Sustained reductions in migraine days, moderate-to-severe headache days and days with acute medication use for HFEM and CM patients taking fremanezumab: Post-hoc analyses from phase 2 trials

Background In phase 2 and 3 studies, fremanezumab, a monoclonal CGRP antibody, was an effective preventive treatment for high-frequency episodic migraine (HFEM) and chronic migraine (CM). Objective Post-hoc analyses evaluated population-wise 50%, 75% and 100% responder rates, and the extent to which individual responders sustained a 50%, 75% and 100% reduction in migraine days, moderate-to-severe (M/S) headache days and days of acute medication use during all three treatment months of the fremanezumab phase 2 studies. Design/methods HFEM patients received either placebo or three once-monthly injections of 225 mg or 675 mg. CM patients received either placebo or three once-monthly injections of 900 mg, or an initial loading dose of 675 mg and subsequent injections of 225 mg. Patients reported headache-related data daily using an electronic diary. Results In the HFEM study, the percent of patients on fremanezumab doses 225 mg and 675 mg were greater compared to the percent of placebo patients with sustained 50% reduction in migraine days (39% and 35% vs. 10% for placebo, both p < 0.0001), M/S headache days (36% and 38% vs. 16% placebo, p = 0.0017 and p = 0.0007 respectively), and acute medication use days (36% and 27% vs. 8% placebo, p < 0.0001 and p = 0.0003). Likewise, although there were fewer patients with sustained 75% reduction, there were increases in the percent of patients on fremanezumab 225 mg and 675 mg in the HFEM study relative to placebo patients in migraine days (19% and 11% vs. 3% placebo, p = 0.0002 and p = 0.0176), M/S headache days (19% and 15% vs. 2% placebo, p = 0.0001 and p = 0.0011) and days of acute medication use (16% and 8% vs. 2% placebo, p = 0.0005 and p = 0.0377). In the CM study, there were increases in the percent of patients on fremanezumab 675/225 mg and 900 mg with 50% sustained reduction in M/S headache days (32% and 40% vs. 15% placebo, p = 0.0058 and p = 0.0002) and days of acute medication use (26% and 22% vs. 11% placebo, p = 0.0098 and p = 0.0492). There were also increases in the percent of patients on fremanezumab 675/225 mg and 900 mg compared to patients on placebo with 75% sustained reduction in M/S headache days (10% and 13% vs. 3%, p = 0.0665 and p = 0.0203). Few patients had 100% sustained reductions in these parameters in either study. Conclusions Post-hoc results must be interpreted with caution; nonetheless, a statistically significant percentage of patients who initially responded to fremanezumab within 1 month sustained this response over the subsequent 2 months. Sustained reduction in individual patients may provide a novel patient-centric, clinically meaningful endpoint for future trials assessing the effectiveness of preventive migraine treatments. Trials are registered as http://clinical trials.gov as NCT02025556 and NCT02021773.

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Reduction in acute migraine-specific and non-specific medication use in patients treated with erenumab: post-hoc analyses of episodic and chronic migraine clinical trials

The Journal of Headache and Pain ◽

10.1186/s10194-021-01292-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Stewart J Tepper ◽

Messoud Ashina ◽

Uwe Reuter ◽

Yngve Hallström ◽

Gregor Broessner ◽

...

Keyword(s):

