E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 evaluate the long term safety of fremanezumab in adult patients with CH. |
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E.2.2 | Secondary objectives of the trial |
There are no secondary objectives and secondary endpoints in this study. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a. The patient is a male or female and 18 to 70 years of age, inclusive, at the start of the
pivotal study.
b. The patient signs and dates the informed consent document.
c. The patient completes either the Phase 3 pivotal study for ECH (Study TV48125-CNS-30056) or the Phase 3 pivotal study for CCH (Study TV48125-CNS-30057) without important protocol deviations related to patient safety and patient compliance and at least 75% diary data completion during the pivotal study. Prior to 15 June 2018, patients from the ECH study and the CCH study were enrolled. After 15 June 2018, only patients who participated in the ECH study (Study TV48125-CNS-30056) will be enrolled for active treatment.
-In addition, patients who do not complete the pivotal efficacy studies, and patients who complete the pivotal efficacy studies but do not wish to continue treatment during this longterm safety study, will be offered to enroll in this study for the purpose of evaluating ADAs and safety (adverse events and concomitant medications) approximately 7.5 months after administration of the last dose of the IMP.
d. Women may be included only if they have a negative beta-human chorionic gonadotropin (β-HCG) test at visit 1, are sterile or postmenopausal, and are not lactating (not applicable for patients participating in safety follow-up only).Definitions of sterile and postmenopausal are given in Appendix E.
e. Women of childbearing potential (WOCBP) whose male partners are potentially fertile (ie, no vasectomy) must use highly effective birth control methods (see Appendix E) for the duration of the study and for 7.5 months after discontinuation of IMP. 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 agree to use, together with their female partners, acceptable birth control methods for the duration of the study and for 7.5 months after administration of IMP. Definitions of women of non-childbearing potential, sterile and postmenopausal women; male contraception; highly effective and acceptable birth control methods including examples are given in Appendix E.
f. The patient must be willing to stop concomitant medications used in clinical practice for the prevention of CH (i.e. verapamil, topiramate, valproate, lithium or methysergide) for the duration of this study. Patients must begin tapering these preventive medications as soon as they begin this study. The period of time needed to taper off these medication will be based on the investigator´s medical judgment but should not exceed 1 month from the beginning of participation in this study [Appendix H].) (not applicable for patients participating in safety follow-up only)
g. 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 (not applicable for patients participating in safety follow-up only).
h. 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 a history of any suicide attempt in the past or current active suicidal
ideation, as measured by the eC-SSRS.
b. Any finding in the 12-lead ECG performed as part of the EOT visit (visit 5) procedures for the pivotal studies considered clinically significant in the judgment of the investigator.
c. 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).
d. Hepatic enzymes (ALT and AST) >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.
e. Serum creatinine >1.5 × the ULN or evidence of clinically significant renal disease in the judgment of the investigator. Patients rolling over only for safety follow-up and ADA who are not receiving study medication are not required to fulfil all inclusion exclusion criteria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
As of 15 June 2018, only patients from the episodic cluster headache (ECH) study (Study TV48125-CNS-30056) will enroll in this study for active treatment. As of 15 June 2018, all chronic cluster headache (CCH) patients included in this study have been asked to discontinue treatment, and are encouraged to continue in the ADA and safety follow-up portion of this study. Data from CCH patients enrolled prior to 15 June 2018 will be evaluated per all objectives of this study.
Safety endpoints are as follows:
•occurrence of adverse events throughout the study
•changes from baseline (day 0 of the Phase 3 pivotal efficacy studies) in clinical laboratory (serum chemistry, hematology, coagulation, and urinalysis) test results
•changes from baseline (day 0 of the Phase 3 pivotal efficacy studies) in vital signs (pulse, systolic and diastolic blood pressure, and oral temperature) measurements
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.
•abnormal standard 12-lead electrocardiogram (ECG) findings
•clinically significant changes in physical examination, including body weight
•occurrence of injection site reactions (ie, erythema, induration, and ecchymosis) and injection site pain
•occurrence of anaphylaxis and hypersensitivity reactions
•use of concomitant medications during the study
•suicidal ideation and behavior as measured by the electronic Columbia Suicide Severity Rating Scale (eC-SSRS)
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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) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.3 | Therapy | Yes |
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 | 5 |
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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End of study is defined as the date the last patient attends the follow-up visit |
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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 | 3 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |