Jurnal 2

1. Judul
High-dose rifapentine with or without moxifloxacin for shortening treatment of
pulmonary tuberculosis: study protocol for TBTC Study 31/ACTG A5349 phase 3
clinical trial
2. Pertanyaan Penelitian
3. Metode penentuan seleksi artikel menggunakan PICO PICO ( population ), I
( Intervetion), C ( Clinik question), O ( Outcome)
P: The study enrolled individuals with pulmonary tuberculosis caused by drug-
susceptible M. tuberculosis Inclusion Participants must have had a sputum
specimen, collected within two weeks of enrollment, that was either positive for
acid-fast bacilli on smear microscopy or positive for M. tuberculosis by
GeneXpert MTB/RIF® (“Xpert”, Cepheid Inc., Sunnyvale, CA) testing with
semi-quantitative result of ‘medium’ or ‘high’ at the site’s laboratory of record for
the trial. Xpert sensitivity is higher than that of smear microscopy, and Xpert
semi-quantitative results of medium or high correlate well with smear
positivity.30,31 This approach maximized the likelihood that a given participant
had culturable M. tuberculosis from sputum, and additionally aligns this study
with the pre-Xpert body of clinical trials literature in terms of severity of
pulmonary tuberculosis based on sputum bacillary burden.
I: Phase 2 clinical trials of tuberculosis treatment have shown that once-daily
regimens in which rifampin is replaced by high dose rifapentine have potent
antimicrobial activity that may be sufficient to shorten overall treatment duration.
Herein we describe the design of an ongoing phase 3 clinical trial testing the
hypothesis that once-daily regimens containing high dose rifapentine in
combination with other anti-tuberculosis drugs administered for four months can
achieve cure rates not worse than the conventional six-month treatment regimen.
C: This phase 3 trial formally tests the hypothesis that augmentation of rifamycin
exposures can shorten tuberculosis treatment to four months. Trial design and
standardized implementation optimize the likelihood of obtaining valid results.
Results of this trial may have important implications for clinical management of
tuberculosis at both individual and programmatic levels.
O: There will be two co-primary efficacy analyses. One will consider the
Microbiologically Eligible analysis population, and the other will consider the
Assessable population. For each, the comparison of Regimen 1 (control regimen)
versus Regimen 3 (2PHZM/2PHM) will be considered first, and, if non-inferiority
criteria are met then the comparison of Regimen 1 versus Regimen 2
(2PHZE/2PH) will be considered (in this approach there is no adjustment for
multiple comparisons). In each comparison, non-inferiority will be assessed by
comparing the upper bound of the 95%, 2-sided confidence interval for the
difference between the proportions of participants who are classified as having an
unfavorable outcome on the intervention regimen vs. the control regimen
 (Regimen 1) to the predefined noninferiority margin of 6.6%. Non-inferiority
must be demonstrated in both analysis populations in order to declare non-
inferiority for an intervention regimen. The Microbiologically Eligible population
and its subset, the Assessable population, are modified intention-to-treat
populations. The Assessable population excludes those participants who
experience an event (e.g. death from violent or accidental cause at any time
during participation) that is unlikely to be related to the disease or to the
intervention, while the Microbiologically Eligible population classifies those non-
assessable participants as unfavorable and thus is closer to an intention-to-treat
population
4. Strategi pencarian artikel :
5. Hasil Review

