Trial Design and Oversight

The CHAMP trial was a phase 3, multicenter, double-blind, placebo-controlled trial funded by the National Institutes of Health.16 An independent data and safety monitoring board that was appointed by the National Institute of Neurological Disorders and Stroke (NINDS) participated in the protocol review and provided trial oversight in collaboration with the NINDS. The trial was conducted under an investigational new drug application with the FDA. Patients were enrolled from 31 sites in the United States. Written permission from a parent or guardian and, when appropriate, child assent were obtained.17 Randomization was stratified according to age (8 to 12 years vs. 13 to 17 years) and the number of headache days on the basis of the diary kept during the 28-day baseline period (4 to 14 [episodic] vs. ≥15 [chronic]).

The authors were responsible for all elements of the trial, including design, data collection, analysis, and interpretation. Data were collected by the site investigators and site trial staff and were transmitted electronically to a data coordinating center for analysis: all data remained confidential and blinded during the trial. All the authors were involved in each stage of the manuscript development and vouch for the accuracy and completeness of the data and analyses and for the fidelity of the trial to the protocol and statistical analysis plan, which are available with the full text of this article at NEJM.org. The data and safety monitoring board and the NINDS reviewed and provided feedback on the manuscript to the authors, who had full editorial control of the manuscript.

The investigational pharmacy at Cincinnati Children’s Hospital Medical Center purchased generic drugs for this trial with the use of grant funds. Trial drugs and placebo were enclosed in capsules to maintain blinding.

Trial Population

Children and adolescents 8 to 17 years of age were eligible for participation. Inclusion criteria16,17 included a diagnosis of migraine with or without aura or chronic migraine without continuous headache, as defined by the International Classification of Headache Disorders, 2nd Edition18; a score on the Pediatric Migraine Disability Assessment Scale (PedMIDAS) of 11 to 139 (range, 0 to 240, with a score of 0 to 10 indicating no disability, 11 to 30 mild disability, 31 to 50 moderate disability, and >50 severe disability)19; and a headache frequency of 4 or more days from a prospective headache diary over a baseline period of 28 days.

Trial Intervention

After the baseline period, eligible patients were randomly assigned in a 2:2:1 ratio to receive oral amitriptyline, topiramate, or placebo, administered in a divided dose of 1 capsule twice daily. The target dose was 1 mg per kilogram of body weight per day for amitriptyline and 2 mg per kilogram per day for topiramate. Dose escalation occurred every 2 weeks over a period of 8 weeks, with dose modification based on side effects. A 16-week constant-dose (maintenance) phase followed at the highest dosage achieved. Site investigators ended drug treatment for patients with severe side effects occurring during the maintenance period of the trial, but these patients were followed for safety monitoring. Decisions regarding cessation of medication and withdrawal from the trial were made with input from the family, site-investigator judgment, and medical-monitor recommendations. After the 24-week treatment period, a 2-week weaning period and a 4-week follow-up occurred. Details of the trial protocol were published previously.16,17

Trial Assessments

Patients completed a daily headache diary, in accordance with the NINDS Common Data Elements.20 A headache day was defined as any day during which a headache occurred within a 24-hour period starting at midnight. The PedMIDAS, which assesses the effect of migraines on school, home, play, and social activities, was used to determine the change in headache-related disability between baseline and the end of the trial. Safety was assessed with the use of adverse-event reports that were collected from parents and patients by means of a structured interview. Weight, height, vital signs, clinical laboratory tests, and physical and neurologic examinations were serially monitored, according to the protocol. Serious adverse events were reported by site investigators, then reviewed on an urgent basis by the medical safety monitor, who determined the potential relationship to treatment. Adverse events were coded with the use of the Medical Dictionary for Regulatory Activities, version 11.0. The Child Depression Inventory (with raw scores ranging from 0 to 54 and higher scores indicating more severe depression),21 Behavior Rating Inventory of Executive Function (BRIEF),22 and electrocardiographic (ECG) measures were used in conjunction with the review of adverse events by the medical monitor on a quarterly basis to further assess safety. Adherence was assessed by means of central analysis of blood levels of amitriptyline or topiramate, depending on the treatment assignment.

Trial Outcomes

The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of the 24-week trial. Four secondary outcomes were headache disability, as measured by absolute change in the PedMIDAS score; the absolute reduction in the number of headache days, from the 28-day baseline period to the final 28-day period of treatment; number of trial completers, as assessed by the percentage of patients who completed the 24-week treatment period; and serious adverse events that emerged during treatment.

Statistical Analysis

We chose the sample size to ensure adequate power, assuming that 50% of the patients receiving placebo versus 70% of those receiving amitriptyline or topiramate would have a reduction in the number of headache days of 50% or more, with a 15% dropout rate. We planned to enroll 675 patients (270 in the amitriptyline group, 270 in the topiramate group, and 135 in the placebo group) to provide at least 85% power to detect all differences between active treatment and placebo and 90% power to detect a difference of 15 percentage points between the two active treatments. Interim assessments for futility as well as efficacy were planned when 225 and 450 patients had completed their 24-week visit. Stopping for futility was to occur if the conditional power based on the prespecified effect for both treatments compared with placebo fell below 20 percentage points.

In November 2014, the first of two planned interim analyses occurred on the basis of data from 225 randomly assigned patients who had completed the trial; another 103 randomly assigned patients subsequently completed the trial, for a total of 328 patients analyzed for the primary outcome, as described below. The conditional power at the time of the interim analysis was 16 percentage points for the comparison between amitriptyline and placebo and 14 percentage points for the comparison between topiramate and placebo, and both met the threshold for futility. After considering all the evidence, including the conditional power calculated in a number of sensitivity analyses (e.g., multiple imputation and observed data only) to assess the effect of missing data, the data and safety monitoring board recommended early closure of the trial for futility. The NINDS accepted the recommendation and closed the trial.

Owing to the early stopping of the trial, the primary efficacy analyses and secondary analyses of disability, headache frequency, and drug discontinuation included all patients who either had complete headache-diary data at the end-point visit or had a date for an expected end-point visit on or before the target date for completion of the last weaning visit in the original closeout plan (February 4, 2015). All randomly assigned patients were included in the safety analyses.

The primary analysis used a logistic-regression model. The models and corresponding odds ratios were adjusted for age and for the number of headache days during the 28-day baseline period. Each was tested with the use of a Bonferroni corrected significance level of 0.017 (i.e., 0.05÷3). These analyses followed the intention-to-treat principle.

For the primary analyses, we imputed an outcome of treatment failure for any patient who either withdrew early for any reason or did not provide headache-diary data at week 24. We used a series of sensitivity analyses to assess the effect of missing data on the primary analysis results. In alternative imputation approaches, we assumed that all patients who withdrew owing to side effects had treatment failures. For all other patients, end points were imputed with the use of a series of sensitivity analyses.

Secondary end points were analyzed with the use of linear regression for continuous variables and binary data methods for categorical variables. These models were adjusted for age and the number of headache days during the baseline period. In the analysis of headache-related disability, we also adjusted for the baseline PedMIDAS score. A multiple-comparisons adjustment similar to that used for the primary analysis was implemented for the secondary comparison of the difference in the change in mean headache days over the 24-week treatment period but not for any of the other secondary comparisons.

Continuous variables were summarized by means, standard deviations, and minimum and maximum variables. Categorical variables were summarized by percentages. Comparisons of baseline variables between trial groups were performed with the use of t-tests for continuous variables and Fisher’s exact test for categorical variables. No adjustments were made for baseline comparisons.

The mean T score from the Child Depression Inventory and the mean BRIEF global composite score (with the raw score converted to a T score of 0 to 100 and higher scores indicating more [or more severe] symptoms for both inventories) were calculated and compared among trial groups at baseline, visit 5, and visit 8. Binary indicators of a Child Depression Inventory T score greater than 80 and an answer of “yes” to the item on suicidal intent or ideation were also compared with the use of Fisher’s exact test among the groups.