Trial Outcomes & Findings for A Study to Explore the Long-Term Safety and Efficacy of Fremanezumab (TEV-48125) for the Prevention of Cluster Headache (NCT NCT03107052)

Last Updated: 2021-11-09

Results Overview

An 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. 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 participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

275 participants

Primary outcome timeframe

Baseline up to follow-up (Week 68)

Results posted on

2021-11-09

Participant Flow

A total of 275 participants with episodic cluster headache (ECH) or chronic cluster headache (CCH) were enrolled in this study.

Participants were assigned to receive treatments in fremanezumab 225 milligrams (mg) monthly, fremanezumab 675/225 mg monthly, or fremanezumab 675 mg quarterly groups; based on their randomization in the pivotal studies TV48125-CNS-30056 (NCT02945046) and TV48125-CNS-30057 (NCT02964338).

Participant milestones

Participant milestones
Measure	Fremanezumab 225 mg Monthly Participants with ECH or CCH who received fremanezumab at 900 mg intravenous (IV) infusion at Week 0 and fremanezumab at 225 mg subcutaneous (SC) injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 milliliter {mL}\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Overall Study STARTED	145	60	70
Overall Study Safety Analysis Set	144	60	71
Overall Study COMPLETED	26	14	29
Overall Study NOT COMPLETED	119	46	41

Reasons for withdrawal

Reasons for withdrawal
Measure	Fremanezumab 225 mg Monthly Participants with ECH or CCH who received fremanezumab at 900 mg intravenous (IV) infusion at Week 0 and fremanezumab at 225 mg subcutaneous (SC) injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 milliliter {mL}\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Overall Study Adverse Event	6	1	2
Overall Study Withdrawal by Subject	9	5	8
Overall Study Protocol Violation	6	0	3
Overall Study Lost to Follow-up	4	0	1
Overall Study Lack of Efficacy	23	7	4
Overall Study Other than specified	4	2	0
Overall Study Study terminated due to futility	67	31	23

Baseline Characteristics

A Study to Explore the Long-Term Safety and Efficacy of Fremanezumab (TEV-48125) for the Prevention of Cluster Headache

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Fremanezumab 225 mg Monthly n=145 Participants Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=60 Participants Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=70 Participants Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.	Total n=275 Participants Total of all reporting groups
Age, Continuous	45.2 years STANDARD_DEVIATION 12.25 • n=5 Participants	46.1 years STANDARD_DEVIATION 11.14 • n=7 Participants	43.2 years STANDARD_DEVIATION 11.40 • n=5 Participants	44.9 years STANDARD_DEVIATION 11.81 • n=4 Participants
Sex: Female, Male Female	51 Participants n=5 Participants	20 Participants n=7 Participants	25 Participants n=5 Participants	96 Participants n=4 Participants
Sex: Female, Male Male	94 Participants n=5 Participants	40 Participants n=7 Participants	45 Participants n=5 Participants	179 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	9 Participants n=5 Participants	3 Participants n=7 Participants	2 Participants n=5 Participants	14 Participants n=4 Participants
Race (NIH/OMB) White	136 Participants n=5 Participants	56 Participants n=7 Participants	68 Participants n=5 Participants	260 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline up to follow-up (Week 68)

Population: Safety analysis set included all participants who received at least 1 dose of study drug.

Outcome measures

Outcome measures
Measure	Fremanezumab 225 mg Monthly n=144 Participants Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=60 Participants Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=71 Participants Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Number of Participants With Adverse Events (AEs) Any AEs	87 Participants	31 Participants	42 Participants
Number of Participants With Adverse Events (AEs) Treatment-related AEs	26 Participants	6 Participants	10 Participants
Number of Participants With Adverse Events (AEs) Serious AEs	8 Participants	2 Participants	1 Participants
Number of Participants With Adverse Events (AEs) AEs leading to discontinuation	6 Participants	1 Participants	2 Participants

PRIMARY outcome

Timeframe: Baseline up to end of treatment (Week 40)

Population: Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'Overall number of participants analyzed' signifies participants with a laboratory result.

