Transcript Gastrointestinal Review Highlights of the CLASS Study Lawrence Goldkind M.D.

Gastrointestinal Review
Highlights of the CLASS Study
Lawrence Goldkind M.D.
Outline of Gastrointestinal
Review of CLASS study
• Review study design highlights
• Review study results
1. Primary analysis: Complicated Ulcer (CSUGIE)
a. ITT
b. Subgroup analyses: aspirin and non-aspirin
2. Composite endpoint- Symptomatic as well as
Complicated ulcers (SX/Complicated)
a. ITT
b. Subgroup analyses of aspirin and non-aspirin
Outline of Gastrointestinal
Review of CLASS study
(continued)
3. High risk populations
•
Conclusions
Design Highlights
• “The null hypothesis being tested is that
there is no difference in the incidence of
clinically significant UGI events* between
Celebrex and each of the NSAID groups
(ibuprofen and diclofenac)” protocol
November 1998
• *Complicated Ulcer (CSUGIEs)
Statistical Plan
• “Two primary treatment comparisons will
be performed: celecoxib vs. ibuprofen and
celecoxib vs. diclofenac.
• A stepwise procedure will be used to
strongly control type-1 error. In this
procedure, the first step is to test the overall
hypothesis whether celecoxib and the
pooled NSAIDs are different.
Statistical plan
(continued)
If the test is not significant, the null
hypothesis is retained and the procedure
stops.
If the test is significant, the second step will
be the pairwise tests between celecoxib and
each of the two NSAIDs.”
(As long as the above conditions were met no alpha
adjustment was considered necessary )
Endpoint Definition
“Complicated Ulcer”
Perforation
Obstruction
Upper Gastrointestinal Bleeding
“Traditional”definition of UGI bleed = clear
evidence of some blood loss with evidence of
gastroduodenal injury
“Alternate”= evidence of imminently life-threatening bleed
with evidence of gastroduodenal injury (transfusion,
orthostasis, 2g/dl drop in Hgb
“Traditional” Definition
Documented Gastroduodenal ulcer or erosion in
addition to one of the following:
1. Hematemesis
2. Active bleeding at time of endoscopy or blood
within the stomach at endoscopy
3. Stigmata of recent bleed (adherent clot or visible
vessel)
Traditional definition of bleeding
(continued)
4. Melena
5. Hemocult positive stool+ fall in Hct of >5% or
Hgb of > 1 g/dl
6. Hemocult positive stool +orthostasis
7. Hemocult positive stool + need for transfusion on
clinical grounds
Design highlights
(continued)
Dose selection:
2X for RA : 800mg
• Proof of COX-2 hypothesis: Dose
dependency of GI safety
• Dose creep: potential phenomenon in
painful chronic conditions (open-label
studies in original NDA suggested majority
of patients increase dose when allowed)
Design highlights
(continued)
• Margin of overall safety when organ
specific major safety claim being
considered ( if overall safety not maintained with
higher dose ? value of organ specific findings)
• 800 mg/day is 1X for chronic use in FAP
• Future indications and doses are unknown
Design Highlights
(continued)
Generalizability
Population: OA and RA
2 comparators
Minimal exclusions
a. renal or hepatic dysfunction or lab abnormality considered
to be clinically significant by the investigator
b. baseline occult GI bleed
c. aspirin allowed ( patients with underlying significant CV
disease included)
Design Highlights
Study Duration:
• “The trial will continue until the anticipated
number of clinically significant UGI events
have been observed in both studies.
Minimum participation for an individual
patient is 26 weeks and maximum study
participation is 52 weeks”
Design Highlights Conclusions
• Chronic exposure to assess chronic safety
• High dose to assess “robustness” of any
safety claim
• Multiple comparators to address
generalizability
• Rigorous and well-defined endpoints
• Large trial size allowed comparative data on
overall safety including uncommon
toxicities
Results
Primary endpoint
Complicated Ulcer : ITT
# of
events
Cumulative
rate
Celebrex
Diclofenac
Ibuprofen
17/3987
10/1996
11/1985
0.62%
0.75%
0.68%
(ns)*
No. per 100
pt. Yr
*log-rank
test
0.73
0.93
(ns)*
0.98
Time to Complicated Ulcer
(CSUGIE )
Traditional definition
Intention to treat population
Subanalyses:
Complicated Ulcers
Non-ASA and ASA users
Non-ASA
Celebrex
Diclofenac
Ibuprofen
4/1551
10/1573
# of events
8/3105
cumulative
rate
0.41% 0.28%
(ns)*
0.83%
(0.037
uncorrected)*
No. per 100
Pt. Yr
*log-rank
test
0.44
0.48
1.14
Time to Complicated Ulcer
(CSUGIE)
Traditional definition
Non-aspirin users
Complicated Ulcer
ASA
Celebrex
# of events
9/882
cumulative
rate
1.60%
*Log-rank
test
Diclofenac
Ibuprofen
6/445
1/412
1.80%
(p=0.5)*
0.41%
(p=0.15)*
Summary of Findings for
Complicated Ulcers
• Primary analysis: No differences between
Celebrex and NSAIDs combined or individually
• Non-ASA: Strong trend favoring Celebrex
compared to ibuprofen. No difference between
Celebrex and diclofenac
• ASA: No differences between Celebrex and
diclofenac. Paradoxical trend favoring ibuprofen
compared to both Celebrex and diclofenac (smaller
sample size, study not stratified based on ASA use)
Other Relevant Analyses
Composite Endpoint
(SX/Complicated)
Original protocol:
“Symptomatic UGI ulcers, documented by endoscopy or
UGI barium x-ray with no evidence of perforation,
bleeding or obstruction will be categorized and
summarized separately.”
