TV48125-CNS-30050

Teva Branded Pharmaceutical Products R&D, Inc

41 Moores Road, Frazer, Pennsylvania, United States, 19355

Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc, 001 215-591-3000, Info.era-clinical@teva.de

Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc, 001 215-591-3000, Info.era-clinical@teva.de

No

No

No

Final

20 Sep 2017

No

Yes

10 Apr 2017

No

• to demonstrate the efficacy 2 dose regimens of TEV-48125, as assessed by the decrease in the monthly average number of migraine days during 12-week period after the 1st dose of study drug relative to the baseline period • to evaluate the safety and tolerability of 2 dose regimens TEV-48125 in the preventive treatment of episodic migraine (EM)

This study was conducted in full accordance with the International Council on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314; European Union Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of GCP in the conduct of clinical trials on medicinal products for human use). Each investigator was responsible for performing the study in accordance with the protocol, ICH guidelines, and GCP, and for collecting, recording, and reporting the data accurately and properly. Agreement of each investigator to conduct and administer this study in accordance with the protocol was documented in separate study agreements with the sponsor and other forms as required by national authorities in the country where the study center is located. Written and/or oral information about the study was provided to all patients in a language understandable by the patients. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each patient before any study procedures or assessments were done. It was explained to the patients that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each patient’s willingness to participate in the study was documented in writing in a consent form that was signed by the patient with the date of that signature indicated. Each investigator kept the original consent forms, and copies were given to the patients.

22 Feb 2016

No

No

Poland: 20

Spain: 5

Czech Republic: 37

Finland: 7

Canada: 14

Israel: 13

Japan: 75

Russian Federation: 25

United States: 679

875

69

0

0

0

0

0

0

853

22

0

Overall Trial (overall period)

Randomised - controlled

The sponsor, investigators, study staff (except for staff involved in bioanalytical analyses), and patients were blinded to treatment assignment.

Yes

Placebo

Solution for injection in pre-filled syringe

Subcutaneous use

Placebo 2.25-mL pre-filled syringes identical in appearance to active intervention. Patients were dosed once approximately every 28 days for a total of 3 times. Study drug was administered at the clinical site.

Fremanezumab

TEV-48125, anti-calcitonin gene-related peptide (anti-CGRP)

Solution for injection in pre-filled syringe

Subcutaneous use

Fremanezumab was provided as a sterile, unpreserved, aqueous solution for injection, supplied in a 2.25-mL pre-filled syringe for single-use administration. The initial dose of 675 mg on Day 0 was given as 3 injections. Study drug was administered at the clinical site.

Placebo

Solution for injection in pre-filled syringe

Subcutaneous use

Placebo 2.25-mL pre-filled syringes identical in appearance to active intervention. Patients were dosed with placebo on Days 28 and 56. Study drug was administered at the clinical site.

Fremanezumab

TEV-48125, anti-calcitonin gene-related peptide (anti-CGRP)

Solution for injection in pre-filled syringe

Subcutaneous use

Fremanezumab was provided as a sterile, unpreserved, aqueous solution for injection, supplied in a 2.25-mL pre-filled syringe for single-use administration. The initial dose of 275 mg on Day 0 was repeated on Days 28 and 56. Study drug was administered at the clinical site.

Placebo

Fremanezumab 675 mg/placebo/placebo

Fremanezumab 225/225/225 mg

Placebo

Fremanezumab 675 mg/placebo/placebo

Fremanezumab 225/225/225 mg

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.

Primary

Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 12)

Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.

Fremanezumab 675 mg/placebo/placebo v Placebo

578

Pre-specified

Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.

Fremanezumab 225/225/225 mg v Placebo

577

Pre-specified

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.

Primary

Day 1 to Week 12

Responder rates were defined as the percentage of total subjects who reached at least a 50% reduction in the monthly average of headache days (as subjectively reported by participants in the study diary) of at least moderate severity relative to the baseline period. For the overall analysis (Month 1-3), patients who discontinued early were considered nonresponders. 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 percentage reduction in monthly average is calculated as: ((baseline value - postbaseline value) / baseline value) * 100

Secondary

Baseline (Days -28 to Day -1), Treatment Month 1, Month 2, Month 3, Month 1-3 (Days 1 – Week 12)

P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.

Fremanezumab 675 mg/placebo/placebo v Placebo

578

Pre-specified

P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.

Fremanezumab 225/225/225 mg v Placebo

577

Pre-specified

P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.

Fremanezumab 675 mg/placebo/placebo v Placebo

578

Pre-specified

P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.

Fremanezumab 225/225/225 mg v Placebo

577

Pre-specified

P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.

Fremanezumab 675 mg/placebo/placebo v Placebo

578

Pre-specified

P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.

Fremanezumab 225/225/225 mg v Placebo

577

Pre-specified

P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use. For the overall analysis, patients who discontinued early were considered nonresponders.

Fremanezumab 675 mg/placebo/placebo v Placebo

578

Pre-specified

P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use. For the overall analysis, patients who discontinued early were considered nonresponders.

Fremanezumab 225/225/225 mg v Placebo

577

Pre-specified

Patients recorded any migraine medications (name of drug, number of tablets/capsules, and the dose in milligrams per tablet/capsule) taken on each day in their electronic headache diary device. Acute migraine-specific medication included triptans or ergots. 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.

