Clinical Study Protocol with Amendment 01

Clinical Study Protocol with Amendment 01

Study Number TV48125-CNS-30050

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Comparing the Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of TEV-48125 Versus Placebo for the Preventive Treatment of Episodic Migraine

Phase 3

Sponsor

Monitors

NCGS, Inc.
288 Meeting Street
Suite 400
Charleston, South Carolina 29401
United States
PRA
4130 Parklake Avenue
Suite 400
Raleigh, NC 27612

Confidentiality Statement

AMENDMENT HISTORY

INVESTIGATOR AGREEMENT

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Comparing the Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of TEV-48125 Versus Placebo for the Preventive Treatment of Episodic Migraine

Principal Investigator:

Tel:

SPONSOR PROTOCOL APPROVAL

COORDINATING INVESTIGATOR AGREEMENT

Coordinating Investigator:
Title:

CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS

Central Institutional Review Board

Central Clinical Laboratory

Electronic Data Capture

Data Management

Electronic Clinical Outcome Assessment

Central Electrocardiogram Evaluation

CLINICAL STUDY PERSONNEL CONTACT INFORMATION

For medical issues, contact the physician listed below:

For operational issues, contact the operational leads listed below:

For serious adverse events:

CLINICAL STUDY PROTOCOL SYNOPSIS

Study TV48125-CNS-30050

• monthly subcutaneous (sc) administration of TEV-48125 at 225 mg
• sc administration of TEV-48125 at 675 mg followed by monthly sc placebo
• monthly sc administration of placebo
  (Note: For this study, monthly dosing refers to dosing approximately every 4 weeks [28 days].)
  Study Population: The study population will be composed of female and male patients, aged 18 to 70 years, inclusive, with a history of migraine (as defined by International Classification of Headache Disorders, revision [ICHD-3] criteria [Classification Committee of the IHS, 2013]) for at least 12 months prior to screening and episodic migraine (EM) prospectively documented via a review of headache data recorded daily in an electronic daily headache diary device during a 28-day run-in period.

• 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 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 EM

• to evaluate the proportion of patients reaching at least reduction in the monthly average number of migraine days with TEV-48125 during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly average number of days of use of any acute headache medications during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the number of migraine days during the 4-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly average number of migraine days during the 12 -week period after the dose of study drug relative to the baseline period in patients not receiving concomitant migraine preventive medications at baseline
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction of migraine-related disability as measured by the Migraine Disability Assessment (MIDAS) questionnaire, at 4 weeks after the last ( ) dose of study drug relative to baseline
• to evaluate the immunogenicity of TEV-48125 and the impact of antidrug antibodies (ADAs) on efficacy and safety during 12 weeks of treatment with TEV-48125

• to demonstrate the efficacy of TEV-48125, as assessed by the decrease in the monthly average number of headache days of at least moderate severity during the 12-week period after the dose of study drug relative to the baseline period
• to evaluate the proportion of patients reaching at least reduction and total ( ) reduction in the monthly average number of migraine days during the 12-week period after the dose of study drug
• to evaluate the proportion of patients reaching at least reduction and at least reduction in the number of migraine days during the 4 -week period after the dose of study drug relative to the baseline period who sustain this level of response over the 12-week period after the dose of study drug
• to demonstrate the efficacy of TEV-48125 in patients who previously used topiramate for migraine, but discontinued, as assessed by the reduction of the monthly average number of migraine days during the 12 -week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125 in patients who previously used onabotulinumtoxinA for migraine, but discontinued, as assessed by the reduction of the monthly average number of migraine days during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the number of migraine days during the 4 -week period after the dose of study drug and the 4 -week period after the last dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly average number of headache days of any severity during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of headache days of at least moderate severity during the 4-week period after each dose of study drug relative to the baseline period
• to evaluate the proportion of patients reaching at least reduction, at least reduction, and total (100%) reduction in the monthly average number of headache days of at least moderate severity during the 12-week period after the dose of study drug
• to evaluate the proportion of patients reaching at least reduction and at least reduction in the number of headache days of at least moderate severity during the 4-week period after the dose of study drug for whom this level of effect is sustained throughout the 12-week period after the dose of study drug
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of headache days of at least moderate severity during the 12-week period after the dose of study drug for patients not receiving concomitant preventive migraine medications relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of headache days of at least moderate severity during the 12-week period after the dose of study drug for patients who used topiramate for migraine in the past relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of headache days of at least moderate severity during the 12-week period after the dose of study drug for patients who used onabotulinumtoxinA for migraine in the past relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly average number of headache hours of any severity during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly average number of headache hours of at least moderate severity during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly average number of days of the use of migraine-specific acute headache medications (triptans and ergot compounds) during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly average number of days with nausea or vomiting during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly average number of days with photophobia and phonophobia during the 12 -week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by a change in quality of life at 4 weeks after the last dose of study drug relative to baseline
• to explore the correlation between pharmacokinetic parameters and drug efficacy
• to explore the relationship between genetic polymorphisms within the CGRP receptor-ligand complex (eg, CALCA, CALCB, CALCRL, CRCP, and RAMP) and migraine-associated genes (eg, PRDM16, AJAP1, TSPAN2, MEF2D, TRPM8, TGFBR2, PHACTR1, FHL5, C7orf10, MMP16, ASTN2, LRP1, APOA1BP, TBC1D7, FUT9, STAT6, ATP5B, and MTHFR) and mode-of-action-related pathways versus hypertension, migraine severity, and safety and efficacy responses
• to explore the relationship between biofluid bone, angiogenic, and inflammatory biomarkers with TEV-48125 concentrations and efficacy responses

Study Endpoints

• proportion of patients reaching at least reduction in the monthly average number of migraine days during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of days of use of any acute headache medications during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the number of migraine days during the 4-week period after the dose of the study drug
• mean change from baseline (28-day run-in period) in the monthly average number of migraine days during the 12 -week period after the dose of study drug in patients not receiving concomitant migraine preventive medications
• mean change from baseline (day 0 ) in disability score, as measured by the MIDAS questionnaire, at 4 weeks after administration of the last ( ) dose of study drug

• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 12-week period after the dose of study drug
• proportion of patients reaching at least reduction and total ( ) reduction in the monthly average number of migraine days during the 12 -week period after the dose of study drug
• proportion of patients reaching at least reduction and at least reduction in the number of migraine days during the 4-week period after the dose of study drug for whom this level of effect is sustained throughout the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of migraine days during the 12-week period after the dose of study drug in patients who used topiramate for migraine in the past
• mean change from baseline (28-day run-in period) in the number of migraine days during the 12-week period after the dose of study drug for patients who used onabotulinumtoxinA for migraine in the past
• mean change from baseline (28-day run-in period) in the number of migraine days during the 4-week period after the dose of the study drug
• mean change from baseline (28-day run-in period) in the number of migraine days during the 4-week period after the last ( ) dose of the study drug
• mean change from baseline (28-day run-in period) in the monthly average number of headache days of any severity during the 12 -week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 4-week period after each dose of study drug
• proportion of patients reaching at least reduction, at least reduction, and total ( ) reduction in the monthly average number of headache days of at least moderate severity during the 12-week period after the dose of study drug
• proportion of patients reaching at least reduction and at least reduction in the number of headache days of at least moderate severity during the 4 -week period after the dose of study drug for whom this level of effect is sustained throughout the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 12-week period after the dose of study drug for patients not receiving concomitant preventive migraine medications
• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 12-week period after the dose of study drug for patients who used topiramate for migraine in the past
• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 12-week period after the 1st dose of study drug for patients who used onabotulinumtoxinA for migraine in the past
• mean change from baseline (28-day run-in period) in the monthly average number of headache hours of any severity during the 12 -week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of headache hours of at least moderate severity during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of days of use of migraine-specific acute headache medications (triptans and ergot compounds) during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of days with nausea or vomiting during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of days with photophobia and phonophobia during the 12-week period after the dose of study drug
• mean change from baseline (day 0 ) in quality of life, as measured by the Migraine-Specific Quality of Life (MSQOL) questionnaire, at 4 weeks after administration of the last ( ) dose of study drug
• mean change from baseline (day 0 ) in the health status, as measured by the EuroQol-5 Dimension, 5 response level version (EQ-5D-5L) questionnaire at 4 weeks after administration of the last dose of study drug
• mean change from baseline (day 0 ) in patient depression status, as measured by the 2-item Patient Health Questionnaire (PHQ-2) and 9-item Patient Health Questionnaire (PHQ-9), at 4 weeks after administration of the last dose of study drug
• mean change from baseline (day 0 ) in patient work productivity and activity impairment, as measured by the Work Productivity and Activity Impairment (WPAI) questionnaire, at 4 weeks after administration of the last ( ) dose of study drug
• assessment of patient satisfaction, as measured by the Patient Global Impression of Change (PGIC) scale, at 4 weeks after administration of the dose of study drug, at 4 weeks after the dose of study drug, and at 4 weeks after the last ( ) dose of study drug
• exploratory correlation of specific genetic polymorphisms and headache response, specific migraine clinical features, and adverse events to medication
• mean change from baseline in exploratory biofluid biomarkers versus treatment, migraine onset/severity, and response status (ie, responders versus nonresponders)
• correlation of exploratory biofluid biomarkers with TEV-48125 concentrations

