Project description:ObjectiveTo evaluate the efficacy and safety of galcanezumab, a humanized monoclonal antibody that selectively binds to calcitonin gene-related peptide, in the preventive treatment of chronic migraine.MethodsA phase 3, randomized, double-blind, placebo-controlled study of LY2951742 in patients with chronic migraine (Evaluation of Galcanezumab in the Prevention of Chronic Migraine [REGAIN]) was a phase 3 study with a 3-month double-blind, placebo-controlled treatment phase and a 9-month open-label extension. Eligible patients 18 to 65 years of age with chronic migraine were randomized 2:1:1 to monthly subcutaneous injections of placebo (n = 558), galcanezumab 120 mg (with a 240-mg loading dose, n = 278), or galcanezumab 240 mg (n = 277). The primary endpoint was the overall mean change from baseline in the number of monthly migraine headache days (MHDs) during the 3-month double-blind treatment phase.ResultsMean number of monthly MHDs at baseline was 19.4 for the total sample. Both galcanezumab dose groups demonstrated greater overall mean reduction in the number of monthly MHDs compared to placebo (placebo -2.7, galcanezumab 120 mg -4.8, galcanezumab 240 mg -4.6) (p < 0.001 for each dose compared to placebo). There were no clinically meaningful differences between galcanezumab doses and placebo on any safety or tolerability outcome except for a higher incidence of treatment-emergent injection-site reaction (p < 0.01), injection-site erythema (p < 0.001), injection-site pruritus (p < 0.01), and sinusitis (p < 0.05) in the galcanezumab 240-mg group relative to placebo.ConclusionsBoth doses of galcanezumab were superior to placebo in reducing the number of monthly MHDs. Galcanezumab appears efficacious, safe, and well tolerated for the preventive treatment of chronic migraine.Clinicaltrialsgov identifierNCT02614261.Classification of evidenceThis interventional study provides Class I evidence that galcanezumab is superior to placebo in the reduction of the number of monthly MHDs.

Project description:ObjectiveTo examine the likelihood of response with continued galcanezumab treatment in patients with episodic or chronic migraine without initial clinical improvement.BackgroundA percentage of patients with migraine may require additional time on pharmacotherapy but discontinue treatment prematurely. Additionally, recognizing when continued treatment is unlikely to provide improvement limits unnecessary exposure.MethodsPost hoc analysis of response after continued galcanezumab treatment was conducted in a subset of patients with episodic (N = 879) and chronic (N = 555) migraine who did not achieve "good" early improvement (episodic, ≥50% reduction in baseline migraine headache days [MHD] and chronic, ≥30% reduction) after 1 month of dosing (NR-1; episodic, n = 450 and chronic, n = 306). This subset was categorized by level of reduction in MHD during 1 month of treatment: "modest" (>30% to <50% fewer MHD for episodic and >10% to <30% fewer MHD for chronic), "limited" (episodic only; >10% to ≤30% fewer MHD), or "minimal/no" early improvement (≤10% fewer MHD to ≤10% more MHD), or "worsening" (>10% more MHD). The percentages of patients having "better" (≥75% fewer MHD for episodic and ≥50% for chronic), "good," or "little-to-no" (≤10% fewer MHD) response during the remaining treatment period were calculated for each category. Similarly, the subset of NR-1 patients who did not achieve "good" early improvement after 2 months of treatment (NR-2; episodic, n = 290 and chronic, n = 240) were categorized by level of their average monthly reduction across 1 and 2 months using similar categories.ResultsOf NR-1 patients with episodic migraine having "modest" early improvement, 62% (96/155) achieved "good" and 20% (31/155) achieved "better" responses with continued treatment. A percentage of patients with "limited" (43%; 46/108) or "minimal/no" (34%; 29/85) early improvement, or "worsening" (20%; 20/102) achieved a "good" response after continued treatment. A percentage of NR-1 patients with chronic migraine having "modest" early improvement achieved "good" (38%; 44/116) and "better" (13%; 15/116) responses with continued treatment. A "good" response was achieved for a percentage of patients with "minimal/no" early improvement (17%; 23/133). Similar patterns were observed for the NR-2 subset, though percentages were lower.ConclusionsGalcanezumab-treated patients with episodic or chronic migraine without response following 1 or 2 months of treatment appear to have a reasonable likelihood of continued improvement in months following initial treatment and this opportunity is more likely in patients showing greater early improvements. While a small percentage of patients with episodic or chronic migraine who experienced worsening in the number of MHD following initial treatment responded with continued treatment, most do not show substantial reduction in MHD. Overall benefit of therapy should be determined collaboratively between the patient and physician.

