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Experience in Acute Gouty Arthritis Studies:Introduction

Agustin Melian, MD

DirectorClinical Research

Merck Research Laboratories (MRL)

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Merck Research Laboratorys Experience withAcute 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

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Agenda

David Daikh, MD, PhD

Design Considerations in Acute Gouty Arthritis Studies

Agustin Melian, MD

Experience with Etoricoxib and Indomethacin in AcuteGouty Arthritis

David Daikh, MD, PhD

Lessons Learned

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Sources of Information

Scientific Literature

Clinical Experience

Data from Etoricoxib/Indomethacin Studies

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Key Points

In appropriately selected patients, acute gouty arthritis is a highlypredictable disease

In the absence of drug intervention, bouts of moderate to

severe acute gouty arthritis do not spontaneously resolve withinthe first 5 to seven days

Although existing gout medications may have side effects, manyare highly efficacious and provide a highly predictable response

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Design Considerationsin Acute Gouty Arthritis Studies

David I. Daikh, MD, PhD

University of California at San FranciscoSan Francisco Veterans Administration

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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

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Henry VIII

B. Franklin

W. Churchill

O. Welles

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

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Pathophysiology

An acute form of peripheral arthritis resulting from the deposition ofmonosodium 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

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Diagnostic CriteriaAcute Gout Study

A)The presence of characteristic urate crystals in the joint fluid (ifat past attack thenC1 andC4 also)

Or

B) A tophus proved to contain urate crystals by chemical or polarized light microscope andC1 andC4

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.

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Treatment of Gout

Prevention

Allopurinol

Probenecid

Colchicine

Diet modification

Alcohol avoidance

Medications (diuretics)

Treatment

NSAIDs

Colchicine

Corticosteroids

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Previous Studies

What quantitative information is available on natural

history of gout to assist in design?

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Acute Gout LiteratureAvailable 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. phenylbutazoneIndomethacin vs. flurbiprofen

Observational

Indomethacin + allopurinol vs. azapropazone

Tenoxicam

Colchicine vs. placebo

Indomethacin vs. ketoprofenEtodolac vs. naproxen

Etodolac vs. naproxen

Indomethacin vs. ketorolac

28

18

47

30

24

20

3329

11

93

10

43

5960

61

20

No. of Patients Year

1973

1978

1979

1979

1980

1983

19851986

1987

1987

1987

1987

19881990

1991

1995

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Nontreatment Observational Study inAcute 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 acutegout

Measurements: Pain, tenderness, swelling erythema andarticular 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)

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Patient Assessment of Painin 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

XX

X

*

**

*

3 4 5 6 7 8 9

N=11

Pa

inSeverity

M

ean(SD)

Study Day

Mean Days sinceonset of attack

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Patient Assessment of Painin a Nontreatment Observational Study

P 0.05 for comparison with baseline: Observed = *, LVCF = . Bellamy et al., Br J Clin Pharmacol. 1987 (24):33-36.

Pa

inSeverity

M

ean(SD)

Study Day

3

2

1

X

Observed

LVCF

4

1 2 3 4 5 6 7

XX

X

*

**

*

3 4 5 6 7 8 9Mean Days since

onset of attack

N=11

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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

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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

P ti t A t f P i

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Patient Assessment of PainPlacebo Controlled Colchicine Study

Ahern et al.

Study Days 2.0

Placebo (N=21)

Colchicine (N=22)

P

ainScore

Mean9

5%CI

0 0.5 1.0 1.5

70

80

60

50

40

30

20

10

Mean Days SinceOnset of Attack 3.51.5 2.0 2.5 3.0

Ahern et al., Aust NZ J Med, 1987, 17; 301-304.

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Literature Supports Conventional Wisdom

Moderate to severe attacks do not resolvespontaneously over first 5 to 7 days

Little to no placebo effect

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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

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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 therapyis available?

Dropouts due to patients who need to rescue may

confound analysis May require an in-patient study due to compliance issues

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Design Issue: Active vs. Placebo Control

Active comparator control

Pros

Standard therapies (NSAIDs, corticosteroids, to a lesserextent colchicine) known to be highly efficacious and arereadily available

More humane; does not withhold therapy from patients inneed

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 bound

D i I A i Pl b C l

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Design Issue: Active vs. Placebo ControlRecommendation to MRL

Active comparator control study

Cons of active comparator control are manageablewhile 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

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Design Issue and Recommendations: Endpoints

Endpoints should assess key characteristics of the diseaseprocess 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

D i I d R d ti

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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 attac

D i I d R d ti

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Design Issue and Recommendations:Patient 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)

D i I

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Design Issue:Timing of Assessments

Primary assessment should integrate response across a clinicallyrelevant 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 otheracute analgesia models due to highly inflammatory natureof disease

Recommendations:

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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

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Assessment of Assay Sensitivity(Is Indomethacin Effective?)

Clinical (qualitative) approach: If the observed response is consistentwith 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, especiallyin 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 ofindomethacin effect

No precedent for setting the minimal effect size

Recommendation: Assessment of Assay

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Recommendation: Assessment of AssaySensitivity (Was Indomethacin Effective?)

Clinical approach is acceptable

Quantitative approach include as supportive

Assessment of Clinical Comparability

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

Approach: Set a boundary for difference fromindomethacin which study drug must fall within

This needed to be based on

Clinical judgment Extrapolation from other conditions

Recommendation: Comparability Bounds

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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 relevantmagnitude of effect on an individual patient basis

Analysis of Statistical Equivalence Between Treatments:

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

ChangefromBaseline

Baseline Value

Randomization

Mean Difference

Over Days 2-5:

Test Drug Minus

Comparator 95% CI

0

Upper Bound of ClinicalEquivalence

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 4Day 2 Day 3 Day 5

BetweenGroupDifference

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Summary of Recommendations: Design Issues

The study of treatment effects in acute gout presents a number offormidable challenges

Relative paucity of data in the literature likely reflects thesechallenges

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

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Experience with Etoricoxib and Indomethacinin Acute Gouty Arthritis

Agustin Melian, MD

DirectorClinical Research

Merck Research Laboratories (MRL)

St d S h f P t l 040 d 049

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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

7-90-2 1-3 4-6Days SinceOnset of Attack

Effi H th

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Efficacy Hypotheses

Primary

Etoricoxib 120 mg will demonstrate clinical efficacycomparable with indomethacin 150 mg in the treatment ofacute gout over 4 days (Days 2-5) as evaluated by PatientsAssessment of Pain

Secondary

Etoricoxib 120 mg will demonstrate clinical efficacycomparable with indomethacin 150 mg in the treatment ofacute gout over 7 days (Days 2-8) as evaluated by PatientsAssessment of Pain

E d i t

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Endpoints

Primary

Patients Assessment of Pain (0- to 4-Likert Scale; None toExtreme)

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; NoPain to Pain, Winces, and Withdraws)

E d i t (C td)

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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)

Endpoint Assessments:

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pTiming

Study Day R/1 2 5

Pain Assessment

Patients Global

Investigators 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

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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 totreat current attack were excluded

Stable baseline gout meds (e.g., colchicine, allopurinol)

Enrollment Characteristics

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Enrollment Characteristics

# of Patients Randomized

Total # of Study Centers# of Centers Who Enrolled1 Patient

Number of Countries Participated

Protocol 040

N=150

4331

11

Protocol 049

N=189

5842

10

Baseline Characteristics

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Protocols 040 and 049 Combined

# Randomized

Mean age (years)

Men (%)

Race (%)

White

Black

Asian

Hispanic

Other

Indomethacin150 mg

N=161

50.9

91.3

44.1

6.8

22.4

18.0

8.7

Etoricoxib120 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

Other Baseline Disease Characteristics

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# 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 mgN=161

72.0

28.0

20.8

50.9

24.5

3.00

16.764.6

18.6

Etoricoxib

120 mgN=178

71.3

28.7

33.3

45.8

20.9

2.88

16.364.6

19.1


TotalN=339

71.7

28.3

27.7

49.7

22.6

2.94

16.564.6

18.9

Patient Disposition

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178 Randomizedto Etoricoxib

161 Randomizedto Indomethacin

8 (4.5%)Discontinued Due to

Lack of Efficacy


Lack of Efficacy


Clinical AE


Clinical AE


Laboratory AE


Laboratory AE


Other Reasons*


Other Reasons*

159 (89.3%)Completed Trial

132 (82%)Completed Trial


Patient Assessment of PainMean Change From Baseline

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Mean Change From BaselineProtocol 040

LS = Least squares. SE = Standard error.

Indomethacin 50 mg TID

0 1 2 3 4 5 6 7 8 9Mean Days Since Onset of Attack

-3

-2

-1

0

LSMeanChangeS

E040


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Mean Change From BaselineProtocol 040 and Observational Study

Indomethacin 50 mg TID Observational Study

0 1 2 3 4 5 6 7 8 9

Mean Days Since Onset of Attack

-3

-2

-1

0

LSMeanChangeS

E040



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Indomethacin 50 mg TID Observational Study

0 1 2 3 4 5 6 7 8 9


-3

-2

-1

0

LSMeanChangeS

E040



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Indomethacin 50 mg TID Observational StudyEtoricoxib 120 mg

0 1 2 3 4 5 6 7 8 9


-3

-2

-1

0

LSMeanChangeS

E040



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Mean Change From BaselineProtocols 040 and 049 and Observational Study

Indomethacin 50 mg TID Observational StudyEtoricoxib 120 mg

0 1 2 3 4 5 6 7 8 9

049

0 1 2 3 4 5 6 7 8 9Mean Days Since Onset of Attack

-3

-2

-1

0

LSMeanChangeS

E040


Consistent Efficacy Demonstrated in SecondaryE d i t A T St di

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Endpoints Across Two Studies

Etoricoxib 120 mg Indomethacin 50 mg TIDLS = Least squares. SE = Standard error. (0 to 3-point Scale).

-3

-2

-10

LSMean

ChangeS

E

049040

Tenderness

0 1 2 5 8


-3

-2

-1

0

0 1 2 5 8

Swelling

Percentage of Patients with Good/Excellent ResponseProtocols 040 and 049

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Protocols 040 and 049

Etoricoxib 120 mg Indomethacin 50 mg TID

Patient GlobalAssessment of

Response to Therapy

Investigator Global

Assessment of

Response to Therapy

0

50

100040 049

2 5 8Mean Days Since Onset of Attack

0

50

100

Percento

fPatientswith

Good/ExcellentResponse

2 5 8

Percentage of Patients with Erythema of the Study JointProtocols 040 and 049

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Protocols 040 and 049

Etoricoxib 120 mg Indomethacin 50 mg TID

1 2 5 8Mean Days Since Onset of Attack

0

20

40

60

80

100

Percent

ageofPatients

with

Erythema

040

1 2 5 8

049

Demonstration of Assay SensitivityClinical (Qualitative) Approach

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Clinical (Qualitative) Approach

Indomethacin the gold standard performs as expected based onclinical experience

There was marked improvement in pain and other clinicalparameters 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 patientsexperienced a clinically meaningful response

Demonstration of Assay SensitivityQuantitative Approach

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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 LikertScale

FDA guidance: 1988 Guidelines for the Clinical Evaluation ofAnti-Inflammatory & Antirheumatic Drugs

60% of effect size in active comparator studies lackingplacebo recommended

Criteria: Upper 95% confidence limit of indomethacin mean

change from baseline over 5 days needs to be -1.46 or better

Indomethacin Treatment EffectPatient Assessment of Pain

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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

-0.50.0

LSMe

anand95%C

I

-1.46=

Comparability Assessment: Patient Assessment of PainLS Mean Change and 95% CI

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LS Mean Change and 95% CI

The prespecified comparability bounds of0.5 for containing the 95% CI for between-group differences are indicatedas dotted lines.

FavorsEtoricoxib

Favors

Indomethaci

-0.7

-0.5-0.3

-0.1

0.1

0.3

0.5

0.7

LSM

eanDifference

and95%C

I

040

AverageOver

Study Days

2 - 5

AverageOver

Study Days

2 - 8

049

AverageOver

Study Days

2 - 5

AverageOver

Study Days

2 - 8

Conclusions

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This acute gout study design is robust

Indomethacin performs reliably and as expected in our studies

Endpoints are highly reproducible between studies and resultsare consistent across endpoints

In replicate studies, etoricoxib and indomethacin performedcomparably based on predefined criteria

Meaningful results can be obtained in the absence of placebo

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Lessons Learned

David I. Daikh, MD, PhD

University of California at San FranciscoSan Francisco Veterans Administration

Lessons Learned andPotential Future Design Considerations

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Potential Future Design Considerations

Lessons learned

Recruitment was very difficult even though it was not aplacebo-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, earlytime 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

Documents

Gout 4