E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066636 |
E.1.2 | Term | Chronic migraine |
E.1.2 | System Organ Class | 100000004852 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• to demonstrate the efficacy of 2 dose regimens 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 1st dose of study drug relative to the baseline period • to evaluate the safety and tolerability of 2 dose regimens of TEV-48125 in the preventive treatment of CM |
|
E.2.2 | Secondary objectives of the trial |
• reduction of monthly average #migraine days during 12wk period after 1st dose relative to baseline • evaluate proportion of patients reaching at least 50% reduction in monthly average # headache days of at least moderate severity during 12wk period after 1st dose relative to baseline • reduction in monthly average # of days of use of any acute headache medications during 12wk period after 1st dose relative to baseline • reduction of the # of headache days of at least moderate severity during 4wk period after 1st dose relative to baseline • reduction in monthly average # of headache days of at least moderate severity during the 12-wk period after 1st dose relative to baseline in patients not receiving concomitant migraine preventive medications at baseline • reduction of migraine related disability measured by HIT-6, at 4wks after last (3rd) dose relative to baseline • immunogenicity and impact of ADAs on efficacy and safety during 12wks of treatment |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a. Males or females aged 18 to 70 years, inclusive, with migraine onset at ≤50 years of age b. Patient signs and dates the informed consent document c. Patient has history of migraine (according to International Classification of Headache Disorders, 3rd revision [ICHD-3] criteria [Classification Committee of the IHS, 2013]) or clinical judgment suggests a migraine diagnosis (not better accounted for by another ICHD-3 diagnosis) for ≥12 months prior to screening d. Patient fulfills the following criteria for CM in prospectively collected baseline information during the 28-day run-in period: - headache occurring on ≥15 days - on ≥8 days, fulfilling any of the following: o ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura o ICHD-3 criteria B and C for 1.2 Migraine with aura o Probable migraine (a migraine subtype where only 1 migraine criterion is missing) o The patient used a triptan or ergot derivative to treat established headache. e. Not using preventive medications (ie, at least 5 half-lives have passed since last use) or using no more than 1 preventive medication 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 37.5 kg/m2 and a total body weight between 45 and 120 kg, inclusive g. All patients must be of nonchild bearing 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 35 U/L) - 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 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 beta-human chorionic gonadotropin (β-HCG) pregnancy test at screening (confirmed by urine dipstick β-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 (~85% 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. |
|
E.4 | Principal exclusion criteria |
a. Patient has received onabotulinumtoxinA for migraine or for any medical or cosmetic reasons requiring injections in the head, face, or neck during the 4 months before screening. b. Patient is using medications containing opioids (including codeine) or barbiturates (including butalbital/aspirin/caffeine, butalbital/paracetamol/caffeine, or any other combination containing butalbital) on more than 4 days per month for the treatment of migraine or for any other reason. c. Patients who have previously failed (lack of efficacy) 2 or more of the clusters of the following medications for treatment of episodic migraine (EM) or CM after adequate therapeutic trial defined as use for at least 3 months at accepted migraine therapeutic doses: - 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. Patient suffers from unremitting headaches, defined as having headaches for more than 80% of the time he/she is awake, and less than 4 days without headache per month. Daily headache is acceptable if patients have headaches 80% or less of the time they are awake on most days. f. Clinically significant hematological, cardiac, renal, endocrine, pulmonary, gastrointestinal, genitourinary, neurologic, hepatic, or ocular disease, at the discretion of the investigator g. 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 h. 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 i. Known infection or history of human immunodeficiency virus, tuberculosis, or chronic hepatitis B or C infection j. Past or current history of cancer in the past 5 years, except for appropriately treated nonmelanoma skin carcinoma k. Pregnant or nursing females l. History of hypersensitivity reactions to injected proteins, including monoclonal antibodies m. Participation in a clinical study of a new chemical entity or a prescription medicine within 2 months prior to study drug administration or 5 half-lives, whichever is longer n. Any prior exposure to a monoclonal antibody targeting the CGRP pathway (AMG 334, ALD304, LY2951742, or TEV-48125) o. Any finding in the baseline 12-lead ECG considered clinically significant in the judgment of the investigator p. 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) q. Hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) >1.5× 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 r. Serum creatinine >1.5× ULN, clinically significant proteinuria, or evidence of renal disease at screening s. History of alcohol or drug abuse during the past 2 years or alcohol or drug dependence during the past 5 years t. 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 u. The patient is a study center or sponsor employee who is directly involved in the study or the relative of such an employee. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the mean change from baseline (28-day run-in period) 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. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
During the 12 week period after the 1st dose of study drug. |
|
E.5.2 | Secondary end point(s) |
•mean change from baseline (28-day run-in period) in the monthly average number of migraine days during the 12-week period after the 1st dose of study drug •proportion of patients reaching at least 50% 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 •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 1st 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 the 1st dose of study drug •mean change from baseline (28-day run-in period) 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 in patients not receiving concomitant migraine preventive medications •mean change from baseline (day 0) in disability score, as measured by the HIT-6 at 4 weeks after administration of the last (3rd) dose of study drug |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
During the 12 week period after the 1st dose of study drug for secondary endpoints in bullets 1, 2, 3 & 5 During the 4-week period after the 1st dose of study drug for secondary endpoint in bullet 4 4 weeks after administration of the last (3rd) dose of study drug for secondary endpoint in bullet 6 |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Czech Republic |
Germany |
Israel |
Japan |
Poland |
Russian Federation |
Spain |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the study is defined as the date the last patient attends the EOT/early withdrawal visit. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |