Clinical Trial Results:
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy, Safety, and Tolerability of Atogepant for the Prevention of Chronic Migraine (Progress)
Summary
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EudraCT number |
2018-004337-32 |
Trial protocol |
FR CZ SE PL DE DK ES GB IT |
Global end of trial date |
20 Jan 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
07 Feb 2023
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First version publication date |
07 Feb 2023
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
3101-303-002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03855137 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Allergan Limited
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Sponsor organisation address |
Allergan Limited Marlow International The Parkway, Marlow Buckinghamshire, United Kingdom, SL7 1YL
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Public contact |
Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
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Scientific contact |
Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
20 Jan 2022
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
20 Jan 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective of this study was to evaluate the efficacy, safety and tolerability of atogepant in subjects with chronic migraine.
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Protection of trial subjects |
All study subjects were required to read and sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
11 Mar 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
China: 28
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Country: Number of subjects enrolled |
Czechia: 117
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Country: Number of subjects enrolled |
Denmark: 5
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Country: Number of subjects enrolled |
France: 10
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Country: Number of subjects enrolled |
Germany: 15
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Country: Number of subjects enrolled |
Italy: 23
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Country: Number of subjects enrolled |
Japan: 157
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Country: Number of subjects enrolled |
Korea, Republic of: 68
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Country: Number of subjects enrolled |
Poland: 49
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Country: Number of subjects enrolled |
Russian Federation: 36
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Country: Number of subjects enrolled |
Spain: 18
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Country: Number of subjects enrolled |
Sweden: 1
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Country: Number of subjects enrolled |
Canada: 14
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Country: Number of subjects enrolled |
Taiwan: 22
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
United States: 214
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Worldwide total number of subjects |
778
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EEA total number of subjects |
238
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
754
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From 65 to 84 years |
24
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Total of 778 subjects were randomised in a 1:1:1 ratio to receive atogepant matching placebo and, atogepant 30 mg twice daily (BID), or atogepant 60 mg once daily (QD) for up to 12 weeks in a double-blind (DB) treatment period followed by a 4 week follow up (FU) period till the end of the study up to approximately 16 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
DB Treatment Period (Day 1 to Week 12)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Data analyst, Carer | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received atogepant-matching placebo tablets, orally, twice BID for 12 weeks in a DB treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Atogepant-matching placebo tablets administered orally.
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Arm title
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Atogepant 60 mg QD | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Atogepant-matching placebo tablets administered orally.
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Investigational medicinal product name |
Atogepant
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Atogepant tablets administered orally.
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Arm title
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Atogepant 30 mg BID | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Atogepant-matching placebo tablets administered orally.
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Investigational medicinal product name |
Atogepant
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Atogepant tablets administered orally.
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Period 2
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Period 2 title |
FU Period (Week 12 to Week 16)
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Atogepant-matching placebo tablets administered orally.
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Arm title
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Atogepant 60 mg QD | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Atogepant-matching placebo tablets administered orally.
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Investigational medicinal product name |
Atogepant
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Atogepant tablets administered orally.
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Arm title
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Atogepant 30 mg BID | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subject sreceived atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Atogepant-matching placebo tablets administered orally.
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Investigational medicinal product name |
Atogepant
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Atogepant tablets administered orally.
