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

• ClinicalTrials.gov Identifier: NCT02638103
• Recruitment Status: Completed
• First Posted: December 22, 2015
• Results First Posted: August 28, 2019
• Last Update Posted: February 28, 2020
• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
• Information provided by (Responsible Party): Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products R&D, Inc. )

Tracking Information

• First Submitted Date: December 18, 2015
• First Posted Date: December 22, 2015
• Results First Submitted Date: June 5, 2019
• Results First Posted Date: August 28, 2019
• Last Update Posted Date: February 28, 2020
• Actual Study Start Date: February 26, 2016
• Actual Primary Completion Date: June 6, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 17, 2020)

• Number of Participants With Adverse Events (AEs) [ Time Frame: Baseline (Day 0) up to follow-up visit (Day 533) ]
  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.
• Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results [ Time Frame: Baseline (Day 0) up to end of treatment (EOT) visit (Day 336) ]
  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.
• Number of Participants With Potentially Clinically Significant Abnormal Hematology Results [ Time Frame: Baseline (Day 0) up to EOT visit (Day 336) ]
  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.
• Number of Participants With Potentially Clinically Significant Abnormal Urinalysis Laboratory Tests Results [ Time Frame: Baseline (Day 0) up to EOT visit (Day 336) ]
  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.
• Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values [ Time Frame: Baseline (Day 0) up to EOT visit (Day 336) ]
  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.
• Number of Participants With Shift From Baseline to Endpoint in Electrocardiogram (ECG) Parameters [ Time Frame: Baseline (Day 0), endpoint (Day 336) ]
  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.
• Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results [ Time Frame: Baseline (Day 0), endpoint (Day 336) ]
  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.
• Number of Participants With Injection Site Reactions [ Time Frame: Baseline (Day -28 to Day -1), Month 12 ]
  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.
• Number of Participants With Suicidal Ideation and Suicidal Behavior as Assessed by the Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) [ Time Frame: Baseline (Day -28 to Day -1), Month 12 ]
  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.

• Original Primary Outcome Measures (submitted: December 18, 2015): Percentage of Participants with Adverse Events [ Time Frame: 533 days (±15 days) ]
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: August 12, 2019)

• Change From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period at Month 12 [ Time Frame: Baseline (Day -28 to Day -1), 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.
• Change From Baseline in Monthly Average Number of Headache Days of Any Severity During the 4-Week Period at Month 12 [ Time Frame: Baseline (Day -28 to Day -1), 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.
• 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 [ Time Frame: Baseline (Day -28 to Day -1), 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.
• 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 [ Time Frame: Baseline (Day -28 to Day -1), Month 12 ]
  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.

Original Other Pre-specified Outcome Measures (submitted: December 18, 2015)

• Mean change from baseline in the number of migraine days [ Time Frame: 533 days (±15 days) ]
• Mean change from baseline in the monthly average of migraine days [ Time Frame: 533 days (±15 days) ]
• Mean change from baseline in the number of headache days of any severity [ Time Frame: 533 days (±15 days) ]
• Mean change from baseline in the monthly average of headache days of any severity [ Time Frame: 533 days (±15 days) ]

Descriptive Information

• Brief Title: Efficacy and Safety of Subcutaneous Administration of Fremanezumab (TEV-48125) for the Preventive Treatment of Migraine
• 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
• Brief 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Migraine

Intervention

• Drug: Fremanezumab
  Fremanezumab will be administered as per the dose and schedule specified in the respective arms.
  Other Name: TEV-48125
• Drug: Placebo
  Placebo matching to fremanezumab will be administered as per schedule specified in the respective arms.

