1 / 28

Oxypurinol for Symptomatic Gout in Allopurinol Intolerant Patients

Oxypurinol for Symptomatic Gout in Allopurinol Intolerant Patients. Lourdes Villalba, M.D. DAAODP, CDER, FDA Arthritis Advisory Committee Meeting June 2, 2004. Goal. Clinical trial design for chronic gout Data from a specific NDA as an example for discussion . Oxypurinol .

ermin
Download Presentation

Oxypurinol for Symptomatic Gout in Allopurinol Intolerant Patients

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. Oxypurinol for Symptomatic Gout in Allopurinol Intolerant Patients Lourdes Villalba, M.D. DAAODP, CDER, FDA Arthritis Advisory Committee Meeting June 2, 2004

  2. Goal • Clinical trial design for chronic gout • Data from a specific NDA as an example for discussion

  3. Oxypurinol • Proposed indication: “Treatment of hyperuricemia in patients with symptomatic gout who are intolerant to allopurinol and have failed either rechallenge or desensitization with allopurinol”

  4. Allopurinol • Effectively reduces serum uric acid (SUA) at doses 300 – 800 mg daily • Active metabolite is oxypurinol • Allopurinol T ½ < 2 hr. • Oxypurinol T ½ : 13 - 29 hr. • Limited data on allopurinol/oxypurinolcomparison

  5. PK Study AAI-US-175 • Open-label, dose linearity, fasted/fed, bioequivalence study (N=42) • Relative bioavailability of single dose of oxypurinol is about 30% of allopurinol • No data on multiple-dose conversion

  6. Allopurinol Safety • Hypersensitivity reactions (2-4%) • Skin (mild to severe; fatal) • Fever, hepatitis, nephritis, hematologic • AHS (allopurinol hypersensitivity syndrome) • Mechanism: type IV ? • Non-immunologic toxicity • renal, liver • animal toxicity: renal, liver, cardiac • Unclear whether hypersensitivity related to allopurinol, oxypurinol or other metabolite

  7. Allopurinol DesensitizationA&R 44(1): 231-238, 2001 For moderate skin intolerance • retrospective evaluation, N=32 • desensitization over one month, mean FU 32 m, mean creatinine 2.8 mg/dL • 88% tolerated doses up to 50-100 mg/d • 13% developed skin reactions that required discontinuation • final SUA 5.3 mg/dL (10.4 start)

  8. OxypurinolCompassionate Use Program (CUP) • 1966 - Open label, uncontrolled (N= 533) • data analysis plan written in 2003. • Less than optimal documentation of: • allopurinol intolerance before entry • efficacy and safety (clinical labs) • baseline and post-baseline data • SUA missing data • baseline (32%) • post-baseline (24%) • Patient disposition (28% lost to FU)

  9. Oxypurinol Protocol (OXPL-213) Initiation: 2000 • SUA as surrogate endpoint • Primary analysis: mean change of at least 2 mg/dL • Safety If study successful: post-marketing study for evaluation of meaningful clinical endpoints

  10. OXPL-213Study Design • Prospective, open-label, uncontrolled, dose-escalation • Base study (N=79) for 14 weeks • Extension (A4) (N=48, ongoing) • Entry criteria • Symptomatic hyperuricemia with documented allopurinol intolerance • Exclusion criteria: • Severe prior reaction to allopurinol • Diuretic and uricosuric agents • Creatinine ≥ 2 mg/dL, ALT ≥ 3x ULN

  11. OXPL-213 Oxypurinol Treatment 100 mg/d x first wk, 200 mg/d x second wk and 300 mg/d wk 3 to 6 - If SUA change <2 mg/dL at wk 6, dose up to 600 mg/d - If SUA change < 2mg/dL at wk 9, dose up to 800 mg/d

  12. OXPL-213 Endpoints • SUA level (no central lab) • Baseline (N=3) • Wk 6 • Wk 9 (only those with SUA drop < 2 mg/dL) • End of study (wk 12, 13 & 14) • Landmark analysis • Change from baseline in the ITT population • Decrease of at least 2 mg/dL (lower bound of 95% CI ≥ 2)

