1-Hershey-Andrew Trial-Design · AssocEd –Headache, Cephalalgia, The Journal of Headache Pain...

11/10/2017

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Trial Design

Andrew D. Hershey, MD, PhD, FAHS

Endowed Chair and Director of Neurology

Co-Director, Headache Center

Cincinnati Children’s Hospital Medical Center

Professor of Pediatrics and Neurology

University of Cincinnati, College of Medicine

Disclosures (ADH)

Support – grants, contracts, honoraria

NIH, CHRF research foundation, Curelator

NIH – Advisory Board, Common Data Elements

Migraine Research Foundation – Advisory Board

Assoc Ed – Headache, Cephalalgia, The Journal of Headache Pain

Advisory Board – Alder, Amgen, Biohaven, Curelator, Depomed, Impax, Lilly, Teva

Outline

• History – Pre and post Randomized, Controlled-studies

• Placebo controlled concept

• Concepts before initiating a Study

• Study types with Headache Examples

• Randomized Controlled Studies

• Crossover

• Placebo run-in

• New study design

• MOST, SMART

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History

• James Lind and scurvy – First Randomized trial – 1747

• Austin Flint and Rheumatic Fever – First Placebo controlled study –1863

• 1944-1946 – First Randomized, Placebo Controlled study

• Antibiotic Patulin in common cold

• Streptomycin in pulmonary tuberculosis

• Strophanthin

• Jellinek – Placebo Responders in Headache Treatment - 1946

History - Jellinek

• 200 subjects

• Drug A made up of a, b and c

• b in short supply

• Treatment A = a, b, and c

• Treatment B = a and c

• Treatment C = a and b

• Treatment D = placebo

Gap Identification

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Gaps in Prevention

• Very limited number of studies in pediatric and adolescent headaches

• Translation from adults studies may be problematic

• Are they really generalizable

• Prevention does not only mean medication

Termiine et al, J Headache Pain, 2011

Gap Identification

• Survey given to Pediatric-Adolescent Section

• Assessed current status of prevention

• Asked what is “Clinically meaningful”

• What they are currently using

• Sample questions

• #3 Meds used

• AMI, Cypro, VPA, Prop, TPM, Other

• #4 Dose of this medication

• #5 How long to tell if work

• #6 Effectiveness level

• >50% reduction HF

• <1/week

• >50% reduction in disability

• Ease of admin

• Cost

• Other

• #7 % reduction that would impact practice

Gap Identification

• Sample questions

• #3 Meds used

• AMI, Cypro, VPA, Prop, TPM, Other

• #4 Dose of this medication

• #5 How long to tell if work

• #6 Effectiveness level

• >50% reduction HF

• <1/week

• >50% reduction in disability

• Ease of admin

• Cost

• Other

• #7 % reduction that would impact practice

0

1

2

3

4

5

6

3a.

Amitriptyline

3b.

Cyproheptadine

3c. Depakote 3d. Propanalol 3e. Topiramate 3f. Other 1

Ranked Prevention - 1 to 6

0

1

2

3

4

5

6

6a. 50% or >

reduction in

headache

frequency

6b. Headache

frequency

reduced to < 1

per week

6c. Low incidence

of side effects

6d. 50 % or >

reduction in

headache

disability

6e. Ease of

administration of

the medicine

6f. Cost of the

medicine

6g. Other criteria

1

Most important clinical effectivenes

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CHAMP Study Staff

Principal Investigators

Andrew Hershey, MD, PhD, FAHS

Scott Powers, PhD, ABPP, FAHS

Christopher Coffey, PhD

Study Leadership Team

Linda Porter, MD, NINDS Project Manager

David Dodick, MD, Medical Safety Monitor

Leigh Ann Chamberlin, CCC Project Manager

Dixie Ecklund, DCC Project Manager

Leslie Korbee, CCC Regulatory Manager

• M. Kabbouche, MD, J. Kacperski, MD, H.L. O’Brien, MD, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH*;

• J. Aceves, MD, Scott and White Healthcare, Temple, TX*;

• D. Arun, MD, Saint Louis University, St. Louis, MO*;

• V. Atluru, MD, Winthrop University Hospital, Mineola, NY*;

• S. Aurora, MD, Stanford Hospitals and Clinics, Palo Alto, CA*;

• N. Bennett, MD, Preferred Clinical Research, Pittsburgh, PA*;

• F. Berenson MD, Atlanta Headache Specialists, Atlanta, GA*;

• J. Bickel, MD, Children’s Mercy Hospital, Kansas City, MO*;

• R. Bjork, MD, Colorado Springs Neurological Associates, Colorado Springs, CO*;

