Gout: Clinical review and trial design issues

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GoutClinical review and trial design issues

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

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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

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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

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Acute gout contd

• 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)

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Trial design considerations
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General Trial Design Informationhttp//www.fda.go
v/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 3571191)

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Acute Gout

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

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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

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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

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Acute gout

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

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Placebo controlled trials?

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

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Approaches with Placebo

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

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Alternatives to placebo controlled trials

• Active comparator and superiority
• Dose controlled studies

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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.

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Domains

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

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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)

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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

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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

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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

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Additional Trial Considerations

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

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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

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Areas for Discussion

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

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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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