhil,b,* Jennifer L Bell MSc,b

313 Natalie Staplin PhD,b,c Jonathan R Emberson PhD,b,c Martin Wiselka PhD,d Andrew Ustianowski

314 PhD,e Einas Elmahi MPhil,f Benjamin Prudon FRCP,g Anthony Whitehouse FRCA,h Timothy

315 Felton PhD,i John Williams MRCP,j Jakki Faccenda MD,k Jonathan Underwood PhD,l J Kenneth

316 Baillie MD PhD,m Lucy C Chappell PhD,n Saul N Faust FRCPCH,o Thomas Jaki PhD,p,q Katie

317 Jeffery PhD,r Wei Shen Lim FRCP,s Alan Montgomery PhD,t Kathryn Rowan PhD,u Joel Tarning

318 PhD,v,w James A Watson DPhil,v,w Nicholas J White FRS,v,w Edmund Juszczak MSc,b,† Richard

319 Haynes DM,b,c,† Martin J Landray PhD.b,c,x,†

320
a
321 Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
b
322 Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
c
323 MRC Population Health Research Unit, University of Oxford, Oxford, United Kingdom
d
324 University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, United

325 Kingdom
e
326 Regional Infectious Diseases Unit, North Manchester General Hospital & University of

327 Manchester, Manchester, United Kingdom


f
328 Research and Development Department, Northampton General Hospital, Northampton, United

329 Kingdom

15
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Hydroxychloroquine for COVID-19 – Preliminary Report

g
330 Department of Respiratory Medicine, North Tees & Hartlepool NHS Foundation Trust,

331 Stockton-on-Tees, United Kingdom


h
332 University Hospitals Birmingham NHS Foundation Trust and Institute of Microbiology &

333 Infection, University of Birmingham, Birmingham, United Kingdom


i
334 University of Manchester and Manchester University NHS Foundation Trust, Manchester,

335 United Kingdom


j
336 James Cook University Hospital, Middlesbrough, United Kingdom
k
337 North West Anglia NHS Foundation Trust, Peterborough, United Kingdom
l
338 Department of Infectious Diseases, Cardiff and Vale University Health Board; Division of

339 Infection and Immunity, Cardiff University, Cardiff, United Kingdom


m
340 Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
n
341 School of Life Course Sciences, King’s College London, London, United Kingdom
o
342 NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University

343 Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton,

344 United Kingdom


p
345 Department of Mathematics and Statistics, Lancaster University, Lancaster, United Kingdom
q
346 MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom
r
347 Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
s
348 Respiratory Medicine Department, Nottingham University Hospitals NHS Trust, Nottingham,

349 United Kingdom


t
350 School of Medicine, University of Nottingham, Nottingham, United Kingdom
u
351 Intensive Care National Audit & Research Centre, London, United Kingdom
v
352 Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol

353 University, Bangkok, Thailand


w
354 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of

355 Oxford, United Kingdom

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Hydroxychloroquine for COVID-19 – Preliminary Report

x
356 NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust,

357 Oxford, United Kingdom

358 *,† equal contribution

359

360 Data Monitoring Committee

361 Peter Sandercock, Janet Darbyshire, David DeMets, Robert Fowler, David Lalloo, Ian Roberts,

362 Janet Wittes.

363 Acknowledgements

364 We would like to thank the many thousands of doctors, nurses, pharmacists, other allied health

365 professionals, and research administrators at 176 NHS hospital organizations across the whole

366 of the UK, supported by staff at the NIHR Clinical Research Network, NHS DigiTrials, Public

367 Health England, Department of Health & Social Care, the Intensive Care National Audit &

368 Research Centre, Public Health Scotland, National Records Service of Scotland, the Secure

369 Anonymised Information Linkage (SAIL) at University of Swansea, and the NHS in England,

370 Scotland, Wales and Northern Ireland. We would especially like to thank the members of the

371 independent Data Monitoring Committee. But above all, we would like to thank the thousands of

372 patients who participated in this study.

373 Funding

374 The RECOVERY trial is supported by a grant to the University of Oxford from UK Research and

375 Innovation/National Institute for Health Research (NIHR) (Grant reference: MC_PC_19056) and

376 by core funding provided by NIHR Oxford Biomedical Research Centre, Wellcome, the Bill and

377 Melinda Gates Foundation, the Department for International Development, Health Data

378 Research UK, the Medical Research Council Population Health Research Unit, the NIHR Health

17
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Hydroxychloroquine for COVID-19 – Preliminary Report

379 Protection Unit in Emerging and Zoonotic Infections, and NIHR Clinical Trials Unit Support

380 Funding. TF is supported by the NIHR Manchester Biomedical Research Centre. TJ received

381 funding from UK Medical Research Council (MC_UU_0002/14). TJ is supported by a NIHR

382 Senior Research Fellowship (NIHR-SRF-2015-08-001). WSL is supported by core funding

383 provided by NIHR Nottingham Biomedical Research Centre. NJW, JAW and JT are part of the

384 Mahidol Oxford Research Unit supported by the Wellcome Trust. Tocilizumab was provided free

385 of charge for this study by Roche Products Limited. AbbVie contributed some supplies of

386 lopinavir-ritonavir for use in the study. Other medication used in the study was supplied from

387 routine National Health Service stock.

388 The views expressed in this publication are those of the authors and not necessarily those of

389 the NHS, the National Institute for Health Research or the Department of Health and Social

390 Care (DHCS).

391 Conflicts of interest

392 The authors have no conflict of interest or financial relationships relevant to the submitted work

393 to disclose. No form of payment was given to anyone to produce the manuscript. All authors

394 have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

395 The Nuffield Department of Population Health at the University of Oxford has a staff policy of not

396 accepting honoraria or consultancy fees directly or indirectly from industry (see

397 https://www.ndph.ox.ac.uk/files/about/ndph-independence-of-research-policy-jun-20.pdf).

398

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Hydroxychloroquine for COVID-19 – Preliminary Report

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482 37. Lenzer J. Covid-19: US gives emergency approval to hydroxychloroquine despite lack of
483 evidence. BMJ 2020; 369: m1335.
484 38. FDA. Revocation of the EUA letter. 2020. https://www.fda.gov/media/138945/download.
485 39. WHO. WHO discontinues hydroxychloroquine and lopinavir/ritonavir treatment arms for COVID-
486 19. 2020. https://www.who.int/news-room/detail/04-07-2020-who-discontinues-hydroxychloroquine-
487 and-lopinavir-ritonavir-treatment-arms-for-covid-19.
488

20
medRxiv preprint doi: https://doi.org/10.1101/2020.07.15.20151852.this version posted July 15, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

Hydroxychloroquine for COVID-19 – Preliminary Report

489 Table and figures

490

491 Table 1: Baseline characteristics by randomized allocation

492 Results are count (%), mean ± standard deviation, or median (inter-quartile range).* No children

493 (aged <18 years) were enrolled. †Includes 6 pregnant women. †† SARS-Cov-2 test results are

494 captured on the follow-up form, so are currently unknown for some. All tests for difference in

495 baseline characteristics between treatment arms give p>0.05. The 'oxygen only' group includes

496 non-invasive ventilation. Severe liver disease defined as requiring ongoing specialist care.

497 Severe kidney impairment defined as estimated glomerular filtration rate <30 mL/min/1.73m2. 9

498 (0.6%) patients allocated to hydroxychloroquine and 9 (0.3%) patients allocated to usual care

499 alone had missing data for days since symptom onset.

500

501 Table 2: Effect of allocation to hydroxychloroquine on main study outcomes

502 RR=rate ratio for the outcomes of 28-day mortality and hospital discharge, and risk ratio for the

503 outcome of receipt of invasive mechanical ventilation or death. CI=confidence interval.

504 * Analyses exclude those on invasive mechanical ventilation at randomization. For the pre-

505 specified composite secondary endpoint of receipt of invasive mechanical ventilation or death

506 the absolute risk difference was 3.3 percentage points (95% CI 0.3 to 6.3).

507

508 Figure 1: Trial profile - Flow of participants through the RECOVERY trial

509 ITT=intention to treat. * Number recruited overall during period that adult participants could be

510 recruited into hydroxychloroquine comparison. # 1516/1561 (97.1%) and 3078/3155 (97.6%)

511 patients have a completed follow-up form at time of analysis. † includes 37/1561 (2.4%) patients

512 in the hydroxychloroquine arm and 89/3155 (2.8%) patients in the usual care arm allocated to

513 tocilizumab in accordance with protocol version 4.0 or later. 6 patients were additionally

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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

Hydroxychloroquine for COVID-19 – Preliminary Report

514 randomized to convalescent plasma vs control (1 [0.1%] patient allocated to hydroxychloroquine

515 arm vs 5 [0.2%] patients allocated to usual care) in accordance with protocol version 6.0.

516 Among the 167 sites that randomized at least 1 patient to the hydroxychloroquine comparison,

517 the median number randomized was 20 patients (inter-quartile range 11 to 41).

518

519 Figure 2: 28−day mortality

520 RR=rate ratio. CI=confidence interval. The RR is derived from the log-rank observed minus

521 expected statistic (O – E) and its variance (V) as the one-step estimate, through the formula

522 exp([O – E] ÷ V), and its 95% CI is given by exp([O – E] ÷ V ± 1.96 ÷ √V) . The number of

523 patients randomized and the number remaining at risk of death at the end of days 7, 14, 21 and

524 28 are shown beneath the plot.

525

526 Figure 3: Effect of allocation to hydroxychloroquine on 28−day mortality by pre-specified

527 characteristics at randomization

528 RR=rate ratio. CI=confidence interval. Subgroup−specific RR estimates are represented by

529 squares (with areas of the squares proportional to the amount of statistical information) and the

530 lines through them correspond to the 95% confidence intervals. The 'oxygen only' group

531 includes patients receiving non-invasive ventilation. The method used for calculating baseline-

532 predicted risk is described in the Supplementary Appendix. One further pre-specified subgroup

533 analysis (ethnicity) will be conducted once data collection is completed.

534

535

22
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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

Hydroxychloroquine for COVID-19 – Preliminary Report

536 Table 1: Baseline characteristics by randomized allocation

Hydroxychloroquine Usual care


(n = 1561) (n = 3155)

Age, years 65.2 (15.2) 65.4 (15.4)


< 70* 925 (59%) 1874 (59%)
≥ 70 to < 80 342 (22%) 630 (20%)
≥ 80 294 (19%) 650 (21%)

Sex
Male 961 (62%) 1974 (63%)
Female† 600 (38%) 1181 (37%)

Number of days since symptom onset 9 [5 to 14] 9 [5 to 13]

Number of days since hospitalisation 3 [1 to 6] 3 [1 to 5]

Respiratory support received


No oxygen received 362 (23%) 750 (24%)
Oxygen only 938 (60%) 1873 (59%)
Invasive mechanical ventilation 261 (17%) 532 (17%)

Comorbidities
Diabetes 427 (27%) 856 (27%)
Heart disease 422 (27%) 789 (25%)
Lung disease 334 (21%) 712 (23%)
Tuberculosis 4 (0%) 9 (0%)
HIV 8 (1%) 13 (0%)
Severe liver disease 18 (1%) 46 (1%)
Severe kidney impairment 111 (7%) 261 (8%)
Any of the above 882 (57%) 1807 (57%)

SARS-Cov-2 test result


Positive 1393 (89%) 2841 (90%)
Negative 153 (10%) 291 (9%)
Test result not yet known†† 15 (1%) 23 (1%)

537
538

23
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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

Hydroxychloroquine for COVID-19 – Preliminary Report

539 Table 2: Effect of allocation to hydroxychloroquine on main study outcomes

Hydroxychloroquine Usual care RR


(n = 1561) (n = 3155) (95% CI)

Primary outcome:
28-day all-cause mortality 418 (26.8%) 788 (25.0%) 1.09 (0.96 to 1.23)

Secondary outcomes:
Discharged from hospital within 28 days 941 (60.3%) 1982 (62.8%) 0.92 (0.85 to 0.99)

Receipt of mechanical ventilation or death* 388/1300 (29.8%) 696/2623 (26.5%) 1.12 (1.01 to 1.25)
Death 308/1300 (23.7%) 572/2623 (21.8%) 1.09 (0.96 to 1.23)
Invasive mechanical ventilation 118/1300 (9.1%) 215/2623 (8.2%) 1.11 (0.89 to 1.37)

540

541

24
Figure 1: Trial profile − Flow of participants through the RECOVERY trial
medRxiv preprint doi: https://doi.org/10.1101/2020.07.15.20151852.this version posted July 15, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

Total recruited #
n=11197

Hydroxychloroquine unavailable (n=639 [6%])


or considered unsuitable (n=3199 [29%])

Number randomized between


hydroxychloroquine and other arms
n=7513 (67%)

Allocated to other active treatment


Lopinavir−ritonavir (n=1010)
Dexamethasone (n=1170)
Azithromycin (n=617)

Number randomized between


hydroxychloroquine and usual care alone
n=4716 (42%)

Allocated hydroxychloroquine Allocated usual care alone


n=1561 (100%) n=3155 (100%)
Received hydroxychloroquine Received hydroxychloroquine
n=1395/1516* (92%) n=13/3078* (0.4%)

Consent withdrawn Consent withdrawn


n=3 (0.2%) n=5 (0.2%)

Proceeded to second Proceeded to second


randomization † randomization †
n=75 (4.8%) n=178 (5.6%)

Included in 28 day ITT analysis Included in 28 day ITT analysis


n=1561 (100%) n=3155 (100%)
Figure 2: Effect of allocation to hydroxychloroquine on 28−day mortality
medRxiv preprint doi: https://doi.org/10.1101/2020.07.15.20151852.this version posted July 15, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

30
RR 1.09 (0.96−1.23) Hydroxychloroquine
Log−rank p=0.18
25
Usual care

20
Mortality, %

15

10

0
0 7 14 21 28
Days since randomization
Number at risk
Active 1561 1337 1227 1161 1125
Control 3155 2750 2525 2410 2346
medRxiv preprint doi: https://doi.org/10.1101/2020.07.15.20151852.this version posted July 15, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .

Figure 3: Effects of allocation to hydroxychloroquine on 28−day mortality


by baseline characteristics
Hydroxychloroquine Usual care RR (95% CI)

2
Age, years (χ1= 0.4; p=0.51)
<70 160/925 (17.3%) 314/1874 (16.8%) 1.04 (0.85−1.25)
≥ 70 <80 126/342 (36.8%) 206/631 (32.6%) 1.16 (0.92−1.46)
≥ 80 132/294 (44.9%) 268/650 (41.2%) 1.13 (0.91−1.41)
2
Sex (χ1= 1.0; p=0.31)
Men 274/961 (28.5%) 543/1974 (27.5%) 1.04 (0.90−1.21)
Women 144/600 (24.0%) 245/1181 (20.7%) 1.19 (0.96−1.47)
2
Days since symptom onset (χ1= 0.0; p=0.97)
≤7 176/622 (28.3%) 338/1275 (26.5%) 1.09 (0.91−1.32)
>7 240/930 (25.8%) 444/1871 (23.7%) 1.10 (0.94−1.29)
2
Respiratory support at randomization (χ1= 0.6; p=0.45)
No oxygen received 57/362 (15.7%) 99/750 (13.2%) 1.22 (0.87−1.70)
Oxygen only 251/938 (26.8%) 473/1873 (25.3%) 1.08 (0.92−1.26)
Invasive mechanical ventilation 110/261 (42.1%) 216/532 (40.6%) 1.03 (0.81−1.30)
2
Baseline risk (χ1= 0.3; p=0.57)
<30% 145/994 (14.6%) 275/1993 (13.8%) 1.06 (0.87−1.30)
≥ 30% <45% 135/317 (42.6%) 245/635 (38.6%) 1.13 (0.91−1.40)
≥ 45% 138/250 (55.2%) 268/527 (50.9%) 1.16 (0.93−1.43)

All participants 418/1561 (26.8%) 788/3155 (25.0%) 1.09 (0.96−1.23)


p=0.18

0.5 0.75 1 1.5 2


Hydroxychloroquine Usual care
better better
a significant disclaimer as follows “Not peer reviewed…should not be relied upon
without context to guide clinical practice”….

Similarly the paper by Yang et at, although in the published literature focuses on
interpretation of retrospective observational data “suggesting” protective effects of HCQ
and goes on to say in its abstract “more randomised controlled studies are needed to
evaluate the efficacy of HCQ (and interferon alpha 2 separately and in combination) for
prophylaxis against COVID-19 …Future studies should give us more definitive
answers”.

By copy of this email I have shared the email string with A/Prof Julian Elliott who is a
coordinator of the National COVID-19 Clinical Evidence taskforce, which was funded
by the Government to analyses emerging research evidence on COVID-19 to provide
frontline healthcare workers with advice, including on potential therapies.

Regards

John Skerritt

Adjunct Prof John Skerritt FTSE FIPAA (Vic)

Deputy Secretary for Health Products Regulation

Department of Health

(The Health Products Regulation Group comprises the Therapeutic Goods Administration and the
Office of Drug Control)

From: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>


Sent: Monday, 21 September 2020 8:13 PM
To: SKERRITT, John
Cc: Greg.Hunt.MP <Greg.Hunt.MP@aph.gov.au>
Subject:
Dear Professor Skerritt,

Just a further follow up to your previous reply.

Firstly, in support of the TGA’s current position on HCQ, you cited this study (Boulware
et al.) ; - for which you noted concluded that HCQ had “no impact on clinical
outcomes”.

I would therefore like to draw to your attention significant criticism of this study which
has just been published , in which it was the noted;

Boulware et al. found a non-significant difference in incidence between HCQ and


placebo group (11.8% vs. 14.3%, p=0.35). However, our re-analysis of the data
suggests HCQ use for Covid-19 is time-sensitive. Early use of HCQ after
exposure appears to confer some protection from symptomatic Covid-19
(p=0.0496).

A similar conclusion was also reached by Watanabe in this paper


https://arxiv.org/abs/2007.09477 ;

In this study, we discussed some inaccuracies in the statistical analysis of


Boulware et al. We also add an original statistical analysis by adopting a
different method, replacing Fisher’s exact test with a simple regression analysis
….

Their conclusion incorrectly states there is no evidence of efficacy, while the


evidence is positive although not conclusive at 95% level with the sample size
and methodology used.

Applying the modifications we have stated in sections 2 and 3, in particular using


a simple linear regression method to their data, we conclude the randomized trial
of Boulware et al. has statistical evidence, at 99% confidence level, that
hydroxychloroquine treatment is time-dependent with a negative slope.

We conclude that, when applied as a prophylaxis, it [HCQ] can significantly


reduce the relative proportion of symptomatic patients if used from 0 to 2 days
after exposure to the virus (71.98% for 0 days, 48.86% for 1 day and 29.33% for
2 days). The predictive value for day 0 can be seen as lower bound for the
expected hydroxychloroquine efficacy if used as a pre-exposure prophylaxis. This
suggests that pre-exposure prophylaxis can be significantly effective.
For 3 and 4 days, we conclude there is no statistical evidence, at 99% level, that
hydroxychloroquine treatment reduces the proportion of symptomatic patients.
Moreover, our results show that the elapsed time between the exposure to the
virus and the beginning of treatment is vital to the effectiveness of the antiviral
use.

We expect the treatment will be more effective when applied to patients in the
viral replication period, before viral load reaches its peak which occurs around 5
days after symptom onset.

Meanwhile, if disease reaches the inflammatory period, typically after 8 days of


symptoms onset and after viral load reaches its peak, we can expected no or little
benefit with the antiviral treatment.

Therefore, the mean time elapsed from exposure to the virus and the start of
treatment in the sample may act as a lurking variable, influencing in a hidden
way the efficacy of treatment. This might explain why many studies have found no
statistical evidence of effectiveness of hydroxychloroquine treatment when used
in hospitalized patients as most of this more severe cases had probably started
treatment long after 4 days from their exposure to the virus.

In addition, it helps to understand why some studies have shown some positive
results of hydroxychloroquine treatment as we can expect this when the
proportion of patients in the beginning of the infection is higher in the sample.
Hence, as described by Boulware et al., two possible applications would be to
apply prophylaxis to health professionals and to contacts of positive patients,
since these two groups would have a greater probability to benefit from
treatment.

Our results suggest there is probably little or no benefit if the treatment is used in
patients infected for too long, like hospitalized severe patients. On the contrary,
they also suggest infected patients may have a large benefit if treated as early as
possible, mostly as pre-prophylaxis treatment where symptoms appear will have
an estimated relative reduction of at least 72%

The conclusions of these two studies concur with your theory about the possibility of a
‘sweet spot’ during the disease stage for which HCQ could be effective in prevention or
treatment of COVID-19 infection may exist.
Further, additional commentary criticising Boulware et al. is contained in his open letter
signed by statisticians, medical researchers, clinicians and other quantitative researchers.
https://drive.google.com/file/d/1NZOJ57fM0RTaHD1t_9w2iua7lUJhOgWT/view

They note;

These three papers [including Boulware et al] nevertheless share at least one
common mistake: the conclusions they draw from their data are wrong. All three
papers lead, explicitly or implicitly to the conclusion that early treatment of
COVID-19 patients with hydroxychloroquine is not effective. In saying that the
conclusions are wrong we are not affirming that hydroxychloroquine is effective.
This is a subtle but important distinction.

Due to the importance of clinical trials in COVID-19 public decision making, we


believe it is fundamental that these three studies correct their conclusions and
publicize these corrections. In a pandemic the urgency of publication is justified
and more errors might appear.

Secondly, in relation to the RECOVERY trial, you stated in your previous email;

“I do not agree that the dose of HCQ used in that trial was excessive – it was a
2000 mg loading dose split over the first 24 hours (see the attached trial
publication). Such loading doses are commonly used in treatment of infectious
diseases – for example for malaria, a 1200 mg loading dose of HCQ is given
compared with the 400-600 mg daily dose usual for rheumatoid arthritis …… I
also contend that it would be inconceivable that the investigators confused
hydroxychloroquine with another agent”

Following is part of a transcript of an interview that the head of the RECOVERY trial,
Martin Landray gave to a journalist at France Soir (a French magazine)

FS : Could you please precise what dosage of HCQ you gave to the patient ?
and the results ?

ML : It is 2400 mg in the first 24 hours and 800 mg from day 2 to day 10. It is
an 10 day course of treatment in total. These are quite high doses to make sure
that the blood levels got high enough to have a chance of killing the virus.
FS : How did you decide on the dosage of HCQ ?

ML : The doses were chosen on the basis of pharmacokinetic modelling and these
are in line with the sort of doses that you used for other diseases such as amoebic
dysentery.

FS : Are there any maximum dosage for HCQ in the UK?

ML : I would have to check but it is much larger than the 2400mg, something like
six or 10 times that. There is no approved dose for Covid patients because it is
not approved for use in Covid patients

FS : Are there any doses considered lethal for HCQ in the UK by the MHRA?

ML : The treating doctors did not report that they thought any of the deaths were
due to hydroxychloroquine. For a new disease such as Covid, there is no there is
no approved dosing protocol. But the HCQ dosage used are not dissimilar to that
used, as I said, in for example amoebic dysentery.

I understand that Martin Landray denied making these comments as reported, however
France Soir recorded the interview and released parts of it on the internet.

From this interview, it is clear that the HCQ dose given in the first 24 hours was 2400mg
not 2000mg. It is also clear that Martin Landray thought that ‘six to ten times’ a higher
dose of HCQ (24,000mg) could be safely given and that the 2400mg HCQ dosage given
in the first 24 hours in Landray’s own words “are not dissimilar to that used, as I said, in
for example amoebic dysentery”.

However, as I understand and as several doctors have pointed out including James
Todaro MD, that Hydroxychloroquine is not used to treat amoebic dysentery, but and
Iodoquinol (a hydroxyquinoline) at a dose of around 2000 mg is.

Further the AMM in France considers that the overdose rate for HCQ is 25mg/kg – thus
for a 70kg patient, anything above 1750mg would be considered an overdose, requiring
immediate emergency hospital care.

And this would not be the first time that Hydroxychloroquine has been confused with
hydroxyquinoline as evidenced in this paper and amazingly, it is still published on the
internet without correction;
The recent FDA approval of Hydroxyquinoline for hospitalized COV patients,
though only for patients where access to clinical trials are unavailable ….

Most of the ongoing and planned trials have rightly focused on hospitalized COV
patients where the need for effective therapies remains critical. However, the
PRINCIPLE trial that is currently being launched to study the effect of
Hydroxyquinoline in older patients with mild symptoms in a primary care setting
will provide useful data that will facilitate the early use of the drug to contain the
disease in future flareups.

The only conclusion that can be drawn from these facts is a medical error in setting the
dose in the RECOVERY trial and that the patients in this trial where given an excessive
and likely toxic dose.

In light of the above, and the recent observational studies that indicate that low dose
HCQ (combined with zinc and administered with the first 5 days after infection) could
be highly effective in reducing both deaths and hospitalisations for Covid patients (that I
attached in the previous emails), I again respectfully suggest that the TGA’s current
recommends the use of hydroxychloroquine to treat COVID-19 can longer be sustained.

And further, I also respectfully suggest that the TGA consider having three separate
recommendations for the use of hydroxychloroquine (HCQ) to treat COVID-19;

1. As a pre-exposure prophylaxis
2. As an early treatment (1-7 days) after first symptoms
3. After admission to hospital.

And that the TGA should at the very minimum change its recommendation on HCQ to
treat Covid for at least as early treatment (1-7 days) after first symptoms.

Yours faithfully,

Craig Kelly MP

Member for Hughes.


From: Kelly, Craig (MP)
Sent: Thursday, 17 September 2020 6:32 PM
To: 'SKERRITT, John' <
Cc: Hunt, Greg (MP) <Greg.Hunt.MP@aph.gov.au>
Subject: RE: hydroxychloroquine [SEC=OFFICIAL]

Dear Professor Skerritt,

Thank you for your reply, it is greatly appreciated.

I also welcome your acknowledgement ‘’that it is possible that a ‘sweet spot’ – a disease
stage or patient population - for which HCQ could be effective in prevention or
treatment of COVID-19 infection may exist’’.

However, if this does in fact prove to be correct, we currently have a situation where the
TGA’s recommendation is being relied upon to deny Australian citizens that test positive
for Covid a treatment that may save their lives.

I also appreciate your advice that there are about 20 significant clinical trials underway.
However, I would re-emphasis the comments from the recent study by Prodromos and
Rumschlag;

Thousands of lives may lie in the balance. …. We also do not believe that
randomized controlled studies are necessary before HCQ is authorized for
general use because the efficacy seen in studies already done indicates that
control patients in such studies might die unnecessarily; and because the time
delay to do any such study would cause yet more deaths by preventing HCQ use
when it is most needed – which is immediately. Our study has shown that good
evidence of efficacy exists; and there is no safety, cost, or supply reason to not
treat now.

Although you may have already read these, I would like to draw to your attention two
further observational studies published over the past few days. Firstly, a study from
Saudi Arabia Sulaiman et al. which found patients treated with HCQ + Zinc had a 43%
reduction in admission to hospitalisation, a 49% reduction in admission to ICU and a
73% in deaths. And secondly, a study from Italy, Lauriola et al., which co-incidentally
also found a 73% reduction in death associated with HCQ+AZ.

These findings are consistent with the results from Scholz et al which found early
treatment with HCQ+AZ+Zinc resulted in 84% lower hospitalizations and 80% lower
deaths. And although not a formal study, in this interview Dr Brian Tyson, a doctor
from California, he discusses how he has treated almost 1,700 Covid positive patients
with zero deaths.

In relation to the 3 other studies you referenced below, these studies including the
RECOVERY trial, did not use HCQ in the manner that is being advocated for by
medical specialists that I have spoken with, which is; combined with zinc and
azithromycin, and given within the first 7 days after symptoms appears (the early the
better) and for high risk patients.

Therefore could I respectfully suggest that the TGA consider having three separate
recommendations for the use of hydroxychloroquine (HCQ) to treat COVID-19;

1. After admission to hospital.


2. As an early treatment (1-7 days) after first symptoms
3. As a pre-exposure prophylaxis

Of these, the TGA’s current recommendation, that the use of hydroxychloroquine (HCQ)
to treat COVID-19 is strongly discouraged, could remain for after admission to hospital,
however given the weight of evidence, I believe it would defy all logic for this same
recommendation to be maintained for early treatment.

Regards,

Craig Kelly MP

Member for Hughes

From: SKERRITT, John


Sent: Sunday, 13 September 2020 8:48 PM
To: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>
Cc: Hunt, Greg (MP) <Greg.Hunt.MP@aph. ov.au>
Cook, Jane
Subject: RE: hydroxychloroquine [SEC=OFFICIAL]

Dear Mr Kelly
Thank you for your email.

I stand by our Department’s advice that the use of hydroxychloroquine (HCQ) to treat
COVID-19 is strongly discouraged outside of a clinical trial. You are correct that this
advice concurs with the recommendations from the National COVID-19 Clinical
Evidence Taskforce. It is also based on the overwhelming balance of evidence thus far,
and the consensus view of major global medicines regulators and health departments,
with whom I am in very regular conduct around the progress of clinical trials for
potential therapeutics for COVID-19.

Our Department’s advice was not just based on the results of the RECOVERY trial,
although I believe that trial was an important and well-conducted one. I do not agree that
the dose of HCQ used in that trial was excessive – it was a 2000 mg loading dose split
over the first 24 hours (see the attached trial publication). Such loading doses are
commonly used in treatment of infectious diseases – for example for malaria, a 1200 mg
loading dose of HCQ is given compared with the 400-600 mg daily dose usual for
rheumatoid arthritis.

I also contend that it would be inconceivable that the investigators confused


hydroxychloroquine with another agent – the trial was conducted across 176 UK
hospitals and the trial design, including the doses used, were approved by the UK
regulator (MHRA) prior to the patients being treated.

I am aware that a couple of early studies were suggestive of positive benefits of HCQ in
COVID but since the time that many of those studies were carried out, a much larger
number of negative studies have been published in the top global refereed medical
journals. For example three studies in the New England Journal of Medicine, which is in
the top 4 global medical journals have shown the following:

https://www.nejm.org/doi/full/10.1056/NEJMoa2019014

Brazilian study of individuals hospitalised with mild to moderate COVID-19 – no effect


of HCQ (800 mg/day) with or without azithromycin on clinical outcomes

https://www.nejm.org/doi/full/10.1056/NEJMoa2016638

US and Canadian study on potential use of HCQ for post exposure prophylaxis (1400 mg
on day 1 then 600 mg a day) - no impact on clinical outcomes
https://www.nejm.org/doi/full/10.1056/nejmoa2012410

Observational study in New York hospitals – 1220 mg HCQ on day 1 then 400 mg daily
– no increase or decrease in risk of intubation or death in COVID-19 infected patients

It is possible that a “sweet spot” – a disease stage or patient population for which HCQ
could be effective in prevention or treatment of COVID-19 infection may exist, and
about 20 significant clinical trials continue in about 8 countries, including at some major
medical centres. In collaboration with the US FDA, the European Medicines Agency and
other major regulators, the TGA is closely monitoring the results of these studies as they
become available.

Yours sincerely

John Skerritt

Adjunct Prof John Skerritt FTSE FIPAA (Vic)

Deputy Secretary for Health Products Regulation

Department of Health

(The Health Products Regulation Group comprises the Therapeutic Goods Administration and the
Office of Drug Control)

From: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>


Sent: Wednesday, 9 Se tember 2020 5:30 PM
To: SKERRITT, John <
Cc: Greg.Hunt.MP <Greg.Hunt.MP@aph.gov.au>
Subject:

Dear Professor Skerritt,


I am writing to you as I am greatly concerned about the TGA’s advice
“that it strongly discourages the use of hydroxychloroquine to treat
COVID-19”.

From the statement on the TGA’s website, this advice appears to be based
upon the recommendations from the National COVID-19 Clinical
Evidence Taskforce. And the Taskforce’s recommendations appear to be
based substantially upon the findings of the RECOVERY trial.

However the evidence appears to show that the RECOVERY trial was
fatally flawed, as in this trial they administered the group of patients taking
HCQ with 2400mg of the drug within the first 24 hours. All evidence
indicates that this was an excessive and toxic dose – 4 to 5 times the
maximum recommended. Further media reports indicate that this excessive
dose was the result of medical negligence where those running the
RECOVERY trial confused the drugs hydroxychloroquine with
hydroxyquinoline.

Therefore, I believe there is a very strong argument that any results of the
RECOVERY should be disregarded in TGA making any recommendation.

I would also like to draw to your attention two meta-analysis studies


released in preprint in the past 48 hours. The first is a study out of France
by the Institut Hospitalo-Universitaire (IHU) Méditerranée Infection,
which will be published in the journal ‘Expert Review of Clinical
Immunology’. This most comprehensive study concluded for Covid-19;

‘’Treatment with an oral combination of hydroxychloroquine,


azithromycin and zinc may REPRESENT THE BEST CURRENT
THERAPEUTIC OPTION in relation to its antiviral and
immunomodulatory effects’’.

The second is a study from the US by Chadwick C Prodromos MD and


Tobias Rumschlag MD in which they concluded;
This study has four important findings. The first is that HCQ
appears to be consistently effective for the treatment of COVID-19
when used early in the course of disease in the outpatient setting,
and is generally more effective the earlier it is used. The second is
that overall HCQ has had efficacy against COVID-19 in a majority
of studies. The third is that there are no unbiased studies showing
a negative effect of HCQ treatment of COVID-19. The fourth is that
HCQ appears to be safe for the treatment of COVID-19 when used
responsibly.

And the authors further noted;

SIGNIFICANCE: We believe our findings have substantial societal


global importance since there have been numerous edicts either
preventing HCQ use for COVID-19 or limiting it to the inpatient
setting which we believe have resulted in many unnecessary deaths.

Our findings showing efficacy and safety of HCQ against COVID-


19 indicate that HCQ should be freely available to patients and
physicians who choose to use it. And it should especially be freely
available to be used on an outpatient basis before hospitalization
where it appears to be more effective and where early fears of fatal
heart arrhythmias

have been shown to be unfounded[45].

This is particularly important because the only drug to show


efficacy, Remdesivir, has shown no significant benefit in a recent
study [46].It is also expensive and not widely available.
Convalescent plasma has shown benefit [47] but even this is not
well validated and plasma is not available in large numbers of
doses.

Thus HCQ with proven efficacy and safety, a cost of 37 cents per
pill and thus a total treatment cost of under 20 dollars[48], versus
3,100 dollars for Remdesivir[49], as well as wide supply chain
availability, would appear to be the best COVID-19 treatment
option available and needs to be widely promoted as such.

Unfortunately the controversies surrounding HCQ have resulted in


physicians being afraid to prescribe it for reasons which have
nothing to do with medicine, and in patients being afraid to take it
due to spurious reports of danger, or fears that is not effective.

It is hoped that this study will disabuse the medical community of


these misapprehensions about efficacy and validate that it is both
efficacious and safe, and needs to be freely

prescribable. Thousands of lives may lie in the balance.

We also do not believe that randomized controlled studies are


necessary before HCQ is authorized for general use because the
efficacy seen in studies already done indicates that control patients
in such studies might die unnecessarily; and because the time delay
to do any such study would cause yet more deaths by preventing
HCQ use when it is most needed – which is immediately. Our study
has shown that good evidence of efficacy exists; and there is no
safety, cost, or supply reason to not treat now.

Unnecessary death from delayed treatment is too high a price to pay


for greater certainty of knowledge. Many may have already died
unnecessarily due to HCQ misinformation and it is imperative that
we do not further add to the toll.

I would also like to point out this meta-study concluded collecting data on
the 3rd August 2020, and therefore it did not include the results from 4
large studies which all found treatment with HCQ was associated with
sustainable reducing in death

· Castelnuovo et al., European J. Internal Medicine,


doi:10.1016/j.ejim.2020.08.019 (Peer Reviewed) – study found
the use of hydroxychloroquine in hospitalised COVID-19
patients was associated with reduced mortality: Retrospective
3,451 hospitalized patients, 30% reduction in mortality with
HCQ after propensity adjustment.

· Catteau et al., Int. J. Antimicrobial Agents,


doi:10.1016/j.ijantimicag.2020.106144 (Peer Reviewed) –
Retrospective study of 8,075 hospitalized patients, 4,542
received low-dose HCQ, 3,533 control - found a 35% lower
mortality for HCQ (17.7% vs. 27.1%)

· Ip et al., medRxiv, doi:10.1101/2020.08.20.20178772


(Preprint) - Retrospective study of 1,274 outpatients, which
found a 47% reduction in hospitalization with HCQ

· Gonzalez et al., medRxiv,


doi:10.1101/2020.08.18.20172874 (Preprint) - Retrospective
study focused on eosinophil recovery with 9,644 hospitalized
patients in Spain, showing lower mortality for HCQ (14.7% vs
29.2%, p<0.001), and AZ (15.3% vs. 18.4%, p<0.001).

In light of this most recent evidence, I respectfully suggest that the TGA’s
current recommends the use of hydroxychloroquine to treat COVID-19
can longer be sustained and should be urgently reviewed.

Regards,

Craig Kelly MP

Member for Hughes

"Important: This transmission is intended only for the use of the addressee and may
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and delete all copies of this transmission."
Thank you again for your reply, however a further meta-analysis study
was released in preprint overnight.

file:///C:/Users/kellyc/Downloads/EfHCQ9-4.pdf

The authors of this study concluded;

This study has four important findings. The first is that HCQ
appears to be consistently effective for the treatment of COVID-19
when used early

in the course of disease in the outpatient setting, and is generally


more effective the earlier it is used. The second is that overall
HCQ has had efficacy against COVID-19 in a majority of
studies. The third is that there are no unbiased studies showing

a negative effect of HCQ treatment of COVID-19. The fourth is


that HCQ appears to be safe for the treatment of COVID-19 when
used responsibly.

And they further noted;

SIGNIFICANCE: We believe our findings have substantial


societal global importance since there have been numerous

edicts either preventing HCQ use for COVID-19 or limiting it to


the inpatient setting which we believe have resulted in many
unnecessary deaths.

Our findings showing efficacy and safety of HCQ against COVID-


19 indicate that HCQ should be freely available to patients and
physicians who choose

to use it. And it should especially be freely available to be used on


an outpatient basis before hospitalization where it appears to be
more effective and where early fears of fatal heart arrhythmias

have been shown to be unfounded[45].

This is particularly important because the only drug to show


efficacy, Remdesivir, has shown no significant benefit in a recent
study [46].It is

also expensive and not widely available. Convalescent plasma


has shown benefit [47] but even this is not well validated and
plasma is not available in large numbers of doses.

Thus HCQ with proven efficacy and safety, a cost of 37 cents per
pill and thus a total treatment cost of under 20 dollars[48], versus
3,100 dollars

for Remdesivir[49], as well as wide supply chain availability,


would appear to be the best COVID-19 treatment option available
and needs to be widely promoted as such.
Unfortunately the controversies surrounding HCQ have resulted
in physicians being afraid to prescribe it for reasons which have
nothing to do with

medicine, and in patients being afraid to take it due to spurious


reports of danger, or fears that is not effective.

It is hoped that this study will disabuse the medical community of


these misapprehensions about efficacy and validate that it is both
efficacious

and safe, and needs to be freely

prescribable.

Thousands of lives may lie in the balance.

We also do not believe that randomized controlled studies are


necessary before HCQ is authorized for general use because the
efficacy seen in studies

already done indicates that control patients in such studies might


die unnecessarily; and because

the time delay to do any such study would cause yet more deaths
by preventing HCQ use when it is most needed – which is
immediately. Our study has shown that good evidence of efficacy
exists; and

there is no safety, cost, or supply reason to not treat now.

Unnecessary death from delayed treatment is too high a price to


pay for greater certainty of knowledge. Many may have already
died unnecessarily

due to HCQ misinformation and it is imperative that we do not


further add to the toll.

In light of the is and numerous other recent studies and the Taskforce’s
reliance upon the RECOVERY trial were patients were overdosed with a
toxic and excessive dose of

HCQ, I most respectfully put it to the Taskforce’s recommendations on


HCQ are no longer sustainable.
Regards,

Craig Kelly MP

Member for Hughes

From: Julian Elliott

Sent: Tuesday, 8 September 2020 5:16 PM

To: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>

Cc: Hunt, Greg (MP) <Greg.Hunt.MP@aph.gov.au>


Subject: Re: Request for Taskforce to review recommendations on HCQ

Dear Mr Kelly,

Thank you for your emails and continued interest in the work of the National
COVID-19 Living Evidence Taskforce. I will pass on these studies and
commentary to the Taskforce evidence team to

ensure the evidence surveillance and synthesis processes they maintain have
captured this work.

As you are aware we are focused on ensuring Australians have access to


safe, best-practice treatment for the management of COVID-19.

We are committed to delivering robust, independent, evidence based ‘living’


guidelines, updated with new research in near real-time in order to give
reliable, up-to-the minute advice to clinicians providing frontline care in this
unprecedented global health
crisis.

We will continue undertaking continuous evidence surveillance to identify and


rapidly synthesise emerging research in order to provide national, evidence-
based guidelines for the clinical care of people with COVID-19.

On behalf of the hundreds of expert clinicians from around Australia who produce and
update the national guidelines, I can assure you we take this responsibility very
seriously and are committed to supporting the best possible care and outcomes for
Australians

with COVID-19.

Best wishes,

Julian
Julian Elliott MBBS FRACP PhD

Director, National COVID-19 Clinical Evidence Taskforce

Chair, Australian Living


Lead, Evidence Systems, Cochrane

Senior Research Fellow, Cochrane Australia,

School of Public Health and Preventive Medicine, Monash University

Infectious Diseases Physician, Alfred Hospital

CEO, Covidence.org
covid19evidence.net.au

livingevidence.org.au
On Tue, 8 Sep 2020 at 12:05, Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>
wrote:

Dear Professor Elliott,

Further to my email yesterday, a further latest study overnight was released by the
Institut Hospitalo-Universitaire (IHU) Méditerranée Infection, which will be
published in the journal ‘Expert Review of Clinical Immunology’ - after under

going peer review.


This most comprehensive study concludes for Covid-19;

‘’Treatment with an oral combination of hydroxychloroquine, azithromycin and zinc


may REPRESENT THE BEST CURRENT THERAPEUTIC OPTION in relation to
its antiviral and immunomodulatory effects’’.
https://www.mediterranee-infection.com/wp-content/uploads/2020/09/ERM-2020-
0073.R1_Proof_hi.pdf

Adding this to recent weight of evidence, it is now longer sustainable that


Australians are denied ‘’the best current therapeutic option” due to out of date
recommendations by the National COVID Evidence Taskforce.

I request you to urgently convene the Taskforce and have them review their
recommendations on HCQ in light of this recent study.
Regards,

Craig Kelly

Sent from my iPad


On 7 Sep 2020, at 7:58 pm, Kelly, Craig (MP)
<Craig.Kelly.MP@aph.gov.au> wrote:

Dear Professor Elliott,

Thank you for your previous reply, however I am greatly


concerned that the National COVID-19 Clinical Evidence
Taskforce has made a serious mistake

in relation to their recommendations on


Hydroxychloroquine.

The follow
is the summary of the evidence that the Taskforce state that
they current rely upon;

Evidence indicates that hydroxychloroquine is potentially


harmful and no more effective than standard care in treating
patients with COVID-19.

What is the evidence informing this recommendation?

Evidence informing this recommendation comes from nine


randomised trials that compared hydroxychloroquine plus
standard care to standard care alone in over 6000 patients [28]
[29][32][41][42][43][44][45][55].

Publication status

The vast majority of evidence is from the RECOVERY trial


which randomised 4716 hospitalised patients with COVID-19—
this trial has reported preliminary results as a preprint but has
yet to

report complete data on adverse or serious adverse events [42].

