# Presentation: 712851

## Gout:Clinical review and trial design issues

- Joel Schiffenbauer
- FDA/DAAODP
- AAC/June 3, 2004

## 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

## 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

## 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

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## Standard approaches to therapy

- Acute gout
- NSAID- several approved
- Colchicine-approved
- Corticosteroids (approved) and ACTH (not approved)

## Trial design considerations

## 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)

## Acute Gout

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

## 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

## 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

## Acute gout

**Superiority vs non-inferiority: **
**Superiority to placebo: preferable but **
**are placebo controlled trials ethical? **

## Placebo controlled trials?

- Pain severity in gout
- Baseline VAS pain scores show little difference from other pain studies

## Approaches with Placebo

**Rescue**
**With time to treatment failure as primary endpoint: early escape design reduces exposure to sub-optimal therapy**

## Alternatives to placebo controlled trials

**Active comparator and superiority**
**Dose controlled studies **

## 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.**

## Domains

- Pain
- Inflammation
- Function
- Patient/physician global assessment of disease/treatment
- HRQOL

## 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)**

## 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**

## 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**

## 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**

## Additional Trial Considerations

**Concomitant medications: **
**other NSAIDs **
**other pain meds**
**low dose ASA (renal clearance)**
**diuretics**
**alternative therapies**
**Diet and alcohol intake**

## 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**

## Areas for Discussion

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

## 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

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