Secondary

Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 12)

Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint

Placebo v Fremanezumab 675 mg/placebo/placebo

578

Pre-specified

Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint

Fremanezumab 225/225/225 mg v Placebo

577

Pre-specified

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.

Secondary

Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 4)

Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint

Fremanezumab 675 mg/placebo/placebo v Placebo

575

Pre-specified

Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint

Fremanezumab 225/225/225 mg v Placebo

577

Pre-specified

A subset of patients (specified in the protocol not to exceed 30%) were allowed to use 1 concomitant migraine preventive medication. This outcome only includes those participants who did not take concomitant preventive migraine medication during this study. A migraine day has been previously defined. 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.

Secondary

Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 12)

Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint.

Fremanezumab 675 mg/placebo/placebo v Placebo

460

Pre-specified

Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint.

Fremanezumab 225/225/225 mg v Placebo

455

Pre-specified

The MIDAS questionnaire is a 5-item instrument developed to assess headache-related disability based on lost days of activity in 3 domains (work, household work, and nonwork) over the previous 3 months. The total score, ie, the sum of the # lost days answered for the first 5 questions, is used for grading of disability, with scores of 0-5 lost days = grade 1 (little or no disability), 6-10 lost days =grade 2 (mild disability), 11-20 lost days = grade 3 (moderate disability), and ≥21 lost days interpreted as grade 4 (severe disability). Negative change from baseline scores indicate a reduction (improvement) in headache-related disability.

Secondary

Baseline (Day 0), Treatment Week 12 (4 weeks after the 3rd dose)

Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint.

Fremanezumab 675 mg/placebo/placebo v Placebo

578

Pre-specified

Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint.

Fremanezumab 225/225/225 mg v Placebo

577

Pre-specified

12-lead ECGs were performed before other assessments (eg, blood draws and administration of questionnaires) and performed in triplicate. The worst postbaseline finding for the patient is summarized. Only patients with both baseline and postbaseline ECGs are included. The ECG was evaluated by the investigator at the time of recording (signed and dated), and the printout was kept in the source documentation file. When potentially clinically significant findings were detected by the investigator, a cardiologist at a central diagnostic center was consulted for a definitive interpretation. Any ECG finding that was judged by the investigator as a potentially clinically significant change (worsening) compared with a baseline value was considered an adverse event. NCS = abnormal, not clinically significant CS = abnormal, clinically significant Shift format is: baseline finding / worst postbaseline finding

Secondary

Baseline (Day 0), Treatment Week 12 (or early withdrawal)

Vital signs were performed before other assessments (eg, blood draws and administration of questionnaires). Vital signs with at least one participant showing potentially clinically significant abnormal findings included: - Pulse Rate Low: <=50 and decrease of >=15 beats per minute - Systolic Blood Pressure Low: <=90 mmHg and decrease of >=20 mmHg - Diastolic Blood Pressure High: >=105 mmHg and increase of >=15 mmHg - Diastolic Blood Pressure Low: <=50 mmHg and decrease of >=15 mmHg - Respiratory Rate Low: <10 breaths / minute

Secondary

Treatment Days 28, 56 and 84. Changes from previous reading may reflect the baseline reading performed on Day 0.

Serum chemistry and hematology laboratory tests with potentially clinically significant abnormal findings included: - Blood Urea Nitrogen (BUN) High: >=10.71 mmol/L - Bilirubin High: >=34.2 umol/L - Alanine Aminotransferase (ALT): >=3*upper limit of normal (ULN) - Aspartate Aminotransferase (AST): >=3*upper limit of normal (ULN) - Gamma Glutamyl Transferase (GGT): >=3*upper limit of normal (ULN) - Hemoglobin: Male: <115 g/L or Female: <=95 g/L - Hematocrit: Male: <0.37 L/L or Female: <0.32 L/L - Leukocytes: >=20*10^9/L or <=3*10^9/L - Eosinophils/Leukocytes: >=10% - Platelets: >=700*10^9/L or <=75*10^9/L

Secondary

Treatment Days 28, 56 and 84 (or early withdrawal)

Urinalysis with potentially clinically significant abnormal findings included: - Blood: >=2 unit increase from baseline - Urine Glucose (mg/dL): >=2 unit increase from baseline - Ketones (mg/dL): >=2 unit increase from baseline - Urine Protein (mg/dL): >=2 unit increase from baseline

Secondary

Treatment Days 28, 56 and 84. Changes from previous reading reflect the baseline reading performed on Day 0.

Shifts in prothrombin time from baseline to endpoint were summarized using patient 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) Shift format is: baseline finding / endpoint finding

Secondary

Baseline (Day 0), Treatment Endpoint (Week 12)

Counts of participants who reported treatment-emergent injection site reactions as AEs are summarized. Preferred terms from MedDRA version 18.1 are offered without a threshold applied.

Secondary

Day 1 to Week 12

The electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) was used to assess the patient’s suicidal ideation (severity and intensity) and behavior (Posner et al 2011). The eC-SSRS Baseline/Screening version was completed by the patient at visit 2, and the eC-SSRS Since Last Visit version was completed by the patient at all other time points. Any positive findings on the eC-SSRS Since Last Visit version required evaluation by a physician or doctoral-level psychologist. Findings after the first dose of study drug using the eC-SSRS Since Last Visit version are summarized.

Secondary

Day 1 to Week 12

Day 1 to Week 12

18.1

Placebo

Fremanezumab 675 mg/placebo/placebo

Fremanezumab 225/225/225 mg