classic studies and pitfalls in clinical trials · 2017-01-26 · classic studies and pitfalls in...
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![Page 1: Classic Studies and Pitfalls in Clinical Trials · 2017-01-26 · Classic Studies and Pitfalls in Clinical Trials Brian G. Feagan MD Senior Scientific Director, Robarts Clinical Trials](https://reader030.vdocuments.mx/reader030/viewer/2022041101/5ed9faac28db2d5ca24930a0/html5/thumbnails/1.jpg)
Classic Studies and Pitfalls in
Clinical Trials
Brian G. Feagan MD
Senior Scientific Director, Robarts Clinical Trials Inc.
Professor of Medicine, Epidemiology and Biostatistics
Western University
London, Ontario, Canada
![Page 2: Classic Studies and Pitfalls in Clinical Trials · 2017-01-26 · Classic Studies and Pitfalls in Clinical Trials Brian G. Feagan MD Senior Scientific Director, Robarts Clinical Trials](https://reader030.vdocuments.mx/reader030/viewer/2022041101/5ed9faac28db2d5ca24930a0/html5/thumbnails/2.jpg)
Topics To Be Covered
• Assessment of trial design - a “consumers” guide
• Standard IBD trial designs - methodological
issues
• Common Pitfalls – examples of what went
wrong!
• New trial designs
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Some Key Issues in Assessing RCTs
• Randomized ?
• Blinded?
• A prior sample size calculation- adequate
statistical power?
• Clinically relevant endpoint?
• Clinically relevant effect size?
• Dropouts/missing data
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Candidate Endpoints
• Mortality
• Hospitalization/Surgery
• Complications
• Symptoms (Patient Reported Outcomes)
• Endoscopy
• Histopathology (UC)
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n=778 randomized to adalimumab
(ADA) 40 mg EOW or weekly, or
placebo, through 56 weeks
Feagan et al. Gastroenterology 2008;135(5):1493-9 8
Kaplan-Meier CD-Related Hospitalization:
CHARM
Placebo
Adalimumab
Days since randomization
50 100 150 200 250 300 350
30
20
10
0
Week 2
3-month hospitalization risk
Placebo (%) 7.3
ADA (%) 1.6 (RR reduction: 78%)
12-month hospitalization risk
Placebo (%) 13.9
ADA (%) 5.9 (RR reduction: 57%)
% H
os
pit
ali
za
tio
n
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Time to Surgery in Patients with Severe UC
Järnerot G et al. Gastroenterology. 2005;128: 1805-11.
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Complications: Growth Failure
• Growth and development a special problem in pediatrics
• Markowitz trial of 6-MP - 3.8 cm increase in height with active treatment vs. placebo
• Only 56 patients required to detect a 3cm difference at an alpha error of 0.05!
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Trial Designs in IBD
R
Induction & maintenance (ACT I & II, PRECiSE-1)
R
Maintenance (ACCENT I, CHARM, P2)
R
Induction only (Targan, CLASSIC-I, Singleton)
R R
Induction & maintenance cross-over (NACSG)
Courtesy William Sandborn
![Page 9: Classic Studies and Pitfalls in Clinical Trials · 2017-01-26 · Classic Studies and Pitfalls in Clinical Trials Brian G. Feagan MD Senior Scientific Director, Robarts Clinical Trials](https://reader030.vdocuments.mx/reader030/viewer/2022041101/5ed9faac28db2d5ca24930a0/html5/thumbnails/9.jpg)
CLASSIC: Adalimumab in Active
Crohn’s Disease
Remission (CDAI < 150) at Week 4
Hanauer S, et al. Gastroenterology. 2004;127:332.
P = 0.36
P = 0.06
P = 0.001
12
18
24
36
0
10
20
30
40
50
60
Placebo
(n = 74)
40/20 mg
(n = 74)
80/40 mg
(n = 75)
160/80 mg
(n = 76)
% o
f S
ub
jec
ts
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Induction Only: What are the issues?
• Timing of primary endpoint
• Not sufficient for regulatory approval
• Patient acceptance
• Dose in maintenance
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Colombel et al. Gastroenterology 2007;132:52
Maintenance Therapy- Adalimumab in
Crohn's Disease: CHARM
***p<0.001 vs placebo
Placebo (n=170) Adalimumab SC, 40 mg EOW (n=172)
Adalimumab SC, 40 mg q-week (n=157)
*** ***
12
36 41
0
100
Remission (CDAI <150)
CDAI ≥100 vs baseline
Patients (%)
*** ***
18
43 49
CDAI ≥70 vs baseline
*** ***
16
41 48
0
100
Patients (%) Remission (CDAI<150) Response
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Median Time to Loss of Response
Through Week 54
Week 2 Responders
Hanauer S. Lancet. 2002 May 4; 359(9317): 1541-9.
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Open-Label Induction Followed by
Randomization of Responders to Maintenance
What Are the Issues?
• Tends to overestimate the effect size
• Duration?
• Analysis – simple proportions vs. survival
• Very feasible- attractive
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ADA 160 mg
Placebo
Ra
nd
om
iza
tion
/ b
as
elin
e
Mayo assessment
Week 0 Week 4 Week 52 Week 2
ADA 80 mg
Placebo
ADA 40 mg eow
Week 8
Placebo
Co
-prim
ary
en
dp
oin
t
(rem
iss
ion
)
Co
-prim
ary
en
dp
oin
t
(rem
iss
ion
)
Week 32 Week 12
Patients could switch to
ADA OL 40 mg eow if
inadequate response
at / after Week 12
Week 20
Ultra 2 Study Design
Data on file Abbott Laboratories
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Randomized Induction and Maintenance -
“Treat Right Through” - What Are the
Issues?
• High risk- insufficient numbers of patients to answer the
maintenance question
• “missing data”
• Potential effects on patient selection
• Need to handle multiplicity of testing
• Estimation of sample size to answer the maintenance
question dependent upon induction efficacy, retention
rate
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Steroid
Dependent
Patients
MTX
At 16 weeks:
remission and off
corticosteroids
Placebo
MTX
Placebo
Outcome:
At 40 weeks:
no ensuing relapse
(CDAI increase of 100
points or introduction
of treatment for active
disease)
2 :1 Yes
1:1
NACSG MTX Design
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Part II Results: Remission at Week 40
0
10
20
30
40
50
60
70
MTX
Placebo
% R
em
issio
n W
eek 4
0
P = 0.015
65.0%
Feagan et al.N Eng J Med. 2000;342:1627-1632
38.9%
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Randomized Induction Followed by Re-
Randomization of Responders to Maintenance
What Are the Issues?
• Logistically complex
• “Funnel effect” – need to overfill the induction
component
• How to handle placebo responders
• Integral to sequential designs (use of open label
“feeder” to power maintenance)
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Lessons Learned: Common Pitfalls
• Lack of clear PK/PD relationship
• Inadequate dose finding
• High placebo rates/poor patient selection/choice
of outcomes
• Type II error
• Poor trial design
• Multiple competing goals
• “Over-engineering”
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• Early drug development
is problematic because
usually small numbers
of patients are evaluated
• Strong PK/PD relationship
is invaluable for establishing
POC and dose proportionality
• e.g., RDP58 therapy for UC
Lack of Clear PK/PD Relationship
0
10
20
30
40
50
60
70
80
% “
Su
ccess”
Placebo RDP58-200 RDP58-300
32%
71% 72%
Travis S. et al. Inflammatory Bowel Disease. 2005;11(8):713-719
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Inadequate Dose Finding
Targan SR et al. N Engl J Med. 1997;337:1029-1035
Clinical remission CDAI score < 150
• Small molecules usually
linear dose relationship
• Monoclonals usually flat
• Assumptions about
effective dose based
on RA data
Treatment Group
Rem
issio
n (
%)
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CLASSIC: Remission at Week 4
Hanauer et al. Gastroenterology. 2006:30(2):232-33
P = 0.36
P = 0.06
P = 0.001
12
18
24
36
0
10
20
30
40
50
60
Placebo
(N = 74)
40/20 mg
(N = 74)
80/40 mg
(N = 75)
160/80 mg
(N = 76)
Perc
en
tag
e o
f S
ub
jects
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The Placebo Effect
• Complex – determined
by multiple factors
• Major issue in IBD trials,
especially CD
• Outcome measure specific
• Can really ruin your day!
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Sargramostim
(Recombinant GMCSF 6 μg/kg/d SQ)
Korzenik JR, et al. N Engl J Med. 2005;98:S247
0
350
100
300
200
Med
ian
CD
AI
Sco
re
Treatment Week
Sargramostim
Placebo
P = 0.75 P = 0.19 P = 0.03 P = 0.006 P = 0.004
4 2 8 6 0
50
250
150 Remission
Response (100-point)
N = 124
Active CD
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High Placebo Rates
80
70
60
50
40
30
20
10
AUS CAN UK BRA RUS UKR
Resp
on
se o
r R
em
issio
n
(%)
80 25 43 28 49 44
placebo sargramostim
Non-Responder Imputation
Countries with 10 or more subjects enrolled
(no. subjects)
NOVEL 1 (USA)
Placebo Response (CDAI ≥ 100 pt decline)
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CDAI and the Placebo Response
• Minimize by:
• Reduce concomitant medication
• Short duration for induction studies
• Reduce the number of clinic visits
• Confirm objective evidence of
inflammation at entry
• Robust endpoints (remission CDAI <150)
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CRP and Placebo-Induced Remission
Will et al. Gastroenterology April 2005;128(4) Suppl 2:A-48 Abstract #338
p<0.001 p<0.001
174 123 104 193
0
5
10
15
20
25
30
35
>5 >7.5 >10 >15
CRP in mg/dL
Pe
rce
nt
Pa
tie
nts
in
R
em
iss
ion
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What is the Role of Endoscopy?
van Dulleman H et al. Gastroenterology1995 Jul;109(1):129-35
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Recent Negotiations with FDA
on Ulcerative Colitis Endpoints
• Entry criteria are
patients with rectal
bleeding and a
minimum of Grade 2
endoscopic changes
(friability)
• Primary endpoint is
no rectal bleeding
and no friability on
endoscopy
Modified Baron = 0
UCCS = 1
Riley score = 0
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MLN-02: Clinical Remission at Week 6
Feagan B. et. Al. N Eng J Med. 2005
Placebo 0.5 mg/kg 2.0 mg/kg
0
5
10
•5
20
25
30
35
Overall P = 0.030
% R
em
issio
n
15%
34%
33%
P = 0.021 P = 0.015
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Type II Errors
Rutgeerts et al. N Engl J Med. 1994;331:842-845
Treatment (weeks)
2 4 8 10
Pa
tie
nts
in
Re
mis
sio
n (
%)
(CD
AI 1
50
)
100
80
60
40
20
0
*
† ‡ ‡
Prednisolone 40 mg qd tapered q 2 wk to 25 mg (N=88)
Budesonide 9 mg qd x 8 wk tapered to 6 mg (N=88)
*P = 0.22; †P <0.001; ‡P = 0.12
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Type II Errors
• 1 - beta = statistical power
• Commonly 10-20%
• Many trials look for huge effect size
• Special problem of non-inferiority trials
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Duration of trial (months)
AZA Placebo
Candy S. Gut. 1995 Nov;37(5):674-8
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Reasons Trials Fail: Over- Engineering
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Trial Design Complexity: ACCENT I
Multiple goals = “over-engineering”
All Patients, n = 573
Infliximab 5 mg/kg
Week 2
Single Dose Group 3 Dose Induction Group Placebo
n = 110
5 mg/kg
n = 113
5 mg/kg
n = 112
Infusion
Week 0
Responders at Week 2
n = 335 (58%)
Evaluation
10 mg/kg Week 14
Week 54
Week 6
Week 22
Week 30
Week 38
Week 46
Hanauer SB et al. Lancet. 2002 May 4;359(9317):1541-9
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ACCENT I: What Questions Were Asked
vs. What Questions Were Answered?
Efficacy in maintenance
Optimal dose in maintenance
x Single vs. three dose induction
Steroid-sparing
x Dose escalation for secondary failure
x Prevention of surgery
x Mucosal healing
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New corticosteroid-
sparing agent vs Placebo
New corticosteroid-
sparing agent vs TNF
antagonist
The Next Generation Trials: Active
Comparators vs. Placebo - Non-inferiority vs.
Superiority ?
Patients
receiving
corticosteroids
Sample
Size (N) Response
Rate
30% vs
45 %
1500 !
