CHAMP: Lessons Learned

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CHAMP: Lessons Learned

Andrew D. Hershey, MD, PhD. FAHS

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Endowed Chair and Director, Neurology Director, Headache Center

Cincinnati Children’s Hospital Medical Center Professor of Pediatrics and Neurology University of Cincinnati, College of Medicine

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Disclosures

Support – grants, contracts, honoraria

NIH CHRF research foundation Curelator

NIH, CHRF research foundation, Curelator

American Headache Society – Board Member

NIH – Advisory Board, Common Data Elements

Mig aine Resea ch Fo ndation Ad iso Boa d

Migraine Research Foundation – Advisory Board

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

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

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Outline

• Background for development of CHAMP

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• NIH and U01 development

• Protocol development

• Study implementation

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Why Migraine

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• Migraine prevalence

– 4 % of young children4 % 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 Impact

– Up to 200,000 lost school days in US

– $17 billion (1998) direct and $17 billion indirect cost$17 billion (1998) direct and $17 billion indirect cost – Individual cost (2006)

• Direct $127 to $7089 • Indirect $709 to $4453

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Prevention

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Why Prevention

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• Limited evidence of efficacy of prevention in children and adolescents

• (will review current status of prevention options) – note that red font means to be added. Includes pharmaceutical – Includes pharmaceutical – CBT – Biofeedback – Biobehavioral

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Cincinnati Children’s Headache Center

• Established in Oct 1996

– collaboration between neurology and psychologycollaboration between neurology and psychology

• Combined Clinical and Research Program on Pediatric Headache

– Local, Regional, National and International referral patterns – Over 700 different Zip CodesOver 700 different Zip Codes

– 23 different states

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Current Personnel

• Nurse Practitioners– Susan L. LeCates, FNP – Shannon Cherney, PNP Faculty

• Neurologist

– Andrew D. Hershey, MD, PhD, FAHS (Director) – Marielle A. Kabbouche, MD, FAHS (Inpatient)

– Mimi Miller, PNP

– Jessica Weberding, PNP – Laura Huss, PNP

• Nurses – Hope L. O’Brien, MD (Education, Young Adult)

- Joanne Kacerski, MD (Post-Traumatic Headache) • Psychologist

– Scott W. Powers, PhD, FAHS (Co-Director) – Anne Lynch-Jordan PhD – Ann Segers – Paula Manning – Judy Bush – Stephanie Pelopodia Social Work – Anne Lynch-Jordan, PhD – Shalonda Slater, PhD – Irina Parkins, PhD – Eileen Chaves, PhD • Headache Medicine Fellow

• Social Work – Diane Kraus • Research

– Antionette Green – Jing Xiang

– Suzanne Hagler, MD _{– Kimberly Leiken}Jing Xiang • Admin Asst.

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Research

• 27 funded research projects

NIH f d d i

2003 (6)

• NIH funded since 2003 (6)

– Migraine Genomics

– MEG

– Treatment

• Publications

121 P i d i

– 121 Peer reviewed manuscripts – 107 Abstracts

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Background

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• Need for prevention

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• A CCHMC partnership

(Headache Center; Behavioral Medicine;

N l Offi f Cli i l d T l ti l R h)

Neurology; Office for Clinical and Translational Research)

• A inter-institution collaboration

(CCHMC – Clinical Coordinating Center & University of Iowa - Data Coordinating Center)

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Introductions to CHAMP Study Staff

Principal Investigators

Andrew Hershey, MD, PhD, FAHS Scott Powers, PhD, ABPP, FAHS, , ,

Christopher Coffey, PhD

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Introductions to CHAMP Study Staff

Study Leadership Team

Linda Porter, MD, NINDS Project Manager David Dodick, MD, Medical Safety Monitor David Dodick, MD, Medical Safety Monitor Leigh Ann Chamberlin, CCC Project Manager Dixie Ecklund, DCC Project Manager

L li K b CCC R l t M

Leslie Korbee, CCC Regulatory Manager

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Methods

• Double-blinded, placebo-controlled, comparative effectiveness

study

• 2:2:1 (AMI:TPM:Placebo)

• 760 subjects

760 subjects

• Age 8 to 17 years old

• 4 to 30 headache days per month

• Up to 40 sites

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CHAMP Study Goals

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

disability 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 and tolerability profiles of AMI, TPM and placebo

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Study Design

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A “3 in 1” study design

D bl bli d d l b t ll d t i l f it i t li l b

• Double-blinded, placebo-controlled trial of amitriptyline vs. placebo • Double-blinded, placebo-controlled trial of topiramate vs. placebo • Double-blinded comparative effectiveness trial of amitriptyline vs • Double blinded, comparative effectiveness trial of amitriptyline vs.

topiramate

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Study Design

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Real World Approach

• Subjects to reflect patients seen in typical headache neurological • 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/dayg/ g/ y

