Comparing Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of TEV-48125 Versus Placebo for the Preventive Treatment of Chronic 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 chronic 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) Versus Placebo for the Preventive Treatment of Chronic 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 250 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 prior to study drug administration 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 the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active 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 675/225/225 mg<br>Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) 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);|

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 Headache Days of At Least Moderate Severity During the 12-Week Period After the First Dose of Study Drug | Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) where the patient (using the electronic headache diary device) reports: - a day with headache pain that lasts ≥4 hours with a peak severity of at least moderate severity or - a day when the patient used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. 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 post-baseline value - baseline value. | Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12) | 
| Participants With Treatment-Emergent Adverse Events (TEAEs) | An adverse event (AE) 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 |
| --- | --- | --- |
| 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 post-baseline value - baseline value. | Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12) | 
| Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Headache Days of At Least Moderate Severity | 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 non-responders. 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 - post-baseline 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 | Participants 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 post-baseline value - baseline value. | Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12) | 
| Change From Baseline in the Number of Headache Days of At Least Moderate Severity During the 4 Week Period After the First Dose of Study Drug | Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) where the patient (using the electronic headache diary device) reports: - a day with headache pain that lasts ≥4 hours with a peak severity of at least moderate severity or - a day when the patient used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. The change is calculated as post-baseline value - baseline value. | Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 4) | 
| Change From Baseline in the Monthly Average Number of Headache Days of At Least Moderate Severity 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. Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of >= moderate severity was defined as a calendar day where the patient (using the electronic headache diary device) reports: - a day with headache pain that lasts ≥4 hours with a peak severity of >= moderate severity or - a day when the patient used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. 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. Change is post-baseline value - baseline value. | Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12) | 
| Change From Baseline in Migraine-Related Disability Score, As Measured by the 6-Item Headache Impact Test (HIT) At Week 12 | The HIT-6 was developed by Kosinski et al (2003) as a short form for reliably assessing the adverse headache impact in clinical practice and clinical research settings. The questionnaire measures the adverse impact of headache on social functioning, role functioning, vitality, cognitive functioning, and psychological distress. It also assesses headache severity. Scores range from 36 to 78, where a higher score indicates a greater impact of headache on the daily life of the patient, i.e. scores ≤49 represent little or no impact, scores between 50 and 55 represent some impact, scores between 56 and 59 represent substantial impact; and scores ≥60 indicate severe impact. Negative change from baseline values indicate less adverse impact of headache. | Baseline, 12 weeks | 
| Electrocardiogram (ECG) Findings 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 participant is summarized. Only participants 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 endpoint) | 
| 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 potentially clinically significant abnormal findings included: - Pulse Rate High: >=120 and increase of >=15 beats per minute - 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 (or endpoint). 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 - Creatinine High: >=177 umol/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 endpoint) | 
| 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 (or endpoint). 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 (eC-SSRS) Results After the First Dose of Study Drug | The electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) was used to assess the participant's suicidal ideation (severity and intensity) and behavior (Posner et al 2011). Suicidal behavior is defined as a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation is defined as a yes answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. The eC-SSRS Baseline/Screening version was completed by the participant at baseline, and the eC-SSRS Since Last Visit version was completed by the participant 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. | Baseline (Day 0), Treatment Days 28, 56, 84 |