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Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Out of 694 subjects who completed the double-blind treatment period, only 517 subjects continued the follow-up period. |
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received atogepant-matching placebo tablets, orally, twice BID for 12 weeks in a DB treatment period. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Atogepant 60 mg QD
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Reporting group description |
Subjects received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Atogepant 30 mg BID
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Reporting group description |
Subjects received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received atogepant-matching placebo tablets, orally, twice BID for 12 weeks in a DB treatment period. | ||
Reporting group title |
Atogepant 60 mg QD
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Reporting group description |
Subjects received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period. | ||
Reporting group title |
Atogepant 30 mg BID
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Reporting group description |
Subjects received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period. | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period. | ||
Reporting group title |
Atogepant 60 mg QD
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Reporting group description |
Subjects received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period. | ||
Reporting group title |
Atogepant 30 mg BID
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Reporting group description |
Subject sreceived atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period. |
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End point title |
Change From Baseline in Mean Monthly Migraine Days Across 12-Week Treatment Period in mITT Population | ||||||||||||||||||||||||
End point description |
Subjects recorded daily duration of migraine in a diary. Migraine day was any calendar day on which the subject experienced a migraine headache. Monthly (4-week) migraine days were defined as the total number of reported migraine days in diary divided by total number of days with diary records during each 4-week period and multiplied by 28. Each 4-week period was averaged. Baseline is defined as the number of migraine days during the last 28 days prior to the randomisation date. Negative change from Baseline indicates improvement. A contrast from Mixed-effects model for repeated measures (MMRM) was used to obtain the average treatment effects across the 12-week treatment period. Modified Intent-to-Treat (mITT) Population=all randomised subjects who received at least 1 dose of study intervention, had an evaluable baseline period of eDiary data, and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during the DB treatment period.
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End point type |
Primary
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End point timeframe |
Baseline to Week 12
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||
Comparison groups |
Placebo v Atogepant 30 mg BID
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Number of subjects included in analysis |
499
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||||||||||||||
P-value |
< 0.0001 [2] | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||||||||||
Point estimate |
-2.41
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-3.48 | ||||||||||||||||||||||||
upper limit |
-1.33 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.547
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Notes [1] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. [2] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. |
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Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||
Comparison groups |
Placebo v Atogepant 60 mg QD
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Number of subjects included in analysis |
502
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||||||||||||||
P-value |
= 0.0009 [4] | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||||||||||
Point estimate |
-1.82
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-2.89 | ||||||||||||||||||||||||
upper limit |
-0.75 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
0.545
|
||||||||||||||||||||||||
Notes [3] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. [4] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. |
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in Mean Monthly Migraine Days Across 12-Week Treatment Period in OTHE Population | ||||||||||||||||||||||||
End point description |
Participants recorded daily duration of migraine in a diary. A migraine day was any calendar day on which the participant experienced a migraine headache. The monthly(4-week) migraine days were defined as the total number of reported migraine days in diary divided by total number of days with diary records during each 4-week period and multiplied by 28. Each 4-week period was averaged. Baseline is defined as the number of migraine days during the last 28 days prior to the randomization date. Negative change from Baseline=improvement. A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period. Off-treatment hypothetical estimand population:all randomized participants who received ≥1 dose of study intervention, had an evaluable baseline period of eDiary data and had ≥1 evaluable postbaseline 4-week period (Weeks 1 to 4, 5 to 8, 9 to 12) of eDiary data during the study, regardless of whether on study treatment or off study treatment.
|
||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
Baseline to Week 12
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||
Comparison groups |
Placebo v Atogepant 30 mg BID
|
||||||||||||||||||||||||
Number of subjects included in analysis |
503
