Background
Calcitonin gene-related peptide plays an important role in migraine pathophysiology. Erenumab, a human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor, is ...being evaluated for migraine prevention.
Methods
In this randomized, double-blind, placebo-controlled, phase 3 study, 577 adults with episodic migraine were randomized to placebo or 70 mg erenumab; 570 patients were included in efficacy analyses. Primary endpoint was change in monthly migraine days. Secondary endpoints were ≥50% reduction in monthly migraine days, change in acute migraine-specific medication treatment days, and ≥5-point reduction in Physical Impairment and Impact on Everyday Activities domain scores measured by the Migraine Physical Function Impact Diary. All endpoints assessed change from baseline at month 3.
Results
Patients receiving erenumab experienced −2.9 days change in monthly migraine days, compared with −1.8 days for placebo, least-squares mean (95% CI) treatment difference of −1.0 (−1.6, −0.5) (p < 0.001). A ≥ 50% reduction in monthly migraine days was achieved by 39.7% (erenumab) and 29.5% (placebo) of patients (OR:1.59 (95% CI: 1.12, 2.27) (p = 0.010). Migraine-specific medication treatment days were reduced by −1.2 (erenumab) and −0.6 (placebo) days, a treatment difference of −0.6 (−1.0, −0.2) (p = 0.002). The ≥5-point reduction rates in Migraine Physical Function Impact Diary – Physical Impairment were 33.0% and 27.1% (OR:1.33 (0.92, 1.90) (p = 0.13) and in Migraine Physical Function Impact Diary – Everyday Activities were 40.4% and 35.8% (OR:1.22 (0.87, 1.71) (p = 0.26). Safety and adverse event profiles of erenumab were similar to placebo. Most frequent adverse events were upper respiratory tract infection, injection site pain, and nasopharyngitis.
Conclusions
As a preventive treatment of episodic migraine, erenumab at a dosage of 70 mg monthly significantly reduced migraine frequency and acute migraine-specific medication use. (Funded by Amgen).
Trial registration
ClinicalTrials.gov, NCT02483585.
Objective
To evaluate non‐invasive vagus nerve stimulation (nVNS) as an acute cluster headache (CH) treatment.
Background
Many patients with CH experience excruciating attacks at a frequency that is ...not sufficiently addressed by current symptomatic treatments.
Methods
One hundred fifty subjects were enrolled and randomized (1:1) to receive nVNS or sham treatment for ≤1 month during a double‐blind phase; completers could enter a 3‐month nVNS open‐label phase. The primary end point was response rate, defined as the proportion of subjects who achieved pain relief (pain intensity of 0 or 1) at 15 minutes after treatment initiation for the first CH attack without rescue medication use through 60 minutes. Secondary end points included the sustained response rate (15‐60 minutes). Subanalyses of episodic cluster headache (eCH) and chronic cluster headache (cCH) cohorts were prespecified.
Results
The intent‐to‐treat population comprised 133 subjects: 60 nVNS‐treated (eCH, n = 38; cCH, n = 22) and 73 sham‐treated (eCH, n = 47; cCH, n = 26). A response was achieved in 26.7% of nVNS‐treated subjects and 15.1% of sham‐treated subjects (P = .1). Response rates were significantly higher with nVNS than with sham for the eCH cohort (nVNS, 34.2%; sham, 10.6%; P = .008) but not the cCH cohort (nVNS, 13.6%; sham, 23.1%; P = .48). Sustained response rates were significantly higher with nVNS for the eCH cohort (P = .008) and total population (P = .04). Adverse device effects (ADEs) were reported by 35/150 (nVNS, 11; sham, 24) subjects in the double‐blind phase and 18/128 subjects in the open‐label phase. No serious ADEs occurred.
Conclusions
In one of the largest randomized sham‐controlled studies for acute CH treatment, the response rate was not significantly different (vs sham) for the total population; nVNS provided significant, clinically meaningful, rapid, and sustained benefits for eCH but not for cCH, which affected results in the total population. This safe and well‐tolerated treatment represents a novel and promising option for eCH. ClinicalTrials.gov identifier: NCT01792817.
