Transcript Gout : Clinical review and trial design issues

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
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
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•
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
•
•
•
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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 remedication, 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 riskbenefit ratio should be studied and added
to the armamentarium
• Rigorous trial design is needed