| 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 | 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 | 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 | PT |
| E.1.2 | Classification code | 10027599 |
| E.1.2 | Term | Migraine |
| 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 | 10066635 |
| E.1.2 | Term | Acute 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 rimegepant compared with placebo in the acute
treatment of migraine in adolescent population (≥ 12 to < 18 years of age) as measured by pain freedom at two hours post-dose. |
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| E.2.2 | Secondary objectives of the trial |
Key Secondary Objective:
To evaluate the efficacy of rimegepant relative to placebo in the acute
treatment of migraine in the combined population of children and
adolescents (≥ 6 to < 18 years of age) as measured by pain freedom at
two hours post-dose.
For the list of the other Secondary Objectives please refer to the study protocol.
|
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetic Sub-study:
Children (≥ 6 to < 12 years of age) who opt to participate in this site-specific sub-study will receive a dose of rimegepant ODT (consistent with their assigned dose at randomization) after all EOT procedures have been performed. PK sampling will occur at 0.5 hour and 2 hours post dose and a trough sample at 4 to 6 hours post dose (actual time recorded). Details concerning the conduct of this sub-study will be described in a separate study manual. |
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| E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent:
a. The participant must be capable of communicating with the site personnel;
b. The participant is able to understand the Informed Assent Form (IAF) and the
participant’s parent(s)/legal representative(s) (according to local regulations) are/is able to read and understand the Informed Consent Form (ICF);
c. The participant has signed the IAF and the participant’s parent(s)/legal representative(s) (according to local regulations) have/has signed the ICF prior to the conduct of any study-specific procedures;
d. The participant and the participant’s parent(s)/legal representative(s) (as required according to local regulations) are/is willing and able to attend study appointments within the specified time windows;
e. The participant must be able to read and comprehend written instructions and be willing to complete all questionnaires under supervision of legal representative(s) as required by the protocol.
2. Target Population:
a. History of migraine (with or without aura) for > 6 months before Screening according to the IHS Classification ICHD-319 specifications for pediatric migraine. History may be verified using both medical records and recall by the participant and/or participant’s parent(s)/legal representative(s);
b. History of 1 to 8 moderate or severe attacks per month during the 2 months prior to enrollment. A history of attacks lasting approximately > 3 hours without treatment. History may be verified using both medical records and recall by the participant and/or participant’s parent(s)/legal representative(s).
c. Participants on prophylactic migraine medication are permitted to remain on therapy if the dose has been stable for at least 12 weeks prior to the Baseline Visit, and the dose is not expected to change during the course of the study;
d. Participants are required to verbally distinguish between migraine and other types of headaches;
e. Participants must have a weight > 40 kg (child cohort weight requirement > 15 kg) at the Screening Visit;
f. Participants must have adequate venous access for blood sampling;
3. Age and Reproductive Status
a. Male and female participants ≥ 6 to < 18 years of age (participants must not reach their 18th birthday during the study);
b. The participant, 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 after study drug administration in such a manner that the risk of pregnancy is minimized. See Section 5.6 for the definition of childbearing potential;
c. The participant, if a female who has experienced menarche, must have a confirmed negative serum and urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) at the Screening Visit and at Day 1 (respectively);
d. Females must not be breastfeeding;
e. No clinically significant abnormality identified on the medical or laboratory evaluation. A participant with a clinical abnormality or laboratory parameters outside the lab normal reference range may be included only if the investigator considers that the finding is not clinically significant and will not introduce additional risk factors and will not interfere with the study procedures. |
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| E.4 | Principal exclusion criteria |
1. Target Disease Exclusion:
a. Participant has a history of cluster headache or hemiplegic migraine headache.
b. The participant has a continuous migraine (defined as an unrelenting headache) during within 1 month prior to Screening Visit;
c. The participant has a history or diagnosis of persistent aura without infarction, migrainous infarction, migraine aura-triggered seizure, 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 participant has a confounding and clinically significant pain syndrome that may interfere with the participant’s ability to participate in this study.
2. Medical History and Concurrent Diseases
a. The participant has any current psychiatric condition that is uncontrolled and/or untreated for a minimum of 6 months prior to the Screening Visit. Participants with a lifetime history of psychosis and/or mania are excluded;
b. History of suicidal behavior or the participant is at risk of self-harm or harm to others;
c. History of major psychiatric disorder. Participants 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.
Participants must have been on a stable dose within the 3 months before the Baseline Visit;
d. The participant has a current diagnosis or history of substance abuse (excluding nicotine and caffeine) or alcohol abuse (DSM-5® criteria) < 2 years prior to the Screening Visit, as verified with legal representative(s) and in the opinion of the Investigator;
e. The participant 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).
f. The participant has a history of cancer.
g. The participant 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 participant 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 participant has had recent or planned surgery, requiring general anesthesia, <8 weeks prior to the Screening Visit.
j. The participant 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 participant has had gastrointestinal surgery that interferes with physiological absorption and motility (i.e., gastric bypass, duodenectomy, or gastric banding).
l. The participant has one or more clinically significant out-of-range vital signs at the Screening or Baseline Visit.
m. The participant 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 human immunodeficiency virus (HIV).
3. Allergies and Adverse Drug Reactions
a. The participant has a history of severe drug allergy or hypersensitivity or known hypersensitivity or intolerance to the excipients in rimegepant.
b. The participant 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. A participant with a clinical abnormality or laboratory parameters outside the reference range may be included only if the investigator considers the finding not clinically significant, that it will not introduce additional risk factors, nor interfere with the study procedures.
b. The participant has evidence of organ dysfunction or any clinically significant deviation from normal on physical examination, vital signs, 12-lead electrocardiogram (ECG), or clinical laboratory determinations beyond what is consistent with the target population.
For the complete list of exclusion criteria please refer to the study protocol |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Pain freedom will be assessed using the number of participants that report no pain at 2 hours post double-blind treatment dose measured on a 4-point numeric rating scale (0=none, 1=mild, 2=moderate, 3=severe) in adolescent population (≥ 12 to < 18 years of age). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 2 hours post double-blind treatmemt |
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| E.5.2 | Secondary end point(s) |
Key secondary endpoint:
- Pain freedom will be assessed using the number of participants that report no pain at 2 hours post double-blind treatment dose in the combined population of children and adolescents (≥ 6 to < 18 years of age). Participants with no pain are those who report 0 on the 4-point numeric scale in adolescents and who report Face 1 on the 5-Face VAS in children. 5-Face VAS in children are converted to 4 categories: Face 5 = ‘severe pain’, Faces 4 and 3 = ‘moderate pain’, Face 2 = ‘mild pain’, Face 1 = ‘no pain’.
Other secondary endpoints:
- Freedom from the most bothersome symptom (MBS) associated with migraine will be assessed using the number of participants that report the absence of their MBS at 2 hours post double-blind treatment dose in the adolescent population.
- The probabilities of requiring rescue medication will be assessed using the numbers of participants that take rescue medication within 24 hours and within 48 hours after administration of double-blind treatment (rimegepant or placebo) in the adolescent population.
- Sustained pain freedom, from 2 to 24 hours post double-blind treatment dose, will be assessed using the number of participants that do not use any rescue medications, and do not experience any headache pain through the time period of interest, in the adolescent population.
- The proportion of participants able to function normally, at 2 hours post double-blind treatment dose, will be assessed using the number of participants that self-report as “normal” on the Functional Disability scale, in the adolescent population.
- Pain freedom will be assessed using the number of participants that report no pain at 2 hours post double-blind treatment dose, measured by a 5-Face VAS.
- Freedom from the most bothersome symptom (MBS) associated with migraine will be assessed using the number of participants that report the absence of their MBS at 2 hours post double-blind treatment dose in children and in the combined population of children and adolescents.
. The probabilities of requiring rescue medication will be assessed using the numbers of participants that take rescue medication within 24 hours and within 48 hours after administration of double-blind study medication (rimegepant or placebo) in children and in the combined population of children and adolescents.
- Sustained pain freedom, from 2 to 24 hours post double-blind treatment dose, will be assessed using the number of participants that do not use any rescue medications, and do not experience any headache pain through the time period of interest, in children and in the combined population of children and adolescents.
- Freedom from photophobia will be assessed by tabulating the number of participants that report the absence of photophobia at 2 hours post double-blind treatment dose in the subset of participants that reported the presence of photophobia at headache baseline, in adolescents, children, and the combined population of children and adolescents.
- Freedom from nausea will be assessed by tabulating the number of participants that report the absence of nausea at 2 hours post double-blind treatment dose in the subset of participants that reported the presence of nausea at headache baseline, in adolescents, children, and the combined population of children and adolescents.
- Pain relief at 2 hours post double-blind treatment dose, will be assessed using the number of participants that report a pain level of moderate or severe at baseline and then report a pain level of none or mild at two hours post double-blind treatment dose in adolescents, children, and the combined population of children and adolescents.
- Time to first report of pain relief will be based on the first time point a participant reports a pain level of none or mild post double-blind treatment dose, in adolescents, children, and the combined population of children and adolescents. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
2 hours post double-blind treatment dose for the key secondary endpoint.
For timepoints for all the other secondar endpoints please refer to the list of endpoints |
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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 | 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 |
| China |
| Mexico |
| United Kingdom |
| United States |
| Poland |
| Spain |
| Sweden |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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