Efficacy and Safety of 2 Dose Regimens of TEV-48125 Versus Placebo for the Preventive Treatment of Episodic Migraine

Study Overview
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Brief Summary
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The study is being conducted to evaluate two doses of TEV-48125 in adult patients with episodic migraine

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Comparing the Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of Fremanezumab (TEV-48125) vs Placebo for the Preventive Treatment of Episodic Migraine

Conditions
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Migraine

Intervention / Treatment
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* Drug: Fremanezumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females aged 18 to 70 years, inclusive, with migraine onset at ≤50 years of age Patient signs and dates the informed consent document Patient has history of migraine according to International Classification of Headache Disorders, or clinical judgment suggests a migraine diagnosis 85% e-diary compliance Total body weight between 99 and 265 lbs, inclusive Additional criteria apply, please contact the investigator for more information Exclusion Criteria: Clinically significant hematological, cardiac, renal, endocrine, pulmonary, gastrointestinal, genitourinary, neurologic, hepatic, or ocular disease, at the discretion of the investigator Evidence or medical history of clinically significant psychiatric issues, including any suicide attempt in the past, or suicidal ideation with a specific plan in the past 2 years History of clinically significant cardiovascular disease or vascular ischemia (such as myocardial, neurological [eg, cerebral ischemia], peripheral extremity ischemia, or other ischemic event) or thromboembolic events (arterial or venous thrombotic or embolic events), such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism Known infection or history of human immunodeficiency virus, tuberculosis, or chronic hepatitis B or C infection Past or current history of cancer in the last 5 years, except for appropriately treated nonmelanoma skin carcinoma Pregnant or nursing females History of hypersensitivity reactions to injected proteins, including monoclonal antibodies Participation in a clinical study of a new chemical entity or a prescription medicine within 2 months or 5 half-lives, whichever is longer 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>Matching Placebo | Drug: Placebo<br>* Placebo 1.5 mL pre-filled syringes identical in appearance to active intervention. Study drug was administered at the clinical site.<br>|
| Experimental: Fremanezumab 675 mg/placebo/placebo<br>Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56. | Drug: Fremanezumab<br>* Fremanezumab was provided as a sterile, unpreserved, aqueous solution for injection, 225 mg/1.5 mL pre-filled syringe for single-use administration. The 675 mg dose was given as 3 injections; doses of 225 mg were given as a single injection. Study drug was administered at the clinical site.<br>* Other names: TEV-48125, anti-calcitonin gene-related peptide (anti-CGRP);Drug: Placebo<br>* Placebo 1.5 mL pre-filled syringes identical in appearance to active intervention. Study drug was administered at the clinical site.<br>|
| Experimental: Fremanezumab 225/225/225 mg<br>Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56. | Drug: Fremanezumab<br>* Fremanezumab was provided as a sterile, unpreserved, aqueous solution for injection, 225 mg/1.5 mL pre-filled syringe for single-use administration. The 675 mg dose was given as 3 injections; doses of 225 mg were given as a single injection. Study drug was administered at the clinical site.<br>* Other names: TEV-48125, anti-calcitonin gene-related peptide (anti-CGRP);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Study Drug | 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 endorsing criteria for migraine with or without aura - a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for probable migraine, a migraine subtype where only 1 migraine criterion is 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 are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as postbaseline value - baseline value. | Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12) | 
| Participants With Adverse Events | An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents usual activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, 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 the patient and required medical intervention to prevent the previously listed serious outcomes. | Day 1 to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Study Drug | Responder rates were defined as the percentage of total subjects who reached at least a 50% reduction in the monthly average of headache days (as subjectively reported by participants in the study diary) of at least moderate severity relative to the baseline period. For the overall analysis (Month 1-3), patients who discontinued early were considered nonresponders. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The percentage reduction in monthly average is calculated as: ((baseline value - postbaseline value) / baseline value) * 100 | Baseline (Days -28 to Day -1), Treatment Month 1, Month 2, Month 3, Month 1-3 (Days 1 - Week 12) | 
| Change From Baseline in the Monthly Average Number of Days of Use of Any Acute Headache Medicine During the 12 Week Period After the First Dose of Study Drug | Patients recorded any migraine medications (name of drug, number of tablets/capsules, and the dose in milligrams per tablet/capsule) taken on each day in their electronic headache diary device. Acute migraine-specific medication included triptans or ergots. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as postbaseline value - baseline value. | Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12) | 
| Change From Baseline in the Number of Migraine Days During the 4 Week Period After the First Dose of Study Drug | 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 endorsing criteria for migraine with or without aura - a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for probable migraine, a migraine subtype where only 1 migraine criterion is 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 are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as postbaseline value - baseline value. | Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 4) | 
| Change From Baseline in the Monthly Average Number of Migraine Days During the 12 Week Period After the First Dose of Study Medication in Patients Not Receiving Concomitant Preventive Migraine Medications | A subset of patients (specified in the protocol not to exceed 30%) were allowed to use 1 concomitant migraine preventive medication. This outcome only includes those participants who did not take concomitant preventive migraine medication during this study. A migraine day has been previously defined. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as postbaseline value - baseline value. | Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12) | 
| Change From Baseline in Migraine-Related Disability Score (MIDAS), As Measured by the Migraine Disability Assessment At 4 Weeks After the Last (3rd) Dose of Study Drug | The MIDAS questionnaire is a 5-item instrument developed to assess headache-related disability based on lost days of activity in 3 domains (work, household work, and nonwork) over the previous 3 months. The total score, ie, the sum of the # lost days answered for the first 5 questions, is used for grading of disability, with scores of 0-5 lost days = grade 1 (little or no disability), 6-10 lost days =grade 2 (mild disability), 11-20 lost days = grade 3 (moderate disability), and ≥21 lost days interpreted as grade 4 (severe disability). Negative change from baseline scores indicate a reduction (improvement) in headache-related disability. | Baseline (Day 0), Treatment Week 12 (4 weeks after the 3rd dose) | 
| Electrocardiogram Finding Shifts From Baseline to Overall | 12-lead ECGs were performed before other assessments (eg, blood draws and administration of questionnaires) and performed in triplicate. The worst post-baseline finding for the patient is summarized. Only patients with both baseline and post-baseline ECGs are included. The ECG was evaluated by the investigator at the time of recording (signed and dated), and the printout was kept in the source documentation file. When potentially clinically significant findings were detected by the investigator, a cardiologist at a central diagnostic center was consulted for a definitive interpretation. Any ECG finding that was judged by the investigator as a potentially clinically significant change (worsening) compared with a baseline value was considered an adverse event. - NCS = abnormal, not clinically significant - CS = abnormal, clinically significant Shift format is: baseline finding / worst post-baseline finding | Baseline (Day 0), Treatment Week 12 (or early withdrawal) | 
| Participants With Vital Signs Potentially Clinically Significant Abnormal Values | Vital signs were performed before other assessments (eg, blood draws and administration of questionnaires). Vital signs with at least one participant showing potentially clinically significant abnormal findings included: - Pulse Rate Low: <=50 and decrease of >=15 beats per minute - Systolic Blood Pressure Low: <=90 mmHg and decrease of >=20 mmHg - Diastolic Blood Pressure High: >=105 mmHg and increase of >=15 mmHg - Diastolic Blood Pressure Low: <=50 mmHg and decrease of >=15 mmHg - Respiratory Rate Low: <10 breaths / minute | Treatment Days 28, 56 and 84. Changes from previous reading may reflect the baseline reading performed on Day 0. | 
| Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results | Serum chemistry and hematology laboratory tests with potentially clinically significant abnormal findings included: - Blood Urea Nitrogen (BUN) High: >=10.71 mmol/L - Bilirubin High: >=34.2 umol/L - Alanine Aminotransferase (ALT): >=3*upper limit of normal (ULN) - Aspartate Aminotransferase (AST): >=3*upper limit of normal (ULN) - Gamma Glutamyl Transferase (GGT): >=3*upper limit of normal (ULN) - Hemoglobin: Male: <115 g/L or Female: <=95 g/L - Hematocrit: Male: <0.37 L/L or Female: <0.32 L/L - Leukocytes: >=20*10^9/L or <=3*10^9/L - Eosinophils/Leukocytes: >=10% - Platelets: >=700*10^9/L or <=75*10^9/L | Treatment Days 28, 56 and 84 (or early withdrawal) | 
| Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results | Urinalysis with potentially clinically significant abnormal findings included: - Blood: >=2 unit increase from baseline - Urine Glucose (mg/dL): >=2 unit increase from baseline - Ketones (mg/dL): >=2 unit increase from baseline - Urine Protein (mg/dL): >=2 unit increase from baseline | Treatment Days 28, 56 and 84. Changes from previous reading reflect the baseline reading performed on Day 0. | 
| Prothrombin Time Shifts From Baseline to Endpoint | Shifts in prothrombin time from baseline to endpoint were summarized using patient counts grouped into three categories: - Low (below normal range) - Normal (within the normal range of 9.4 to 12.5 seconds) - High (above normal range) Shift format is: baseline finding / endpoint finding | Baseline (Day 0), Treatment Endpoint (Week 12) | 
| Injection Site Reaction Adverse Events | Counts of participants who reported treatment-emergent injection site reactions as AEs are summarized. Preferred terms from MedDRA version 18.1 are offered without a threshold applied. | Day 1 to Week 12 | 
| Participants With Positive Electronic Columbia Suicide Severity Rating Scale Results After the First Dose of Study Drug | The electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) was used to assess the patient's suicidal ideation (severity and intensity) and behavior (Posner et al 2011). The eC-SSRS Baseline/Screening version was completed by the patient at visit 2, and the eC-SSRS Since Last Visit version was completed by the patient at all other time points. Any positive findings on the eC-SSRS Since Last Visit version required evaluation by a physician or doctoral-level psychologist. Findings after the first dose of study drug using the eC-SSRS Since Last Visit version are summarized. | Day 1 to Week 12 |