A Study Comparing the Efficacy and Safety of Fremanezumab (TEV-48125) for the Prevention of Chronic Cluster Headache (CCH)

A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation.

A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) ≥1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. Mean change from baseline in monthly average number of CH attacks during 4-week period after administration of first dose of study drug (based on Week 0 to 4 data) and during 4-week period after administration of third dose of study drug (based on Week 8 to 12 data) is reported.

A maximum of 2 concomitant preventive medications for CH were allowed during the study. Participants must have been on a stable dose and regimen of the concomitant medication for at least 2 weeks before screening and throughout the study. Baseline data and the mean change from baseline in the overall weekly average number of days with the use of cluster-specific acute headache medications (triptans and ergot compounds) during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported.

Baseline data and the mean change from baseline in the overall weekly average number of days oxygen was used to treat CCH during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported.

The PPSI assessment was developed to measure pain intensity and was adjusted for CH symptoms improvement. Participants marked the level of CH-associated pain and indicated if pain is "1=much worse," "2=moderately worse," "3=slightly worse," "4=unchanged," "5=slightly improved," "6=moderately improved," or "7=much improved" compared with 4 weeks prior. PPSI was defined as the change in pain that corresponds with a minimal rating of "5=slightly improved." Data at Week 1 was recorded on Day 7 in the electronic diary device at home. Week 12 data also included assessment at the early withdrawal visit for participants who discontinued the study early.

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. Severity was rated by the Investigator on a scale of mild, moderate and severe, with severe as an AE that 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 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.

Serum chemistry, hematology, urinalysis laboratory tests with potentially clinically significant abnormal findings included: Alanine Aminotransferase (units/liter [U/L]) ≥3*upper limit of normal (ULN); Aspartate Aminotransferase (U/L) ≥3*ULN; Bilirubin (Total) ≥34.2 micromole/liter (umol/L); Blood Urea Nitrogen ≥10.71 millimole (mmol)/L; Creatinine ≥177 umol/L; Gamma Glutamyl Transferase (U/L) ≥3*ULN; hemoglobin less than (<)115 grams (g)/L (males) or less than or equal to (≤)95 g/L (females); leukocytes ≥20*10^9/L or ≤3*10^9/L; Eosinophils/Leukocytes ≥10%; Hematocrit <0.37 L/L (males) and <0.32 L/L (females); platelets ≥700*10^9/L or ≤75*10^9/L; blood ≥2 unit increase from baseline; urine glucose (milligrams/decilitre [mg/dL]) ≥2 U increase from baseline; ketones (mg/dL) ≥2 U increase from baseline; urine protein (mg/dL) ≥2 U increase from baseline. 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) 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.

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. 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.

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, hypersensitivity, swelling, rash, and flushing. 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.