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [5] | ||||||||||||||||||||||||
P-value |
= 0.0001 [6] | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||||||||||
Point estimate |
-2.24
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-3.31 | ||||||||||||||||||||||||
upper limit |
-1.16 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
0.547
|
||||||||||||||||||||||||
Notes [5] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. [6] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||
Comparison groups |
Placebo v Atogepant 60 mg QD
|
||||||||||||||||||||||||
Number of subjects included in analysis |
506
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [7] | ||||||||||||||||||||||||
P-value |
= 0.0024 [8] | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||||||||||
Point estimate |
-1.66
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-2.72 | ||||||||||||||||||||||||
upper limit |
-0.59 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
0.544
|
||||||||||||||||||||||||
Notes [7] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. [8] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. |
|
|||||||||||||||||
End point title |
Change From Baseline in Mean Monthly Headache Days Across 12-Week Treatment Period in mITT Population | ||||||||||||||||
End point description |
Subjects recorded daily total duration of a headache in a diary. A headache day is any calendar day on which the subject experienced a headache pain lasting 2 hours or longer unless an acute headache medication was used after the start of the headache. The monthly (4-week) headache days were defined as the total number of reported headache days in the diary divided by the total number of days with diary records during each 4-week period and multiplied by 28. Each 4-week period was averaged. Baseline is defined as the number of headache days during the last 28 days prior to the randomisation date. Negative change from Baseline indicates improvement. MMRM was used for analysis. mITT Population included all randomised subjects who received at least 1 dose of study intervention, had an evaluable baseline period of eDiary data, and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during the double-blind treatment period.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline to Week 12
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 30 mg BID
|
||||||||||||||||
Number of subjects included in analysis |
499
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [9] | ||||||||||||||||
P-value |
< 0.0001 [10] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
-2.32
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-3.38 | ||||||||||||||||
upper limit |
-1.26 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.541
|
||||||||||||||||
Notes [9] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. [10] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. |
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 60 mg QD
|
||||||||||||||||
Number of subjects included in analysis |
502
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [11] | ||||||||||||||||
P-value |
= 0.0009 [12] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
-1.87
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-2.93 | ||||||||||||||||
upper limit |
-0.81 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.538
|
||||||||||||||||
Notes [11] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. [12] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. |
|
|||||||||||||||||
End point title |
Change From Baseline in Mean Monthly Acute Medication use Days Across 12-Week Treatment Period in mITT Population | ||||||||||||||||
End point description |
An acute medication use day was defined as any day on which a subject reports, per eDiary, the intake of allowed medication(s) to treat an acute migraine. The monthly (4-week) acute medication use days were defined as the total number of reported acute medication use days in the diary divided by the total number of days with diary records during each 4-week period and multiplied by 28. Each 4-week period was averaged. Baseline is defined as the number of migraine days during the last 28 days prior to the randomisation date. A negative change from Baseline indicates improvement. A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period. mITT Population included all randomised subjects who received at least 1 dose of study intervention, had an evaluable baseline period of eDiary data, and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during the double-blind treatment period.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline to Week 12
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 30 mg BID
|
||||||||||||||||
Number of subjects included in analysis |
499
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [13] | ||||||||||||||||
P-value |
< 0.0001 [14] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
-2.63
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-3.63 | ||||||||||||||||
upper limit |
-1.63 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.51
|
||||||||||||||||
Notes [13] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. [14] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. |
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 60 mg QD
|
||||||||||||||||
Number of subjects included in analysis |
502
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [15] | ||||||||||||||||
P-value |
= 0.0009 [16] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
-2.13
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-3.13 | ||||||||||||||||
upper limit |
-1.13 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.508
|
||||||||||||||||
Notes [15] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. [16] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. |
|
|||||||||||||||||
End point title |
Change From Baseline in the Headache Impact Test (HIT-6) Total Score at Week 12 in Off-treatment Hypothetical Estimand (OTHE) Population | ||||||||||||||||
End point description |
