E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Migraine and major depressive disorder (MDD) |
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E.1.1.1 | Medical condition in easily understood language |
Migraine and major depressive disorder (MDD) |
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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 | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10027603 |
E.1.2 | Term | Migraine headaches |
E.1.2 | System Organ Class | 100000004852 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025453 |
E.1.2 | Term | Major depressive disorder NOS |
E.1.2 | System Organ Class | 100000004873 |
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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 evaluate the efficacy of monthly 225 mg sc fremanezumab in adult patients with migraine and MDD |
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E.2.2 | Secondary objectives of the trial |
-To evaluate the efficacy of monthly 225 mg sc of fremanezumab in adult patients with migraine and MDD on the reduction of MDD symptoms -To evaluate the efficacy of monthly 225 mg sc fremanezumab in adult patients with migraine and MDD in terms of responder rates in monthly migraine days -To evaluate the efficacy of monthly 225 mg sc fremanezumab in adult patients with migraine and MDD in terms of improving quality of life -To evaluate the efficacy of monthly 225 mg sc fremanezumab in adult patients with migraine and MDD in terms of improving disability -To evaluate the safety and tolerability of monthly 225 mg sc and quarterly 675 mg sc fremanezumab in adult patients with migraine and MDD |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a. The patient is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in this protocol. b. The patient is male or female and 18 to 70 years of age, inclusive. c. The patient has a diagnosis of migraine with onset at ≤50 years of age. d. Prior to the screening visit (V1), the patient has a 12-month history of either: -migraine (according to ICHD-3 criteria) or -headache consistent with migraine (ie, migraine diagnosis not better accounted for by another ICHD-3 diagnosis) e. The patient fulfills the following criteria for migraine in a prospectively collected diary during the 28-day baseline period: -on ≥4 days, headache attacks qualified as migraine based on the following ICHD-3 criteria: -ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura -headache has at least 2 of the following 4 characteristics: unilateral location; pulsating quality; moderate or severe pain intensity; and aggravation by, or causing avoidance of, routine physical activity (eg, walking or climbing stairs) -during headache, at least one of the following: nausea and/or vomiting; photophobia and phonophobia -ICHD-3 criteria B and C for 1.2 Migraine with aura -1 or more of the following fully reversible aura symptoms: visual, sensory, speech and/or language, motor, brainstem, retinal -at least 2 of the following 4 characteristics: at least 1 aura symptom spreads gradually over ≥5 minutes, and/or 2 or more symptoms occur in succession; each individual aura symptom lasts 5 to 60 minutes; at least 1 aura symptom is unilateral; the aura is accompanied, or followed within 60 minutes, by headache not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack has been excluded -probable migraine (a migraine subtype where only 1 migraine criterion is missing) -triptan or ergot derivative used to treat an established headache. f. The patient agrees not to initiate any migraine preventive medications during the study. Up to 30% of patients, however, may take a single such medication previously prescribed for the treatment of migraine. g. The patient has a history of MDD according to the DSM-V criteria at least 12 months prior to the screening visit (V1). Patients may take a single medication prescribed for the treatment of depression as long as the dose of that medication has been stable for at least 8 weeks prior to the screening visit (V1) and expects to remain at the stable dose throughout the study. h. The patient has a PHQ-9 score of at least 10 at the screening visit (V1). i. The patient has a Mini Mental State Examination score of at least 26 points at the screening visit (V1). j. The patient is in good health in the opinion of the investigator as determined by medical evaluation, including medical and psychiatric history, physical examination, laboratory tests, and cardiac monitoring. k. The patient has a body weight >-45 kg and a body mass index within the range of 17.5 to 34.9 kg/m2, inclusive. l. The patient demonstrated compliance with the electronic headache diary during the 28-day baseline period by entry of headache data on a minimum of 24 days cumulative during the 28-day baseline period (~75% diary compliance). m. Women may be included only if they have a negative serum beta-human chorionic gonadotropin test at the screening visit (V1), are sterile or postmenopausal, and are not lactating (not applicable for patients participating in safety follow-up only). n. Women of child-bearing potential whose male partners are potentially fertile (ie, no vasectomy) must use highly effective birth control methods for the duration of the study and for 6 months after discontinuation of IMP. o. Men must be sterile or, if they are potentially fertile/reproductively competent (not congenitally sterile) and their female partners are of child-bearing potential, must use a condom for the duration of the study and for 6 months after discontinuation of IMP. For the purpose of this study, vasectomized men must use a condom if their partners are of child-bearing potential. p. The patient must be willing and able to comply with study restrictions, to remain at the clinic for the required duration during the study, and to return to the clinic for the follow-up evaluations, as specified in this protocol.
