Joop vanoene 6thannualwien_1

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Invited presentation held at the 6th Annual Future of Clinical Trials conference in Vienna, October 26-27, 2010

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Joop vanoene 6thannualwien_1

  1. 1. Applicability of naturalisticprinciples in a clinical study: PROMPT Joop C. van Oene, PhD
  2. 2. Clinical development rate of paramount importance  Speeding-up approval/licensing processes is important to gain time to – provide better care earlier – reduce trial performance costs by being more efficient – start rewarding long-term investments earlier – leave longer profitable period (till patent expiry) – exploit competitive advantage
  3. 3. Recruitment problems are often rate-limiting  Recruitment rate may be slowed down by – Low incidence/prevalence of the disease – Logistic factors related to finding patients, obtaining informed consent, proper investigational facilities, etc o tackeled by raising sponsor involvement/investment – Psychologic factors related to motivational level of o investigators (doctors) o trial subjects (patients)
  4. 4. How motivate Doctors to participate CONs  loss of time involved in study approval and performance - usually financially compensated PROs  explore new treatment options for own patients  contribute to the advancement of medical knowledge  be recognised for that effort by colleagues and institution  generate funds from revenues
  5. 5. How motivate Patients to participate “WHAT’S IN IT FOR ME?” will be the patient’s first question !! CONs  loss of time (for work, education, leisure): usually not compensated for  loss of money (travel costs, drink&eat): can be partly or fully reimbursed PROs  explore new, alternative and potentially better treatment options  receive (supposedly) active treatment for free  obtain better insight/control of the disorder through tighter monitoring during trial as compared to standard-of-care
  6. 6. What are the implications for clinical study design Both doctors and patients want to test the new treatment by experiencing its therapeutic and adverse effects to conclude on its merits for future/continued use  To be able to draw such conclusions they should ideally – Know for sure which treatment is taken -> open-label medication – Be allowed to adjust/optimize the dose -> flexible dosing – Compare to no treatment (or placebo) and, if available, to alternative treatment(s) – Compare to the effects in similar patients
  7. 7. Where do the regular RCTs fall short  Randomization (treatment is imposed as is the dose) – neither doctor nor patient has any choice – may involve a low or even zero dose (placebo) leading to trial discontinuation for lack of efficacy – may involve a (too) high dose leading to trial discontinuation for of lack of tolerance  Blinding (often double-blind): – patient and/or doctor are unaware of medication type and/or dose RESULT: patient and doctor are both uncertain about the interpretation of the trial results and the potential effectiveness of the investigational drug -> reduced motivation to participate or continue with the study
  8. 8. What does “naturalistic” mean [Cambridge Advanced Learners Dictionary:]  Naturalism – (in art and literature) showing people and experiences as they really are, instead of suggesting that they are better than they really are or representing them in a fixed style  Naturalistic adjective – showing things as they really are …
  9. 9. How does „naturalistic‟ work in clinical studies  To mimick everyday clinical practice, use – open-label study medication with – flexible dosing (within specified range) at least during an early part of the study to – optimise patient-preferred dosing by finding the best balance of therapeutic effects and side effects  Combination with a randomized, (double-blind), comparative phase is recommended to enable – answering scientific questions, draw solid conclusions – meet ethics requirements (avoid “seeding” impression)
  10. 10. Where to fit in the clinical development program  Early-phase clinical studies (I-IIIa) focus on the investigational drug, their primary goal is to – demonstrate that the drug is efficacious in the patient  Late-phase clinical studies (IIIb-IV) focus on the patient, their primary goal is to – find out how the patient benefits most from the drug Statement Naturalistic features fit best in late-phase clinical studies but should be incorporated as early as possible in the development program to raise predictive power of the trial results for everyday clinical practice
  11. 11. Will a naturalistic design facilitate recruitment  A naturalistic study design is expected to positively influence the motivation of both doctors and patients because it will – Raise doctor’s experience with handling (side) effects of the drug in relation to dosing – Position the doctor better to treat future patients in the most appropriate manner – Assure the patient of getting active treatment and achieving the most suitable dose for his/her condition
  12. 12. PROlonged Migraine Prevention with Topiramate (PROMPT) Protocol: TOPMAT-MIG-303 EudraCT: 2005-000321-29 running: Dec 2003 - May 2006 primary publication: Lancet Neurol 2007;6:1054-62
  13. 13. PROMPT rationale  Topiramate had been registered for the prevention of migraine in most European countries  Label text did not limit the treatment duration with topiramate  Various local/national guidelines, however, demanded revision of migraine preventive therapy after 4-6 months of treatment, but  No evidence was available from clinical studies to support the validity of these guidelines PROMPT was set up to address this issue
