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INTRODUCTORY REMARKS

INTRODUCTORY REMARKS. CHALLENGES IN STUDY OF DRUG EFFECTS IN LUPUS. Multiple organ / tissue manifestations Variable short and long term course Mixture of pathology - disease and drug toxicity Disease activity indices Treatment malleability (esp. steroids). LUPUS TRIALS.

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INTRODUCTORY REMARKS

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  1. INTRODUCTORY REMARKS

  2. CHALLENGES IN STUDY OF DRUG EFFECTS IN LUPUS • Multiple organ / tissue manifestations • Variable short and long term course • Mixture of pathology - disease and drug toxicity • Disease activity indices • Treatment malleability (esp. steroids)

  3. LUPUS TRIALS • Disease activity assessment in lupus • SLEDAI, SLAM, BILAG, ECLAM (others: SIS, LAI; some updated)* • RCT assessment (domains) • activity • damage • drug toxicity • health related quality-of-life • *ref: Strand JRheum 26:490, 1999

  4. SLE Disease Activity Index SLEDAI • Derivation: Toronto (1992), Delphi process of physicians/statisticians (Bombardier: A&R 35:630) • Metric: static measure; timeframe=10 days • Content: 24 components, weighted (four categories: 1, 2, 4, 8; fatigue / steroid use not included.

  5. SLEDAI Components / Weights 8 seizure, psychosis, organic brain syndrome, visual disturbance, cranial nerve disorder, lupus headache, CVA, vasculitis 4 arthritis, myositis, urinary casts hematuria, proteinuria, pyuria 2 rash, alopecia, mucosal ulcers, pleurisy, pericarditis, low complement, high DNA 1 fever, low platelets, low WBC

  6. Systemic Lupus Activity Measure: SLAM • Derivation: Boston (1989) Judgment re. components of 1983 ACR definition of lupus, plus patient and physician VAS global (Liang:A&R 32:1107) • Metric: static measure; timeframe=1 month • Content: 2 globals, 24 clinical, 7 laboratory, 1 “other” component; weighted (< 4 categories: absent --> severe); fatigue included; steroid use not.

  7. SLAM Components by System 3 Constitutional (incl. fatigue) 4 Integument 3 Eye 2 Reticuloendothelial 2 Pulmonary 3 Cardiovascular 1 Gastrointestinal 5 Neuromotor 1 Joints 7 Laboratory + 1 “other” + 2 globals = 34 in TOTAL

  8. British Isles Lupus Assessment Group: BILAG • Derivation: UK (1988) Consensus of physicians regarding trigger to change therapy (QJMed 69:927, & 86:447) • Metric: Transition measure (4 states) • “Action” = urgent need for DMARD (high dose steroids or immunosuppressive rx) • “Beware” = watch +/- low dose steroids / HCQ • “Content” = static or inactive • “Dull” = no involvement • Content: 8 organ systems, weighted: A=9, B=4, C=1, D=0; fatigue / steroid use included.

  9. European Consensus Lupus Activity Measure: ECLAM • Derivation: Europe (1992) - Optimization of statistical model of patient (704) database from 14 countries, using MD global as gold standard (Clin Exp Rheum 10:5541) • Metric: static measure; time frame=1-3mo • Content: Fatigue included; steroid use not

  10. Performance Characteristics (“Validation”) • Intrinsic content • validity (“truth” per Omeract filter) • reliability (“discrimination”) • responsiveness to change (“discrimination”) • feasibility (“feasibility”) • Extrinsic setting • observational studies (cohort) • controlled trials***

  11. Recent trials in mild-moderate lupus (not lupus nephritis) Canadian HCQ v PLC (NEJM 324:150, 1991) n=47 6mo • design/analysis: withdrawal/survival • endpoint: time to clinical flare / severe exacerbation CSSRD HCQ v PLC (JRheum 21:1457, 1994) n=71 1yr • design/analysis: standard/comparison of means • endpoints: many (publication: 4 grades of arthritis) Brazilian MTX v PLC (JRheum 26:1275, 1999) n=41 6mo • design/analysis:standard+pred. change/comparison means • endpoints = SLEDAI, pain VAS, (prednisone use)

  12. Other DHEA RCTs in lupus • 3mo, mild-mod lupus, n=28 (van Vollenhoven, A&R 38:1826,1995) • endpoints=SLEDAI, globals, prednisone dose • 6mo, severe lupus, n=21 (vanVollenhoven, Lupus 8:181,1999) • EP=stabilization (w/o new rx) of primary organ involvement (nephritis, hematologic, serositis) • 6mo, mild-mod lupus, n=120 (Taiwan-see my review) • endpoint=mean change in SLAM at 6mo • GL97-01-ongoing: 12 mo, male lupus, n=40

  13. Early Discussions • Two trials 94-01 191 patients, 3 arms: 200mg,100mg, plc 95-02 381 patients, 2 arms: 200mg, plc • Steroid sparing = meaningful endpoint (would carry evidentiary weight in an NDA) • By-patient assessments offer both less controversy about interpretation AND more clinically intuitiveness to patient and doctor • Dimensions of the overall safety database