Three other studies, which contribute 125 patients to the results,


are also published as preprints and have therefore not been peer
reviewed [29][41][45]. In

addition to our daily evidence surveillance processes, we follow


up with the corresponding author every two months to request
an update on the study's publication status.
Study characteristics

There was significant variability in disease severity among


patients included in the trials: two trials were of mild
illness (776 patients) [43][44],

two of mild or moderate (665 patients) [45][55],

three of moderate (122 patients) [28][29][41], one

of mild, moderate and severe (150 patients) [32],

and one of moderate and severe (4716 patients) [42].

Mean or median age ranged from 41 to 65 years in the


hydroxychloroquine groups and from 39 to 65 years in the
standard care groups. The proportion of women was 42%
(range 36 to 72%) in the hydroxychloroquine groups and 40%
(range

20 to 66%) in the standard care groups.

What are the main results?

Hydroxychloroquine probably has little or no impact on the two


critical outcomes of death and the need for mechanical
ventilation. For every 1000 patients given hydroxychloroquine,
15 more are likely to die compared to those receiving

standard care (RR 1.07, CI 95% 0.97 to 1.19; 5886 patients in 6


studies) and 8 more are likely to require ventilating (RR 1.11, CI
95% 0.90 to 1.36; 4548 patients in 3 studies).

Hydroxychloroquine probably increases the risk of adverse


events, with 296 more patients per 1000 experiencing one or
more adverse events with hydroxychloroquine compared to
standard care (RR 2.71, CI 95% 1.40 to 5.26; 1380 patients

in 7 studies). Since serious adverse events were rare,


hydroxychloroquine may make little or no difference compared
to standard care (27 events; 1350 patients in 6 studies; 4 fewer
per 1000 with hydroxychloroquine (RR 0.83, CI 95% 0.39 to
1.76)).

For all other outcomes—virological clearance, hospitalisation


and discharge from hospital—we are uncertain if
hydroxychloroquine makes a difference compared to standard
care.

Our confidence in the results

Certainty of the evidence for risk of dying, need for mechanical


ventilation and discharge from hospital is moderate (due to
serious imprecision). Certainty is moderate for adverse events
(due to serious risk of bias), low for

serious adverse events (due to serious inconsistency and


imprecision) and very low for both virological clearance and
hospitalisation (due to serious risk of bias and very serious
imprecision).

Additional information

According to the Therapeutic Goods Administration known


acute harms for hydroxychloroquine include prolonged QT
interval and lowered convulsive threshold. Long-term harms of
relevance include retinopathy and chronic cardiomyopathy [34].

There are several known and potential interactions with other


drugs [34].

Overdose of hydroxychloroquine may have potentially fatal


complications. In pregnancy, it is only recommended

when benefits outweigh harms [34].


I would note the following in relation to the above;

1.

Of the nine randomised trials, none of these trials


looked at HCQ in the context that doctors that advocate
for drug say it is effective as a treatment for Covid –
that is; It is given in combination with zinc and is
given early

(within the first 5 days after infection) and given to


high risk patients.

2.

The Taskforce’s recommendations are heavily


weighted by the results of the RECOVERY trial, (4716
patients out of 6000). In the RECOVERY trial a total
of 1,542 patients were randomized

to receive hydroxychloroquine compared to 3,132


patients randomized to standard of care - this resulted
in a

mortality at 28 days of 25.7% hydroxychloroquine vs.


23.5% usual care.

3.

However the RECOVERY trial has been widely


discredited, as it gave sick patients an excessive and
toxic dose of 2400 mg of HCQ (4 -6 times the
recommended dose) in the first 24 hours. This level of
dosage is far in excess of

that being recommended by doctors that advocate for


HCQ as a treatment (400 mg per day)

4.

The French medical authorities

consider the overdose rate for hydroxychloroquine

is 25mg/kg of hydroxychloroquine, i.e. for a 75kg


patient, 1875mg for one day – and if such an overdose
occurs, this requires immediate emergency hospital
care.
5.

Therefore it is clear that the RECOVERY trial


overdosed patients with

hydroxychloroquine, and as the Taskforce’s own


recommendations note, that an

‘Overdose of hydroxychloroquine may have potentially


fatal complications’. So it wasn’t only an overdose – it
was a potentially fatal overdose.

6.

The French magazine

France Soir interviewed the authors of the


RECOVERY trial and asked about the size of the dose.
The studies author is reported as saying;

"that the chosen dosage is in line with the dosages


used for other diseases such as amoebic dysentery".
Reading these comments , Professor Peronne said:
“It is the first time that I learn that we use
hydroxychloroquine in amoebic dysentery, in super-
toxic doses for humans. The classic treatment for
colonic amoebiasis is the hydroxyquinoline
combination of tiliquinol

and tilbroquinol, the trade name of which is Intetrix.


The capsules contain 50 mg of tiliquinol and 50 mg of
tilbroquinol. Dosage: 4 capsules per day.

I think he confused hydroxychloroquine with


hydroxyquinoline.

This man, who calls himself a doctor, is incompetent


and dangerous."

7.

Therefore, given that the RECOVERY trial


administered fatal overdoses of

hydroxychloroquine to very ill Covid patients, in the


late stage of their illness - it should be no surprise that
more died when overdosed.

8.

The evidence shows that the RECOVERY trial was


medical negligence of the highest order with

1,542 sick COVID patients mistakenly given a


potentially fatal overdose, so its no surprise that over
27.5% didn’t recover. Therefore the RECOVERY trial
should be totally disregarded for any consideration of
the

effectiveness of HCQ as a treatment for Covid, and yet


through its weight of numbers, the RECOVERY trial
forms the basis of the

National COVID-19 Clinical Evidence Taskforce’s


recommendations on HCQ/.

9.

If the numbers from the RECOVERY trial are removed


from the National COVID-19 Clinical Evidence
Taskforce analysis, the Taskforce’s current
recommendation cannot be sustained by the findings of
other eight studies.

10.

There is not a single clinical trial that has looked at


HCQ in the context that doctors that advocate for drug
say it is effective as a treatment for Covid – that is; it is
given in combination with zinc and given early (within

the first 5 days after infection) and given to high risk


patients. However, there are multiple recent
observational studies (several peer-reviewed) that
indicate that HCQ is highly effective at reducing both
deaths and hospitalisations. Including;


Castelnuovo et al.,

European J. Internal Medicine,


doi:10.1016/j.ejim.2020.08.019 (Peer Reviewed) –

study found the use of hydroxychloroquine in


hospitalised COVID-19 patients was associated
with reduced mortality: Retrospective 3,451
hospitalized patients,

30% reduction in mortality with HCQ after


propensity adjustment.


Catteau et al., Int. J. Antimicrobial Agents,
doi:10.1016/j.ijantimicag.2020.106144

(Peer Reviewed) – Retrospective study of 8,075


hospitalized patients, 4,542 received low-dose
HCQ, 3,533 control - found
a 35% lower mortality for HCQ (17.7% vs.
27.1%)


Ip et al.,

medRxiv, doi:10.1101/2020.08.20.20178772
(Preprint) -

Retrospective study of 1,274 outpatients, which


found

a 47% reduction in hospitalization with HCQ


Arshad et al.,

Int. J. Infect. Dis., July 1 2020,


doi:10.1016/j.ijid.2020.06.099 (Peer Reviewed) -

HCQ decreases mortality from 26.4% to 13.5%


(HCQ) or 20.1% (HCQ+AZ). Propensity

Hong et al.,

Infect. Chemother., 2020, 52:e43 (Peer Reviewed)


-

HCQ 1-4 days from diagnosis was the only


protective factor against prolonged viral shedding
found, OR 0.111, p=0.001.

57.1% viral clearance with 1-4 days delay vs.


22.9% for 5+ days delayed treatment. Authors
report that early administration of HCQ
significantly ameliorates inflammatory cytokine
secretion and that COVID-19 patients

should be administrated HCQ as soon as possible.


Sbidian et al., medRxiv,
doi:10.1101/2020.06.16.20132597 (Preprint)

- Retrospective study of 4,642 hospitalized patients


in France showing

significantly faster discharge with HCQ and


HCQ+AZ.


Ayerbe et al.,

Journal of Thrombosis and Thrombolysis, doi:


10.1007/s11239-020-02162-z (Peer Reviewed) -
2075 hospital patients in Spain.

HCQ reduces mortality from 30%

to 13%.


Yu et al.,

Science China Life Sciences, 2020 May 15, 1-7,


doi:10.1007/s11427-020-1732-2 (Peer Reviewed)

Study found low Dose of Hydroxychloroquine


Reduces Fatality of Critically Ill Patients With
COVID-19 - Retrospective, 550 critically ill
patients.

19% fatality for HCQ versus 47% for non-HCQ


Esper et al.,

Prevent Senior Institute, São Paulo, Brazil


(Preprint) -

Empirical treatment with hydroxychloroquine and


azithromycin for suspected cases of COVID.

636 patients. HCQ+AZ reduced hospitalization


79% when used within 7 days (65% overall).

Gonzalez et al.,

medRxiv, doi:10.1101/2020.08.18.20172874
(Preprint) -

Retrospective study focused on eosinophil


recovery with 9,644 hospitalized patients in Spain,
showing

lower mortality for HCQ (14.7% vs 29.2%,

p<0.001), and AZ (15.3% vs. 18.4%, p<0.001).

11.

Certainly it’s possible to pick at the edges of each of


these observational studies, however the statistical
probability that they are all wrong, is approaching zero.

12.

Based on the above facts I would respectfully make the


following urgent recommendations for the Taskforce;

a.
Any findings from the RECOVERY trial are
disregarded due to the toxic overdosing of patients
b.
The Taskforces make separate recommendations
for HCQ for; Prophylaxis, Early Treatment and
Late Treatment

c.
The Taskforce make urgent recommends to state
chief medical officers to remove their ban on
doctors prescribing HCQ to treat Covid.

Regards,

Craig Kelly MP

Member for Hughes


From: Julian Elliott

Sent: Saturday, 15 August 2020 2:46 PM

To: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>

Cc: Hunt, Greg (MP)


<Greg.Hunt.MP@aph.gov.au>

Subject: Re: Questions to the the National Covid Evidence Taskforce

Dear Mr Kelly,
Thank you for your email and interest in the work of the National
COVID-19 Clinical Evidence Taskforce. Hundreds of expert clinicians
from around Australia contribute many hours

every week to review the latest research on COVID-19 and to maintain


up to date, evidence-based recommendations for their peers - so they
can provide the best care possible for people with COVID-19.

The Taskforce is a consortium of 29 national peak clinical groups,


including major medical colleges and specialists societies. The
recommendations of the Taskforce are developed

by expert clinical panels, and then approved with complete consensus


by our senior clinical expert panel and the Taskforce Steering
Committee, comprising senior representatives from all 29
national organisations.

Our responsibility is to provide the best possible guidance for


Australian clinicians, balancing the potential benefits and harms of any
recommendation. This is a responsibility

that is taken very seriously by all involved in the Taskforce.


I have provided responses to your questions below. I would also
highlight that the Taskforce uses a world-leading 'living evidence'
approach, which combines rigorous, evidence-based

methods and rapid, weekly updating. This enables the Taskforce to


modify and update recommendations rapidly in response to the
publication of new COVID-19 research evidence. As such, as new
evidence emerges regarding the use of hydroxychloroquine, or other

medications, these will be rapidly reviewed by the Taskforce.

While it is unfortunate that trials to date have not demonstrated a benefit


from hydroxychloroquine, it is important that Australians are aware
there are effective treatments for

COVID-19. These are remdesivir, an antiviral medication originally


developed to treat Ebola, which reduces the time to recovery in people
with moderate, severe or critical COVID-19; and dexamethasone, a
very cheap, widely used anti-inflammatory medication

which substantially reduces mortality in people with more severe forms


of COVID-19 who require oxygen or ventilation.
Best wishes,

Julian

--
Julian Elliott MBBS FRACP PhD

Director, National COVID-19 Clinical Evidence Taskforce

Chair, Australian Living Evidence Consortium


Lead, Evidence Systems, Cochrane

Senior Research Fellow, Cochrane Australia,

School of Public Health and Preventive Medicine, Monash University

Infectious Diseases Physician, Alfred Hospital

CEO, Covidence.org
covid19evidence.net.au

livingevidence.org.au
On Fri, 14 Aug 2020 at 13:23, Kelly, Craig (MP)
<Craig.Kelly.MP@aph.gov.au> wrote:

Dear

I would appreciate if you could forward this email to the

Executive Director of The National Covid Evidence Taskforce,

Associate Professor Julian Elliott.


Regards,

Craig Kelly

Dear Associate Professor Elliott,

I would greatly appreciate if you would be able to advise on the following;

1.

Can you confirm that the National Covid Evidence Taskforce’s recommendation
in regards to Hydroxychloroquine (that it is not recommended), is based solely
upon the review of nine randomised trials

that compared ‘Hydroxychloroquine plus standard care’ to ‘standard care’ alone,


with the vast majority of the evidence coming from the RECOVERY trial ?
As per globally-adopted methods and standards for evidence synthesis
and guideline development, we will always use the best available
evidence. Where randomised trial evidence is

available, this provides the highest quality evidence as it effectively


controls for known and unknown confounding factors. Fortunately, for
the question of whether hydroxychloroquine is safe and effective for the
treatment of COVID-19 there is substantial

randomised trial evidence and so the Taskforce guideline panels have


used this evidence to inform their recommendations.

The RECOVERY trial contributes substantially to the evidence


available on the use of hydroxychloroquine for the treatment of
COVID-19; its relative contribution varies across outcomes.
2.

Proponents for using Hydroxychloroquine (HCQ) as a treatment for COVID-19,


argue not for HCQ as a standalone treatment, but as part of

a combination that includes; Zinc, Azithromycin and HCQ. For example Dr.
Zelenko argues; “It’s not about HCQ. It is about … Zinc, HCQ & Azithromycin”.

Can you confirm that of nine studies that the National Covid Evidence Taskforce
has reviewed in reaching its recommendation on Hydroxychloroquine, that none
of these studies looked at

the combination of Zinc, HCQ & Azithromycin ?

The Taskforce expert guideline panels review any and all potential
treatments of COVID-19. To date, no randomised trials have been
published on the combination of zinc, hydroxychloroquine

and azithromycin for the treatment of COVID-19.


3.

Does the National Covid Evidence Taskforce make any recommendation in


respect of using

a combination of Zinc, HCQ & Azithromycin separately from its


recommendation not to use Hydroxychloroquine at all ?

The Taskforce recommends "Use of hydroxychloroquine may still be


considered in the context of randomised

trials with appropriate ethical approval, such as combination therapies that


include hydroxychloroquine."

