| 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 | 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 | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10082019 |
| E.1.2 | Term | Episodic migraine |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 fremanezumab as compared to placebo for the preventive treatment of episodic migraine (EM) |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the safety and tolerability of fremanezumab in the preventive treatment of episodic migraine (EM)
-To further demonstrate the efficacy of fremanezumab as compared to placebo for the preventive treatment of episodic migraine (EM)
-To evaluate the immunogenicity of fremanezumab and the impact of antidrug antibodies (ADAs) on clinical outcomes in patients exposed to fremanezumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a. The patient is a male or female between the ages of 6 to 17 years (inclusive) on the day of randomization to study drug/IMP.
b. The patient’s parent(s) or legal guardian(s) must give written informed consent, and the patient must give assent (in accordance with local regulations). Note: In some countries, patients aged 15 to 17 years (inclusive) may give written informed consent; however, the patient’s parent(s) or legal guardian(s) must be informed, per local regulations.
c. The patient has a clinical history of recurrent headache consistent with the diagnosis of migraine for at least 6 months before screening, consistent with the ICHD-3 criteria (Headache Classification Committee of the IHS 2013), and a history of ≤14 headache days per month in each of the 3 months prior to screening (visit 1).
d. The patient or parent/caregiver has maintained a prospectively collected headache diary during a 28-day baseline period in which at least 4 migraine days and ≤ 14 headache days were recorded on 6 to 14 days inclusive. Migraine days have at least 1 of the following migraine characteristics:
-head pain of moderate to severe intensity lasting for 2 or more hours in duration and accompanied by either throbbing quality, predominantly unilateral location, or aggravation with normal activities.
-headache is accompanied by a migraine-associated symptom, such as photophobia, phonophobia, abdominal pain, nausea, or vomiting.
-headache is preceded by an aura, as described by ICHD-3 criteria.
-headache was treated by a nonsteroidal anti-inflammatory drug (NSAID), paracetamol, triptan, or ergot preparation.
e. The patient does not have chronic daily headache. For the purposes of this study, chronic daily headache is operationally defined as <4 headache-free days during the 28-day baseline period.
f. Not using migraine preventive medications or using no more than 2 migraine preventive medications for migraine or other medical condition, as long as the dose and regimen have been stable for at least 2 months prior to screening (visit 1). A list of migraine preventive medications allowed for the duration of the study for approximately 30% of patients is presented in Appendix C. Note: A person is considered to be not using migraine preventive medications when at least 5 half-lives have passed since the last use of the medication prior to screening (visit 1) or at least 4 months have passed since the last use of Onabotulinium toxin A or B prior to screening (visit 1). The use of other agents that are not included
in Appendix C but used for migraine prevention is permitted during the study; however, these patients will not be counted toward the approximately 30% patient limit threshold.
g. Females who are postmenarchal or ≥12 years of age may be included only if they have a negative beta-human chorionic gonadotropin (β-HCG) test at baseline or are sterile.
h. Females who are postmenarchal or ≥12 years of age and sexually active must use highly effective birth control methods with their male partners for the duration of the study (ie, starting at screening) and for 6 months after the last dose of IMP. Males who are sexually active with female partners must use a condom for the duration of the study and for 6 months after the last administration of IMP.
i. The patient/caregiver has demonstrated compliance with the electronic headache diary during the 28-day baseline period by entry of headache data on a minimum of 21 out of 28 days (approximately 75% diary compliance).
j. The patient is in good health, as determined by a medical and psychiatric history, medical examination, 12-lead ECG, serum chemistry, hematology, coagulation, urinalysis, and serology.
k. The patient/caregiver must be willing and able to comply with study requirements and return to the clinic as required for the duration of the study.
l. The patient weighs at least 17.0 kg on the day of randomization to study drug/IMP.
m. The patient has a body mass index ranging from the 5th to 120% of the 95th
percentile, inclusive, at screening absed on local standard.
n. The patient has received all recommended age-appropriate vaccines
according to local standard of care and schedule prior to screening. |
|
| E.4 | Principal exclusion criteria |
a. The patient is using medications containing opioids (including codeine) or barbiturates (including Fiorinal®, Fioricet®, or any other combination containing butalbital) for the treatment of migraine during the 3 months prior to the day of the screening visit.
b. The patient has used an intervention/device (eg, scheduled nerve block or transcranial magnetic stimulation) for the treatment of migraine or in the head or neck area for any condition during the 2 months prior to the day of the screening visit.
c. The patient has any clinically significant cardiovascular (including congenital cardiac anomalies or thromboembolic events), endocrine, gastrointestinal, genitourinary, hematologic, hepatic, immunologic, neurologic, ophthalmic, pulmonary, renal disease, or complications of an infection, at the discretion of the investigator.
d. The patient has a current history of a clinically significant psychiatric condition, at the discretion of the investigator. Any prior history of a suicide attempt, or a history of suicidal ideation with a specific plan within the past 2 years, must be excluded.
e. The patient has an ongoing infection or a known history of human
immunodeficiency virus (HIV) infection, tuberculosis, Lyme disease,
chronic hepatitis B or C, or a known active infection of COVID-19.
f. The patient has a past or current history of cancer.
