Efficacy, Safety, and Tolerability of Atogepant for the Prevention of Chronic Migraine

• ClinicalTrials.gov Identifier: NCT03855137
• Recruitment Status: Completed
• First Posted: February 26, 2019
• Results First Posted: February 14, 2023
• Last Update Posted: February 14, 2023
• Sponsor: Allergan
• Information provided by (Responsible Party): Allergan

Tracking Information

• First Submitted Date: February 25, 2019
• First Posted Date: February 26, 2019
• Results First Submitted Date: January 18, 2023
• Results First Posted Date: February 14, 2023
• Last Update Posted Date: February 14, 2023
• Actual Study Start Date: March 11, 2019
• Actual Primary Completion Date: January 20, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 18, 2023)

• Change From Baseline in Mean Monthly Migraine Days Across 12-Week Treatment Period in mITT Population [ Time Frame: Baseline to Week 12 ]
  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 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.
• Change From Baseline in Mean Monthly Migraine Days Across 12-Week Treatment Period in Off-Treatment Hypothetical Estimand Population [ Time Frame: Baseline to Week 12 ]
  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 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.

Original Primary Outcome Measures (submitted: February 25, 2019)

Change from baseline in mean monthly migraine days across the treatment period [ Time Frame: 12 Weeks ]

Efficacy assessments will be based on information recorded by the participant. An eDiary will be used daily at home to collect data on headache duration, headache characteristics, symptoms, and acute medication use, which will be collectively applied to define migraine days and headache days

Current Secondary Outcome Measures (submitted: January 18, 2023)

• Change From Baseline in Mean Monthly Headache Days Across 12-Week Treatment Period in mITT Population [ Time Frame: Baseline to Week 12 ]
  Participants recorded daily total duration of a headache in a diary. A headache day is 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. 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 randomization date. Negative change from Baseline indicates improvement. A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period.
• Change From Baseline in Mean Monthly Headache Days Across 12-Week Treatment Period in Off-Treatment Hypothetical Estimand Population [ Time Frame: Baseline to Week 12 ]
  Participants recorded daily total duration of a headache in a diary. A headache day is 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. 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 randomization date. Negative change from Baseline indicates improvement. A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period.
• Change From Baseline in Mean Monthly Acute Medication Use Days Across 12-Week Treatment Period in mITT Population [ Time Frame: Baseline to Week 12 ]
  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.
• Change From Baseline in Mean Monthly Acute Medication Use Days Across 12-Week Treatment Period in Off-treatment Hypothetical Estimand Population [ Time Frame: Baseline to Week 12 ]
  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.
• Percentage of Participants With at Least a 50% Reduction in 3-Month Average of Monthly Migraine Days in mITT Population [ Time Frame: Baseline to Week 12 ]
  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.
• Percentage of Participants With at Least a 50% Reduction in 3-Month Average of Monthly Migraine Days in Off-Treatment Hypothetical Estimand Population [ Time Frame: Baseline to Week 12 ]
  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.
• Change From Baseline in Migraine Specific Quality of Life Questionnaire, Version 2.1 (MSQ v2.1) Role Function-Restrictive Domain Score at Week 12 in Off-Treatment Hypothetical Estimand Population [ Time Frame: At Week 12 ]
  The MSQ v2.1 is a 14-item questionnaire designed to measure health-related quality of life impairments attributed to migraine in the past 4 weeks. It is divided into 3 domains: Role Function Restrictive (question numbers 1-7, score ranges 7 to 42) assesses how migraines limit one's daily social and work-related activities; Role Function Preventive (question numbers 8-11, score ranges 4 to 24) assesses how migraines prevent these activities; and the Emotional Function (question numbers 12-14, score ranges 3 to 18) domain assesses the emotions associated with migraines. Participants respond to items using a 6-point scale ranging from none of the time to all of the time. Raw dimension scores are computed as a sum of item responses and rescaled to a 0 to 100 scale, where higher scores indicate better quality of life. A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period.
• Change From Baseline in Mean Monthly Performance of Daily Activities Domain Score of the AIM-D Across 12-Week Treatment Period in mITT Population [ Time Frame: Baseline to Week 12 ]
  The AIM-D is a 11-item patient-reported outcome (PRO) measure that assesses the impact of migraine on the performance of daily activities which include, 7 items: difficulty with household chores, errands, leisure activities at home, leisure or social activities outside the home, strenuous physical activities, concentrating, and thinking clearly and physical impairment; 4 items: difficulty walking, moving body, bending forward, moving head 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. The raw performance of daily activities domain scores were transformed to 0-100 scale, with higher scores indicating greater impact of migraine (higher disease burden). A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period.
• Change From Baseline in Mean Monthly Physical Impairment Domain Score of the AIM-D Across 12-Week Treatment Period in mITT Population [ Time Frame: Baseline to Week 12 ]
  The AIM-D is a 11-item PRO measure that assesses the impact of migraine on the performance of daily activities which includes 7 items: difficulty with household chores, errands, leisure activities at home, leisure or social activities outside the home, strenuous physical activities, concentrating, and thinking clearly and physical impairment; 4 items: difficulty walking, moving body, bending forward, moving head 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. The raw physical impairment domain scores were transformed to 0-100 scale, with higher scores indicating greater impact of migraine (higher disease burden). A contrast from MMRM was used to obtain the average treatment effects across the 12-week treatment period.
• Change From Baseline in the Headache Impact Test (HIT-6) Total Score at Week 12 in Off-Treatment Hypothetical Estimand Population [ Time Frame: At Week 12 ]
  HIT-6 is a 6-question assessment used to measure the impact headaches have on a participant'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 participant'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). MMRM was used for the analyses.