4.
Has the National Covid Evidence Taskforce reviewed any studies (including
observational studies) that looked at using

a combination of Zinc, HCQ & Azithromycin ?

See above.

5.

Professor Rirsh argues that COVID-19 has two main stages. At the ‘first stage’, it
is a flu-like illness, and when not treated, high-risk patients may progress to the
‘second stage’ when the

virus causes severe pneumonia and attacks many organs, including the heart.

Can you confirm that of the nine studies that the National Covid Evidence
Taskforce has reviewed in reaching its recommendation on Hydroxychloroquine,
that none of these studies looked at the patients
in the first stage, and the studies relied upon only looking at patients in the
second stage, in a hospital setting ?

These stages are usually referred to as mild, moderate, severe and


critical disease, with mild disease roughly equating to the 'first stage'.
The studies included in these analyses

included participants with a range of disease severity at the time of


inclusion (as per the Summary text under Research Evidence):

"two trials were of mild illness (776 patients) [43][44],

two of mild or moderate (665 patients) [45][55], three of moderate (122


patients) [28][29][41], one

of mild, moderate and severe (150 patients) [32], and one of moderate and
severe (4716 patients) [42]."
6.

Has the National Covid Evidence Taskforce reviewed any studies (including
observational studies) that looked at using either HCQ alone or a combination of
Zinc, HCQ & Azithromycin in patients

in the first stage (or early stage prior to hospitalisation) ?

See above.

7.

Does the National Covid Evidence Taskforce make the same recommendation on
HQC in both stages ?
Yes, for all patients regardless of disease severity.

8.

In the RECOVERY trial, the initial dose of HCQ given to patients in the first 24
hours was 2400 mg.

a)

How does this 2400 mg compare with the normal maximum


recommended doses ?

b)

Does the National Covid Evidence Taskforce consider that 2400 mg


of HCQ administered in the first 24 hours is an excessive dose ?

c)

Does the National Covid Evidence Taskforce considered that 2400


mg of HCQ administered in the first 24 hours could be a toxic dose ?
d)

Could giving sick patients an excessive and toxic dose of HCQ have
distorted the resulted of the RECOVERY trial and lead to
unintended consequences ?

e)

Given that the National Covid Evidence Taskforce recommendations


were based upon “the vast majority of the evidence” from this
RECOVERY trial, could this result in the Taskforces
recommendations

being flawed or unreliable and urgently requiring reassessment ?

The high first day dose given in the RECOVERY trial was a 'loading
dose' with the aim of rapidly achieving concentrations that were
hypothesised to be effective for the treatment

of COVID-19. The toxicity (adverse effects and serious adverse effects)


of the dosing of hydroxychloroquine used in the RECOVERY study are
reported in the trial publications (pre-print and peer reviewed).

The Taskforce recommendation to not use hydroxychloroquine for the


treatment of COVID-19 is based on the randomised trials published to
date, which in pooled analyses showed no

benefit. It is unlikely a lower dose would show a benefit.

9.

What evidence has the National Covid Evidence Taskforce’s reviewed, that
investigated the risks for low level and short term (5-7 days) usage of HCQ alone,
or in combination with Zinc and Azithromycin

I have listed below the doses and duration of hydroxychloroquine used


in the randomised trials supporting the hydroxychloroquine treatment
recommendation.
Chen J 400mg daily for 5 days

Chen Z 400mg daily for 5 days

Tang W 1200mg daily for 3 days, followed by 800mg daily for 2-


3 weeks total

Chen CP 400mg twice a day, then 200mg twice a day for 6 days

Chen L 200mg twice a day for 10 days

Horby P 800mg at 0 and 6 hours, 400mg at 12 hours and then


twice a day for 9 days

Mitja O 800mg on day 1, then 400mg once daily for 6 days

Skipper C 800mg once, 600mg in 6 to 8 hours, then 600mg daily


for 4 days

Cavalcanti A 400mg twice a day for 7 days (+/- azithromycin)


10.

Is the National Covid Evidence Taskforce’s recommendation ‘’do not use HCQ for
the treatment for of COVID-19’’ made for all levels of dosages (either alone or in
combination with Zinc Azithromycin)

irrespective of the length or timing of the treatment ?

The Taskforce expert guideline panels use the best available evidence.
Based on currently published evidence, as I described above, no dosing
of hydroxychloroquine has been shown

to be safe and effective for the treatment of COVID-19, hence the


Taskforce recommendation not to use hydroxychloroquine applies to all
dosing.

Given the time critical nature of the issues confronting the nation currently, I
would greatly appreciate your earliest

reply.
Regards,

Craig Kelly

Federal Member for Hughes

Shop 1, 9 - 15 East Pde Sutherland NSW 2232

Phone: 9521 6262 Fax: 9545 0927


www.craigkelly.com.au

http://www.facebook.com/CraigKellyMP

<image001.jpg>
From: Kelly, Craig (MP)
To: SKERRITT, John
Cc: Greg.Hunt.MP
Subject: HCQ : New studies and media censorship
Date: Monday, 28 September 2020 9:37:48 PM
Attachments: OPEN LETTER TO Final.pdf

Dear Professor Skerritt,

I am writing to you on two issues.

Firstly, I would like to draw your attention to several new published papers on HCQ;

Karatza et al., (Peer Reviewed) – in this paper from Greece, its appears the authors
have moved beyond the question of if HCQ is safe and effective, and moved on to
what is the optimum level of dose. Their conclusion stated;

Based on the results from simulations performed and the currently published
knowledge regarding HCQ in COVID-19 treatment, this study provides evidence
that a high loading dose followed by sparse doses could offer significant benefits
to the patients.

Zreiq et al., (Peer Reviewed) and published in the Journal of Pharmaceutical


Research International which noted;

“Among all treatment modalities, antimalarial hydroxychloroquine ranked the


highest cure rate. Therefore, this drug is considered as the first-line of COVID-19
treatment.”

Gaspertetti et al., (Peer reviewed) which looked into the safety of HCQ and
concluded;

“HCQ administration is safe for a short-term treatment for patients with COVID-
19 infection regardless of the clinical setting of delivery …”

Secondly, the Member for Dawson George Christensen and myself have written an open
letter (copy attached) to the Chief Medical Officer of Queensland and we had made
arrangements for this to be published (at our expense) in major newspapers in the Eastern
states. However, we were advised late today that these newspapers refused to publish this
letter, and they advised that this was because they had received instructions from the
TGA not to print anything in regards to Hydroxychloroquine.

Keeping in mind that I believe that refusing to publish a letter written by two members of
Parliament (even when payment is offered to buy space in that newspaper) is inconsistent
with our constitutionally enshrined rights of free political communication, I ask you to
confirm that TGA’s instruction to our media prohibits or does not prohibit the publication
of this letter in major newspapers by two members of the Federal Parliament.

Given that our open letter relates to a decision that will made this week, your urgent reply
on this issue would be greatly appreciated.

Regards,
Craig Kelly MP
Member for Hughes

From: SKERRITT, John <John.Skerritt@health.gov.au>


Sent: Tuesday, 22 September 2020 9:27 PM
To: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>
Cc: Hunt, Greg (MP) <Greg.Hunt.MP@aph.gov.au>;
; SKERRITT, John

Subject: RE: hydroxychloroquine and COVID-19 [SEC=OFFICIAL]

Dear Mr Kelly

Thank you for your further email providing suggestions that hydroxychloroquine (HCQ) may be
effective at specific early time points in COVID infection.

While the analysis looks of potential interest, it is worth emphasising that the paper you have
quoted from Watanabe is not peer reviewed, the normal evidence standard for publication in
medical journals. Indeed the website on which it has been published states a significant
disclaimer as follows “Not peer reviewed…should not be relied upon without context to guide
clinical practice”….

Similarly the paper by Yang et at, although in the published literature focuses on interpretation
of retrospective observational data “suggesting” protective effects of HCQ and goes on to say in
its abstract “more randomised controlled studies are needed to evaluate the efficacy of HCQ (and
interferon alpha 2 separately and in combination) for prophylaxis against COVID-19 …Future
studies should give us more definitive answers”.

By copy of this email I have shared the email string with A/Prof Julian Elliott who is a coordinator
of the National COVID-19 Clinical Evidence taskforce, which was funded by the Government to
analyses emerging research evidence on COVID-19 to provide frontline healthcare workers with
advice, including on potential therapies.

Regards

John Skerritt

Adjunct Prof John Skerritt FTSE FIPAA (Vic)


Deputy Secretary for Health Products Regulation
Department of Health
(The Health Products Regulation Group comprises the Therapeutic Goods Administration and the
Office of Drug Control)

From: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>


Sent: Monday, 21 September 2020 8:13 PM
To: SKERRITT, John
Cc: Greg.Hunt.MP <Greg.Hunt.MP@aph.gov.au>
Subject:

Dear Professor Skerritt,

Just a further follow up to your previous reply.

Firstly, in support of the TGA’s current position on HCQ, you cited this study (Boulware et
al.) ; - for which you noted concluded that HCQ had “no impact on clinical outcomes”.

I would therefore like to draw to your attention significant criticism of this study which has
just been published , in which it was the noted;
Boulware et al. found a non-significant difference in incidence between HCQ and placebo
group (11.8% vs. 14.3%, p=0.35). However, our re-analysis of the data suggests HCQ use
for Covid-19 is time-sensitive. Early use of HCQ after exposure appears to confer some
protection from symptomatic Covid-19 (p=0.0496).

A similar conclusion was also reached by Watanabe in this paper


https://arxiv.org/abs/2007.09477 ;

In this study, we discussed some inaccuracies in the statistical analysis of Boulware et al.
We also add an original statistical analysis by adopting a different method, replacing
Fisher’s exact test with a simple regression analysis ….

Their conclusion incorrectly states there is no evidence of efficacy, while the evidence is
positive although not conclusive at 95% level with the sample size and methodology used.

Applying the modifications we have stated in sections 2 and 3, in particular using a simple
linear regression method to their data, we conclude the randomized trial of Boulware et
al. has statistical evidence, at 99% confidence level, that hydroxychloroquine treatment is
time-dependent with a negative slope.

We conclude that, when applied as a prophylaxis, it [HCQ] can significantly reduce the
relative proportion of symptomatic patients if used from 0 to 2 days after exposure to the
virus (71.98% for 0 days, 48.86% for 1 day and 29.33% for 2 days). The predictive value
for day 0 can be seen as lower bound for the expected hydroxychloroquine efficacy if used
as a pre-exposure prophylaxis. This suggests that pre-exposure prophylaxis can be
significantly effective.
For 3 and 4 days, we conclude there is no statistical evidence, at 99% level, that
hydroxychloroquine treatment reduces the proportion of symptomatic patients.
Moreover, our results show that the elapsed time between the exposure to the virus and
the beginning of treatment is vital to the effectiveness of the antiviral use.

We expect the treatment will be more effective when applied to patients in the viral
replication period, before viral load reaches its peak which occurs around 5 days after
symptom onset.

Meanwhile, if disease reaches the inflammatory period, typically after 8 days of


symptoms onset and after viral load reaches its peak, we can expected no or little benefit
with the antiviral treatment.

Therefore, the mean time elapsed from exposure to the virus and the start of treatment
in the sample may act as a lurking variable, influencing in a hidden way the efficacy of
treatment. This might explain why many studies have found no statistical evidence of
effectiveness of hydroxychloroquine treatment when used in hospitalized patients as
most of this more severe cases had probably started treatment long after 4 days from
their exposure to the virus.

In addition, it helps to understand why some studies have shown some positive results of
hydroxychloroquine treatment as we can expect this when the proportion of patients in
the beginning of the infection is higher in the sample. Hence, as described by Boulware et
al., two possible applications would be to apply prophylaxis to health professionals and to
contacts of positive patients, since these two groups would have a greater probability to
benefit from treatment.

Our results suggest there is probably little or no benefit if the treatment is used in
patients infected for too long, like hospitalized severe patients. On the contrary, they also
suggest infected patients may have a large benefit if treated as early as possible, mostly
as pre-prophylaxis treatment where symptoms appear will have an estimated relative
reduction of at least 72%

The conclusions of these two studies concur with your theory about the possibility of a
‘sweet spot’ during the disease stage for which HCQ could be effective in prevention or
treatment of COVID-19 infection may exist.

Further, additional commentary criticising Boulware et al. is contained in his open letter
signed by statisticians, medical researchers, clinicians and other quantitative researchers.
https://drive.google.com/file/d/1NZOJ57fM0RTaHD1t 9w2iua7lUJhOgWT/view

They note;

These three papers [including Boulware et al] nevertheless share at least one common
mistake: the conclusions they draw from their data are wrong. All three papers lead,
explicitly or implicitly to the conclusion that early treatment of COVID-19 patients with
hydroxychloroquine is not effective. In saying that the conclusions are wrong we are not
affirming that hydroxychloroquine is effective. This is a subtle but important distinction.

Due to the importance of clinical trials in COVID-19 public decision making, we believe it
is fundamental that these three studies correct their conclusions and publicize these
corrections. In a pandemic the urgency of publication is justified and more errors might
appear.

Secondly, in relation to the RECOVERY trial, you stated in your previous email;

“I do not agree that the dose of HCQ used in that trial was excessive – it was a 2000 mg
loading dose split over the first 24 hours (see the attached trial publication). Such loading
doses are commonly used in treatment of infectious diseases – for example for malaria, a
1200 mg loading dose of HCQ is given compared with the 400-600 mg daily dose usual
for rheumatoid arthritis …… I also contend that it would be inconceivable that the
investigators confused hydroxychloroquine with another agent”

Following is part of a transcript of an interview that the head of the RECOVERY trial, Martin
Landray gave to a journalist at France Soir (a French magazine)
FS : Could you please precise what dosage of HCQ you gave to the patient ? and the
results ?

ML : It is 2400 mg in the first 24 hours and 800 mg from day 2 to day 10. It is an 10 day
course of treatment in total. These are quite high doses to make sure that the blood
levels got high enough to have a chance of killing the virus.

FS : How did you decide on the dosage of HCQ ?

ML : The doses were chosen on the basis of pharmacokinetic modelling and these are in
line with the sort of doses that you used for other diseases such as amoebic dysentery.

FS : Are there any maximum dosage for HCQ in the UK?

ML : I would have to check but it is much larger than the 2400mg, something like six or 10
times that. There is no approved dose for Covid patients because it is not approved for
use in Covid patients

FS : Are there any doses considered lethal for HCQ in the UK by the MHRA?

ML : The treating doctors did not report that they thought any of the deaths were due to
hydroxychloroquine. For a new disease such as Covid, there is no there is no approved
dosing protocol. But the HCQ dosage used are not dissimilar to that used, as I said, in for
example amoebic dysentery.

