| 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 | 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 | 100000004852 |
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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 prospectively test for superiority of atogepant 30 mg QD and atogepant 60 mg QD versus placebo for the prevention of migraine in participants with episodic migraine who have previously failed 2 to 4 classes of oral medications for the prophylaxis of migraine |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of atogepant 30 mg QD and atogepant 60 mg QD versus placebo for the prophylaxis of headache.
To evaluate the effect of atogepant 30 mg QD and atogepant 60 mg QD versus placebo on acute medication use.
To evaluate the effect of atogepant 30 mg QD and atogepant 60 mg QD versus placebo on the proportion of participants with at least 50% reduction from baseline in monthly migraine days.
To evaluate the effect of atogepant 30 mg QD and atogepant 60 mg QD versus placebo on the impact of migraine on daily activities as assessed by MSQ v2.1 Role Function-Restrictive domain score.
For the European Union only:
To evaluate the effect of atogepant 30 mg QD and atogepant 60 mg QD versus placebo on the impact of headaches on daily functioning as assessed by HIT-6. |
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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 |
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| E.3 | Principal inclusion criteria |
1.01 Male or female participants ages 18 (or age of legal majority) to 80 years, inclusive, at Visit 1
2.01 At least a 1-year history of migraine with or without aura consistent with a diagnosis according to the ICHD-3, 2018.
2.02 Age of the participant at the time of migraine onset < 50 years
2.03 History of 4 to 14 migraine days per month on average in the 3 months prior to Visit 1 in the investigator’s judgment
2.04 4 to 14 migraine days in the 28-day baseline period per eDiary (Note: A randomization cap of 20% will be instituted to ensure that the planned randomized participants include no more than 20% of participants with 4 to <8 migraine days at baseline.)
2.05 Completed at least 20 out of 28 days in the eDiary during the baseline period and is able to read, understand, and complete the study questionnaires and eDiary per investigator’s judgment.
2.06 Participants must meet all the below 2 criteria. Participants must have:
a. Failed oral migraine prophylaxis medications from 2 to 4 of the medication classes as listed below:
i. Propranolol, metoprolol, atenolol, bisoprolol, timolol, or nadolol;
ii. Topiramate;
iii. Flunarizine;
iv. Valproate or divalproex;
v. Amitriptyline or nortriptyline;
vi. Venlafaxine or desvenlafaxine;
vii. Lisinopril;
viii. Candesartan;
ix. Locally approved products (eg, oxeterone or pizotifen)
b. Failed one AND failed or be not suitable for a second treatment from a different medication class as listed below:
i. Propranolol OR metoprolol;
ii. Topiramate;
iii. Flunarizine;
iv. Amitriptyline
2.07 At least 80% of the randomized participants need to meet the below criteria:
Failed at least 2 treatments from different medication classes as listed below:
i. Propranolol OR metoprolol;
ii. Topiramate;
iii. Flunarizine;
iv. Amitriptyline
3.01 Male participants willing to minimize the risk of inducing pregnancy for the duration of the clinical study and follow-up period.
A male participant must agree to use contraception during the intervention period and for at least 3 days after the last dose of study intervention refrain from donating sperm during this period.
Female participants willing to minimize the risk of inducing pregnancy for the duration of the clinical study and follow-up period.
A female participant is eligible to participate if she is not pregnant (ie, has a negative urine pregnancy result at the Screening Visit (Visit 1) and Randomization Visit (Visit 2), is not planning to become pregnant during the course of the study, is not breastfeeding, and fulfills at least one of the following conditions:
a. Not a WOCBP as defined in Appendix 7 of the protocol
OR
b. A WOCBP who agrees to follow the contraceptive guidance of using a medically acceptable and effective contraceptive method as defined in Appendix 7 of the protocol during the intervention period and for 3 days after the last dose of study intervention.