Original Secondary Outcome Measures (submitted: February 25, 2019)

• Change from baseline in mean monthly headache days across the 12-week treatment period [ Time Frame: 12 Weeks ]
  Efficacy assessments will be based on information recorded by the participant. An eDiary will be used daily at home to collect data on headache duration, headache characteristics, symptoms, and acute medication use, which will be collectively applied to define migraine days and headache days
• Change from baseline in mean monthly acute medication use days across the 12-week treatment period [ Time Frame: 12 Weeks ]
  Efficacy assessments will be based on information recorded by the participant. An eDiary will be used daily at home to collect data on headache duration, headache characteristics, symptoms, and acute medication use, which will be collectively applied to define migraine days and headache days
• Proportion of participants with at least a 50% reduction in mean monthly migraine days across the 12-week treatment period [ Time Frame: 12 Weeks ]
  Efficacy assessments will be based on information recorded by the participant. An eDiary will be used daily at home to collect data on headache duration, headache characteristics, symptoms, and acute medication use, which will be collectively applied to define migraine days and headache days
• Change from baseline in MSQ v2.1 Role Function-Restrictive domain score at Week 12 [ Time Frame: 12 Weeks ]
  The MSQ v2.1 is a 14-item questionnaire designed to measure health-related quality-of-life impairments attributed to migraine in the past 4 weeks. It is divided into 3 domains: Role Function Restrictive assesses how migraines limit one's daily social and work-related activities; Role Function Preventive assesses how migraines prevent these activities; and the Emotional Function domain assesses the emotions associated with migraines. Participants respond to items using a 6-point scale ranging from "none of the time" to "all of the time." Raw dimension scores are computed as a sum of item responses and rescaled to a 0 to 100 scale, where higher scores indicate better quality of life.
• Change from baseline in mean monthly performance of daily activities domain score of the AIM-D across the 12-week treatment period [ Time Frame: 12 Weeks ]
  The Activity Impairment in Migraine - Diary (AIM-D) is a 9-item PRO measure that assesses the impact of migraine on the performance of daily activities and physical impairment. Participants are asked to rate the level of difficulty experienced in the past 24 hours with performance of daily activities and physical impairment using a 6-point rating scale ranging from "Not difficult at all," "A little difficult, "Somewhat difficult," "Very difficult," "Extremely difficult," and "I could not do it at all."
• Change from baseline in mean monthly physical impairment domain score of the AIM-D across the 12-week treatment period [ Time Frame: 12 Weeks ]
  The Activity Impairment in Migraine - Diary (AIM-D) is a 9-item PRO measure that assesses the impact of migraine on the performance of daily activities and physical impairment. Participants are asked to rate the level of difficulty experienced in the past 24 hours with performance of daily activities and physical impairment using a 6-point rating scale ranging from "Not difficult at all," "A little difficult, "Somewhat difficult," "Very difficult," "Extremely difficult," and "I could not do it at all."

