Efficacy and Safety of Subcutaneous Administration of Fremanezumab (TEV-48125) for the Preventive Treatment of Migraine

Migraine Clinical Trial

— HALO  

Official title:

A Multicenter, Randomized, Double-Blind, Parallel-Group Study Evaluating the Long-Term Safety, Tolerability, and Efficacy of Subcutaneous Administration of Fremanezumab (TEV-48125) for the Preventive Treatment of Migraine

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02638103
• Other study ID #: TV48125-CNS-30051
• Secondary ID: 2015-004550-18
• Status: Completed
• Phase: Phase 3
• Start date: February 26, 2016
• Est. completion date: December 8, 2018

Study information

• Verified date: November 2021
• Source: Teva Branded Pharmaceutical Products R&D, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A study to evaluate the long-term safety, tolerability, and efficacy of subcutaneous (SC) administration of TEV-48125 in adult participants with chronic migraine (CM) or episodic migraine (EM). Participants with CM or EM who complete the pivotal efficacy studies of TEV-48125 (TV48125-CNS-30049 [NCT02621931] and TV48125-CNS-30050 [NCT02629861]) and agree to participate in this study; and new participants meeting eligibility criteria (not rolling over from pivotal studies), will be enrolled in this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1890
• Est. completion date: December 8, 2018
• Est. primary completion date: June 6, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

Participants Rolling Over from the Pivotal Efficacy Studies:

• Participant must have signed and dated the informed consent document.
• Participant must have completed the pivotal efficacy study without major protocol violations.
• Additional criteria apply, please contact the investigator for more information.

Participants Not Rolling Over from the Pivotal Efficacy Studies:

• Males or females aged 18 to 70 years, inclusive, with migraine onset at less than or equal to (=) 50 years of age.
• Participant signed and dated the informed consent document.
• Participant has a history of migraine or clinical judgment suggests a migraine diagnosis.
• Participant fulfills the criteria for EM or CM with prospectively collected baseline information during the 28-day run-in period.
• Body mass index (BMI) of 17.5 to 37.5 kilograms/square meter (kg/m^2) and a total body weight between 45 and 120 kg, inclusive.
• All participants must be of non-childbearing potential.

1. Participants must simultaneously use 2 forms of highly effective contraception methods.

2. Participants will remain abstinent throughout the study.

• Female participants of childbearing potential must have a negative serum beta-human chorionic gonadotropin (ß-HCG) pregnancy test prior at screening (confirmed by urine dipstick ß-HCG pregnancy test at baseline).
• The participant must be willing and able to comply with study restrictions, to remain at the clinic for the required duration during the study period, and to return to the clinic for the follow-up evaluation.
• Additional criteria apply, please contact the investigator for more information Exclusion Criteria:

Participants Rolling Over from the Pivotal Efficacy Studies:

• Pregnant or nursing females
• Compliance with daily diary entry lower than 75 percent (%) at the last month of the double-blind treatment period of the pivotal efficacy study.
• Additional criteria apply, please contact the investigator for more information.

Participants Not Rolling Over from the Pivotal Efficacy Studies:

• Clinically significant findings 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 [for example; 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 past 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 before study drug administration or 5 half-lives, whichever is longer.
• History of alcohol or drug abuse during the past 2 years, or alcohol or drug dependence during the past 5 years.
• The participant cannot participate or successfully complete the study, in the opinion

of their healthcare provider or the investigator, for any of the following reasons:

1. mentally or legally incapacitated or unable to give consent for any reason.

2. in custody due to an administrative or a legal decision, under guardianship, or institutionalized.

3. unable to be contacted in case of emergency.

4. has any other condition, which, in the opinion of the investigator, makes the participant inappropriate for inclusion in the study.

• Participant is a study center or sponsor employee who is directly involved in the study or the relative of such an employee.
• Additional criteria apply, please contact the investigator for more information.

Related Conditions & MeSH terms

• Migraine
• Migraine Disorders

Intervention

Drug:
• Fremanezumab
Fremanezumab will be administered as per the dose and schedule specified in the respective arms.
• Placebo
Placebo matching to fremanezumab will be administered as per schedule specified in the respective arms.