HIT-6 is a 6-question assessment used to measure the impact headaches have on a subject’s ability to function on the job, at school, at home, and in social situations. It assesses the effect that headaches have on normal daily life and the subject’s ability to function. Responses are based on frequency using a 5-point scale ranging from “never” to “always.” The HIT-6 total score, which ranges from 36 to 78, is the sum of the responses - each of which is assigned a score ranging from 6 points (never) to 13 points (always). Off-treatment hypothetical estimand population:subjects receiving ≥1 dose of drug, had an evaluable baseline period, ≥1 evaluable postbaseline 4-week period(Weeks 1-4, 5-8, 9-12) of eDiary data, regardless of on study or off study treatment.MMRM was used for the analyses.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
At Week 12
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 30 mg BID
|
||||||||||||||||
Number of subjects included in analysis |
503
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [17] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
-3.3
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-4.67 | ||||||||||||||||
upper limit |
-1.93 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.697
|
||||||||||||||||
Notes [17] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. |
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 60 mg QD
|
||||||||||||||||
Number of subjects included in analysis |
506
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0001 [18] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
-2.66
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-4.02 | ||||||||||||||||
upper limit |
-1.3 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.69
|
||||||||||||||||
Notes [18] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. |
|
|||||||||||||||||
End point title |
Change From Baseline in Migraine Specific Quality of Life (QoL) Questionnaire, Version 2.1 (MSQ v2.1) Role Function-Restrictive Domain Score at Week 12 in OTHE Population | ||||||||||||||||
End point description |
MSQ v2.1=14-item questionnaire measuring health-related QoL impairments for migraine in past 4 weeks,divided into 3 domains:Role Function Restrictive(question no.1-7,score ranges 7-42)assesses how migraines limits daily social, work-related activities;Role Function Preventive(question no.8-11,score ranges 4-24)assesses how migraine prevent activities;Emotional Function(question no.12-14,score ranges 3-18) assesses emotions.Subjects respond using 6-point scale ranging from none to all time.Raw dimension score=sum of item responses rescaled to 0 to 100,higher scores=better quality of life.Contrast from MMRM was used to obtain average treatment effects across 12-week treatment period.Off-treatment hypothetical estimand population:subjects receiving ≥1 dose of drug, had an evaluable baseline period, ≥1 evaluable postbaseline 4-week period(Weeks 1-4, 5-8, 9-12) of eDiary data, regardless of on study or off study treatment.Subjects analysed=no. of subjects with data available for analyses.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
At Week 12
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 30 mg BID
|
||||||||||||||||
Number of subjects included in analysis |
503
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [19] | ||||||||||||||||
P-value |
< 0.0001 [20] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
7.43
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
3.77 | ||||||||||||||||
upper limit |
11.09 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
1.864
|
||||||||||||||||
Notes [19] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. [20] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. |
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 60 mg QD
|
||||||||||||||||
Number of subjects included in analysis |
506
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [21] | ||||||||||||||||
P-value |
= 0.0018 [22] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
5.78
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
2.15 | ||||||||||||||||
upper limit |
9.41 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
1.848
|
||||||||||||||||
Notes [21] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. [22] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. |
|
|||||||||||||||||
End point title |
Change From Baseline in Mean Monthly Performance of Daily Activities Domain Score of the AIM-D Across 12-Week Treatment Period in mITT Population | ||||||||||||||||
End point description |
AIM-D= 11-item patient-reported outcome(PRO) measure assessing impact of migraine on performance of daily activities and physical impairment using 6-point rating scale where 0=not difficult at all,1=a little difficult,2=somewhat difficult,3=very difficult,4=extremely difficult, and5=I could not do it at all. Raw performance of daily activities domain scores were transformed to 0-100 scale, with higher scores indicating greater impact of migraine (higher disease burden). Baseline=number of migraine days during last 28 days prior to randomisation date.Contrast from MMRM was used to obtain average treatment effects across 12-week treatment period.mITT Population=all randomised subjects receiving at least 1 dose of study intervention,had an evaluable baseline period of eDiary data,had at least 1 evaluable post-baseline 4-week period(Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during double-blind treatment period.Subjects analysed=number of subjects with data available for analyses.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline to Week 12
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 30 mg BID
|
||||||||||||||||
Number of subjects included in analysis |
451
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [23] | ||||||||||||||||
P-value |
= 0.0003 [24] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
-4.85
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-6.75 | ||||||||||||||||
upper limit |
