An Efficacy and Safety Study of Fremanezumab in Adults With Migraine

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, safety, and tolerability of monthly and quarterly subcutaneous (sc) injections of fremanezumab compared with sc injections of placebo in participants with chronic migraine (CM) or episodic migraine (EM) who have responded inadequately to 2 to 4 classes of prior preventive treatments. Approximately equal numbers of participants from each subgroup (CM and EM) are randomized in blinded-fashion 1:1:1 into one of 3 treatments for the subgroup - 2 active treatments and 1 placebo treatment- consisting of monthly injections for 3 months (up to Week 12). Then all participants continue into an open-label extension of 3 months (up to Week 24) during which everyone is administered sc injections of fremanezumab.

Official Title
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A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study With an Open-Label Period to Evaluate the Efficacy and Safety of Fremanezumab for the Prophylactic Treatment of Migraine in Patients With Inadequate Response to Prior Preventive Treatments

Conditions
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Migraine Prophylaxis

Intervention / Treatment
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* Drug: Fremanezumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant has a diagnosis of migraine with onset at ≤50 years of age. Body weight ≥45 kilograms. The participant has a history of migraine for ≥12 months prior to screening. Women of childbearing potential (WOCBP) whose male partners are potentially fertile (that is; no vasectomy) must use highly effective birth control methods for the duration of the study and the follow-up period and for 6.0 months after discontinuation of investigational medicinal product (IMP) Men must be sterile, or if they are potentially fertile/reproductively competent (not surgically [that is; vasectomy] or congenitally sterile) and their female partners are of childbearing potential, must use, together with their female partners, acceptable birth control methods for the duration of the study and for 6.0 months after discontinuation of the investigational medicinal product (IMP). Additional criteria apply, please contact the investigator for more information. Exclusion Criteria: At the time of screening visit, participant is receiving any preventive migraine medications, regardless of the medical indication for more than 5 days and expects to continue with these medications. Participant has received onabotulinumtoxinA for migraine or for any medical or cosmetic reasons requiring injections in the head, face, or neck during the 3 months before screening visit. The participant has used an intervention/device (for example; scheduled nerve blocks and transcranial magnetic stimulation) for migraine during the 2 months prior to screening. The participant uses triptans/ergots as preventive therapies for migraine. Participant uses non-steroidal anti-inflammatory drugs (NSAIDs) as preventive therapy for migraine on nearly daily basis for other indications. Note: Low dose aspirin (for example; 81 mg) used for cardiovascular disease prevention is allowed. Additional criteria apply, please contact the investigator for more information.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Double-blind (DB) period: Participants with CM or EM will receive 3 injections of placebo 1.5 milliliters (mL) SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56. Open-label (OL) period: Participants with CM or EM will receive fremanezumab (TEV-48125) 225 milligrams (mg) SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140. | Drug: Fremanezumab<br>* Fremanezumab will be administered per dose and schedule specified in the arm.<br>* Other names: TEV-48125;Drug: Placebo<br>* Placebo matching to fremanezumab will be administered per schedule specified in the arm.<br>|
| Experimental: Fremanezumab Quarterly<br>DB period: Participants with CM or EM will receive fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56). OL period: Participants with CM or EM will receive fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140. | Drug: Fremanezumab<br>* Fremanezumab will be administered per dose and schedule specified in the arm.<br>* Other names: TEV-48125;Drug: Placebo<br>* Placebo matching to fremanezumab will be administered per schedule specified in the arm.<br>|