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Study Design

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Primary and Secondary Outcomes

G t th 50% d ti i i i f

• Greater than 50% reduction in migraine frequency • Absolute reduction in monthly migraine frequency • Reduction in migraine disability

• Reduction in migraine disability • Tolerability of drug therapies

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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 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 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 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

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Exclusion Criteria (2)

5. Subjects who have previously failed an adequate trial of AMI or TPM for prophylaxis of at least 3 months duration at dosesp p y recommended for migraine relief because of lack of efficacy or adverse events*

6. Current use of disallowed medications/products: opioids, 6. Current use of disallowed medications/products: opioids, antipsychotics, antimanics, barbiturates, benzodiazepines, muscle relaxants, sedatives, tramadol, nutraceuticals, SSRIs, or SSNRIs 7 Known history of allergic reaction or anaphylaxis to AMI or 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

of the QT interval greater than or equal to 440 msec

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Exclusion Criteria (3)

9. Subject is pregnant or has a positive pregnancy test 10 Subject is sexually active and not using a medically 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 andq g baseline visit**

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Exclusion Criteria (4)

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

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(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 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

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Study Interventions

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• Subjects randomized 2:2:1 (AMI: TPM: Placebo) • AMI– up to 1mg/ kg

• AMI– up to 1mg/ kg • TPM– up to 2mg/ kg

• BID regimen to assure blinding and tolerability

– AMI – placebo in am, AMI in pm – TPM – bid dosing

• 8-week titration with modification for tolerability • 16-week constant dose maintenance

• 6 week wash-out/end of study drug

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Subject Selection

• 675 subjects

• Migraine without or with aura by ICHD-II • 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 yearsAges 8 17 years

• Up to 40 research sites across the USA

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Study Design

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Flow of Events

Visit 1 V 2 _{V 5, 6, 7} _{Phone 1 & 2}

V 3,4 Titrate Randomize

Screen Treat Washout/Final

V 8

4 weeks 0 weeks 8 weeks 12 weeks 4 weeks 6 weeks

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Titration Methodology

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• Dosage increases at 2 week intervals

• For standard titration final dose starts at week 8 • 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

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– If modification occurs, final dose starts at week 10

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Titration Methodology

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Dosage Titration Plan

Terminate from Study Dispense Study Drug Potential Dispense of Study Drug 4 10 5 1 5 11 14 18 3 4 9 13 10 14 18 20 1 7 2 8 1 2 16 1 9 21 31 1 2 4 25 2 6 27 22 2 3 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

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Standard Titration

6 7

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Hold

6 7

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Hold and Titrate

6 7

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Reduction and Hold

6 7

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Reduction, Hold and Titrate

6 7

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Primary Outcome

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

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 • A 20 percentage point difference from placebo in this reduction effect is

considered clinically meaningful by pediatric headache experts

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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)

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

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Site Staff Certification

• Site feasibility questionnaires – (Details of info obtained)(Details of info obtained)

• Site Investigators and staff checked against FDA debarred list • Site phone calls

– Discussion with investigators and coordinators – Discussion with investigators and coordinators – (Details of phone calls)

– Principal Investigators interview un-vetted Site Investigators

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Site Staff Certification

• Site Selection by tiers – First level

• well experienced investigators in pediatric migraine

– Headache Medicine Certification perferred

• Facilities to perform all study procedures

– Pharmacy – Labs

– Storage

• Able to attend first investigator meeting in LA – Second level

• Lower level of experience • Limited facilities

• Delayed start due to attendance of investigator meeting

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Site Staff Certification

• Site Documentation – CV’s

– medical licensure

– human subject protection training – COI for CCC review

– Site delegation of responsibility log submitted to CCC / DCCSite delegation of responsibility log submitted to CCC / DCC – Signed 1572

– Protocol signature page to CCC

• Site Investigators and staff complete CHAMP Study training

• Access granted to study eCRF after site IRB approval documentation • Access granted to study eCRF after site IRB approval documentation

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Baseline Results

• Results from baseline paper added.

Comparison of subjects randomized vs non randomized – Comparison of subjects randomized vs non-randomized – Headache characterization

• Generalizability

– Graphic representation of no change during baseline

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CHAMP Insights

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• Discussion of what we learned

NIH and U01 – NIH and U01

– Multi-site coordination – Real World approach

• Future

Results of primary analysis – Results of primary analysis

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Conclusion – What we learned

• Procedural

NIH is able and willing to work with us on filling a gap and creating a – NIH is able and willing to work with us on filling a gap and creating a

multi-site study

– Set up and design issues are critical

– Well organized, supportive, consistent team approach – Clear “Go - No Go” points

– Surprises happenSu p ses appe

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Conclusion – What we learned

• Initial Results

Baseline demonstrates accomplished “Real World” approach – Baseline demonstrates accomplished “Real World” approach

• Future

– Primary results to comey – Multiple other findings