-2.95 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.968
|
||||||||||||||||
Notes [23] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. [24] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. |
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 60 mg QD
|
||||||||||||||||
Number of subjects included in analysis |
457
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [25] | ||||||||||||||||
P-value |
= 0.0009 [26] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
-3.38
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-5.27 | ||||||||||||||||
upper limit |
-1.49 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.963
|
||||||||||||||||
Notes [25] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. [26] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. |
|
|||||||||||||||||
End point title |
Percentage of Subjects With at Least a 50% Reduction in 3-Month Average of Monthly Migraine Days in mITT Population | ||||||||||||||||
End point description |
Data is reported for 50% responders averaged at each 4-week period. 50% responders are subjects with at least a 50 percent reduction from baseline in monthly migraine days. Subjects recorded daily duration of migraine in a diary. A migraine day was any calendar day on which the subject experienced a migraine headache. The monthly (4-week) migraine days were equal to total number of reported migraine days in diary divided by total number of days with diary records in each 4-week period multiplied by 28. The values are rounded off to the first decimal value. mITT Population included all randomised subjects who received at least 1 dose of study intervention, had an evaluable baseline period of eDiary data, and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during the double-blind treatment period.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
At Week 12
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 30 mg BID
|
||||||||||||||||
Number of subjects included in analysis |
499
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [27] | ||||||||||||||||
P-value |
= 0.0003 [28] | ||||||||||||||||
Method |
Logistic regression | ||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||
Point estimate |
2.13
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
1.45 | ||||||||||||||||
upper limit |
3.14 | ||||||||||||||||
Notes [27] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. [28] - Logistic regression for each atogepant group versus placebo with baseline monthly migraine days as covariate,stratification of region,acute medication overuse,migraine prevention medication and number of failures,treatment group as fixed factors. |
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 60 mg QD
|
||||||||||||||||
Number of subjects included in analysis |
502
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [29] | ||||||||||||||||
P-value |
= 0.0009 [30] | ||||||||||||||||
Method |
Logistic regression | ||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||
Point estimate |
2.04
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
1.38 | ||||||||||||||||
upper limit |
3 | ||||||||||||||||
Notes [29] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. [30] - Logistic regression for each atogepant group versus placebo with baseline monthly migraine days as covariate,stratification of region,acute medication overuse,migraine prevention medication and number of failures,treatment group as fixed factors. |
|
|||||||||||||||||
End point title |
Change From Baseline in Mean Monthly Physical Impairment Domain Score of the AIM-D Across 12-Week 12 Treatment Period in mITT Population | ||||||||||||||||
End point description |
AIM-D= 11-item PRO measure that assesses impact of migraine on performance of daily activities and physical impairment using a 6-point rating scale where 0=not difficult at all, 1=a little difficult, 2=somewhat difficult, 3=very difficult, 4=extremely difficult, and 5=I could not do it at all. Raw physical impairment domain scores were transformed to 0-100 scale, with higher scores indicating greater impact of migraine (higher disease burden). Baseline is defined as the number of migraine days during last 28 days prior to the randomisation date. A contrast from MMRM was used to obtain average treatment effects across 12-week treatment period. mITT Population=all randomised subjects who received at least 1 dose of study intervention, had an evaluable baseline period of eDiary data, and had at least 1 evaluable post-baseline 4-week period (Weeks 1 to 4, 5 to 8, and 9 to 12) of eDiary data during DB treatment period. Subjects analysed=number of subjects with data available for analyses.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline to Week 12
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 30 mg BID
|
||||||||||||||||
Number of subjects included in analysis |
451
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [31] | ||||||||||||||||
P-value |
= 0.0003 [32] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
-4.19
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-5.95 | ||||||||||||||||
upper limit |
-2.43 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.897
|
||||||||||||||||
Notes [31] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. [32] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. |
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 60 mg QD
|
||||||||||||||||
Number of subjects included in analysis |
457
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [33] | ||||||||||||||||
P-value |
= 0.0025 [34] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
-2.71
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-4.47 | ||||||||||||||||
upper limit |
-0.96 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.893
|
||||||||||||||||
Notes [33] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. [34] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. |
|
|||||||||||||||||
End point title |
Change From Baseline in Mean Monthly Headache Days Across 12-Week Treatment Period in OTHE Population | ||||||||||||||||