I understand that Martin Landray denied making these comments as reported, however
France Soir recorded the interview and released parts of it on the internet.
From this interview, it is clear that the HCQ dose given in the first 24 hours was 2400mg
not 2000mg. It is also clear that Martin Landray thought that ‘six to ten times’ a higher
dose of HCQ (24,000mg) could be safely given and that the 2400mg HCQ dosage given in
the first 24 hours in Landray’s own words “are not dissimilar to that used, as I said, in for
example amoebic dysentery”.

However, as I understand and as several doctors have pointed out including James Todaro
MD, that Hydroxychloroquine is not used to treat amoebic dysentery, but and Iodoquinol
(a hydroxyquinoline) at a dose of around 2000 mg is.

Further the AMM in France considers that the overdose rate for HCQ is 25mg/kg – thus for
a 70kg patient, anything above 1750mg would be considered an overdose, requiring
immediate emergency hospital care.

And this would not be the first time that Hydroxychloroquine has been confused with
hydroxyquinoline as evidenced in this paper and amazingly, it is still published on the
internet without correction;

The recent FDA approval of Hydroxyquinoline for hospitalized COV patients, though only
for patients where access to clinical trials are unavailable ….

Most of the ongoing and planned trials have rightly focused on hospitalized COV patients
where the need for effective therapies remains critical. However, the PRINCIPLE trial that
is currently being launched to study the effect of Hydroxyquinoline in older patients with
mild symptoms in a primary care setting will provide useful data that will facilitate the
early use of the drug to contain the disease in future flareups.

The only conclusion that can be drawn from these facts is a medical error in setting the
dose in the RECOVERY trial and that the patients in this trial where given an excessive and
likely toxic dose.

In light of the above, and the recent observational studies that indicate that low dose HCQ
(combined with zinc and administered with the first 5 days after infection) could be highly
effective in reducing both deaths and hospitalisations for Covid patients (that I attached in
the previous emails), I again respectfully suggest that the TGA’s current recommends the
use of hydroxychloroquine to treat COVID-19 can longer be sustained.

And further, I also respectfully suggest that the TGA consider having three separate
recommendations for the use of hydroxychloroquine (HCQ) to treat COVID-19;

1. As a pre-exposure prophylaxis
2. As an early treatment (1-7 days) after first symptoms
3. After admission to hospital.
And that the TGA should at the very minimum change its recommendation on HCQ to treat
Covid for at least as early treatment (1-7 days) after first symptoms.

Yours faithfully,
Craig Kelly MP
Member for Hughes.

From: Kelly, Craig (MP)


Sent: Thursday, 17 September 2020 6:32 PM
To: 'SKERRITT, John'
Cc: Hunt, Greg (MP) <Greg.Hunt.MP@aph.gov.au>
Subject: RE: hydroxychloroquine [SEC=OFFICIAL]

Dear Professor Skerritt,

Thank you for your reply, it is greatly appreciated.

I also welcome your acknowledgement ‘’that it is possible that a ‘sweet spot’ – a disease
stage or patient population - for which HCQ could be effective in prevention or treatment
of COVID-19 infection may exist’’.

However, if this does in fact prove to be correct, we currently have a situation where the
TGA’s recommendation is being relied upon to deny Australian citizens that test positive
for Covid a treatment that may save their lives.

I also appreciate your advice that there are about 20 significant clinical trials underway.
However, I would re-emphasis the comments from the recent study by Prodromos and
Rumschlag;

Thousands of lives may lie in the balance. …. We also do not believe that
randomized controlled studies are necessary before HCQ is authorized for general
use because the efficacy seen in studies already done indicates that control patients
in such studies might die unnecessarily; and because the time delay to do any such
study would cause yet more deaths by preventing HCQ use when it is most needed –
which is immediately. Our study has shown that good evidence of efficacy exists;
and there is no safety, cost, or supply reason to not treat now.

Although you may have already read these, I would like to draw to your attention two
further observational studies published over the past few days. Firstly, a study from Saudi
Arabia Sulaiman et al. which found patients treated with HCQ + Zinc had a 43% reduction
in admission to hospitalisation, a 49% reduction in admission to ICU and a 73% in deaths.
And secondly, a study from Italy, Lauriola et al., which co-incidentally also found a 73%
reduction in death associated with HCQ+AZ.

These findings are consistent with the results from Scholz et al which found early
treatment with HCQ+AZ+Zinc resulted in 84% lower hospitalizations and 80% lower
deaths. And although not a formal study, in this interview Dr Brian Tyson, a doctor from
California, he discusses how he has treated almost 1,700 Covid positive patients with zero
deaths.

In relation to the 3 other studies you referenced below, these studies including the
RECOVERY trial, did not use HCQ in the manner that is being advocated for by medical
specialists that I have spoken with, which is; combined with zinc and azithromycin, and
given within the first 7 days after symptoms appears (the early the better) and for high risk
patients.

Therefore could I respectfully suggest that the TGA consider having three separate
recommendations for the use of hydroxychloroquine (HCQ) to treat COVID-19;

1. After admission to hospital.


2. As an early treatment (1-7 days) after first symptoms
3. As a pre-exposure prophylaxis

Of these, the TGA’s current recommendation, that the use of hydroxychloroquine (HCQ) to
treat COVID-19 is strongly discouraged, could remain for after admission to hospital,
however given the weight of evidence, I believe it would defy all logic for this same
recommendation to be maintained for early treatment.

Regards,
Craig Kelly MP
Member for Hughes

From: SKERRITT, John


Sent: Sunday, 13 September 2020 8:48 PM
To: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>
Cc: Hunt, Greg (MP) <Greg.Hunt.MP@aph.gov.au>;
Cook, Jane
Subject: RE: hydroxychloroquine [SEC=OFFICIAL]

Dear Mr Kelly

Thank you for your email.

I stand by our Department’s advice that the use of hydroxychloroquine (HCQ) to treat COVID-19
is strongly discouraged outside of a clinical trial. You are correct that this advice concurs with the
recommendations from the National COVID-19 Clinical Evidence Taskforce. It is also based on the
overwhelming balance of evidence thus far, and the consensus view of major global medicines
regulators and health departments, with whom I am in very regular conduct around the progress
of clinical trials for potential therapeutics for COVID-19.

Our Department’s advice was not just based on the results of the RECOVERY trial, although I
believe that trial was an important and well-conducted one. I do not agree that the dose of HCQ
used in that trial was excessive – it was a 2000 mg loading dose split over the first 24 hours (see
the attached trial publication). Such loading doses are commonly used in treatment of infectious
diseases – for example for malaria, a 1200 mg loading dose of HCQ is given compared with the
400-600 mg daily dose usual for rheumatoid arthritis.

I also contend that it would be inconceivable that the investigators confused hydroxychloroquine
with another agent – the trial was conducted across 176 UK hospitals and the trial design,
including the doses used, were approved by the UK regulator (MHRA) prior to the patients being
treated.

I am aware that a couple of early studies were suggestive of positive benefits of HCQ in COVID
but since the time that many of those studies were carried out, a much larger number of
negative studies have been published in the top global refereed medical journals. For example
three studies in the New England Journal of Medicine, which is in the top 4 global medical
journals have shown the following:

https://www.nejm.org/doi/full/10.1056/NEJMoa2019014
Brazilian study of individuals hospitalised with mild to moderate COVID-19 – no effect of HCQ
(800 mg/day) with or without azithromycin on clinical outcomes

https://www.nejm.org/doi/full/10.1056/NEJMoa2016638
US and Canadian study on potential use of HCQ for post exposure prophylaxis (1400 mg on day 1
then 600 mg a day) - no impact on clinical outcomes

https://www.nejm.org/doi/full/10.1056/nejmoa2012410
Observational study in New York hospitals – 1220 mg HCQ on day 1 then 400 mg daily – no
increase or decrease in risk of intubation or death in COVID-19 infected patients

It is possible that a “sweet spot” – a disease stage or patient population for which HCQ could be
effective in prevention or treatment of COVID-19 infection may exist, and about 20 significant
clinical trials continue in about 8 countries, including at some major medical centres. In
collaboration with the US FDA, the European Medicines Agency and other major regulators, the
TGA is closely monitoring the results of these studies as they become available.

Yours sincerely

John Skerritt

Adjunct Prof John Skerritt FTSE FIPAA (Vic)


Deputy Secretary for Health Products Regulation
Department of Health
(The Health Products Regulation Group comprises the Therapeutic Goods Administration and the
Office of Drug Control)

From: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>


Sent: Wednesday, 9 September 2020 5:30 PM
To: SKERRITT, John
Cc: Greg.Hunt.MP <Greg.Hunt.MP@aph.gov.au>
Subject:

Dear Professor Skerritt,

I am writing to you as I am greatly concerned about the TGA’s advice “that it


strongly discourages the use of hydroxychloroquine to treat COVID-19”.

From the statement on the TGA’s website, this advice appears to be based
upon the recommendations from the National COVID-19 Clinical Evidence
Taskforce. And the Taskforce’s recommendations appear to be based
substantially upon the findings of the RECOVERY trial.

However the evidence appears to show that the RECOVERY trial was fatally
flawed, as in this trial they administered the group of patients taking HCQ
with 2400mg of the drug within the first 24 hours. All evidence indicates
that this was an excessive and toxic dose – 4 to 5 times the maximum
recommended. Further media reports indicate that this excessive dose was
the result of medical negligence where those running the RECOVERY trial
confused the drugs hydroxychloroquine with hydroxyquinoline.

Therefore, I believe there is a very strong argument that any results of the
RECOVERY should be disregarded in TGA making any recommendation.

I would also like to draw to your attention two meta-analysis studies


released in preprint in the past 48 hours. The first is a study out of France by
the Institut Hospitalo-Universitaire (IHU) Méditerranée Infection, which will
be published in the journal ‘Expert Review of Clinical Immunology’. This
most comprehensive study concluded for Covid-19;
‘’Treatment with an oral combination of hydroxychloroquine,
azithromycin and zinc may REPRESENT THE BEST CURRENT
THERAPEUTIC OPTION in relation to its antiviral and
immunomodulatory effects’’.

The second is a study from the US by Chadwick C Prodromos MD and Tobias


Rumschlag MD in which they concluded;

This study has four important findings. The first is that HCQ appears
to be consistently effective for the treatment of COVID-19 when used
early in the course of disease in the outpatient setting, and is generally
more effective the earlier it is used. The second is that overall HCQ has
had efficacy against COVID-19 in a majority of studies. The third is
that there are no unbiased studies showing a negative effect of HCQ
treatment of COVID-19. The fourth is that HCQ appears to be safe for
the treatment of COVID-19 when used responsibly.

And the authors further noted;

SIGNIFICANCE: We believe our findings have substantial societal


global importance since there have been numerous edicts either
preventing HCQ use for COVID-19 or limiting it to the inpatient setting
which we believe have resulted in many unnecessary deaths.

Our findings showing efficacy and safety of HCQ against COVID-19


indicate that HCQ should be freely available to patients and physicians
who choose to use it. And it should especially be freely available to be
used on an outpatient basis before hospitalization where it appears to
be more effective and where early fears of fatal heart arrhythmias
have been shown to be unfounded[45].

This is particularly important because the only drug to show efficacy,


Remdesivir, has shown no significant benefit in a recent study [46].It is
also expensive and not widely available. Convalescent plasma has
shown benefit [47] but even this is not well validated and plasma is
not available in large numbers of doses.
Thus HCQ with proven efficacy and safety, a cost of 37 cents per pill
and thus a total treatment cost of under 20 dollars[48], versus 3,100
dollars for Remdesivir[49], as well as wide supply chain availability,
would appear to be the best COVID-19 treatment option available and
needs to be widely promoted as such.

Unfortunately the controversies surrounding HCQ have resulted in


physicians being afraid to prescribe it for reasons which have nothing
to do with medicine, and in patients being afraid to take it due to
spurious reports of danger, or fears that is not effective.

It is hoped that this study will disabuse the medical community of


these misapprehensions about efficacy and validate that it is both
efficacious and safe, and needs to be freely
prescribable. Thousands of lives may lie in the balance.

We also do not believe that randomized controlled studies are


necessary before HCQ is authorized for general use because the
efficacy seen in studies already done indicates that control patients in
such studies might die unnecessarily; and because the time delay to do
any such study would cause yet more deaths by preventing HCQ use
when it is most needed – which is immediately. Our study has shown
that good evidence of efficacy exists; and there is no safety, cost, or
supply reason to not treat now.

Unnecessary death from delayed treatment is too high a price to pay


for greater certainty of knowledge. Many may have already died
unnecessarily due to HCQ misinformation and it is imperative that we
do not further add to the toll.

I would also like to point out this meta-study concluded collecting data on
the 3rd August 2020, and therefore it did not include the results from 4 large
studies which all found treatment with HCQ was associated with sustainable
reducing in death

· Castelnuovo et al., European J. Internal Medicine,


doi:10.1016/j.ejim.2020.08.019 (Peer Reviewed) – study found the
use of hydroxychloroquine in hospitalised COVID-19 patients was
associated with reduced mortality: Retrospective 3,451
hospitalized patients, 30% reduction in mortality with HCQ
after propensity adjustment.

· Catteau et al., Int. J. Antimicrobial Agents,


doi:10.1016/j.ijantimicag.2020.106144 (Peer Reviewed) –
Retrospective study of 8,075 hospitalized patients, 4,542 received
low-dose HCQ, 3,533 control - found a 35% lower mortality for
HCQ (17.7% vs. 27.1%)

· Ip et al., medRxiv, doi:10.1101/2020.08.20.20178772


(Preprint) - Retrospective study of 1,274 outpatients, which found
a 47% reduction in hospitalization with HCQ

· Gonzalez et al., medRxiv, doi:10.1101/2020.08.18.20172874


(Preprint) - Retrospective study focused on eosinophil recovery
with 9,644 hospitalized patients in Spain, showing lower
mortality for HCQ (14.7% vs 29.2%, p<0.001), and AZ (15.3%
vs. 18.4%, p<0.001).

In light of this most recent evidence, I respectfully suggest that the TGA’s
current recommends the use of hydroxychloroquine to treat COVID-19 can
longer be sustained and should be urgently reviewed.

Regards,

Craig Kelly MP
Member for Hughes

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OPEN LETTER TO Dr JEANNETTE YOUNG – QUEENSLAND CHIEF HEALTH OFFICER
29th September 2020

Dear Dr Young,

On this Friday, 2nd October 2020, the order you previously made under s362B of the Public Health Act 2005 (QLD), which criminalised the
prescribing of Hydroxychloroquine (HCQ) by doctors in Queensland to treat Covid-19 expires, and we call on you not to take any action to
extend this order.

