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

1

Experience in Acute Gouty Arthritis Studies:Introduction

Agustin Melian, MD

DirectorClinical 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 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

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.

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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. phenylbutazoneIndomethacin vs. proquazoneSulindac vs. phenylbutazoneFenoprofen vs. phenylbutazoneFeprazone vs. phenylbutazoneIndomethacin vs. meclofenamateFlurbiprofen vs. phenylbutazoneIndomethacin vs. flurbiprofenObservationalIndomethacin + allopurinol vs. azapropazoneTenoxicamColchicine vs. placeboIndomethacin vs. ketoprofenEtodolac vs. naproxenEtodolac vs. naproxenIndomethacin vs. ketorolac

28184730242033291193104359606120

No. of Patients Year

1973197819791979198019831985198619871987198719871988199019911995

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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)

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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

XX

X

**

**

3 4 5 6 7 8 9

N=11

Pai

n S

ever

ityM

ean

(SD

)

Study Day

Mean Days sinceonset of attack

16

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.

Pai

n S

ever

ityM

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

19

Patient Assessment of PainPlacebo Controlled Colchicine Study

Ahern et al.

Study Days 2.0

Placebo (N=21)

Colchicine (N=22)

Pai

n S

core

Mea

n ±

95%

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.

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 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

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

Cha

nge

from

Bas

elin

e

Baseline Value

Randomization

Mean DifferenceOver Days 2-5:

Test Drug MinusComparator 95% CI

0

Upper Bound of ClinicalEquivalence

Lower Bound of ClinicalEquivalence

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

Bet

wee

n G

roup

Diff

eren

ce

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 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

7-90-2 1-3 4-6Days SinceOnset 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 8R/1 2 5

Pain Assessment

Patient’s GlobalInvestigator’s Global

Study Joint TendernessStudy 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

4331

11

Protocol 049

N=189

5842

10

44

Baseline CharacteristicsProtocols 040 and 049 Combined

# Randomized

Mean age (years)Men (%)

Race (%)WhiteBlackAsianHispanicOther

Indomethacin150 mg

N=161

50.991.3

44.16.8

22.418.0

8.7

Etoricoxib120 mg

N=178

50.096.1

46.16.2

22.518.5

6.7

Total

N=339

50.593.7

45.16.5

22.418.3

7.7

45

# Randomized

Disease type (%)Monoarticular goutPolyarticular gout

Baseline pain (%)ModerateSevereExtreme

Mean baseline pain (Likert)

Time from onset to randomization (%)Day of onset1 Day 2 Days (within 48 hours)

Indomethacin150 mg

N=161

72.028.0

20.850.924.53.00

16.764.618.6

Etoricoxib120 mg

N=178

71.328.7

33.345.820.92.88

16.364.619.1

Other Baseline Disease CharacteristicsProtocols 040 and 049 Combined

Total

N=339

71.728.3

27.749.722.62.94

16.564.618.9

46

178 Randomized to Etoricoxib

161 Randomized to 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 Disposition Protocols 040 and 049 Combined

47

Patient Assessment of PainMean Change From Baseline

Protocol 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

LS M

ean

Cha

nge

S

E

040

48


Protocol 040 and Observational Study

Indomethacin 50 mg TID Observational Study


-3

-2

-1

0

LS M

ean

Cha

nge

S

E

040


49



Indomethacin 50 mg TID Observational Study


-3

-2

-1

0

LS M

ean

Cha

nge

S

E

040


50



Indomethacin 50 mg TID Observational Study Etoricoxib 120 mg


-3

-2

-1

0

LS M

ean

Cha

nge

S

E

040


51


Protocols 040 and 049 and Observational Study

Indomethacin 50 mg TID 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


-3

-2

-1

0

LS M

ean

Cha

nge

S

E

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 M

ean

Cha

nge

S

E

049040

Tenderness

0 1 2 5 8Mean Days Since Onset of Attack

-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


Patient Global Assessment 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

Per

cent

of P

atie

nts

with

Goo

d/E

xcel

lent

Res

pons

e

2 5 8

e110e120Bars4049 May 25, 2004

54

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


1 2 5 8Mean Days Since Onset of Attack

0

20

40

60

80

100

Per

cent

age

of

Pa

tient

s

w

ith E

ryth

ema

040

1 2 5 8

ery.byplot.4049.cindyw May 25, 2004

049

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.

040 049Average Over Study Days 2 to 5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

LS M

ean

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 M

ean

Diff

eren

ce

a

nd 9

5% C

I

040

AverageOver

Study Days2 - 5

AverageOver

Study Days2 - 8

e.diffA.10.4049B May 25, 2004

049

AverageOver

Study Days2 - 5

AverageOver

Study Days2 - 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 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

Documents

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