• monthly sc administration of TEV-48125 at 225 mg
• sc administration of 675 mg of TEV-48125 at visit 2 followed by monthly sc placebo
• monthly sc administration of placebo

• Patients randomized to receive TEV-48125 at 225 mg will receive 225 mg of TEV-48125 as 1 active injection ( ) and two placebo injections at visit 2 and 225 mg of TEV- 48125 as 1 active injection ( ) at visits 3 and 4 .
• Patients randomized to receive TEV-48125 placebo will receive 675 mg of TEV-48125 as 3 active injections ( ) at visit 2 and placebo as single injection at visits 3 and 4 .
• Patients randomized to receive placebo will receive three placebo injections at visit 2 and single placebo injection at visits 3 and 4 .

• headache occurring on and days
• on days, fulfilling any of the following:
• ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura (Appendix D)
• ICHD-3 criteria B and C for 1.2 Migraine with aura (Appendix D)
• Probable migraine (a migraine subtype where only 1 migraine criterion is missing)
• The patient used a triptan or ergot derivative to treat an established headache
  e. Not using preventive medications (presented in Appendix B) (ie, at least 5 half-lives have passed since last use) or using no more than 1 preventive medication (presented in Appendix A) for migraine or other medical conditions (eg, propranolol used for hypertension) if the dose and regimen have been stable for at least 2 months prior to beginning the 28-day run-in period.
  f. Body mass index of 17.5 to and a total body weight between 45 and 120 kg , inclusive
  g. All patients must be of nonchildbearing potential, defined as:
• women surgically sterile by documented complete hysterectomy, bilateral oophorectomy, or bitubal ligations or confirmed to be postmenopausal (at least 1 year since last menses and follicle-stimulating hormone above )
• men surgically sterile by documented vasectomy
  or
  if of childbearing potential, patients must meet any of the following criteria:
• Patients must simultaneously use 2 forms of highly effective contraception methods (defined in Section 5.2) with their partners during the entire study period and for 7.5 months after the last dose of study drug.
• Sexual abstinence is only considered a highly effective method if defined as refraining from heterosexual intercourse in the defined period. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a study, and withdrawal are not acceptable methods of contraception.
  h. Female patients of childbearing potential must have negative a serum beta-human chorionic gonadotropin ( -HCG) pregnancy test at screening (confirmed by urine dipstick -HCG pregnancy test at baseline).
  i. The patient demonstrated compliance with the electronic headache diary during the run-in period by entry of headache data on a minimum of 24 out of 28 days ( diary compliance).
  j. The patient is in good health as determined by a medical and psychiatric history, medical examination, 12-lead electrocardiogram (ECG), serum chemistry, hematology, coagulation, and urinalysis.
  k. The patient must be willing and able to comply with study restrictions, to remain at the clinic for the required duration during the study period, and to return to the clinic for the follow-up evaluation, as specified in this protocol.

• cluster A: divalproex sodium and sodium valproate
• cluster B: flunarizine and pizotifen
• cluster C: amitriptyline, nortriptyline, venlafaxine, and duloxetine
• cluster D: atenolol, nadolol, metoprolol, propranolol, and timolol
  d. Patient has used an intervention/device (eg, scheduled nerve blocks and transcranial magnetic stimulation) for migraine during the last 2 months prior to screening.
  e. Clinically significant hematological, cardiac, renal, endocrine, pulmonary, gastrointestinal, genitourinary, neurologic, hepatic, or ocular disease, at the discretion of the investigator
  f. Evidence or medical history of clinically significant psychiatric issues, including any suicide attempt in the past, or suicidal ideation with a specific plan in the past 2 years.
  g. History of clinically significant cardiovascular disease or vascular ischemia (such as myocardial, neurological [eg, cerebral ischemia], peripheral extremity ischemia, or other ischemic event) or thromboembolic events (arterial or venous thrombotic or embolic events), such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism
  h. Known infection or history of human immunodeficiency virus, tuberculosis, or chronic hepatitis B or C infection
  i. Past or current history of cancer in the past 5 years, except for appropriately treated nonmelanoma skin carcinoma
  j. Pregnant or nursing females
  k. History of hypersensitivity reactions to injected proteins, including monoclonal antibodies

1. Participation in a clinical study of a new chemical entity or a prescription medicine within 2 months before study drug administration or 5 half-lives, whichever is longer
   m. Any prior exposure to a monoclonal antibody targeting the CGRP pathway (AMG 334, ALD304, LY2951742, or TEV-48125)
   n. Any finding in the baseline 12-lead ECG considered clinically significant in the judgment of the investigator
   o. Any finding that, in the judgment of the investigator, is a clinically significant abnormality, including serum chemistry, hematology, coagulation, and urinalysis test values (abnormal tests may be repeated for confirmation)
   p. Hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) the upper limit of the normal range (ULN) after confirmation in a repeat test or suspected hepatocellular damage that fulfills criteria for Hy's law at screening
   q. Serum creatinine the ULN, clinically significant proteinuria, or evidence of renal disease at screening
   r. History of alcohol or drug abuse during the past 2 years, or alcohol or drug dependence during the past 5 years
   s. The patient cannot participate or successfully complete the study, in the opinion of their healthcare provider or the investigator, for any of the following reasons:

• mentally or legally incapacitated or unable to give consent for any reason
• in custody due to an administrative or a legal decision, under guardianship, or institutionalized
• unable to be contacted in case of emergency
• has any other condition, which, in the opinion of the investigator, makes the patient inappropriate for inclusion in the study
  t. The patient is a study center or sponsor employee who is directly involved in the study or the relative of such an employee.

Measures and Time Points:

• exploratory efficacy endpoints derived from headache data (ie, occurrence of headache, duration of headache, maximum severity of headache, and acute migraine-specific medication use), which are collected daily using an electronic headache diary device
• PHQ-2/PHQ-9 (Note: Patients will first respond to the PHQ-2. They will respond to questions 3 through 9 [unique questions] of the PHQ-9 only if the PHQ-2 is positive.)
• MSQOL questionnaire
• EQ-5D-5L questionnaire
• PGIC scale
• WPAI questionnaire

• inquiries about adverse events
• inquiries about concomitant medication usage
• safety laboratory tests (serum chemistry, hematology, coagulation, and urinalysis)
• serum/urine -HCG test (women of childbearing potential only)
• 12-lead ECGs
• vital signs measurements (systolic and diastolic blood pressure, pulse, temperature, and respiratory rate)
• physical examinations, including body weight
• injection site reaction (ie, erythema, induration, ecchymosis, and pain) assessments
• electronic Columbia-Suicide Severity Rating Scale (eC-SSRS)

Pharmacokinetics/Biomarkers/Immunogenicity Measures and Time Points:

Allowed and Disallowed Medications Before and During the Study:

Statistical Considerations:

• a calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a headache meeting criteria for migraine with or without aura
• a calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a headache meeting 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)