Summary Background Calcitonin gene-related peptide (CGRP) is crucial in the pathophysiology of migraine. We assessed the safety, tolerability, and efficacy of ALD403, a genetically engineered ...humanised anti-CGRP antibody, for migraine prevention. Methods In this randomised, double-blind, placebo-controlled, exploratory, proof-of-concept phase 2 trial, patients aged 18–55 years with five to 14 migraine days per 28-day period were randomly assigned (1:1) via an interactive web response system to receive an intravenous dose of ALD403 1000 mg or placebo. Site investigators, patients, and the sponsor were masked to treatment allocation during the study. The primary objective was to assess safety at 12 weeks after infusion. The primary efficacy endpoint was the change from baseline to weeks 5–8 in the frequency of migraine days, as recorded in patient electronic diaries. Patients were followed up until 24 weeks for exploratory safety and efficacy analyses. Safety and efficacy analyses were done by intention to treat. This study is registered with ClinicalTrials.gov , NCT01772524. Findings Between Jan 28, 2013, and Dec 23, 2013, of 174 patients randomly assigned at 26 centres in the USA, 163 received either ALD403 (n=81) or placebo (n=82). Adverse events were experienced by 46 (57%) of 81 patients in the ALD403 group and 43 (52%) of 82 in the placebo group. The most frequent adverse events were upper respiratory tract infection (placebo 6 7% patients vs ALD403 7 9% patients), urinary tract infection (4 5% vs 1 1%), fatigue (3 4% vs 3 4%), back pain (4 5% vs 3 4%), arthralgia (4 5% vs 1 1%), and nausea and vomiting (2 2% vs 3 4%). Six serious adverse events were reported by three patients and were judged to be unrelated to study drug: in the ALD403 group, one patient had four serious adverse events and one had one serious adverse event, and in the placebo group, one patient had one serious adverse event. There were no differences in vital signs or laboratory safety data between the two treatment groups. The mean change in migraine days between baseline and weeks 5–8 was −5·6 (SD 3·0) for the ALD403 group compared with −4·6 (3·6) for the placebo group (difference −1·0, 95% CI −2·0 to 0·1; one-sided p=0·0306). Interpretation No safety concerns were noted with an intravenous dose of ALD403 1000 mg. This study also provides preliminary evidence for the efficacy of ALD403 in the preventive treatment of migraine in patients with a high monthly frequency of migraine days. Funding Alder Biopharmaceuticals.
Galcanezumab, a humanized monoclonal antibody that selectively binds to the calcitonin gene-related peptide, has demonstrated in previous Phase 2 and Phase 3 clinical studies (≤6-month of treatment) ...a reduction in the number of migraine headache days and improved patients' functioning. This study evaluated the safety and tolerability, as well as the effectiveness of galcanezumab for up to 12 months of treatment in patients with migraine.
Patients diagnosed with episodic or chronic migraine, 18 to 65 years old, that were not exposed previously to galcanezumab, were randomized to receive galcanezumab 120 mg or 240 mg, administered subcutaneously once monthly for a year. Safety and tolerability were evaluated by frequency of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events (AEs) leading to study discontinuation. Laboratory values, vital signs, electrocardiograms, and suicidality were also analyzed. Additionally, overall change from baseline in the number of monthly migraine headache days, functioning, and disability were assessed.
One hundred thirty five patients were randomized to each galcanezumab dose group. The majority of patients were female (> 80%) and on average were 42 years old with 10.6 migraine headache days per month at baseline. 77.8% of the patients completed the open-label treatment phase, 3.7% of patients experienced an SAE, and 4.8% discontinued due to AEs. TEAEs with a frequency ≥ 10% of patients in either dose group were injection site pain, nasopharyngitis, upper respiratory tract infection, injection site reaction, back pain, and sinusitis. Laboratory values, vital signs, or electrocardiograms did not show anyclinically meaningful differences between galcanezumab dosesOverall mean reduction in monthly migraine headache days over 12 months for the galcanezumab dose groups were 5.6 (120 mg) and 6.5 (240 mg). Level of functioning was improved and headache-related disability was reduced in both dose groups.
Twelve months of treatment with self-administered injections of galcanezumab was safe and associated with a reduction in the number of monthly migraine headache days. Safety and tolerability of the 2 galcanezumab dosing regimens were comparable.
ClinicalTrials.gov as NCT02614287 , posted November 15, 2015. These data were previously presented as a poster at the International Headache Congress 2017: PO-01-184, Late-Breaking Abstracts of the 2017 International Headache Congress. (2017). Cephalalgia, 37(1_suppl), 319-374.
Objective
Evaluate the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a monoclonal antibody (mAb) targeting the calcitonin gene‐related peptide (CGRP) ...ligand or receptor (CGRP mAb) for the preventive treatment of migraine.
Background
The efficacy of CGRP mAbs for the preventive treatment of migraine and the small molecule CGRP receptor antagonist rimegepant for acute treatment has been demonstrated in randomized controlled clinical trials. Over the past few years, the US Food and Drug Administration has approved 4 CGRP mAbs for the preventive treatment of migraine and 2 small molecule CGRP receptor antagonists for the acute treatment of migraine. A previous case report of 2 patients receiving concomitant treatment with rimegepant and erenumab suggested that rimegepant may be safely used as acute treatment in patients who are also receiving a preventive regimen involving CGRP mAbs. We report here 13 additional patients with migraine who simultaneously used rimegepant and either erenumab, fremanezumab, or galcanezumab and assess the rate of on‐treatment adverse events (AEs).
