scholarly journals Galcanezumab in chronic migraine

Neurology ◽  
2018 ◽  
Vol 91 (24) ◽  
pp. e2211-e2221 ◽  
Author(s):  
Holland C. Detke ◽  
Peter J. Goadsby ◽  
Shufang Wang ◽  
Deborah I. Friedman ◽  
Katherine J. Selzler ◽  
...  
Keyword(s):  
Injection Site ◽  
Chronic Migraine ◽  
Injection Site Reaction ◽  
Treatment Phase ◽  
Preventive Treatment ◽  
Controlled Study ◽  
Open Label ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo

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.ClinicalTrials.gov 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.

Efficacy and safety of erenumab (AMG334) in chronic migraine patients with prior preventive treatment failure: A subgroup analysis of a randomized, double-blind, placebo-controlled study

Cephalalgia ◽  
2018 ◽  
Vol 38 (10) ◽  
pp. 1611-1621 ◽  
Author(s):  
Messoud Ashina ◽  
Stewart Tepper ◽  
Jan Lewis Brandes ◽  
Uwe Reuter ◽  
Guy Boudreau ◽  
...  
Keyword(s):  
Chronic Migraine ◽  
Preventive Treatment ◽  
Controlled Study ◽  
Acute Migraine ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Safety Issues ◽  
Subgroup Analyses ◽  
Specific Medication

Background Erenumab was effective and well tolerated in a pivotal clinical trial of chronic migraine. Here, we evaluated efficacy and safety of monthly erenumab (70 mg or 140 mg) versus placebo in the subgroup of patients who had previously failed preventive treatment(s) (≥ 1, ≥ 2 prior failed medication categories) and in patients who had never failed. Methods Subgroup analyses evaluated change from baseline in monthly migraine days; achievement of ≥ 50% and ≥ 75% reduction in monthly migraine days; and change in monthly acute migraine-specific medication days. Adverse events were evaluated for each subgroup. Results Treatment with both doses of erenumab resulted in greater reductions in monthly migraine days (primary endpoint) at Month 3 (treatment difference [95% CI], never failed subgroup: −2.2 [−4.1, −0.3] for 70 mg and −0.5 [−2.4, 1.5] for 140 mg; ≥ 1 prior failed medication categories subgroup: −2.5 [−3.8, −1.2], for 70 mg and −3.3 [−4.6, −2.1] for 140 mg; ≥ 2 prior failed medication categories subgroup: −2.7 [−4.2, −1.2], for 70 mg and −4.3 [−5.8, −2.8] for 140 mg). Similar results were observed in the monthly acute migraine-specific medication days endpoint, and in the achievement of ≥ 50% and ≥ 75% reduction in monthly migraine days. There were no new or unexpected safety issues. Conclusion Erenumab showed consistent efficacy in chronic migraine patients who had failed prior preventive treatments and was well tolerated across subgroups.

scholarly journals Evaluation of injection-site-related adverse events with galcanezumab: a post hoc analysis of Phase 3 studies in participants with migraine

2020 ◽  
Author(s):  
Virginia L. Stauffer ◽  
Shufang Wang ◽  
Jo Bonner ◽  
ByungKun Kim ◽  
Rohit Bhandari ◽  
...  
Keyword(s):  
Injection Site ◽  
Injection Site Reaction ◽  
Treatment Phase ◽  
Site Reaction ◽  
Open Label ◽  
Double Blind ◽  
Exposure Analysis ◽  
Injection Site Reactions ◽  
Post Hoc ◽  
Site Pain