Clinical Study Protocol with Amendment 01

TABLE OF CONTENTS

1. BACKGROUND INFORMATION ..... 33
   1.1. Introduction ..... 33
   1.2. Name and Description of Investigational Product ..... 34
   1.3. Findings from Nonclinical and Clinical Studies ..... 34
   1.3.1. Nonclinical Studies ..... 34
   1.3.2 Clinical Studies ..... 35
   1.3.2.1. Clinical Pharmacology Studies ..... 35
   1.3.2.2. Clinical Safety and Efficacy Studies ..... 36
   1.4. Known and Potential Risks and Benefits to Human Patients ..... 37
   1.4.1. Known and Potential Risks and Benefits of TEV-48125 ..... 37
   1.4.1.1. Risks of TEV-48125 ..... 37
   1.4.1.2. Benefits of TEV-48125 ..... 37
   1.4.2. Overall Risk and Benefit Assessment for This Study ..... 38
   1.5. Selection of Drugs and Dosages ..... 38
   1.5.1. Justification for Dosage of Active Drug ..... 38
   1.5.2. Justification for Use of Placebo ..... 39
   1.6. Compliance Statement ..... 39
   1.7. Population to be Studied and Justification ..... 39
   1.8. Location and Timing of Study ..... 40
2. PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..... 41
   2.1. Purpose of the Study ..... 41
   2.2. Study Objectives ..... 41
   2.2.1. Primary Objectives ..... 41
   Clinical Study Protocol with Amendment 01 Study TV48125-CNS-30050
   2.2.2. Secondary Objectives ..... 41
   2.2.3. Exploratory Objectives ..... 42
   2.3. Study Endpoints ..... 44
   2.3.1. Primary Efficacy Endpoint ..... 44
   2.3.2. Secondary Efficacy Endpoints ..... 44
   2.3.3. Exploratory Efficacy Endpoints ..... 44
   2.3.4. Safety and Tolerability Endpoints ..... 46
   2.3.5. Pharmacokinetic/Immunogenicity/Biomarker Endpoints ..... 46
   2.3.5.1. Pharmacokinetic Endpoints ..... 46
   2.3.5.2. Immunogenicity Endpoint ..... 46
   2.3.5.3. Biomarker Endpoints ..... 47
3. STUDY DESIGN ..... 48
   3.1. General Design and Study Schema ..... 48
   3.2. Justification for Study Design ..... 50
   3.3. Primary and Secondary Efficacy Measures and Time Points ..... 51
   3.3.1. Primary Efficacy Measure and Time Points ..... 51
   3.3.2. Secondary Efficacy Measure and Time Points ..... 51
   3.4. Safety and Tolerability Measures and Time Points ..... 51
   3.5. Pharmacokinetic, Biomarker, and Immunogenicity Measures and Time Points ..... 52
   3.5.1. Pharmacokinetic Measures and Time Points ..... 52
   3.5.2. Immunogenicity Measures and Time Points ..... 52
   3.5.3. Biomarker Measures and Time Points ..... 52
   3.6. Exploratory/Other Efficacy Measures and Time Points ..... 52
   3.7. Randomization and Blinding ..... 52
   3.8. Maintenance of Randomization and Blinding ..... 53
   3.8.1. Randomization ..... 53
   3.8.2 Blinding/Unblinding ..... 53
   3.8.3. Data Monitoring Committee ..... 54
   3.9. Drugs Used in the Study ..... 54
   3.9.1. Investigational Product ..... 54
   3.9.2. Placebo ..... 54
   3.10. Drug Supply and Accountability ..... 54
   Placebo-Controlled Study-Episodic Migraine
   Clinical Study Protocol with Amendment 01 Study TV48125-CNS-30050
   3.10.1. Drug Storage and Security ..... 54
   3.10.2. Drug Accountability ..... 54
   3.11. Duration of Patient Participation and Justification ..... 55
   3.12. Stopping Rules and Discontinuation Criteria ..... 55
   3.13. Source Data Recorded on the Case Report Form ..... 56
   3.14. Study Procedures ..... 56
   3.14.1. Procedures for Screening (Visit 1[Day -28]) ..... 60
   3.14.2. Procedures Before Study Drug Treatment ..... 61
   3.14.2.1. 28-Day Run-In Period (Days -28 Through -1) ..... 61
   3.14.2.2. Baseline (Visit 2 [Day 0 ( ± 3 Days)]) ..... 61
   3.14.3. Procedures During Study Drug Treatment ..... 62
   3.14.3.1. Double-Blind Treatment Period (Visits 2 Through 5 [Day 0 Through Day 84 Days]) ..... 62
   3.14.4. Procedures After Study Drug Treatment ..... 64
   3.14.5. Unscheduled Visits ..... 64
4. SELECTION AND WITHDRAWAL OF PATIENTS ..... 66
   4.1. Patient Inclusion Criteria ..... 66
   4.2. Patient Exclusion Criteria ..... 67
   4.3. Justification for Key Inclusion and Exclusion Criteria ..... 69
   4.4. Withdrawal Criteria and Procedures ..... 69
5. TREATMENT OF PATIENTS ..... 71
   5.1. Drugs Administered During the Study ..... 71
   5.2. Restrictions ..... 72
   5.3. Prior and Concomitant Therapy or Medication ..... 72
   5.3.1. Prior Medications and Therapeutic Failures of Migraine Preventives: ..... 72
   5.3.2. Concomitant Therapies and Medications ..... 72
   5.4. Procedures for Monitoring Patient Compliance ..... 73
   5.5. Total Blood Volume ..... 73
6. ASSESSMENT OF EFFICACY ..... 74
   6.1. Primary Efficacy Measure and Justification ..... 74
   6.2 Migraine Disability Assessment ..... 74
   6.3. Two-Item Patient Health Questionnaire/9-Item Patient Health Questionnaire ..... 75
   6.4. Migraine-Specific Quality of Life Questionnaire ..... 75
   Clinical Study Protocol with Amendment 01 Study TV48125-CNS-30050
   6.5. EuroQol-5 Dimension Questionnaire ..... 75
   6.6. Patient Global Impression of Change Scale ..... 75
   6.7. Work Productivity and Activity Impairment Questionnaire ..... 76
7. ASSESSMENT OF SAFETY ..... 77
   7.1. Adverse Events ..... 77
   7.1.1. Definition of an Adverse Event ..... 77
   7.1.2. Recording and Reporting Adverse Events ..... 78
   7.1.3. Severity of an Adverse Event ..... 79
   7.1.4. Relationship of an Adverse Event to the Study Drug ..... 79
   7.1.5. Serious Adverse Events ..... 80
   7.1.5.1. Definition of a Serious Adverse Event ..... 80
   7.1.5.2. Expectedness ..... 80
   7.1.5.3. Reporting a Serious Adverse Event ..... 81
   7.1.6. Protocol-Defined Adverse Events of Special Interest ..... 82
   7.1.7. Withdrawal Due to an Adverse Event ..... 83
   7.1.8. Overdose of Study Drug ..... 83
   7.1.9. Protocol Deviations Because of an Adverse Event ..... 83
   7.2. Pregnancy ..... 84
   7.3. Clinical Laboratory Tests ..... 84
   7.3.1. Serum Chemistry ..... 85
   7.3.2. Hematology ..... 85
   7.3.3. Coagulation ..... 86
   7.3.4 Urinalysis ..... 86
   7.3.5. Other Clinical Laboratory Tests ..... 87
   7.3.5.1. Human Chorionic Gonadotropin Tests ..... 87
   7.3.5.2. Follicle-Stimulating Hormone Tests ..... 87
   7.4. Vital Signs ..... 87
   7.5. Electrocardiography ..... 87
   7.6. Physical Examinations ..... 88
   7.7. Electronic Columbia-Suicide Severity Rating Scale ..... 88
   7.8. Concomitant Therapy or Medication ..... 88
   7.9. Immunogenicity ..... 88
   7.10. Injection Site Assessments ..... 89
   Clinical Study Protocol with Amendment 01 Study TV48125-CNS-30050
   7.11. Methods and Timing of Assessing, Recording, and Analyzing Safety Data ..... 89
8. ASSESSMENT OF PHARMACOKINETICS/ BIOMARKERS/ IMMUNOGENICITY ..... 90
   8.1. Pharmacokinetic Variables ..... 90
   8.1.1. Specimen Sampling and Handling ..... 90
   8.1.2. Shipment and Analysis of Samples ..... 90
   8.2. Immunogenicity Testing ..... 91
   8.2.1. Blood Sampling and Handling. ..... 91
   8.2.2. Shipment and Analysis of Samples ..... 91
   8.3. Assessment of Exploratory Biofluid Biomarkers ..... 91
   8.3.1. Pharmacogenomic Assessment ..... 92
   8.3.2. Specimen Sampling and Handling ..... 92
   8.3.3. Shipment and Analysis of Samples ..... 93
   8.4. Methods and Timing of Assessing, Recording, and Analyzing Clinical Pharmacology Data ..... 93
9. STATISTICS ..... 94
   9.1. Sample Size and Power Considerations ..... 94
   9.2. Analysis Sets ..... 94
   9.2.1. Intent-to-Treat Analysis Set ..... 94
   9.2.2. Safety Analysis Set ..... 94
   9.2.3. Full Analysis Set ..... 94
   9.2.4. Additional Analysis Sets ..... 94
   9.3. Data Handling Conventions ..... 94
   9.4. Study Population ..... 95
   9.4.1. Patient Disposition ..... 95
   9.4.2. Demographic and Baseline Characteristics ..... 95
   9.5. Efficacy Analysis ..... 95
   9.5.1. Primary Endpoint ..... 95
   9.5.2. Secondary Endpoints ..... 96
   9.5.3. Exploratory Endpoints ..... 96
   9.5.4. Planned Method of Analysis ..... 98
   9.5.4.1. Primary Efficacy Analysis ..... 98
   9.5.4.2. Sensitivity Analysis ..... 98
   Clinical Study Protocol with Amendment 01 Study TV48125-CNS-30050
   9.5.4.3. Secondary Efficacy Analysis ..... 98
   9.5.4.4. Exploratory Efficacy Analysis ..... 98
   9.6. Multiple Comparisons and Multiplicity ..... 98
   9.7. Safety and Tolerability Endpoints and Analysis ..... 98
   9.7.1. Safety and Tolerability Endpoints ..... 99
   9.7.2. Safety Analysis ..... 99
   9.8. Pharmacokinetic Analysis ..... 100
   9.9. Biomarker Analysis ..... 100
   9.10. Pharmacokinetic/Pharmacodynamic Analysis ..... 100
   9.11. Immunogenicity Analysis ..... 100
   9.12. Planned Interim Analysis ..... 100
   9.13. Reporting Deviations from the Statistical Plan ..... 100
10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ..... 101
11. QUALITY CONTROL AND QUALITY ASSURANCE ..... 102
    11.1. Protocol Amendments and Protocol Deviations and Violations ..... 102
    11.1.1. Protocol Amendments ..... 102
    11.1.2. Protocol Violations ..... 102
    11.2. Information to Study Personnel ..... 102
    11.3. Study Monitoring ..... 103
    11.4. Clinical Product Complaints ..... 103
    11.4.1. Product Complaint Information Needed from the Investigational Center ..... 104
    11.4.2. Handling the Study Drug at the Investigational Center ..... 104
    11.4.3. Adverse Events or Serious Adverse Events Associated with a Product Complaint ..... 105
    11.4.4. Documenting a Product Complaint ..... 105
    11.5. Audit and Inspection ..... 105
12. ETHICS ..... 106
    12.1. Informed Consent ..... 106
    12.2. Health Authorities and Independent Ethics Committees/Institutional Review Boards ..... 106
    12.3. Confidentiality Regarding Study Patients ..... 106
    12.4. Declaration of the End of the Clinical Study ..... 107
    12.5. Registration of the Clinical Study ..... 107
13. DATA HANDLING, DATA QUALITY CONTROL, AND RECORD KEEPING ..... 108
    13.1. Data Collection ..... 108
    13.2. Data Quality Control ..... 108
    13.3. Archiving of Case Report Forms and Source Documents ..... 109
    13.3.1. Sponsor Responsibilities ..... 109
    13.3.2. Investigator Responsibilities ..... 109
14. FINANCING AND INSURANCE ..... 111
15. REPORTING AND PUBLICATION OF RESULTS ..... 112
16. REFERENCES ..... 113
17. SUMMARY OF CHANGES TO PROTOCOL TV48125-CNS-30049 ..... 116
    17.1. Amendment 01 Dated 30 March 2016 ..... 116
    17.2. Administrative Letter Dated 01 March 2016 ..... 149
    17.3. Administrative Letter Dated 22 January 2016 ..... 151
    APPENDIX A. PREVENTIVE MEDICATIONS ALLOWED FOR THE DURATION OF THE STUDY ..... 152
    APPENDIX B. DISALLOWED MEDICATIONS FOR THE DURATION OF THE STUDY ..... 153
    APPENDIX C. NATIONAL INSTITUTES OF HEALTH PATIENT EDUCATION GUIDELINES OF JUNE 2012 ..... 154
    APPENDIX D. ICHD-3 DIAGNOSTIC CRITERIA ..... 161
    APPENDIX E. GUIDANCE ON SAFETY MONITORING ..... 162
    APPENDIX F. CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS ..... 165
    Clinical Study Protocol with Amendment 01Study TV48125-CNS-30050
    LIST OF TABLES
    Table 1: Study Procedures and Assessments ..... 57
    Table 2: Blood Volumes ..... 73
    Table 3: Severity of Pain Scale for Injection Site Assessments ..... 89
    Table 4: Changes to the Protocol ..... 117

