Clinical Trials. Hans-Christoph Diener Senior Professor of Clinical Neuroscienes Medical Faculty University Duisburg-Essen Germany

Clinical Trials Hans-Christoph Diener Senior Professor of Clinical Neuroscienes Medical Faculty University Duisburg-Essen Germany

Conflict of Interest Statement German Research Council German Ministry of Education and Reserach EU Addex Alder Allergan Almirall Amgen Astra-Zeneca Bayer BMS Böhringer- Ingelheim Chordate Coherex CoLucid Eisai Electrocore Endo Pharmac. GSK Janssen-Cilag J&J Labrys Lilly MAP Menarini Medtronic MSD Neuroscore Novartis Novo Nordisk Pfizer Sanofi-Aventis Schering Solvay St. Jude Medical Teva Weber & Weber Wyeth

Why Clinical Trials? The only way to evaluate the efficacy of a drug, device or procedure Evaluate safety and tolerability Prerequisite for approval by health authorities Prerequisite for reimbursement IHS published guidelines on the conduct of controlled trials Tfelt-Hansen P, Diener HC et al, Cephalalgia 2012;32:6-38 3

Overview Choice of primary endpoint in migraine trials Requirement for placebo Treatment comparator Safety trials Primary endpoint in migraine prevention trials Open-label long-term follow-up Trials in refractory headache Trials in children and adolescents Investigation of treatment termination 4

Choice of primary endpoint in migraine trials FDA and EMA requirements In trials investigating the efficacy of drugs for the treatment of acute migraine attacks: Pain free after 2 hours Free of nausea Free of vomiting Free of photophobia Free of phonophobia Requires that symptoms are present at time of drug intake 6

Choice of primary endpoint in migraine trials My proposal In trials investigating the efficacy of drugs for the treatment of acute migraine attacks: Pain free after 2 hours Relief from the most bothersome additional symptom Endpoint is more relevant for patients 7

Treatment of migraine attacks and placebo How does expectation affect the treatment outcome? Kam-Hansen et al, Science Translational Medicine, 2014: 6(1):218ra5. doi: 10.1126/scitranslmed.3006175 9

Study design 6 migraine attacks were treated, information given alternated Kam-Hansen et al, Science Translational Medicine, 2014: 6(1):218ra5. doi: 10.1126/scitranslmed.3006175 10

Effect on expectation on the treatment success 50% of the treatment response is driven by expectation Kam-Hansen et al, Science Translational Medicine, 2014: 6(1):218ra5. doi: 10.1126/scitranslmed.3006175 11

Zolmitriptan in the treatment of migraine attacks 1058 patients were included Primary endpoint: complete headache response (no recurrence) 39% zolmitriptan 38% sumatriptan 32% placebo Zolmitriptan and sumatriptan are not effective???? 12

Zolmitriptan for the treatment of acute migraine attacks 13

Placebo in randomized trials Placebo killed the study 14

Placebo in randomized headache trials Conclusions Placebo is needed in efficacy trials We need to know and control factors influencing the placebo response Uneven randomization Expectation Particular populations: children and adolescents 15

Are we sure that both drugs are superior to placebo in this population?

PREEMPT Pooled Analysis: ~70% of Patients* Achieved 50% Reduction in Headache Days at 56 Weeks 1 Headache Days/28 Days (Mean Change From Baseline) Headache Days/28 Days Change in Headache Days: Primary Endpoint 2 Week 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 0-2 -4 Week 24 Primary Endpoint Botulinum Toxin Type A Placebo -6 p<0.001-8 -10-12 -14 p<0.001 p<0.001p<0.001 Double-Blind Phase p<0.001 p<0.001 p<0.001 p=0.008p=0.01 p=0.007 p=0.047 p=0.019 p=0.011 p=0.019 Open-Label Phase How would Botox compare to topiramate? 18

a Similar efficacy for topiramate and propranolol 19

Combination analgesics for acute migraine attacks 1 active, 4 comparators and 1 placebo 20

a 21

Conclusion Both trials in the treatment of acute migraine attacks and migraine prevention require placebo control and a comparator Exceptions are trials which recruit treatment refractory patients 22

Telcagepant for the treatment of menstrual migraine Study terminated due to liver toxicity 24

Safety trials Conclusions Open label safety trials should run parallel to randomized phase 2 and phase 3 trials 25

Onabotulinumtoxin A in chronic migraine Trial missed the primary endpoint 27

aa Trial was positive on the primary endpoint 28

Choice of primary endpoint in migraine prevention Conclusions The preferred primary endpoint is either migraine days or headache days 29

Headache Days/28 Days (Mean Change From Baseline) Headache Days/28 Days 31 PREEMPT Pooled Analysis: Mean Change From Baseline in Headache Days (Primary) At Week 56, ~70% of patients achieved 50% reduction in headache days (from baseline) Week 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56-2 -4 Week 24 Primary Endpoint BOTOX Placebo -6 p < 0.001-8 -10-12 -14 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 Double-Blind Phase p < 0.001 p = 0.008 p = 0.01 p = 0.007 p = 0.047 p = 0.019 p = 0.011 p = 0.019 Open-Label Phase Mean ± standard error. The double-blind phase included 688 subjects in the BOTOX group and 696 in the placebo group. Headache days at baseline: 19.9 BOTOX group vs 19.8 placebo group, p=0.498. Aurora SK et al. Presented at IHC 2009.

Pro Comparator Allows for comparison with other trials and substances Sensitivity test

Contra active comparator New preventive therapies will be used in patients who Failed approved preventive therapy (efficacy) Had contraindications Did not tolerate treatment

Contra Comparator Increased sample size Requires test of prior treatment failure (easy in treatment of acute attacks) Which comparator to choose? Patients will only be prepared to participate in a trial with injectable medication if they see a realistic chance to get active drug

Active Comparator Select adherence as the primary endpoint e.g. topiramate versus new drug for 6 months Offer patients blinded cross-over Offer patients long-term open-label treatment after randomized portion of trial

Trials in treatment refractory patients Conclusions Do we need to establish treatment failure prospectively? Experience from the zolmitriptan trial No need for a comparator 37

Migraine prevention trials Age groups Children 6-11 years Adolescents 12-17 years Very difficult to recruit children in trials with injectable medication and biologicals Sample size almost impossible to estimate

Primary Endpoint Migraine days Headache days Children have difficulties to distinguish headache from migraine Adolescents are able to differentiate

Duration of Placebo Phase 3 months versus 6 months 3 months is enough Almost all recent trials showed a stable difference between active drug and placebo after 3 months Open-label phase for 9 months for all study participants recommended

Active comparator Active comparator versus placebo alone Parents of children and adolescents willing to participate in a randomized trial will only be prepared to do so if available treatments have failed Unethical to expose patients to a treatment that was not tolerated or was ineffective before

Treatment trials in children and adolescents Conclusions Randomized, placebo-controlled trials are requested by FDA and EMA Almost impossible to do in children Consider large placebo effect 43

A randomized trial to investigate what happens if prophylaxis is terminated 45

Cessation trials can teach us on the course of migraine 46

End of treatment trials Conclusion Important information to see whether a rebound occurs 47

Final conclusions Choice of primary endpoint in migraine trials Requirement for placebo Treatment comparator Safety trials Primary endpoint in migraine prevention trials Open-label long-term follow-up Trials in refractory headache Trials in children and adolescents Investigation of treatment termination 48