Powers SW, Coffey CS, Chamberlin LA, Ecklund DJ, Klingner EA, Yankey JW,
Korbee LL, Porter LL, Hershey AD; CHAMP Investigators.. Trial of Amitriptyline,
Topiramate, and Placebo for Pediatric Migraine. N Engl J Med. 2016 Oct 27.
Background Which, medication, if any, to use to prevent the headache of pediatric migraine has not been established. Methods We conducted a randomized, double-blind, placebo-controlled trial of amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. 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 a 24-week trial. Secondary outcomes were headache-related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment. Results A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between-group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P=0.26; topiramate vs. placebo, P=0.48; amitriptyline vs. topiramate, P=0.49). There were also no significant between-group differences in headache-related disability, headache days, or the percentage of patients who completed the 24-week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt. Conclusions There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281 ).
A study of amitriptyline and topiramate in children with migraine has been halted early owing to futility.
The analysis of data from the Childhood and Adolescent Migraine Prevention (CHAMP) trial showed that neither of these preventive medications was more effective than placebo in reducing headache frequency or headache-related frequency, and both were associated with higher rates of adverse events (AEs).
Given the "null outcome" and the adverse events reported, "the data do not show a favorable risk-benefit profile for the use of these therapies in pediatric migraine prevention, at least over the 24-week duration of the trial," the authors write.
While amitriptyline and topiramate may be effective in treating headaches in adults, the study results "put doctors in a little bit of a conundrum" when it comes to children, commented lead author Scott W. Powers, PhD, a pediatric psychologist at the Department of Pediatrics, University of Cincinnati College of Medicine, Ohio….
The trial randomly assigned 361 children, mean age 14 years, who were mostly female (68%) and white (70%) and had a mean of 11 headache days per month. The study compared amitriptyline with placebo, topiramate with placebo, and the two drugs against each other.
"Our purpose was to create a 'real world' study that would enroll the type of patients that practitioners see every day," said Dr Powers. "Our hypothesis was that we would find one of these medicines to be the most effective with the least amount of side effects so that pediatricians and family medicine doctors would have sort of a first-line prevention approach for such a chronic, common illness as migraine."
In November 2014, it was determined that criteria for the a priori futility cutoff — below 20% compared with placebo — were met and that adding participants was unlikely to change the outcome. 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. Study organizers decided to close down the study.
At that time, researchers had complete data on 225 children and adolescents, with another 103 participants in the midst of finishing the trial, for a total 328 patients to analyze for the primary outcome (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group)…
Dr Powers noted that placebos are "not inert" and "actually change the brain." He and his colleagues hypothesized that half of the kids would get better on placebo and that 70% of them would improve on the medicines.
"The findings were kind of upside down; it was 61% of placebo and around 50% to 55% on the drugs who got better. It wasn't statistically different, but it was in the opposite numerical direction than what you would have predicted," he said…
If there's any "positive news," it's that kids do get a lot better on these therapies, said Dr Powers. "There's a 50% reduction in migraine frequency, and headache disability is pretty much down to little to none — but it's not because of the chemical in the medicine that they have been given."
What was surprising to the investigators, said Dr Powers, was the fact that "it was so clear so early" that the active drugs were no better than placebo.
The findings were clear not just for the primary outcome but for disability outcomes on PedMIDAS and other secondary outcomes, including study completers, said Dr Powers.
"So it was so consistently not going to be effective, and to all of us investigators, once we had seen the information, it made perfect sense that closing the study was what we needed to do."
There were also side effects to consider. A total of 852 AEs occurred (301 with amitriptyline, 419 with topiramate, and 132 with placebo) in 272 patients. There were no deaths.
AEs that occurred significantly more often in the amitriptyline than in the placebo group were fatigue (30% vs 14%; P = .01) and dry mouth (25% vs 12%; P = .03).
AEs that occurred significantly more often in the topiramate group than in the placebo group were paresthesia (31% vs 8%; P < .001) and decreased weight (8% vs 0%; P = .02).
Commenting for Medscape Medical News, Kenneth J. Mack, MD, PhD, professor of neurology and of pediatrics, Mayo Clinic, Rochester, Minnesota, agreed that nonpharmacologic approaches might be the next step in light of this new study.
The "big question" now is "where do we go from here?" said Dr Mack. "Most likely, one response will be to use more behavioral approaches for the treatment of headache pain."
Dr Mack described the study as "well designed and of the highest quality."
"It did not show the expected results, but that is why we have to do studies like this."
Dr Powers has disclosed no relevant financial relationships.
For anyone brave enough to dive into treating adolescent migraiwne and headache, this trial comes as a severe disappointment. As pediatric providers, we often lament the lack of randomized trial evidence in children, and it is both disappointing and sobering that the two drugs suggested by experts and previous trials to offer the best opportunity for prevention of migraine had so little effect.ReplyDelete
On the positive side, the notable placebo effect, regression to the mean over time, or true improvement over time (just three of the potential competing hypotheses to explain the lack of differences) offer some hope for patients and providers. In an accompanying editorial, Jackson commented that the marked placebo response rate in this study is commonly seen in headache trials.
Jackson also offers some good advice for how to respond to these findings. Rather than providers taking the approach that "nothing works," we should focus on working with patients on nonpharmacologic approaches; being a supportive medical source; and considering use of less potentially problematic medications, such as acetaminophen or ibuprofen, as prophylaxis. Of course, the data available for nonpharmacologic approaches to preventing headache are also woefully thin, and long-term use of ibuprofen or acetaminophen poses problems. However, focusing on hope for improvement is an important aspect of treatment and appears to be a reasonable expectation for both patients and providers.