LIST OF FIGURES

1. BACKGROUND INFORMATION

1.1. Introduction

1.2 Name and Description of Investigational Product

1.3 Findings from Nonclinical and Clinical Studies

1.3.1. Nonclinical Studies

1.3.2 Clinical Studies

1.3.2.1 Clinical Pharmacology Studies

1.3.2.2 Clinical Safety and Efficacy Studies

1.4. Known and Potential Risks and Benefits to Human Patients

1.4.1. Known and Potential Risks and Benefits of TEV-48125

1.4.1.1. Risks of TEV-48125

1.4.1.2. Benefits of TEV-48125

1.4.2. Overall Risk and Benefit Assessment for This Study

1.5. Selection of Drugs and Dosages

1.5.1. Justification for Dosage of Active Drug

1.5.2. Justification for Use of Placebo

1.6. Compliance Statement

1.7. Population to be Studied and Justification

1.8. Location and Timing of Study

2. PURPOSE OF THE STUDY AND STUDY OBJECTIVES

2.1. Purpose of the Study

2.2 Study Objectives

2.2.1. Primary Objectives

• 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 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 EM

2.2.2 Secondary Objectives

• to evaluate the proportion of patients reaching at least reduction in the monthly average number of migraine days with TEV-48125 during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly average number of days of use of any acute headache medications during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the number of migraine days during the 4 -week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly average number of migraine days during the 12 -week period after the dose of study drug relative to the baseline period in patients not receiving concomitant migraine preventive medications at baseline
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction of migraine-related disability as measured by the Migraine Disability Assessment (MIDAS) questionnaire, at 4 weeks after the last dose of study drug relative to baseline
• to evaluate the immunogenicity of TEV-48125 and the impact of antidrug antibodies (ADAs) on efficacy and safety during 12 weeks of treatment with TEV-48125