End point description |
Participants recorded daily total duration of a headache in a diary. Headache day:any calendar day on which the participant experienced a headache pain lasting 2 hours or longer unless an acute headache medication was used after the start of the headache.Monthly (4-week) headache days:the total number of reported headache days in the diary divided by the total number of days with diary records during each 4-week period multiplied by 28. Each 4-week period was averaged. Baseline:the number of headache days during last 28 days prior to the randomization date. Negative change from Baseline=improvement.A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period. OTHE population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline to Week 12
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 30 mg BID
|
||||||||||||||||
Number of subjects included in analysis |
503
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [35] | ||||||||||||||||
P-value |
= 0.0002 [36] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
-2.14
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-3.2 | ||||||||||||||||
upper limit |
-1.09 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.539
|
||||||||||||||||
Notes [35] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. [36] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. |
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 60 mg QD
|
||||||||||||||||
Number of subjects included in analysis |
506
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [37] | ||||||||||||||||
P-value |
= 0.0024 [38] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
-1.72
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-2.78 | ||||||||||||||||
upper limit |
-0.67 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.536
|
||||||||||||||||
Notes [37] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. [38] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. |
|
|||||||||||||||||
End point title |
Change From Baseline in Mean Monthly Acute Medication Use Days Across 12-Week Treatment Period in OTHE | ||||||||||||||||
End point description |
An acute medication use day is defined as any day on which a participant reports, per eDiary, the intake of allowed medication(s) to treat an acute migraine. The monthly (4-week) acute medication use days were defined as the total number of reported acute medication use days in the diary divided by the total number of days with diary records during each 4-week period and multiplied by 28. Each 4-week period was averaged. Baseline is defined as the number of migraine days during the last 28 days prior to the randomization date. A negative change from Baseline indicates improvement. A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period. OTHE population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline to Week 12
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 30 mg BID
|
||||||||||||||||
Number of subjects included in analysis |
503
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [39] | ||||||||||||||||
P-value |
= 0.0002 [40] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
-2.52
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-3.52 | ||||||||||||||||
upper limit |
-1.53 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.507
|
||||||||||||||||
Notes [39] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. [40] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. |
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 60 mg QD
|
||||||||||||||||
Number of subjects included in analysis |
506
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [41] | ||||||||||||||||
P-value |
= 0.0024 [42] | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Least Squares Mean Difference | ||||||||||||||||
Point estimate |
-2.09
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-3.09 | ||||||||||||||||
upper limit |
-1.1 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.505
|
||||||||||||||||
Notes [41] - MMRM model=treatment group,visit,stratification by acute medication overuse,migraine prevention medication use and number of failures,region,and treatment group-by-visit as fixed factors and baseline and baseline-by-visit interaction as covariates. [42] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. |
|
|||||||||||||||||
End point title |
Percentage of Participants With at Least a 50% Reduction in 3-Month Average of Monthly Migraine Days in OTHE | ||||||||||||||||
End point description |
Data is reported for 50% responders averaged at each 4-week period. 50% responders are participants with at least a 50 percent reduction from baseline in 3-month average of monthly migraine days. Participants recorded daily duration of migraine in a diary. A migraine day was any calendar day on which the participant experienced a migraine headache. The monthly (4-week) migraine days is equal to total number of reported migraine days in diary divided by total number of days with diary records in each 4-week period multiplied by 28. The values are rounded off to the first decimal value. OTHE population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline to Week 12
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 30 mg BID
|
||||||||||||||||
Number of subjects included in analysis |
503
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [43] | ||||||||||||||||
P-value |
= 0.0006 [44] | ||||||||||||||||
Method |
Logistic regression | ||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||
Point estimate |
2.03
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
1.38 | ||||||||||||||||
upper limit |
2.98 | ||||||||||||||||
Notes [43] - Logistic regression for each atogepant group versus placebo with baseline monthly migraine days as covariate,stratification of region,acute medication overuse,migraine prevention medication and number of failures,treatment group as fixed factors. [44] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. |