Project description:BACKGROUND:Focus on the frequency of migraine pain may undervalue the total burden of migraine as pain duration and severity may present unique, additive burden. A composite measure of total pain burden (TPB; frequency, severity, and duration) may provide a more comprehensive characterization of pain burden and treatment response in patients with episodic migraine (EM) or chronic migraine (CM). The impact of galcanezumab versus placebo on TPB among patients with EM or CM was analyzed. METHODS:Patients from randomized, double-blind, placebo-controlled episodic (two 6-month studies pooled) and chronic migraine (3-month) studies received once-monthly subcutaneous injection of galcanezumab 120?mg or placebo. A post hoc analysis of TPB for a given month was calculated as severity-weighted duration by multiplying duration (hours) and maximum pain severity (0?=?none, 1?=?mild, 2?=?moderate, 3?=?severe) of migraine for each day and summing these over the days in a month. Least square mean change from baseline in monthly TPB across Months 1-6 (EM, N?=?444 galcanezumab, N?=?894 placebo) and Months 1-3 (CM, N?=?278 galcanezumab, N?=?558 placebo) were compared using a mixed-model repeated measures model. Correlation of the Migraine Specific Quality of Life Questionnaire (MSQ) and Migraine Disability Assessment Scale (MIDAS) to TPB at baseline was assessed. RESULTS:At baseline, the duration of migraine on a given migraine headache day accounted for the greatest unique proportion of variability (EM, 57.4% and CM, 61.1%) to TPB after adjusting for frequency of migraine headache days and maximum pain severity. The decrease from baseline in monthly TPB was greater with galcanezumab than placebo for patients with EM (68.6 versus 36.2) and CM (102.6 versus 44.4). The average percent reduction of TPB from baseline was significantly greater with galcanezumab compared with placebo in patients with EM (50.8% versus 17.2%) and CM (29.7% versus 11.0%). In patients with EM and CM, TPB correlated with MSQ total score (r?=?-?0.35 and r?=?-?0.37) and MIDAS (r?=?0.34 and r?=?0.32). CONCLUSIONS:Greater reduction in TPB was seen in patients with EM and CM treated with galcanezumab 120?mg once-monthly injection relative to placebo. Discussing TPB supports patient-centric conversations regarding treatment expectations when clinicians are evaluating options for migraine prevention. TRIAL REGISTRATION:ClinicalTrials.gov : # NCT02614183 (I5Q-MC-CGAG; EVOLVE-1), # NCT02614196 (I5Q-MC-CGAH; EVOLVE-2), and # NCT02614261 (I5Q-MC-CGAI; REGAIN) - all 3 trials were registered on 23 November 2015.

Project description:BACKGROUND:Maintenance of effect following treatment with galcanezumab compared to placebo in adult patients with episodic or chronic migraine was evaluated. METHODS:In 2 similarly designed studies of patients with episodic migraine (6?months) and 1 study of patients with chronic migraine (3?months), patients randomized in a 1:1:2 ratio received a subcutaneous injection of galcanezumab 120?mg/month (after an initial loading dose of 240?mg) or 240?mg/month or placebo. Maintenance of effect during the double-blind phase was evaluated based on a comparison of the percentages of galcanezumab- and placebo-treated patients with maintenance of 30, 50, 75, and 100% response (defined as ?30, ?50, ?75, and 100% reduction from baseline in monthly migraine headache days [MHD]) at an individual patient level. Logistic regression analyses were used for between treatment comparisons. RESULTS:A total of 1773 adult patients with episodic migraine (n?=?444 for galcanezumab 120?mg; n?=?435 for galcanezumab 240?mg; n?=?894 for placebo for 2 studies pooled) and 1113 patients with chronic migraine (n?=?278 for galcanezumab 120?mg; n?=?277 for galcanezumab 240?mg; n?=?558 for placebo) were evaluated. In patients with episodic migraine, ?50% response was maintained in 41.5 and 41.1% of galcanezumab-treated patients (120?mg and 240?mg, respectively) for ?3 consecutive months (until patient's endpoint) and 19.0 and 20.5%, respectively, for 6 consecutive months and was significantly greater than the 21.4 and 8.0% of placebo-treated patients at ?3 and 6?months consecutively (P?<?0.001). Approximately 6% of galcanezumab-treated patients maintained ?75% response all 6?months versus 2% of placebo-treated patients. Few galcanezumab-treated patients maintained 100% response. In patients with chronic migraine, 29% of galcanezumab-treated patients maintained ?30% response all 3?months compared to 16% of placebo patients while ?50% response was maintained in 16.8 and 14.6% of galcanezumab-treated patients (120?mg and 240?mg) and was greater than placebo (6.3%; p?<?0.001). Few patients maintained ?75% response. CONCLUSIONS:Treatment with galcanezumab 120?mg or 240?mg demonstrated statistically significant and clinically meaningful persistence of effect in patients with episodic migraine (?3 and 6 consecutive months) and in patients with chronic migraine (for 3?months). STUDY IDENTIFICATION AND TRIAL REGISTRATION:Study Identification: EVOLVE-1 (I5Q-MC-CGAG); EVOLVE-2 (I5Q-MC-CGAH); REGAIN (I5Q-MC-CGAI) TRIAL REGISTRATION: ClinicalTrials.gov ; NCT02614183 (EVOLVE-1); NCT02614196 (EVOLVE-2); NCT02614261 (REGAIN).

