# Presentation: 218265

## 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

## Time to Complicated Ulcer (CSUGIE )

- Traditional definition
- Intention to treat population

## Slide 18

## Subanalyses: Complicated Ulcers Non-ASA and ASA users

## Non-ASA

## Time to Complicated Ulcer (CSUGIE)

- Traditional definition
- Non-aspirin users

## Slide 22

## Complicated Ulcer ASA

## 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 pre-specified

## 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         26 /1996            36/1985
- Cumulative          1.95%       1.91 %      2.84%
- rate                                              (ns) *          (p=0.017 uncorrected)*
- No./100 pt yr.       1.85             2.41             3.21
- *log-rank test

## Time to Composite: SX/Complicated Ulcer

- Intention to treat population

## Slide 29

## Composite:SX/Complicated UlcerNon-ASA

-                     _Celebrex_   _diclofenac_   _ibuprofen_
- # of events           21/3105            10/1551             28/1573
- Cumulative          1.13%      0.92%         3.00%
- rate                                           (p=0.3)*         (p <0.001 uncorrected)*
- No./100 pt yr.             1.16              1.19                3.20
- * log-rank test

## Time to Composite: SX/Complicated Ulcer

- Non-ASA

## Slide 32

## Composite: SX/Complicated UlcerASA

-                     _Celebrex_   _diclofenac_   _ibuprofen_
- # of events           22/882                16/445                8/412
- cumulative        4.94%        5.31%         3.33%
- rate                                         (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

-                     Celebrex     diclofenac      ibuprofen
- # events                17/3987               5/1996                  9/1985
- Cumulative         0.68%             0.35%             0.61%
- rate                                              (ns)                     (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 co-administration 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

## Slide 46