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

Phase 3

Completed

Conditions: Migraine

Interventions: Drug: Fremanezumab
Drug: Placebo

Registration Number: NCT02629861

Lead Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 875

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fremanezumab 225/225/225 mg	Fremanezumab	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Placebo	Placebo	Matching Placebo
Fremanezumab 675 mg/placebo/placebo	Fremanezumab	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.
Fremanezumab 675 mg/placebo/placebo	Placebo	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.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in the Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Study Drug	Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12)	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.
Participants With Adverse Events	Day 1 to Week 12	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.

Secondary Outcome Measures

Name	Time	Method
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	Baseline (Days -28 to Day -1), Treatment Month 1, Month 2, Month 3, Month 1-3 (Days 1 - Week 12)	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
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	Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12)	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.
Change From Baseline in the Number of Migraine Days During the 4 Week Period After the First Dose of Study Drug	Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 4)	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.
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	Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12)	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.
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results	Treatment Days 28, 56 and 84 (or early withdrawal)	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
Electrocardiogram Finding Shifts From Baseline to Overall	Baseline (Day 0), Treatment Week 12 (or early withdrawal)	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
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	Baseline (Day 0), Treatment Week 12 (4 weeks after the 3rd dose)	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.
Participants With Vital Signs Potentially Clinically Significant Abnormal Values	Treatment Days 28, 56 and 84. Changes from previous reading may reflect the baseline reading performed on Day 0.	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
Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results	Treatment Days 28, 56 and 84. Changes from previous reading reflect the baseline reading performed on Day 0.	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
Prothrombin Time Shifts From Baseline to Endpoint	Baseline (Day 0), Treatment Endpoint (Week 12)	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
Participants With Positive Electronic Columbia Suicide Severity Rating Scale Results After the First Dose of Study Drug	Day 1 to Week 12	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.
Injection Site Reaction Adverse Events	Day 1 to Week 12	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.