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Comparison groups |
Placebo v Atogepant 60 mg QD
|
||||||||||||||||
Number of subjects included in analysis |
506
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [45] | ||||||||||||||||
P-value |
= 0.0024 [46] | ||||||||||||||||
Method |
Logistic regression | ||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||
Point estimate |
1.9
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
1.29 | ||||||||||||||||
upper limit |
2.79 | ||||||||||||||||
Notes [45] - Logistic regression for each atogepant group versus placebo with baseline monthly migraine days as covariate,stratification of region,acute medication overuse,migraine prevention medication and number of failures,treatment group as fixed factors. [46] - Adjusted p-value using graphical approach to control the overall type 1 error rate for multiple comparisons. |
|
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Adverse events information
|
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Timeframe for reporting adverse events |
From first dose of study drug up to end of study (Up to approximately 16 weeks)
|
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Adverse event reporting additional description |
Safety population included all participants who received at least 1 dose of study intervention and was used for serious adverse events and non-serious adverse events.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.0
|
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Reporting groups
|
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Reporting group title |
Placebo
|
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Reporting group description |
Subjects received atogepant-matching placebo tablets, orally, BID for 12 weeks in a DB treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Atogepant 60 mg QD
|
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Reporting group description |
Subjects received atogepant 60 mg, orally, QD along with atogepant-matching placebo 30 mg as morning dose followed by atogepant-matching placebo 30 mg and 60 mg as evening doses for up to 12 weeks in a DB treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Atogepant 30 mg BID
|
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Reporting group description |
Subjects received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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08 Apr 2019 |
The following changes were implemented with Amendment 1: Added instructions for study conducted in China and Canada. Clarified primary and secondary endpoints for China, and Canada. Clarified prohibited medications. Updated laboratory parameters. Updated the subgroup analyses. Corrected the study diagram for the estimand framework. Updated the definition of failed migraine preventive medication. |
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23 Sep 2019 |
The following changes were implemented with Amendment 2: Added instructions for study conducted in Japan. Added instruction regarding Visit 8 (follow-up) for subjects in Japan and China who may rollover to a regional, long-term, extension, safety study. Clarified secondary efficacy endpoints for Europe and Canada, and for all other regions except Europe and Canada. Updated description of the AIM-D health outcomes measure and endpoints. Described the Hochberg procedure to be used to control the overall Type I error rate at a 0.05 level (2-sided) for multiple comparisons of 2 atogepant doses with placebo for the primary efficacy endpoint, only for the analysis in Japan. Described weekly data analysis procedures for other efficacy analyses. Described planned subgroup analyses to evaluate consistency of treatment across regions and subpopulations. Updated description of safety analysis. Clarified criteria for sexual abstinence to be considered as a highly effective contraceptive method. Added a benefit/risk assessment. Added definition of the end of the study. Clarified exclusion criterion based on hypersensitivity to study interventions. Clarified the instructions regarding prohibited medication/treatments. Clarified instructions for the subjects. Clarified instructions regarding assessment of causality of adverse events. Added definition of adverse reaction, serious adverse reaction, and suspected unexpected serious adverse reaction. Clarified instruction regarding changes to the protocol. |
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29 May 2020 |
The following changes were implemented with Amendment 3: Updated the requirements by French authorities. Updated the enrollment criteria based on data review of recent migraine prevention studies. Clarified the randomization and stratification process to include region. Clarified participation in Visit 8/EOS for rollover subjects, by region and respective long-term safety extension study, and added information to allow for subjects to roll over to the respective open-label (OL) long-term extension study. Adapted description of regions for consistency with stratification. Clarified the description of the ITT and mITT population, and the analysis population for off-treatment hypothetical estimand for the primary efficacy analysis to support filing in Europe.Clarified primary endpoint and added the statistical model term ‘region’ to the MMRM model for primary analysis. Clarified the AIM-D related secondary endpoint, based on psychometric evidence of the AIM-D consisting of 2 domains, performance of daily activities and physical impairment. Clarified secondary endpoints and statistical analysis model for secondary analysis. Outlined conduct of study when remote visits are necessary due to COVID-19. Updated the Close Out Visit to comply with Russian requirement. Updated the masking/blinding and dosage schedule. Updated the additional efficacy endpoints.Clarified that 50% responder will be assessed for each individual. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |