1 / 46

Gastrointestinal Review Highlights of the CLASS Study

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

sachi
Download Presentation

Gastrointestinal Review Highlights of the CLASS Study

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

  2. 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

  3. Outline of Gastrointestinal Review of CLASS study(continued) 3. High risk populations • Conclusions

  4. 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)

  5. 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.

  6. 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 )

  7. 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

  8. “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)

  9. 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

  10. 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)

  11. 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

  12. 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)

  13. 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”

  14. 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

  15. Results

  16. Primary endpoint Complicated Ulcer : ITT

  17. Time to Complicated Ulcer (CSUGIE ) Traditional definition Intention to treat population

  18. Subanalyses: Complicated Ulcers Non-ASA and ASA users

  19. Non-ASA

  20. Time to Complicated Ulcer (CSUGIE) Traditional definition Non-aspirin users

  21. Complicated Ulcer ASA

  22. 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)

  23. Other Relevant AnalysesComposite 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

  24. Composite Endpoint(SX/Complicated) Clinically relevant endpoint Pre-specified ascertainment of data

  25. Composite EndpointSX/Complicated UlcerITT 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

  26. Time to Composite: SX/Complicated Ulcer Intention to treat population

  27. Composite:SX/Complicated UlcerNon-ASA Celebrexdiclofenacibuprofen # 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

  28. Time to Composite: SX/Complicated Ulcer Non-ASA

  29. Composite: SX/Complicated UlcerASA Celebrexdiclofenacibuprofen # 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

  30. 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

  31. 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

  32. “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

  33. 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)

  34. High risk populations Relative RiskComplicated ulcer Age > 75 Hx of UGI bleed ASA Celebrex 5 3.6 4.0 NSAID 5.8 7.1 1.8 (comparators)

  35. 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)

  36. 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) ?

  37. 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

  38. 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 .

  39. 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

  40. 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.

  41. 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

More Related