Project description:OBJECTIVE:To characterize adult patients with episodic migraine who achieved 100% response to galcanezumab treatment. BACKGROUND:Galcanezumab is a humanized monoclonal antibody that selectively binds to the calcitonin gene-related peptide (CGRP) and has demonstrated efficacy in reducing migraine headache days (MHD) in patients with episodic and chronic migraine. METHODS:A post hoc analysis of the proportion of patients with 100% response (100% reduction from baseline in monthly MHD) was calculated for each month from pooled data of 2 double-blind, 6-month galcanezumab studies in patients with episodic migraine (4 to 14 MHD and ?2 migraine attacks per month at baseline). The patients were randomized (1:1:2) to monthly subcutaneous galcanezumab, 120 mg (after 240 mg initial loading dose) or 240 mg, or placebo. A generalized linear mixed model with effects for baseline MHD, treatment, month, and treatment-by-month interaction was used to estimate the mean monthly response rate. RESULTS:The analysis included 1739 patients treated with galcanezumab, 120 mg (n = 436) or 240 mg (n = 428), or placebo (n = 875). The mean monthly 100% response rate on an average month in the 6-month double-blind phase was greater for galcanezumab 120 mg (13.5%) and 240 mg (14.3%) groups vs placebo (5.9%) with odds ratios of 2.5 (95% confidence interval [CI] 1.9, 3.2) and 2.6 (95% CI 2.0, 3.4), respectively (P < .001). The rate of 100% monthly response increased at each month over the 6-month double-blind phase with higher rates for galcanezumab dose groups (9 to 21%) than placebo (2 to 10%) (P < .02). Evaluation of 100% response by the number of months showed a greater proportion of galcanezumab-treated patients in either dose group, compared to placebo, were able to achieve a 100% response (P < .001 up to 3 months); however, though greater than placebo, few galcanezumab patients had ?4 months of 100% response (P < .02). The proportions of patients with 100% response were greatest in the last 3 months of the treatment. Considering the average number days between nonconsecutive MHD across the 6-month period (not just during the times of 100% response), the duration of migraine headache-free periods in the galcanezumab groups was 29 days for those with at least 1 month of 100% response and 55 days for those with at least 3 months of 100% response. This gap was approximately 6 to 11 times greater than the mean gap of 5 days observed at baseline. CONCLUSIONS:More than a third of the patients with episodic migraine treated with galcanezumab 120 mg or 240 mg achieved 100% response for at least 1 month. More patients had 100% monthly response in the last 3 months of the 6-month double-blind period. For those with 100% response for at least 1 month, the average time between nonconsecutive MHD for the entire treatment period was nearly 1 month and approached 2 months for patients with 3 or more months of 100% response.