Methods
This was a substudy nested within a multicenter, open‐label, long‐term safety study in adults with 2‐14 monthly migraine attacks of moderate to severe pain intensity. A subgroup experiencing 2‐8 monthly attacks and taking a stable dose of a CGRP mAb also took rimegepant 75 mg as needed up to once daily for acute treatment for 12 weeks.
Results
The 13 patients (11 women 85%; mean age 49.9 years) enrolled in the substudy were being treated with CGRP mAbs (erenumab n = 7, fremanezumab n = 4, or galcanezumab n = 2). Mean (SD) time in the rimegepant treatment period was 9.6 (4.6) weeks. Mean (SD) 4‐week rimegepant exposure was 7.8 (5.5) doses; a total of 224 doses were taken. Five (38%) patients reported ≥1 on‐treatment AE. Of these, 2 (15%) patients had mild or moderate nasopharyngitis; no other AEs occurred in ≥2 patients. Three patients had AEs of mild or moderate severity that were considered potentially treatment‐related. No patients had serious AEs, AEs leading to discontinuation, or aminotransferase levels >3× the upper limit of normal.
Conclusion
Rimegepant, when used as an oral acute treatment in patients receiving CGRP mAbs as preventive treatment, was well tolerated; no safety issues were identified. Studies involving larger patient populations are needed to confirm these findings.
Objective
To determine the efficacy, tolerability, and safety of ascending doses of Adhesive Dermally-Applied Microarray (ADAM) zolmitriptan versus placebo for acute migraine treatment.
Background
...ADAM is a novel patient-administered system for intracutaneous drug administration. In a phase 1 pharmacokinetic study, zolmitriptan administered using ADAM had much faster absorption than oral administration with higher exposure in the first two hours.
Methods
This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 2b/3 study evaluating ADAM zolmitriptan 1 mg, 1.9 mg, and 3.8 mg versus placebo. Co-primary endpoints were pain freedom and freedom from most bothersome other migraine-associated symptom 2 hours post-dose.
Results
Of patients treated with ADAM zolmitriptan 3.8 mg or placebo, 41.5% and 14.2%, respectively were pain-free 2 hours post-dose (p = 0.0001) and 68.3% and 42.9% were free from their most bothersome other symptom (p = 0.0009). Due to the fixed sequential testing methodology, formal statistical significance was not established for secondary endpoints. However, the proportion of patients who were photophobia-free, phonophobia-free, and nausea-free at 2 hours post-dose was higher in the ADAM zolmitriptan 3.8 mg group compared with placebo, as were the percentages of patients who were pain-free, and who experienced pain relief up to 48 hours post-dose. Systemic adverse events were consistent with previous triptan trials, and included dizziness, paresthesia, muscle tightness, and nausea, all of which occurred in < 5% of patients in any group. Application site reactions were generally mild and resolved within 48 hours, although erythema and bruising persisted for longer periods in some patients.
Conclusion
ADAM zolmitriptan 3.8 mg provides effective relief of migraine headache and associated most bothersome symptoms compared with placebo, and is well-tolerated.
ClinicalTrials.gov
NCT02745392
Objectives
To address the need for long-term lasmiditan data, the GLADIATOR study evaluated the safety (primary) and efficacy (secondary) of lasmiditan for the intermittent, acute treatment of ...migraine attacks for up to 1 year.
Methods
In this prospective, randomized, open-label, Phase 3 study, patients who had completed either of two single-attack studies were offered the opportunity to be randomized 1:1 to lasmiditan 100 mg or 200 mg. Patients were asked to use lasmiditan as the first treatment for each new migraine attack of at least moderate severity. Assessments occurred at baseline and at prespecified time increments up to 48 hours after each dose of study drug using an electronic diary, and safety was assessed throughout the study. Migraine Disability Assessment (MIDAS) was assessed at each visit.
Results
As of the cut-off date for this interim analysis (6 March 2018), 1978 patients had received ≥ 1 lasmiditan dose and treated 19,058 migraine attacks. Overall, treatment-emergent adverse events (TEAEs) were similar to those in the single-attack studies and included dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%). The frequency of TEAEs generally decreased with subsequent attacks. No treatment-related serious adverse events and no cardiovascular TEAEs potentially due to vasoconstriction were observed. For both lasmiditan doses, efficacy measures were generally consistent over study quarters and treated attacks. Overall, across all treated attacks at 2 hours post-dose, pain freedom was observed in 26.9% of the attacks treated with lasmiditan 100 mg and 32.4% of the attacks treated with lasmiditan 200 mg. MIDAS total scores decreased over time.