Locations

Country	Name	City	State
Canada	Teva Investigational Site 11120	Calgary
Canada	Teva Investigational Site 11124	Hamilton	Ontario
Canada	Teva Investigational Site 11121	Montreal
Canada	Teva Investigational Site 11122	Newmarket	Ontario
Canada	Teva Investigational Site 11123	Sarnia
Czechia	Teva Investigational Site 54144	Brno
Czechia	Teva Investigational Site 54141	Kunratice
Czechia	Teva Investigational Site 54145	Pardubice
Czechia	Teva Investigational Site 54142	Prague 4
Czechia	Teva Investigational Site 54143	Praha
Czechia	Teva Investigational Site 54146	Praha 3
Finland	Teva Investigational Site 40017	Helsinki
Finland	Teva Investigational Site 40018	Helsinki
Finland	Teva Investigational Site 40016	Turku
Israel	Teva Investigational Site 80096	Holon
Israel	Teva Investigational Site 80099	Jerusalem
Israel	Teva Investigational Site 80098	Nahariya
Israel	Teva Investigational Site 80097	Netanya
Israel	Teva Investigational Site 80100	Ramat Gan
Israel	Teva Investigational Site 80095	Tel Aviv
Japan	Teva Investigational Site 84072	Chofu-shi
Japan	Teva Investigational Site 84066	Kagoshima-shi
Japan	Teva Investigational Site 84069	Kai
Japan	Teva Investigational Site 84073	Kawasaki
Japan	Teva Investigational Site 84067	Kyoto
Japan	Teva Investigational Site 84062	Osaka-shi
Japan	Teva Investigational Site 84070	Saitama
Japan	Teva Investigational Site 84061	Sendai-shi
Japan	Teva Investigational Site 84063	Shinjuku-ku
Japan	Teva Investigational Site 84068	Shizuoka
Japan	Teva Investigational Site 84065	Tochigi
Japan	Teva Investigational Site 84064	Tokyo
Japan	Teva Investigational Site 84071	Toyonaka
Poland	Teva Investigational Site 53363	Krakow
Poland	Teva Investigational Site 53364	Krakow
Poland	Teva Investigational Site 53366	Lublin
Poland	Teva Investigational Site 53365	Poznan
Poland	Teva Investigational Site 53367	Warsaw
Russian Federation	Teva Investigational Site 50395	Kazan
Russian Federation	Teva Investigational Site 50399	Kazan
Russian Federation	Teva Investigational Site 50394	Moscow
Russian Federation	Teva Investigational Site 50400	Moscow
Russian Federation	Teva Investigational Site 50396	Nizhniy Novgorod
Russian Federation	Teva Investigational Site 50398	Nizhniy Novgorod
Russian Federation	Teva Investigational Site 50397	Ufa
Spain	Teva Investigational Site 31207	Madrid
Spain	Teva Investigational Site 31208	Pamplona
Spain	Teva Investigational Site 31205	Valladolid
Spain	Teva Investigational Site 31206	Zaragoza
United States	Teva Investigational Site 13609	Akron	Ohio
United States	Teva Investigational Site 13625	Akron	Ohio
United States	Teva Investigational Site 13634	Akron	Ohio
United States	Teva Investigational Site 13588	Albuquerque	New Mexico
United States	Teva Investigational Site 13576	Amherst	New York
United States	Teva Investigational Site 13539	Ann Arbor	Michigan
United States	Teva Investigational Site 13537	Atlanta	Georgia
United States	Teva Investigational Site 13620	Atlanta	Georgia
United States	Teva Investigational Site 13629	Aurora	Colorado
United States	Teva Investigational Site 13541	Austin	Texas
United States	Teva Investigational Site 13577	Birmingham	Alabama
United States	Teva Investigational Site 13628	Birmingham	Alabama
United States	Teva Investigational Site 13604	Boise	Idaho
United States	Teva Investigational Site 13590	Boston	Massachusetts
United States	Teva Investigational Site 13557	Boulder	Colorado
United States	Teva Investigational Site 13635	Bradenton	Florida
United States	Teva Investigational Site 13560	Bristol	Tennessee
United States	Teva Investigational Site 13585	Chicago	Illinois
United States	Teva Investigational Site 13621	Chicago	Illinois
United States	Teva Investigational Site 13533	Cincinnati	Ohio
United States	Teva Investigational Site 13624	Cincinnati	Ohio
United States	Teva Investigational Site 13569	Cleveland	Ohio
United States	Teva Investigational Site 13593	Colorado Springs	Colorado
United States	Teva Investigational Site 13626	Columbus	Ohio
United States	Teva Investigational Site 13623	Dallas	Texas
United States	Teva Investigational Site 13612	Denver	Colorado
United States	Teva Investigational Site 13633	Denver	Colorado
