Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial

Background

Rimegepant is a calcitonin gene-related peptide receptor antagonist that has shown efficacy and safety in the acute treatment of migraine. We aimed to compare the efficacy of rimegepant with placebo for preventive treatment of migraine.

Methods

We did a multicentre, phase 2/3, randomised, double-blind, placebo-controlled trial at 92 sites in the USA. Adults with at least a 1-year history of migraine were recruited. After a 4-week observation period, eligible participants were randomised using an interactive web response system to oral rimegepant 75 mg or matching placebo every other day for 12 weeks (double-blind treatment phase). The primary efficacy endpoint was change from the 4-week observation period in the mean number of migraine days per month in the last 4 weeks of the double-blind treatment phase (weeks 9–12). Participants who received at least one dose of their assigned study medication and who had 14 days or more of data in the observation period and 14 days or more of data for at least one 4-week interval during the double-blind treatment phase were analysed for efficacy. Those who received at least one dose of study medication were analysed for safety. This study is registered with ClinicalTrials.gov, NCT03732638.

Findings

Between Nov 14, 2018, and Aug 30, 2019, 1591 participants were recruited and assessed for eligibility, of whom 747 were randomly allocated either rimegepant (n=373) or placebo (n=374). 695 participants were included in the analysis for efficacy, of whom 348 were assigned rimegepant and 347 were allocated placebo. Rimegepant was superior to placebo on the primary endpoint of change in the mean number of migraine days per month during weeks 9–12. The change from the observation period in mean number of migraine days per month during weeks 9–12 was −4·3 days (95% CI –4·8 to –3·9) with rimegepant and −3·5 days (–4·0 to –3·0) with placebo (least squares mean difference −0·8 days, 95% CI −1·46 to −0·20; p=0·0099). 741 participants received study medication and were included in the safety analysis. 133 (36%) of 370 patients who received rimegepant reported an adverse event, compared with 133 (36%) of 371 who received placebo. Seven (2%) participants who received rimegepant and four (1%) who received placebo discontinued the study due to an adverse event; no patients died.

Interpretation

Taken every other day, rimegepant was effective for preventive treatment of migraine. Tolerability was similar to that of placebo, and no unexpected or serious safety issues were noted.

Funding

Biohaven Pharmaceuticals.

The Lancet, VOLUME 397, ISSUE 10268, P51-60, JANUARY 02, 2021

Association of Migraine With Aura and Other Risk Factors With Incident Cardiovascular Disease in Women

Question  Is there an association between migraine with aura and cardiovascular disease (CVD) incidence rates in women, relative to that of other major vascular risk factors?

Findings  In this cohort study that included 27 858 female health professionals aged at least 45 years, the adjusted incidence rate of major CVD was 3.36 per 1000 person-years for women who reported migraine with aura and 2.11 per 1000 person-years for women who reported migraine without aura or no migraine, a difference that was statistically significant.

Meaning  Among female health professionals aged at least 45 years, self-reported migraine with aura was associated with increased incidence rates of CVD, but the clinical importance of this finding remains to be determined.

Reference: JAMA. 2020;323(22):2281-2289.

Manual acupuncture versus sham acupuncture and usual care for prophylaxis of episodic migraine without aura: multicentre, randomised clinical trial

Objective To assess the efficacy of manual acupuncture as prophylactic treatment for acupuncture naive patients with episodic migraine without aura.

Design Multicentre, randomised, controlled clinical trial with blinded participants, outcome assessment, and statistician.

Setting Seven hospitals in China, 5 June 2016 to 15 November 2018.

Participants 150 acupuncture naive patients with episodic migraine without aura.

Interventions 20 sessions of manual acupuncture at true acupuncture points plus usual care, 20 sessions of non-penetrating sham acupuncture at heterosegmental non-acupuncture points plus usual care, or usual care alone over 8 weeks.

Main outcome measures Change in migraine days and migraine attacks per four weeks during weeks 1-20 after randomisation compared with baseline (four weeks before randomisation).