2.2.3 Exploratory Objectives

• to demonstrate the efficacy of TEV-48125, as assessed by the decrease in the monthly average number of headache days of at least moderate severity during the 12-week period after the dose of study drug relative to the baseline period
• to evaluate the proportion of patients reaching at least reduction and total (100%) reduction in the monthly average number of migraine days during the 12-week period after the dose of study drug
• to evaluate the proportion of patients reaching at least reduction and at least reduction in the number of migraine days during the 4 -week period after the dose of study drug relative to the baseline period who sustain this level of response over the 12-week period after the dose of study drug
• to demonstrate the efficacy of TEV-48125 in patients who previously used topiramate for migraine, but discontinued, as assessed by the reduction of the monthly average number of migraine days during the 12 -week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125 in patients who previously used onabotulinumtoxinA for migraine, but discontinued, as assessed by the reduction of the monthly average number of migraine days during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the number of migraine days during the 4 -week period after the dose of study drug and the 4 -week period after the last dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly average number of headache days of any severity during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of headache days of at least moderate severity during the 4-week period after each dose of study drug relative to the baseline period
• to evaluate the proportion of patients reaching at least reduction, at least reduction, and total ( ) reduction in the monthly average number of headache days of at least moderate severity during the 12 -week period after the dose of study drug
• to evaluate the proportion of patients reaching at least reduction and at least reduction in the number of headache days of at least moderate severity during the 4 -week period after the dose of study drug for whom this level of effect is sustained throughout the 12-week period after the dose of study drug
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of headache days of at least moderate severity during the 12-week period after the
  dose of study drug for patients not receiving concomitant preventive migraine medications relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of headache days of at least moderate severity during the 12-week period after the dose of study drug for patients who used topiramate for migraine in the past relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of headache days of at least moderate severity during the 12-week period after the dose of study drug for patients who used onabotulinumtoxinA for migraine in the past relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly average number of headache hours of any severity during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly average number of headache hours of at least moderate severity during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly average number of days of the use of migraine-specific acute headache medications (triptans and ergot compounds) during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly average number of days with nausea or vomiting during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly average number of days with photophobia and phonophobia during the 12-week period after the dose of study drug relative to the baseline period
• to demonstrate the efficacy of TEV-48125, as assessed by a change in quality of life at 4 weeks after the last dose of study drug relative to baseline
• to explore the correlation between pharmacokinetic parameters and drug efficacy
• to explore the relationship between genetic polymorphisms within the CGRP receptor-ligand complex (eg, CALCA, CALCB, CALCRL, CRCP, and RAMP) and migraine-associated genes (eg, PRDM16, AJAP1, TSPAN2, MEF2D, TRPM8, TGFBR2, PHACTR1, FHL5, C7orf10, MMP16, ASTN2, LRP1, APOA1BP, TBC1D7, FUT9, STAT6, ATP5B, and MTHFR) and mode-of-action-related pathways versus hypertension, migraine severity, and safety and efficacy responses
• to explore the relationship between biofluid bone, angiogenic, and inflammatory biomarkers with TEV-48125 concentrations and efficacy responses

2.3 Study Endpoints

2.3.1. Primary Efficacy Endpoint

2.3.2 Secondary Efficacy Endpoints

• proportion of patients reaching at least reduction in the monthly average number of migraine days during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of days of use of any acute headache medications during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the number of migraine days during the 4 -week period after the dose of the study drug
• mean change from baseline (28-day run-in period) in the monthly average number of migraine days during the 12 -week period after the dose of study drug in patients not receiving concomitant migraine preventive medications
• mean change from baseline (day 0 ) in disability score, as measured by the MIDAS questionnaire, at 4 weeks after administration of the last dose of study drug

2.3.3. Exploratory Efficacy Endpoints

• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 12-week period after the dose of study drug
• proportion of patients reaching at least reduction and total ( ) reduction in the monthly average number of migraine days during the 12-week period after the dose of study drug
• proportion of patients reaching at least reduction and at least reduction in the number of migraine days during the 4 -week period after the dose of study drug for whom this level of effect is sustained throughout the 12 -week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of migraine days during the 12 -week period after the dose of study drug in patients who used topiramate for migraine in the past
• mean change from baseline (28-day run-in period) in the number of migraine days during the 12-week period after the dose of study drug for patients who used onabotulinumtoxinA for migraine in the past
• mean change from baseline (28-day run-in period) in the number of migraine days during the 4 -week period after the dose of the study drug
• mean change from baseline (28-day run-in period) in the number of migraine days during the 4 -week period after the last dose of the study drug
• mean change from baseline (28-day run-in period) in the monthly average number of headache days of any severity during the 12 -week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 4-week period after each dose of study drug
• proportion of patients reaching at least reduction, at least reduction, and total (100%) reduction in the monthly average number of headache days of at least moderate severity during the 12-week period after the 1st dose of study drug
• proportion of patients reaching at least reduction and at least reduction in the number of headache days of at least moderate severity during the 4 -week period after the dose of study drug for whom this level of effect is sustained throughout the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 12-week period after the dose of study drug for patients not receiving concomitant preventive migraine medications
• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 12 -week period after the dose of study drug for patients who used topiramate for migraine in the past
• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 12 -week period after the dose of study drug for patients who used onabotulinumtoxinA for migraine in the past
• mean change from baseline (28-day run-in period) in the monthly average number of headache hours of any severity during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of headache hours of at least moderate severity during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of days of use of migraine-specific acute headache medications (triptans and ergot compounds) during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of days with nausea or vomiting during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of days with photophobia and phonophobia during the 12-week period after the dose of study drug
• mean change from baseline (day 0 ) in quality of life, as measured by the Migraine-Specific Quality of Life (MSQOL) questionnaire, at 4 weeks after administration of the last ( ) dose of study drug
• mean change from baseline (day 0 ) in the health status, as measured by the EuroQol-5 Dimension, 5 response level version (EQ-5D-5L) questionnaire at 4 weeks after administration of the last ( ) dose of study drug
• mean change from baseline (day 0 ) in patient depression status, as measured by the 2-item Patient Health Questionnaire (PHQ-2) and 9-item Patient Health Questionnaire (PHQ-9), at 4 weeks after administration of the last ( ) dose of study drug
• mean change from baseline (day 0 ) in patient work productivity and activity impairment, as measured by the Work Productivity and Activity Impairment (WPAI) questionnaire, at 4 weeks after administration of the last ( ) dose of study drug
• assessment of patient satisfaction, as measured by the Patient Global Impression of Change (PGIC) scale, at 4 weeks after administration of the dose of study drug, at 4 weeks after the dose of study drug, and at 4 weeks after the last ( ) dose of study drug

2.3.4. Safety and Tolerability Endpoints

• occurrence of adverse events throughout the study
• abnormal standard 12-lead ECG findings
• changes from baseline in vital signs (systolic and diastolic blood pressure, pulse, temperature, and respiratory rate) measurements
• changes from baseline in clinical laboratory (serum chemistry, hematology, coagulation, and urinalysis) test results
• abnormal physical examination findings
• abnormal local injection site tolerability findings (ie, erythema, induration, ecchymosis) and occurrence of injection site pain
• suicidal ideation and behavior as suggested by the electronic Columbia-Suicide Severity Scale (eC-SSRS)

2.3.5 Pharmacokinetic/Immunogenicity/Biomarker Endpoints

2.3.5.1 Pharmacokinetic Endpoints

2.3.5.2. Immunogenicity Endpoint

2.3.5.3. Biomarker Endpoints

• exploratory correlation of specific genetic polymorphisms and headache response, specific migraine clinical features, and adverse events to medication
• mean change from baseline in exploratory biofluid biomarkers versus treatment, migraine onset/severity, and response status (ie, responders versus nonresponders)
• correlation of exploratory biofluid biomarkers with TEV-48125 concentrations

3. STUDY DESIGN

3.1. General Design and Study Schema

• monthly sc administration of TEV-48125 at 225 mg
• sc administration of 675 mg of TEV-48125 at visit 2 followed by monthly sc placebo
• monthly sc administration of placebo
  (Note: For this study, monthly dosing refers to dosing approximately every 4 weeks [28 days].)
  Randomization will be performed using electronic interactive response technology (IRT). Patients will be stratified based on gender, country, and baseline preventive migraine medication use (yes, no) to ensure balance for the covariates (treatment group, preventive migraine medication use, country, and gender). The total number of patients receiving concomitant preventive medication during the study will not exceed of the total sample size of the study.

