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Randomized Clinical Trials in Rheumatology: Reporting Safety and Outcome Measures

Yusuf Yazıcı, MD Assistant Professor of Medicine, NYU School of Medicine Director, Seligman Center for Advanced Therapeutics NYU Hospital for Joint Diseases. Randomized Clinical Trials in Rheumatology: Reporting Safety and Outcome Measures. Overview.

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Randomized Clinical Trials in Rheumatology: Reporting Safety and Outcome Measures

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  1. Yusuf Yazıcı, MD Assistant Professor of Medicine, NYU School of Medicine Director, Seligman Center for Advanced Therapeutics NYU Hospital for Joint Diseases Randomized Clinical Trials in Rheumatology:Reporting Safety and Outcome Measures

  2. Overview Ioannidis J, Lau J. JAMA 2001;285:437–443. • RCT trials are the leading source of data in determining treatment choices • Good source of efficacy data • Completeness of safety reporting is inadequate • Methodological concerns • Reporting selective results • Errors in reporting • Focus on: • Time to event • Standardized incidence ratios (SIR) • Radiographic data reporting • Adequate sample size • False impression of safety • Disease activity assessment measures

  3. Time to adverse event

  4. Time to adverse event • Problem in reporting AEs in RCT • Time to event • Clue to causality • When to expect AEs in clinical care • Instantaneous risk might be different for drugs, but the cumulative risk will be similar • ‘Average risk’ does not reflect the true risk faced by patients, especially when decisions are being made at the beginning of treatment

  5. Risk of adverse effects related to drug exposure Collet JP, Bolvin JF. In: Pharmacoepidemiology, 3rd Edn, Strom BL ed. 2000.

  6. An increased frequency of lymphomas, tuberculosis and demyelinating CNS disease has been associated TNF inhibitor use SEER database Based on annual incidence in the population, which is expected to be evenly distributed If there is some skewing as to time of malignancies in the treatment arm, this would make comparisons based on an annual incidence inaccurate TNF inhibitors and lymphomas • Brown SL, et al. Arthritis Rheum 2002;3151–3158. • Yazici Y, Yazici H. Arthritis Rheum 2004; 50: S302

  7. TNF inhibitors and lymphomas 1. Brown SL, et al. Arthritis Rheum 2002;46:3151–3158; 2. Yazici H. Arthritis Rheum 2003;48:2389. • TNF inhibitor use and lymphoma development, as reported to the Federal Drug Administration (FDA)1 • Twenty-six lymphomas • Fourteen occurred within 2 months of use • Non-Hodgkin’s lymphoma (NHL) • Two-monthly incidence in normal population 3/100,000 • Ten out of 16 occurred in 2 months2 • Two-monthly NHL occurrence in etanercept users =10/100,000 • Nearly 3-4 times

  8. Tumor necrosis factor-α antagonist use and demyelinating CNS disease Nine cases among 77,152 users of etanercept during a 19-month period They noted that this frequency was not different from that found in the general population – 4–6/100,000 per annum Half of the cases occurred within 4 months of etanercept use Four-monthly incidence risk of etanercept use of 5.8/100,000 Four-monthly risk in the general population on the other hand would be 2.0/100,000, if the upper limit, 6.0/100,000, quoted for the general population is used Demyelinating central nervous system disease Mohan N, et al. Arthritis Rheum 2001;44:2862–2869.

  9. Risk of coccidioidomycosis in patients treated with TNF-α antagonists Thirteen cases of coccidioidomycosis associated with TNF-α therapy were reported Again seven out of 13 cases developed within 2 months of starting TNF-α therapy Coccidioidomycosis and TNF inhibitors Bergstrom L, et al. Arthritis Rheum 2004;50:1959–1966.

  10. Summary of malignancies in randomized controlled trials Median: 19 weeks Bongartz T, et al. JAMA 2006;295:2275–2285.

  11. Time to neoplasia 14 12 10 8 Number of neoplasms 6 4 2 0 0–12 13–24 25–36 37–48 49–60 61–72 72+ Weeks Based on data from Bongartz T, et al. JAMA 2006;295:2275–2285, courtesy of Dr H Yazici

  12. Infections Curtis JR, et al. Arthritis Rheum 2007;56:1125–1133.

  13. Infections Curtis JR, et al. Arthritis Rheum 2007; 56:1125–1133. • Hospital medical records with claims database reviewed • Median follow up of 17 months • Tumor necrosis factor-based treatment compared with MTX (or other DMARD-based) treatment • Reviewed 187 out of 217 suspected bacterial infections • TNF-α antagonist =65 in 2393 exposed persons (2.7%) • DMARD =58 in 2933 exposed persons (2.0%) • Number needed to harm =143 • Median time from exposure to medication to infection was <30 days for both groups • 93% occurred in 90 days • Multivariable adjustment approximately two times in TNF-α versus MTX

  14. Increased early risk Curtis JR, et al. Arthritis Rheum 2007; 56:1125–1133. • In the first 6 months • Thirty-two infections in TNF-α cohort • Nineteen infections in DMARD cohort • Adjusted hazard ratio of infection in the first 6 months after start of treatment • TNF-α compared with MTX controls was 4.2(95% confidence intervals [CI] 2.0-88.8) • Similar to JAMA paper

  15. Surveillance, epidemiology and end-results database (SEER) • If timing of a malignancy is not evenly distributed, we should not be using a yearly rate to compare incidence rates • SEER = 12 expected lymphomas in RA patients over 12 months, 1 per month • TNF-α = 12 seen in RCT • Conclusion is that there is no difference • TNF-α lymphoma – Eight in the first 4 months = 2/month – Four in the last 8 months = 0.5/month • In the case of lymphoma development • Using annual incidence risk in the general population as a comparator is inappropriate • Development of such lymphomas was within the few months after drug initiation in more than 50% of these patients1 • The expected random occurrence of lymphomas in the general population would make the real risk look smaller2

  16. As more than half of these cases occur during the first months of therapy, quarterly or monthly (rather than annual) incidence risks in the normal population should be used for comparison Increased incidence risks for TNF-α antagonist-related adverse events (AEs) would necessitate a reexamination of the screening protocols and patient selection criteria used for these therapies Does not carry the same message for the practicing physician Variable period comparison needs to be used 2-, 3-, 4-, 6-monthly rates Excluding events in the first 60–180 days Not done with other AEs No strong evidence base for doing so Tumor necrosis factor, time to AE

  17. Time to adverse event reporting in randomized controlled trials Yazici Y, Yazici H. Ann Rheum Dis 2007;66:124–127. • All RCT of cyclo-oxygenase-2 (COX-2) inhibitors and TNF-α inhibitors • Industry-sponsored RCTs (91%) • One-third gave time to AE in the report either as a table, text or Kaplan-Meier curve • No better reporting for serious adverse event (SAE) • Eight out of 17 RA–TNF-α trials reporting malignancy used the Surveillance, Epidemiology and End Results (SEER) database

  18. Time to adverse event and serious adverse event Yazici Y, Yazici H. Ann Rheum Dis 2007;66:124–127. COX-2=cyclo-oxygenase-2; TNF-α=tumor necrosis factor-α; RCT=randomized controlled trial; AE=adverse event; SAE=serious/severe adverse event; SIR=standardized incidence ratio; SEER=Surveillance, Epidemiology and End-Results.

  19. Patient years

  20. Patient years Paterson KR. BMJ 1995;310:1470. • Commonly used in RCT: ‘patient–years’ to define the time frame of AE incidence • What is the problem? • Relatively rare idiosyncratic drug reactions usually occur early in the treatment course and in only a few individuals • Apart from the few with AEs, remaining patients who are prescribed the drug will never get these reactions however long they use the drug

  21. Patient years • AE 20% chance in the first month, and not seen after • 100 patients followed for one year • 80% of patients after one year will have no AE • 20/100 patient years • One more year, no one gets AE • 20/200 patient years =10/100 patient years • Nothing has changed in the absolute risk when it is started in a new patient.

