1 - hershey-andrew champ-trial-design-outcomes-context ......• resume titration as tolerated •...

6/2/2017

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CHAMP Trial:

Design, Outcomes, Context, and

Lessons Learned

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

Support – grants, contracts, honoraria

NIH, CHRF research foundation, Curelator

American Headache Society – Board Member

NIH – Advisory Board, Common Data Elements

Migraine Research Foundation – Advisory Board

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

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

Outline

• Why - Background for development of CHAMP

• Who – Clinical Coordinating, Data Coordinating, Sites

• How - Protocol development

• What• Baseline Results

• Study Results

• Where do we go from here• Implications on treatment

• Implications from other studies

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Why Migraine

• Migraine prevalence

• 4 % of young children

• Up to 10.5% of children age 5-15

• Up to 28% age 15-19

• Adults 12% (17.1% women, 5.6% men)

• Migraine pathophysiology

• Migraine as a genetic disease

• Early intervention may have lifetime implications

• Migraine Impact

• Up to 200,000 lost school days in US

• $17 billion (1998) direct and $17 billion indirect cost

• Individual cost (2006)

• Direct $127 to $7089

• Indirect $709 to $4453

• Chronic Mig vs Episodic Mig (2016)

• CM – Direct ($4943), Indirect ($3300)

• EM – Direct ($1705), Indirect ($943)

• Pharma – CM ($3925), EM ($1196)

• Potential progression to refractory headaches if not treated

Why Migraine – Global Burden of DiseaseGBD 2015 Disease and Injury Incidence and Prevalence Collaborators, Lancet, Oct 8, 2016

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

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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

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Most important clinical effectivenes

• Why• Children and Adolescents are impacted by migraine

• There are significant gaps

• Who

• How

• What

• Where

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Cincinnati Children’s Headache Center

• Established in Oct 1996

• collaboration between neurology and psychology

• Combined Clinical and Research Program on Pediatric Headache

• Local, Regional, National and International referral patterns

• Over 700 different Zip Codes

• 23 different states

• Patients from North America, South America and Central America, Asia

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• A CCHMC partnership (Headache Center; Behavioral Medicine;

Neurology; Office for Clinical and Translational Research)

• A inter-institution collaboration (CCHMC – Clinical Coordinating

Center & University of Iowa - Data Coordinating Center)

• A national effort (involving over 40 sites)

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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.

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• Who• Cincinnati Children’s, Univ of Iowa, NIH – NINDS and NICHD,

• all of our sites.

• How

• What

• Where

Childhood and Adolescent Migraine Prevention Study A 40-site Randomized Clinical Trial

U01 NS076788 (2011-2016)

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

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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

19Protocol - Hershey, et al, Headache 2013

Study Design

Primary and Secondary Outcomes

• Greater than 50% reduction in migraine frequency

• Absolute reduction in monthly migraine frequency

• Reduction in migraine disability

• Tolerability of drug therapies


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


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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


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


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Study Design

Flow of Events


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


Titration Methodology

27

Terminate from Study

Dispense Study Drug

Potential Dispense of Study Drug

1

2 8

3

4

9

12 16

13

10

5

6 7

1

5

11

14 18

2017

19 21

24 25 26 2722 23

0 weeks

Visit 2

+2 Weeks

Phone Visit

+4 Weeks

Visit 3

+6 Weeks

Phone Visit

+8 Weeks

Visit 4

+10 Weeks

Delayed Visit 4

+12 Weeks

Visit 5

Dosage Titration Plan

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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

Primary Outcome

• A ≥ 50% reduction in headache frequency from the 4 week baseline period to the last 4 weeks of this 24-week trial

• Headache frequency is defined as the number of days with headache for a given 4 week period

• A 20 percentage point difference from placebo in this reduction effect is considered clinically meaningful by pediatric headache experts


Secondary Outcomes

• Reduction in migraine disability score on PedMIDAS (Time Frame: end of the week baseline period to the last 4 weeks of the 24-week trial)

• Safety and tolerability of amitriptyline and topiramate (Time Frame: visit 2 until the last 4 weeks of the 24-week trial)

• Occurrence of treatment-emergent serious adverse events (Time Frame: visit 2 to the last 4 weeks of the 24-week trial)

• Reduction in absolute migraine frequency (Time Frame: 4 week baseline period to the last 4 weeks of the 24-week trial)


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Simulation – Odds of significant result

Protocol - Hershey, et al, Headache 2013



• Who and Where• Cincinnati Children’s, Univ of Iowa, NIH – NINDS and NICHD,


• How• NIH sponsored, U01 – Multi-site study

• Childhood and Adolescent Migraine Prevention Study - CHAMP

• What

• Where

Baseline Results

Protocol - Powers, et al, Headache 2016

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CHAMP results

• Primary - > 50% reduction in headache frequency (day)• 28 days prior to randomization vs 28 days prior to end of treatment phase

• Secondary• Headache Disability – PedMIDAS; compare randomization to end of treatment

• Tolerability – whether or not subject completed entire 24 weeks

• Additional Secondary• Absolute reduction in headache frequency

• Side effects

CHAMP results – Consort

Primary (>50%)

• Primary – all subjects without data considered failures

• Last Observation Carried Forward – most recent visit with 28 day calendar

• Multiple Imputation – methods with multiple chains

• Observed data – all subjects with baseline and last 28 days

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Primary (>50% distribution)

Results - Secondary

• PedMIDAS • Tolerability

0

10

20

30

40

50

AMI TPM PLC

Initial Final Imputed

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

AMI TPM PLC

Secondary - Additional

• Headache Frequency • Side Effects• 852 Adverse events

• 301 in Amitriptyline

• 30% fatigue (vs 14% placebo)

• 419 in Topiramate

• 31% parasthesia (vs 8% placebo)

• 132 in Placebo

• 12 Serious adverse events

• 6 in amitriptyline

• 4 in topiramate

• 2 in placebo

0

2

4

6

8

10

12

AMI TPM PLC

Initial Final Imputed

0

20

40

60

80

100

AMI TPM PLC

CDI (Child Depression Index)

Baseline Visit 5 Visit 8

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CHAMP Results

• Simulations

• Follow-Up• 3, 6,12 months

• 18, 24, 36 months

• Genomics• RNASeq

• DNASeq

• Adherence

• Trajectory

• Process

• Migraine Characteristics response

• Predictors of response

?



• Who and Where• Cincinnati Children’s, Univ of Iowa, NIH – NINDS and NICHD,


• How• NIH sponsored, U01 – Multi-site study

• Childhood and Adolescent Migraine Prevention Study - CHAMP

• What• Primary results – all three arms treated headaches, but no difference

• Side effects in topiramate and amitriptyline, but not placebo

• Where

Where do we go from here?

• Children and adolescents with real world migraine get better• 50 to 70% with a >50% reduction in headache frequency

• Mean frequency at end down to almost 1 per week

• Thus, multidisciplinary care works

• Biochemical effect of medication is not the reason

• Is the reason expectation of response?

• What do we do with the 30-40% that don’t get better?

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Expectation of ResponseCormier et al, Pain 2016

Where do we go from here?

• What will you do Monday when you treat your headache patients?

• What are the other options?

• What does this say about the adult studies?

Thank you

1 - hershey-andrew champ-trial-design-outcomes-context ......• resume titration as tolerated •...

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