Acute Gouty Arthritis

1
Experience in Acute Gouty Arthritis Studies:
Introduction
Agustin Melian, MD
Director
Clinical Research
Merck Research Laboratories (MRL)

2
Merck Research Laboratory’s 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; 324:1488-92
 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 Francisco
San 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
Henry VIII
B. Franklin
W. Churchill
O. Welles
Acute Gout:
King 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 (> 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 Criteria†
Acute 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
Indomethacin vs. phenylbutazone
Indomethacin vs. proquazone
Sulindac vs. phenylbutazone
Fenoprofen vs. phenylbutazone
Feprazone vs. phenylbutazone
Indomethacin vs. meclofenamate
Flurbiprofen vs. phenylbutazone
Indomethacin vs. flurbiprofen
Observational
Indomethacin + allopurinol vs. azapropazone
Tenoxicam
Colchicine 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
No. of Patients Year
1973
1978
1979
1979
1980
1983
1985
1986
1987
1987
1987
1987
1988
1990
1991
1995

14
Nontreatment Observational Study in
Acute Gouty Arthritis
Bellamy 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
P  0.05 for comparison with baseline: Observed = *. Bellamy et al., Br J Clin Pharmacol. 1987 (24):33-36.
3
2
1
X
Observed
4
1 2 3 4 5 6 7
X
X
X
*
*
*
*
3 4 5 6 7 8 9
N=11
Pain
Severity
Mean
(SD)
Study Day
Mean Days since
onset of attack

16
in a Nontreatment Observational Study
P  0.05 for comparison with baseline: Observed = *, LVCF = †. Bellamy et al., Br J Clin Pharmacol. 1987 (24):33-36.
Pain
Severity
Mean
(SD)
Study Day
3
2
1
X
Observed
LVCF
4
1 2 3 4 5 6 7
X
X
X
†
†
†
†
*
*
*
*
3 4 5 6 7 8 9
Mean Days since
onset of attack
N=11

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
Placebo Controlled Colchicine Study
Ahern et al.
Study Days 2.0
Placebo (N=21)
Colchicine (N=22)
Pain
Score
Mean
±
95%CI
0 0.5 1.0 1.5
70
80
60
50
40
30
20
10
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
 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
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 Recommendations:
Patient 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 Recommendations:
Patient Selection (Cont’d)
 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
Change
from
Baseline
Baseline Value
Randomization
Mean Difference
Over Days 2-5:
Test Drug Minus
Comparator 95% CI
0
Upper Bound of Clinical
Equivalence
Lower Bound of Clinical
Equivalence
0.5
-0.5
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0
Day 4
Day 2 Day 3 Day 5
Between
Group
Difference

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
Director
Clinical Research
Merck Research Laboratories (MRL)

37
Study Schema for Protocols 040 and 049
Etoricoxib 120 mg QD (N~80)
Indomethacin 50 mg TID (150 mg Daily) (N~80)
Screen/
Randomize/
Dose
Study Day 8
48 Hours
Maximum
R/1 2 5
Onset of
Attack
7-9
0-2 1-3 4-6
Days Since
Onset of Attack

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 Patient’s
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 Patient’s
Assessment of Pain

39
Endpoints
 Primary
– Patient’s 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
– Patient’s Global Assessment of Response to Therapy (0- to 4-
Likert Scale; Poor to Excellent)
– Investigator’s 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 (Cont’d)
 Other Secondary
– Investigator’s 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 Assessments:
Timing
Study Day 8
R/1 2 5
Pain Assessment
Patient’s Global
Investigator’s Global
Study Joint Tenderness
Study Joint Swelling
Study Joint Erythema
3 4 6 7
x x x x x x x x x
x x x
x x x x
4 hrs

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
# of Patients Randomized
Total # of Study Centers
# of Centers Who Enrolled 1 Patient
Number of Countries Participated
Protocol 040
N=150
43
31
11
Protocol 049
N=189
58
42
10

44
Baseline Characteristics
Protocols 040 and 049 Combined
# Randomized
Mean age (years)
Men (%)
Race (%)
White
Black
Asian
Hispanic
Other
Indomethacin
150 mg
N=161
50.9
91.3
44.1
6.8
22.4
18.0
8.7
Etoricoxib
120 mg
N=178
50.0
96.1
46.1
6.2
22.5
18.5
6.7
Total
N=339
50.5
93.7
45.1
6.5
22.4
18.3
7.7

45
# Randomized
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)
Indomethacin
150 mg
N=161
72.0
28.0
20.8
50.9
24.5
3.00
16.7
64.6
18.6
Etoricoxib
120 mg
N=178
71.3
28.7
33.3
45.8
20.9
2.88
16.3
64.6
19.1
Other Baseline Disease Characteristics
Total
N=339
71.7
28.3
27.7
49.7
22.6
2.94
16.5
64.6
18.9

46
178 Randomized
to Etoricoxib
161 Randomized
to Indomethacin
8 (4.5%)
Discontinued Due to
Lack of Efficacy
9 (5.6%)
Discontinued Due to
Lack of Efficacy
7 (3.9%)
Discontinued Due to
Clinical AE
13 (8.1%)
Discontinued Due to
Clinical AE
1 (0.6%)
Discontinued Due to
Laboratory AE
0 (0.0%)
Discontinued Due to
Laboratory AE
3 (1.7%)
Discontinued Due to
Other Reasons*
7 (4.3%)
Discontinued Due to
Other Reasons*
159 (89.3%)
Completed Trial
132 (82%)
Completed Trial
Patient Disposition

47
Mean Change From Baseline
Protocol 040
LS = Least squares. SE = Standard error.
 Indomethacin 50 mg TID
0 1 2 3 4 5 6 7 8 9
Mean Days Since Onset of Attack
-3
-2
-1
0
LS
Mean
Change

SE
040

48
Protocol 040 and Observational Study
 Indomethacin 50 mg TID  Observational Study
0 1 2 3 4 5 6 7 8 9
-3
-2
-1
0
LS
Mean
Change

SE
040

49
0 1 2 3 4 5 6 7 8 9
-3
-2
-1
0
LS
Mean
Change

SE
040

50
 Etoricoxib 120 mg
0 1 2 3 4 5 6 7 8 9
-3
-2
-1
0
LS
Mean
Change

SE
040

51
Protocols 040 and 049 and Observational Study
 Etoricoxib 120 mg
0 1 2 3 4 5 6 7 8 9
e10C.4049.cindyw May 25, 2004
049
alt slide 5
0 1 2 3 4 5 6 7 8 9
-3
-2
-1
0
LS
Mean
Change

SE
040

52
Consistent Efficacy Demonstrated in Secondary
Endpoints Across Two Studies
 Etoricoxib 120 mg  Indomethacin 50 mg TID
LS = Least squares. SE = Standard error. (0 to 3-point Scale).
-3
-2
-1
0
LS
Mean
Change

SE
049
040
Tenderness
0 1 2 5 8
-3
-2
-1
0
Etoricoxib
0 1 2 5 8
e130.210.4049.cindyw May 25, 2004
Indomethacin
Swelling

53
Percentage of Patients with Good/Excellent Response
Protocols 040 and 049
Etoricoxib 120 mg Indomethacin 50 mg TID
Patient Global
Assessment of
Response to Therapy
Investigator Global
Assessment of
Response to Therapy
0
50
100
040 049
2 5 8
0
50
100
Percent
of
Patients
with
Good/Excellent
Response
2 5 8
e110e120Bars4049 May 25, 2004

54
Percentage of Patients with Erythema of the Study Joint
Protocols 040 and 049
Etoricoxib 120 mg Indomethacin 50 mg TID
1 2 5 8
0
20
40
60
80
100
Percentage
of
Patients
with
Erythema
040
1 2 5 8
ery.byplot.4049.cindyw May 25, 2004
049

55
Demonstration of Assay Sensitivity
Clinical (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 Effect
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.
040 049
Average Over Study Days 2 to 5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
LS
Mean
and
95%
CI
indo10.4049.cindyw May 20, 2004
-1.46=

58
Comparability Assessment: Patient Assessment of Pain
LS Mean Change and 95% CI
The prespecified comparability bounds of ±0.5 for containing the 95% CI for between-group differences are indicated
as dotted lines.
Favors
Etoricoxib
Favors
Indomethacin
-0.7
-0.5
-0.3
-0.1
0.1
0.3
0.5
0.7
LS
Mean
Difference
and
95%
CI
040
Average
Over
Study Days
2 - 5
Average
Over
Study Days
2 - 8
e.diffA.10.4049B May 25, 2004
049
Average
Over
Study Days
2 - 5
Average
Over
Study Days
2 - 8

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 Francisco
San Francisco Veterans Administration

61
Lessons Learned and
Potential 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

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