# Presentation: 077138

## 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
- 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

## 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*

## 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

## 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

## 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

## Proposed Patient Reported Outcomes for Chronic Gout Treatment

- Jane T. Osterhaus, PhD

## 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)

## 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

## 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

## Disease-Specific Arthritis Measure

- Health Assessment Questionnaire - disability index (HAQ-DI)
- 8 domains (dressing & grooming, arising, eating, walking, hygiene, reach, grip, activities)
- 20 items

## 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

## 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

## 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