United States	Teva Investigational Site 13563	East Hartford	Connecticut
United States	Teva Investigational Site 13568	Encino	California
United States	Teva Investigational Site 13631	Englewood	Colorado
United States	Teva Investigational Site 13601	Eugene	Oregon
United States	Teva Investigational Site 13627	Evanston	Illinois
United States	Teva Investigational Site 13618	Fremont	Nebraska
United States	Teva Investigational Site 13546	Fullerton	California
United States	Teva Investigational Site 13597	Gainesville	Florida
United States	Teva Investigational Site 13542	Golden Valley	Minnesota
United States	Teva Investigational Site 13544	Greensboro	North Carolina
United States	Teva Investigational Site 13574	Greensboro	North Carolina
United States	Teva Investigational Site 13615	Greer	South Carolina
United States	Teva Investigational Site 13607	Hialeah	Florida
United States	Teva Investigational Site 13596	Indianapolis	Indiana
United States	Teva Investigational Site 13559	Jacksonville	Florida
United States	Teva Investigational Site 13591	Jenkintown	Pennsylvania
United States	Teva Investigational Site 13534	Kansas City	Missouri
United States	Teva Investigational Site 13605	Las Vegas	Nevada
United States	Teva Investigational Site 13578	Lebanon	New Hampshire
United States	Teva Investigational Site 13602	Little Rock	Arkansas
United States	Teva Investigational Site 13540	Long Beach	California
United States	Teva Investigational Site 13566	Louisville	Kentucky
United States	Teva Investigational Site 13575	Martinsville	New Jersey
United States	Teva Investigational Site 13551	Memphis	Tennessee
United States	Teva Investigational Site 13603	Metairie	Louisiana
United States	Teva Investigational Site 13600	Morgantown	West Virginia
United States	Teva Investigational Site 13556	Mount Pleasant	South Carolina
United States	Teva Investigational Site 13614	Murray	Utah
United States	Teva Investigational Site 13532	Nashville	Tennessee
United States	Teva Investigational Site 13552	Nashville	Tennessee
United States	Teva Investigational Site 13589	New Bedford	Massachusetts
United States	Teva Investigational Site 13584	Ocala	Florida
United States	Teva Investigational Site 13561	Oklahoma City	Oklahoma
United States	Teva Investigational Site 13587	Orlando	Florida
United States	Teva Investigational Site 13567	Palm Beach Gardens	Florida
United States	Teva Investigational Site 13553	Pembroke Pines	Florida
United States	Teva Investigational Site 13554	Philadelphia	Pennsylvania
United States	Teva Investigational Site 13579	Phoenix	Arizona
United States	Teva Investigational Site 13606	Phoenix	Arizona
United States	Teva Investigational Site 13582	Pikesville	Maryland
United States	Teva Investigational Site 13616	Pinellas Park	Florida
United States	Teva Investigational Site 13565	Plainview	New York
United States	Teva Investigational Site 13611	Plano	Texas
United States	Teva Investigational Site 13622	Princeton	New Jersey
United States	Teva Investigational Site 13545	Raleigh	North Carolina
United States	Teva Investigational Site 13632	Redlands	California
United States	Teva Investigational Site 13571	Redondo Beach	California
United States	Teva Investigational Site 13619	Saint Louis	Missouri
United States	Teva Investigational Site 13572	San Antonio	Texas
United States	Teva Investigational Site 13573	San Diego	California
United States	Teva Investigational Site 13538	Santa Monica	California
United States	Teva Investigational Site 13594	Santa Rosa	California
United States	Teva Investigational Site 13564	Seattle	Washington
United States	Teva Investigational Site 13586	Seattle	Washington
United States	Teva Investigational Site 13536	Springfield	Missouri
United States	Teva Investigational Site 13550	Stamford	Connecticut
United States	Teva Investigational Site 13608	Uniontown	Pennsylvania
United States	Teva Investigational Site 13630	Virginia Beach	Virginia
United States	Teva Investigational Site 13595	Walnut Creek	California
United States	Teva Investigational Site 13543	Watertown	Massachusetts
United States	Teva Investigational Site 13581	West Jordan	Utah
United States	Teva Investigational Site 13598	Wichita	Kansas
United States	Teva Investigational Site 13617	Wichita	Kansas