Chronic Migraine ◽

Medication Overuse Headache ◽

Medication Use ◽

Electronic Diary ◽

Double Blind ◽

Acute Medication ◽

Specific Medication ◽

Acute Headache ◽

Post Hoc ◽

Change In Mean

Abstract Background In patients with migraine, overuse of acute medication, including migraine-specific medication (MSM) such as triptans and ergots, can lead to adverse health outcomes, including development of medication overuse headache. Here, we examined the effect of erenumab on reducing acute medication use, in particular MSM, in patients with episodic migraine (EM) and chronic migraine (CM). Methods The current post-hoc analyses were based on data from the double-blind treatment phase (DBTP) of two erenumab studies, a pivotal EM (N = 955) and a pivotal CM (N = 667) trial, and their respective extensions. Patients were administered subcutaneous placebo or erenumab (70 or 140 mg) once monthly. Daily acute headache medication use (including MSM and non-MSM) was recorded using an electronic diary during a 4-week pretreatment baseline period until the end of the treatment period. Outcome measures included change in monthly acute headache medication days (HMD) in acute headache medication users at baseline, and changes in monthly MSM days (MSMD) in MSM users at baseline and non-MSMD in non-MSM users at baseline. Results In total, 60 and 78 % of patients (all acute headache medication users) with EM and CM used MSM at baseline, respectively. For acute headache medication users, the change in mean monthly acute HMD over Months 4, 5 and 6 compared with the pre-DBTP was 1.5, 2.5, and 3.0 for placebo, erenumab 70 mg and 140 mg, respectively for the EM study. The respective change in monthly MSMD in MSM users was 0.5, 2.1 and 2.8, and in monthly non-MSMD in non-MSM users was 2.3, 2.6, and 2.7. In the acute headache medication users at baseline, the change in monthly acute HMD at Month 3 compared with pre-DBTP was 3.4, 5.5, and 6.5 for placebo, erenumab 70 mg and 140 mg, respectively for the CM study. The respective change in monthly MSMD in MSM users was 2.1, 4.5, and 5.4, and in monthly non-MSMD in non-MSM users was 5.9, 6.4, and 6.6. Reductions in MSMD versus placebo were sustained in the extension periods of both studies. Erenumab was also associated with a higher proportion of MSM users achieving ≥ 50 %, ≥ 75 and 100 % reduction from baseline in monthly MSMD versus placebo in both EM and CM. Conclusions In both EM and CM, treatment with erenumab is associated with a significant and sustained reduction in the use of acute headache medication, in particular MSM. Trial registrations NCT02456740; NCT02066415; NCT02174861.

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Early and sustained symptom improvement with umeclidinium/vilanterol versus monotherapy in COPD: a post hoc analysis of the EMAX randomised controlled trial

Therapeutic Advances in Respiratory Disease ◽

10.1177/1753466620926949 ◽

2020 ◽

Vol 14 ◽

pp. 175346662092694

Author(s):

Edward M Kerwin ◽

Isabelle H Boucot ◽

Claus F Vogelmeier ◽

Francois Maltais ◽

Ian P Naya ◽

...

Keyword(s):

Rescue Medication ◽

Controlled Trial ◽

Medication Use ◽

Symptom Improvement ◽

Chronic Obstructive ◽

Electronic Diary ◽

Double Blind ◽

Clinical Trial Registration ◽

Bronchodilator Therapy ◽

Post Hoc

Background: In chronic obstructive pulmonary disease (COPD), both the time needed for patients to gain symptom improvement with long-acting bronchodilator therapy and whether an early response is predictive of a sustained response is unknown. This study aimed to investigate how quickly meaningful symptom responses are seen in patients with COPD with bronchodilator therapy and whether these responses are sustained. Methods: Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a 24-week, double-blind, double-dummy, parallel-group trial that randomised patients to umeclidinium/vilanterol (UMEC/VI), umeclidinium or salmeterol. Daily Evaluating Respiratory Symptoms in COPD (E-RS:COPD) score and rescue salbutamol use were captured via an electronic diary and analysed initially in 4-weekly periods. Post hoc analyses assessed change from baseline in daily E-RS:COPD score and rescue medication use weekly (Weeks 1–8), and association between E-RS:COPD responder status at Weeks 1–4 and later time points. Results: In the intent-to-treat population ( n = 2425), reductions from baseline in E-RS:COPD scores and rescue medication use were apparent from Day 2 with all treatments. Treatment differences for UMEC/VI versus either monotherapy plateaued by Week 4–8 and were sustained at Weeks 21–24; improvements were consistently greater with UMEC/VI. For all treatments, most patients (60–85%) retained their Weeks 1–4 E-RS:COPD responder/non-responder status at Weeks 21−24. Among patients receiving UMEC/VI who were E-RS:COPD responders at Weeks 1–4, 70% were responders at Weeks 21–24. Conclusion: Patients with symptomatic COPD had greater potential for early symptom improvements with UMEC/VI versus either monotherapy. This benefit was generally maintained for 24 weeks. Early monitoring of treatment response can provide clinicians with an early indication of a patient’s likely longer-term response to prescribed bronchodilator treatment and will facilitate appropriate early adjustments in care. Clinical Trial Registration: NCT03034915, 2016-002513-22 (EudraCT Number). The reviews of this paper are available via the supplemental material section.

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The Effect of Beginning Treatment With Fremanezumab on Headache and Associated Symptoms in the Randomized Phase 2 Study of High Frequency Episodic Migraine: Post-Hoc Analyses on the First 3 Weeks of Treatment

Headache The Journal of Head and Face Pain ◽

10.1111/head.13446 ◽

2018 ◽

Vol 59 (3) ◽

pp. 383-393 ◽

Cited By ~ 18

Author(s):

Stephen D. Silberstein ◽

Alan M. Rapoport ◽

Pippa S. Loupe ◽

Ernesto Aycardi ◽

Mirna McDonald ◽

...

Keyword(s):

High Frequency ◽

Episodic Migraine ◽

Phase 2 ◽

Phase 2 Study ◽

Associated Symptoms ◽

Post Hoc ◽

Randomized Phase 2

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Long-term safety, tolerability, and efficacy of fremanezumab in migraine

Neurology ◽

10.1212/wnl.0000000000010600 ◽

2020 ◽

Vol 95 (18) ◽

pp. e2487-e2499 ◽

Cited By ~ 2

Author(s):

Peter J. Goadsby ◽

Stephen D. Silberstein ◽

Paul P. Yeung ◽

Joshua M. Cohen ◽

Xiaoping Ning ◽

...

Keyword(s):

Injection Site ◽

Medication Use ◽

Preventive Treatment ◽

Episodic Migraine ◽

Double Blind ◽

Moderate Severity ◽

Humanized Monoclonal Antibody ◽

Parallel Group ◽

Acute Headache

ObjectiveTo assess the long-term safety, tolerability, and efficacy of fremanezumab, a fully humanized monoclonal antibody approved for the preventive treatment of migraine.MethodsA 52-week, multicenter, randomized, double-blind, parallel-group study evaluated fremanezumab monthly or quarterly in adults with chronic migraine (CM) or episodic migraine (EM). Safety and tolerability were assessed by adverse event (AE) monitoring (performed by the investigators), systematic local injection-site assessments (immediately and 1 hour after injection), laboratory/vitals assessments, and immunogenicity testing. Prespecified exploratory evaluations included change from baseline in the monthly number of migraine days, headache days of at least moderate severity, and days with any acute headache medication use. Change from baseline in headache-related disability (6-item Headache Impact Test scores) was also measured.ResultsOf 1,890 patients enrolled, 551 and 559 patients with CM received quarterly and monthly dosing; 394 and 386 patients with EM received quarterly or monthly, respectively. The most commonly reported AEs were injection-site reactions (induration 33%, pain 31%, and erythema 26%). Fremanezumab reduced monthly migraine days (CM quarterly −7.2 days, CM monthly −8.0 days, EM quarterly −5.2 days, EM monthly −5.1 days) and headache days of at least moderate severity (CM quarterly −6.4 days, CM monthly −6.8 days, EM quarterly −4.4, EM monthly −4.2 days) from baseline to 12 months. Reductions in any acute headache medication use and headache-related disability were also maintained over 12 months.ConclusionsFremanezumab quarterly and fremanezumab monthly were well tolerated and demonstrated sustained improvements in monthly migraine days, headache days, and headache-related disability for up to 12 months in patients with migraine.ClinicalTrials.govNCT02638103.Classification of evidenceThis study provides Class IV evidence that long-term fremanezumab treatment is safe, well tolerated, and effective at sustaining reductions in monthly migraine and headache days.

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Medication overuse in a subgroup analysis of phase 3 placebo-controlled studies of galcanezumab in the prevention of episodic and chronic migraine

Cephalalgia ◽

10.1177/0333102420966658 ◽

2020 ◽

pp. 033310242096665

Author(s):

David W Dodick ◽

Erin G Doty ◽

Sheena K Aurora ◽

Dustin D Ruff ◽

Virginia L Stauffer ◽

...

Keyword(s):

Chronic Migraine ◽

Subgroup Analysis ◽

Repeated Measures ◽

Migraine Headache ◽

Medication Overuse ◽

Preventive Treatment ◽

Episodic Migraine ◽

Phase 3 ◽

Double Blind ◽

Acute Medication

Introduction Acute medication overuse is prevalent in patients with migraine. Methods In three phase 3, double-blind, randomized, placebo-controlled studies, patients with episodic migraine (EVOLVE-1 and EVOLVE-2) or chronic migraine (REGAIN) were randomized 2:1:1 to monthly subcutaneous injections of placebo or galcanezumab 120 or 240 mg for 3 or 6 months. This subgroup analysis evaluated mean changes in the number of monthly migraine headache days in each treatment among patients with versus without baseline acute medication overuse via mixing modelling with repeated measures. Results The percentages of patients with baseline medication overuse in placebo, galcanezumab 120-mg and 240-mg groups, respectively, were 19.4%, 17.3%, and 19.3% for EVOLVE-1/-2 (pooled; post hoc), and 63.4%, 64.3%, and 64.1% for REGAIN ( a priori). Both galcanezumab doses demonstrated significant improvement compared with placebo for overall least squares mean change in monthly migraine headache days in patients with baseline medication overuse in both the episodic and chronic migraine studies ( p ≤ 0.001). Furthermore, both galcanezumab doses reduced average monthly medication overuse rates compared to placebo ( p < 0.001) in both patient populations with medication overuse at baseline. Conclusions Galcanezumab appears to be effective for the preventive treatment of episodic and chronic migraine in patients who overuse acute medications. Trial registration: ClinicalTrials.gov Identifiers: NCT02614183, NCT02614196, and NCT02614261

