Dataset Information

Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment.

ABSTRACT:

Objective

To report efficacy and safety of galcanezumab in adults with chronic cluster headache.

Background

Galcanezumab is a humanized monoclonal antibody that binds to calcitonin gene-related peptide and inhibits its biological activity.

Methods

This study comprised a prospective baseline period, a 12-week double-blind, placebo-controlled treatment period, and a 52-week open-label period. Up to six protocol-specified concomitant preventive medications were allowed if patients were on a stable dose for 2 months prior to the prospective baseline period. Patients were randomized 1:1 to monthly subcutaneous galcanezumab (300?mg) or placebo. The primary endpoint was overall mean change from baseline in weekly attack frequency with galcanezumab compared to placebo. Key secondary endpoints were ?50% response rate and percentage of patients meeting sustained response. Results from the double-blind treatment period are reported.

Results

A total of 237 patients were randomized and treated (120 placebo; 117 galcanezumab). At baseline, the mean age was 45 years and 63% were using ?1 preventive drug. The primary endpoint was not met; mean change in weekly attack frequency was -4.6 placebo versus -5.4 galcanezumab (p?=?0.334). Key secondary endpoints also were not met. Injection site-related treatment-emergent adverse events were more common in the galcanezumab than the placebo group, with significantly more injection site erythema.

Conclusion

Treatment with galcanezumab 300?mg did not achieve its primary and key secondary endpoints. This study underscores the potential distinct biology of cCH as well as the significant unmet need for safe, effective, and well-tolerated preventive treatment. The safety profile of galcanezumab in cCH is consistent with that observed in trials of episodic CH and migraine.

Trial registration

NCT02438826; https://www.clinicaltrials.gov/ct2/show/NCT02438826.

SUBMITTER: Dodick DW

PROVIDER: S-EPMC7787002 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Publications

Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment.

Dodick David W DW Goadsby Peter J PJ Lucas Christian C Jensen Rigmor R Bardos Jennifer N JN Martinez James M JM Zhou Chunmei C Aurora Sheena K SK Yang Jyun Yan JY Conley Robert R RR Oakes Tina T

Cephalalgia : an international journal of headache 20200212 9

<h4>Objective</h4>To report efficacy and safety of galcanezumab in adults with chronic cluster headache.<h4>Background</h4>Galcanezumab is a humanized monoclonal antibody that binds to calcitonin gene-related peptide and inhibits its biological activity.<h4>Methods</h4>This study comprised a prospective baseline period, a 12-week double-blind, placebo-controlled treatment period, and a 52-week open-label period. Up to six protocol-specified concomitant preventive medications were allowed if pati ...[more]

PMID: 32050782

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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: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:ObjectiveThe objective of the study was to assess the tolerability and safety of galcanezumab in patients with chronic cluster headache (CH) with up to 15 months of treatment.BackgroundChronic CH is a highly debilitating disease with a substantial and unmet medical need.MethodsPatients were randomized to receive placebo or galcanezumab (300 mg) monthly for 12 weeks, followed by an optional 52-week open-label extension and 16-week posttreatment follow-up (washout). This is a secondary analysis and long-term follow-up of a previously conducted clinical trial. The safety analysis included patients who received galcanezumab at any time during the study. Outcomes included adverse events (AEs), discontinuations, laboratory values, vital signs, electrocardiograms (ECGs), and suicidality ratings.ResultsA total of 233 patients received at least one galcanezumab dose. The mean exposure was 341 days. Galcanezumab-treated patients were mostly male (n = 169/233; 72.5%) with a mean age of 44.9 (±10.9) years. Treatment-emergent adverse events (TEAEs) were reported by 185 patients (n = 185/233; 79.4%), 23 patients (n = 23/233; 9.9%) reported serious adverse events (SAEs), and 18 patients (n = 18/233; 7.7%) discontinued due to AEs. The SAE CH was reported by three patients. The most common TEAEs (>10%) were nasopharyngitis (n = 41/233; 17.6%) and injection site pain (n = 33/233; 14.2%). 27.5% of patients (n = 64/233) had TEAEs related to injection sites. Likely hypersensitivity events, including injection site rash, injection site urticaria, and injection site hypersensitivity were reported (n = 14/233; 6.0%). There were past histories of suicidal ideation (n = 55/237; 23.2%) and suicidal behavior (n = 9/236; 3.8%). During the study, 15 patients (n = 15/230; 6.5%), seven with previous history, reported suicidal ideation. One patient had a nonfatal suicide attempt during the open-label extension and an aborted attempt during the washout. There were no new safety findings compared with the placebo-controlled treatment period in laboratory values, vital signs, or ECGs.ConclusionsGalcanezumab 300 mg monthly had a favorable tolerability and safety profile in patients with chronic CH with up to 15 months of treatment.

