| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Migraine (with or without aura) |
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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 | PT |
| E.1.2 | Classification code | 10052787 |
| E.1.2 | Term | Migraine without aura |
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10027607 |
| E.1.2 | Term | Migraine with aura |
| 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 | 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy of rimegepant to placebo as a preventive treatment for migraine in adolescents (≥ 12 to <18 years of age) with episodic migraine, as measured by the reduction from baseline in the mean number of migraine days per month over the entire course of the double-blind treatment phase. |
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| E.2.2 | Secondary objectives of the trial |
● To compare the efficacy of rimegepant to placebo on the proportion of subjects that have at least a 50% reduction from baseline in the mean number of moderate to severe migraine days per month over the entire course of the double-blind treatment phase in adolescents with episodic migraine.
● To compare the efficacy of rimegepant to placebo on the reduction from baseline in the mean number of migraine days per month in the first 4 weeks of the double-blind treatment phase in adolescents with episodic migraine.
● To compare the change from baseline in the Pediatric Quality of Life (PedsQLTM) 4.0 Generic Core Scales total score at Week 12 of the double-blind treatment phase between rimegepant and placebo in adolescents with episodic migraine. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent
2. Target Population
Subject has at least a 6 month history of migraine (with or without aura) consistent with a Diagnosis according to the International Classification of Headache Disorders, 3rd Edition1, and including the following:
a) 14 or less headache days per month during the 3 month period prior to the Screening Visit
b) 6 or more migraine days during the Observation Period
c) 14 or less headache days during the Observation Period
d) Pediatric Migraine Disability Assessment Scale (PedMIDAS) Disability Score of >10 to ≤50, indicating mild (score of 11 to 30) or moderate (score of 31 to 50) disruption in daily activities, as assessed at the Baseline (Randomization) Visit
e) Ability to verbally distinguish migraine attacks from tension/cluster or other types of headaches
f) Migraine attacks, on average, lasting 4 - 72 hours if untreated
g) Subjects on prophylactic migraine medication are permitted to remain on therapy if the dose has been stable for at least 3 months (12 weeks) prior to the Screening Phase, and the dose is not expected to change during the course of the study.
i. Subjects may remain on one (1) medication with possible migraine prophylactic effects, excluding CGRP antagonists [biologic or small molecule], during the double-blind treatment phase.
ii. Concomitant use of a CGRP antagonist, such as erenumab, fremanezumab, or Nurtec, is prohibited.
iii. Subjects who previously discontinued prophylactic migraine medication must have done so at least 90 days prior to the Screening Visit.
h) Subjects with contraindications for use of triptans may be included provided they meet all other study entry criteria
i) Subjects must have a weight of ≥40 kg (child cohort requirement ≥15 kg) at the Screening Visit.
j) Subjects must have adequate venous access for blood sampling.
3. Age and Reproductive Status
a) Male and female subjects ≥ 6 to <18 years; subjects must be less than 18 at the time of signing assent / consent.
b) The subject, if a female who is sexually active and of childbearing potential (defined as females who have experienced menarche), or a male who is sexually active, must be willing to use one of the following acceptable methods of contraception to avoid
pregnancy throughout the study and for 60 days for females and 90 days for males after study drug administration in such a manner that the risk of pregnancy is minimized.
i. sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk in relation to the duration of the clinical study, in line with the preferred and usual lifestyle of the subject)
ii. simultaneous use of a male condom and, for the female partner, hormonal contraceptives (containing estrogen and progestogen or progestogen-only and associated with the inhibition of ovulation) or intra-uterine contraceptive device (with or a without hormone release system) used since at least 4 weeks prior to study drug administration.
iii. simultaneous use of a male condom and, for the female partner, a diaphragm or cervical cap with intravaginally applied spermicide.
c) The subject, females who has experienced menarche, must have a confirmed negative pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) at the Screening Visit, Pre-Randomization Evaluation Visit, and at Baseline (Randomization) Visit.
d) Females must not be breastfeeding. |
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| E.4 | Principal exclusion criteria |
1. Target Disease Exclusion
a) Subjects with a history of basilar migraine, cluster headaches, or hemiplegic migraine
b) The subject has a continuous migraine (defined as an unrelenting headache) within 1 month prior to Screening Visit.
c) The subject has a history or diagnosis of complications of migraine (including persistent aura without infarction, migrainous infarction, and migraine-aura triggered seizure) (ICHD-3 version 2018),1 chronic tension-type headache, hypnic headache, cluster headache, hemicrania continua, new daily persistent headache, or unusual migraine subtypes such as hemiplegic migraine (sporadic and familial), ophthalmoplegic migraine, or migraine with neurological accompaniments that are not typical of migraine aura (diplopia, altered consciousness, or long duration).
d) The subject has a confounding and clinically significant pain syndrome that may interfere with the subject’s ability to participate in this study.