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy, Safety, and Tolerability of Atogepant for the Prevention of Chronic Migraine
• Official Title: 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)
• Brief Summary: This study evaluated the efficacy, safety and tolerability of atogepant in participants with chronic migraine. This study included a 12-week treatment period.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Chronic Migraine

Intervention

• Drug: Atogepant 30 mg
  Tablets containing 30 mg atogepant
• Drug: Atogepant 60 mg
  Tablets containing 60 mg atogepant
• Drug: Placebo
  30 mg/60 mg tablets containing atogepant-matching placebo

Study Arms

• Placebo Comparator: Placebo
  Participants received atogepant-matching placebo tablets, orally, twice daily (BID) for 12 weeks in a double-blind (DB) treatment period.
  Intervention: Drug: Placebo
• Active Comparator: Atogepant 30 mg BID
  Participants received atogepant 30 mg tablet, orally, BID and atogepant-matching placebo tablets orally, BID for up to 12 weeks in a DB treatment period.
  Interventions:

  • Drug: Atogepant 30 mg
  • Drug: Placebo
• Active Comparator: Atogepant 60 mg QD
  Participants received atogepant 60 mg, orally, once daily (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.
  Interventions:

  • Drug: Atogepant 60 mg
  • Drug: Placebo

Publications *

• Boinpally R, McNamee B, Yao L, Butler M, McGeeney D, Borbridge L, Periclou A. A Single Supratherapeutic Dose of Atogepant Does Not Affect Cardiac Repolarization in Healthy Adults: Results From a Randomized, Single-Dose, Phase 1 Crossover Trial. Clin Pharmacol Drug Dev. 2021 Sep;10(9):1099-1107. doi: 10.1002/cpdd.940. Epub 2021 May 4.
• Min KC, Kraft WK, Bondiskey P, Colon-Gonzalez F, Liu W, Xu J, Panebianco D, Mixson L, Dockendorf MF, Matthews CZ, Boinpally R. Atogepant Is Not Associated With Clinically Meaningful Alanine Aminotransferase Elevations in Healthy Adults. Clin Transl Sci. 2021 Mar;14(2):599-605. doi: 10.1111/cts.12917. Epub 2020 Nov 24.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 18, 2023): 778
• Original Estimated Enrollment (submitted: February 25, 2019): 750
• Actual Study Completion Date: January 20, 2022
• Actual Primary Completion Date: January 20, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• At least a 1-year history of chronic migraine (CM) consistent with a diagnosis according to the International Classification of Headache Disorders, 3rd Edition (ICHD-3), 2018
• Age of the participant at the time of migraine onset < 50 years

• Confirmation of headache/migraine headache day frequency as follows:

  • History of, on average, ≥ 15 headache days per month in the 3 months prior to Visit 1 in the opinion of the investigator AND
  • >=15 headache days during the 4-week screening/baseline period per the electronic diary (eDiary) AND
  • >=8 days during the 4-week screening/baseline period that qualify as being a migraine day per the eDiary
• Participants must be using a medically acceptable and effective method of birth control during the course of the entire study

Exclusion Criteria:

• Has a history of migraine, accompanied by diplopia or decreased level of consciousness, or retinal migraine
• Has a current diagnosis of new persistent daily headache, trigeminal autonomic cephalgia (eg, cluster headache), or painful cranial neuropathy
• History of an inadequate response to > 4 medications (2 of which have different mechanisms of action) prescribed for the prevention of migraine
• Woman is pregnant, planning to become pregnant during the course of the study, or currently lactating. Women of childbearing potential must have a negative urine pregnancy test at Visit 1 and Visit 2.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, China, Czechia, Denmark, France, Germany, Italy, Japan, Korea, Republic of, Poland, Russian Federation, Spain, Sweden, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03855137
• Other Study ID Numbers: 3101-303-002; 2018-004337-32 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols, analyses plans, clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: For details on when studies are available for sharing visit, please refer to the link below.
• Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Use Agreement (DUA). For more information on the process, or to submit a request, visit the following link.
• URL: https://vivli.org/ourmember/abbvie/

• Current Responsible Party: Allergan
• Original Responsible Party: Same as current
• Current Study Sponsor: Allergan
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: ALLERGAN INC.; Allergan

• PRS Account: Allergan
• Verification Date: January 2023