New study shows Topamax provides sustained reduction in migraine days for 12 months

A new long-term study into migraine prevention presented for the first time at the 13th International Headache Conference showed that patients who continued with the migraine prophylaxis (preventive) treatment, Topamax® (topiramate), for up to a year experienced a sustained reduction in number of migraine days per month, with significant associated benefits on quality of life measures.1-3

The PROMPT (PROlonged Migraine Prevention with Topiramate) study was a phase III, 12-month, multicentre, double-blind, randomized, placebo-controlled study conducted to investigate the continued effectiveness of topiramate in reducing the number of migraine days beyond 6 months, as well as the impact of discontinued treatment after 6 months.

A total of 818 adults were enrolled in PROMPT, and 559 patients completed the initial 6-month open-label phase. Of that total, 512 progressed to the double-blind phase.

All patients were treated with topiramate for the first 6 months of the trial, and then either continued with topiramate treatment into the second 6-month stage of the study or switched to placebo. In the open-label phase, topiramate treatment was initiated at a daily dose of 25 mg and increased in weekly 25 mg increments to effective dose by week 22. Patients remained on that dose through week 26 and then were either randomized to continue to receive that dose in the double-blind phase or placebo. Other migraine prevention therapies were prohibited throughout the entire study.

The primary endpoint in the PROMPT trial was the change in the number of migraine days during the last 4 weeks of the double-blind phase versus the last 4 weeks of the open-label phase. At the study conclusion, findings suggested a significant increase in migraine days in the placebo group (+1.2 migraine days per 4 weeks) compared with a sustained reduction in topiramate-treated patients, where the mean number of monthly migraine days remained virtually unchanged (+0.1 day) [p = 0.0011].

Secondary efficacy parameters included number of withdrawals, change in the duration and severity of migraine headaches, change in the number of acute medication intakes, change in Quality of Life (QoL) questionnaire scores, and change in patient satisfaction over the double-blind phase. To assess the secondary efficacy parameters, the Migraine Disability Assessment Test (MIDAS) and the short form 12 (SF-12) general health status questionnaire were completed at the start and end of the open-label phase, and at the end of the double-blind phase. The 6-item Headache Impact Test (HIT-6) was completed at weeks 0, 8 and 26 of the open-label phase, and at weeks 8 and 26 of the double-blind phase.

Patients’ satisfaction with the efficacy and tolerability of study medication was evaluated at the end of the open-label and double-blind phase using a 5-point scale (very good, good, reasonable, moderate or poor).

Open-Label Phase Results

During the first 6 months of treatment with topiramate in the open-label stage, the number of migraine days decreased by one third, consistent with observations from previous clinical trials.^1-3 The mean number of migraine days was significantly reduced by more than 3 days a month, from 8.9 days at baseline to 5.8 days after topiramate treatment [p < 0.0001].

The number of days of acute medication use also was much lower during the last four weeks of topiramate therapy (4.0 + 3.6) as compared with baseline (6.1 + 3.1; [p < 0.001]).

The most frequent adverse event (AE) was paraesthesia, which was experienced by approximately half of patients; followed by fatigue (13%), disturbances in attention (12%), decreased appetite (11%) and weight reduction (9%).

Double-Blind Phase Results

The number of monthly migraine days remained virtually unchanged in the topiramate group (+0.1 migraine days per 4 weeks; [p = 0.0011]) whereas patients who had been switched to placebo experienced a significant increase in migraine days with an average rise of more than 1 migraine day per month.

Overall, the level of disability was significantly less in patients who remained on topiramate for the entire year, versus those who were randomized to the placebo group after 6 months.

At the end of the double-blind phase, the mean MIDAS score increased (deteriorated) by +6.1 points in patients who switched from topiramate to placebo, compared with no change in the topiramate group [p = 0.0046]. There also was a significant decrease (deterioration) in the SF-12 score in placebo (-3.1 + 8.1) compared with topiramate (-0.6 + 8.2; [p < 0.001 between groups]). Patients who continued taking topiramate required less acute medication to manage their migraines than those taking placebo (+1.1 days versus +0.2 days, respectively; [p < 0.001]).

Patients’ treatment satisfaction was significantly better in the topiramate group than in the placebo group. Topiramate patients scoring "very good" on satisfaction with efficacy at the end of the double-blind phase was 10% higher than in the placebo group (59% versus 49%, respectively).

Adverse events were reported by 68% of topiramate-treated patients versus 59% of patients in the placebo group. The most common AE was paraesthesia in both treatment groups.

"Current guidelines recommend that the use of migraine prevention therapy be evaluated after 4 – 6 months of treatment. This new study provides additional data regarding the potential effectiveness of preventive therapy, topiramate, beyond 6 months of treatment," remarked Professor Hans-Christoph Diener from the University of Duisburg-Essen (Germany) and one of the principal investigators in the PROMPT study.

"It is important for patients to discuss their migraine therapy and its effects with their healthcare professional before making any treatment decisions."

About PROMPT

The study design consisted of a number of key stages. Following a 4 – 8 week baseline stage without any treatment in which it was confirmed that patients had established frequent migraine (>4 migraine days every 4 weeks), study subjects entered a 26-week open-label phase where all received treatment with topiramate. Adult patients were enrolled from 88 neurology clinics located in 21 countries in Europe and the Middle East.

Topiramate treatment was initiated at a daily dose of 25 mg and increased in weekly 25 mg increments to a target dose of 100 mg/day, which also was the median dose in the various phases of the study. Final doses could be adjusted between 50 and 200 mg per day but were kept steady for the last month of the open-label phase.

After this open-label stage, patients then entered the double-blind phase of the study where they were randomized to continue at their optimised dose of topiramate or switched to placebo for a further 26 weeks.

Over the 12 months of the PROMPT study, topiramate was generally well tolerated, with side effects consistent with those previously observed in shorter-duration trials. Overall, the most commonly reported side effects during the study were paraesthesia, fatigue, disturbances in attention, decreased appetite and weight reduction.

The number of discontinuations in the double-blind phase was not statistically significantly different between topiramate and placebo-treated participants.

The PROMPT study was conducted in European countries by Janssen-Cilag, the company that markets Topamax in Europe.

(Source: 13th International Headache Conference : Janssen-Cilag : July 2007)