4.01 Written informed consent and participant privacy information (eg, Written Authorization for Use and Release of Health and Research Study Information [US sites] and written Data Protection consent [EU sites]) obtained from the participant prior to any study-related procedures. |
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| E.4 | Principal exclusion criteria |
For the full exclusion criteria verbiage, please refer to section 5.2 of the protocol
1.01 Any clinically significant hematologic, endocrine, pulmonary, hepatic, gastrointestinal, or neurologic disease
1.02 Participant has any other concurrent pain condition that, in the opinion of the investigator, may significantly impact the current headache disorder
1.03 In the opinion of the investigator, confounding psychiatric conditions, dementia, epilepsy, or significant neurological disorders other than migraine
1.04 History of malignancy in the 5 years prior to Visit 1, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer
1.05 History of any prior gastrointestinal procedures or gastrointestinal conditions that may affect the absorption or metabolism of study intervention; participants with prior gastric bariatric interventions which have been reversed are not excluded
1.06 Clinically significant cardiovascular or cerebrovascular disease per the investigator’s opinion
1.07 Significant risk of self-harm based on clinical interview and responses on the C-SSRS, or of harm to others in the opinion of the investigator; participants must be excluded if they report suicidal ideation with intent, with or without a plan, in the past 6 months or report suicidal behavior in the 6 months prior to Visit 1 or Visit 2 assessments
1.08 At Visit 1, a user of recreational or illicit drugs or has had a history within the past year of drug or alcohol abuse or dependence
2.01 Has ≥ 15 headache days per month on average across the 3 months prior to Visit 1 in the investigator’s judgment
2.02 Has ≥ 15 headache days in the 28-day baseline period per eDiary
2.03 Difficulty distinguishing migraine headaches from tension-type or other headaches
2.04 Has a history of migraine accompanied by diplopia or decreased level of consciousness or retinal migraine as defined by ICHD-3, 2018
2.05 Has a current diagnosis of chronic migraine, new persistent daily headache, medication overuse headache, trigeminal autonomic cephalgia (eg, cluster headache), or painful cranial neuropathy as defined by ICHD-3, 2018
3.01 Usage during 30 days prior to Visit 1 and throughout the study period of and requirement for any medication, diet, or non-pharmacological treatment that is on the list of prohibited concomitant medications or treatments that cannot be discontinued or switched to an allowable alternative medication or treatment. This includes concomitant medications with demonstrated efficacy for the prevention of migraine regardless of indication.
3.02 Usage of therapeutic or cosmetic botulinum toxin injections into areas of the head, face, or neck within 6 months prior to Visit 1 and throughout the study period.
3.03 Usage of butalbital-containing analgesics >2 days/month, triptans or ergots ≥ 10 days/month, or simple analgesics ≥ 15 days/month, or any usage of opioid-containing medications in the 3 months prior to Visit 1 per investigator’s judgment, or during the baseline period is excluded.
3.04 Previous exposure to:
• Atogepant
• Injectable monoclonal antibodies blocking the CGRP pathway within the last 6 months prior to Visit 1
• Ubrogepant
• Rimegepant
• Any other oral investigational CGRP-RA
3.05 History of hypersensitivity or clinically significant adverse reaction to a CGRP-RA or hypersensitivity to any component of the study interventions.
4.01 Currently participating or has participated in a study with an investigational compound or device within 30 days prior to Visit 1
5.01 Hypertension as defined by sitting systolic blood pressure > 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg at Visits 1 or Visit 2. Vital sign measurements that exceed these limits may be repeated only once
5.02 An ECG with clinically significant abnormalities at screening as determined by the investigator
5.03 QTcF > 450 msec for males and QTcF > 470 msec for females at Visit 1 based on the ECG report of the central reviewer
5.04 Clinically significant laboratory values (see protocol section 5.2)
5.05 Positive result on the urine drug screen at Visit 1 unless explained by concomitant medication use
5.06 History of acute hepatitis within 6 months of screening ; or chronic hepatitis; or a positive result on anti-hepatitis A IgM antibody, hepatitis B surface antigen, anti–hepatitis C antibody or anti-hepatitis E IgM antibody testing at screening
6.01 Employed by or is an immediate family member of one of the investigators, study staff, or sponsor
6.02 Participant has a condition or is in a situation which in the investigator's opinion may put the participant at significant risk, may confound the study results, or may interfere significantly with the participant’s participation in the study
6.03 Any medical or other reasons that, in the investigator’s opinion, might indicate that the participant is unsuitable for the study |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in mean monthly migraine days across the 12-week treatment period. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline to Week 12. Baseline is defined as the number of migraine days during the last 28 days of the baseline phase (ie, Day -28 to -1) |
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| E.5.2 | Secondary end point(s) |
Change from baseline in mean monthly headache days across the 12-week treatment period.
Change from baseline in mean monthly acute medication use days across the 12-week treatment period.
Achievement of at least a 50% reduction in mean monthly migraine days across the 12-week treatment period.
Change from baseline in MSQ v2.1 Role Function-Restrictive domain score at Week 12
Change from baseline in the HIT-6 total score at Week 12 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From baseline to Week 12. Baseline is defined as the number of migraine days during the last 28 days of the baseline phase (ie, Day -28 to -1) |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 |
| Tolerability of atogepant will also be evaluated |
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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 | 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 66 |
| 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 |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Sweden |
| United Kingdom |
| United States |
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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
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The end of the study is defined as the date of the last visit of the last participant in the study.
A participant is considered to have completed the study if he/she has not been terminated early and has completed all phases of the study including the last scheduled procedure shown in the schedule of activities. |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 29 |
| 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 | 8 |
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