2-sided = 0.5
Beta = 0.20
Assumptions:
Non- inferiority
Clinically insignificant difference 7.5%
Superiority
Clinically significant difference 15%
320
30%, one-sided 95 %CI /
MCID12.5%
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Novel RCT Designs:
Cluster Randomization
• Groups of patients randomized (not individuals)
• Cluster can be a practice, hospital, community
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Reasons for Adopting
Cluster Randomization
• To avoid treatment group “contamination”
• Administrative convenience
• To obtain cooperation of investigators
• Ethical considerations
• To enhance patient compliance
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Bland (2004)
Cluster Randomization Trials
Published 1981-2003
1 2003
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Impact of Cluster Randomization on the
Design and Analysis of a Trial
• Degree of similarity in outcomes within a cluster
must be accounted for in design and analysis
• Can be quantified by an ICC = ρ [~Pearson’s r ]
• ρ = 1.0 = absolute correlation versus
• ρ = 0.0 = absolute independence
• Reduces efficiency of statistical testing/inflates
sample size
• Inferences at cluster level - no penalty, therefore
efficient for policy questions
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REACT I: 40 GI COMMUNITY PRACTICES
Cluster Randomization
20 practices 20 practices
Treatment
Algorithm
Usual
Care
Each practice to provide data on 60 patients
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Therapeutic Algorithm for Active Luminal CD (Moderate Risk)
GCS (Bud vs Pred depending on
disease activity and localization)
Yes
TNF Antagonist + AZA or MTX (GCS as needed)
Evaluate in 4 wks - remission? (HBS ≤ 4)
Taper GCS Add TNF Antagonist + AZA or MTX
5-ASA
Antibiotics
Re-evaluate in 12 wks - remission?
Yes
Continue Combination
Maintenance Therapy
No
No Yes
Continue Combination
Maintenance Therapy Consider
Resection
Taper GCS, re-evaluate
in 12 wks - remission?
Re-evaluate in 12 wks - remission?
No
Re-evaluate in 12 wks - remission?
Yes No
No Maintenance Therapy
Increase TNF Antagonist to weekly dose
Switch Antimetabolite
Re-evaluate in 12 wks - remission?
No Yes
Continue Combination
Maintenance Therapy
Switch TNF Blocker Continue Combination
Maintenance Therapy Re-evaluate in 12 wks - remission?
Without Fistula
Yes No
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REACT
Primary Efficacy Measure
• Proportion of patients in remission at the
practice level at the end of the 12-month follow-
up period
• Remission is defined as a Harvey-Bradshaw
score (HBS) ≤ 4 without the use of steroids for
the treatment of CD
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REACT: Time to first hospitalization,
surgery or complication
34.7%
27.4%
10
20
30
40
Time (months)
Ho
sp
italisati
on
, su
rgery
or
co
mp
licati
on
s (
%)
HR (95% CI) = 0.73 (0.62, 0.86), p <0.001
0 0 3 6 9 12 15 18 21 24
Conventional management
Early combined
immunosuppression
Khanna R, et al. Lancet. 2015 Nov 7;386(10006):1825–34
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Early Combined
Immunosuppression
N (%)
Conventional
Management
N (%)
P Value
Worsening Crohn’s disease
Abscess 32 (3.0) 33 (3.7) 0.36
Fistula 29 (2.7) 39 (4.3) 0.03
Stricture/bowel obstruction 67 (6.2) 82 (9.1) 0.01
Serious worsening disease 98 (9.0) 96 (10.7) 0.65
Serious extra-intestinal
manifestations
47 (4.3) 50 (5.6) 0.37
Serious drug-related complications 10 (0.9) 10 (1.1) 0.84
Deaths
Cardiovascular 2 (0.2) 5 (0.5)
Thromboembolic 1 (0.1) 1 (0.1)
Cancer 3 (0.3) 2 (0.2)
Infection 1 (0.1) 1 (0.1)
Other 0 (0.0) 1 (0.1)
Total Mortality 7 (0.7) 10 (1.1) 0.33b
REACT: Serious Disease and
Drug-Related Complications and Mortality
Khanna R, et al. Lancet. 2015 Nov 7;386(10006):1825–34
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Three Key Differences: REACT II vs. REACT I
1. Decision – making driven by endoscopy
2. Protocolized usual care arm
3. Deep remission as the primary outcome