• H. Blume, MD, Seattle Children’s Hospital, Seattle, WA*;

• J. Cohen, MD, The Headache Institute at Roosevelt Hospital, New York, NY; D. Chrusciel, MD, Oklahoma Health Sciences, Oklahoma City, OK*;

• M. DiSabella, DO, Children’s National Medical Center, Washington, DC;

• L. Matthew Frank, MD, Eastern Virginia Medical School, Norfolk, VA*;

• A. Gelfand, MD, P. Goadsby, MD, University of California-San Francisco Headache Center, San Francisco, CA*;

• H. Jacobs, MD, University of Maryland School of Medicine, Baltimore, MD*;

• S. Kedia, MD, Children’s Hospital Colorado, Aurora, CO*;

• L. Kerr, MD, Primary Children’s Medical Center, Salt Lake City, UT*;

• A. LeBel, MD, Boston Children’s Hospital, Waltham, MA*;

• D. Lebron, MD, LeBonheur Children’s Hospital, Memphis, TN*;

• S. Linder, MD, David B. Owen, MD, Dallas Pediatric Neurology Associates, Dallas, TX*;

• K. Mack, MD, Mayo Clinic, Rochester, MN;

• H. Markley, MD, New England Regional Headache Center, Worcester, MA*;

• J. McVige, MD, Dent Neurological Institute, Amherst, NY*;H

• . Murali, MD, Marshfield Clinic, Marshfield, WI*;

• A. Pakalnis, MD, Nationwide Children’s Hospital, Columbus, OH*;

• E. Pearlman, MD, Children’s Hospital at Memorial University Medical Center, Savannah, GA;

• K. Ridel, MD, Josephson Wallack Munshower Neurology Research, Indianapolis, IN*;

• D. Rothner, MD, The Children’s Hospital, The Cleveland Clinic, Cleveland, OH*;

• J. Rothrock, MD, J. Lopez, MD, Renown Neuroscience Institute, University of Nevada, Reno School of Medicine, Reno, Nevada*;

• R. Simmons, MD, Schenectady Neurological Consultants, Schenectady, NY*;

• M. Sowell, MD, University of Louisville Health Sciences Center, Louisville, KY*;

• C. Szperka, MD, Children’s Hospital of Philadelphia, Philadelphia, PA;

• M. Victorio, MD, Akron Children’s Hospital, Akron, OH*;

• P. Winner, DO, Premiere Research Institute, West Palm Beach, FL*;

• M. Yonker, MD, Phoenix Children’s Medical Group, Phoenix, AZ*.

*denotes sites that enrolled a participant. (31 out of 35)

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CHAMP Study Goals

• Outcome for Aims 1-3 – reduction in migraine frequency and disability

• Aim 1: Determine if amitriptyline (AMI) is superior to placebo

• Aim 2: Determine if topiramate (TPM) is superior to placebo

• Aim 3: Determine superiority for AMI vs TPM

• Aim 4: To prospectively and systematically determine the safety and tolerability profiles of AMI, TPM and placebo

Protocol - Hershey, et al, Headache 2013

Definitions

• Headache Frequency

• Headache Day – any headache in 24 hour period midnight to midnight

• Headache Episode – any headache, start to headache free

• Migraine Day – any headache with ICHD Migraine characteristics in 24 hour period

• Migraine Episode – any migraine from start to headache free

Study Design

Real World Approach

• Subjects to reflect patients seen in typical headache, neurological and pediatric practice

• Subjects are children and adolescents, ages 8 to 17 years old

• Consistent headache frequency that indicates need for prophylaxis (>4 headaches per month)

• Standardized dosing of most commonly used preventative medication

• AMI 1 mg/kg/day

• TPM 2 mg/kg/day

15Protocol - Hershey, et al, Headache 2013

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Study Design

Primary and Secondary Outcomes

• Greater than 50% reduction in headache frequency

• Absolute reduction in monthly headache frequency

• Reduction in migraine disability

• Tolerability of drug therapies

• Treatment emergent side effects

16Protocol - Hershey, et al, Headache 2013 - https://clinicaltrials.gov/show/NCT01581281

Inclusion Criteria

1. Diagnosis: Migraine with or without aura (International Classification of Headache Disorders, 2nd Edition (ICHD-II) or chronic migraine (ICHD-II revised.)

2. Frequency: Migraine frequency based upon prospective headache diary of 28 days must be ≥ 4. Migraine frequency

defined as any migraine during one day in the 28 day baseline period*

• * Migraine frequency is defined as the period from the onset to the stop time of painful migraine symptoms not to

exceed 24 hours with the clock starting at midnight. If painful symptoms last longer than 24 hours, this is

considered a new and distinct migraine headache. If painful symptoms recur within 24 hours of initial onset, this

is considered part of the initial migraine episode and would be counted as one migraine.

3. PedMIDAS: PedMIDAS Disability Score > 10, indicating at least mild disruption in daily activities and < 140, indicating extreme disability that may require more comprehensive, multi-component therapy

4. Age: Females or males 8-17 years, inclusive


Exclusion Criteria (1)

1. Continuous migraine defined as an unrelenting headache for a 28 day period

2. Weight less than 30 kg or greater than 120 kg

3. Unwilling to avoid taking non-specific acute medication such as NSAIDS (e.g., ibuprofen), more than 3 times per

week, or migraine specific acute medications such as triptans more than 6 times per month

4. Currently taking other prophylactic anti-migraine medication within a period equivalent to 2 weeks of that

medication before entering the screening phase, or the use of Botulinum toxin (Botox®) within 3 months of

entering the screening phase

5. Subjects who have previously failed an adequate trial of AMI or TPM for prophylaxis of at least 3 months

duration at doses recommended for migraine relief because of lack of efficacy or adverse events*

6. Current use of disallowed medications/products: opioids, antipsychotics, antimanics, barbiturates,

benzodiazepines, muscle relaxants, sedatives, tramadol, nutraceuticals, SSRIs, or SSNRIs


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Exclusion Criteria (2)

7. Known history of allergic reaction or anaphylaxis to AMI or TPM

8. Abnormal findings on ECG at baseline, particularly lengthening of the QT interval greater than or equal to 440 msec

9. Subject is pregnant or has a positive pregnancy test

10. Subject is sexually active and not using a medically acceptable form of contraception

11. Diagnosis of epilepsy or other neurological diseases.

12. History of kidney stones

13. Inability to swallow pills after using behavioral techniques if indicated between screening visit and baseline visit**

14. Present psychiatric disease as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV)

(e.g. psychosis, bipolar disorder, major depression, generalized anxiety disorder), alcohol or drug dependence, or

documented developmental delays or impairments (e.g., autism, cerebral palsy, or mental retardation) that, in the

opinion of the site investigator, would interfere with adherence to study requirements or safe participation in the trial

15. Any and all other diagnoses or conditions which in the opinion of the site investigator, that would prevent the patient

from being a suitable candidate for the study or interfere with the medical care needs of the study subject


Subject Selection

• 675 subjects

• Migraine without or with aura by ICHD-II

• Frequency allows

• Episodic (>4 headaches per month)

• Chronic (>14 headaches per month)

• Continuous disallowed

• Ages 8-17 years

• Up to 40 research sites across the USA


Study Design

Flow of Events


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Titration Methodology

• Dosage increases at 2 week intervals

• For standard titration, final dose starts at week 8

• Modification allowed for tolerability

• Options

• Hold dose (no maximum number)

• Decrease dose (allowed once)

• Resume titration as tolerated

• If modification occurs, final dose starts at week 10


Simulation – Odds of significant result

Protocol - Hershey, et al, Headache 2013

CHAMP results –Protocol - Hershey, et al, Headache 2013Baseline - Powers, et al, Headache 2016

N Engl J Med 2017; 376:115-124 January 12, 2017 DOI: 10.1056/NEJMoa1610384http://www.nejm.org/doi/suppl/10.1056/NEJMoa1610384/suppl_file/nejmoa1610384_

appendix.pdfhttps://clinicaltrials.gov/show/NCT01581281

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CHAMP results – Consort

CHAMP - Supplementary

Source Documents

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Published online 10/27/2016

Is there a placebo problem

Where do we go from here?

• Traditional RTC model

• Doesn’t work because of high level of Expectation

• By the time studies done in kids, already “proven effective” in adults

• Modifications

• Placebo run in

• Placebo run in with survival curve

• Cross over

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Expectation of ResponseCormier et al, Pain 2016

Controlling for Placebo





• Modifications

• Placebo run in

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Double Diamond Design

• Zolmitriptan Nasal Spray

• Rizatriptan





• Modifications

• Placebo run in


Are Placebo Studies Ethical in Pain

• Helsinki Report update

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• Modifications

• Placebo run in


• Cross over

• New Models

• SMART design (Sequential, Multiple Assignment, Randomized Trials)

Conclusions

• Study should start my filling a gap

• Question of Clinically meaningful result

• What design is best

• Consider novel designs in development phase

• Consider pathophysiological basis and biomarkers

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