Fremanezumab

including local injection site reaction/pain

(systolic and diastolic blood pressure, pulse, temperature, and respiratory rate), height, and weight measurements

Columbia-Suicide Severity Rating Scale (C-SSRS) The C-SSRS is an assessment tool that evaluates suicidal ideation and behavior. Scale range: Yes or No response to 10 questions, with minimum to maximum range of 0 to 10. Lower score represents better outcomes.

A migraine day was defined as a calendar day where the participant reported either of the following: A calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a headache meeting the criteria for migraine with or without aura or; a calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a headache meeting the criteria for probable migraine, a migraine subtype where only 1 migraine criterion is missing; a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine specific medications (triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over 12-week period/number of days with assessments recorded in e-diary for 12-week period) \* 28. Least square (LS) mean was calculated using analysis of covariance (ANCOVA).

A migraine day was defined as a day with any of the following: A day (0:00 to 23:59) with at least 2 hours of headache with ≥2 migraine symptom(s) or day (0:00 to 23:59) demonstrating a headache treated with migraine medications (e.g., non-steroidal anti-inflammatory drugs \[NSAIDs\], paracetamol etc.), or a headache associated with aura. Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over 12-week period/number of days with assessments recorded in electronic diary (e-diary) for 12-week period) \* 28. Least square (LS) mean was calculated using analysis of covariance (ANCOVA).

A migraine day was defined as when at least 1 of the following situations occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for migraine with or without aura; a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours 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.

A migraine day was defined as when at least 1 of the following situations occurred: - a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for migraine with or without aura - a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for probable migraine, a migraine subtype where only 1 migraine criterion is missing - a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific medications (triptans and ergot compounds) Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) \* 28. The change is calculated as postbaseline value - baseline value.

An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents usual activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) where the patient (using the electronic headache diary device) reports: - a day with headache pain that lasts ≥4 hours with a peak severity of at least moderate severity or - a day when the patient used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) \* 28. The change is calculated as post-baseline value - baseline value.

An adverse event (AE) was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents usual activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

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.

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.

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.

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.

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.

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.

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 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.

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.

A headache day was defined as a day when a participant reported a headache of at least moderate severity. 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. Least square (LS) mean was calculated using analysis of covariance (ANCOVA) model with the duration of post traumatic headache history (less than 12 month since the brain injury or greater or equal to 12 month since the brain injury) and treatment as fixed effects and the baseline monthly average number of headache days of at least moderate severity as a covariate.