Experience in Acute Gouty Arthritis Studies: Introduction

1
Experience in Acute Gouty Arthritis
StudiesIntroduction

• Agustin Melian, MD
• DirectorClinical ResearchMerck Research
  Laboratories (MRL)

2
Merck Research Laboratorys Experience with Acute
Gout Studies

• 1999 Conceptualize and design studies
• Ralph Schumacher, MD U of Penn and Philadelphia
  VA
• David Daikh, MD, PhD, UCSF and San Francisco VA
• Study 040
• Published 2002 Schumacher et al. British Medical
  Journal. 2002 3241488-92
• Study 049
• Published 2004 Rubin et al. Arthritis
  Rheumatism. February 5, 2004 50 (2) 598-606

3
Agenda

• David Daikh, MD, PhD
• Design Considerations in Acute Gouty Arthritis
  Studies
• Agustin Melian, MD
• Experience with Etoricoxib and Indomethacin in
  Acute Gouty Arthritis
• David Daikh, MD, PhD
• Lessons Learned

4
Sources of Information

• Scientific Literature
• Clinical Experience
• Data from Etoricoxib/Indomethacin Studies

5
Key Points

• In appropriately selected patients, acute gouty
  arthritis is a highly predictable disease
• In the absence of drug intervention, bouts of
  moderate to severe acute gouty arthritis do not
  spontaneously resolve within the first 5 to seven
  days
• Although existing gout medications may have side
  effects, many are highly efficacious and provide
  a highly predictable response

6
Design Considerations in Acute Gouty Arthritis
Studies

• David I. Daikh, MD, PhD
• University of California at San FranciscoSan
  Francisco Veterans Administration

7
Topics

• Pathophysiology and Clinical Expression of
  Disease
• Literature
• Design Issues and Recommendations to Merck
  Research Laboratories
• Control/Comparator
• Patient Selection
• Endpoints
• Timing of Assessments
• Approach to Data Analysis

8
Acute GoutKing of the Diseases, Disease of the
Kings
9
Pathophysiology

• An acute form of peripheral arthritis resulting
  from the deposition of monosodium urate crystals
  in one or more joints
• Most common in first metatarsophalangeal joints
  especially the big toe, heels, ankles and knees
• Causes
• Overproduction of uric acid
• Under excretion of uric acid
• Chronic hyperuricemia is necessary but not
  sufficient for the development of gout
• Usually idiopathic (gt 99) but can be secondary
  to hyperuricemia due to
• Rare inherited metabolic disorders
• High dietary purine content
• Impaired renal urate secretion
• Chronic renal insufficiency of any cause
• Alcohol

10
Diagnostic CriteriaAcute Gout Study

• A) The presence of characteristic urate crystals
  in the joint fluid (if at past attack then C1
  and C4 also)
• Or
• B) A tophus proved to contain urate crystals by
  chemical or polarized light microscope and C1 and
  C4
• Or
• C) Presence of 6 of the following 12 clinical,
  laboratory, and X-ray phenomenon

1) Maximum inflammation developed within 1 day 2)
More than 1 attack of acute arthritis 3) Presents
with monoarticular arthritis 4) Redness is
observed over the affected joint(s) 5) First
metatarsophalangeal pain or swelling 6)
Unilateral first metatarsophalangeal joint attack
7) Unilateral tarsal joint attack 8) Tophus is
suspected 9) Hyperuricemia 10) Asymmetric
swelling within a joint 11) Subcortical cysts
without erosions on X-ray 12) Joint fluid culture
negative for organisms
Wallace et al., Arth and Rheum. 1977 (20)
895-900.
11
Treatment of Gout

• Prevention
• Allopurinol
• Probenecid
• Colchicine
• Diet modification
• Alcohol avoidance
• Medications (diuretics)

• Treatment
• NSAIDs
• Colchicine
• Corticosteroids

12
Previous Studies

• What quantitative information is available on
  natural history of gout to assist in design?

13
Acute Gout Literature Available in 1999 at Time
of MRL Study Design
Drug
No. of Patients
Year
Indomethacin vs. phenylbutazone Indomethacin vs.
proquazone Sulindac vs. phenylbutazone Fenoprofen
vs. phenylbutazone Feprazone vs.
phenylbutazone Indomethacin vs.
meclofenamate Flurbiprofen vs. phenylbutazone Indo
methacin vs. flurbiprofen Observational Indomethac
in allopurinol vs. azapropazone Tenoxicam Colchi
cine vs. placebo Indomethacin vs.
ketoprofen Etodolac vs. naproxen Etodolac vs.
naproxen Indomethacin vs. ketorolac
28 18 47 30 24 20 33 29 11 93 10 43 59 60 61 20
1973 1978 1979 1979 1980 1983 1985 1986 1987 1987
1987 1987 1988 1990 1991 1995
14
Nontreatment Observational Study in Acute Gouty
ArthritisBellamy et al. 1987

• Rationale to serve as natural history data for
  future studies
• Design
• Entry criteria Classical podagra with a prior
  history of acute gout
• Measurements Pain, tenderness, swelling erythema
  and articular skin temperature (0- to 4-point
  scales)
• Observed in an in patient setting with bed rest
  provided
• Baseline characteristics
• Mean time from onset of attack to entry was 2.8
  days (range of 1-5 days)
• Baseline pain was severe to very severe
• Mean pain at entry was 3.73 (SD 0.47)

15
Patient Assessment of Pain in a Nontreatment
Observational Study
4
3
X

X
Pain Severity Mean (SD)

N11
X
2

X

1
Study Day
1
2
3
4
5
6
7
Mean Days since onset of attack
3
4
5
6
7
8
9
P ? 0.05 for comparison with baseline Observed
. Bellamy et al., Br J Clin Pharmacol. 1987
(24)33-36.
16
Patient Assessment of Pain in a Nontreatment
Observational Study
4

3

X



X
Pain Severity Mean (SD)

N11
X
2

X

1
Study Day
1
2
3
4
5
6
7
Mean Days since onset of attack
3
4
5
6
7
8
9
P ? 0.05 for comparison with baseline Observed
, LVCF . Bellamy et al., Br J Clin
Pharmacol. 1987 (24)33-36.
17
Conclusions Nontreatment Observational Study

• Essentially no resolution over first 5 days from
  onset of attack
• Minimal resolution over first 7 days from onset
  of attack

18
Placebo-Controlled Colchicine Study

• Design Patients with podagra
• Study duration 48 hours
• Entry criteria Crystal proven gout
• Observed in an in patient setting with bedrest
  provided
• Measurements
• Pain (100 mm VAS 0 No Pain, 100 Maximal
  Pain)
• Overall clinical score
• Comprised of pain, tenderness, swelling, and
  erythema
• Baseline characteristics
• Mean time from onset of attack to randomization
  was 38 hours
• Estimated mean pain at randomization was 60-70 mm

19
Patient Assessment of PainPlacebo Controlled
Colchicine StudyAhern et al.
80
70
60
50
Placebo (N21)
Pain Score Mean 95CI
40
30
20
Colchicine (N22)
10
Study Days
2.0
0
0.5
1.0
1.5
Mean Days Since Onset of Attack
3.5
1.5
2.0
2.5
3.0
Ahern et al., Aust NZ J Med, 1987, 17 301-304.
20
Literature Supports Conventional Wisdom

• Moderate to severe attacks do not resolve
  spontaneously over first 5 to 7 days
• Little to no placebo effect

21
Issues Considered in the Design of Gout Studies

• Control/comparator
• Placebo versus active comparator control
• If active comparator, what comparator is
  appropriate
• Patient selection
• Endpoints
• Timing of assessments

22
Design Issue Active vs. Placebo Control

• Placebo control
• Pros
• Could simplify interpretation of results
• Cons
• Patients and referring physicians understand how
  painful the disease is and know that standard
  medications work
• Extremely difficult/impossible to enroll
• Is it ethical to withhold treatment when
  effective therapy is available?
• Dropouts due to patients who need to rescue may
  confound analysis
• May require an in-patient study due to compliance
  issues

23
Design Issue Active vs. Placebo Control

• Active comparator control
• Pros
• Standard therapies (NSAIDs, corticosteroids, to a
  lesser extent colchicine) known to be highly
  efficacious and are readily available
• More humane does not withhold therapy from
  patients in need
• Minimizes enrollment/dropout concerns to make a
  short-term, acute study possible
• Cons
• More complex statistical requirements
• Demonstration of assay sensitivity
• Assignment of clinically meaningful comparability
  bounds

24
Design Issue Active vs. Placebo Control
Recommendation to MRL

• Active comparator control study
• Cons of active comparator control are manageable
  while those of a placebo control are not
• Indomethacin 50 mg TID as the active comparator
• FDA approved treatment for acute gout
• Clinical gold standard
• Most commonly prescribed treatment for acute gout
• IMS database
• Most often used active comparator

25
Design Issue and Recommendations Endpoints

• Endpoints should assess key characteristics of
  the disease process as well as a global
  assessment of response to therapy
• Primary
• Pain Symptom of primary importance to patients
• Secondary
• Tenderness
• Swelling
• Global assessments by both patients and
  investigator
• Exploratory
• Erythema More difficult to assess

26
Design Issue and RecommendationsPatient
Selection

• Should a minimum degree of pain be required?
• Patients with mild disease may resolve more
  quickly
• Need minimum degree of pain to observe treatment
  effect
• Recommendation Patients should require moderate,
  severe, or extreme pain at baseline
• Should maximum amount of time since onset be
  mandated?
• Need to balance time required to seek medical
  advice versus the time to spontaneous resolution
• Recommendation Enroll within 2 days of the onset
  of an attack

27
Design Issue and RecommendationsPatient
Selection (Contd)

• Can patients who self medicated prior to
  enrollment be randomized?
• Prior Treatment will confound study results
• Recommendation
• No NSAIDs or corticosteroids taken for the
  current attack
• Patients on stable preventive therapy allowed to
  enroll (e.g., colchicine, allopurinol)

28
Design Issue Timing of Assessments

• Primary assessment should integrate response
  across a clinically relevant time period
• Need to choose time in which spontaneous
  resolution unlikely
• Additional assessment of pain should evaluate a
  typical treatment period
• Limited information regarding onset of treatment
  effect
• Onset of effect in this disease might take longer
  than other acute analgesia models due to highly
  inflammatory nature of disease

29
Recommendations Timing of Assessments

• Primary time period over Study Days 2-5
• Spontaneous resolution unlikely during this time
  period
• Secondary time period over Study Days 2-8
• A 7-day treatment period is typical for patients
  with acute gouty arthritis
• Onset of treatment effect should be explored
• Collect Assessment of Pain at 4 hours after
  initial dose on Day 1

30
Assessment of Assay Sensitivity (Is Indomethacin
Effective?)

• Clinical (qualitative) approach If the observed
  response is consistent with clinical
  expectations then the effect is attributed to
  the treatment
• Indomethacin is a reliable, approved comparator
• Gold standard for treatment
• Predictable response
• Gouty attacks do not resolve spontaneously over 5
  days, especially in patients with moderate to
  severe disease
• Placebo effect is small
• Quantitative approach
• Set a boundary for response which indomethacin
  must exceed
• Need sufficient data from literature to determine
  magnitude of indomethacin effect
• No precedent for setting the minimal effect size

31
Recommendation Assessment of Assay Sensitivity
(Was Indomethacin Effective?)

• Clinical approach is acceptable
• Quantitative approach include as supportive

32
Assessment of Clinical Comparability (Is the
Test Drug Effective?)

• Approach Set a boundary for difference from
  indomethacin which study drug must fall within
• This needed to be based on
• Clinical judgment
• Extrapolation from other conditions

33
Recommendation Comparability Bounds (Was the
Test Drug Effective?)

• Boundary set at 0.5 for 0- to 4-point scale
• More stringent than Delphi consensus for OA
• 0.7 on a 0- to 4-point Likert Scale
• Consistent with judgment of clinically relevant
  magnitude of effect on an individual patient
  basis

34
Analysis of Statistical Equivalence Between
Treatments Test Drug vs. Active Comparator
Baseline Value
Upper Bound of Clinical
0
Equivalence
0.5
-0.5
-1.0
Mean Difference Over Days 2-5 Test Drug
Minus Comparator
-1.5
0
Between Group Difference
Change from Baseline
-2.0
95 CI
-2.5
-3.0
-0.5
Lower Bound of Clinical
-3.5
Equivalence
-4.0
Randomization
Day 4
Day 2
Day 3
Day 5
35
Summary of Recommendations Design Issues

• The study of treatment effects in acute gout
  presents a number of formidable challenges
• Relative paucity of data in the literature likely
  reflects these challenges
• Key design issues
• Active vs. placebo control
• Challenges of comparator control manageable while
  those of a placebo control were not
• Endpoints
• Choose those that define the disease
• Timing of Assessments
• Choose period least likely to be affected by
  spontaneous resolution

36
Experience with Etoricoxib and Indomethacin in
Acute Gouty Arthritis

• Agustin Melian, MD
• DirectorClinical ResearchMerck Research
  Laboratories (MRL)

37
Study Schema for Protocols 040 and 049
Etoricoxib 120 mg QD (N80)
48 Hours Maximum
Indomethacin 50 mg TID (150 mg Daily) (N80)
Screen/ Randomize/Dose
Onset of Attack
Study Day
8
R/1
2
5
Days SinceOnset of Attack
7-9
0-2
1-3
4-6
38
Efficacy Hypotheses

• Primary
• Etoricoxib 120 mg will demonstrate clinical
  efficacy comparable with indomethacin 150 mg in
  the treatment of acute gout over 4 days (Days
  2-5) as evaluated by Patients Assessment of Pain
• Secondary
• Etoricoxib 120 mg will demonstrate clinical
  efficacy comparable with indomethacin 150 mg in
  the treatment of acute gout over 7 days (Days
  2-8) as evaluated by Patients Assessment of Pain

39
Endpoints

• Primary
• Patients Assessment of Pain (0- to 4-Likert
  Scale None to Extreme)
• Primary time period Days 2-5
• Secondary time period Days 2-8
• Exploratory time period 4 hours after the
  initial dose (Day 1)
• Key Secondary
• Patients Global Assessment of Response to
  Therapy (0- to 4-Likert Scale Poor to Excellent)
• Investigators Global Assessment of Response to
  Therapy (0- to 4-Likert Scale None to Excellent)
• Assessment of Study Joint Tenderness (0- to
  3-point scale No Pain to Pain, Winces, and
  Withdraws)

40
Endpoints (Contd)

• Other Secondary
• Investigators Assessment of Study Joint Swelling
  (0- to 3-point scale None to Bulging beyond
  joint margins)
• Proportion of Patients Discontinuing Due to Lack
  of Efficacy
• Exploratory
• Proportion of Patients Exhibiting Erythema of the
  Study Joint (Present/Absent/Not Assessable)

41
Endpoint AssessmentsTiming
8
R/1
2
5
3
4
6
7
Study Day
4 hrs
x
x
x
x
x
x
x
x
x
Pain Assessment
Patients Global Investigators Global
x
x
x
Study Joint Tenderness Study Joint
Swelling Study Joint Erythema
x
x
x
x
42
Selection Criteria

• Randomized within 48 hours of attack onset
• Met Wallace Criteria for diagnosis for acute gout
• Moderate, severe, or extreme pain
• Patients who took NSAIDs/COXIBs/corticosteroids
  to treat current attack were excluded
• Stable baseline gout meds (e.g., colchicine,
  allopurinol)

43
Enrollment Characteristics
Protocol 040
Protocol 049
of Patients Randomized
N150
N189
Total of Study Centers of Centers Who
Enrolled ?1 Patient Number of Countries
Participated
43 31 11
58 42 10
44
Baseline CharacteristicsProtocols 040 and 049
Combined
45
Other Baseline Disease CharacteristicsProtocols
040 and 049 Combined
Indomethacin150 mg
Etoricoxib120 mg
Total
Randomized
N161
N178
N339
Disease type () Monoarticular
gout Polyarticular gout Baseline pain
() Moderate Severe Extreme Mean baseline pain
(Likert) Time from onset to randomization
() Day of onset 1 Day 2 Days (within 48
hours)
72.0 28.0 20.8 50.9 24.5 3.00 16.7 64.6 18.6
71.3 28.7 33.3 45.8 20.9 2.88 16.3 64.6 19.1
71.7 28.3 27.7 49.7 22.6 2.94 16.5 64.6 18.9
46
Patient Disposition Protocols 040 and 049
Combined
47
Patient Assessment of PainMean Change From
BaselineProtocol 040
? Indomethacin 50 mg TID
LS Least squares. SE Standard error.
48
Patient Assessment of PainMean Change From
BaselineProtocol 040 and Observational Study
? Indomethacin 50 mg TID
? Observational Study
LS Least squares. SE Standard error.
49
Patient Assessment of PainMean Change From
BaselineProtocol 040 and Observational Study
? Indomethacin 50 mg TID
? Observational Study
LS Least squares. SE Standard error.
50
Patient Assessment of PainMean Change From
BaselineProtocol 040 and Observational Study
? Indomethacin 50 mg TID
? Observational Study
? Etoricoxib 120 mg
LS Least squares. SE Standard error.
51
Patient Assessment of PainMean Change From
BaselineProtocols 040 and 049 and Observational
Study
? Indomethacin 50 mg TID
? Observational Study
? Etoricoxib 120 mg
LS Least squares. SE Standard error.
52
Consistent Efficacy Demonstrated in Secondary
Endpoints Across Two Studies
LS Least squares. SE Standard error. (0 to
3-point Scale).
53
Percentage of Patients with Good/Excellent
Response Protocols 040 and 049
Patient Global Assessment of Response to Therapy
Investigator Global Assessment of Response to
Therapy
Indomethacin 50 mg TID
Etoricoxib 120 mg
54
Percentage of Patients with Erythema of the Study
JointProtocols 040 and 049
Etoricoxib 120 mg
Indomethacin 50 mg TID
55
Demonstration of Assay SensitivityClinical
(Qualitative) Approach

• Indomethacin the gold standard performs as
  expected based on clinical experience
• There was marked improvement in pain and other
  clinical parameters in patients treated with
  indomethacin
• Treatment effects were rapid Seen within 4 hours
• The majority of improvement occurs within the
  first 24-48 hours
• By day 2 (the second day of dosing) the majority
  of patients experienced a clinically meaningful
  response

56
Demonstration of Assay Sensitivity Quantitative
Approach

• Indomethacin change from baseline in ketoprofen
  study
• Only study with pain on a Likert and associated
  variability
• Note 0-3 Likert Scale re-scaled on 0- to 4-point
  Likert Scale
• FDA guidance 1988 Guidelines for the Clinical
  Evaluation of Anti-Inflammatory Antirheumatic
  Drugs
• 60 of effect size in active comparator studies
  lacking placebo recommended
• Criteria Upper 95 confidence limit of
  indomethacin mean change from baseline over 5
  days needs to be -1.46 or better

57
Indomethacin Treatment EffectPatient Assessment
of Pain LS Mean Change and 95 CI 0- to 4-point
Likert Scale
The prespecified benchmark of -1.46 for the LS
mean change, used for defining a 'response' in
the indomethacin group is indicated by a dotted
line.
58
Comparability Assessment Patient Assessment of
Pain LS Mean Change and 95 CI
Favors Indomethacin
Favors Etoricoxib
The prespecified comparability bounds of 0.5 for
containing the 95 CI for between-group
differences are indicated as dotted lines.
59
Conclusions

• This acute gout study design is robust
• Indomethacin performs reliably and as expected in
  our studies
• Endpoints are highly reproducible between studies
  and results are consistent across endpoints
• In replicate studies, etoricoxib and indomethacin
  performed comparably based on predefined criteria
• Meaningful results can be obtained in the absence
  of placebo

60
Lessons Learned

• David I. Daikh, MD, PhD
• University of California at San FranciscoSan
  Francisco Veterans Administration

61
Lessons Learned andPotential Future Design
Considerations

• Lessons learned
• Recruitment was very difficult even though it was
  not a placebo-controlled trial
• Potential considerations for future studies
• Collect additional onset data
• May be beneficial to evaluate earlier times
• Explore use of pain measurement over multiple,
  early time points
• Explore use of stop watch
• Explore use of alternative scales to enhance
  precision
• 0- to 10-point Numeric Rating Scale
• 10 cm Visual Analog Scale
• Consider adding a physical function measure