Conclusions
The interim results of this long-term study showed intermittent lasmiditan (100 mg and 200 mg) to be generally well tolerated and efficacious for the acute treatment of migraine over a 1-year period.
Trial registration number: NCT02565186; https://clinicaltrials.gov/ct2/show/NCT02565186
Eptinezumab, an anti-calcitonin gene-related peptide monoclonal antibody recently approved in the United States for preventive treatment of migraine in adults, was found to be well tolerated in ...double-blind, placebo-controlled studies in patients with episodic and chronic migraine. The objective of the PREVAIL study was to evaluate the long-term safety, immunogenicity, and impact on patient-reported outcomes of repeat doses of eptinezumab in patients with chronic migraine.
PREVAIL was an open-label, phase 3 trial comprising a 48-week treatment phase followed by a second 48-week treatment phase. Adults with chronic migraine received eptinezumab 300 mg by 30-min intravenous administration every 12 weeks for up to 8 doses. Patients were followed for 20 weeks after the final infusion (end-of-study visit at week 104).
Overall, 128 adults (mean age, 41.5 years) with chronic migraine were included. During the 2 years, the most frequently reported treatment-emergent adverse events were nasopharyngitis (14.1%), upper respiratory tract infection (7.8%), sinusitis (7.8%), influenza (6.3%), bronchitis (5.5%), and migraine (5.5%). The rate of study-drug discontinuation due to adverse events was 6.3%, which included 3 patients with infusion-related hypersensitivity. The incidence of anti-eptinezumab antibodies peaked at week 24 and declined despite continued dosing, to nondetectable levels at week 104. Improvements in patient-reported outcomes were observed at first assessment (week 4) and generally sustained through week 104.
In adults with chronic migraine, eptinezumab 300 mg demonstrated a favorable safety profile, limited long-term immunogenicity, early and sustained reductions in migraine-related burden, and improvements in health-related quality of life over 2 years.
ClinicalTrials.gov (Identifier: NCT02985398 ).
Background
Subcutaneous erenumab reduced monthly migraine days and increased the likelihood of achieving a ≥ 50% reduction at all monthly assessment points tested in 2 pivotal trials in episodic ...migraine (EM) and chronic migraine (CM). Early efficacy of migraine preventive medications is an important treatment characteristic to patients. Delays in achievement of efficacy can result in failed adherence. The objective of these post-hoc analyses were to evaluate efficacy in the first 4 weeks after initial subcutaneous administration of erenumab 70 mg, erenumab 140 mg, or placebo.
Methods
There is no generally accepted methodology to measure onset of action for migraine preventive medications. We used a comprehensive approach with data from both studies to evaluate change from baseline in weekly migraine days (WMD), achievement of ≥ 50% reduction in WMD, and proportion of patients experiencing migraine measured on a daily basis. The 7-day moving averages were overlaid with observed data.
Results
In both studies (EM:
N
= 955; CM:
N
= 667), there was evidence of onset of efficacy of erenumab vs. placebo during the first week of treatment, which in some cases reached nominal significance. For EM the changes in WMD were (least squares mean LSM 95% CI): placebo, − 0.1 (− 0.3, 0.0); erenumab 70 mg, − 0.3 (− 0.5, − 0.2)
p
= 0.130; erenumab 140 mg, − 0.6 (− 0.7, − 0.4)
p
< 0.001. For CM the changes were: placebo, − 0.5 (− 0.8, − 0.3); erenumab 70 mg, − 0.9 (− 1.2, − 0.7)
p
= 0.047; erenumab 140 mg, − 0.8 (− 1.1, − 0.5)
p
= 0.18. Achievement of ≥ 50% reduction in WMD was observed as early as Week 1 (adjusted OR 95% CI erenumab vs placebo) in EM: erenumab 70 mg, 1.3 (1.0, 1.9)
p
= 0.097; erenumab 140 mg, 2.0 (1.4, 2.7)
p
< 0.001. A similar outcome was observed for CM: erenumab 70 mg, 1.8 (1.1, 2.8)
p
= 0.011; erenumab 140 mg, 1.9 (1.2, 2.9)
p
= 0.009. Seven-day moving averages of observed data showed each treatment arm differed from placebo by Week 1 (OR 95% CI): in EM Day 3 for erenumab 140 mg, 0.7 (0.5, 1.0)
p
= 0.031 and at Day 7 for 70 mg, 0.6 (0.4, 0.8)
p
= 0.002; in CM: Day 6 for erenumab 70 mg, 0.6 (0.4, 0.9)
p
= 0.022 and at Day 7 for 140 mg, 0.7 (0.4, 1.0);
p
= 0.038.
Conclusion
Erenumab showed early onset of efficacy with separation from placebo within the first week of treatment in both chronic and episodic migraine patients.
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