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

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 2

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 3

Sources of Information  Scientific Literature  Clinical Experience  Data from Etoricoxib/Indomethacin Studies 4

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 5

Design Considerations in Acute Gouty Arthritis Studies David I. Daikh, MD, PhD University of California at San Francisco San Francisco Veterans Administration 6

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 7

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

Henry VIII W. Churchill

8

B. Franklin O. Welles

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 9

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.

10

Treatment of Gout

Prevention

 Allopurinol  Probenecid  Colchicine  Diet modification  Alcohol avoidance  Medications (diuretics)

Treatment

 NSAIDs  Colchicine  Corticosteroids 11

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

12

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 13 No. of Patients 10 43 59 60 61 20 28 18 47 30 24 20 33 29 11 93 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) 14

Patient Assessment of Pain in a Nontreatment Observational Study 4 3 2 1 Observed

X * X * X * X * N=11

Study Day 1 2 3 4 5 6 7 Mean Days since onset of attack 3 4 5 6 7 8 P  0.05 for comparison with baseline: Observed = *. Bellamy et al.,

Br J Clin Pharmacol

. 1987 (24):33-36. 15 9

Patient Assessment of Pain in a Nontreatment Observational Study 4 3 2 1 Observed LVCF

X * † X * † X * † X * † N=11

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. 16

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 17

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 18

Patient Assessment of Pain Placebo Controlled Colchicine Study Ahern et al.

80 70 60 50 40 30 20 10 Placebo (N=21) Colchicine (N=22) Study Days 0 Mean Days Since Onset of Attack 1.5

0.5

2.0

1.0

2.5

Ahern et al.,

Aust NZ J Med

, 1987, 17; 301-304. 19 1.5

3.0

2.0

3.5

Literature Supports Conventional Wisdom  Moderate to severe attacks do not resolve spontaneously over first 5 to 7 days  Little to no placebo effect 20

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 21

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 22

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 23

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 24

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 25

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 26

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) 27

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 28

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 29

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 30

Recommendation: Assessment of Assay Sensitivity (Was Indomethacin Effective?)  Clinical approach is acceptable  Quantitative approach – include as supportive 31

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 32

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 33

Analysis of Statistical Equivalence Between Treatments: Test Drug vs. Active Comparator Baseline Value 0 -0.5

-1.0

-1.5

-2.0

-2.5

-3.0

-3.5

-4.0

Randomization Day 2 Mean Difference Over Days 2-5: Test Drug Minus Comparator Day 3 Day 4 34 Day 5 0.5

Upper Bound of Clinical Equivalence 0 95% CI -0.5

Lower Bound of Clinical Equivalence

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 35

Experience with Etoricoxib and Indomethacin in Acute Gouty Arthritis Agustin Melian, MD Director Clinical Research Merck Research Laboratories (MRL) 36

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

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 38

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) 39

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) 40

Endpoint Assessments: Timing

Study Day R/1

4 hrs Pain Assessment

x x 2 x 3 4 x x 5 6 x x 7 8 x x

Patient’s Global Investigator’s Global

x

Study Joint Tenderness Study Joint Swelling Study Joint Erythema

x x x x x x

41

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) 42

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 43

Baseline Characteristics Protocols 040 and 049 Combined # Randomized Mean age (years) Men (%) Race (%) White Black Asian Hispanic Other Etoricoxib 120 mg N=178 50.0

96.1

Indomethacin 150 mg N=161 50.9

91.3

Total N=339 50.5

93.7

46.1

6.2

22.5

18.5

6.7

44.1

6.8

22.4

18.0

8.7

45.1

6.5

22.4

18.3

7.7

44

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) Etoricoxib 120 mg N=178 71.3

28.7

33.3

45.8

20.9

2.88

45 16.3

64.6

19.1

Indomethacin 150 mg N=161 72.0

28.0

20.8

50.9

24.5

3.00

16.7

64.6

18.6

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

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

0 Patient Assessment of Pain Mean Change From Baseline Protocol 040 and Observational Study 040 -1 -2 -3 0 1 2 3 4 5 6 7 8 9 Mean Days Since Onset of Attack  Indomethacin 50 mg TID  Observational Study LS = Least squares. SE = Standard error. 48

0 Patient Assessment of Pain Mean Change From Baseline Protocol 040 and Observational Study 040 -1 -2 -3 0 1 2 3 4 5 6 7 8 9 Mean Days Since Onset of Attack  Indomethacin 50 mg TID  Observational Study LS = Least squares. SE = Standard error. 49

0 Patient Assessment of Pain Mean Change From Baseline Protocol 040 and Observational Study 040 -1 -2 -3 0 1 2 3 4 5 6 7 8 9 Mean Days Since Onset of Attack  Etoricoxib 120 mg  Indomethacin 50 mg TID  Observational Study LS = Least squares. SE = Standard error. 50

Patient Assessment of Pain Mean Change From Baseline Protocols 040 and 049 and Observational Study 0 040 049 -1 -2 -3 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Mean Days Since Onset of Attack  Etoricoxib 120 mg  Indomethacin 50 mg TID e10C.4049.cindyw May 25, 2004 Observational Study LS = Least squares. SE = Standard error. 51

Consistent Efficacy Demonstrated in Secondary Endpoints Across Two Studies 040 049 0 -1 -2 -3 0 -1 -2 Tenderness Swelling -3 0 1 2 5 8 0 1 2 5 Mean Days Since Onset of Attack 8  Etoricoxib 120 mg Etoricoxib  LS = Least squares. SE = Standard error. (0 to 3-point Scale).

Indomethacin 50 mg TID Indomethacin e130.210.4049.cindyw May 25, 2004 52

Percentage of Patients with Good/Excellent Response Protocols 040 and 049 100 040 049 50 Patient Global Assessment of Response to Therapy 0 100 50 Investigator Global Assessment of Response to Therapy 0 2 5 8 2 5 Mean Days Since Onset of Attack Etoricoxib 120 mg 53 8

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

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 55

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 56

Indomethacin Treatment Effect Patient Assessment of Pain LS Mean Change and 95% CI: 0- to 4-point Likert Scale 0.0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

040 049 Average Over Study Days 2 to 5 -1.46

= indo10.4049.cindyw May 20, 2004 † 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.

57

Comparability Assessment: Patient Assessment of Pain LS Mean Change and 95% CI 0.7

0.5

0.3

0.1

-0.1

-0.3

-0.5

-0.7

040 049 Favors Indomethacin Average Over Study Days 2 - 5 Average Over Study Days 2 - 8 Average Over Study Days 2 - 5 Average Over Study Days 2 - 8 Favors Etoricoxib e.diffA.10.4049B May 25, 2004 The prespecified comparability bounds of ± 0.5 for containing the 95% CI for between-group differences are indicated as dotted lines.

58

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 59

Lessons Learned David I. Daikh, MD, PhD University of California at San Francisco San Francisco Veterans Administration 60

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 61