Μεθοδολογία Διατροφικής Έρευνας

Παρουσίαση Κλινικής δοκιμής

Η περίληψη
Ο σκοπός της έρευνας
Τα άτομα της μελέτης
Οι ομάδες
παρέμβασης.
Ο σχεδιασμός της έρευνας
 Σχεδιασμός μελέτης

Mediterranean diet
Randomization

19 months
48 months open follow-up
randomized (delay in
period stopping)

Control diet – AHA Step I diet

Premature
discontinuation
at 27 mo (!)
 Σχεδιασμός μελέτης
• Start year: 1998
• Parallel randomized trial, single blinded
• Secondary prevention of CHD among myocardial infarction (MI)
survivors
• Primary outcomes: re-infarctions and cardiac death
• Secondary outcomes: coronary bypass surgery, angioplasty and
their complications, stroke, angina, heart failure, pulmory embolism,
thrombophlebitis
• N= 605 (90% were males age 53.5 years)
• Slightly more than 60% of the patients received beta-blockers
• Recruitment: during the hospitalization due to MI
 Comparison of the Diets
Item Experimental Control
Total calories 1947 2088*
Total fat 30.4% 33.6%*
Saturated fat 8% 11.7%
Dietary cholesterol 203 mg/dl 312 mg/dl*
Alcohol Same Same
Olive oil None None
MUFA n-9 Increased*
PUFA Increased*
n-3/n-6 fatty acids Increased*
Fiber 18.6
Αποτελέσματα
 Αποτελέσματα

100 Experimenta Canola oil–

based
% Without Event

l margarine, fiber,
low cholesterol,
90 low saturated
fat, fruits,
Control vegetables

80
P = 0.0001
70
1 2 3 4 5
Year
Αποτελέσματα
 Αποτελέσματα

Myocardial infarction plus Preceding plus minor events

cardiovascular death requiring hospital admission,
-72% including recurrent stable
angina, restenosis -47%
Myocardial infarction plus
cardiovascular death plus major
secondary events -67%
Συζήτηση των ευρημάτων
 Strengths
• Randomised trial with free supplementation of margarine. Feeding
of any food item is likely to improve compliance to diet (which is
notoriously poor in long term trials)
• Diets were relatively well reported, even if fiber intake was reported
only at 4 years (15.5 g/day in cotrols and 18.6 g.day in
Mediterranean group)
• Medical attention is likely to have been quite similar in between the
groups
• Drops out is very low at 27 months (<8%)
• Well documente4d end points
• Well documented medications
 Weaknesses
• Glucose levels of patients were neither monitored nor reported. It is not
known if incidene of diabetes or IGT was equally distributed among
groups
• A small difference in weight gain between the groups favoring active
group
• The changes is dietary intakes were modest or even subtle, and
underlying the importance of free supplementantion
• The mechanistic model behind the observed effects is vague and
inadequately proven in later trials.
• Currently, statins are routinely prescribed to MI survivors. It is not
known if Lyon Diet would yield good results on top of widely prescribed
statin treatment.
• The results have not been re-produced in any other long term outcome
trial.
Υπάρχει όμως και η κριτική…
• These results are quite impressive. However, limitations in study
methods raise questions about the true impact of this diet on risk of
recurrent heart disease and related measures. Specifically, the
baseline diet was only assessed in the experimental group at the
start of the study. The control group's diet was only assessed at the
conclusion. This was done to avoid influencing the dietary behavior
of these subjects.
– Thus, it's not clear whether there were any dietary
changes made by the control group.
• Dietary data at the final visit are reported for only 83 out of 303
subjects (30%) in the control group and 144 out of 302 (less
than 50%) in the experimental group.
– The diet of the other subjects who completed the study is unknown. This raises
questions about the role of diet in explaining the results reported for recurrent
coronary events.
Μεθοδολογία Διατροφικής Έρευνας
Παρουσίαση Κλινικής δοκιμής
H περίληψη
Σκοπός της κλινικής δοκιμής
Σχεδιασμός
Τα άτομα της μελέτης

CVD risk: NAI (≥ 3 ΠΚ)

Εκδήλωση CVD: ΟΧΙ
Παρεμβάσεις στις ομάδες ΜΔ

Δεν έγιναν:
•Θερμιδικοί περιορισμοί
•Ενθάρρυνση ↑ΦΔ

Διαιτολόγοι
•κατάρτιζαν κάθε 3 μήνες τα άτομα
•αξιολογούσαν με διατρ. εργαλεία
την προσκόλληση στη ΜΔ
Παρεμβάσεις στην ομάδα
ελέγχου

Περιορισμός!!
Ελλιπής υποστήριξη τα
3 πρώτα χρόνια
 Παρεμβάσεις

Processed and red meat was restricted in both groups and

fish encouraged in both groups
Μετρήσεις
Καταληκτικά σημεία

Αξιολόγηση μέσα από

1.Επικοινωνία με
εθελοντές
2.Επικοινωνία με οικ.
Γιατρούς
3.Ετήσια αξιολόγηση
ιατρικού ιστορικού
4.National Death Index
 Σχεδιασμός μελέτης

a) Mediterranean diet including free

extra virgin olive oil daily

Randomization of
patients (high risk b) Mediterranean diet including free
patients in primary nut mix daily
care, Spanish n= 7447)
c) Low fat diet, no free delivery of
any food items
Mean follow-up 4,8 years

Drops out rates were very low. 11.4% of participants were lost in control group
and 5,4% in Med Diet groups
Στατιστική ανάλυση
Παρόμοιες
αγωγές

Παρόμοια
συμμόρφ
ωση στη
ΜΔ
 Βασικά χαρακτηριστικά
Οκτώβριος 2003- Ιούνιος 2009: 8713 άτομα συγκεντρώθηκαν

7447 άτομα τυχαία καταμερίστηκαν στις 3 ομάδες

Διάρκεια follow-up: 4.8 χρόνια

Μετά την 1η αξιολόγηση: 2.8% των ατόμων αξιολογήθηκαν μόνο με βάση το ιατρικό
ιστορικό

Δεκέμβρης 2010: 7% των ατόμων χάθηκαν στα 2 χρόνια follow-up

Drop-out rates
Λόγω χαμηλότερης
Control group 11.3% διατρ. παρέμβασης
Mediterranean groups 4.9%
Χαρακτηριστικά ατόμων που αποχώρησαν Vs αυτών που παρέμειναν στη μελέτη :
•Πιο νέοι (κατά 1.4 χρόνια)
•Αυξημένου BMI
•Αυξημένου waist/hip ratio
•Χαμηλότερο σκορ συμμόρφωσης στη ΜΔ (κατά 1.0 μονάδα)
Αποτελέσματα
 Αποτελέσματα
Primary End-point Total mortality

The Kaplan-Meyer curves diverged No effect on all-cause mortality was

soon after the trial started apparent
Risk of composite cardiovascular
end point was reduced by 30% in
both Med Diet groups vs controls
Ανάλυση ανά ομάδες
 Συζήτηση των ευρημάτων

•Incidence of fatal cardiovascular

events was not significantly different
between groups
•Total mortality was not significantly
different between groups
 Συζήτηση των ευρημάτων
• This is the largest randomised study ever on
Mediterranean diet. Thus, the results will have strong
and lasting impact.
• Done in modern era
• The results are in line with surrogate marker trials
(short RCTs) prospective cohort studies.
– Thus, Mediterranean diet pattern has the most robust evidence
supporting its effect in cardiovascular health
• This is the first randomized trial on diet demonstrating a
clear benefit in terms of strokes
Περιορισμοί μελέτης
Για την ομάδα ελέγχου:
•Αλλαγή του πρωτοκόλλου κατά
τη διάρκεια της μελέτης
•Ελλιπής διατρ. παρέμβαση τα
3 πρώτα χρόνια

Για την ομάδα ελέγχου:

•Απώλειες στο follow-up κυρίως
στην ομάδα ελέγχου ατόμων
↑CVD risk→βελτιωμένο
προφίλ ατόμων ομάδας
ελέγχου;

Πρόβλημα γενίκευσης στο

γενικό πληθυσμό και σε
άτομα χαμηλότερου CVD
risk
Από τη θεωρία, στην πράξη, στην κλινική αξιολόγηση …

ΚΡΙΤΙΚΗ ΑΞΙΟΛΟΓΗΣΗ ΜΙΑΣ

ΚΛΙΝΙΚΗΣ ΔΟΚΙΜΗΣ
 Μια κλινική περίπτωση…

• Γυναίκα, 67 ετών,
– υπερτασική, με ρυθμισμένα
επίπεδα ΑΠ υπό
φαρμακευτική αγωγή,
– προσέρχεται στο εξωτερικό
καρδιολογικό ιατρείο με
αίσθημα παλμών.
 … διάγνωση