Trial Locations

Locations (140): Teva Investigational Site 13536
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Springfield, Missouri, United States
Teva Investigational Site 13609
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Akron, Ohio, United States
Teva Investigational Site 13634
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Akron, Ohio, United States
Teva Investigational Site 13626
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Columbus, Ohio, United States
Teva Investigational Site 13585
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Chicago, Illinois, United States
Teva Investigational Site 13590
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Boston, Massachusetts, United States
Teva Investigational Site 13569
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Cleveland, Ohio, United States
Teva Investigational Site 13596
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Indianapolis, Indiana, United States
Teva Investigational Site 13605
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Las Vegas, Nevada, United States
Teva Investigational Site 13533
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Cincinnati, Ohio, United States
Teva Investigational Site 40018
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Helsinki, Finland
Teva Investigational Site 13572
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San Antonio, Texas, United States
Teva Investigational Site 13598
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Wichita, Kansas, United States
Teva Investigational Site 13552
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Nashville, Tennessee, United States
Teva Investigational Site 13561
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Oklahoma City, Oklahoma, United States
Teva Investigational Site 13612
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Denver, Colorado, United States
Teva Investigational Site 84072
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Chofu-shi, Japan
Teva Investigational Site 84069
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Kai, Japan
Teva Investigational Site 84070
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Saitama, Japan
Teva Investigational Site 84062
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Osaka-shi, Japan
Teva Investigational Site 11120
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Calgary, Canada
Teva Investigational Site 11122
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Newmarket, Canada
Teva Investigational Site 11123
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Sarnia, Canada
Teva Investigational Site 13546
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Fullerton, California, United States
Teva Investigational Site 13632
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Redlands, California, United States
Teva Investigational Site 13595
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Walnut Creek, California, United States
Teva Investigational Site 13538
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Santa Monica, California, United States
Teva Investigational Site 13568
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Encino, California, United States
Teva Investigational Site 13593
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Colorado Springs, Colorado, United States
Teva Investigational Site 13544
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Greensboro, North Carolina, United States
Teva Investigational Site 11121
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Montreal, Canada
Teva Investigational Site 84064
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Tokyo, Japan
Teva Investigational Site 13625
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Mogadore, Ohio, United States
Teva Investigational Site 13608
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Uniontown, Pennsylvania, United States
Teva Investigational Site 54143
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Praha, Czechia
Teva Investigational Site 13607
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Hialeah, Florida, United States
Teva Investigational Site 13559
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Jacksonville, Florida, United States
Teva Investigational Site 13589
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New Bedford, Massachusetts, United States
Teva Investigational Site 13618
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Fremont, Nebraska, United States
Teva Investigational Site 13575
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Raritan, New Jersey, United States
Teva Investigational Site 13565
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Plainview, New York, United States
Teva Investigational Site 13563
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East Hartford, Connecticut, United States
Teva Investigational Site 13635
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Bradenton, Florida, United States
Teva Investigational Site 13543
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Wellesley Hills, Massachusetts, United States
Teva Investigational Site 13582
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Pikesville, Maryland, United States
Teva Investigational Site 13620
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Atlanta, Georgia, United States
Teva Investigational Site 13537
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Atlanta, Georgia, United States
Teva Investigational Site 13627
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Evanston, Illinois, United States
Teva Investigational Site 13617
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Wichita, Kansas, United States
Teva Investigational Site 13574
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Greensboro, North Carolina, United States
Teva Investigational Site 13591
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Jenkintown, Pennsylvania, United States
Teva Investigational Site 13615
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Greer, South Carolina, United States
Teva Investigational Site 13578
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Lebanon, New Hampshire, United States
Teva Investigational Site 13601
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Eugene, Oregon, United States
Teva Investigational Site 13564
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Seattle, Washington, United States
Teva Investigational Site 13532
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Nashville, Tennessee, United States
Teva Investigational Site 13556
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Mount Pleasant, South Carolina, United States
Teva Investigational Site 80098
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Nahariya, Israel
Teva Investigational Site 13614
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Murray, Utah, United States
Teva Investigational Site 54141
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Kunratice, Czechia
Teva Investigational Site 13623
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Dallas, Texas, United States
Teva Investigational Site 80099
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Jerusalem, Israel
Teva Investigational Site 11124
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Hamilton, Ontario, Canada
Teva Investigational Site 54144
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Brno, Czechia
Teva Investigational Site 40017
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Helsinki, Finland
Teva Investigational Site 80100
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Ramat Gan, Israel
Teva Investigational Site 80096
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Holon, Israel
Teva Investigational Site 13611
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Plano, Texas, United States
Teva Investigational Site 84073
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Kawasaki, Japan
Teva Investigational Site 53365
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Poznan, Poland
Teva Investigational Site 84068
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Shizuoka, Japan
Teva Investigational Site 31206
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Zaragoza, Spain
Teva Investigational Site 31205
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Valladolid, Spain
Teva Investigational Site 54145
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Pardubice, Czechia
Teva Investigational Site 54142
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Prague-4-Krc, Czechia
Teva Investigational Site 54146
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Praha 3, Czechia
Teva Investigational Site 13631
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Englewood, Colorado, United States
Teva Investigational Site 13633
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Denver, Colorado, United States
Teva Investigational Site 13594
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Santa Rosa, California, United States
Teva Investigational Site 13545
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Raleigh, North Carolina, United States
Teva Investigational Site 13606
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Phoenix, Arizona, United States
Teva Investigational Site 13577
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Birmingham, Alabama, United States
Teva Investigational Site 13628
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Birmingham, Alabama, United States
Teva Investigational Site 13579
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Phoenix, Arizona, United States
Teva Investigational Site 13602
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Little Rock, Arkansas, United States
Teva Investigational Site 13540
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Long Beach, California, United States
Teva Investigational Site 13571
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Redondo Beach, California, United States
Teva Investigational Site 13573
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San Diego, California, United States
Teva Investigational Site 13557
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Boulder, Colorado, United States
Teva Investigational Site 13550
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Stamford, Connecticut, United States
Teva Investigational Site 13553
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Pembroke Pines, Florida, United States
Teva Investigational Site 13584
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Ocala, Florida, United States
Teva Investigational Site 13567
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West Palm Beach, Florida, United States
Teva Investigational Site 13621
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Chicago, Illinois, United States
Teva Investigational Site 13604
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Meridian, Idaho, United States
Teva Investigational Site 13542
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Golden Valley, Minnesota, United States
Teva Investigational Site 13619
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Saint Louis, Missouri, United States
Teva Investigational Site 13576
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Amherst, New York, United States
Teva Investigational Site 13624
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Cincinnati, Ohio, United States
Teva Investigational Site 84061
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Sendai-shi, Japan
Teva Investigational Site 13560
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Bristol, Tennessee, United States
Teva Investigational Site 13554
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Philadelphia, Pennsylvania, United States
Teva Investigational Site 13581
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West Jordan, Utah, United States
Teva Investigational Site 13586
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Seattle, Washington, United States
Teva Investigational Site 13600
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Morgantown, West Virginia, United States
Teva Investigational Site 80097
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Netanya, Israel
Teva Investigational Site 84066
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Kagoshima, Japan
Teva Investigational Site 80095
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Tel Aviv, Israel
Teva Investigational Site 84063
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Shinjuku-ku, Japan
Teva Investigational Site 84067
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Kyoto, Japan
Teva Investigational Site 84065
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Tochigi, Japan
Teva Investigational Site 84071
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Toyonaka, Japan
Teva Investigational Site 53363
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Krakow, Poland
Teva Investigational Site 53366
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Lublin, Poland
Teva Investigational Site 53367
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Warsaw, Poland
Teva Investigational Site 50399
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Kazan, Russian Federation
Teva Investigational Site 50395
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Kazan, Russian Federation
Teva Investigational Site 50400
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Moscow, Russian Federation
Teva Investigational Site 50396
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Nizhniy Novgorod, Russian Federation
Teva Investigational Site 50394
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Moscow, Russian Federation
Teva Investigational Site 50398
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Nizhniy Novgorod, Russian Federation
Teva Investigational Site 50397
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Ufa, Russian Federation
Teva Investigational Site 31207
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Madrid, Spain
Teva Investigational Site 31208
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Pamplona, Spain
Teva Investigational Site 13616
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Pinellas Park, Florida, United States
Teva Investigational Site 13603
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Metairie, Louisiana, United States
Teva Investigational Site 13630
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Virginia Beach, Virginia, United States
Teva Investigational Site 53364
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Krakow, Poland
Teva Investigational Site 40016
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Turku, Finland
Teva Investigational Site 13539
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Ann Arbor, Michigan, United States
Teva Investigational Site 13629
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Aurora, Colorado, United States
Teva Investigational Site 13587
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Orlando, Florida, United States
Teva Investigational Site 13555
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Orlando, Florida, United States
Teva Investigational Site 13534
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Kansas City, Missouri, United States
Teva Investigational Site 13551
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Orlando, Florida, United States
Teva Investigational Site 13566
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Louisville, Kentucky, United States
Teva Investigational Site 13599
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Orlando, Florida, United States
Teva Investigational Site 13541
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Austin, Texas, United States
Teva Investigational Site 13597
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Gainesville, Florida, United States
Teva Investigational Site 13588
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Albuquerque, New Mexico, United States