Abstract Background: Injection-site reactions have been reported with biologicals. In this post hoc analysis of Phase 3 studies in participants with migraine, we provide a comprehensive overview and detailed summary of injection-site reaction with galcanezumab. Methods: Data were obtained from two randomised clinical studies in participants with episodic migraine (EVOLVE-1 and EVOLVE-2), one randomised study in participants with chronic migraine (REGAIN) and one open-label study (Study CGAJ) in participants with episodic or chronic migraine. The injection-site reactions were measured for two different cohorts: 1) six-month double-blind treatment phase in the EVOLVE-1 and EVOLVE-2 studies and three-month double-blind treatment phase in the REGAIN study, where participants received placebo and galcanezumab (placebo-controlled analysis set); 2) three month double-blind (Month 0 to Month 3; 1:1:placebo:galcanezumab) + nine months open-label extension phase (Month 3 to Month 12) of REGAIN and twelve month open-label phase of Study CGAJ, where participants received only galcanezumab (galcanezumab exposure analysis set).Results: A total of 477 participants in the placebo-controlled analysis set (galcanezumab 240 mg, 166/730 [22.7%]; galcanezumab 120 mg, 128/705 [18.2%]; placebo, 183/1451 [12.6%]) reported at least one injection-site reaction. Most of the injection-site reactions were reported as injection-site pain, unspecified injection-site reaction, injection-site erythema, and injection-site pruritus. The incidence of injection-site pain was highest among all reported Injection-site reactions and were reported with similar frequency by participants receiving galcanezumab (galcanezumab 120mg, 10.1%; galcanezumab 240 mg, 11.6%) and placebo (9.5%) and was the most common injection-site reaction reported within 60 minutes of injection (~86% of participants). The frequency of unspecified injection-site reaction, injection-site erythema and injection-site pruritus was significantly (P<0.001) higher in participant receiving galcanezumab versus placebo. In the galcanezumab exposure analysis set participants received up to 12 doses and the frequency of injection-site reactions reported for both doses combined was 21.8%. The reporting of injection-site reactions did not increase with the number of doses received. No ISR-related serious adverse events were reported in both the placebo-controlled and galcanezumab exposure analysis sets.Conclusions: The most common adverse event of galcanezumab is injection-site reactions. However, these events were generally mild-to-moderate in severity, non-serious, resolved spontaneously, and discontinuations due to injection-site reactions were low (1%).

scholarly journals Efficacy and safety of erenumab in Japanese migraine patients with prior preventive treatment failure or concomitant preventive treatment: subgroup analyses of a phase 3, randomized trial

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Koichi Hirata ◽  
Fumihiko Sakai ◽  
Takao Takeshima ◽  
Noboru Imai ◽  
Yasuhiko Matsumori ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Preventive Treatment ◽  
Controlled Study ◽  
Acute Migraine ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Subgroup Analyses ◽  
Specific Medication

Abstract Background These subgroup analyses of a Phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of erenumab 70 mg in Japanese migraine patients with/without prior preventive treatment failure(s) (“failed-yes” and “failed-no” subgroups) and with/without concomitant preventive treatment (“concomitant preventive-yes” and “concomitant preventive-no” subgroups). Methods Overall, 261 patients were randomized; 130 and 131 patients to erenumab 70 mg and placebo, respectively. Subgroup analyses evaluated the change from baseline to Months 4–6 in mean monthly migraine days (MMD) (primary endpoint), achievement of a ≥50% reduction in mean MMD, and change from baseline in mean monthly acute migraine-specific medication (MSM) treatment days. Treatment-emergent adverse events were also evaluated. Results Of the 261 patients randomized, 117 (44.8%) and 92 (35.3%) patients were in the failed-yes and concomitant preventive-yes subgroups, respectively. Erenumab 70 mg demonstrated consistent efficacy across all subgroups, with greater reductions from baseline in mean MMD versus placebo at Months 4–6 (treatment difference versus placebo [95% CI], failed-yes: − 1.9 [− 3.3, − 0.4]; failed-no: − 1.4 [− 2.6, − 0.3]; concomitant preventive-yes: − 1.7 [− 3.3, 0.0]; concomitant preventive-no: − 1.6 [− 2.6, − 0.5]). Similar results were seen for achievement of ≥50% reduction in mean MMD and change from baseline in mean monthly acute MSM treatment days. The safety profile of erenumab 70 mg was similar across subgroups, and similar to placebo in each subgroup. Conclusion Erenumab was associated with clinically relevant improvements in all efficacy endpoints and was well tolerated across all subgroups of Japanese migraine patients with/without prior preventive treatment failure(s) and with/without concomitant preventive treatment. Trial registration Clinicaltrials.gov. NCT03812224. Registered January 23, 2019.