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E.4 | Principal exclusion criteria |
a. The patient uses medications containing opioids (incl. codeine) or barbiturates (incl. butalbital/aspirin/caffeine, butalbital/paracetamol/caffeine, or any other combination containing butalbital) on more than 4 days during the 28-day baseline period for the treatment of migraine or for any other reason. b. The patient has failed 4 or more different medication classes to treat depression. c. If in the clinical judgment of the investigator/qualified psychiatrist, the patient’s antidepressant medication needs to be changed or dose-adjusted during the 28-day baseline period. d. The patient has used an intervention/device for migraine/depression at any time. e. The patient has used electroconvulsive therapy at any time. f. The patient suffers from constant/nearly constant headache, 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 patient has headaches 80% or less of the time he/she is awake on most days. g. The patient has clinically significant disease (e.g. hematological, cardiac, renal, endocrine, pulmonary etc.), at the discretion of the investigator. h. The patient has evidence/medical history of other clinically significant psychiatric issues that, in the opinion of the investigator, could jeopardize or would compromise the patient’s ability to participate in this study incl. panic/bipolar disorder, schizophrenia, any suicide attempt in the past, suicidal ideation, or other psychoactive spectrum disorders incl. schizoaffective/delusional disorder, depression with psychotic features, and catatonic disorder in the past 6 months. i. The patient has a history of clinically significant cardiovascular disease/vascular ischemia or thromboembolic events (arterial/venous thrombotic/embolic events), e.g. cerebrovascular accident (incl. transient ischemic attacks), deep vein thrombosis, or pulmonary embolism. j. The patient has a known infection/history of HIV, tuberculosis, any history of Lyme disease, or chronic hepatitis B/C infection. k. The patient has a past/current history of cancer, except for appropriately treated non-melanoma skin carcinoma. l. The patient is a pregnant/nursing female or plans to become pregnant during the study, incl. the 6-month period after the administration of the last dose. m. The patient has a history of hypersensitivity reactions to injected proteins, incl. monoclonal antibodies. n. The patient has participated in a clinical study of a new chemical entity or a prescription medicine within 2 months of the screening visit (V1) or 3 months in case of biologics if the half-life of the biologics is unknown or 5 half-lives, whichever is longer, or is currently participating in another study of an IMP (or a medical device). o. The patient has failed treatment with any monoclonal antibodies targeting the CGRP pathway or have taken the medications within 5 half-lives of the screening visit or take them during the study. p. The patient has any finding in the baseline 12-lead electrocardiogram considered clinically significant in the judgment of the investigator. q. The patient has any finding that, in the judgment of the investigator, is a clinically significant abnormality, incl. serum chemistry, hematology, coagulation, and urinalysis test values. r. The patient has hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) >1.5 × the upper limit of the normal range after confirmation in a repeat test or suspected hepatocellular damage that fulfills the criteria for Hy’s law at the screening visit. s. The patient has serum creatinine >1.5 × the upper limit of normal range, clinically significant proteinuria, or evidence of renal disease at the screening visit. t. The patient has any clinically significant uncontrolled medical condition (treated/ untreated). u. The patient has a history of alcohol/drug abuse in the opinion of the investigator v. The patient cannot participate/successfully complete the study, in the opinion of their healthcare provider/investigator, for reasons as: -mentally/legally incapacitated or unable to give consent -in custody due to an administrative/a legal decision, under tutelage, or being admitted to a sanitarium/social institution -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 w. The patient is a study center/sponsor employee who is directly involved in the study or the relative of such an employee. x. The patient has any disorder that may interfere with the absorption, distribution, metabolism, or excretion of IMP. y. The patient is vulnerable. z. The patient previously participated in this study. aa. The patient has evidence/medical history of psychotic symptoms as per DSM-V criteria such as delusions, hallucinations, or disorganized speech in the past 1 month. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Mean change in the monthly average number of migraine days from the 28-day baseline period during the 12-week period after the first dose of study drug |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 weeks after the first dose of study drug |
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E.5.2 | Secondary end point(s) |
Efficacy: -Mean change in depression symptoms from randomization visit (day 1) to week 8 after the first dose of study drug as measured by HAM-D 17 -Number of patients with 50% or more reduction from the 28-day baseline period until 12 weeks after the first dose of study drug, in the monthly average number of migraine days -Mean change in quality of life from randomization visit (day 1) to week 12 after the first dose of study drug as measured by the MSQoL questionnaire, role functionrestrictive and role function-preventive domains -Mean change from randomization visit (day 1) in disability score for overall impact, as measured by CGI-S and HIT-6, to the following time points after administration of the first dose of study drug: -weeks 4 and 8 (CGI-S) -week 12 (CGI-S and HIT-6)
Safety and tolerability: -occurrence of adverse events throughout the study -changes from randomization visit (day 1) in vital signs (pulse, systolic and diastolic blood pressure, body temperature, and respiratory rate) measurements -abnormal physical examination findings including body weight -use of concomitant medication for adverse events during the study -number (%) of patients who did not complete the study due to adverse events -occurrence of severe hypersensitivity/anaphylaxis reactions -suicidal ideation and behavior as suggested by eC-SSRS |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: -Mean change in depression symptoms: week 8 after the first dose of study drug -Number of patients with 50% or more reduction in the monthly average number of migraine days: 12 weeks after the first dose of study drug -Mean change in quality of life: week 12 after the first dose of study drug -Mean change in disability score for overall impact after administration of the first dose of study drug: weeks 4 and 8 (CGI-S), week 12 (CGI-S and HIT-6)
Safety and tolerability: throughout the study
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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 | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
The 12-week double-blind treatment phase is followed by a 12-week open-label extension phase |
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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 | 2 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
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 |
Czech Republic |
Finland |
France |
Germany |
Greece |
Israel |
Italy |
Poland |
Russian Federation |
Spain |
Ukraine |
United Kingdom |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |