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Clinical Trials

Hans-Christoph DienerSenior Professor of Clinical Neuroscienes

Medical Faculty University Duisburg-EssenGermany

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

Titel

• 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

Tfelt-Hansen P, Diener HC et al, Cephalalgia 2012;32:6-38

IHS published guidelines on the conduct of controlled trials

Why Clinical Trials?

3

http://www.spiegel.de/fotostrecke/fotostrecke-49622-2.html

Titel

• 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

Overview

4


Titel


trials



• Safety trials


trials





Overview

5


Titel

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

FDA and EMA requirements

Requires that symptoms are present at time of drug intake

Choice of primary endpoint in migraine trials

6


Titel

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

My proposal

Endpoint is more relevant for patients

Choice of primary endpoint in migraine trials

7


Titel


trials



• Safety trials


trials





Overview

8


Titel

Kam-Hansen et al, Science Translational Medicine, 2014: 6(1):218ra5. doi:

10.1126/scitranslmed.3006175

How does expectation affect the treatment outcome?

Treatment of migraine attacks and placebo

9


Titel



6 migraine attacks were treated, information given alternated

Study design

10


Titel



50% of the treatment response is driven by expectation

Effect on expectation on the treatment success

11


Titel

Zolmitriptan and sumatriptan are not effective????

Zolmitriptan in the treatment of migraine attacks

12

• 1058 patients were included

• Primary endpoint: complete headache

response (no recurrence)

• 39% zolmitriptan

• 38% sumatriptan

• 32% placebo


Titel

Zolmitriptan for the treatment of acute migraine attacks

13


Titel

Placebo killed the study

Placebo in randomized trials

14


Titel

• 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

Conclusions

Placebo in randomized headache trials

15


Titel


trials



• Safety trials


trials





Overview

16


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

18

Change in Headache Days: Primary Endpoint2

PREEMPT Pooled Analysis:

~70% of Patients* Achieved ≥50% Reduction in

Headache Days at 56 Weeks1

-14

-12

-10

-8

-6

-4

-2

00 4 8 12 16 20 24 28 32 36 40 44 48 52 56

He

ad

ac

he

Da

ys

/28

Da

ys

Week

p<0.001p<0.001

p<0.001

p<0.001

p<0.001

Double-Blind Phase Open-Label Phase

Botulinum Toxin Type A

Placebo

Week 24

Primary Endpoint

p<0.001

p<0.001p=0.008

p=0.01p=0.007

p=0.019p=0.047

p=0.011p=0.019

He

ad

ac

he

Da

ys

/28

Da

ys

(Me

an

Ch

an

ge

Fro

m B

as

eli

ne

)

How would Botox compare to topiramate?

Titel

Similar efficacy for topiramate and propranolol

19

• a


Titel

1 active, 4 comparators and 1 placebo

Combination analgesics for acute migraine attacks

20


Titel

a

21


Titel

• 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

Conclusion

22


Titel


trials



• Safety trials


trials





Overview

23


Titel

24

Study terminated due to liver toxicity

Telcagepant for the treatment of menstrual migraine


Titel

• Open label safety trials should run parallel to

randomized phase 2 and phase 3 trials

• Conclusions

Safety trials

25


Titel


trials



• Safety trials


trials





Overview

26


Titel

Trial missed the primary endpoint

Onabotulinumtoxin A in chronic migraine

27


Titel

aa

28

Trial was positive on the primary endpoint


Titel

• The preferred primary endpoint is either migraine days

or headache days

Conclusions

Choice of primary endpoint in migraine prevention

29


Titel


trials



• Safety trials


trials





Overview

30


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)

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.

-14

-12

-10

-8

-6

-4

-2

00 4 8 12 16 20 24 28 32 36 40 44 48 52 56

He

adac

he

Day

s/2

8 D

ays

Week

p < 0.001p < 0.001

p < 0.001

p < 0.001

p < 0.001

Double-Blind Phase Open-Label Phase

BOTOX®

Placebo

Week 24 Primary Endpoint

He

adac

he

Day

s/2

8 D

ays

(Me

an C

han

ge F

rom

Bas

elin

e)

p < 0.001

p < 0.001p = 0.008

p = 0.01p = 0.007

p = 0.019

p = 0.047

p = 0.011p = 0.019

Aurora SK et al. Presented at IHC 2009.

Titel


trials



• Safety trials


trials





Overview

32


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

Titel

• Do we need to establish treatment failure prospectively?

• Experience from the zolmitriptan trial

• No need for a comparator

Conclusions

Trials in treatment refractory patients

37


Titel


trials



• Safety trials


trials





Overview

38


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

Titel

• Randomized, placebo-controlled trials are requested by

FDA and EMA

• Almost impossible to do in children

• Consider large placebo effect

Conclusions

Treatment trials in children and adolescents

43


Titel


trials



• Safety trials


trials





Overview

44


Titel

A randomized trial to investigate what happens if prophylaxis is terminated

45


Titel

Cessation trials can teach us on the course of migraine46


Titel

• Important information to see whether a rebound occurs

Conclusion

End of treatment trials

47


Titel


trials



• Safety trials


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Final conclusions

48


Documents

Clinical Trials - cdn.ymaws.com · • Amgen • Astra-Zeneca • Bayer • BMS • Böhringer-Ingelheim • Chordate • Coherex • CoLucid • Eisai • Electrocore • Endo Pharmac