scholarly journals Evaluation of injection-site-related adverse events with galcanezumab: a post hoc analysis of Phase 3 studies in participants with migraine

2020 ◽  
Author(s):  
Virginia Stauffer ◽  
Shufang Wang ◽  
Jo Bonner ◽  
ByungKun Kim ◽  
Rohit Bhandari ◽  
...  
Keyword(s):  
Injection Site ◽  
Injection Site Reaction ◽  
Treatment Phase ◽  
Site Reaction ◽  
Open Label ◽  
Double Blind ◽  
Exposure Analysis ◽  
Injection Site Reactions ◽  
Post Hoc ◽  
Site Pain

Abstract Background: Injection-site reactions have been reported with biologicals. In this post hoc analysis of Phase 3 studies in participants with migraine, we provide a comprehensive overview and detailed summary of injection-site reaction with galcanezumab.Methods: Data were obtained from two randomised clinical studies in participants with episodic migraine (EVOLVE-1 and EVOLVE-2), one randomised study in participants with chronic migraine (REGAIN) and one open-label study (Study CGAJ) in participants with episodic or chronic migraine. The injection-site reactions were measured for two different cohorts: 1) six-month double-blind treatment phase in the EVOLVE-1 and EVOLVE-2 studies and three-month double-blind treatment phase in the REGAIN study, where participants received placebo and galcanezumab (placebo-controlled analysis set); 2) three month double-blind (Month 0 to Month 3; 1:1:placebo:galcanezumab) + nine months open-label extension phase (Month 3 to Month 12) of REGAIN and twelve month open-label phase of Study CGAJ, where participants received only galcanezumab (galcanezumab exposure analysis set).Results: A total of 477 participants in the placebo-controlled analysis set (galcanezumab 240 mg, 166/730 [22.7%]; galcanezumab 120 mg, 128/705 [18.2%]; placebo, 183/1451 [12.6%]) reported at least one injection-site reaction. Most of the injection-site reactions were reported as injection-site pain, unspecified injection-site reaction, injection-site erythema, and injection-site pruritus. The incidence of injection-site pain was highest among all reported Injection-site reactions and were reported with similar frequency by participants receiving galcanezumab (galcanezumab 120mg, 10.1%; galcanezumab 240 mg, 11.6%) and placebo (9.5%) and was the most common injection-site reaction reported within 60 minutes of injection (~86% of participants). The frequency of unspecified injection-site reaction, injection-site erythema and injection-site pruritus was significantly (P<0.001) higher in participant receiving galcanezumab versus placebo. In the galcanezumab exposure analysis set participants received up to 12 doses and the frequency of injection-site reactions reported for both doses combined was 21.8%. The reporting of injection-site reactions did not increase with the number of doses received. No ISR-related serious adverse events were reported in both the placebo-controlled and galcanezumab exposure analysis sets.Conclusions: The most common adverse event of galcanezumab is injection-site reactions. However, these events were generally mild-to-moderate in severity, non-serious, resolved spontaneously, and discontinuations due to injection-site reactions were low (1%).Trial registration: Clinicaltrials.gov identifier: NCT02614183, NCT02614196, NCT02614261, NCT02614287.

OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial

Cephalalgia ◽  
2010 ◽  
Vol 30 (7) ◽  
pp. 804-814 ◽  
Author(s):  
HC Diener ◽  
DW Dodick ◽  
SK Aurora ◽  
CC Turkel ◽  
RE DeGryse ◽  
...  
Keyword(s):  
Adverse Events ◽  
Chronic Migraine ◽  
Primary Efficacy ◽  
Primary Efficacy Endpoint ◽  
Efficacy And Safety ◽  
Open Label ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Open Label Phase