Figure 1: Overall Study Schema

3.2. Justification for Study Design

3.3. Primary and Secondary Efficacy Measures and Time Points

3.3.1. Primary Efficacy Measure and Time Points

3.3.2. Secondary Efficacy Measure and Time Points

3.4. Safety and Tolerability Measures and Time Points

• inquiries about adverse events
• inquiries about concomitant medication usage
• safety laboratory tests (serum chemistry, hematology, coagulation, and urinalysis)
• serum/urine beta-human chorionic gonadotropin ( -HCG) test (women of childbearing potential only)
• 12-lead ECGs
• vital signs measurements (systolic and diastolic blood pressure, pulse, temperature, and respiratory rate)
• physical examinations, including body weight
• injection site reaction (ie, erythema, induration, ecchymosis, and pain) assessments
• eC-SSRS

3.5. Pharmacokinetic, Biomarker, and Immunogenicity Measures and Time Points

3.5.1. Pharmacokinetic Measures and Time Points

3.5.2. Immunogenicity Measures and Time Points

3.5.3. Biomarker Measures and Time Points

3.6. Exploratory/Other Efficacy Measures and Time Points

• exploratory efficacy endpoints derived from headache data (ie, occurrence of headache, duration of headache, maximum severity of headache, and acute migraine-specific medication use), which are collected daily using an electronic headache diary device
• PHQ-2/PHQ-9 (Note: Patients will first respond to the PHQ-2. They will respond to questions 3 through 9 [unique questions] of the PHQ-9 only if the PHQ-2 is positive.)
• MSQOL questionnaire
• EQ-5D-5L questionnaire
• PGIC scale completed
• WPAI questionnaire

3.7. Randomization and Blinding

3.8. Maintenance of Randomization and Blinding

3.8.1 Randomization

3.8.2 Blinding/Unblinding

3.8.3 Data Monitoring Committee

3.9. Drugs Used in the Study

3.9.1. Investigational Product

3.9.2 Placebo

3.10. Drug Supply and Accountability

3.10.1. Drug Storage and Security

3.10.2. Drug Accountability

3.11. Duration of Patient Participation and Justification

3.12. Stopping Rules and Discontinuation Criteria

3.13. Source Data Recorded on the Case Report Form

3.14. Study Procedures

3.14.1. Procedures for Screening (Visit 1[Day -28])

• Obtain written informed consent before any other study-related procedures are performed.
• Record demographic characteristic including race.
• Review inclusion/exclusion criteria.
• Review medical and psychiatric history.
• Review medication history.
• Perform vital signs measurements (includes systolic and diastolic blood pressure, pulse, body temperature, and respiratory rate).
• Perform triplicate 12-lead ECGs.
• Perform a physical examination, including height and weight. Body mass index will be calculated from the screening height and weight.
• Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis).
• Perform serum -HCG test (women of childbearing potential only).
• Perform FSH test (postmenopausal women only).

3.14.2. Procedures Before Study Drug Treatment

3.14.2.1. 28-Day Run-In Period (Days - 28 Through -1)

3.14.2.2. Baseline (Visit 2 [Day 0 ( Days)])

• Review inclusion/exclusion criteria.
• Review headache diary.
• Review study compliance.
• Perform vital signs measurements (includes systolic and diastolic blood pressure, pulse, body temperature, and respiratory rate).
• Perform triplicate 12-lead ECGs.
• Perform a physical examination (including weight).
• Inquire about adverse events.
• Inquire about/review concomitant medications.
• Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis).
• Perform urine test (women of childbearing potential only).
• Obtain a blood sample for plasma TEV-48125 concentration determination.
• Obtain a blood sample for serum ADA assessment.
• Obtain a urine sample for biomarker analysis.
• Obtain an blood sample ( 6 mL each for serum and plasma and 6.5 mL for ribonucleic acid [RNA]) for serum, plasma, and RNA biomarker analysis.
• Complete the eC-SSRS Baseline/Screening version.
• Administer the MIDAS questionnaire, MSQOL questionnaire, EQ-5D-5L questionnaire, WPAI questionnaire, and PHQ-2/PHQ-9 (Note: Patients will respond first to the PHQ-2. They will respond to questions 3 through 9 [unique questions] of the PHQ-9 only if the PHQ-2 is positive.)
  In addition, a blood sample for pharmacogenomics (deoxyribonucleic acid [DNA]) may be obtained from patients who consent to pharmacogenomics analysis.

3.14.3. Procedures During Study Drug Treatment

3.14.3.1. Double-Blind Treatment Period (Visits 2 Through 5 [Day 0 Through Day 84 Days])

3.14.3.1.1. Visit 2 (Day 0 [ Days]/Dose 1)

• Perform local injection site assessment immediately and 1 hour after study drug administration. Additional assessments may be performed based on the severity of any observed injection site reaction. See Section 7.9 for additional details.
• Inquire about postdose adverse events before the patient leaves the study center.

3.14.3.1.2. Visits 3 and 4 (Day Days]/Dose 2 and Day Days]/Dose 3)

• Review headache diary.
• Review study compliance.
• Perform vital signs measurements (includes systolic and diastolic blood pressure, pulse, body temperature, and respiratory rate).
• Inquire about adverse events.
• Inquire about/review concomitant medications.
• Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis).
• Perform urine -HCG test (women of childbearing potential only).
• Obtain a blood sample for plasma TEV-48125 concentration determination.
• Obtain a blood sample for serum ADA assessment (visit 3 only).
• Obtain a urine sample for biomarker analysis (visit 4 only).
• Obtain an blood sample ( 6 mL each for serum and plasma and 6.5 mL for RNA) for serum, plasma, and RNA biomarker analysis (visit 4 only).
• Complete the eC-SSRS Since Last Visit version.
• Administer the MSQOL questionnaire and the PGIC scale.

• Perform local injection site assessment immediately and 1 hour after study drug administration. Additional assessments may be performed based on the severity of any observed injection site reaction. See Section 7.9 for additional details.
• Inquire about postdose adverse events before the patient leaves the study center.

3.14.3.1.3. End-of-Treatment Visit (Visit 5 [Day 84 ( Days)])

• Review headache diary. (Note: Patients will return the electronic headache diary device at the EOT visit.)
• Review study compliance.
• Perform vital signs measurements (includes systolic and diastolic blood pressure, pulse, body temperature, and respiratory rate).
• Perform triplicate 12-lead ECGs.
• Perform physical examination (including weight).
• Inquire about adverse events.
• Inquire about/review concomitant medications.
• Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis).
• Perform a urine -HCG test (women of childbearing potential only).
• Obtain a 4 -mL blood sample for plasma TEV-48125 concentration determination.
• Obtain a blood sample for serum ADA assessment.
• Obtain a urine sample for biomarker analysis.
• Obtain an blood sample ( 6 mL each for serum and plasma and 6.5 mL for RNA) for serum, plasma, and RNA biomarker analysis.
• Complete eC-SSRS Since Last Visit version.
• Administer the MIDAS questionnaire, MSQOL questionnaire, EQ-5D-5L questionnaire, PGIC scale, WPAI questionnaire, and PHQ-2/PHQ-9. (Note: Patients will respond first to the PHQ-2. They will respond to questions 3 through 9 [unique questions] of the PHQ-9 only if the PHQ-2 is positive.)
  In addition, a single blood sample for pharmacogenomics (DNA) may be obtained from patients who consent to pharmacogenomics analysis if the sample is not obtained at an earlier visit.

3.14.4. Procedures After Study Drug Treatment

3.14.5. Unscheduled Visits

• Review headache diary.
• Review study compliance.
• Perform vital signs measurements (including systolic and diastolic blood pressure, pulse, body temperature, and respiratory rate).
• Inquire about adverse events.
• Inquire about/review concomitant medications.

4. SELECTION AND WITHDRAWAL OF PATIENTS

4.1. Patient Inclusion Criteria

• headache occurring on and days
• on days, fulfilling any of the following:
• ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura (Appendix D)
• ICHD-3 criteria B and C for 1.2 Migraine with aura (Appendix D)
• Probable migraine (a migraine subtype where only 1 migraine criterion is missing)
• The patient used a triptan or ergot derivative to treat an established headache.
  e. Not using preventive medications (presented in Appendix B) (ie, at least 5 half-lives have passed since last use) or using no more than 1 preventive medication (presented in Appendix A) for migraine or other medical conditions (eg, propranolol used for hypertension) if the dose and regimen have been stable for at least 2 months prior to beginning the 28-day run-in period.
  f. Body mass index of 17.5 to and a total body weight between 45 and 120 kg , inclusive
  g. All patients must be of nonchildbearing potential, defined as:
• women surgically sterile by documented complete hysterectomy, bilateral oophorectomy, or bitubal ligations or confirmed to be postmenopausal (at least 1 year since last menses and follicle-stimulating hormone [FSH] above )
• men surgically sterile by documented vasectomy
  or
  if of childbearing potential, patients must meet any of the following criteria:
• Patients must simultaneously use 2 forms of highly effective contraception methods (defined in Section 5.2) with their partners during the entire study period and for 7.5 months after the last dose of study drug.
• Sexual abstinence is only considered a highly effective method if defined as refraining from heterosexual intercourse in the defined period. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a study, and withdrawal are not acceptable methods of contraception.
  h. Female patients of childbearing potential must have a negative serum -HCG pregnancy test at screening (confirmed by urine dipstick -HCG pregnancy test at baseline).
  i. The patient demonstrated compliance with the electronic headache diary during the run-in period by entry of headache data on a minimum of 24 out of 28 days ( diary compliance).
  j. The patient is in good health as determined by a medical and psychiatric history, medical examination, 12-lead ECG, serum chemistry, hematology, coagulation, and urinalysis.
  k. The patient must be willing and able to comply with study restrictions, to remain at the clinic for the required duration during the study period, and to return to the clinic for the follow-up evaluation as specified in this protocol.

