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

2. 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. 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. 4 Sources of Information Scientific Literature Clinical Experience Data from Etoricoxib/Indomethacin Studies

5. 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. 6 Design Considerations in Acute Gouty Arthritis Studies David I. Daikh, MD, PhD University of California at San Francisco San Francisco Veterans Administration

7. 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. 8 Henry VIII B. Franklin W. Churchill O. Welles Acute Gout: King of the Diseases, Disease of the Kings

9. 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. 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. 11 Treatment of Gout Prevention Allopurinol Probenecid Colchicine Diet modification Alcohol avoidance Medications (diuretics) Treatment NSAIDs Colchicine Corticosteroids

12. 12 Previous Studies What quantitative information is available on natural history of gout to assist in design?

13. 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 Indomethacin vs. ketorolac 28 18 47 30 24 20 33 29 11 93 10 43 59 60 61 20 No. of PatientsYear 1973 1978 1979 1980 1983 1985 1986 1987 1988 1990 1991 1995

14. 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. 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 1234567 X X X * * * * 3456789 N=11 Pain Severity Mean (SD) Study Day Mean Days since onset of attack

16. 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. Pain Severity Mean (SD) Study Day 3 2 1 X Observed LVCF 4 1234567 X X X † † † † * * * * 3456789 Mean Days since onset of attack N=11

17. 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. 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. 19 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 00.51.01.5 70 80 60 50 40 30 20 10 Mean Days Since Onset of Attack 3.51.52.02.53.0 Ahern et al., Aust NZ J Med, 1987, 17; 301-304.

20. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 31 Recommendation: Assessment of Assay Sensitivity (Was Indomethacin Effective?) Clinical approach is acceptable Quantitative approach – include as supportive

32. 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. 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. 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 -0.5 0 Day 4Day 2Day 3Day 5 Between Group Difference

35. 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. 36 Experience with Etoricoxib and Indomethacin in Acute Gouty Arthritis Agustin Melian, MD Director Clinical Research Merck Research Laboratories (MRL)

37. 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/125 Onset of Attack 7-90-21-34-6 Days Since Onset of Attack

38. 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. 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. 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. 41 Endpoint Assessments: Timing Study Day 8R/125 Pain Assessment Patient’s Global Investigator’s Global Study Joint Tenderness Study Joint Swelling Study Joint Erythema 3467 xxxxxxxxx xxx xxxx 4 hrs

42. 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. 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. 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. 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 Protocols 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

46. 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 Protocols 040 and 049 Combined

47. 47 Patient Assessment of Pain Mean Change From Baseline Protocol 040 LS = Least squares. SE = Standard error.  Indomethacin 50 mg TID

48. 48 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.

49. 49 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.

50. 50 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.

51. 51 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.

52. 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).

53. 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

54. 54 Percentage of Patients with Erythema of the Study Joint Protocols 040 and 049 Etoricoxib 120 mgIndomethacin 50 mg TID

55. 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. 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. 57 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.

58. 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

59. 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. 60 Lessons Learned David I. Daikh, MD, PhD University of California at San Francisco San Francisco Veterans Administration

61. 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