By allowing this order to lapse, you would bring an end to the unprecedented interference in the sanctity of the Doctor/Patient relationship.
This has denied Queensland doctors the freedom to prescribe a medical treatment that many doctors worldwide believe is highly effective to
substantially reduce the risk of death in Covid-19 patients, especially those in high risk groups.

In light of the growing weight of recently published medical evidence (much of it peer-reviewed) which has found that HCQ is; relatively safe,
reduces deaths, and reduces the need for the hospitalisations in Covid-19 patients (when administered under the supervision of a doctor),
extending the current ban and thereby denying Queenslanders access to this medical treatment, could be both a breach of Human Rights and
potentially constitute ‘Crimes Against Humanity’.

In considering your decision, I also remind you of the principle ‘ Primum non nocere’ - First do no harm, therefore the applicable standard you
must apply in considering an extension of this ban, is that you must be able to demonstrate ‘beyond all reasonable doubt’ that HCQ is both
ineffective to treat Covid-19 and is so unsafe, that doctors cannot be trusted to prescribe it. Therefore, in considering your decision, I draw to
your attention the following;

1. The advice from the National Evidence Covid Taskforce, (that HCQ is not recommended) is substantially reliant upon the results of the
‘Recovery Trial’. However, this trial has since been discredited and debunked, given that patients administered HCQ in this trial were loaded up
with an excessive toxic overdose of 2400mg within the first 24 hours. Further, medical experts have suggested that the reason for such an
excessive dose, was that it was likely that those setting up this trial may have confused Hydroxychloroquine with Hydroxyquinoline.

2. Two of the most recent studies, only published last week, from North America and Europe have concluded that HCQ is relatively safe to
treat Covid-19 patients. The first study published on 25th September 2020 in EP Europace, a journal of the European Society of Cardiology,
with lead author Dr. Alessio Gasperetti of Monzino Cardiology Centre, Milan, Italy and University Hospital Zurich, Switzerland concluded that,
‘’HCQ administration is safe for a short-term treatment of patients with Covid-19 infection ...”

3. Several earlier studies which concluded that HCQ was ‘ineffective’, have since undergone comprehensive detailed reanalysis, which have
found that the original conclusions were not only in error, but that the data indicates the exact opposite, that HCQ is effective for treating
Covid-19.

4. There is now a very significant body of studies that have found HCQ is associated with substantially reducing both death and hospitalisations
in Covid-19 patients. All these studies can be found at this website. https://c19study.com/ . And rather than detailing all these studies in this
letter, I would specifically draw to your attention a meta-analysis study by Prodromos et al., which concluded;

"HCQ has been shown to have consistent clinical efficacy for COVID-19 when it is used early in the outpatient setting, and in
general would appear to work better the earlier it is used. Overall HCQ is effective against COVID-19. There is no credible evidence
that HCQ results in worsening of COVID-19. HCQ has been shown to be safe for the treatment of COVID-19 when responsibly
used."

5. There is no longer a supply issue with HCQ in Australia. It is well known that Mr. Clive Palmer has sourced over 30 million doses of HCQ
which he donated free of charge to the nation, and these supplies sit ready and available in the national medical stockpile.

In summary, whatever justification you have had in making the original order has collapsed and is no longer valid. As is often said; ‘When the
facts change, I change my opinion - what do you do ?’ Therefore, we trust that you will do the right thing by all Queenslanders and in fact all
Australians and not extend this order.

Yours faithfully,

George Christensen MP Craig Kelly MP


Craig Kelly
Member for Dawson Member for Hughes
From: Kelly, Craig (MP)
To: SKERRITT, John
Cc: Greg.Hunt.MP;
Subject: 618 Second Opinions
Date: Wednesday, 30 September 2020 9:08:46 PM

Dear Professor Skerritt,

Thank you for your reply, it was greatly appreciated late at night.

Also, I would like to draw to your attention an online open-letter signed by 618 doctors
from Belgium stating;

‘’There is an affordable, safe and efficient therapy available for those who do show severe
symptoms of disease in the form of HCQ (hydroxychloroquine), zinc and azithromycin.

‘’Rapidly applied this therapy leads to recovery and often prevents hospitalisation. Hardly
anyone has to die now.’’

‘’This effective therapy has been confirmed by the clinical experience of colleagues in the
field with impressive results.’’

https://docs4opendebate.be/en/open-letter/

I would again respectfully request the most urgent re-consideration of the TGA’s and
Covid National Evidence Taskforce recommendations on HCQ to treat covid.

Regards,
Craig Kelly
Sent from my iPad

On 28 Sep 2020, at 10:08 pm, SKERRITT, John


<John.Skerritt@health.gov.au> wrote:

Mr Kelly

Thanks for your email.

I can confirm unreservedly that have been no such instructions from TGA to
newspapers “not to print anything in regards to hydroxychloroquine”.
And frankly, I doubt that the media would accept such direction from a government
department in any event.

It is important, however, to clarify that promotion of prescription medicines to the


general public is not legal in Australia, in contrast to the situation in the USA.
It is possible that the legal advisers to the newspapers considered this in their
advice to you and Mr Christensen.

Regards
John Skerritt
Adjunct Prof John Skerritt FTSE FIPAA (Vic)
Deputy Secretary for Health Products Regulation
Department of Health
(The Health Products Regulation Group comprises the Therapeutic Goods
Administration and the Office of Drug Control)

From: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>


Sent: Monday, 28 September 2020 9:38 PM
To: SKERRITT, John
Cc: Greg.Hunt.MP <Greg.Hunt.MP@aph.gov.au>
Subject: HCQ : New studies and media censorship

Dear Professor Skerritt,

I am writing to you on two issues.

Firstly, I would like to draw your attention to several new published papers on
HCQ;

Karatza et al., (Peer Reviewed) – in this paper from Greece, its appears
the authors have moved beyond the question of if HCQ is safe and
effective, and moved on to what is the optimum level of dose. Their
conclusion stated;

Based on the results from simulations performed and the currently


published knowledge regarding HCQ in COVID-19 treatment, this
study provides evidence that a high loading dose followed by sparse
doses could offer significant benefits to the patients.

Zreiq et al., (Peer Reviewed) and published in the Journal of


Pharmaceutical Research International which noted;

“Among all treatment modalities, antimalarial hydroxychloroquine


ranked the highest cure rate. Therefore, this drug is considered as the
first-line of COVID-19 treatment.”

Gaspertetti et al., (Peer reviewed) which looked into the safety of HCQ
and concluded;

“HCQ administration is safe for a short-term treatment for patients


with COVID-19 infection regardless of the clinical setting of delivery …”
Secondly, the Member for Dawson George Christensen and myself have
written an open letter (copy attached) to the Chief Medical Officer of
Queensland and we had made arrangements for this to be published (at our
expense) in major newspapers in the Eastern states. However, we were
advised late today that these newspapers refused to publish this letter, and
they advised that this was because they had received instructions from the
TGA not to print anything in regards to Hydroxychloroquine.

Keeping in mind that I believe that refusing to publish a letter written by two
members of Parliament (even when payment is offered to buy space in that
newspaper) is inconsistent with our constitutionally enshrined rights of free
political communication, I ask you to confirm that TGA’s instruction to our
media prohibits or does not prohibit the publication of this letter in major
newspapers by two members of the Federal Parliament.

Given that our open letter relates to a decision that will made this week, your
urgent reply on this issue would be greatly appreciated.

Regards,
Craig Kelly MP
Member for Hughes

From: SKERRITT, John


Sent: Tuesday, 22 September 2020 9:27 PM
To: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>
Cc: Hunt, Greg (MP) <Greg.Hunt.MP@aph.gov.au>; Develin, Sam
< >;
; SKERRITT, John

Subject: RE: hydroxychloroquine and COVID-19 [SEC=OFFICIAL]

Dear Mr Kelly

Thank you for your further email providing suggestions that hydroxychloroquine
(HCQ) may be effective at specific early time points in COVID infection.

While the analysis looks of potential interest, it is worth emphasising that the paper
you have quoted from Watanabe is not peer reviewed, the normal evidence
standard for publication in medical journals. Indeed the website on which it has
been published states a significant disclaimer as follows “Not peer reviewed…should
not be relied upon without context to guide clinical practice”….

Similarly the paper by Yang et at, although in the published literature focuses on
interpretation of retrospective observational data “suggesting” protective effects of
HCQ and goes on to say in its abstract “more randomised controlled studies are
needed to evaluate the efficacy of HCQ (and interferon alpha 2 separately and in
combination) for prophylaxis against COVID-19 …Future studies should give us more
definitive answers”.

By copy of this email I have shared the email string with A/Prof Julian Elliott who is
a coordinator of the National COVID-19 Clinical Evidence taskforce, which was
funded by the Government to analyses emerging research evidence on COVID-19
to provide frontline healthcare workers with advice, including on potential
therapies.

Regards

John Skerritt

Adjunct Prof John Skerritt FTSE FIPAA (Vic)


Deputy Secretary for Health Products Regulation
Department of Health
(The Health Products Regulation Group comprises the Therapeutic Goods
Administration and the Office of Drug Control)

From: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>


Sent: Monday, 21 September 2020 8:13 PM
To: SKERRITT, John
Cc: Greg.Hunt.MP <Greg.Hunt.MP@aph.gov.au>
Subject:

Dear Professor Skerritt,

Just a further follow up to your previous reply.

Firstly, in support of the TGA’s current position on HCQ, you cited this study
(Boulware et al.) ; - for which you noted concluded that HCQ had “no impact
on clinical outcomes”.

I would therefore like to draw to your attention significant criticism of this


study which has just been published , in which it was the noted;
Boulware et al. found a non-significant difference in incidence between HCQ
and placebo group (11.8% vs. 14.3%, p=0.35). However, our re-analysis of
the data suggests HCQ use for Covid-19 is time-sensitive. Early use of HCQ
after exposure appears to confer some protection from symptomatic Covid-
19 (p=0.0496).

A similar conclusion was also reached by Watanabe in this paper


https://arxiv.org/abs/2007.09477 ;
In this study, we discussed some inaccuracies in the statistical analysis of
Boulware et al. We also add an original statistical analysis by adopting a
different method, replacing Fisher’s exact test with a simple regression
analysis ….

Their conclusion incorrectly states there is no evidence of efficacy, while the


evidence is positive although not conclusive at 95% level with the sample
size and methodology used.

Applying the modifications we have stated in sections 2 and 3, in particular


using a simple linear regression method to their data, we conclude the
randomized trial of Boulware et al. has statistical evidence, at 99%
confidence level, that hydroxychloroquine treatment is time-dependent with
a negative slope.

We conclude that, when applied as a prophylaxis, it [HCQ] can significantly


reduce the relative proportion of symptomatic patients if used from 0 to 2
days after exposure to the virus (71.98% for 0 days, 48.86% for 1 day and
29.33% for 2 days). The predictive value for day 0 can be seen as lower
bound for the expected hydroxychloroquine efficacy if used as a pre-
exposure prophylaxis. This suggests that pre-exposure prophylaxis can be
significantly effective.

For 3 and 4 days, we conclude there is no statistical evidence, at 99% level,


that hydroxychloroquine treatment reduces the proportion of symptomatic
patients. Moreover, our results show that the elapsed time between the
exposure to the virus and the beginning of treatment is vital to the
effectiveness of the antiviral use.

We expect the treatment will be more effective when applied to patients in


the viral replication period, before viral load reaches its peak which occurs
around 5 days after symptom onset.

Meanwhile, if disease reaches the inflammatory period, typically after 8


days of symptoms onset and after viral load reaches its peak, we can
expected no or little benefit with the antiviral treatment.

Therefore, the mean time elapsed from exposure to the virus and the start
of treatment in the sample may act as a lurking variable, influencing in a
hidden way the efficacy of treatment. This might explain why many studies
have found no statistical evidence of effectiveness of hydroxychloroquine
treatment when used in hospitalized patients as most of this more severe
cases had probably started treatment long after 4 days from their exposure
to the virus.

In addition, it helps to understand why some studies have shown some


positive results of hydroxychloroquine treatment as we can expect this when
the proportion of patients in the beginning of the infection is higher in the
sample. Hence, as described by Boulware et al., two possible applications
would be to apply prophylaxis to health professionals and to contacts of
positive patients, since these two groups would have a greater probability to
benefit from treatment.

Our results suggest there is probably little or no benefit if the treatment is


used in patients infected for too long, like hospitalized severe patients. On
the contrary, they also suggest infected patients may have a large benefit if
treated as early as possible, mostly as pre-prophylaxis treatment where
symptoms appear will have an estimated relative reduction of at least 72%

The conclusions of these two studies concur with your theory about the
possibility of a ‘sweet spot’ during the disease stage for which HCQ could be
effective in prevention or treatment of COVID-19 infection may exist.

Further, additional commentary criticising Boulware et al. is contained in his


open letter signed by statisticians, medical researchers, clinicians and other
quantitative researchers.
https://drive.google.com/file/d/1NZOJ57fM0RTaHD1t_9w2iua7lUJhOgWT/view

They note;

These three papers [including Boulware et al] nevertheless share at least


one common mistake: the conclusions they draw from their data are wrong.
All three papers lead, explicitly or implicitly to the conclusion that early
treatment of COVID-19 patients with hydroxychloroquine is not effective. In
saying that the conclusions are wrong we are not affirming that
hydroxychloroquine is effective. This is a subtle but important distinction.

Due to the importance of clinical trials in COVID-19 public decision making,


we believe it is fundamental that these three studies correct their
conclusions and publicize these corrections. In a pandemic the urgency of
publication is justified and more errors might appear.

Secondly, in relation to the RECOVERY trial, you stated in your previous email;

“I do not agree that the dose of HCQ used in that trial was excessive – it was
a 2000 mg loading dose split over the first 24 hours (see the attached trial
publication). Such loading doses are commonly used in treatment of
infectious diseases – for example for malaria, a 1200 mg loading dose of
HCQ is given compared with the 400-600 mg daily dose usual for
rheumatoid arthritis …… I also contend that it would be inconceivable that
the investigators confused hydroxychloroquine with another agent”
Following is part of a transcript of an interview that the head of the RECOVERY
trial, Martin Landray gave to a journalist at France Soir (a French magazine)
FS : Could you please precise what dosage of HCQ you gave to the patient
? and the results ?

ML : It is 2400 mg in the first 24 hours and 800 mg from day 2 to day 10. It
is an 10 day course of treatment in total. These are quite high doses to
make sure that the blood levels got high enough to have a chance of killing
the virus.

FS : How did you decide on the dosage of HCQ ?

ML : The doses were chosen on the basis of pharmacokinetic modelling and


these are in line with the sort of doses that you used for other diseases such
as amoebic dysentery.

FS : Are there any maximum dosage for HCQ in the UK?

ML : I would have to check but it is much larger than the 2400mg,


something like six or 10 times that. There is no approved dose for Covid
patients because it is not approved for use in Covid patients

FS : Are there any doses considered lethal for HCQ in the UK by the
MHRA?

ML : The treating doctors did not report that they thought any of the deaths
were due to hydroxychloroquine. For a new disease such as Covid, there is
no there is no approved dosing protocol. But the HCQ dosage used are not
dissimilar to that used, as I said, in for example amoebic dysentery.

I understand that Martin Landray denied making these comments as reported,


however France Soir recorded the interview and released parts of it on the
internet.

From this interview, it is clear that the HCQ dose given in the first 24 hours
was 2400mg not 2000mg. It is also clear that Martin Landray thought that ‘six
to ten times’ a higher dose of HCQ (24,000mg) could be safely given and that
the 2400mg HCQ dosage given in the first 24 hours in Landray’s own words
“are not dissimilar to that used, as I said, in for example amoebic dysentery”.

However, as I understand and as several doctors have pointed out including


James Todaro MD, that Hydroxychloroquine is not used to treat amoebic
dysentery, but and Iodoquinol (a hydroxyquinoline) at a dose of around 2000
mg is.

Further the AMM in France considers that the overdose rate for HCQ is
25mg/kg – thus for a 70kg patient, anything above 1750mg would be
considered an overdose, requiring immediate emergency hospital care.

And this would not be the first time that Hydroxychloroquine has been
confused with hydroxyquinoline as evidenced in this paper and amazingly, it is
still published on the internet without correction;

The recent FDA approval of Hydroxyquinoline for hospitalized COV patients,


though only for patients where access to clinical trials are unavailable ….

Most of the ongoing and planned trials have rightly focused on hospitalized
COV patients where the need for effective therapies remains critical.
However, the PRINCIPLE trial that is currently being launched to study the
effect of Hydroxyquinoline in older patients with mild symptoms in a
primary care setting will provide useful data that will facilitate the early use
of the drug to contain the disease in future flareups.

The only conclusion that can be drawn from these facts is a medical error in
setting the dose in the RECOVERY trial and that the patients in this trial where
given an excessive and likely toxic dose.

In light of the above, and the recent observational studies that indicate that
low dose HCQ (combined with zinc and administered with the first 5 days after
infection) could be highly effective in reducing both deaths and
hospitalisations for Covid patients (that I attached in the previous emails), I
again respectfully suggest that the TGA’s current recommends the use of
hydroxychloroquine to treat COVID-19 can longer be sustained.

And further, I also respectfully suggest that the TGA consider having three
separate recommendations for the use of hydroxychloroquine (HCQ) to treat
COVID-19;

1. As a pre-exposure prophylaxis
2. As an early treatment (1-7 days) after first symptoms
3. After admission to hospital.

And that the TGA should at the very minimum change its recommendation on
HCQ to treat Covid for at least as early treatment (1-7 days) after first
symptoms.

Yours faithfully,
Craig Kelly MP
Member for Hughes.
From: Kelly, Craig (MP)
Sent: Thursday, 17 September 2020 6:32 PM
To: 'SKERRITT, John'
Cc: Hunt, Greg (MP) <Greg.Hunt.MP@aph.gov.au>
Subject: RE: hydroxychloroquine [SEC=OFFICIAL]

Dear Professor Skerritt,

Thank you for your reply, it is greatly appreciated.

I also welcome your acknowledgement ‘’that it is possible that a ‘sweet spot’ –


a disease stage or patient population - for which HCQ could be effective in
prevention or treatment of COVID-19 infection may exist’’.

However, if this does in fact prove to be correct, we currently have a situation


where the TGA’s recommendation is being relied upon to deny Australian
citizens that test positive for Covid a treatment that may save their lives.

I also appreciate your advice that there are about 20 significant clinical trials
underway. However, I would re-emphasis the comments from the recent
study by Prodromos and Rumschlag;

Thousands of lives may lie in the balance. …. We also do not believe


that randomized controlled studies are necessary before HCQ is
authorized for general use because the efficacy seen in studies already
done indicates that control patients in such studies might die
unnecessarily; and because the time delay to do any such study would
cause yet more deaths by preventing HCQ use when it is most needed –
which is immediately. Our study has shown that good evidence of
efficacy exists; and there is no safety, cost, or supply reason to not treat
now.

Although you may have already read these, I would like to draw to your
attention two further observational studies published over the past few days.
Firstly, a study from Saudi Arabia Sulaiman et al. which found patients treated
with HCQ + Zinc had a 43% reduction in admission to hospitalisation, a 49%
reduction in admission to ICU and a 73% in deaths. And secondly, a study from
Italy, Lauriola et al., which co-incidentally also found a 73% reduction in death
associated with HCQ+AZ.
These findings are consistent with the results from Scholz et al which found
early treatment with HCQ+AZ+Zinc resulted in 84% lower hospitalizations and
80% lower deaths. And although not a formal study, in this interview Dr Brian
Tyson, a doctor from California, he discusses how he has treated almost 1,700
Covid positive patients with zero deaths.

In relation to the 3 other studies you referenced below, these studies


including the RECOVERY trial, did not use HCQ in the manner that is being
advocated for by medical specialists that I have spoken with, which is;
combined with zinc and azithromycin, and given within the first 7 days after
symptoms appears (the early the better) and for high risk patients.

Therefore could I respectfully suggest that the TGA consider having three
separate recommendations for the use of hydroxychloroquine (HCQ) to treat
COVID-19;

1. After admission to hospital.


2. As an early treatment (1-7 days) after first symptoms
3. As a pre-exposure prophylaxis

Of these, the TGA’s current recommendation, that the use of


hydroxychloroquine (HCQ) to treat COVID-19 is strongly discouraged, could
remain for after admission to hospital, however given the weight of evidence,
I believe it would defy all logic for this same recommendation to be
maintained for early treatment.

Regards,
Craig Kelly MP
Member for Hughes

From: SKERRITT, John


Sent: Sunday, 13 September 2020 8:48 PM
To: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>
Cc: Hunt, Greg (MP) <Greg.Hunt.MP@aph.gov.au>;
Cook, Jane
Subject: RE: hydroxychloroquine [SEC=OFFICIAL]

Dear Mr Kelly

Thank you for your email.

I stand by our Department’s advice that the use of hydroxychloroquine (HCQ) to


treat COVID-19 is strongly discouraged outside of a clinical trial. You are correct
that this advice concurs with the recommendations from the National COVID-19
Clinical Evidence Taskforce. It is also based on the overwhelming balance of
evidence thus far, and the consensus view of major global medicines regulators and
health departments, with whom I am in very regular conduct around the progress
of clinical trials for potential therapeutics for COVID-19.

Our Department’s advice was not just based on the results of the RECOVERY trial,
although I believe that trial was an important and well-conducted one. I do not
agree that the dose of HCQ used in that trial was excessive – it was a 2000 mg
loading dose split over the first 24 hours (see the attached trial publication). Such
loading doses are commonly used in treatment of infectious diseases – for example
for malaria, a 1200 mg loading dose of HCQ is given compared with the 400-600 mg
daily dose usual for rheumatoid arthritis.

I also contend that it would be inconceivable that the investigators confused


hydroxychloroquine with another agent – the trial was conducted across 176 UK
hospitals and the trial design, including the doses used, were approved by the UK
regulator (MHRA) prior to the patients being treated.

I am aware that a couple of early studies were suggestive of positive benefits of


HCQ in COVID but since the time that many of those studies were carried out, a
much larger number of negative studies have been published in the top global
refereed medical journals. For example three studies in the New England Journal of
Medicine, which is in the top 4 global medical journals have shown the following:

https://www.nejm.org/doi/full/10.1056/NEJMoa2019014
Brazilian study of individuals hospitalised with mild to moderate COVID-19 – no
effect of HCQ (800 mg/day) with or without azithromycin on clinical outcomes

https://www.nejm.org/doi/full/10.1056/NEJMoa2016638
US and Canadian study on potential use of HCQ for post exposure prophylaxis
(1400 mg on day 1 then 600 mg a day) - no impact on clinical outcomes

https://www.nejm.org/doi/full/10.1056/nejmoa2012410
Observational study in New York hospitals – 1220 mg HCQ on day 1 then 400 mg
daily – no increase or decrease in risk of intubation or death in COVID-19 infected
patients

It is possible that a “sweet spot” – a disease stage or patient population for which
HCQ could be effective in prevention or treatment of COVID-19 infection may exist,
and about 20 significant clinical trials continue in about 8 countries, including at
some major medical centres. In collaboration with the US FDA, the European
Medicines Agency and other major regulators, the TGA is closely monitoring the
results of these studies as they become available.

Yours sincerely

John Skerritt

Adjunct Prof John Skerritt FTSE FIPAA (Vic)


Deputy Secretary for Health Products Regulation
Department of Health
(The Health Products Regulation Group comprises the Therapeutic Goods
Administration and the Office of Drug Control)

From: Kelly, Craig (MP) <Craig.Kelly.MP@aph.gov.au>


Sent: Wednesday, 9 September 2020 5:30 PM
To: SKERRITT, John
Cc: Greg.Hunt.MP <Greg.Hunt.MP@aph.gov.au>
Subject:

Dear Professor Skerritt,

I am writing to you as I am greatly concerned about the TGA’s


advice “that it strongly discourages the use of hydroxychloroquine
to treat COVID-19”.

From the statement on the TGA’s website, this advice appears to


be based upon the recommendations from the National COVID-
19 Clinical Evidence Taskforce. And the Taskforce’s
recommendations appear to be based substantially upon the
findings of the RECOVERY trial.

However the evidence appears to show that the RECOVERY trial


was fatally flawed, as in this trial they administered the group of
patients taking HCQ with 2400mg of the drug within the first 24
hours. All evidence indicates that this was an excessive and toxic
dose – 4 to 5 times the maximum recommended. Further media
reports indicate that this excessive dose was the result of medical
negligence where those running the RECOVERY trial confused the
drugs hydroxychloroquine with hydroxyquinoline.

Therefore, I believe there is a very strong argument that any


results of the RECOVERY should be disregarded in TGA making
any recommendation.

I would also like to draw to your attention two meta-analysis


studies released in preprint in the past 48 hours. The first is a
study out of France by the Institut Hospitalo-Universitaire (IHU)
Méditerranée Infection, which will be published in the journal
‘Expert Review of Clinical Immunology’. This most comprehensive
study concluded for Covid-19;

‘’Treatment with an oral combination of


hydroxychloroquine, azithromycin and zinc may REPRESENT
THE BEST CURRENT THERAPEUTIC OPTION in relation to its
antiviral and immunomodulatory effects’’.

The second is a study from the US by Chadwick C Prodromos MD


and Tobias Rumschlag MD in which they concluded;

This study has four important findings. The first is that HCQ
appears to be consistently effective for the treatment of
COVID-19 when used early in the course of disease in the
outpatient setting, and is generally more effective the
earlier it is used. The second is that overall HCQ has had
efficacy against COVID-19 in a majority of studies. The
third is that there are no unbiased studies showing a
negative effect of HCQ treatment of COVID-19. The fourth
is that HCQ appears to be safe for the treatment of COVID-
19 when used responsibly.

And the authors further noted;

SIGNIFICANCE: We believe our findings have substantial


societal global importance since there have been numerous
edicts either preventing HCQ use for COVID-19 or limiting it
to the inpatient setting which we believe have resulted in
many unnecessary deaths.

Our findings showing efficacy and safety of HCQ against


COVID-19 indicate that HCQ should be freely available to
patients and physicians who choose to use it. And it should
especially be freely available to be used on an outpatient
basis before hospitalization where it appears to be more
effective and where early fears of fatal heart arrhythmias
have been shown to be unfounded[45].

This is particularly important because the only drug to show


efficacy, Remdesivir, has shown no significant benefit in a
recent study [46].It is also expensive and not widely
available. Convalescent plasma has shown benefit [47] but
even this is not well validated and plasma is not available in
large numbers of doses.

Thus HCQ with proven efficacy and safety, a cost of 37


cents per pill and thus a total treatment cost of under 20
dollars[48], versus 3,100 dollars for Remdesivir[49], as well
as wide supply chain availability, would appear to be the
best COVID-19 treatment option available and needs to be
widely promoted as such.

Unfortunately the controversies surrounding HCQ have


resulted in physicians being afraid to prescribe it for reasons
which have nothing to do with medicine, and in patients
being afraid to take it due to spurious reports of danger, or
fears that is not effective.

It is hoped that this study will disabuse the medical


community of these misapprehensions about efficacy and
validate that it is both efficacious and safe, and needs to be
freely
prescribable. Thousands of lives may lie in the balance.

We also do not believe that randomized controlled studies


are necessary before HCQ is authorized for general use
because the efficacy seen in studies already done indicates
that control patients in such studies might die
unnecessarily; and because the time delay to do any such
study would cause yet more deaths by preventing HCQ use
when it is most needed – which is immediately. Our study
has shown that good evidence of efficacy exists; and there is
no safety, cost, or supply reason to not treat now.

Unnecessary death from delayed treatment is too high a


price to pay for greater certainty of knowledge. Many may
have already died unnecessarily due to HCQ misinformation
and it is imperative that we do not further add to the toll.

I would also like to point out this meta-study concluded collecting


data on the 3rd August 2020, and therefore it did not include the
results from 4 large studies which all found treatment with HCQ
was associated with sustainable reducing in death

· Castelnuovo et al., European J. Internal Medicine,


doi:10.1016/j.ejim.2020.08.019 (Peer Reviewed) – study
found the use of hydroxychloroquine in hospitalised
COVID-19 patients was associated with reduced
mortality: Retrospective 3,451 hospitalized patients,
30% reduction in mortality with HCQ after
propensity adjustment.

· Catteau et al., Int. J. Antimicrobial Agents,


doi:10.1016/j.ijantimicag.2020.106144 (Peer Reviewed)
– Retrospective study of 8,075 hospitalized patients,
4,542 received low-dose HCQ, 3,533 control - found a
35% lower mortality for HCQ (17.7% vs. 27.1%)

· Ip et al., medRxiv,
doi:10.1101/2020.08.20.20178772 (Preprint) -
Retrospective study of 1,274 outpatients, which found a
47% reduction in hospitalization with HCQ

· Gonzalez et al., medRxiv,


doi:10.1101/2020.08.18.20172874 (Preprint) -
Retrospective study focused on eosinophil recovery with
9,644 hospitalized patients in Spain, showing lower
mortality for HCQ (14.7% vs 29.2%, p<0.001), and
AZ (15.3% vs. 18.4%, p<0.001).
In light of this most recent evidence, I respectfully suggest that
the TGA’s current recommends the use of hydroxychloroquine to
treat COVID-19 can longer be sustained and should be urgently
reviewed.

Regards,

Craig Kelly MP
Member for Hughes

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