4.2. Patient Exclusion Criteria

• cluster A: divalproex sodium and sodium valproate
• cluster B: flunarizine and pizotifen
• cluster C : amitriptyline, nortriptyline, venlafaxine, and duloxetine
• cluster D : atenolol, nadolol, metoprolol, propranolol, and timolol
  d. Patient has used an intervention/device (eg, scheduled nerve blocks and transcranial magnetic stimulation) for migraine during the last 2 months prior to screening
  e. Clinically significant hematological, cardiac, renal, endocrine, pulmonary, gastrointestinal, genitourinary, neurologic, hepatic, or ocular disease, at the discretion of the investigator
  f. Evidence or medical history of clinically significant psychiatric issues, including any suicide attempt in the past, or suicidal ideation with a specific plan in the past 2 years
  g. History of clinically significant cardiovascular disease or vascular ischemia (such as myocardial, neurological [eg, cerebral ischemia], peripheral extremity ischemia, or other ischemic event) or thromboembolic events (arterial or venous thrombotic or embolic events) such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism
  h. Known infection or history of human immunodeficiency virus, tuberculosis, or chronic hepatitis B or C infection
  i. Past or current history of cancer in the past 5 years, except for appropriately treated nonmelanoma skin carcinoma
  j. Pregnant or nursing females
  k. History of hypersensitivity reactions to injected proteins, including monoclonal antibodies

1. Participation in a clinical study of a new chemical entity or a prescription medicine within 2 months before study drug administration or 5 half-lives, whichever is longer
   m. Any prior exposure to a monoclonal antibody targeting the CGRP pathway (AMG 334, ALD304, LY2951742, or TEV-48125)
   n. Any finding in the baseline 12-lead ECG considered clinically significant in the judgment of the investigator
   o. Any finding that, in the judgment of the investigator, is a clinically significant abnormality, including serum chemistry, hematology, coagulation, and urinalysis test values (abnormal tests may be repeated for confirmation)
   p. Hepatic enzymes (ALT, AST, and ALP) more than the upper limit of the normal range (ULN) after confirmation in a repeat test or suspected hepatocellular damage that fulfills criteria for Hy's law at screening
   q. Serum creatinine the ULN, clinically significant proteinuria (urine dipstick +4 ), or evidence of renal disease at screening
   r. History of alcohol or drug abuse during the past 2 years, or alcohol or drug dependence during the past 5 years
   s. The patient cannot participate or successfully complete the study, in the opinion of their healthcare provider or the investigator, for any of the following reasons:

• mentally or legally incapacitated or unable to give consent for any reason
• in custody due to an administrative or a legal decision, under guardianship, or institutionalized
• unable to be contacted in case of emergency
• has any other condition, which, in the opinion of the investigator, makes the patient inappropriate for inclusion in the study
  t. The patient is a study center or sponsor employee who is directly involved in the study or the relative of such an employee

4.3. Justification for Key Inclusion and Exclusion Criteria

4.4. Withdrawal Criteria and Procedures

5. TREATMENT OF PATIENTS

5.1. Drugs Administered During the Study

• Patients randomized to receive monthly TEV-48125 at 225 mg will receive 225 mg of TEV-48125 as 1 active injection ( ) and two placebo injections at visit 2 and 225 mg of TEV-48125 as 1 active injection ( ) at visits 3 and 4.
• Patients randomized to receive TEV-48125 at placebo/placebo will receive 675 mg of TEV-48125 as 3 active injections ( ) at visit 2 and placebo as a single injection at visits 3 and 4 .
• Patients randomized to receive placebo will receive three placebo injections at visit 2 and a single placebo injection at visits 3 and 4 .

5.2 Restrictions

• combined (estrogen and gestagen) oral contraceptives, hormone implants, hormone rings, contraceptive patch, and hormone injectables initiated at least 7 days before study drug administration
• intrauterine device in place for a period of at least 2 months before study drug administration
• barrier methods of contraception: condoms with spermicide for males, diaphragm with spermicide for females, and portio cap with spermicide for females
• vasectomy for male partners of female patients

5.3. Prior and Concomitant Therapy or Medication

5.3.1. Prior Medications and Therapeutic Failures of Migraine Preventives:

5.3.2 Concomitant Therapies and Medications

5.4. Procedures for Monitoring Patient Compliance

5.5. Total Blood Volume

6. ASSESSMENT OF EFFICACY

6.1. Primary Efficacy Measure and Justification

• mild headache
• moderate headache
• severe headache

6.2 Migraine Disability Assessment

6.3. Two-Item Patient Health Questionnaire/9-Item Patient Health Questionnaire

6.4 Migraine-Specific Quality of Life Questionnaire

6.5. EuroQol-5 Dimension Questionnaire

6.6. Patient Global Impression of Change Scale

6.7. Work Productivity and Activity Impairment Questionnaire

7. ASSESSMENT OF SAFETY

7.1. Adverse Events

7.1.1 Definition of an Adverse Event

• intercurrent illnesses
• physical injuries
• events possibly related to concomitant medication
• significant worsening (change in nature, severity, or frequency) of the disease under study or other pre-existing conditions (Note: A condition recorded as pre-existing that is intermittently symptomatic [eg, headache] and that occurs during this study should be recorded as an adverse event.)
• drug interactions
• events occurring during diagnostic procedures of this study or during any follow-up period of this study
• laboratory or diagnostic test abnormalities that result in the withdrawal of the patient from the study, are associated with clinical signs and symptoms or a serious adverse event, require medical treatment or further diagnostic work-up, or are considered by the investigator to be clinically significant (Note: Abnormal laboratory test results at the screening visit that preclude a patient from entering the study or receiving study drug are not considered adverse events.)
• all events of possible drug-induced liver injury with hyperbilirubinemia (defined as AST or ALT times the ULN, plus either total bilirubin times the ULN or INR

1.5) or Hy's Law events require immediate study treatment cessation and reporting as a serious adverse event. Refer to Appendix E for guidance regarding monitoring patients with elevated liver function tests.

7.1.2. Recording and Reporting Adverse Events

7.1.3. Severity of an Adverse Event

7.1.4. Relationship of an Adverse Event to the Study Drug

7.1.5. Serious Adverse Events

7.1.5.1. Definition of a Serious Adverse Event

• death
• a life-threatening adverse event (ie, the patient was at immediate risk of death from the event as it occurs); does not include an event that, had it occurred in a more severe form, might have caused death
• inpatient hospitalization or prolongation of existing hospitalization, which means that hospital inpatient admission and/or prolongation of hospital stay were required for treatment of an adverse event, or that they occurred as a consequence of the event. Hospitalizations scheduled prior to study entry will not be considered serious adverse events, unless there was worsening of the pre-existing condition during the patient's participation in this study
• persistent or significant disability or incapacity (refers to a substantial disruption of one's ability to conduct normal life functions)
• a congenital anomaly/birth defect
• an important medical event that may not result in death, be life-threatening, or require hospitalization, but may jeopardize the patient and may require medical intervention to prevent one of the outcomes listed in this definition. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or the development of drug dependency or drug abuse. Note: Any suspected transmission of an infectious agent via a medicinal product is considered an important medical event.