Results Among 150 randomised patients (mean age 36.5 (SD 11.4) years; 123 (82%) women), 147 were included in the full analysis set. Compared with sham acupuncture, manual acupuncture resulted in a significantly greater reduction in migraine days at weeks 13 to 20 and a significantly greater reduction in migraine attacks at weeks 17 to 20. The reduction in mean number of migraine days was 3.5 (SD 2.5) for manual versus 2.4 (3.4) for sham (adjusted difference −1.4, 95% confidence interval −2.4 to −0.3; P=0.005) at weeks 13 to 16 and 3.9 (3.0) for manual versus 2.2 (3.2) for sham (adjusted difference −2.1, −2.9 to −1.2; P<0.001) at weeks 17 to 20. At weeks 17 to 20, the reduction in mean number of attacks was 2.3 (1.7) for manual versus 1.6 (2.5) for sham (adjusted difference −1.0, −1.5 to −0.5; P<0.001). No severe adverse events were reported. No significant difference was seen in the proportion of patients perceiving needle penetration between manual acupuncture and sham acupuncture (79% v 75%; P=0.891).

Conclusions Twenty sessions of manual acupuncture was superior to sham acupuncture and usual care for the prophylaxis of episodic migraine without aura. These results support the use of manual acupuncture in patients who are reluctant to use prophylactic drugs or when prophylactic drugs are ineffective, and it should be considered in future guidelines.

Trial registration Clinicaltrials.gov NCT02765581.

Reference: BMJ 2020;368:m697

Ubrogepant for the Treatment of Migraine

BACKGROUND

Ubrogepant is an oral, small-molecule calcitonin gene–related peptide receptor antagonist for acute migraine treatment.

METHODS

We conducted a randomized trial to evaluate the efficacy, safety, and side-effect profile of ubrogepant. We assigned adults with migraine, with or without aura, in a 1:1:1 ratio to receive an initial dose of placebo, ubrogepant at a dose of 50 mg, or ubrogepant at a dose of 100 mg for treatment of a single migraine attack, with the option to take a second dose. The coprimary efficacy end points were freedom from pain at 2 hours after the initial dose and absence of the most bothersome migraine-associated symptom at 2 hours. Secondary end points included pain relief (at 2 hours), sustained pain relief (from 2 to 24 hours), sustained freedom from pain (from 2 to 24 hours), and absence of symptoms associated with migraine (photophobia, phonophobia, and nausea) at 2 hours.

RESULTS

A total of 1672 participants were enrolled; 559 were assigned to receive placebo, 556 to receive 50 mg of ubrogepant, and 557 to receive 100 mg of ubrogepant. The percentage of participants who had freedom from pain at 2 hours was 11.8% in the placebo group, 19.2% in the 50-mg ubrogepant group (P=0.002, adjusted for multiplicity, for the comparison with placebo), and 21.2% in the 100-mg ubrogepant group (P<0.001). The percentage of participants who had freedom from the most bothersome symptom at 2 hours was 27.8% in the placebo group, 38.6% in the 50-mg ubrogepant group (P=0.002), and 37.7% in the 100-mg ubrogepant group (P=0.002). Adverse events within 48 hours after the initial or optional second dose were reported in 12.8% of participants in the placebo group, in 9.4% in the 50-mg ubrogepant group, and in 16.3% in the 100-mg ubrogepant group. The most common adverse events were nausea, somnolence, and dry mouth (reported in 0.4 to 4.1%); these events were more frequent in the 100-mg ubrogepant group (reported in 2.1 to 4.1%). Serious adverse events reported within 30 days in the ubrogepant groups included appendicitis, spontaneous abortion, pericardial effusion, and seizure; none of the events occurred within 48 hours after the dose.

CONCLUSIONS

A higher percentage of participants who received ubrogepant than of those who received placebo had freedom from pain and absence of the most bothersome symptom at 2 hours after the dose. The most commonly reported adverse events were nausea, somnolence, and dry mouth. Further trials are needed to determine the durability and safety of ubrogepant for acute migraine treatment and to compare it with other drugs for migraine. (Funded by Allergan; ClinicalTrials.gov number, NCT02828020. opens in new tab.)

Reference: N Engl J Med 2019; 381:2230-2241

Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine

Question  Is ubrogepant, an oral calcitonin gene–related peptide receptor antagonist, effective in the acute treatment of migraine?

Findings  In this randomized clinical trial that included 1686 participants, rates of pain freedom at 2 hours were significantly greater with ubrogepant 50 mg (21.8%) or 25 mg (20.7%) than with placebo (14.3%). Rates of freedom from the most bothersome migraine-associated symptom at 2 hours were significantly greater with the 50-mg (38.9%) dose but not the 25-mg (34.1%) dose vs placebo (27.4%).

Meaning  Acute treatment of migraine with ubrogepant compared with placebo led to significantly greater rates of pain freedom at 2 hours with both the 50-mg and 25-mg doses, and freedom from the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose.

Reference: JAMA. 2019;322(19):1887-1898.

Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS)

Background

Antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor have shown efficacy in the prevention of migraine attacks. We investigated the efficacy and tolerability of fremanezumab, a fully humanised CGRP antibody, in patients with migraine who had previously not responded to two to four classes of migraine preventive medications.

Methods

The randomised, double-blind, placebo-controlled, parallel-group, phase 3b FOCUS trial was done at 104 sites (including hospitals, medical centres, research institutes, and group practice clinics) across Belgium, the Czech Republic, Denmark, Finland, France, Germany, Italy, the Netherlands, Poland, Spain, Sweden, Switzerland, the UK, and the USA. We enrolled participants aged 18–70 years with episodic or chronic migraine who had documented failure to two to four classes of migraine preventive medications in the past 10 years. Failure was defined as no clinically meaningful improvement after at least 3 months of therapy at a stable dose, as per the treating physician’s judgment; discontinuation because of adverse events that made treatment intolerable; or treatment contraindicated or unsuitable for the preventive treatment of migraine for the patient. Participants were randomly assigned (1:1:1) by electronic interactive response technology to subcutaneously administered quarterly fremanezumab (month 1, 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: 225 mg in episodic migraine and 675 mg in chronic migraine; months 2 and 3: 225 mg in both migraine subgroups), or matched monthly placebo for 12 weeks. The primary outcome was mean change from baseline in the monthly average number of migraine days during the 12-week treatment period. This trial is registered with ClinicalTrials.gov, number NCT03308968, and is now completed.

Findings

Between Nov 10, 2017, and July 6, 2018, 838 participants with episodic (329 [39%]) or chronic (509 [61%]) migraine were randomly assigned to placebo (n=279), quarterly fremanezumab (n=276), or monthly fremanezumab (n=283). Reductions from baseline in monthly average migraine days over 12 weeks were greater versus placebo (least-squares mean [LSM] change −0·6 [SE 0·3]) with quarterly fremanezumab (LSM change −3·7 [0·3]; LSM difference vs placebo −3·1 [95% CI −3·8 to −2·4]; p<0·0001) and with monthly fremanezumab (LSM change −4·1 [0·34]; LSM difference vs placebo −3·5 [−4·2 to −2·8]; p<0·0001). Adverse events were similar for placebo and fremanezumab. Serious adverse events were reported in four (1%) of 277 participants with placebo, two (<1%) of 276 with quarterly fremanezumab, and four (1%) of 285 with monthly fremanezumab.

Interpretation

Fremanezumab was effective and well tolerated in patients with difficult-to-treat migraine who had previously not responded to up to four classes of migraine preventive medications.

Funding

Teva Pharmaceuticals.

Reference  The Lancet, VOLUME 394, ISSUE 10203, P1030-1040, SEPTEMBER 21, 2019

Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine

Background

Rimegepant, a small molecule calcitonin gene-related peptide receptor antagonist, has shown efficacy in the acute treatment of migraine using a standard tablet formulation. The objective of this trial was to compare the efficacy, safety, and tolerability of a novel orally disintegrating tablet formulation of rimegepant at 75 mg with placebo in the acute treatment of migraine.

Methods

In this double-blind, randomised, placebo-controlled, multicentre phase 3 trial, adults aged 18 years or older with history of migraine of at least 1 year were recruited to 69 study centres in the USA. Participants were randomly assigned to receive rimegepant (75 mg orally disintegrating tablet) or placebo and instructed to treat a single migraine attack of moderate or severe pain intensity. The randomisation was stratified by the use of prophylactic medication (yes or no), and was carried out using an interactive web response system that was accessed by each clinical site. All participants, investigators, and the sponsor were masked to treatment group assignment. The coprimary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 h postdose. The efficacy analyses used the modified intention-to-treat population, which included all patients who were randomly assigned, had a migraine attack with pain of moderate or severe intensity, took a dose of rimegepant or placebo, and had at least one efficacy assessment after administration of the dose. The safety analyses included all randomly assigned participants who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT03461757, and is closed  to accrual.

Findings

Between Feb 27 and Aug 28, 2018, 1811 participants were recruited and assessed for eligibility. 1466 participants were randomly assigned to the rimegepant (n=732) or placebo (n=734) groups, of whom 1375 received treatment with rimegepant (n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepant n=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tablet was superior to placebo for freedom from pain (21% vs 11%, p<0·0001; risk difference 10, 95% CI 6–14) and freedom from the most bothersome symptom (35% vs 27%, p=0·0009; risk difference 8, 95% CI 3–13). The most common adverse events were nausea (rimegepant n=11 [2%]; placebo n=3 [<1%]) and urinary tract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant in each treatment group had a transaminase concentration of more than 3 × the upper limit of normal; neither was related to study medication, and no elevations in bilirubin greater than 2 × the upper limit of normal were reported. Treated participants reported no serious adverse events.

Interpretation

In the acute treatment of migraine, a single 75 mg dose of rimegepant in an orally disintegrating tablet formulation was more effective than placebo. Tolerability was similar to placebo, with no safety concerns.

Funding

Biohaven Pharmaceuticals.

Reference: The Lancet, VOLUME 394, ISSUE 10200, P737-745, AUGUST 31, 2019

Rimegepant, an Oral Calcitonin Gene–Related Peptide Receptor Antagonist, for Migraine

BACKGROUND

Calcitonin gene–related peptide receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene–related peptide receptor antagonist that may be effective in acute migraine treatment.

METHODS

In a multicenter, double-blind, phase 3 trial, we randomly assigned adults with at least a 1-year history of migraine and two to eight migraine attacks of moderate or severe intensity per month to receive rimegepant orally at a dose of 75 mg or matching placebo for the treatment of a single migraine attack. The primary end points were freedom from pain and freedom from the most bothersome symptom (other than pain) identified by the patient, both of which were assessed 2 hours after the dose of rimegepant or placebo was administered.

RESULTS

A total of 1186 patients were randomly assigned to receive rimegepant (594 patients) or placebo (592 patients); of these, 537 patients in the rimegepant group and 535 patients in the placebo group could be evaluated for efficacy. The overall mean age of the patients evaluated for efficacy was 40.6 years, and 88.7% were women. In a modified intention-to-treat analysis, the percentage of patients who were pain-free 2 hours after receiving the dose was 19.6% in the rimegepant group and 12.0% in the placebo group (absolute difference, 7.6 percentage points; 95% confidence interval [CI], 3.3 to 11.9; P<0.001). The percentage of patients who were free from their most bothersome symptom 2 hours after the dose was 37.6% in the rimegepant group and 25.2% in the placebo group (absolute difference, 12.4 percentage points; 95% CI, 6.9 to 17.9; P<0.001). The most common adverse events were nausea and urinary tract infection.

