1. Gout : Clinical review and trial design issues Joel Schiffenbauer FDA/DAAODP AAC/June 3, 2004

2. Gout Caused by deposition of monosodium urate crystals around and in the tissues of the joint Three distinct stages: a)asymptomatic hyperuricemia; b)acute intermittent gout; c)chronic tophaceous gout

3. Acute intermittent gout Initial episode usually follows decades of asymptomatic hyperuricemia Characterized by intense pain and inflammation (warmth, swelling, erythema) Usually begins as monoarticular involvement with first MTP joint

4. Acute gout cont’d Natural course varies with improvement/resolution in days to one to two weeks During intercritical periods joints are virtually free of symptoms although crystal may be found

7. Standard approaches to therapy Acute gout –NSAID- several approved –Colchicine-approved –Corticosteroids (approved) and ACTH (not approved)

8. Trial design considerations

9. General Trial Design Information http://www.fda.gov/cder/guidance ICH E9: Statistical principles for clinical trials ICH E10: Choice of control group and related issues in clinical trials RA guidance OA guidance CONSORT (Consolidated Standards of Reporting Trials) recommendations (Lancet 2001; 357:1191)

10. Acute Gout Gout is –a unique medical disorder that deserves specific studies and its own labeled indication OR –a model of acute pain

11. Diagnostic criteria Is documentation of crystals critical? –At time of flare? –Any previous documentation? Are clinical criteria sufficient to serve as entry criteria into trial? For example, ACR classification of acute gouty arthritis in which 6/12 clinical/lab/x-ray criteria may be utilized

12. Some ACR clinical criteria More than one attack of acute arthritis Maximal inflammation developed within one day Attack of monoarticular arthritis First MTP joint painful or swollen Suspected tophus Hyperuricemia

13. Acute gout Superiority vs non-inferiority: –Superiority to placebo: preferable but are placebo controlled trials ethical?

14. Placebo controlled trials? Pain severity in gout Baseline VAS pain scores show little difference from other pain studies

15. Approaches with Placebo Rescue –With time to treatment failure as primary endpoint: early escape design reduces exposure to sub-optimal therapy

16. Alternatives to placebo controlled trials Active comparator and superiority Dose controlled studies

17. Alternatives to placebo controlled trials Active comparator and non-inferiority –If non-inferiority which comparator (dosing intervals) and what is non-inferiority margin? –Are there historical adequately controlled trials and of similar design to support non-inferiority studies? –If no placebo and non-inferiority, issue of sensitivity of trial- how do we know that any drug works? Pain resolves spontaneously.

18. Domains Pain Inflammation Function Patient/physician global assessment of disease/treatment HRQOL

19. Acute gout Primary outcome –What is the value of reduction in pain as the primary outcome? pain (PID, PR, time to onset, time to re- medication, multi-dose efficacy etc) –Is there value in additional endpoints beyond pain? inflammation (measures of inflammation may be difficult to standardize)

20. Outcomes –Rescue: time to rescue; number using rescue in 24/48 hours etc –Time to complete/80%/50% resolution –Responder index such as number of subjects with good to excellent pain relief in XX time

21. Acute Gout Endpoints When to measure response to therapy? first hour ? first 8 hours? first 24 hours? over one week? Time weighted average? Or a combination of the above

22. Additional Trial Considerations Is there value in stratification by: – renal function –by uric acid level –by tophi –by number of joints involved-polyarticular vs mono-articular

23. Additional Trial Considerations Concomitant medications: –other NSAIDs –other pain meds –low dose ASA (renal clearance) –diuretics –alternative therapies Diet and alcohol intake

24. Additional Trial Considerations Single vs multiple dose efficacy How long attack present before randomization? Previous therapy allowed? Withdrawal of previous therapy associated with flare Acute on chronic

25. Areas for Discussion Inclusion/exclusion criteria Superiority vs non-inferiority: placebo control Domains to study Outcome measures and timing Other issues: stratification, concomitant medications

26. Conclusions Gout is a common disorder New therapies that provide improved risk- benefit ratio should be studied and added to the armamentarium Rigorous trial design is needed