| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| episodic and chronic migraine |
|
| E.1.1.1 | Medical condition in easily understood language |
| episodic and chronic migraine |
|
| 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 |
|
| 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 |
| The primary objective of the study is to demonstrate the efficacy of Fremanezumab administered as monthly and quarterly subcutaneous (sc) injections to adult patients with migraine with inadequate response to 2 to 4 classes of prior preventive treatments as compared with placebo |
|
| E.2.2 | Secondary objectives of the trial |
A secondary objective of the study is to further evaluate the efficacy of Fremanezumab administered as monthly and quarterly sc injections to adult patients with migraine with inadequate response to 2 to 4 classes of prior preventive treatments as compared with placebo.
A further secondary objective of the study is to evaluate the safety and tolerability of fremanezumab administered as monthly and quarterly sc injections to adult patients with migraine with inadequate response to 2 to 4 classes of prior preventive treatments as compared with placebo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a. The patient is capable of giving signed informed consent
b. Male or female patient aged 18 to 70 years, inclusive.
c. The patient has a diagnosis of migraine with onset at ≤50 years of age.
d. The patient is in good health in the opinion of the investigators as determined by medical history, physical examination, laboratory tests, and ECG.
e. Body weight greater than 45 kg and body mass index (BMI) within the range 17.5 to 34.9 kg/m2 (inclusive).
f. The patient has a history of migraine (according to ICHD-3 criteria [IHS 2013]) or clinical judgment suggests a migraine diagnosis (not better accounted for by another ICHD-3 diagnosis) for ≥12 months prior to screening.
g. The patient fulfills the following criteria for CM or EM in prospectively collected baseline information during the 28-day run-in period:
For patients with CM:
- Headache occurring on ≥15 days
- On ≥8 days, fulfilling any of the following:
○ ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura
○ ICHD-3 criteria B and C for 1.2 Migraine with aura
○ 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
For patients with EM:
-Headache occurring on ≥6 days but <15
-On ≥4 days, fulfilling any of the following:
○ ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura
○ ICHD-3 criteria B and C for 1.2 Migraine with aura
○ 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
h. At the time of screening, the patient must have documented inadequate response to 2 to 4 classes of prior preventive migraine medications (as defined in Appendix H) within the past 10 years (in medical chart or by treating physician’s confirmation; see Appendix I for acceptable documentation of previous treatment failure). Inadequate response to prior preventive migraine medications (including valproic acid) is defined as: no clinically meaningful improvement per treating physician’s judgment, after at
least 3 months of therapy at a stable dose considered appropriate for migraine prevention according to accepted country guidelines, or when treatment has to be interrupted because of adverse events that made it intolerable for the patient, or the medication (as defined in Appendix H) is contraindicated or unsuitable for the prophylactic treatment of migraine for the patient. The 3- month period does not apply if the drug is intolerable or contraindicated. If onabotulinumtoxinA is the previous preventive medication, at least 2 sets of injections and 3 months must have
passed since the last set of injections prior to the screening visit.
i. The patient agrees not to initiate any preventive migraine medications (as defined in Appendix H) during the run-in period double-blind treatment periodand open-label period. At the screening visit, at least 5 half-lives of these medications must have passed since the patient has been on any migraine preventive medication as defined in Appendix H.
j. Other prescription medications not in Appendix H must have been on stable doses for at least 2 months at the screening visit with no expectation to change during the double-blind treatment period of the study.
k. The patient demonstrated compliance with the electronic headache diary during the run-in period by entry of headache data on a minimum of 24 days cumulative during the run-in period (~85% diary compliance).
l. Women may be included only if they have a negative serum beta-human chorionic gonadotropin (β-HCG) test at screening, are sterile, or postmenopausal. Definitions of sterile and postmenopausal are given in Appendix E.
m. Women of childbearing potential (WOCBP) whose male partners are potentially fertile (ie, no vasectomy) must use highly effective birth control methods for the duration of the study and the follow-up period (ie, starting at screening) and for 6.0 months after discontinuation of IMP (for details of WOCBP, sterile, and
postmenopausal women, see Appendix E).
n. Men must be sterile, or if they are potentially fertile/reproductively competent (not surgically [eg, vasectomy] or congenitally sterile) and their female partners are of childbearing potential, must use, together with their female partners, acceptable birth control methods for the duration of the study and for 6.0 months after discontinuation of the IMP.
o. 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 evaluations, as specified in this protocol.