Project description:PurposeTo evaluate secondary outcomes including changes in functioning and disability associated with galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, in patients with chronic migraine.MethodsPatients randomly received galcanezumab (120 mg n?=?278, 240 mg n?=?277) or placebo (n?=?558) during 3 months of double-blind treatment, followed by a 9-month open-label extension. The Migraine-Specific Quality-of-Life Questionnaire v2.1 (MSQv2.1) measured the impact of migraine on patient functioning. The Migraine Disability Assessment (MIDAS) quantified headache-related disability. Changes from baseline were analyzed with mixed model repeated measures or analysis of covariance.ResultsTotal MSQ score at baseline was 44.88?±?18.02 (mean?±?SD), indicating significant functional impairment. At Month 3, least squares (LS) mean change?±?SE in total MSQ for galcanezumab-treated patients were 20.51?±?1.49 (120 mg) and 20.49?±?1.49 (240 mg), both statistically significantly greater vs placebo-treated patients (14.55?±?1.21; both P?<?0.001). Total MIDAS score at baseline was 67.24?±?57.31 (mean?±?SD). At Month 3, LS mean change?±?SE from baseline in total MIDAS for galcanezumab-treated patients was statistically significantly greater than placebo for 120 mg group (placebo:?-?11.53?±?3.38 vs 120 mg:?-?20.27?±?4.07; P?<?0.05) but not for 240 mg group (-?17.02?±?4.05). At Month 12, within-group mean changes from baseline for total MSQ (28.56?±?1.19 previous placebo; 29.53?±?1.51 previous 120 mg; 25.83?±?1.49 previous 240 mg) and MIDAS scores (-?28.47?±?2.95 previous placebo;?-?31.47?±?3.69 previous 120 mg;?-?31.13?±?3.62 previous 240 mg) were statistically significant (P?<?0.001) for the open-label treatment population regardless of previous double-blind treatment assignment.ConclusionsGalcanezumab-treated patients with chronic migraine reported statistically significant improvements in functioning and disability, representing a clinically significant change.Trial registrationClinicalTrials.gov registry: NCT02614261. Registered 25 November 2015.

Project description:BACKGROUND:Patients with high-frequency episodic migraine (HFEM) have a greater disease burden than those with low-frequency episodic migraine (LFEM). Acute treatment overuse increases the risk of migraine chronification in patients with HFEM. Galcanezumab, a humanized monoclonal antibody binding calcitonin gene-related peptide (CGRP), is effective for migraine prevention with a favorable safety profile. Here, we investigate whether there are differences in galcanezumab efficacy in patients with LFEM or with HFEM. METHODS:Data were pooled from two double-blind, placebo-controlled phase 3 trials; EVOLVE-1 and EVOLVE-2. Patients were 18-65?years old, experienced 4-14 monthly migraine headache days (MHDs) for ?1?year prior, with onset at <?50?years of age. Migraine headaches were tracked via electronic patient-reported outcome system and randomization was stratified by low (LFEM; 4-7 monthly MHDs) or high (HFEM; 8-14 monthly MHDs) frequency. Subgroup analysis compared the HFEM and LFEM subgroups with a linear or generalized linear mixed model repeated measures approach. RESULTS:The intent-to-treat patients (N?=?1773) had a mean age of 41.3?years, were mostly white (75%), female (85%), and 66% of patients had HFEM. In both the LFEM and HFEM subgroups, the overall (Months 1-6) and monthly changes from baseline in monthly MHDs and monthly MHDs with acute medication use compared with placebo were statistically significantly reduced for galcanezumab 120-mg and 240-mg. Galcanezumab (120-mg and 240-mg) significantly decreased the overall and monthly MHDs with nausea and/or vomiting, and with photophobia and phonophobia versus placebo in patients with LFEM or HFEM. In both subgroups, the mean overall (Months 1-6) and monthly percentages of patients with ?50%, ?75%, and 100% reduction in monthly MHDs from baseline were statistically significantly greater in patients receiving either dose of galcanezumab versus placebo. Galcanezumab (120-mg and 240-mg) significantly improved the Migraine-Specific Quality of Life Questionnaire role function-restrictive domain score as well as the Migraine Disability Assessment total score versus placebo for patients with LFEM or HFEM. There were no significant subgroup-by-treatment interactions. CONCLUSIONS:Galcanezumab was as effective in patients with HFEM as in those with LFEM. Associated symptoms, quality of life, and disability were similarly improved in patients with HFEM or LFEM. TRIAL REGISTRATION:NCT02614183 , NCT02614196 .