  13. OXPL-213 Baseline characteristics • Mean age 61 yr (27 to 83) • 52% male • Mean SUA 10.1 mg/dL (7.7 – 13.7) • Mean Creatinine 1.3 mg/dL (0.8 – 2.2) • Failed prior rechallenge or desensitization (N=26)

  14. OXPL-213 Baseline characteristics • Concomitant medications at entry Colchicine 34 (43) Low dose ASA 5 (6) Diuretics 42 (53) NSAIDS/COX-2 39 (49) N (%)

  15. OXPL-213 Baseline characteristics • History of prior allopurinol intolerance • Skin (63) • Hepatic (7) • Renal (4) • Malaise (6) • Hepatic, renal, malaise (1) • Fever (1)

  16. OXPL-213 Results (SUA) • ITT analysis at wk 14 (N= 79) • Mean change from baseline • 1.78 mg/dL (95% CI 1.47, 2.08) • p < 0.001 (rejects null hypothesis that change = zero) • Completer analysis at wk 14 (N = 54) • Mean change from baseline • 2.32 mg/dL (95% CI 2.07, 2.57)

  17. OXPL-213 Results • Final mean SUA in ITT population: 8.0 mg/dL • Patients who achieved SUA of: ≤ 6 mg/dL ≤ 5 mg/dL ITT (N=79) 10 (13%) 2 (3%) Completers (N=54) 9 (17%) 2 (4%) - No evidence of dose response

  18. OXPL-213Results • Gouty flares: N=12 (15%) • 5 during base study • 4 during open extension • 3 during both base and extension • Tophi complications (N=4) • infection, drainage, pain • Oxypurinol effect or spontaneous flare?

  19. OXPL-213 Deaths Deaths (N=5) • 1 during base study (pancreatic ca.) • 4 during extension • 1 end-stage liver disease • 1 sudden death • 1 GI/COPD • 1 sepsis

  20. OXPL-213Serious Adverse Events (AEs) Base study (14 weeks) • 7 events • 2 MI • 1 CHF (? MI) Extension (ongoing) • 15 events • 1 MI • 1 unstable angina

  21. OXPL-213 Base study Discontinuations N=25 • 16 skin • 1 liver • 1 thrombocytopenia • 1 pancreatic carcinoma (death) • 1 protocol violator • 5 miscellaneous

  22. OXPL-213 Base study Discontinuations(cont’d) • Miscellaneous (N=5) • monitor decision (fever, chills, skin sensitivity, polyarthralgias, viral syndrome) • hypersensitivity NOS • fever, chills, allergic rhinitis • nausea/vomiting • elevation of ALT and BUN /protocol violator

  23. OXPL-213 Base study Discontinuations Summary • 70% skin intolerance • 70% within first wk • Most same as prior intolerance • None of them considered serious

  24. OXPL-213 Base and Extension Re-challenged patients (n=26) Discontinuations Hypersensitivity reactions (N=10, 40%) • 7 base study (5 skin, 1 liver, 1 nausea) • 1 after completion of base study (skin) • 2 during extension (skin) Deaths (N=3) • 1 base study • 2 during extension (1 sepsis, 1 end stage liver disease)

  25. OXPL-213 Summary • 79 enrolled • 54 completed Base study • 48 entered open extension • 37 available in safety population • 10 and 2 patients achieved SUA ≤ 6 mg/dL and ≤ 5 mg/dL, respectively, at 14 wk • 12 had gouty flares (8 in base study)

  26. OXPL-213 Summary Adverse events in base study • No serious hypersensitivity • Similar to prior allopurinol intolerance • 70% within first week (100 mg/day) • 70% skin • Others: liver, thrombocytopenia, “viral syndrome” • Population: • no prior serious intolerance • excluded moderate/severe renal insufficiency

  27. Oxypurinol Challenge Define a population for a favorable risk benefit: • Benefit: modest decrease in SUA • Risk: intolerance

  28. Discussion Points • Value of SUA as a surrogate • change vs. target SUA level? • Additional endpoints: flares? • Eligibility • baseline SUA • concomitant medications/diet • renal insufficiency • Duration • Control group • Safety assessments

More Related