| Experimental: Fremanezumab Monthly<br>DB period: Participants with CM will receive fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM will receive fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). OL period: Participants with CM or EM will receive fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140. | Drug: Fremanezumab<br>* Fremanezumab will be administered per dose and schedule specified in the arm.<br>* Other names: TEV-48125;Drug: Placebo<br>* Placebo matching to fremanezumab will be administered per schedule specified in the arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DB Period: Change From Baseline in Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Fremanezumab | A migraine day was defined as when at least 1 of the following situations occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for migraine with or without aura; a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for probable migraine, a migraine subtype where only 1 migraine criterion was missing; a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific medications (triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in e-diary over relevant period)*28. Change was calculated as post-baseline value - baseline value. | Baseline (Day -28 to Day -1), up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DB Period: Percentage of Participants Reaching at Least 50 Percent (%) Reduction From Baseline in Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Fremanezumab | A migraine day was defined as when at least 1 of the following situations occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for migraine with or without aura; a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for probable migraine, a migraine subtype where only 1 migraine criterion was missing; a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific medications (triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in e-diary over relevant period)*28. | Baseline (Day -28 to Day-1), up to Week 12 | 
| DB Period: Change From Baseline in Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-Week Period After the First Dose of Fremanezumab | A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) demonstrating at least 4 consecutive hours of headache of at least moderate severity or; a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific acute medications (triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) * 28. The change was calculated as post-baseline value - baseline value. LS mean calculated using ANCOVA model with treatment, gender, region, special group of treatment failure (yes/no), migraine classification (EM/CM), and treatment*migraine classification as fixed effects and baseline number of headache days of at least moderate severity and years since onset of migraine as covariates. | Baseline (Day -28 to Day -1), up to Week 12 | 
| DB Period: Change From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period After the First Dose of Fremanezumab | A migraine day was defined as when at least 1 of following occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for migraine with or without aura; a calendar day demonstrating at least 4 consecutive hours of a headache meeting criteria for probable migraine, a migraine subtype where only 1 migraine criterion was missing; a calendar day demonstrating a headache of any duration that was treated with migraine-specific medications. Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in e-diary over relevant period)*28. LS mean calculated using ANCOVA model with treatment, gender, region, special group of treatment failure (yes/no), migraine classification (EM/CM), and treatment*migraine classification as fixed effects, and baseline number of migraine days and years since onset of migraines as covariates. | Baseline (Day -28 to Day -1), up to Week 4 | 
| DB Period: Percentage of Participants Reaching at Least 50% Reduction From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period After the First Dose of Fremanezumab | A migraine day was defined as when at least 1 of the following situations occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for migraine with or without aura; a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for probable migraine, a migraine subtype where only 1 migraine criterion was missing; a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific medications (triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in e-diary over relevant period)*28. | Baseline (Day -28 to Day-1), up to Week 4 | 
| DB Period: Change From Baseline in Monthly Average Number of Days of Use of Any Acute Headache Medications During the 12-Week Period After the First Dose of Fremanezumab | Baseline data and the mean change from baseline in the monthly average number of days of use of any acute headache medications during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported. Least Squares (LS) mean calculated using analysis of covariance (ANCOVA) model with treatment, gender, region, special group of treatment failure (yes/no), migraine classification (EM/CM), and treatment*migraine classification as fixed effects, and baseline number of migraine days and years since onset of migraines as covariates. | Baseline (Day -28 to Day -1), up to Week 12 | 