Objectives: This is the second of a pair of studies designed to evaluate the efficacy and safety of onabotulinumtoxinA (BOTOX®) for prophylaxis of headaches in adults with chronic migraine. Methods: PREEMPT 2 was a phase 3 study, with a 24-week, double-blind, placebo-controlled phase, followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections of onabotulinumtoxinA (155U–195U; n = 347) or placebo ( n = 358) every 12 weeks for two cycles. The primary efficacy endpoint was mean change in headache days per 28 days from baseline to weeks 21–24 post-treatment. Results: OnabotulinumtoxinA was statistically significantly superior to placebo for the primary endpoint, frequency of headache days per 28 days relative to baseline (−9.0 onabotulinumtoxinA/−6.7 placebo, p < .001). OnabotulinumtoxinA was significantly favoured in all secondary endpoint comparisons. OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few patients (3.5% onabotulinumtoxinA/1.4% placebo) discontinued due to adverse events. Conclusions: The results of PREEMPT 2 demonstrate that onabotulinumtoxinA is effective for prophylaxis of headache in adults with chronic migraine. Repeated onabotulinumtoxinA treatments were safe and well tolerated.

scholarly journals Mitapivat (AG-348) in Adults with Pyruvate Kinase Deficiency Who Are Not Regularly Transfused: A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled Study (ACTIVATE) in Progress

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4791-4791
Author(s):  
Eduard J. van Beers ◽  
Malia P. Judge ◽  
Lei Hua ◽  
Chris Mix
Keyword(s):  
Research Funding ◽  
Fixed Dose ◽  
Controlled Study ◽  
Open Label ◽  
Employment Equity ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Dose Period ◽  
Equity Ownership

Background: Pyruvate kinase (PK) deficiency is an under-recognized hereditary disease that causes lifelong hemolytic anemia. Mutations in the PKLR gene lead to reduced red cell PK (PK-R) enzyme activity, resulting in defective glycolysis and decreased lifespan of red blood cells. Mitapivat (AG-348) is a novel, first-in-class, oral, small-molecule allosteric activator of PK-R under clinical testing as the first targeted, disease-altering therapy for PK deficiency. The DRIVE PK study (NCT02476916; a phase 2, open-label, dose-ranging trial in adults with PK deficiency who are not regularly transfused) demonstrated that twice-daily (BID) dosing with mitapivat for >6 months was well tolerated and induced rapid, substantial, and durable responses (Grace et al. ASH 2017). Of 52 enrolled subjects, 26 (50%) had a maximum hemoglobin (Hb) increase of >1 g/dL in the 6-month treatment period. Among these 26 subjects, the mean maximum Hb increase was 3.4 g/dL, and 25 (96%) had ≥1 missense PKLR mutation. Based on these findings, mitapivat has entered phase 3 development in PK deficiency. The design of the ongoing phase 3 ACTIVATE study and its extension study are reported here, with an update on country/site activation. Methods: ACTIVATE is a phase 3, multicenter, randomized, double-blind, placebo-controlled study (NCT03548220) evaluating the efficacy and safety of mitapivat. Adults with PK deficiency who are not regularly transfused (≤4 transfusion episodes in the previous year and no transfusions in the prior 3 months) will be randomized in a 1:1 ratio to mitapivat (administered orally, BID) or matched placebo. Additional criteria include baseline Hb ≤10.0 g/dL and adequate organ function. Subjects who are homozygous for the R479H mutation or have 2 non-missense mutations (without the presence of another missense mutation) in PKLR will be excluded. The study consists of a screening period of up to 42 days, a 12-week dose optimization period, and a 12-week fixed-dose period (Figure). During the dose optimization period, mitapivat or matched placebo are titrated up to each subject's individually optimized dose, with an initial dose of 5 mg BID for all subjects and potentially 2 sequential dose increases (from 5 to 20 mg BID and from 20 to 50 mg BID), depending on safety and Hb change. The primary endpoint is the Hb response, defined as the proportion of subjects who achieve an increase of ≥1.5 g/dL in Hb sustained over at least 2 of the last 3 visits in the fixed-dose period. The average change in Hb during the fixed-dose period is considered a key secondary endpoint to further evaluate the magnitude of the treatment effect. Other secondary efficacy endpoints, such as markers of hemolysis and hematopoietic activity, will be evaluated to support the efficacy evaluation and confirm the mechanism of action, and safety is included as a secondary objective and endpoint. Two questionnaires, one specifically designed to measure the signs and symptoms of PK deficiency and the other designed to evaluate their impact on patients' lives, are also included for their validation and to further evaluate the efficacy of the treatment. All subjects who complete the study have the opportunity to enroll in an open-label extension study (NCT03853798) in which all participants will receive mitapivat for up to 192 weeks. An independent data monitoring committee will review the study data periodically and provide safety oversight. The ACTIVATE study is currently ongoing. Disclosures van Beers: Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Judge:Agios: Employment, Equity Ownership. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Mix:Agios: Employment, Equity Ownership.