Composite endpoint of SX/complicated ulcers not prespecified
Composite Endpoint
(SX/Complicated)
Clinically relevant endpoint
Pre-specified ascertainment of data
Composite Endpoint
SX/Complicated Ulcer
ITT
Celebrex diclofenac ibuprofen
# of events
43/3987
Cumulative
rate
1.95%
No./100 pt yr.
1.85
*log-rank test
26 /1996
1.91 %
(ns) *
2.41
36/1985
2.84%
(p=0.017 uncorrected)*
3.21
Time to Composite:
SX/Complicated Ulcer
Intention to treat population
Composite:SX/Complicated Ulcer
Non-ASA
Celebrex diclofenac ibuprofen
# of events
21/3105
Cumulative
rate
1.13%
No./100 pt yr.
1.16
* log-rank test
10/1551
0.92%
(p=0.3)*
1.19
28/1573
3.00%
(p <0.001 uncorrected)*
3.20
Time to Composite:
SX/Complicated Ulcer
Non-ASA
Composite: SX/Complicated Ulcer
ASA
Celebrex diclofenac ibuprofen
# of events
cumulative
rate
22/882
4.94%
16/445
8/412
5.31%
3.33%
(p=0.15ns)*
(p=0.46)*
(uncorrected)
* log-rank test
Conclusions of Composite:
SX/Complicated Ulcer
• Pre-specified ascertainment of data but not
a pre-specified endpoint
• Clinically relevant endpoint
• Strong trend in favor of Celebrex compared
to ibuprofen in non-ASA users
• No difference between Celebrex and
diclofenac in non-ASA users
Conclusions of Composite:
SX/Complicated Ulcer
(continued)
• In ASA users there was a paradoxical trend
favoring ibuprofen compared to both
Celebrex and diclofenac. Similar to pattern
seen in primary endpoint: complicated ulcer
“Alternate” Definition of
Bleed/Major Bleed
Hematemesis, melena or Hemocult positive stool in
the face of a gastroduodenal ulcer or erosion plus
1. drop in Hgb of > 2g/dl with adequate hydration or
if urgent transfusion required, final hemoglobin
after equilibration of < pre-bleed level
OR
2. Orthostatic hypotension or supine BP under 90/60
Complicated Ulcer
Using Pre-specified “Alternate” more serious
definitions of Bleed/Major Bleed
# events
Cumulative
rate
Celebrex
diclofenac
17/3987
5/1996
0.68%
0.35%
(ns)
ibuprofen
9/1985
0.61%
(ns)
High risk populations
Relative Risk
Complicated ulcer
Age > 75
Hx of UGI bleed
ASA
Celebrex
5
3.6
4.0
NSAID
5.8
7.1
1.8
(comparators)
High risk populations
Relative Risk
Composite: SX/Complicated ulcer
Age > 75
Hx of UGI bleed
ASA use
Celebrex
3.5
4.3
3.7
NSAID
3.7
3.4
2.3
(comparators)
High Risk Populations
• If age and history of ulcer complication are
independent risk factors for ulcer
disease...Findings of high risk in association with
a therapy may represent intrinsic risk rather than
drug effect (no causality) ?
OR
• Interaction between underlying and drug related
risk may produce an exaggerated/ higher risk
attributable to therapy (causality) ?
Overall Conclusions
• No statistically significant differences were shown
for the entire population for the primary
endpoint of complicated ulcer between Celebrex
and the NSAID comparators- combined or
individually
• Relevant endpoint of the composite of
SX/Complicated Ulcers suggested a difference
between Celebrex and ibuprofen in favor of
Celebrex. No difference was seen between
Celebrex and diclofenac
Overall Conclusions
(continued)
Hypothesis Generating Findings
• Co-administration of aspirin was associated with
an increased and similar risk of complicated
ulcers in both Celebrex and diclofenac groups
( @ 4-fold)
• The same trend was seen at the broader Composite
endpoint of SX/Complicated Ulcer
.
Overall Conclusions
(continued)
Hypothesis Generating Findings
• The ibuprofen group requiring low dose aspirin
experienced a lower rate of complicated ulcers
than either of the other two groups. This trend was
also seen in the composite endpoint of
SX/complicated ulcer
Overall Conclusions
(continued)
• It is unclear whether the paradoxical findings
associated with the concomitant use of aspirin and
ibuprofen represent random findings or whether
they represent a true differential interaction
between aspirin and NSAIDs in terms of UGI
toxicity.
Overall Conclusions
• Further study is needed to clarify the safety of coadministration of aspirin and NSAIDs/COX-2
selective agents
• No conclusions regarding safety of Celebrex
compared to traditional less selective COX
inhibitors as a group are possible