| DB Period: Change From Baseline in Monthly Average Number of Headache Days of at Least Moderate Severity During the 4-Week Period After the First Dose of Fremanezumab | A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) demonstrating at least 4 consecutive hours of headache of at least moderate severity or; a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific acute medications (triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) * 28. The change was calculated as post-baseline value - baseline value. LS mean calculated using ANCOVA model with treatment, gender, region, special group of treatment failure (yes/no), migraine classification (EM/CM), and treatment*migraine classification as fixed effects, and baseline number of headache days of at least moderate severity and years since onset of migraines as covariates. | Baseline (Day -28 to Day -1), up to Week 4 | 
| DB Period: Number of Participants With Adverse Events (AEs) and Who Did Not Complete the Study Due to AEs | An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severe AE was defined as inability to carry out usual activities. Treatment-related AEs were defined as AEs with possible, probable, definite, or missing relationship to study drug. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline (Day 0) up to Week 12 | 
| OL Period: Number of Participants With AEs and Who Did Not Complete the Study Due to AEs | An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severe AE was defined as inability to carry out usual activities. Treatment-related AEs were defined as AEs with possible, probable, definite, or missing relationship to study drug. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Week 12 up to Week 24 | 
| DB Period: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | Criteria for potentially clinically significant abnormal serum chemistry values included: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and lactate dehydrogenase (LDH) (units/liter [U/L]): greater than or equal to (≥) 3*upper limit of normal (ULN); Blood Urea Nitrogen (BUN): ≥10.71 millimoles/liter (mmol/L); creatinine: ≥177 micromoles/liter (µmol/L); bilirubin (total): ≥34.2 µmol/L; and uric acid: ≥625 µmol/L (men), and ≥506 µmol/L (women). A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 12 | 
| OL Period: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results | Criteria for potentially clinically significant abnormal serum chemistry values included: ALT, AST, ALP, GGT, and LDH (U/L): ≥3*ULN; BUN: ≥10.71 mmol/L; creatinine: ≥177 µmol/L; bilirubin (total): ≥34.2 µmol/L; and uric acid: ≥625 µmol/L (men), and ≥506 µmol/L (women). A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Week 12 up to Week 24 | 
| DB Period: Number of Participants With Potentially Clinically Significant Abnormal Hematology Results | Criteria for potentially clinically significant abnormal hematology values included: hemoglobin: less than (<) 115 grams/liter (g/L) (in men) or less than or equal to (≤) 95 g/L (in women), hematocrit: <0.37 L/L (in men) or <0.32 L/L (in women), leukocytes: ≥20*10^9/L or ≤3*10^9/L, eosinophils: >=10%, platelets: ≥700*10^9/L or ≤75*10^9/L, and absolute neutrophil count (ANC): ≤1*10^9/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 12 | 
| OL Period: Number of Participants With Potentially Clinically Significant Abnormal Hematology Results | Criteria for potentially clinically significant abnormal hematology values included: hemoglobin: <115 g/L (in men) or ≤95 g/L (in women), hematocrit: <0.37 L/L (in men) or <0.32 L/L (in women), leukocytes: ≥20*10^9/L or ≤3*10^9/L, eosinophils: >=10%, platelets: ≥700*10^9/L or ≤75*10^9/L, and ANC: ≤1*10^9/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Week 12 up to Week 24 | 
| DB Period: Number of Participants With Potentially Clinically Significant Abnormal Coagulation Laboratory Test Results | Criteria for potentially clinically significant abnormal coagulation values included: prothrombin international normalized ratio (INR): greater than (>) 1.5. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 12 | 
| OL Period: Number of Participants With Potentially Clinically Significant Abnormal Coagulation Laboratory Test Results | Criteria for potentially clinically significant abnormal coagulation values included: prothrombin INR: >1.5. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Week 12 up to Week 24 | 
| DB Period: Number of Participants With Potentially Clinically Significant Abnormal Urinalysis Laboratory Tests Results | Criteria for potentially clinically significant abnormal urinalysis values included: urine glucose (milligrams/deciliter [mg/dL]): ≥2 unit increase from baseline, ketones (mg/dL): ≥2 unit increase from baseline, urine total protein (mg/dL): ≥2 unit increase from baseline, and haemoglobin ≥2 unit increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 12 | 