Project description:BackgroundCluster headache (CH) is a highly disabling primary headache disorder. To date, characterization of outcomes in the preventive treatment of episodic CH, including precise definitions of clinically meaningful attack frequency reduction and impact on acute treatment management, is lacking.MethodsThis was a Phase 3, randomized, double-blind, placebo-controlled study in patients (men or women aged 18-65 years) diagnosed with episodic CH as defined by the International Classification of Headache Disorders-3 beta criteria. In this post hoc analysis, we evaluated the median time-to-first occurrence of ?50, ?75, or 100% reduction from baseline in CH attack frequency, and impact on acute medication use. An anchor-based assessment of clinically relevant attack frequency reduction using the Patient Global Impression of Improvement (PGI-I) scores at Week 4 was also assessed.ResultsThe median time-to-first occurrence of ?50, ?75, or 100% reduction from baseline in CH attacks was consistently shorter (9-10 days sooner) with galcanezumab vs placebo (median [95% confidence interval, 95% CI]: ?50%, 5 days [4.0 to 7.0] vs 14 days [6.0 to 19.0]; ?75%, 11 days [7.0 to 16.0] vs 21 days [13.0 to 26.0]; 100%, 22 days [16.0 to 37.0] vs 32 days [23.0 to 34.0]). Mean reduction from baseline in the overall frequency of weekly pooled acute medication use across Weeks 1-3 was significantly greater with galcanezumab vs placebo (11.0 vs 5.5; odds ratio, OR [95% CI]: 5.52 [1.02, 10.01]; P value = .017). Patients reporting "much better" on the PGI-I experienced a median weekly CH attack reduction of approximately 43% from baseline across Weeks 1-3. The overall odds of achieving an attack reduction threshold of 43% across Weeks 1-3 was significantly higher with galcanezumab vs placebo (Weeks 1-3: OR [95% CI], 2.60 [1.3 to 5.3]).ConclusionsFaster median time-to-first occurrence of response rates, lower frequency of pooled acute medications use, and a greater proportion of patients achieving a response anchored by patient-reported improvement were observed for galcanezumab vs placebo.

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:Galcanezumab is a novel monoclonal antibody that target to calcitonin gene-related peptide (CGRP). It has been tested for the preventive treatment of migraine and episodic cluster headache by multiple randomized clinical trials (RCTs) and have been found to reduce headache frequency. METHODS:We systematically searched PubMed and Embase on Cochrane Central Register of Controlled Trials (CENTRAL) from the earliest date to August 1, 2019. Relative risk (RR) and weighted mean difference (WMD) were used to evaluate clinical outcomes. RESULTS:Seven studies were pooled with 3889 patients. Subcutaneous injection of Galcanezumab at 120?mg, 240?mg leads to a statistically significant response rate for the treatment of migraine compared with placebo (120?mg: RR?=?1.51; 95% CI, 1.33 to 1.70; P?<?0.001; 240?mg: RR?=?1.58; 95% CI, 1.43 to 1.76; P?<?0.001). Among them, 120?mg group has the same treatment efficacy with 240?mg group (50% response: RR?=?1.06; 95% CI, 0.92 to 1.22; P?=?0.425; 75% response: RR?=?1.07; 95% CI, 0.94 to 1.23; P?=?0.301; 100% response; RR?=?1.06; 95% CI, 0.81 to 1.37; P?=?0.682; MHD: RR?=?-?0.08; 95% CI, -?0.55 to -?0.40; P?=?0.748) while related to a lower risk for adverse events for the treatment of migraine (120?mg RR?=?1.06; 95% CI, 0.99 to 1.14; P?=?0.084; 240?mg: RR?=?1.17; 95% CI, 1.09 to 1.25; P?<?0.001). 300?mg per month galcanezumab is effective for the prevention of episodic cluster headache measured by at least 50% reduction of cluster headache frequency at week 3 (RR?=?1.36; 95% CI, 1.00-1.84; P?=?0.048). CONCLUSIONS:Use of galcanezumab is related to a significantly reduced monthly headache frequency compared with placebo for the treatment of migraine and episodic cluster headache, 120?mg has the same treatment efficacy with 240?mg group while related to a lower risk for adverse effects for the treatment of migraine. 300?mg per month galcanezumab is effective for the prevention of episodic cluster headache with no significantly increased adverse events.

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: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).

Dataset Information

Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment.

Objective

Background

Methods

Results

Conclusion

Trial registration

Publications

Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment.

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