7.1.5.2. Expectedness

7.1.5.3. Reporting a Serious Adverse Event

7.1.5.3.1. Investigator Responsibility

• study number
• investigator and investigational center identification
• patient number
• onset date and detailed description of adverse event
• investigator's assessment of the relationship of the adverse event to the study drug (no reasonable possibility, reasonable possibility)
  Additional information may include the following:
• age and sex of patient
• date of dose of study drug
• date and amount of last administered dose of study drug
• action taken
• outcome, if known
• severity
• explanation of assessment of relatedness
• concomitant therapy (including doses, routes, and regimens) and treatment of the event
• pertinent laboratory or other diagnostic test data
• medical history
• results of dechallenge/rechallenge, if known
• for an adverse event resulting in death:
• cause of death (whether or not the death is related to study drug)
• autopsy findings (if available)

7.1.5.3.2. Sponsor Responsibility

• altering existing research by modifying the protocol
• discontinuing or suspending the study
• altering the process of informed consent by modifying the existing consent form and informing current study participants of new findings
• modifying listings of expected toxicities to include adverse events newly identified as related to TEV-48125

7.1.6. Protocol-Defined Adverse Events of Special Interest

7.1.7. Withdrawal Due to an Adverse Event

7.1.8. Overdose of Study Drug

7.1.9 Protocol Deviations Because of an Adverse Event

7.2. Pregnancy

• For a spontaneous abortion, report as a serious adverse event.
• For an elective abortion due to developmental anomalies, report as a serious adverse event.
• For an elective abortion not due to developmental anomalies, report on the pregnancy form; do not report as an adverse event.

7.3 Clinical Laboratory Tests

• abnormal but not a clinically significant worsening from baseline
• abnormal and a clinically significant worsening from baseline

7.3.1. Serum Chemistry

• calcium
• phosphorus
• sodium
• potassium
• chloride
• carbon dioxide
• magnesium
• glucose
• blood urea nitrogen
• creatinine
• ALT
• AST
• total bilirubin
• direct bilirubin
• indirect bilirubin (calculated)
• lactate dehydrogenase
• GGT
• ALP
• albumin
• creatine phosphokinase
• total protein

7.3.2. Hematology

• hemoglobin
• hematocrit
• red blood cell (RBC) count

• RBC indices
• mean corpuscular volume
• mean corpuscular hemoglobin concentration
• RBC distribution width
• platelet count
• white blood cell (WBC) count and differential count (absolute values and percentages)
• neutrophils
• lymphocytes
• eosinophils
• monocytes
• basophils

7.3.3. Coagulation

• prothrombin time
• partial thromboplastin time
• INR

7.3.4. Urinalysis

• color and appearance
• specific gravity
• pH
• blood (hemoglobin)
• glucose
• albumin
• protein
• ketones
• leukocyte esterase
• nitrite
• direct bilirubin

• microscopic
• bacteria
• RBCs
• WBCs
• casts
• crystals

7.3.5. Other Clinical Laboratory Tests

7.3.5.1. Human Chorionic Gonadotropin Tests

7.3.5.2 Follicle-Stimulating Hormone Tests

7.4. Vital Signs

7.5. Electrocardiography

7.6. Physical Examinations

7.7. Electronic Columbia-Suicide Severity Rating Scale

7.8. Concomitant Therapy or Medication

7.9. Immunogenicity

7.10. Injection Site Assessments

• Injection-site erythema, injection-site induration, and injection-site ecchymosis will be graded according to measurements: absent, 5 mm to (mild), to (moderate), and (severe). Induration must be assessed by careful superficial palpation avoiding pressuring or squeezing the injection site.
• Injection-site pain will be measured as summarized in Table 3.

7.11. Methods and Timing of Assessing, Recording, and Analyzing Safety Data

8. ASSESSMENT OF PHARMACOKINETICS/ BIOMARKERS/ IMMUNOGENICITY

8.1 Pharmacokinetic Variables

8.1.1. Specimen Sampling and Handling

8.1.2 Shipment and Analysis of Samples

• Set A samples will be transported (frozen) with a temperature data logger, by next-day courier, to the central laboratory.
• Set B samples will either be sent to the same laboratory as that for set A on a subsequent day, by next-day courier, or be retained at the investigational center until the study is completed and the clinical study report has been issued (unless shipment to another facility is requested by the sponsor).
  Samples will be analyzed using a validated method. Timing of the initiation of sample analysis will be determined by the Teva Pharmaceuticals bioanalytical representative responsible for the bioanalysis. Refer to the laboratory manual for additional details.

8.2 Immunogenicity Testing

8.2.1. Blood Sampling and Handling

8.2.2 Shipment and Analysis of Samples

• Set A samples will be transported (frozen) with a temperature data logger, by next-day courier, to the central laboratory.
• Set B samples will either be sent to the same laboratory as that for set A on a subsequent day, by next-day courier, or be retained at the investigational center until the study is completed and the clinical study report has been issued (unless shipment to another facility is requested by the sponsor).

8.3. Assessment of Exploratory Biofluid Biomarkers

8.3.1. Pharmacogenomic Assessment

8.3.2 Specimen Sampling and Handling

8.3.3. Shipment and Analysis of Samples

8.4 Methods and Timing of Assessing, Recording, and Analyzing Clinical Pharmacology Data

9. STATISTICS

9.1. Sample Size and Power Considerations

9.2 Analysis Sets

9.2.1. Intent-to-Treat Analysis Set

9.2.2 Safety Analysis Set

9.2.3. Full Analysis Set

9.2.4. Additional Analysis Sets

9.3. Data Handling Conventions

9.4. Study Population

9.4.1. Patient Disposition

9.4.2. Demographic and Baseline Characteristics

9.5. Efficacy Analysis

• A calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a headache endorsing criteria for migraine with or without aura
• A calendar day (0:00 to 23:59) demonstrating at least 2 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)

9.5.1 Primary Endpoint

9.5.2 Secondary Endpoints

• proportion of patients reaching at least reduction in the monthly average number of migraine days during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of days of use of any acute headache medications during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the number of migraine days during the 4 -week period after the dose of the study drug
• mean change from baseline (28-day run-in period) in the monthly average number of migraine days during the 12 -week period after the dose of study drug in patients not receiving concomitant migraine preventive medications
• mean change from baseline (day 0 ) in disability score, as measured by the MIDAS questionnaire, at 4 weeks after administration of the last dose of study drug

9.5.3. Exploratory Endpoints

• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 12-week period after the dose of study drug
• proportion of patients reaching at least reduction and total ( ) reduction in the monthly average number of migraine days during the 12-week period after the dose of study drug
• proportion of patients reaching at least reduction and at least reduction in the number of migraine days during the 4 -week period after the dose of study drug for whom this level of effect is sustained throughout the 12 -week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of migraine days during the 12 -week period after the dose of study drug in patients who used topiramate for migraine in the past
• mean change from baseline (28-day run-in period) in the number of migraine days during the 12-week period after the dose of study drug for patients who used onabotulinumtoxinA for migraine in the past
• mean change from baseline (28-day run-in period) in the number of migraine days during the 4 -week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the number of migraine days during the 4 -week period after the last dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of headache days of any severity during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 4-week period after each dose of study drug
• proportion of patients reaching at least reduction, at least reduction, and total (100%) reduction in the monthly average number of headache days of at least moderate severity during the 12-week period after the 1st dose of study drug
• proportion of patients reaching at least reduction and at least reduction in the number of headache days of at least moderate severity during the 4-week period after the dose of study drug for whom this level of effect is sustained throughout the 12 -week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 12-week period after the dose of study drug for patients not receiving concomitant preventive migraine medications
• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 12 -week period after the dose of study drug for patients who used topiramate for migraine in the past
• mean change from baseline (28-day run-in period) in the number of headache days of at least moderate severity during the 12 -week period after the dose of study drug for patients who used onabotulinumtoxinA for migraine in the past
• mean change from baseline (28-day run-in period) in the monthly average number of headache hours of any severity during the 12 -week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of headache hours of at least moderate severity during the 12-week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of days of use of migraine-specific acute headache medications (triptans and ergot compounds) during the 12 -week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of days with nausea or vomiting during the 12 -week period after the dose of study drug
• mean change from baseline (28-day run-in period) in the monthly average number of days with photophobia and phonophobia during the 12-week period after the dose of study drug
• mean change from baseline (day 0 ) in quality of life, as measured by the MSQOL questionnaire, at 4 weeks after administration of the last ( ) dose of study drug
• mean change from baseline (day 0 ) in the health status, as measured by the EQ-5D-5L questionnaire at 4 weeks after administration of the last ( ) dose of study drug
• mean change from baseline (day 0 ) in patient depression status, as measured by the PHQ-2 and PHQ-9, at 4 weeks after administration of the last ( ) dose of study drug