  14. 14. PROMPT objectives  Primary Objective – evaluate the continued efficacy (beyond 6 months) of topiramate in the prophylaxis of migraine  Secondary Objectives – determine the preferred topiramate dose – evaluate the use of acute medication
  15. 15. PROMPT trial design  4-8 weeks : prospective baseline [no preventive treatment] – 4 weeks if number of migraine days is at least 4 per month – 8 weeks if this number has not been reached in the first month  6 months : open label (OL) treatment with topiramate – dose 50-200 mg/day determined by patient’s preference – individually preferred dose is fixed for month 6  6 months : double-blind (DB) treatment with topiramate or placebo – determined by randomization (1:1) – same dose (number of tablets) as in month-6 of open-label treatment  0-1 week : run-out – trial medication tapered off in 1 week if >100 mg/day – trial medication stopped immediately if <100 mg/day
  16. 16. PROMPT dosing Baseline Open-Label Phase Double-Blind Phase Run-Out Phase Phase Titration Flexible dose Fixed dose Fixed dose Taper off 200 mg/d 200 mg/d TOPIRAMATE TOPIRAMATE 100 75 50 25 50 mg/d 50 mg/d No Treatment PLACEBO 4 (8) weeks 4 weeks 18 weeks 4 weeks 1 week 25 weeks 1 weekScreening Week 0 Week 26 Week 52 (Enrollment) (Randomization) (Completion)
  17. 17. PROMPT key selection criteria Inclusion criteria • Aged 18-80 years inclusive • Meets the IHS criteria for migraine* • Established history of migraine for > 1 year • At least 4 monthly migraine days during the previous 3 months • Capable of keeping trial records and having signed the ICF * Headache Classification Committee of the International Headache Society Cephalalgia 1988;8(Suppl 7):1-96.
  18. 18. PROMPT primary endpoint  Primary efficacy parameter – Change in the number of migraine days during the last 4 weeks of the double-blind phase relative to the last 4 weeks of the open-label phase  Hypothesis (pre-trial) – Difference between topiramate and placebo group is (at least) 1.0 migraine day per 4 weeks
  19. 19. PROMPTRECRUITMENT AND TRIAL SAMPLE
  20. 20. PROMPT participation  21 countries / 88 sites* / 954 subjects  954 Screened  136 Screen Failures = 14.3% [ est. 25% ]  818 Enrolled OL phase 259 Early Terminated = 31.6% [ est. 35% ]  45 Not Randomized = 8.1% [ est. 20% ]  514 Randomized DB phase = 53.9% of Screened [ est. 39% ] * ) 1 more site with 10 subjects was disqualified and left out of the analysis 15
  21. 21. PROMPT subject recruitment
  22. 22. Demographic and Baseline Characteristics mean Enrolled Randomized median (range) N = 818 N = 514 Age, years 39.8 40.1 40 (18-69) 40 (18-69) Height, cm 166.0 165.8 165 (140-194) 165 (140-194) Weight, kg 69.8 70.6 67 (45-151) 68 (45-151) BMI, kg/m² 25.3 25.6 24.5 (16.4-52.5) 24.9 (16.6-52.1) Gender, male/female % 13 / 87 13 / 87 Number of monthly migraine days at start 8.9 8.7 8.0 (0.0-28) 8.0 (3.3-28)
  23. 23. PROMPT records in baseline/OL phase  Migraine observations 29,935  Acute medication observations 28,031  Adverse event observations 2,877  Concomitant medication observations 1,866  Trial medication observations 4,665
  24. 24. PROMPTTOPIRAMATE DOSING
  25. 25. Flexible dosing of topiramate (OL phase) Distribution of the last daily doses (N = 818) 50 40 % Subjects 30 20 10 0 12,5 25 50 75 100 125 150 175 200 Topiramate dose (mg/day)
  26. 26. Fixed dosing of trial medication (DB phase) Distribution of the last daily doses topiramate (N=254) placebo (N=258) 50 40 % Subjects 30 20 10 0 0 25 50 75 100 125 150 175 200 Dose (mg/day)
  27. 27. PROMPT EFFICACY RESULTSChange in monthly migraine days
  28. 28. PROMPT primary efficacy parameter (OL phase) Mean number of migraine days per 4 weeks intent-to-treat analysis (n=811) completer analysis (n=559)10 8,9 8,8 8 5,8 6 4,8 4 2 0 *** ***-2-4 -3,1 -4,0-6 Baseline Month 6 Baseline Month 6 migraine days change in migraine days *** p <0.0001 versus baseline
  29. 29. PROMPT time course of migraine days Mean number of migraine days per 4 weeks (observed cases) All OL (N=811) Topiramate DB (N=253) Placebo DB (N=257) * p < 0.05 10 OL PHASE DB PHASE 9 8 7 * 6 5 4 3 2 1 0 0 10 20 30 40 50 60 Time (weeks)
  30. 30. PROMPT primary efficacy parameter (DB phase) Mean change in number of migraine days per 4 weeks topiramate placebo Primary *** endpoint 1,6 1,4 *** ** 1,2 1,2 1,0 0,8 ** 0,6 0,4 0,2 0,1 0,0 -0,2 Start Week Week Week Week Last 4 -0,4 DB +4 +8 +16 +26 weeks ** p<0.01 vs. topiramate *** p<0.001 vs. topiramate
  31. 31. PROMPT acute medication days (OL phase)Mean number of days per 4 weeks with acute medication intake any acute triptans analgesics 7 6,1 6 5,0 5 4,2 3,7 4 3,0 3 1,9 2 1 *** *** *** 0 -1 -2 -1,3 -1,1 -2,0 -3 Base- End- Base- End- Base- End- line point line point line point acute medication days change in acute medication days *** p <0.0001 versus start
  32. 32. PROMPT change in Kg body weight versus baseline (observed cases) topiramate-topiramate topiramate-placebo 0 10 20 30 40 50 60 0 -0,5 OL PHASE DB PHASE -1 -1,5 -2 -2,5 -3 *** -3,5 *** -4 -4,5 *** p < 0.001 Time (weeks)
  33. 33. PROMPT conclusions  Efficacy – The primary efficacy parameter after withdrawal of study medication was positive, showing an increase in the number of migraine days with placebo versus no change with topiramate.  Safety – Adverse events were similar to those observed in previous studies both in nature and in frequency of occurrence.
  34. 34. Naturalistic principle conclusions  Attractive to investigators as treating physicians - “hands-on experience”  Motivating for patients - helpful in patient recruitment  Prerequisite to obtain insight into patient-preferred dosages  Powerful in combination with double-blind, randomized part in order to meet both scientific standards and ethics requirements

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