Sponsors (1)

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

Countries where clinical trial is conducted

United States,  Canada,  Czechia,  Finland,  Israel,  Japan,  Poland,  Russian Federation,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period at Month 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 (for CM participants) or at least 2 consecutive hours (for EM participants) 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 (for CM participants) or at least 2 consecutive hours (for EM participants) 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), Month 12
Other	Change From Baseline in Monthly Average Number of Headache Days of Any Severity During the 4-Week Period at Month 12	Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of any severity for both CM and EM participants was defined as a calendar day (00:00 to 23:59) where the participant (using the electronic headache diary device) reports: a day with headache pain that lasts at least 4 hours with a peak severity of any severity or; a day when the participant used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. 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.	Baseline (Day -28 to Day -1), Month 12
Other	Percentage of Participants With At Least 50% Reduction From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period at Month 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 (for CM participants) or at least 2 consecutive hours (for EM participants) 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 (for CM participants) or at least 2 consecutive hours (for EM participants) 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), Month 12
Other	Percentage of Participants With At Least 50% Reduction From Baseline in Monthly Average Number of Headache Days of at Least Moderate Severity During the 4-Week Period	Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of at least moderate severity for both CM and EM participants was defined as a calendar day (00:00 to 23:59) where the participant (using the electronic headache diary device) reports: a day with headache pain that lasts at least 4 hours with a peak severity of at least moderate severity or; a day when the participant used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. 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.	Baseline (Day -28 to Day -1), Month 12
Primary	Number of Participants With Adverse Events (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 follow-up visit (Day 533)
Primary	Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results	Potentially clinically significant abnormal serum chemistry findings included: Blood Urea Nitrogen (BUN): greater than or equal to (>=) 10.71 millimoles/liter (mmol/L), creatinine: >=177 micromoles/liter (µmol/L), bilirubin: >=34.2 µmol/L, Alanine Aminotransferase (ALT) (units/liter [U/L]): >=3*upper limit of normal (ULN) Aspartate Aminotransferase (AST) (U/L): >=3*ULN, and Gamma Glutamyl Transferase (GGT) (U/L): >=3*ULN. 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 end of treatment (EOT) visit (Day 336)
Primary	Number of Participants With Potentially Clinically Significant Abnormal Hematology Results	Potentially clinically significant abnormal hematology findings included: hemoglobin: less than (<) 115 grams/liter (g/L) (in males) or less than or equal to (<=) 95 g/L (in females), hematocrit: <0.37 L/L (in male) or <0.32 L/L (in female), leukocytes: >=20*10^9/L or <=3*10^9/L, eosinophils/leukocytes: >=10%, and platelets: >=700*10^9/L or <=75*10^9/L. 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 EOT visit (Day 336)
Primary	Number of Participants With Potentially Clinically Significant Abnormal Urinalysis Laboratory Tests Results	Potentially clinically significant abnormal urinalysis findings included: blood: >=2 unit increase from baseline, urine glucose (milligrams/decilitre [mg/dL]): >=2 unit increase from baseline, ketones (mg/dL): >=2 unit increase from baseline, urine protein (mg/dL): >=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 (Day 0) up to EOT visit (Day 336)
Primary	Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values	Potentially clinically significant abnormal vital signs findings 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 centigrade and change of >=1.1 degrees centigrade. 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 EOT visit (Day 336)
Primary	Number of Participants With Shift From Baseline to Endpoint 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 - endpoint value (last observed post-baseline 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 (Day 0), endpoint (Day 336)
Primary	Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results	Coagulation parameters included: prothrombin time (PT) (seconds), prothrombin international normalized ratio (INR), activated partial thromboplastin time (aPTT) (seconds). Shifts represented as Baseline - endpoint value (last observed post-baseline value). Shifts from baseline to endpoint were summarized using participant 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). A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.	Baseline (Day 0), endpoint (Day 336)
Primary	Number of Participants With Injection Site Reactions	Number of participants who reported treatment-emergent injection site reactions are summarized. Preferred terms from MedDRA version 18.1 were offered without a threshold applied. Injection site reactions included injection site induration, pain, erythema, haemorrhage, pruritus, swelling, bruising, rash, urticaria, warmth, dermatitis, haematoma, inflammation, discolouration, discomfort, hypersensitivity, hypoaesthesia, irritation, oedema, papule, paraesthesia, vesicles and pallor. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.	Baseline (Day -28 to Day -1), Month 12
Primary	Number of Participants With Suicidal Ideation and Suicidal Behavior as Assessed by the Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS)	eC-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. Suicidal behavior was 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 was defined as a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent.	Baseline (Day -28 to Day -1), Month 12