  22. Patient years (2) Paterson KR. BMJ 1995;310:1470. • Unduly inflate the denominator of the related incidence ratio; potential of under-representing AE • Late-onset AEs are also likely to be missed when we use patient–years • In short, only “…when an event is (or is believed to be) likely to occur at anystage during continuous treatment with a drug then an eventrate with a time component (rate per person year, etc) has atrue meaning” • Not clear whether more than one event per patient goes into the numerator

  23. Patient years (3) Paterson KR. BMJ 1995;310:1470. If more than one AE/patient is included in a numerator, statistics done with that incidence ratio will be erroneous An AE can repeat itself, like skin rashes in TNF-α antagonist use in any one patient This leads to over-representation of the said individual in tests of significance

  24. “Statistics are like swimwear – what they reveal is suggestive but what they conceal is vital.” –Ashish Mahajan, Lancet 2007

  25. Reporting radiographic outcomes in RA RCTs

  26. Conventional wisdom… Schett et al. Arthritis Rheum 2008

  27. Conventional wisdom… “…studies of anti-TNF therapy plus MTX, compared with the effect with MTX alone, have shown that although MTX is relatively effective at relieving clinical symptoms, it has little or no effect on underlying radiological progression.” • Emery P, McInnes IB, van Vollenhoven R, Kraan MC. Rheumatology (Oxford) 2008

  28. Etanercept versus methotrexate Klareskog L, et al. Lancet 2004;363:675–681. ACR=American College of Rheumatology; MTX=methotrexate.

  29. Adalimumab versus methotrexate Breedveld FC, et al. Arthritis Rheum 2006;54:26–37. §p<0.001 vs ADA alone and p=0.022 vs MTX alone; †p<0.001 vs ADA alone and p=0.002 vs MTX alone; #p=0.043 vs ADA alone; *p<0.001 vs ADA alone and vs MTX alone; ACR=American College of Rheumatology; ADA=adalimumab; MTX=methotrexate.

  30. PREMIER X-ray Breedveld FC, et al. Arthritis Rheum 2006;54:26–37. MTX=methotrexate.

  31. Demographic and study characteristics of four methotrexate-naïve randomized controlled trials Yazici Y, Yazici H. Clin Exp Rheumatol 2008;26:449–452.

  32. 12-month efficacy and radiographic outcomes in four methotrexate-naïve randomized controlled studies Yazici Y, Yazici H. Clin Exp Rheumatol 2008;26:449–452. ACR=American College of Rheumatology, NNT=number needed to treat; ERA=Early RA; ETA=etanercept; NR=not reported; NR*=values not given, only depicted in graphic form; MTX=methotrexate; TNF=tumor necrosis factor inhibitor; TEMPO=Trial of Etanercept and MTX with radiographic Patient Outcomes; IFX=infliximab; ADA=adalimumab.

  33. Radiographic outcomes in four methotrexate-naïve randomized controlled trials 6 5.7 5 4 3.7 3 Sharp scale 2.8 3 2 1.59 1.3 1 1 0.52 0.4 –0.54 0 ERA ETA ERA MTX TEMPO TEMPO TEMPO ASPIRE IFX+MTX ASPIRE MTX PREMIER ADA+MTX PREMIER ADA PREMIER MTX ETA+MTX ETA MTX Sharp score Yazici Y, Yazici H. Clin Exp Rheumatol 2008;26:449–452.

  34. Radiographic outcomes in four methotrexate-naïve randomized controlled trials 450 400 350 300 250 Sharp scale 200 150 100 50 5.7 2.8 3.7 3 1 1.59 1.3 –0.54 0.52 0.4 0 ERA ETA ERA MTX TEMPO TEMPO TEMPO ASPIRE IFX+MTX ASPIRE MTX PREMIER ADA+MTX PREMIER ADA PREMIER MTX ETA+MTX ETA MTX Sharp score Yazici Y, Yazici H. Clin Exp Rheumatol 2008;26:449–452.

  35. 1.3 (PREMIER combo) vs 5.7 (PREMIER MTX alone) • 1.3/448=0.003 • 5.7/448=0.01 • 0.01-0.003=0.007 • Similar to saying pain score of 49.8 (combo) vs 49.1 (alone) is clinically significant and should lead to treatment change/preference

  36. Abatacept: limited inhibition of radiographic progression – mean change in total Sharp scores (Genant modification) 4 Placebo + MTX (n=195) 3 Abatacept 10 mg/kg + MTX (n=391) 2.3 50%inhibition 2 Mean changefrom baseline 1 * 1.2 0 -1 0 6 12 Months Kremer J, et al. Ann Intern Med 2006;144:865–876; Genant H, et al. Ann Rheum Dis 2005;64(Suppl III):56. Abstract OP001. *p<0.05 vs placebo + MTX; †p<0.01 vs placebo + MTX. MTX=methotraxate; JSN=joint space narrowing.