Study Arms

• Experimental: TEV-48125 225 mg Monthly: New/Placebo Rollover Participants
  Participants with CM who were randomized to the placebo treatment group or participants who do not rollover from the pivotal efficacy study, will receive fremanezumab 675 milligrams (mg) SC as loading dose (3 injections of fremanezumab 225 mg/1.5 milliliters [mL] on Day 0) followed by 11 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5mL on Days 28, 56, 112, 140, 196, 224, 280, and 308). Participants with EM who were randomized to the placebo treatment group or participants who do not rollover from the pivotal efficacy study, will receive 12 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 0, 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).
  Interventions:

  • Drug: Fremanezumab
  • Drug: Placebo
• Experimental: TEV-48125 225 mg Monthly: Active Rollover Participants
  Participants with CM who were randomized to the active treatment group (Fremanezumab 675/225 mg) in the pivotal efficacy study, will receive fremanezumab 675 mg SC as loading dose (3 injections of fremanezumab 225 mg/1.5 mL on Day 0) followed by 11 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5mL and 2 injections of placebo 1.5 mL on Days 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5mL on Days 28, 56, 112, 140, 196, 224, 280, and 308). Participants with EM who were randomized to the active treatment group (Fremanezumab 225 mg) in the pivotal efficacy study, will receive 12 monthly SC doses of fremanezumab at 225 mg (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL on Days 0, 84, 168, and 252; and 1 injection of fremanezumab 225 mg/1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).
  Interventions:

  • Drug: Fremanezumab
  • Drug: Placebo
• Experimental: TEV-48125 675 mg Quarterly: New/Placebo Rollover Participants
  Participants with CM or EM who were randomized to the placebo treatment group or participants who do not rollover from the pivotal efficacy study, will receive fremanezumab 675 mg SC once every 3 months for 12 months for a total of 4 doses (3 injections of fremanezumab 225 mg/1.5 mL on Days 0, 84, 168, and 252; and 1 injection of placebo 1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).
  Interventions:

  • Drug: Fremanezumab
  • Drug: Placebo
• Experimental: TEV-48125 675 mg Quarterly: Active Rollover Participants
  Participants with CM or EM who were randomized to the active treatment group (Fremanezumab 675 mg) in the pivotal efficacy study, will receive fremanezumab 675 mg SC once every 3 months for 12 months for a total of 4 doses (3 injections of fremanezumab 225 mg/1.5 mL on Days 0, 84, 168, and 252; and 1 injection of placebo 1.5 mL on Days 28, 56, 112, 140, 196, 224, 280, and 308).
  Interventions:

  • Drug: Fremanezumab
  • Drug: Placebo

Publications *

• Goadsby PJ, Silberstein SD, Yeung PP, Cohen JM, Ning X, Yang R, Dodick DW. Long-term safety, tolerability, and efficacy of fremanezumab in migraine: A randomized study. Neurology. 2020 Nov 3;95(18):e2487-e2499. doi: 10.1212/WNL.0000000000010600. Epub 2020 Sep 10.
• Buse DC, Gandhi SK, Cohen JM, Ramirez-Campos V, Cloud B, Yang R, Cowan RP. Improvements across a range of patient-reported domains with fremanezumab treatment: results from a patient survey study. J Headache Pain. 2020 Sep 4;21(1):109. doi: 10.1186/s10194-020-01177-4.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 26, 2018): 1890
• Original Estimated Enrollment (submitted: December 18, 2015): 1842
• Actual Study Completion Date: December 8, 2018
• Actual Primary Completion Date: June 6, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 (β-HCG) pregnancy test prior at screening (confirmed by urine dipstick β-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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Czechia, Finland, Israel, Japan, Poland, Russian Federation, Spain, United States
• Removed Location Countries: Czech Republic, Denmark, Germany, Hungary, Italy, Ukraine

Administrative Information

• NCT Number: NCT02638103
• Other Study ID Numbers: TV48125-CNS-30051; 2015-004550-18 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products R&D, Inc. )
• Study Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
• Collaborators: Not Provided

Investigators

• Study Director: Teva Medical Expert, MD; Teva Pharmaceuticals USA

• PRS Account: Teva Pharmaceutical Industries
• Verification Date: February 2020