Serum chemistry tests with potentially clinically significant abnormal findings included: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH) each ≥3\*upper limit of normal (ULN); Blood urea nitrogen (BUN) ≥10.71 millimole (mmol)/L; Bilirubin (Total) ≥34.2 micromole/liter (umol/L); and Creatinine ≥177 umol/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

Outcome measures

Outcome measures
Measure	Fremanezumab 225 mg Monthly n=129 Participants Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=55 Participants Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=67 Participants Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Results: Serum Chemistry	2 Participants	0 Participants	1 Participants

PRIMARY outcome

Timeframe: Baseline up to end of treatment (Week 40)

Population: Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'Overall number of participants analyzed' signifies participants with a laboratory result.

Hematology tests with potentially clinically significant abnormal findings included: hemoglobin less than or equal to (≤)115 grams (g)/L (males) or ≤95 g/L (females), leukocytes count ≥20\*10\^9/L or ≤3\*10\^9/L, eosinophils ≥10%, hematocrit \<0.37 L/L (males) and \<0.32 L/L (females), platelets count ≥700\*10\^9/L or ≤75\*10\^9/L, absolute neutrophil count (ANC) ≤1\*10\^9/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

Outcome measures

Outcome measures
Measure	Fremanezumab 225 mg Monthly n=129 Participants Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=55 Participants Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=67 Participants Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Results: Hematology	6 Participants	3 Participants	0 Participants

PRIMARY outcome

Timeframe: Baseline up to end of treatment (Week 40)

Population: Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'Overall number of participants analyzed' signifies participants with a laboratory result.

Urinalysis laboratory tests with potentially clinically significant abnormal findings included: haemoglobin, urine glucose, ketones, urine total protein each ≥2 unit (U) increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

Outcome measures

Outcome measures
Measure	Fremanezumab 225 mg Monthly n=129 Participants Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=55 Participants Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=67 Participants Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Results: Urinalysis	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Baseline up to end of treatment (Week 40)

Population: Safety analysis set included all participants who received at least 1 dose of study drug.

Coagulation parameters included: prothrombin time (PT) (seconds) and prothrombin international normalized ratio (INR). 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). Missing PT and prothrombin INR shift data are also presented. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

Outcome measures

Outcome measures
Measure	Fremanezumab 225 mg Monthly n=144 Participants Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=60 Participants Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=71 Participants Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results Prothrombin INR · High-High	4 Participants	2 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results Prothrombin INR · Missing	23 Participants	8 Participants	6 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results PT · Low-Low	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results PT · Low-Normal	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results PT · Low-High	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results PT · Normal-Low	1 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results PT · Normal-Normal	99 Participants	39 Participants	59 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results PT · Normal-High	6 Participants	5 Participants	1 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results PT · High-High	4 Participants	4 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results PT · High-Low	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results PT · High-Normal	11 Participants	4 Participants	5 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results PT · Missing	23 Participants	8 Participants	6 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results Prothrombin INR · Low-Low	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results Prothrombin INR · Low-Normal	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results Prothrombin INR · Low-High	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results Prothrombin INR · Normal-Low	1 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results Prothrombin INR · Normal-Normal	103 Participants	42 Participants	61 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results Prothrombin INR · Normal-High	6 Participants	4 Participants	1 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results Prothrombin INR · High-Low	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results Prothrombin INR · High-Normal	7 Participants	4 Participants	3 Participants

PRIMARY outcome

Timeframe: Baseline up to follow-up (Week 68)

Population: Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'Overall number of participants analyzed' signifies participants with a vital sign result.

Potentially clinically significant abnormal vital signs findings included: Pulse rate ≥120 beats per minute (bpm) and increase from baseline of ≥15 bpm, or ≤50 bpm and decrease from baseline of ≥15 bpm; Systolic blood pressure ≤90 millimeters of mercury (mmHg) and decrease from baseline of ≥20 mmHg, or ≥180 mmHg and increase from baseline of ≥20 mmHg; Diastolic blood pressure ≤50 mmHg and decrease from baseline of ≥15 mmHg, or ≥105 mmHg and increase from baseline of ≥15 mmHg; Temperature \>38.3 degrees celsius (°C). A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

Outcome measures

Outcome measures
Measure	Fremanezumab 225 mg Monthly n=139 Participants Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=57 Participants Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=68 Participants Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values	6 Participants	4 Participants	2 Participants

PRIMARY outcome

Timeframe: Baseline up to follow-up (Week 68)

Population: Safety analysis set included all participants who received at least 1 dose of study drug.