| OL Period: Number of Participants With Potentially Clinically Significant Abnormal Urinalysis Laboratory Tests Results | Criteria for potentially clinically significant abnormal urinalysis values included: urine glucose (mg/dL): ≥2 unit increase from baseline, ketones (mg/dL): ≥2 unit increase from baseline, urine total protein (mg/dL): ≥2 unit increase from baseline, and haemoglobin ≥2 unit increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Week 12 up to Week 24 | 
| DB Period: Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values | Criteria for potentially clinically significant abnormal vital signs values included: pulse rate: ≤50 beats/minute (bpm) and decrease of ≥15 bpm, or ≥120 bpm and increase of ≥15 bpm; systolic blood pressure: ≤90 millimeters of mercury (mmHg) and decrease of ≥20 mmHg, or ≥180 mmHg and increase of ≥20 mmHg; diastolic blood pressure: ≤50 mmHg and decrease of ≥15 mmHg or ≥105 mmHg and increase of ≥15 mmHg; respiratory rate: <10 breaths/minute; and body temperature ≥38.3 degrees celsius and change of ≥1.1 degrees celsius. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 12 | 
| OL Period: Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values | Criteria for potentially clinically significant abnormal vital signs values included: pulse rate: ≤50 bpm and decrease of ≥15 bpm, or ≥120 bpm and increase of ≥15 bpm; systolic blood pressure: ≤90 mmHg and decrease of ≥20 mmHg, or ≥180 mmHg and increase of ≥20 mmHg; diastolic blood pressure: ≤50 mmHg and decrease of ≥15 mmHg or ≥105 mmHg and increase of ≥15 mmHg; respiratory rate: <10 breaths/minute; and body temperature ≥38.3 degrees celsius and change of ≥1.1 degrees celsius. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Week 12 up to Week 24 | 
| DB Period: Number of Participants With Shift From Baseline to Week 12 in Electrocardiogram (ECG) Parameters | ECG parameters included: heart rate, PR interval, QRS interval, QT interval corrected using the Fridericia formula (QTcF), QT interval corrected using the Bazett's formula (QTcB) and RR interval. Shifts represented as Baseline - Week 12 value. Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline, Week 12 | 
| OL Period: Number of Participants With Shift From Baseline to Week 24 in ECG Parameters | ECG parameters included: heart rate, PR interval, QRS interval, QT interval corrected using the Fridericia formula (QTcF), QT interval corrected using the Bazett's formula (QTcB) and RR interval. Shifts represented as Baseline - Week 24 value. Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline, Week 24 | 
| DB Period: Number of Participants Who Received Concomitant Medications for Adverse Events | Concomitant medications included: agents acting on the renin-angiotensin system, all other therapeutic products (for example: homeopathic preparation), allergens, analgesics, anesthetics, anti-parkinson drugs, antianemic preparations, antibacterials for systemic use, antibiotics and chemotherapeutics for dermatological use, antidiarrheals, intestinal antiinflammatory/antiinfective agents, antiemetic, antiepileptics, antifungals for dermatologiocal use, antigout preparations, antihemorrhagics, antihistamines for systemic use, antihypertensives, antiinflammatory and antirheumatic products, antimycotics for systemic use, antipruritics, antipsoriatics, antivirals for systemic use, beta blocking agents, blood substitutes and perfusion solutions, cardiac therapy, corticosteroids, cough and cold preparations, diagnostic radiopharmaceuticals, diuretics, thyroid therapy, urologicals, vaccines, psycoleptics, psycoanaleptics, ophthalmologicals, muscle relaxants, drugs used in diabetes etc. | Baseline up to Week 12 | 
| OL Period: Number of Participants Who Received Concomitant Medications for Adverse Events | Concomitant medications included: agents acting on the renin-angiotensin system, all other therapeutic products (for example: homeopathic preparation), allergens, analgesics, anesthetics, anti-parkinson drugs, antianemic preparations, antibacterials for systemic use, antibiotics and chemotherapeutics for dermatological use, antidiarrheals, intestinal antiinflammatory/antiinfective agents, antiemetic, antiepileptics, antifungals for dermatologiocal use, antigout preparations, antihemorrhagics, antihistamines for systemic use, antihypertensives, antiinflammatory and antirheumatic products, antimycotics for systemic use, antipruritics, antipsoriatics, antivirals for systemic use, beta blocking agents, blood substitutes and perfusion solutions, cardiac therapy, corticosteroids, cough and cold preparations, diagnostic radiopharmaceuticals, diuretics, thyroid therapy, urologicals, vaccines, psycoleptics, psycoanaleptics, ophthalmologicals, muscle relaxants, drugs used in diabetes etc. | Week 12 up to Week 24 |