scholarly journals Efficacy and safety of fremanezumab in clinical trial participants aged ≥60 years with episodic or chronic migraine: pooled results from 3 randomized, double-blind, placebo-controlled phase 3 studies

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Stephanie J. Nahas ◽  
Steffen Naegel ◽  
Joshua M. Cohen ◽  
Xiaoping Ning ◽  
Lindsay Janka ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Chronic Migraine ◽  
Preventive Treatment ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Link Type ◽  
Trial Participants

Abstract Background Although migraine is less common in older people, preventive treatment of migraine in these individuals may be more challenging due to the presence of multiple comorbidities and polypharmacy. Additionally, evidence for migraine treatment efficacy, safety, and tolerability is limited in this population. We evaluated efficacy, safety, and tolerability of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene–related peptide (CGRP), in clinical trial participants aged ≥60 years with episodic migraine (EM) or chronic migraine (CM). Methods This analysis included data from 3 randomized, double-blind, placebo-controlled phase 3 studies: the HALO EM study, HALO CM study, and FOCUS study in participants with EM or CM and prior inadequate response to 2–4 migraine preventive medication classes. Participants in all studies were randomized 1:1:1 to receive 12 weeks of subcutaneous treatment with quarterly fremanezumab (Months 1/2/3: EM/CM, 675 mg/placebo/placebo), monthly fremanezumab (Months 1/2/3: EM, 225 mg/225 mg/225 mg; CM, 675 mg/225 mg/225 mg), or matched monthly placebo. Results These pooled analyses included 246 participants aged ≥60 years. Reductions in monthly migraine days from baseline over 12 weeks were significantly greater with fremanezumab (least-squares mean change from baseline [standard error]: quarterly fremanezumab, − 4.3 [0.59]; monthly fremanezumab, − 4.6 [0.54]) versus placebo (placebo, − 2.3 [0.57]; both P < 0.01 vs placebo). As early as Week 1, significant reductions from baseline in weekly migraine days were observed with fremanezumab versus placebo (both P < 0.01). With fremanezumab treatment versus placebo, a significantly higher proportion of participants achieved ≥50% reduction in monthly migraine days, and significant improvements in disability and quality-of-life outcomes were observed (P < 0.05). Proportions of participants experiencing serious adverse events and adverse events leading to discontinuation were low and similar in the fremanezumab and placebo groups. Efficacy and safety results were comparable to the overall pooled population (N = 2843). Conclusions This pooled subgroup analysis demonstrates that fremanezumab treatment is efficacious and well-tolerated over 12 weeks in participants aged ≥60 years with EM or CM. These data may help healthcare providers with clinical decision making and preventive treatment selection for older patients with migraine. Trial registration ClinicalTrials.gov identifiers: HALO CM: NCT02621931; HALO EM: NCT02629861; FOCUS: NCT03308968.

scholarly journals Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study

2021 ◽  
Author(s):  
Ravi Savarirayan ◽  
Louise Tofts ◽  
Melita Irving ◽  
William R. Wilcox ◽  
Carlos A. Bacino ◽  
...  
Keyword(s):  
Growth Velocity ◽  
Bone Growth ◽  
Growth Factor Receptor ◽  
Extension Study ◽  
Controlled Study ◽  
Open Label ◽  
Phase 3 ◽  
Double Blind ◽  
Pathogenic Variants ◽  
Growth Promoting

Abstract Purpose Achondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported. Methods After completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 μg/kg/day. Results In children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected. Conclusion Vosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.

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