CONCLUSIONS

Treatment of a migraine attack with the oral calcitonin gene–related peptide receptor antagonist rimegepant resulted in a higher percentage of patients who were free of pain and free from their most bothersome symptom than placebo. (Funded by Biohaven Pharmaceuticals; ClinicalTrials.gov number, NCT03237845opens in new tab.)

Reference N Engl J Med 2019; 381:142-149

Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful

Background

A substantial proportion of patients with migraine does not respond to, or cannot tolerate, oral preventive treatments. Erenumab is a novel CGRP-receptor antibody with preventive efficacy in migraine. We assessed its efficacy and tolerability in patients with episodic migraine in whom previous treatment with two-to-four migraine preventives had been unsuccessful.

Methods

LIBERTY was a 12-week, double-blind, placebo-controlled randomised study at 59 sites in 16 countries. Eligible patients were aged 18–65 years and had a history of episodic migraine with or without aura for at least 12 months, had migraine for an average of 4–14 days per month during the 3 months before screening, and had been treated unsuccessfully (in terms of either efficacy or tolerability, or both) with between two and four preventive treatments. Eligible participants were randomly assigned (1:1) to receive either erenumab 140 mg (via two 70 mg injections) or placebo every 4 weeks subcutaneously for 12 weeks. Randomisation was by interactive response technology and was stratified by monthly frequency of migraine headache (4–7 vs 8–14 migraine days per month) during the baseline phase. Cenduit generated the randomisation list and assigned participants to groups. Participants, investigators, people doing various assessments, and the study sponsor were masked to treatment assignment. The primary endpoint was the proportion of patients achieving a 50% or greater reduction in the mean number of monthly migraine days during weeks 9–12. Efficacy was measured in the full analysis set, which included all randomly assigned patients who started their assigned treatment and completed at least one post-baseline monthly migraine day measurement. Safety and tolerability were assessed by recording adverse events and by physical examination, assessment of vital signs, clinical laboratory assessments, and electrocardiography. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT03096834. The trial is closed to new participants, but the open-label extension phase is ongoing.

Findings

Between March 20, 2017, and Oct 27, 2017, 246 participants were randomly assigned, 121 to the erenumab group and 125 to the placebo group. 95 of 246 (39%) participants had previously unsuccessfully tried two preventive drugs, 93 (38%) had tried three, and 56 (23%) had tried four. At week 12, 36 (30%) patients in the erenumab had a 50% or greater reduction from baseline in the mean number of monthly migraine days, compared with 17 (14%) in the placebo group (odds ratio 2·7 [95% CI 1·4–5·2]; p=0·002). The tolerability and safety profiles of erenumab and placebo were similar. The most frequent treatment-emergent adverse event was injection site pain, which occurred in seven (6%) participants in both groups.

Interpretation

Compared with placebo, erenumab was efficacious in patients with episodic migraine who previously did not respond to or tolerate between two and four previous migraine preventive treatments. Erenumab might be an option for patients with difficult-to-treat migraine who have high unmet needs and few treatment options.

Funding

Novartis Pharma.

Reference: 
The Lancet, VOLUME 392, ISSUE 10161, P2280-2287, NOVEMBER 24, 2018

Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine

Question  Is the monoclonal antibody fremanezumab effective in preventing episodic migraine?

Findings  In this randomized clinical trial that included 875 adults with episodic migraine in whom multiple medication classes had not previously failed, fremanezumab compared with placebo resulted in significantly fewer monthly migraine days with monthly dosing (–1.5 days) and with a single higher dose at baseline (–1.3 days) over 12 weeks.

Meaning  Fremanezumab as a preventive treatment for episodic migraine reduced the mean number of monthly migraine days over a 12-week period compared with placebo. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy.

Reference: JAMA. 2018;319(19):1999-2008.