Project description:ImportanceMigraine is a disabling neurological disease characterized by severe headache attacks. Treatment options reduce migraine frequency for many patients, but adverse effects lead to discontinuation in many patients.ObjectiveTo demonstrate that galcanezumab is superior to placebo in the prevention of episodic migraine with or without aura.Design, setting, and participantsThe EVOLVE-1 (Evaluation of LY2951742 in the Prevention of Episodic Migraine 1) trial was a double-blind, randomized, placebo-controlled (January 11, 2016, to March 22, 2017) trial comparing galcanezumab (120 mg and 240 mg) vs placebo. Patients received treatments once monthly for 6 months (subcutaneous injection via prefilled syringe) and were followed up for 5 months after their last injection. It was a multicenter, clinic-based study involving 90 sites in North America. Participants in the study were adults (aged 18 to 65 years) with at least a 1-year history of migraine, 4 to 14 migraine headache days per month and a mean of at least 2 migraine attacks per month within the past 3 months, and were diagnosed prior to age 50 years. During the study, no other preventive medications were allowed. A total of 1671 patients were assessed; 809 did not meet study entry or baseline criteria, and 858 were included in the intent-to-treat population.InterventionsPatients were randomized (2:1:1) to monthly placebo, galcanezumab, 120 mg, and galcanezumab, 240 mg.Main outcomes and measuresThe primary outcome was overall mean change from baseline in the number of monthly migraine headache days during the treatment period. Secondary measures included at least 50%, at least 75%, and 100% reduction in monthly migraine headache days, migraine headache days with acute medication use, and scores from the Migraine-Specific Quality of Life questionnaire, Patient Global Impression of Severity, and Migraine Disability Assessment. Treatment-emergent adverse events and serious adverse events were reported.ResultsOf the 1671 patients assessed, 858 (mean age, 40.7 years; 718 women [83.7%]) met study entry criteria and received at least 1 dose of investigational product. The primary objective was met for both galcanezumab doses; treatment with galcanezumab significantly reduced monthly migraine headache days (both P < .001) by 4.7 days (120 mg) and 4.6 days (240 mg) compared with placebo (2.8 days). All key secondary objectives were also significant after multiplicity adjustment. There were no meaningful differences between 120-mg and 240-mg doses of galcanezumab on measures of efficacy. Completion rate during treatment was high (81.9%; n = 718), and the incidence of discontinuation owing to adverse events was less than 5% across all treatment groups.Conclusions and relevanceGalcanezumab 120-mg and 240-mg monthly injections provided clinical benefits and improved functioning. The incidence rate of adverse events was low, demonstrating the favorable tolerability profile of galcanezumab.Trial registrationClinicalTrials.gov Identifier: NCT02614183.

Project description:OBJECTIVE:To evaluate onset of effect of galcanezumab in patients with episodic migraine. BACKGROUND:Galcanezumab is a monoclonal antibody that binds to calcitonin gene-related peptide and is indicated for preventive treatment of migraine. DESIGN/METHODS:Data on the primary outcome measure were analyzed from 2 previously published double-blind, Phase 3 studies (EVOLVE-1 [N = 858] and EVOLVE-2 [N = 915]) wherein adult patients with episodic migraine were randomized to receive monthly subcutaneous injections of galcanezumab 120 mg (with 240-mg loading dose) or 240 mg or placebo for up to 6 months. Monthly onset of effect was defined as the earliest month at which galcanezumab achieved and subsequently maintained statistical superiority to placebo on the mean change from baseline in the number of monthly migraine headache days (MHDs). If onset occurred in Month 1, weekly onset was evaluated and defined as the earliest week at which galcanezumab statistically separated from placebo and maintained statistical separation for remaining weeks in that month. Day of onset of effect was also analyzed, as were monthly and weekly onset, for occurrence of ?50% reduction from baseline in number of MHDs. RESULTS:For both studies, change from baseline in monthly MHDs showed a statistically significant separation of galcanezumab from placebo at Month 1 and each subsequent month (each P < .001). Analysis of the first month for both studies indicated onset of effect in the first week, with galcanezumab-treated patients having significantly higher odds of having fewer MHDs in the first week (odds ratio [95% confidence interval] for EVOLVE-1, 2.71 [2.00, 3.66], and for EVOLVE-2, 2.88 [2.16, 3.86]; both P < .001) and each subsequent week compared with placebo-treated patients (P ? .004). Daily analysis showed onset of effect at Day 1 (first day after injection day). Galcanezumab also demonstrated superiority to placebo on occurrence of ?50% reduction in MHDs starting at Week 1 (percentage of patients with 50% response in galcanezumab group vs placebo group for EVOLVE-1, 54.3% vs 32.4% [P < .001], and for EVOLVE-2, 59.4% vs 38.0% [P < .001]). CONCLUSION:Rapid onset of preventive effect on the first day after injection of galcanezumab was confirmed in both studies of episodic migraine.

Dataset Information

Efficacy of Galcanezumab for Migraine Prevention in Patients With a Medical History of Anxiety and/or Depression: A Post Hoc Analysis of the Phase 3, Randomized, Double-Blind, Placebo-Controlled REGAIN, and Pooled EVOLVE-1 and EVOLVE-2 Studies.

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