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Arthritis Drugs Advisory Committee TAP Pharmaceutical Products Inc. June 2, 2004

Arthritis Drugs Advisory Committee TAP Pharmaceutical Products Inc. June 2, 2004. Hyperuricemia and Chronic Gout. Nancy Joseph-Ridge, MD Therapeutic Area Head, Rheumatology/Internal Medicine. Management of Hyperuricemia. Treatment of hyperuricemia is indicated for Gout Tophaceous gout

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Arthritis Drugs Advisory Committee TAP Pharmaceutical Products Inc. June 2, 2004

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  1. Arthritis Drugs Advisory CommitteeTAP Pharmaceutical Products Inc.June 2, 2004

  2. Hyperuricemia and Chronic Gout Nancy Joseph-Ridge, MD Therapeutic Area Head, Rheumatology/Internal Medicine

  3. Management of Hyperuricemia • Treatment of hyperuricemia is indicated for • Gout • Tophaceous gout • Renal calculi due to uric acid • Goal - reduce and maintain serum urate < 6.0 mg/dl NEJM 334(7): 445-451, 1996; . Ruddy: Kelley’s Textbook of Rheumatology 6th ed. Chapter 89: 1339-1348. 2001 Harrison’s Principles of Internal Medicine 14th ed. Part Thirteen, Chapter 344: 2158-2165, 1998. Goldman:Cecil Textbook of Medicine 21st ed. Chapter 299, 1542-1548, 2000. Rheumatic Disease Clinics of NA. 26(3): 1-11, 2000

  4. Management of Hyperuricemia • Treatment of hyperuricemia with allopurinol (2-10 years) • 57 subjects studied prospectively for 10 years • Serum UA < 6.0 mg/dl was associated with • Reduction in tophus size • Fewer crystals in joint fluid aspirates • Fewer gout attacks over 2 years JRheum 28(3):577-580,2001

  5. Recent Publication on Urate Lowering Agents and Reduction of Tophi • 63 patients treated with allopurinol, benzbromarone, or both • Tophi measured using calipers • Mean duration until tophi resolution 20.8±10.2 months • Resolution rates and serum urate levels: • Allopurinol: 0.57 ± 0.18*mm/month, 5.37 ± 0.79 mg/dL • Benzbromarone: 1.21 ± 0.67 mm/month; 4.22 ± 1.01 mg/dL • Combined: 1.53 ± 0.45 mm/month; 3.97 ± 0.76 mg/dL *P<0.01; Arth and Rheum (Arth Care & Res), 47(4):356-360, 2002

  6. Clinical Trial Design • Primary Endpoint – maintenance of reduction in serum urate < 6.0 mg/dL • Secondary Endpoints – clinical • Tophi reduction • Reduction in Gout Flares • Inclusion of comparator • e.g., allopurinol and/or placebo • Minimally demonstrate equivalence to comparator • Consider safety dose • e.g., 2 x maximum clinical dose

  7. Clinical Trial Design – Cont’d • Long Term Controlled Clinical Studies • One study at least 1 year duration • Study Population • Inclusion of subjects with renal impairment and other co-morbidities • A proportion of subjects with high baseline serum urate

  8. Proposed Patient Reported Outcomes for Chronic Gout Treatment Jane T. Osterhaus, PhD

  9. Humanistic Burden of gout deserves better understanding • Renewed interest in gout treatments • Prevalence of gout expected to increase • Aging population • Obesity • Type 2 diabetes mellitus • Patient Reported Outcomes (PROs) are an important source of information (HRQOL, functional status, work productivity)

  10. No existing guidance on PROs for gout clinical trials • Gout is a chronic disease with bothersome symptoms (pain, swelling, tophi) • Reasonable to consider measuring: • Functioning • Well-being • Symptom relief • Satisfaction with treatment

  11. General Health Status Measures to include in chronic gout clinical trials • SF-36 • 8 general domains • Reliable & valid • Used in randomized controlled trials in various therapeutic areas • Allow comparisons across conditions

  12. Disease-Specific Arthritis Measure • Health Assessment Questionnaire - disability index (HAQ-DI) • 8 domains (dressing & grooming, arising, eating, walking, hygiene, reach, grip, activities) • 20 items

  13. Disease-Specific Aspects of Gout • No gout-specific PRO in the literature • Focuses on specific aspects of condition not captured in general assessments, but still important to patients • TAP has developed Gout Assessment Questionnaire (GAQ) • 21 items • 7 domains • Gout Concern • Well-Being • Productivity • Gout Pain and Severity • Treatment Satisfaction • Treatment Convenience • Treatment Bother

  14. Current Status of GAQ • Good internal consistency • Adequate reliability (for initial use) • Ongoing: • Confirm scales • More experience in different gout populations • Understand relationship with clinical measures • Understand change over time

  15. Timing of measures • Initiation of therapy may result in more acute gout flares • May take up to 1 year for total body urate load to decrease to normal • Evaluate longer term data when considering impact of gout treatment from patients perspective

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