# Presentation: 052840

## Experience in Acute Gouty Arthritis Studies:Introduction

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

## 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

## 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

## Sources of Information 

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

## 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

## Design Considerations in Acute Gouty Arthritis Studies

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

## 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

## Acute Gout:King of the Diseases, Disease of the Kings

- Acute Gout:King of the Diseases, Disease of the Kings

## 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

## 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.

## Treatment of Gout

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

**Treatment**
-  NSAIDs
-  Colchicine
-  Corticosteroids

## Previous Studies

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

## 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

## 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)

## 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**

- 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

## Patient Assessment of Pain 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**

- 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**

## 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

## 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

## Patient Assessment of Pain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.

## Literature Supports Conventional Wisdom

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

## 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

## 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

## 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

## 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

## 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

## 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

## 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)

## 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

## 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

## 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

## Recommendation: Assessment of Assay Sensitivity (Was Indomethacin Effective?)

- Clinical approach is acceptable
- Quantitative approach – include as supportive

## 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

## 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

## Analysis of Statistical Equivalence Between Treatments: Test Drug vs. Active Comparator

- 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

## 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

## Experience with Etoricoxib and Indomethacin in Acute Gouty Arthritis

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

## 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 SinceOnset of Attack

## 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

## 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)

## 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)

## 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

## 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)

## 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

## Baseline CharacteristicsProtocols 040 and 049 Combined

- Baseline CharacteristicsProtocols 040 and 049 Combined

## Other Baseline Disease CharacteristicsProtocols 040 and 049 Combined

- # 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)

- Indomethacin150 mg

- N=161

- 72.0
- 28.0
- 20.8
- 50.9
- 24.5
- 3.00
- 16.7
- 64.6
- 18.6

- Etoricoxib120 mg

- N=178

- 71.3
- 28.7
- 33.3
- 45.8
- 20.9
- 2.88
- 16.3
- 64.6
- 19.1

- Other Baseline Disease CharacteristicsProtocols 040 and 049 Combined

- Total

- N=339

- 71.7
- 28.3
- 27.7
- 49.7
- 22.6
- 2.94
- 16.5
- 64.6
- 18.9

## Patient Disposition  Protocols 040 and 049 Combined

- Patient Disposition  Protocols 040 and 049 Combined

## Patient Assessment of PainMean Change From BaselineProtocol 040 

- LS = Least squares.  SE = Standard error.

**** Indomethacin 50 mg TID

## Patient Assessment of PainMean Change From BaselineProtocol 040 and Observational Study

**** Indomethacin 50 mg TID

**** Observational Study

- LS = Least squares.  SE = Standard error.

## Patient Assessment of PainMean Change From BaselineProtocol 040 and Observational Study

**** Indomethacin 50 mg TID

**** Observational Study

- LS = Least squares.  SE = Standard error.

## Patient Assessment of PainMean Change From BaselineProtocol 040 and Observational Study

**** Indomethacin 50 mg TID

**** Observational Study

****** **Etoricoxib 120 mg

- LS = Least squares.  SE = Standard error.

## Patient Assessment of PainMean Change From BaselineProtocols 040 and 049 and Observational Study

**** Indomethacin 50 mg TID

**** Observational Study

****** **Etoricoxib 120 mg

- LS = Least squares.  SE = Standard error.

## Consistent Efficacy Demonstrated in Secondary Endpoints Across Two Studies

- LS = Least squares.  SE = Standard error.  (0 to 3-point Scale).

## 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

## Percentage of Patients with Erythema of the Study JointProtocols 040 and 049

- Etoricoxib 120 mg

- Indomethacin 50 mg TID

## 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

## 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

## Indomethacin Treatment EffectPatient 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.

## 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

## 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

## Lessons Learned

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

## 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