| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Episodic Cluster headache (ECH) |
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| E.1.1.1 | Medical condition in easily understood language |
| Episodic Cluster headache (ECH) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| 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 this study is to demonstrate the efficacy of fremanezumab in the prevention of episodic cluster headache (ECH) in adult patients.
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| E.2.2 | Secondary objectives of the trial |
A secondary objectives of this study are
1. to further demonstrate the efficacy of fremanezumab in the prevention of ECH in adult patients.
2. to evaluate the safety of fremanezumab in adult patients with ECH. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a.Patients are capable of giving signed informed consent as described in Appendix D which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
b.The patient is a man or woman 18 to 70 years of age, inclusive.
c.The patient has a history of ECH according to ICHD-3 beta criteria (Headache Classification Committee of the IHS 2013) for ≥12 months prior to screening including the following:
-Attacks of severe, strictly unilateral pain which is orbital, supraorbital, temporal or in any combination of these sites, lasting 15 to 180 minutes and occurring from once daily every other day to 8 times a day for more than half of the time when the disorder is active
-The pain is associated with at least 1 of the following symptoms or signs: ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, forehead and facial sweating, miosis and/or ptosis and/or eyelid oedema, and/or sense of restlessness or agitation.
-CH attacks occurring in periods lasting from 7 days to 1 year, separated by pain-free periods lasting at least 1 month.
-CH attacks have started no more than 2 weeks (15 days, inclusive) prior to screening and, based on the patient’s previous medical history, it is expected that the patient’s CH attacks will continue for ≥6 weeks after the screening visit.
d.The patient has a total body weight of ≥45 kg
e.The patient is not using or using a maximum of 2 concomitant medications that are commonly prescribed as preventive treatments for CH , regardless of the indication for which the medication was prescribed. Patients must be on a stable dose and regimen for at least 2 weeks prior to screening and throughout the study.
f.The patient has demonstrated compliance with the electronic headache diary during the run-in period by entry of headache data on 85% of days during the run-in period.
g.The patient has at least 7 CH attacks during the run-in period.
h.The patient is in good health in the opinion of the investigator as determined by a medical and psychiatric history; medical examination; 12 lead ECG; and serum chemistry, hematology, coagulation, and urinalysis.
i.Women may be included only if they have a negative serum beta-human chorionic gonadotropin (β-HCG) test at screening, are sterile, or postmenopausal.
j.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 (ie, starting at screening) and for 7.5 months after discontinuation of IMP.
k.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 7.5 months after discontinuation of the IMP. Definitions of WOCBP, sterile, and postmenopausal women; male contraception; and highly effective and acceptable birth control methods
l.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.
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| E.4 | Principal exclusion criteria |
a.The patient has used short corticosteroid cycle to treat the current CH cycle.
b.The patient reports using butalbital on more than 7 days during the 4 weeks prior to screening or using butalbital on more than 3 days during the screening/run-in period.
c.The patient reports using opioids on more than 15 days during the 4 weeks prior to screening or using opioids on more than 4 days during the screening/run-in period.
d.The patient has used an intervention/device (eg, scheduled nerve blocks) for headache during the 4 weeks prior to screening.
e.The patient has clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, genitourinary, cardiac, neurologic, hepatic, or ocular disease at the discretion of the investigator.
f.The patient has evidence or medical history of clinically significant psychiatric issues determined at the discretion of the investigator.
g.The patient has a history of any suicide attempt in the past or current active suicidal ideation, as measured by the eC-SSRS.
h.The patient has a 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.The patient has known infection or history of human immunodeficiency virus, tuberculosis, or chronic hepatitis B or C infection.
j.The patient has a past or current history of cancer in the past 5 years, except for appropriately treated non-melanoma skin carcinoma.
k.The patient is pregnant or nursing.
l.The patient has a history of hypersensitivity reactions to injected proteins, including monoclonal antibodies.
m.The patient has participated in a clinical study of a new chemical entity or a prescription medicine within 2 months or 5 half-lives before administration of the first dose of the IMP, whichever is longer.
n.The patient has participated in a clinical study of a monoclonal antibody, unless it is known that the patient received placebo during the study.
o.The patient has a history of prior exposure to a monoclonal antibody targeting the CGRP pathway (AMG 334, ALD304, LY2951742, or fremanezumab).
p.The patient has any finding in the baseline 12 lead ECG 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, including serum chemistry, hematology, coagulation, and urinalysis test values (abnormal tests may be repeated for confirmation).
r.The patient has hepatic enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) >1.5 × the upper limit of normal (ULN) range after confirmation in a repeat test, or the patient has suspected hepatocellular damage that fulfills criteria for Hy’s law at screening.
s.The patient has serum creatinine >1.5 × the ULN or evidence of clinically significant renal disease in the judgement of the investigator.
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 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 the study
u.The patient is an employee of the sponsor/participating study center who is directly involved in the study or is the relative of such an employee.
v.The patient has an implant for neurostimulation used in the treatment of CH.
w.The patient is a member of a vulnerable population (eg, people kept in detention).
x.The patient has a history of alcohol abuse prior to screening.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint of this study is the mean change from baseline (run-in period) in the weekly average number of cluster headache (CH) attacks during the 4-week period after administration of the first dose of the IMP, ie, based on week 0 to 4 data. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1.the proportion of patients with a ≥50% reduction from baseline (run-in period) in the weekly average number of CH attacks during the 4 week period after the first dose of the IMP, ie, based on week 0 to 4 data
2.the mean change from baseline (run-in period) in the number of CH attacks during the 12 week period after administration of the first dose of the IMP, ie, based on week 0 to 12 data
3.the mean change from baseline (run-in period) in the number of CH attacks during the 4 week period after administration of the third dose of the IMP, ie, based on week 8 to 12 data
4.the mean change from baseline (run-in period) in the weekly average number of days with use of cluster-specific acute headache medications (triptans and ergot compounds) during the 12 week period after administration of the first dose of the IMP, ie, based on week 0 to 12 data
5.the mean change from baseline (run-in period) in the weekly average number of days oxygen is used to treat ECH during the 12-week period after administration of the first dose of the IMP, ie, based on week 0 to 12 data
6.assessment of patient’s perceived improvement, as measured by the Patient-Perceived Satisfactory Improvement (PPSI) at 1, 4, 8, and 12 weeks after administration of the first dose of the IMP relative to baseline (day 0)
The secondary safety endpoints are as follows:
1.occurrence of adverse events throughout the study
2.clinical laboratory (serum chemistry, hematology, coagulation, and urinalysis) test results at each visit
3.vital signs (systolic and diastolic blood pressure, oral temperature, and pulse rate) measurements at each visit. Note: Oxygen saturation will be measured in cases of suspected anaphylaxis and severe hypersensitivity. Respiratory rate will also be measured in these cases but not as a standard vital sign.
4.12 lead electrocardiogram (ECG) findings at screening, baseline, and week 12
5.use of concomitant medication during the study
6.clinically significant changes in physical examinations, including body weight
7.injection site reaction (ie, erythema, induration, and ecchymosis) and injection site pain assessments
8.occurrence of hypersensitivity/anaphylaxis reactions
9.suicidal ideation and behavior as measured by the electronic Columbia Suicide Severity Rating Scale (eC-SSRS)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy:
1. week 4,
2. week 12
3. week 8 to 12
4-6. week 12
Safety:
1-9. Week 12
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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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Different dosing regimen of fremanezumab |
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| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Australia |
| Canada |
| Finland |
| Germany |
| Israel |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Sweden |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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