  14. MEDICAL REVIEW

  15. Outline • Comments on designs: 94-01 and 95-02 • Population characteristics: 94-01 and 95-02 • Efficacy results: 94-01 and 95-02 • Discussion of SLEDAI>2 signal • Safety

  16. Design: Trial 94-01 • Steroid-sparing design - few precedents • inherently more variable because one is measuring “downstream” from signs and symptoms • “Steroid stuck” patients - difficult to define • failed taper w/in 12mo + stable x 6wk, or • no failed taper but stable x 3mo

  17. Design: Trial 94-01 Two “primary” endpoints 1: Achieving durable reduction to physiological dose prednisone (7.5mg/d) “Subpart E endpoint” Clinically more demanding endpoint, but not a essential one 2: Mean % change in prednisone dose potentially more sensitive endpoint

  18. Design: Trial 94-01 • Timeline • first patient enrolled June 6, 1994 • last patient completed May 28, 1996 • blind broken April 21, 1997 • Amendment, March 21, 1997 • added baseline SLEDAI to covariates for primary analysis (logistic regression model)

  19. Patients: Trial 94-01 GL701-200 GL701-100 PLC (n= 64) (n=63) (n=64) • age 40 40 41 • race (%w/b) 55/27 57/25 69/27 • pre-menopausal (%) 75 59 59 • prednisone (mg) 13.7 13.7 15.2 • entry SLEDAI 5.9 5.3 6.4

  20. Withdrawals: Trial 94-01Survival analyses P values* 200mg v PLC 100mg v PLC all cause 0.80 0.74 inefficacy 0.50 0.77 adverse event 0.35 0.71 *log rank

  21. Efficacy results: Trial 94-01 • 1st primary endpoint (durable pred<7.5mg) • GL701 200mg 35/64 (55%) p=0.11 • GL701 100mg 28/63 (44%) p=0.66 • PLC 26/64 (41%) • 2nd primary endpoint (% change pred.) mean median • GL701 200mg 30% 53% • GL701 100mg 14% 41% • PLC 36% 50%

  22. SLEDAI>2 subset: Trial 94-01(Hypothesis generating) Achieving durable prednisone 200mg vs plc p=0.18* 100mg vs plc p=0.75 *adjusted for baseline prednisone; unadjusted p=0.031

  23. SLEDAI>2 subset: Trial 94-01 Mean % change in prednisone mean median 200mg GL701 arm 22% 50% 100mg GL701 arm 0% 33% placebo arm 26% 33%

  24. SLEDAI categories: Trial 94-01ENDPOINT= % responders GL701-200 GL701-100 PLC (n=64) (n=63) (n=64) SLEDAI 0-2 63 (12/19) 62 (10/16) 68 (13/19) 2-4 56 (5/9) 44 (8/18) 33 (5/15) 4-8 50 (12/24) 44 (7/16) 31 (4/13) >8 50 (6/12) 23 (3/13) 23 (4/17) Note: small numbers

  25. SLEDAI Categories: Trial 94-01 ENDPOINT= mean % change of prednisone from baseline GL701-200 GL701-100 PLC (n=64) (n=63) (n=64) SLEDAI 0-2 50 54 60 2-4 47 23 20 4-8 18 10 30 >8 11 44 27 Note: small numbers

  26. Design: Trial 95-02 • By-patient, dichotomous endpoint but used logistic regression model to incorporate covariates • Endpoint designed to capture totality of drug effect (no precedents) • Prednisone fixed (unlike Trial 94-01) • Started before Trial 94-01 completed

  27. Endpoints: Trial 95-02 • Primary endpoint = “responder,” defined as • no deterioration in 4 measures - SLEDAI, SLAM, Krupp Fatigue Severity scale (KFSS), and patient global (PG), PLUS • no “clinical deterioration” (long list) • Secondary endpoint = mean change from baseline in 4 variables (SLEDAI, SLAM, KFSS, PG)

  28. Design: Trial 95-02 • Timeline • first patient enrolled March 7, 1996 • last patient completed April 2, 1999 • Amendments • August 4, 1997: increase enrollment by 50 and require SLEDAI>2 for entry • April 21, 1999: instituted a uterine / breast monitor program for post-menopausal patients • Statistical Analysis Plan - next slide

  29. Statistical Analysis PlanTrial 95-02 • Communications during 1998 and 1999 modified population using SLEDAI>2 modified responder definition (“window”) modified population using 60d treatment • Final version: April 30, 1999

  30. Patients: Trial 95-02 GL701 PLC (n=189) (n=192) age 44.4 43.8 race (%w/b/other) 77/12/11 71/17/12 pre-menopausal (%) 56 54 mean pred. dose (mg) 3.5 3.7 cytotoxic rx (%) 17 15 baseline SLEDAI 6.6 (0-18) 5.8(0-24)

  31. Withdrawals: Trial 95-02Survival analyses PLC vs GL701 P value* all cause 0.08 inefficacy 0.53 adverse event 0.04 *log rank

  32. Efficacy results: Trial 95-02 • Primary (all-randomized) analysis - “responders” by protocol definition • GL701 58/189 (31%) p=0.436* • PLC 52/192 (27%) * logistic regression • Secondary analyses • mean change in 4 parameters, and investigator global, SF36 -- all with p>0.25 (see next slide) • time to withdrawal (all cause), by log rank -- p=0.08 trend in favor of PLC

  33. Efficacy results: Trial 95-02 Secondary endpoints GL701 PLC P value SLEDAI -2.2 -1.8 0.25 SLAM -2.9 -2.9 0.38 KFSS -0.3 -0.3 0.45 PG -5.1 -4.7 0.86

  34. SLEDAI>2 Patients (n=293) Trial 95-02 • No. of responders GL701: 55/147 p=0.127 PLC: 42/146 • Individual measures (mean change) • SLEDAI p=0.15 • SLAM p=0.19 • KFSS p=0.61 • PG p=0.06

  35. SLEDAI>2 + Rx>2mo Patients (n=265) Trial 95-02 No. of Responders GL701 56/132 PLC 42/133 p=0.068

  36. Same subset (SLED>2, rx>2mo)Using modified window (n=265) Trial 95-02 No. of Responders GL701 87/132 PLC 65/133 p=0.005

  37. Summary: Responder AnalysesTrial 95-02 All patients n=381 p=0.436 • 58/189 vs 52/192 Subset: >60d rx n=346 p=0.254 • 60/170 vs 52/176 Subset: SLEDAI>2 n=293 p=0.127 • 55/147 vs 42/146 Subset: >60d rx, SL.>2 n=265 p=0.068 • 56/132 vs 42/133 • 87/132 vs 65/133 (new window) p=0.005

  38. Safety- general • Per this database • physiologically expected - hormonal effects • abdominal pain signal? - from one trial • renal signal? - needs further exploration • Background aspects to the overall database • effects of chronic hormonal exposure • long-term consequences of lipid alterations

  39. Adverse Events with p<0.05Trial 94-01 GL701-200 GL701-100 PLC acne 44%* 44%* 12% abdominal pain 22%* 11% 6% hypertension 13%* 3% 2% stomatitis 16% 24%* 9% LE rash 6% 14% 20%* sinusitis 8% 6% 20%* *statistically significant greater event rate

  40. Adverse Events with p<0.05*Trial 95-02 GL701 PLC acne 33%* 14% hirsutism 16%* 2% stomatitis 15% 23%* myalgia 22% 36%* *statistically significantly greater event rate

  41. OUTSTANDING ISSUES REGARDING THE WEIGHT OF THE EVIDENCE • Consistency of results across endpoints • Is analysis of withdrawals a method to balance efficacy and safety? • Which analyses rise, on clinical grounds, to a level of importance here?

  42. EXTRA SLIDES

  43. SLEDAI Categories: Trial 95-02 % responders (primary endpoint) GL701 PLC (n=189) (n=192) SLEDAI 0-2 7% (3/42) 22% (10/46) 2-4 31% (9/29) 28% (11/40) 4-8 46% (30/65) 35% (24/68) >8 30% (16/53) 18% (7/38)

  44. KJ extra: Risk / benefit • Will the indication, if demonstrated, have shrunk so much as to suggest inadequate R/B? e.g. women / pre-menopausal / with mild-mod disease / SLEDAI>2 / ... • If a clear efficacy demonstration were made in a major clinical subset of lupus, what overall database size (#/duration) and characteristics are reasonable?

  45. KJ extra: Moving forward • Dredging this database • by dominant organ involvement at outset • further explore DHEA-S levels and presence (or recent use) of prednisone re. response • Make data available to academic methodologists interested in lupus measurements - will move much slower w/o • Closely look at the kidney - ensure not renal lupus signal (w/ another pilot, if needed)

  46. KJ extra: Moving forward - caution • DHEA may have a physiological role in counteracting (hormonally, somehow) some lupus features, but it may have an equally predictable physiologic toxicity profile which engages just as early (or earlier) and, essentially, counterbalances efficacy all along the way.

  47. KJ extra: Additional RCTs - preparatory • Assess loss of information with dichotomous outcomes versus clarity of statistics (and interpretability to naïve clinicians • Readdress “steroid stuck” • Get “domain” agreement (like w/ OA) • control of experiment wide alpha (multiplicity)

  48. KJ extra: Lupus RCTs - intrinsic problems • Need direct, public discussion of RCT design/conduct/analysis/interpretation issues in lupus -- what venues? • Biggest issues, in my mind • face validity for lupus (can’t adapt from other settings) • controlling experiment-wide alpha (i.e. multiplicity)

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