Το ΗΚΓ
έδειξε
παρουσία
πλήρους
αρρυθμίας
(κολπικής
μαρμαρυγής).
 … θεραπευτική αγωγή
• Καθώς η ασθενής ανέφερε έναρξη της
αρρυθμίας μέσα στο τελευταίο 3ωρο,
– ακολούθησε φαρμακευτική ανάταξη, με τη χορήγηση
αμιοδαρόνης.
• Η ασθενής εξέρχεται με οδηγίες για συνέχιση της
ΑΥ αγωγής, β-αποκλειστή,
• και με βάση το CHADS-VASC σκορ (=2),
– χρήζει προφύλαξης για θρομβοεμβολικής νόσου
με χορήγηση αντιπηκτικής αγωγής.
 … ιατρικό συμβούλιο
Ακολούθησε
συζήτηση για
τον τύπο της
αντιπηκτικής
αγωγής.

– Το «γνωστό» κουμαρινικό αντιπηκτικό

(Sintrom), ή
– το «νέο» αντιπηκτικό αναστολέα θρομβίνης
(dabigatran / pradaxa 110 mg, 150 mg)?
… ιατρική βάση των ενδείξεων
Ο σχεδιασμός της μελέτης …
… χορηγίες
Καταληκτικά σημεία …
Καταληκτικά σημεία …
Τυχαιοποίηση & τυφλοποίηση
Μελέτη μη-υπεροχής …
 RE-LY
A Non-Inferiority Clinical Trial

Atrial fibrillation with ≥ 1 Risk Factor

Absence of contraindications
951 centers in 44 countries

Blinded Event
Adjudication R
Open Blinded

Warfarin Adjusted Dabigatran Dabigatran

INR 2.0 – 3.0 110 mg BID 150 mg BID
N=6,000 N=6,000 N=6,000

Connolly SJ, et al. NEJM 2009; 361:1139-1151

 RE-LY
Stroke Prevention 150 mg - 34% Fewer Strokes

Non-inferiority Superiority
Dabigatran 110 p-value p-value
vs. Warfarin <0.001 0.34

Margin = 1.46
Dabigatran 150
vs. Warfarin <0.001 <0.001

0.50 0.75 1.00 1.25 1.50

Dabigatran better HR (95% CI) Warfarin better
 RE-LY
Stroke Prevention 150 mg - 34% Fewer Strokes
 RE-LY
Study Outcomes

Efficacy
• Both doses of dabigatran were non-inferior to warfarin on the primary endpoint
– reduction of the incidence of stroke including hemorrhagic and systemic
embolism; p<0.001
• Dabigatran 150 mg BID was superior to warfarin on the primary endpoint by 34%
– RR 0.66, 95% CI, 0.53-0.82; p<0.001
Safety
• No significant difference in the rate of major bleeding for dabigatran 150 mg BID
compared to warfarin
– 3.11 vs 3.36 %/yr; p=0.31
• Rate of major bleeding with dabigatran 110 mg BID (2.71%/yr) was 20% lower
compared to warfarin; p=0.003
 RE-LY
MORTALITY REDUCTION DABIGATRAN VS WARFARIN

• Lower death rate with dabigatran:

– Vascular death
2.69% vs 2.43 and 2.28%* (p=0.04 for 150 mg)
– All cause death
4.13% vs 3.75 and 3.64% (p=0.05 for 150 mg)

*Dabigatran 110 mg and 150 mg

 RE-LY
BLEEDING DABIGATRAN VS WARFARIN

• More bleeding with warfarin:

– Life-threatening bleeding
1.8% vs 1.2 and 1.5%* (p<0.001, 0.04)
– Intracranial bleeding
0.7% vs 0.2 and 0.3% (p<0.001, <0.001)
– Major plus minor bleeding
18.2% vs 14.6 and 16.4% (p<0.001, 0.002)