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. Missing ECG shift data are also presented. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

Outcome measures

Outcome measures
Measure	Fremanezumab 225 mg Monthly n=144 Participants Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=60 Participants Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=71 Participants Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Normal / Normal	76 Participants	30 Participants	46 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Normal / Abnormal NCS	16 Participants	6 Participants	4 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Normal / Abnormal CS	1 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Abnormal NCS / Normal	15 Participants	7 Participants	4 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Abnormal NCS / Abnormal NCS	23 Participants	12 Participants	12 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Abnormal NCS / Abnormal CS	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Abnormal CS / Normal	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Abnormal CS / Abnormal NCS	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Abnormal CS / Abnormal CS	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Missing	13 Participants	5 Participants	5 Participants

PRIMARY outcome

Timeframe: Baseline up to follow-up (Week 68)

Population: ITT analysis set included all participants who were enrolled in this study for long-term safety evaluation, regardless if they received study treatment or not.

A complete physical examination included the following organ systems: general appearance; head, eyes, ears, nose, and throat; chest and lungs; heart; abdomen; musculoskeletal; skin; lymph nodes; and neurological. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

Outcome measures

Outcome measures
Measure	Fremanezumab 225 mg Monthly n=145 Participants Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=60 Participants Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=70 Participants Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Number of Participants With Abnormal Physical Examination Findings	22 Participants	8 Participants	7 Participants

PRIMARY outcome

Timeframe: Baseline up to Week 36

Population: Safety analysis set included all participants who received at least 1 dose of study drug.

Number of participants who reported treatment-emergent injection site reactions are summarized. Preferred terms from Medical Dictionary for Regulatory Activities (MedDRA) version 18.1 were offered without a threshold applied. Injection site reactions included injection site erythema, induration, pain, haemorrhage, bruising, rash, warmth, and pruritus. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

Outcome measures

Outcome measures
Measure	Fremanezumab 225 mg Monthly n=144 Participants Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=60 Participants Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=71 Participants Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Number of Participants With Injection Site Reactions Injection site induration	13 Participants	4 Participants	5 Participants
Number of Participants With Injection Site Reactions Injection site pain	6 Participants	1 Participants	3 Participants
Number of Participants With Injection Site Reactions Injection site erythema	7 Participants	1 Participants	1 Participants
Number of Participants With Injection Site Reactions Injection site haemorrhage	2 Participants	0 Participants	0 Participants
Number of Participants With Injection Site Reactions Injection site pruritus	2 Participants	0 Participants	0 Participants
Number of Participants With Injection Site Reactions Injection site bruising	0 Participants	1 Participants	0 Participants
Number of Participants With Injection Site Reactions Injection site rash	0 Participants	0 Participants	1 Participants
Number of Participants With Injection Site Reactions Injection site warmth	1 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Baseline up to Week 36

Population: Safety analysis set included all participants who received at least 1 dose of study drug.

A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

Outcome measures

Outcome measures
Measure	Fremanezumab 225 mg Monthly n=144 Participants Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=60 Participants Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=71 Participants Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Number of Participants With Hypersensitivity/Anaphylaxis Reactions	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Baseline up to follow-up (Week 68)

Population: Safety analysis set included all participants who received at least 1 dose of study drug.

Concomitant medications included: agents acting on the renin-angiotensin system, all other therapeutic products (homeopathic), allergens, analgesics, anesthetics, anti-parkinson drugs, antianemic preparations, antibacterials, antibiotics and chemotherapeutics for dermatological use, antidiarrheals, intestinal antiinflammatory/antiinfective agents, antiemetic, antiepileptics, antifungals for dermatologiocal use, antigout preparations, antihemorrhagics, antihistamines for systemic use, antihypertensives, antiinflammatory and antirheumatic products, antimycotics for systemic use, antipruritics, antipsoriatics, antivirals for systemic use, beta blocking agents, blood substitutes and perfusion solutions, cardiac therapy, corticosteroids, cough and cold preparations, diagnostic radiopharmaceuticals, diuretics, thyroid therapy, urologicals, vaccines, psycoleptics, psycoanaleptics, ophthalmologicals, muscle relaxants, drugs used in diabetes. Baseline refers to values from the pivotal studies.

Outcome measures

Outcome measures
Measure	Fremanezumab 225 mg Monthly n=144 Participants Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=60 Participants Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=71 Participants Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Number of Participants Who Received Concomitant Medications	140 Participants	56 Participants	68 Participants

PRIMARY outcome

Timeframe: Baseline up to follow-up (Week 68)

Population: ITT analysis set included all participants who were enrolled in this study for long-term safety evaluation, regardless if they received study treatment or not.

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 refers to the baseline values from the pivotal studies.

Outcome measures

Outcome measures
Measure	Fremanezumab 225 mg Monthly n=145 Participants Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=60 Participants Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=70 Participants Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Number of Participants With Suicidal Ideation and Suicidal Behavior as Assessed by the Electronic Columbia Suicide Severity Rating Scale (eC-SSRS)	7 Participants	1 Participants	3 Participants

Adverse Events

Fremanezumab 225 mg Monthly

Serious events: 8 serious events

Other events: 31 other events

Deaths: 0 deaths

Fremanezumab 675/225 mg Monthly

Serious events: 2 serious events

Other events: 11 other events

Deaths: 0 deaths

Fremanezumab 675 mg Quarterly

Serious events: 1 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Fremanezumab 225 mg Monthly n=144 participants at risk Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=60 participants at risk Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=71 participants at risk Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Cardiac disorders Acute myocardial infarction	0.69% 1/144 • Number of events 1 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/60 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/71 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
Eye disorders Amaurosis fugax	0.00% 0/144 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/60 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	1.4% 1/71 • Number of events 1 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
Hepatobiliary disorders Cholecystitis	0.69% 1/144 • Number of events 1 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/60 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/71 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
Hepatobiliary disorders Cholelithiasis	0.69% 1/144 • Number of events 1 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/60 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/71 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
Infections and infestations Influenza	0.00% 0/144 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	1.7% 1/60 • Number of events 1 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/71 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Intentional overdose	0.69% 1/144 • Number of events 1 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/60 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/71 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.69% 1/144 • Number of events 1 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/60 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/71 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Road traffic accident	0.69% 1/144 • Number of events 1 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/60 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/71 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Rotator cuff syndrome	0.00% 0/144 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	1.7% 1/60 • Number of events 1 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/71 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
Nervous system disorders Carotid artery stenosis	0.00% 0/144 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/60 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	1.4% 1/71 • Number of events 1 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
Nervous system disorders Cluster headache	2.1% 3/144 • Number of events 3 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/60 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/71 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/144 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	1.7% 1/60 • Number of events 1 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/71 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.

Other adverse events

Other adverse events
Measure	Fremanezumab 225 mg Monthly n=144 participants at risk Participants with ECH or CCH who received fremanezumab at 900 mg IV infusion at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and fremanezumab at 225 mg SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection \[225 mg/1.5 mL\] at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Fremanezumab 675/225 mg Monthly n=60 participants at risk Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; received fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.	Fremanezumab 675 mg Quarterly n=71 participants at risk Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; received fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 and 36; and single placebo SC injection at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Gastrointestinal disorders Nausea	1.4% 2/144 • Number of events 3 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	5.0% 3/60 • Number of events 4 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/71 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
General disorders Injection site induration	9.0% 13/144 • Number of events 44 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	6.7% 4/60 • Number of events 13 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	7.0% 5/71 • Number of events 10 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
General disorders Oedema peripheral	0.00% 0/144 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	5.0% 3/60 • Number of events 3 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	0.00% 0/71 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
Infections and infestations Nasopharyngitis	11.1% 16/144 • Number of events 18 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	8.3% 5/60 • Number of events 8 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	9.9% 7/71 • Number of events 8 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.
Infections and infestations Sinusitis	2.8% 4/144 • Number of events 4 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	5.0% 3/60 • Number of events 4 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.	2.8% 2/71 • Number of events 2 • Baseline up to Week 68 Safety population included all participants who received at least 1 dose of study drug.

Additional Information

Director, Clinical Research

Teva Branded Pharmaceutical Products, R&D Inc.

Phone: 1-888-483-8279

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.
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Restriction type: OTHER