| 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.1.2 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 |
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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 | 10066636 |
| E.1.2 | Term | Chronic migraine |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 test investigational medicinal product (IMP) as compared to placebo IMP for the preventive treatment of chronic migraine (CM) |
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| E.2.2 | Secondary objectives of the trial |
-To evaluate the safety and tolerability of test IMP in the preventive treatment of chronic migraine (CM)
-To further demonstrate the efficacy of test IMP as compared to placebo IMP for the preventive treatment of chronic migraine (CM)
-To evaluate the immunogenicity of test IMP and the impact of antidrug antibodies (ADAs) on clinical outcomes in participants exposed to test IMP. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a. The participants is a male or female between the ages of 6 to 17 years (inclusive) on the day of randomization to test IMP/ placebo IMP.
b. The participant’s parent(s) or legal guardian(s) must give written informed consent, and the participant must give assent (in accordance with local regulations). Note: In some countries, participants aged 15 to 17 years (inclusive) may give written informed consent; however, the participant's parent(s) or legal guardian(s) must be informed, per local regulations.
c. The participant has a clinical history of recurrent headache consistent with the diagnosis of migraine for at least 6 months before screening, consistent with ICHD-3 criteria (Headache Classification Committee of the IHS 2013), and a history of ≥15 headache days per month on average during the 3 months prior to screening (visit 1).
d. The participant or parent/caregiver has maintained a prospectively collected headache diary during a 28-day baseline period in which headache days were recorded on 15 or more days, and 8 or more of these headache days had 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. This criterion was deleted
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).
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 Onabotulinum 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 towards the 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 trial (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 trial and for 6 months after the last administration of IMP. Further details are included in Section 13.1.
i. The participant/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 participant is in good health, as determined by a medical and psychiatric history, medical examination, 12-lead electrocardiogram (ECG), serum chemistry, hematology, coagulation, urinalysis, and serology.
k. The participant/caregiver must be willing and able to comply with trial requirements and return to the clinic as required for the duration of the trial.
l. The participant weighs at least 17.0 kg on the day of randomization to test IMP/placebo IMP.
m. The participant has a body mass index ranging from the 5th to 120% of the 95th percentile, inclusive, at screening, based on the local standard.
n. The participant has received all recommended age-appropriate vaccines according to local standard of care and schedule prior to screening.
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| E.4 | Principal exclusion criteria |
a. The participant 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 participant 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 participant 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 participant 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 participant has an ongoing infection or a known history of human immunodeficiency virus infection, tuberculosis, Lyme disease, chronic hepatitis B or C, or a known active infection of COVID-19.
f. The participant has a past or current history of cancer.
g. The participant is pregnant or nursing.
h. The participant has a history of hypersensitivity reactions to injected proteins, including monoclonal antibodies (mAbs), or a history of Stevens-Johnson Syndrome or toxic epidermal necrolysis syndrome, or the participant is concomitantly using lamotrigine.
i. The participant has participated in another trial 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 trial of an IMP (or a medical device).
j. The participant has had exposure to a mAb targeting the calcitonin gene-related peptide (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 trial
(Trial TV48125-CNS-10141).
l. In the judgment of the investigator, the participant has an abnormal finding on the baseline 12-lead ECG considered clinically significant.
m. In the judgment of the investigator, the participant 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 participant 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 participant has serum creatinine more than 1.5× the ULN, clinically significant proteinuria (urine dipstick +4), an estimated glomerular filtration rate (eGFR) of <90 mL/min/1.73m2, as calculated by the revised Schwartz formula (GFR=[0.413xHt]/serum creatinine), or evidence of renal disease during the 28-day baseline period.
p. The participant has any history of alcohol or drug abuse. The definition of alcohol or drug abuse, including marijuana, is based on the investigator's clinical judgement.
q. In the judgment of the investigator, the participant cannot fully participate in or successfully complete the trial for its full duration for any of the following reasons:
-The participant is mentally or legally incapacitated or unable to give assent/consent for any reason.
-The participant is in custody due to an administrative or a legal decision or is in residential treatment.
-The participant/caregiver is unable to be contacted in case of emergency.
-The participant has any other condition, which, in the opinion of the investigator, makes the patient inappropriate for inclusion in the trial.
-The participant is a relative of a trial center or sponsor employee who is directly involved in the trial.
r. Vulnerable participant (eg, people kept in detention) whose vulnerability is based on a condition other than the age required for trial eligibility.
s. The participant 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 trial, the participant may receive a live attenuated vaccine.
t. The participant has a known hypersensitivity to the active substance or to any of the excipients of the IMP.
u. The participant has a current or past medical history of hemiplegic migraine.
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| 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 of at least moderate severity during the 12-week period after the first dose of IMP |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks after the first dose of IMP |
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| E.5.2 | Secondary end point(s) |
Efficacy endpoints:
-Mean change from baseline (28-day baseline period) in monthly average number of migraine days during the 12-week period after the first dose of IMP
-Proportion of participants reaching at least 50% reduction in the monthly average number of migraine days of
during the 12-week period after the first dose IMP
-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 IMP
-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 IMP
-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 IMP
Safety and tolerability endpoints:
-Occurrence of adverse events throughout the trial, 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)
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| 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 IMP
-Proportion of participants reaching at least 50% reduction in the monthly average number of migraine days: week 12 after first dose of IMP
-Mean change from baseline in the monthly average number of days of use if any acute headache medications: week 12 after first dose of IMP
-Mean change from baseline (day 1) in migraine-related disability score: week 12 after first dose of IMP
-Mean change from baseline in quality of life: week 12 after first dose of IMP
-Proportion of participants developing ADA throughout the trial: week 12 after first dose of IMP
Safety and tolerability: throughout the trial
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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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | 8 |
| 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 |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 6 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| 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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