*Dabigatran 110 mg and 150 mg

 RE-LY
BLEEDING DABIGATRAN VS WARFARIN
Ανεπιθύμητες παρενέργειες …
 Dabigatran: FDA Status
• Pradaxa trade name
• For the prevention of stroke in patients with non-
valvular atrial fibrillation (SPAF):
– Pradaxa 150 mg BID FDA approved (Oct. 2010)
– Pradaxa approved in EU, Canada and Japan
• 150 mg BID for SPAF
– 150 mg for CrCl >30 mL / min
– 75 mg for CrCl 15-30 mL / min
Ανάλυση κόστους …
 Το ιατρικό συμβούλιο …
• Αποφάσισε τη χορήγηση του
• Pradaxa 150 mg
– αφού έλαβε υπόψη και άλλα στοιχεία της
ασθενούς …
Η αξία των κλινικών δοκιμών …

ΣΥΜΠΕΡΑΣΜΑΤΑ
 Είναι σημαντικές…

• Προτείνουν αιτιολογικές συσχετίσεις

• Εξετάζουν την αποτελεσματικότητα
μιας νέας θεραπείας
• Συμβάλλουν στην πρόληψη μιας νόσου
ή κατάστασης
 «μήνυμα για το σπίτι…»
Ο σχεδιασμός και η εκτέλεση κλινικών
μελετών απαιτούν υψηλής στάθμης
επιστημονικά και ηθικά προσόντα…
Ορολογία …
ΓΛΩΣΣΑΡΙ ΚΛΙΝΙΚΩΝ
ΔΟΚΙΜΩΝ
 Πηγές …

• CDISC Clinical Research Glossary v 6.0

– http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltri
als/CRO%2FSponsor/CDISC-Clinical-Research-Glossary/Article
Standard/Article/detail/648647?contextCategoryId=44907

• Acronyms, Abbreviations, and Initials

– http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltri
als/CRO%2fSponsor/Acronyms-Abbreviations-and-
Initials/ArticleStandard/Article/detail/648650
 Ορολογία

• Sponsor
• Investigator
• Sub-investigator
• Sponsor-Investigator
• CRO
• CRA, CCRA
• Monitor
• Study Coordinator, CCRC
 Sponsor

• An individual, company, institution, or

organization that takes responsibility for the
initiation and management of a clinical trial,
although may or may not be the main funding
organization.
• A corporation or agency whose employees
conduct the investigation is considered a
sponsor and the employees are considered
investigators.
 Primary Investigator (PI)

• An individual who actually conducts a clinical

investigation
• (i.e., under whose immediate direction the test article
is administered or dispensed to, or used involving a
subject, or, in the event of an investigation conducted
by a team of individuals, is the responsible leader of
that team).
 Sub-investigator

• Any member of the clinical trial team

designated and
• supervised by the investigator at a trial site to
perform critical trial-related procedures and/or
to make important trial-related decisions (e.g.,
associates, residents, research fellows).
 Delegation of Responsibility

• List of individuals to whom the PI has delegated

authority to conduct
– assessments,
– procedures,
– data capture,
– informed consent process, or
– any aspect of the clinical trial
 Sponsor-Investigator

• An individual who both initiates and conducts,

alone or with others, a clinical trial and under
whose immediate direction the investigational
product is administered to, dispensed to, or used
by a subject.
– NOTE: The term does not include any person other
than an individual (i.e., it does not include a
corporation or an agency). The obligations of a
sponsor-investigator include both those of a sponsor
and those of an investigator.
 Contract Research Organization

• … είναι εταιρείες οι οποίες αναλαμβάνουν

την διεξαγωγή μιας κλινικής δοκιμής, από
τη σύλληψη της ιδέας μέχρι την έγκριση
από τον αρμόδιο ΕΟΦ …
 CRA, CCRA, Monitor

• Person employed by a sponsor or CRO acting on a

sponsor's behalf, who monitors the progress of
investigator sites participating in a clinical study.
– Responsible for determining that a trial is being conducted in
accordance with the protocol and GCP guidance.
– At some sites (primarily in academic settings), clinical research
coordinators are called CRAs.

• A monitor's duties may include but are not limited to

helping to plan and initiate a trial, assessing the conduct
of trials, and assisting in data analysis, interpretation,
and extrapolation.
 Clinical Research Coordinator

• Person who handles most of the administrative

responsibilities of a clinical trial on behalf of a site
investigator, acts as liaison between investigative site
and sponsor, and reviews all data and records before a
monitor's visit.

– Synonyms: trial coordinator, study coordinator, research

coordinator, clinical coordinator, research nurse, protocol nurse.
 Συμπληρωματική ορολογία

• Protocol
– Protocol deviation
– Protocol violation
– Protocol amendment