  37. A new way of assessing radiographic outcomes: cumulative probability plots 40 30 Increasing score 20 10 Change in total Sharp score Unchanged 0 Decreasing score –10 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Cumulative probability Landewe R, van der Heijde D. Arthritis Rheum 2004;50:699–706.

  38. Probability curves

  39. BeSt study: design Group 2Step-up Combo Group 1Sequential Mono Group 3Initial Combo Group 4 IFX + MTX n=121 n=126 n=133 n=128 MTX 15 mg MTX 15 mg MTX 7.5 mg/wk + SSA + pred 607.5 mg/day MTX 25 mg + IFX 3 mg/kg n=120 MTX 25 mg + SSA + pred MTX 25 mg MTX 25 mg MTX + IFX 10 mg/kg SSA MTX + SSA MTX + CsA + pred MTX + SSA + HCQ Leflunomide SSA MTX + IFX n=25 MTX + SSA + HCQ + pred Leflunomide MTX + IFX Leflunomide n=49 MTX + IFX MTX + CSA + pred Gold Gold n=12 Gold MTX + CSA + pred MTX + CsA + pred AZA + pred AZA + pred Leflunomide AZA + pred Gold Goekoop-Ruiterman YP, et al. Arthritis Rheum 2005;52:3381–90.

  40. BeSt study Goekoop-Ruiterman YP, et al. Ann Intern Med 2007;146:406–15.

  41. Objective: 18-month study to determine whether closely monitored step-up therapy with non-biologic DMARDs would result in significantly better outcomes than routine care Study population: 110 patients aged 18–75 years with RA of <5 years’ duration and active disease (Disease activity score [DAS] >2.4) Outcomes: Primary: % of patients achieving a DAS score of <2.4 Secondary: % of patients achieving remission (DAS score <1.6) % of patients achieving American College of Rheumatology–20, 50 and 70 responses TICORA: intensive versus routine control of disease activity in rheumatoid arthritis Grigor C, et al. Lancet 2004;364:263–269. TICORA=Tight Control of Rheumatoid Arthritis.

  42. TICORA: intensive versus routine control of disease activity in rheumatoid arthritis (2) • Intensive care group: • Monthly review of disease activity and measurement of DAS • Intra-articular corticosteroid injection of swollen joints as required • Intramuscular corticosteroid injection given as ‘bridge therapy’ during first 3 months of a new DMARD • Structured escalation of therapy if DAS >2.4 after 3 months of a new DMARD: • SSZ  MTX + SSZ + HCQ  MTX (up to 25 mg/wk); SSZ (up to 5 g/d)  prednisolone 7.5 mg/d  switch to MTX + CSA  switch to leflunomide • Routine care group: • Review every 3 months (with no measure of DAS) • Management at the discretion of attending rheumatologist (i.e. DMARD therapy; intra-articular, intramuscular and/or oral corticosteroids) Grigor C, et al. Lancet 2004;364:263–269. TICORA=Tight Control of Rheumatoid Arthritis.

  43. Tight control for rheumatoid arthritis: TICORA study

  44. Tight control for rheumatoid arthritis: TICORA study (2) Grigor, et al. Lancet 2004;364:263–269. *Mantel-Haenszel procedure used. EULAR=European Union League Against Rheumatism; ACR=American College of Rheumatology.

  45. TICORA 2 • 96 RA patients, with <1 yr of disease • No previous DMARDs (except HCQ) • DAS28 every month, treatment adjusted • IA as needed • Primary outcome was DAS28 • Blinded assessment • 85% had erosions at baseline • DAS28 6.9 Saunders SA et al. Arthritis Rheum 2008;58:1310-17

  46. TICORA 2

  47. TICORA 2

  48. TICORA 2

  49. ‘Efficacy versus safetyversus efficacy and safety trials’

  50. ‘Efficacy and safety’ randomized controlled trials Yazici Y, et al. Rheumatology 2008;47:1054–1057. • Trend of increasing number of RCT called ‘efficacy and safety’ trials • All RCT of TNF-α inhibitors in RA, psoriatic arthritis (PsA) and ankylosing spondylitis (AS) • Only original reports • ‘Efficacy’, ‘safety’ or ‘efficacy and safety’ • Power for safety and efficacy • Type II error • Power • Alpha • Beta • Expected treatment effects in both arms

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