GoutGout::Clinical review and trial Clinical review and trial

design issuesdesign issues

Joel SchiffenbauerJoel SchiffenbauerFDA/DAAODPFDA/DAAODP

AAC/June 3, 2004AAC/June 3, 2004

GoutGout

• 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 goutAcute 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’dAcute 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

Standard approaches to therapyStandard approaches to therapy

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

approved)

Trial design considerationsTrial design considerations

General Trial Design InformationGeneral Trial Design Informationhttp://www.fda.gov/cder/guidancehttp://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 GoutAcute Gout

• Gout is – a unique medical disorder that deserves

specific studies and its own labeled indication

OR– a model of acute pain

Diagnostic criteriaDiagnostic 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 criteriaSome 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 goutAcute gout

• Superiority vs non-inferiority: – Superiority to placebo: preferable but

• are placebo controlled trials ethical?

Placebo controlled trials?Placebo controlled trials?

• Pain severity in gout

• Baseline VAS pain scores show little difference from other pain studies

Approaches with PlaceboApproaches with Placebo

• Rescue– With time to treatment failure as primary

endpoint: early escape design reduces exposure to sub-optimal therapy

Alternatives to placebo controlled Alternatives to placebo controlled trialstrials

• Active comparator and superiority

• Dose controlled studies

Alternatives to placebo controlled Alternatives to placebo controlled trialstrials

• 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.

DomainsDomains

• Pain

• Inflammation

• Function

• Patient/physician global assessment of disease/treatment

• HRQOL

Acute goutAcute 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)

OutcomesOutcomes

– 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 EndpointsAcute 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 ConsiderationsAdditional 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 ConsiderationsAdditional Trial Considerations

• Concomitant medications: – other NSAIDs – other pain meds– low dose ASA (renal clearance)– diuretics– alternative therapies

• Diet and alcohol intake

Additional Trial ConsiderationsAdditional 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 DiscussionAreas for Discussion

• Inclusion/exclusion criteria

• Superiority vs non-inferiority: placebo control

• Domains to study

• Outcome measures and timing

• Other issues: stratification, concomitant medications

ConclusionsConclusions

• 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