2. Medical History and Concurrent Diseases
a) The subject has any current psychiatric condition that is uncontrolled and/or untreated for a minimum of 6 months prior to the Screening Visit. Subjects with a lifetime history of psychosis and/or mania are excluded.
b) History of suicidal behavior or the subject is at risk of self-harm or harm to others.
c) History of major psychiatric disorder. Subjects with anxiety disorder and/or mild major depressive disorder are permitted in the study if they are considered by the investigator to be stable and are taking no more than 1 medication for each disorder. Subjects must have
been on a stable dose within the 3 months before the Baseline Visit. However, subjects with a current diagnosis of major depressive disorder requiring treatment with atypical antipsychotics and subjects with schizophrenia, bipolar disorder, or borderline personality
disorder are excluded.
d) The subject has a current diagnosis or history of substance abuse (excluding nicotine and caffeine) or alcohol abuse (DSM-5®23 criteria) < 2 years prior to the Screening Visit, as verified with legal representative(s) and in the opinion of the Investigator.
e) The subject has reported current use of, or has tested positive at the Screening visit for, drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, opiates, MDMA, methamphetamines, oxycodone, phencyclidine).
i. Detectable levels of cocaine, amphetamine, and phencyclidine (PCP) in the drug screen are exclusionary. Subjects who are positive for amphetamines, and who are on a prescribed amphetamine medication for an approved indication (e.g. ADHD) will be allowed into the study at the Investigator’s discretion.
f) The subject has a history of cancer.
g) The subject has any other disorder for which the treatment takes priority over treatment of migraine or is likely to interfere with study treatment or safety assessments.
h) The subject has a history of moderate or severe head trauma or other neurological disorder (including seizure disorder) or systemic medical disease that is, in the investigator’s opinion, likely to affect central nervous system functioning.
i) The subject has had recent or planned surgery, requiring general anesthesia, <8 weeks prior to the Screening Visit.
j) The subject has or has had one or more of the following conditions that is/are considered clinically relevant in the context of the study:
i. Uncontrolled hypertension
ii. Cardiovascular disease
iii. Cardiomyopathy
iv. Serious heart rhythm abnormalities
v. Cerebrovascular disease (for example CNS Vascular ischemia)
vi. Thromboembolic event
vii. Diabetes
viii. Raynaud’s disease
ix. Life-threatening allergy (for example, anaphylaxis)
k) The subject has had gastrointestinal surgery that interferes with physiological absorption and motility (i.e., gastric bypass, duodenectomy, or gastric banding).
l) The subject has one or more clinically significant out-of-range vital signs at the Screening or Baseline (Randomization) Visit.
m) The subject has a current diagnosis of viral hepatitis or a history of liver disease.
n) The subject has a known history of hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV), or HIV
3. Allergies and Adverse Drug Reactions
a) The subject has a history of severe drug allergy or hypersensitivity or known hypersensitivity or intolerance to the excipients in rimegepant.
b) The subject has a history of anaphylaxis, documented hypersensitivity reaction, or clinically significant reaction to any drug.
4. ECG and Laboratory Test Findings
a) Clinically significant abnormality identified on the medical or laboratory evaluation.
i. Serum creatinine value >1.5 times the upper limit of the reference range
ii. Serum total bilirubin > 1 x ULN (Only abnormal values of between 1-1.5x ULN may be repeated once for assessment of eligibility during the screening period.)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline (observation period) in the mean number of migraine days per month over the entire course (Weeks 1 to 12) of the double-blind treatment phase in adolescents with episodic migraine |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoints for evaluation of Primary EndPoint:
over the entire course (Weeks 1 to 12) of the double-blind treatment phase |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoints:
● Achievement of at least a 50% reduction from baseline in the mean number of moderate to severe migraine days per month over the entire course of the double-blind treatment phase in adolescents with episodic migraine.
● Change from baseline in the mean number of migraine days per month in the first 4 weeks (Weeks 1 through 4) of the double-blind treatment phase in adolescents with episodic migraine.
● The mean change from baseline in the Pediatric Quality of Life (PedsQL) total score at Week 12 of the double-blind treatment phase in adolescents with episodic migraine.
Refer to Protocol for full list of Secondary endpoints |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints for evaluation of Key Secondary Endpoints:
● Achievement of at least a 50% reduction from baseline in the mean number of moderate to severe migraine days per month over the entire course of the double-blind treatment phase in adolescents with episodic migraine.
● Change from baseline in the mean number of migraine days per month in the first 4 weeks (Weeks 1 through 4) of the double-blind treatment phase in adolescents with episodic migraine.
● The mean change from baseline in the PedsQL total score at Week 12 of the double-blind treatment phase in adolescents with episodic migraine.
For timepoints for all the other secondary endpoints please refer to the Protocol |
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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 | 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 |
| There is an optional open-label, extension phase following the double-blind, treatment phase |
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| 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 | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Austria |
| France |
| Italy |
| Poland |
| Sweden |
| United Kingdom |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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