|
|
| E.4 | Principal exclusion criteria |
a. At time of screening visit, patient is receiving any preventive migraine medications, regardless of the medical indication (as defined in Appendix H) for more than 5 days and expects to continue with these medications
b. Patient has received onabotulinumtoxinA for migraine or for any medical or cosmetic reasons requiring injections in the head, face, or neck during the 3 months before screening visit
c. Patient uses medications containing opioids (including codeine) or barbiturates (including butalbital/aspirin/caffeine [Fiorinal®, Actavis plc], butalbital/paracetamol/caffeine [Fioricet®, Cardinal Health], or any other combination containing butalbital) on more than 4 days during the run-in period for the treatment of migraine or for any other reason
d. Patient has used an intervention/device (eg, scheduled nerve blocks and transcranial magnetic stimulation) for migraine during the 2 months prior to screening
e. Patient uses triptans/ergots as preventive therapies for migraine
f. Patient uses non-steroidal anti-inflammatory drugs (NSAIDs) as preventive therapy for migraine on nearly daily basis for other indications. Note: Low dose aspirin (eg, 81 mg) used for cardiovascular disease prevention is allowed
g. 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 patient has headaches 80% or less of the time he/she is awake on most days
h. Patient has a clinically significant hematological, cardiac, renal, endocrine, pulmonary, gastrointestinal, genitourinary, neurologic, hepatic, or ocular disease that, in opinion of investigator, could jeopardize or would compromise the patient’s ability to participate in this study
i. Evidence or medical history of clinically significant psychiatric issues that, in opinion of investigator, could jeopardize or would compromise patient’s ability to participate in this study including major depression, panic disorder, or generalized anxiety disorder, any suicide attempt in the past or suicidal ideation with a specific plan the past two years prior to screening or current suicidal ideation as measured by eC-SSRS
j. History of clinically significant cardiovascular disease or vascular ischemia (such as myocardial, neurological [e.g., 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
k. History of human immunodeficiency virus, tuberculosis, or chronic hepatitis B or C infection
l. Past or current history of cancer, except for appropriately treated non-melanoma skin carcinoma in last 5 years
m. Pregnant or lactating female patients or female patients who plan to become pregnant during the study
n. Participation in clinical study of a new chemical entity or a prescription medicine within 2 months before screening (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 medical device)
o. Any prior exposure to a monoclonal antibody targeting the CGRP pathway (such as AMG 334, ALD304, LY2951742, or fremanezumab)
p. Any finding in the baseline 12-lead ECG considered clinically significant in the judgment of the investigator
q. Any finding that, in 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)
r. Hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) >1.5 × the upper limit of the normal (ULN) range after confirmation in a repeat test or suspected hepatocellular damage that fulfills criteria for Hy’s law at screening
s. Serum creatinine >1.5 × the ULN, clinically significant proteinuria, or evidence of renal disease at screening
t. Patient has history of alcohol abuse during 2 years prior to screening
u. Patient has history of drug abuse during past 2 years or drug dependence during past 5 years
v. Patient cannot participate or successfully complete study, in opinion of their healthcare provider or 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 tutelage, or being admitted to a sanitarium or 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 study
w. Patient is a study center or sponsor employee who is directly involved in study or the relative of such an employee
x. Patient has been previously screen failed for study |
|
| 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 migraine days during the 12-week period after the 1st dose
of fremanezumab |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Final study assessments will be performed at visit 8 (end-of-treatment
[EOT] visit), approximately 4 weeks after administration of last dose of fremanezumab. |
|
| E.5.2 | Secondary end point(s) |
- proportion of patients reaching at least 50% reduction in the monthly average number of migraine days during the 12-week period after the
1st dose of fremanezumab
- 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 fremanezumab
- mean change from baseline (28-day run-in period) in the monthly average number of migraine days during the 4-week period after the 1st dose of
fremanezumab
-proportion of patients reaching at least 50% reduction in the monthly average number of migraine days during the 4-week period after the
1st dose of fremanezumab
- 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 fremanezumab
- 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 fremanezumab
-occurrence of adverse events throughout the study
-clinical laboratory (serum chemistry, hematology, coagulation and urinalysis) test results at specified time points
-vital signs (systolic and diastolic blood pressure, oral temperature, and pulse rate) measurements at each visit. Note: In addition, oxygen saturation and respiratory rate will be measured in cases of suspected anaphylaxis and severe hypersensitivity
-12-lead ECG findings at specified time points
-use of concomitant medication for adverse events during the study
-number (%) of patients who did not complete the
study due to adverse events
-clinically significant changes in physical examinations, including body weight
-occurrence of severe hypersensitivity/anaphylaxis reactions
-suicidal ideations and behaviors as measured by the eC-SSRS |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Final study assessments will be performed at visit 8 (end-of-treatment
[EOT] visit), approximately 4 weeks after administration of last dose of fremanezumab. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| a 12-week double-blind, placebo-controlled treatment period followed by a 12-week open-label period |
|
| 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 | 6 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 93 |
| 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 |
| Belgium |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| 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
|
|
| 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 | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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