g. The patient is pregnant or nursing
h. The patient has a history of hypersensitivity reactions to injected
proteins, including mAbs, or a history of Stevens-Johnson Syndrome or
toxic epidermal necrolysis syndrome, or the patient is concomitantly
using lamotrigine.
i. The patient has participated in another study of an IMP (or a medical
device) within the 30 days (or 90 days for biologics) or 5 half-lives
previous to the day of the screening visit (whichever is longer), or is
currently participating in another study of an IMP (or a medical device).
j. The patient has had exposure to a mAb targeting the CGRP pathway
(erenumab, eptinezumab, galcanezumab, fremanezumab) during the 6
months previous to the day of the screening visit.
k. Previous participation in the Phase 1 pharmacokinetics study (Study
TV48125-CNS-10141).
l. In the judgment of the investigator, the patient has an abnormal
finding on the baseline 12-lead ECG considered clinically significant.
m. In the judgment of the investigator, the patient has a significantly
abnormal finding during the 28-day baseline period, including
hematology, blood chemistry, coagulation tests, or urinalysis
values/findings (abnormal tests may be repeated for confirmation).
n. The patient has hepatic enzymes (alanine aminotransferase [ALT],
aspartate aminotransferase [AST], alkaline phosphatase [ALP]) more
than 1.5× the upper limit of normal (ULN) during the 28-day baseline
period, after confirmation in a repeat test, or suspected hepatocellular
damage that fulfills the criteria for Hy's law.
o. The patient has serum creatinine more than 1.5× the ULN, clinically
significant proteinuria (urine dipstick +4), an estimated glomerular
filtration rate of <75 mL/min/1.73m2, as calculated by the revised Schwartz
formula (eGFR=[0.413xHt]/Serum Creatinine), or evidence of renal disease
during the 28-day baseline period.
p. The patient has any history of alcohol or drug abuse. The definition of
alcohol or drug abuse, including marijuana, is based on the
investigator's clinical judgment.
q. In the judgment of the investigator, the patient cannot fully
participate in or successfully complete the study for its full duration for
any of the following reasons:
-The patient is mentally or legally incapacitated, or unable to give
assent/consent for any reason.
-The patient is in custody due to an administrative or a legal decision or
is in residential treatment.
-The patient/caregiver is unable to be contacted in case of emergency.
-The patient has any other condition, which, in the opinion of the
investigator, makes the patient inappropriate for inclusion in the study.
-The patient is a relative of a study center or sponsor employee who is
directly involved in the study.
r. Vulnerable patients (eg, people kept in detention) whose vulnerability
is based on a condition other than the age required for study eligibility.
s. The patient received a live attenuated vaccine (eg, intranasal flu
vaccine, and measles, mumps, and rubella vaccine) within the 12-week
period prior to screening. Note: If a medical need arises during the
study, the patient may receive a live attenuated vaccine.
t. The patient has a known hypersensitivity to the active substance or to
any of the excipients of the study drug.
u. The patient has a current or past medical history of hemiplegic
migraine. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Mean change from baseline (28-day baseline period) in the monthly average number of migraine days during the 12-week period after the first dose of study drug. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks after the first dose of study drug |
|
| E.5.2 | Secondary end point(s) |
Efficacy endpoints:
-Mean change from baseline (28-day baseline period) in monthly average number of headache days of at least moderate severity during the 12-week period after the first dose of study drug
-Proportion of patients reaching at least 50% reduction in the monthly average number of migraine days during the 12 week period after the first dose of study drug
-Mean change from baseline (28-day baseline period) in the monthly average number of days of use of any acute headache medications during the 12-week period after the first dose of study drug
-Mean change from baseline (day 1) in migraine-related disability score, as measured by the Pediatric Migraine Disability Assessment (PedMIDAS) questionnaire, at 12 weeks after administration of the first dose of study drug
-Mean change from baseline (day 1) in quality of life, as measured by the Pediatric Quality of Life Inventory (PedsQL), at 12 weeks after
administration of the first dose of study drug
-Proportion of patients developing antidrug antibodies (ADAs)
throughout the study. The impact of ADAs on safety and efficacy will be analyzed if the number of ADA-positive patients allows.
Safety and tolerability endpoints:
-Occurrence of adverse events throughout the study, including local injection site reaction/pain
-Abnormal standard 12-lead electrocardiogram (ECG) findings
-Changes from baseline in vital signs (systolic and diastolic blood pressure, pulse, temperature, and respiratory rate), height, and weight measurements
-Changes from baseline in clinical laboratory (serum chemistry, hematology, coagulation, and urinalysis) test results
-Abnormal physical examination findings
-Suicidal ideation and behavior as suggested by the Columbia-Suicide Severity Rating Scale (C-SSRS)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Mean change from baseline in monthly average number of migraine days: week 12 after first dose of study drug
-Proportion of patients reaching at least 50% reduction in the monthly average number: week 12 after first dose of study drug
-Mean change from baseline in the monthly average number of days of use if any acute headache medications: week 12 after first dose of study drug
-Mean change from baseline (day 1) in migraine-related disability score: week 12 after first dose of study drug
-Mean change from baseline in quality of life: week 12 after first dose of study drug
-Proportion of patients developing ADAs: week 12 after first dose of
study drug
Safety and tolerability: throughout the study |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 4 |
| 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 | 30 |
| 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 |
| Israel |
| United States |
| Finland |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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