Penulis, Tahun Desain Penelitian Sampel Hasil penelitian

1. Susan E. Desain of Sample of The primary There will be two
Dorman S31/A5349 is a objective of the trial is to co-primary efficacy
2. Payam multicenter evaluate whether four-month analyses. One will
Nahid randomized rifapentine-containing consider the
3. Ekaterina controlled phase 3 regimens can produce Microbiologically
Kurbatova non-inferiority trial outcomes that are non-inferior Eligible analysis
Stefan, that compares two to (i.e., “not worse than”) population, and the
4. William J. four-month standard sixmonth therapy. other will consider
Burman regimens with the Therefore, the trial is designed the Assessable
5. KwokChiu standard six-month as a non-inferiority study. The population. For each,
Chang regimen for non-inferiority margin is the comparison of
(2020) treating drug- 6.6%. We assumed a Regimen 1 (control
susceptible proportion of 15% regimen) versus
pulmonary unfavorable outcomes for the Regimen 3
tuberculosis in standard regimen arm (2PHZM/2PHM)
HIV-negative and (Microbiologically Eligible will be
HIV-positive population). This rate is based considered first, and,
patients. Both of on observed results for the if non-inferiority
the four-month control arm (modified criteria are met then
regimens contain intention to treat [MITT] the comparison of
high-dose analysis group) in recently Regimen 1 versus
rifapentine instead completed phase 3 clinical Regimen 2
of rifampin, with trials that used similar (2PHZE/2PH) will
ethambutol outcome definitions as be considered (in
replaced by S31/A5349 -- 14.4% this approach there is
moxifloxacin in unfavorable in the RIFAQUIN no adjustment for
one regimen. All trial,50 13.2% in the Oflotub multiple
drugs are trial,51 and 16% in the comparisons). In
administered seven ReMOX trial.24 Based on each comparison,
days per week, and TBTC phase 2 trial non-inferiority will
under direct experience18,42 and be assessed by
observation at least considering the anticipated comparing the upper
five days per week. increasing use of rapid bound of the 95%, 2-
The primary molecular resistance testing sided confidence
outcome is during S31/A5349, the interval for the
tuberculosis proportion of enrolled difference between
disease-free participants who would be the proportions of
survival at twelve found to be late exclusions participants who are
months after study due to microbiological classified as having
treatment ineligibility was estimated at an unfavorable
assignment. A total 12%. The proportion of outcome on the
of 2500 enrolled patients who would intervention regimen
participants will be be found to be “not vs. the control
randomized; this assessable” was estimated at regimen (Regimen 1)
gives 90% power to 12%.24,50 Total required to the predefined
show non- sample size was calculated to noninferiority
inferiority with a be 2500, with approximately margin of 6.6%.
6.6% margin of 612 assessable per arm. With Non-inferiority must
non-inferiority the expected 15% unfavorable be demonstrated in
outcomes among those who both analysis
are assessable, a 6.6% non- populations in order
inferiority margin and a two- to declare non-
sided 5% type 1 error rate, the inferiority for an
study will have 90% power to intervention
test the primary hypothesis regimen. The
among the Assessable Microbiologically
subgroup. Justification for Eligible population
non-inferiority margin A 6% and its subset, the
margin of non-inferiority has Assessable
been used in other recent trials population, are
of single-drug substitution modified intention-
treatment shortening trials to-treat populations.
(REMoxTB, OFLOTUB, The Assessable
RIFAQUIN)24,50,51. The population excludes
justification of the 6% margin those participants
is published in the online who experience an
supplements with those papers event (e.g. death
and is based on a meta- from violent or
analysis of historical trials accidental cause at
including six-mon any time during
participation) that is
unlikely to be related
to the disease or to
the intervention,
while the
Microbiologically
Eligible population
classifies those non-
assessable
participants as
unfavorable and thus
is closer to an
 intention-to-treat
population.

6. Keseimpulan
Study S31/A5349 is a phase 3 clinical trial that is the culmination of over 15 years of
work to determine if optimized rifamycin dosing–in the form of rifapentine administered
daily at a dose of 1200 mg — can meaningfully shorten the required duration of
treatment for pulmonary tuberculosis. A finding of non-inferiority of one or both
rifapentine regimens, with good safety and tolerability, would open up a new shorter
course treatment option for a broad group of tuberculosis patients. If the rifapentine
regimens do not meet the noninferiority threshold, this would not exclude the possibility
that optimized high doses of rifampin could shorten treatment, including through
stratified medicine approaches,66 but our findings would underscore the need for
additional trials that include newly developed drugs.
7. Daftar Pustaka

World Health Organization. Global tuberculosis report 2018. Geneva, Switzerland: World Health
Organization; 2018 Report No.: 978-92-4-156564-6