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Factors predicting the probability of relapse after discontinuation of migraine preventive treatment with topiramate

Cephalalgia ◽

10.1177/0333102409359709 ◽

2010 ◽

Vol 30 (11) ◽

pp. 1290-1295 ◽

Cited By ~ 2

Author(s):

Jean Schoenen ◽

Uwe Reuter ◽

Hans-Christoph Diener ◽

Joop Pfeil ◽

Susanne Schwalen ◽

...

Keyword(s):

Impact Test ◽

Preventive Treatment ◽

Patient Characteristics ◽

Potential Contribution ◽

Open Label ◽

Double Blind ◽

Predicting Factors ◽

Acute Medication ◽

Post Hoc ◽

Headache Impact

Introduction: Demographic and clinical variables were examined in a post hoc analysis of the PROlonged Migraine Prevention with Topiramate (PROMPT) study to determine potential contribution to relapse. Methods: After a six-month open-label (OL) topiramate phase, patients were randomised to continue topiramate or switch to placebo in a six-month double-blind (DB) phase. ‘Relapse’ was investigated in terms of change in monthly migraine days after randomisation compared with the month before randomisation, and was analysed during the first (‘initial relapse’) and last month (‘sustained relapse’) of the DB phase. More than 40 potential predicting factors were entered into analyses of variance and covariance. Results: For initial relapse, variable-by-treatment interactions were significant for the Headache Impact Test (HIT-6) at DB baseline, and decline in acute medication intake or reporting of ‘anxiety’ in the OL phase. For sustained relapse, no statistically significant interactions were observed. Conclusion: Relapse after topiramate discontinuation in migraine prophylaxis appears to be unaffected by patient characteristics or baseline migraine frequency.

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Effects of fremanezumab on the use of acute headache medication and associated symptoms of migraine in patients with episodic migraine

Cephalalgia ◽

10.1177/0333102419885905 ◽

2019 ◽

Vol 40 (5) ◽

pp. 470-477 ◽

Cited By ~ 2

Author(s):

Jan Lewis Brandes ◽

David Kudrow ◽

Paul P Yeung ◽

Fumihiko Sakai ◽

Ernesto Aycardi ◽

...

Keyword(s):

Monoclonal Antibody ◽

Medication Use ◽

Preventive Treatment ◽

Episodic Migraine ◽

Phase 3 ◽

Humanized Monoclonal Antibody ◽

Calcitonin Gene ◽

Associated Symptoms ◽

Acute Headache ◽

To Receive

Background Fremanezumab, a fully humanized monoclonal antibody targeting calcitonin gene-related peptide, has demonstrated efficacy for the preventive treatment of migraine in adults. Objective To evaluate the effect of fremanezumab treatment on acute headache medication use and migraine-associated symptoms in patients with episodic migraine. Methods In the Phase 3 HALO trial, patients with episodic migraine were randomized to receive subcutaneous fremanezumab monthly (225 mg at baseline, weeks 4 and 8), fremanezumab quarterly (675 mg at baseline, placebo at weeks 4 and 8), or placebo over a 12-week period. The secondary endpoint was change from baseline in the monthly number of days with use of any acute headache mediation or migraine-specific acute headache medication; exploratory endpoints were change from baseline in the monthly number of days with nausea or vomiting, photophobia, or phonophobia. Results Of 875 patients randomized, 865 were included in the analysis (monthly, n = 287; quarterly, n = 288; placebo, n = 290). Baseline mean ± standard deviation days with: Any acute headache medication use (monthly: 7.7 ± 3.4; quarterly: 7.8 ± 3.7; placebo: 7.7 ± 3.6), migraine-specific acute headache medication use (6.1 ± 3.1; 6.6 ± 3.1; 7.1 ± 3.0), nausea or vomiting (4.5 ± 3.6; 4.9 ± 3.7; 4.5 ± 3.3) and photophobia and phonophobia (5.5 ± 4.1; 6.3 ± 4.1; 6.0 ± 3.9) were similar among treatment arms. Fremanezumab reduced the number of days of acute headache medication use ([least-squares mean change vs. placebo] monthly: −1.4 [95% confidence interval: −1.84, −0.89], p < 0.001; quarterly: −1.3 [−1.76, −0.82], p < 0.001) and migraine-specific acute headache medication use (monthly: −2.2 [−2.80, −1.56], p < 0.001; quarterly: −2.2 [−2.81, −1.58], p < 0.001) compared with placebo. Fremanezumab also reduced nausea or vomiting, photophobia, and phonophobia compared with placebo. Conclusions Fremanezumab reduced the need for acute headache medications, including migraine-specific medications, while treating migraine-associated symptoms in patients with episodic migraine. Trial registration Clinicaltrials.gov NCT02629861

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Determining the Evolution of Headache Among Regular Users of a Daily Electronic Diary via a Smartphone App: Observational Study (Preprint)

10.2196/preprints.26401 ◽

2020 ◽

Author(s):

Bianca Raffaelli ◽

Jasper Mecklenburg ◽

Lucas Hendrik Overeem ◽

Simon Scholler ◽

Markus A Dahlem ◽

...

Keyword(s):

Care Management ◽

Daily Basis ◽

Episodic Migraine ◽

Electronic Diary ◽

Migraine Frequency ◽

Major Development ◽

Acute Medication ◽

Headache Diary ◽

Basic Version ◽

Headache Care

BACKGROUND Smartphone-based apps represent a major development in health care management. Specifically in headache care, the use of electronic headache diaries via apps has become increasingly popular. In contrast to the soaring volume of available data, scientific use of these data resources is sparse. OBJECTIVE In this analysis, we aimed to assess changes in headache and migraine frequency, headache and migraine intensity, and use of acute medication among people who showed daily use of the headache diary as implemented in the freely available basic version of the German commercial app, M-sense. METHODS The basic version of M-sense comprises an electronic headache diary, documentation of lifestyle factors with a possible impact on headaches, and evaluation of headache patterns. This analysis included all M-sense users who had entered data into the app on a daily basis for at least 7 months. RESULTS We analyzed data from 1545 users. Mean MHD decreased from 9.42 (SD 5.81) at baseline to 6.39 (SD 5.09) after 6 months (<i>P</i><.001; 95% CI 2.80-3.25). MMD, AMD, and migraine intensity were also significantly reduced. Similar results were found in 985 users with episodic migraine and in 126 users with chronic migraine. CONCLUSIONS Among regular users of an electronic headache diary, headache and migraine frequency, in addition to other headache characteristics, improved over time. The use of an electronic headache diary may support standard headache care.

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Determining the Evolution of Headache Among Regular Users of a Daily Electronic Diary via a Smartphone App: Observational Study

JMIR mhealth and uhealth ◽

10.2196/26401 ◽

2021 ◽

Vol 9 (7) ◽

pp. e26401

Author(s):

Bianca Raffaelli ◽

Jasper Mecklenburg ◽

Lucas Hendrik Overeem ◽

Simon Scholler ◽

Markus A Dahlem ◽

...

Keyword(s):

Care Management ◽

Daily Basis ◽

Episodic Migraine ◽

Electronic Diary ◽

Migraine Frequency ◽

Major Development ◽

Acute Medication ◽

Headache Diary ◽

Basic Version ◽

Headache Care

Background Smartphone-based apps represent a major development in health care management. Specifically in headache care, the use of electronic headache diaries via apps has become increasingly popular. In contrast to the soaring volume of available data, scientific use of these data resources is sparse. Objective In this analysis, we aimed to assess changes in headache and migraine frequency, headache and migraine intensity, and use of acute medication among people who showed daily use of the headache diary as implemented in the freely available basic version of the German commercial app, M-sense. Methods The basic version of M-sense comprises an electronic headache diary, documentation of lifestyle factors with a possible impact on headaches, and evaluation of headache patterns. This analysis included all M-sense users who had entered data into the app on a daily basis for at least 7 months. Results We analyzed data from 1545 users. Mean MHD decreased from 9.42 (SD 5.81) at baseline to 6.39 (SD 5.09) after 6 months (P<.001; 95% CI 2.80-3.25). MMD, AMD, and migraine intensity were also significantly reduced. Similar results were found in 985 users with episodic migraine and in 126 users with chronic migraine. Conclusions Among regular users of an electronic headache diary, headache and migraine frequency, in addition to other headache characteristics, improved over time. The use of an electronic headache diary may support standard headache care.

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