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    Summary
    EudraCT Number:2019-003448-58
    Sponsor's Protocol Code Number:3101-304-002
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-06-02
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2019-003448-58
    A.3Full title of the trial
    A Phase 3, Multicenter, Randomized, Double-blind, Placebo controlled, Parallel-group Study to Evaluate the Efficacy, Safety, and Tolerability of Oral Atogepant for the Prophylaxis of Migraine in Participants with Episodic Migraine Who Have Previously Failed 2 to 4 Classes of Oral Prophylactic Treatments (ELEVATE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Atogepant for prophylaxis of migraine in participants who failed previous oral prophylactic treatments
    A.3.2Name or abbreviated title of the trial where available
    ELEVATE
    A.4.1Sponsor's protocol code number3101-304-002
    A.5.4Other Identifiers
    Name:INDNumber:114780
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAllergan Limited
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAllergan Sales LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAllergan Ltd.
    B.5.2Functional name of contact pointCTRG
    B.5.3 Address:
    B.5.3.1Street AddressMarlow International, Parkway
    B.5.3.2Town/ cityMarlow, Buckinghamshire
    B.5.3.3Post codeSL7 1YL
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailML-CTRG@Allergan.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAtogepant
    D.3.2Product code AGN-241689
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAtogepant
    D.3.9.1CAS number 1374248-81-3
    D.3.9.2Current sponsor codeAGN-241689
    D.3.9.3Other descriptive nameMK-8031; L-004880174-008A; L-004880174; C11051808-H
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAtogepant
    D.3.2Product code AGN-241689
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAtogepant
    D.3.9.1CAS number 1374248-81-3
    D.3.9.2Current sponsor codeAGN-241689
    D.3.9.3Other descriptive nameMK-8031; L-004880174-008A; L-004880174; C11051808-H
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Episodic migraine
    E.1.1.1Medical condition in easily understood language
    Episodic migraine
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.0
    E.1.2Level LLT
    E.1.2Classification code 10082019
    E.1.2Term Episodic migraine
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To prospectively test for superiority of atogepant 30 mg QD and atogepant 60 mg QD versus placebo for the prevention of migraine in participants with episodic migraine who have previously failed 2 to 4 classes of oral medications for the prophylaxis of migraine
    E.2.2Secondary objectives of the trial
    To evaluate the effect of atogepant 30 mg QD and atogepant 60 mg QD versus placebo for the prophylaxis of headache.

    To evaluate the effect of atogepant 30 mg QD and atogepant 60 mg QD versus placebo on acute medication use.

    To evaluate the effect of atogepant 30 mg QD and atogepant 60 mg QD versus placebo on the proportion of participants with at least 50% reduction from baseline in monthly migraine days.

    To evaluate the effect of atogepant 30 mg QD and atogepant 60 mg QD versus placebo on the impact of migraine on daily activities as assessed by MSQ v2.1 Role Function-Restrictive domain score.

    For the European Union only:
    To evaluate the effect of atogepant 30 mg QD and atogepant 60 mg QD versus placebo on the impact of headaches on daily functioning as assessed by HIT-6.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetics
    E.3Principal inclusion criteria
    1.01 Male or female participants ages 18 (or age of legal majority) to 80 years, inclusive, at Visit 1

    2.01 At least a 1-year history of migraine with or without aura consistent with a diagnosis according to the ICHD-3, 2018.

    2.02 Age of the participant at the time of migraine onset < 50 years

    2.03 History of 4 to 14 migraine days per month on average in the 3 months prior to Visit 1 in the investigator’s judgment

    2.04 4 to 14 migraine days in the 28-day baseline period per eDiary (Note: A randomization cap of 20% will be instituted to ensure that the planned randomized participants include no more than 20% of participants with 4 to <8 migraine days at baseline.)

    2.05 Completed at least 20 out of 28 days in the eDiary during the baseline period and is able to read, understand, and complete the study questionnaires and eDiary per investigator’s judgment.

    2.06 Participants must meet all the below 2 criteria. Participants must have:
    a. Failed oral migraine prophylaxis medications from 2 to 4 of the medication classes as listed below:
    i. Propranolol, metoprolol, atenolol, bisoprolol, timolol, or nadolol;
    ii. Topiramate;
    iii. Flunarizine;
    iv. Valproate or divalproex;
    v. Amitriptyline or nortriptyline;
    vi. Venlafaxine or desvenlafaxine;
    vii. Lisinopril;
    viii. Candesartan;
    ix. Locally approved products (eg, oxeterone or pizotifen)

    b. Failed one AND failed or be not suitable for a second treatment from a different medication class as listed below:
    i. Propranolol OR metoprolol;
    ii. Topiramate;
    iii. Flunarizine;
    iv. Amitriptyline

    2.07 At least 80% of the randomized participants need to meet the below criteria:
    Failed at least 2 treatments from different medication classes as listed below:
    i. Propranolol OR metoprolol;
    ii. Topiramate;
    iii. Flunarizine;
    iv. Amitriptyline

    3.01 Male participants willing to minimize the risk of inducing pregnancy for the duration of the clinical study and follow-up period.
    A male participant must agree to use contraception during the intervention period and for at least 3 days after the last dose of study intervention refrain from donating sperm during this period.
    Female participants willing to minimize the risk of inducing pregnancy for the duration of the clinical study and follow-up period.
    A female participant is eligible to participate if she is not pregnant (ie, has a negative urine pregnancy result at the Screening Visit (Visit 1) and Randomization Visit (Visit 2), is not planning to become pregnant during the course of the study, is not breastfeeding, and fulfills at least one of the following conditions:
    a. Not a WOCBP as defined in Appendix 7 of the protocol
    OR
    b. A WOCBP who agrees to follow the contraceptive guidance of using a medically acceptable and effective contraceptive method as defined in Appendix 7 of the protocol during the intervention period and for 3 days after the last dose of study intervention.

    4.01 Written informed consent and participant privacy information (eg, Written Authorization for Use and Release of Health and Research Study Information [US sites] and written Data Protection consent [EU sites]) obtained from the participant prior to any study-related procedures.
    E.4Principal exclusion criteria
    For the full exclusion criteria verbiage, please refer to section 5.2 of the protocol

    1.01 Any clinically significant hematologic, endocrine, pulmonary, hepatic, gastrointestinal, or neurologic disease

    1.02 Participant has any other concurrent pain condition that, in the opinion of the investigator, may significantly impact the current headache disorder

    1.03 In the opinion of the investigator, confounding psychiatric conditions, dementia, epilepsy, or significant neurological disorders other than migraine

    1.04 History of malignancy in the 5 years prior to Visit 1, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer

    1.05 History of any prior gastrointestinal procedures or gastrointestinal conditions that may affect the absorption or metabolism of study intervention; participants with prior gastric bariatric interventions which have been reversed are not excluded

    1.06 Clinically significant cardiovascular or cerebrovascular disease per the investigator’s opinion

    1.07 Significant risk of self-harm based on clinical interview and responses on the C-SSRS, or of harm to others in the opinion of the investigator; participants must be excluded if they report suicidal ideation with intent, with or without a plan, in the past 6 months or report suicidal behavior in the 6 months prior to Visit 1 or Visit 2 assessments

    1.08 At Visit 1, a user of recreational or illicit drugs or has had a history within the past year of drug or alcohol abuse or dependence

    2.01 Has ≥ 15 headache days per month on average across the 3 months prior to Visit 1 in the investigator’s judgment

    2.02 Has ≥ 15 headache days in the 28-day baseline period per eDiary

    2.03 Difficulty distinguishing migraine headaches from tension-type or other headaches

    2.04 Has a history of migraine accompanied by diplopia or decreased level of consciousness or retinal migraine as defined by ICHD-3, 2018

    2.05 Has a current diagnosis of chronic migraine, new persistent daily headache, medication overuse headache, trigeminal autonomic cephalgia (eg, cluster headache), or painful cranial neuropathy as defined by ICHD-3, 2018

    3.01 Usage during 30 days prior to Visit 1 and throughout the study period of and requirement for any medication, diet, or non-pharmacological treatment that is on the list of prohibited concomitant medications or treatments that cannot be discontinued or switched to an allowable alternative medication or treatment. This includes concomitant medications with demonstrated efficacy for the prevention of migraine regardless of indication.

    3.02 Usage of therapeutic or cosmetic botulinum toxin injections into areas of the head, face, or neck within 6 months prior to Visit 1 and throughout the study period.

    3.03 Usage of butalbital-containing analgesics >2 days/month, triptans or ergots ≥ 10 days/month, or simple analgesics ≥ 15 days/month, or any usage of opioid-containing medications in the 3 months prior to Visit 1 per investigator’s judgment, or during the baseline period is excluded.

    3.04 Previous exposure to:
    • Atogepant
    • Injectable monoclonal antibodies blocking the CGRP pathway within the last 6 months prior to Visit 1
    • Ubrogepant
    • Rimegepant
    • Any other oral investigational CGRP-RA

    3.05 History of hypersensitivity or clinically significant adverse reaction to a CGRP-RA or hypersensitivity to any component of the study interventions.

    4.01 Currently participating or has participated in a study with an investigational compound or device within 30 days prior to Visit 1

    5.01 Hypertension as defined by sitting systolic blood pressure > 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg at Visits 1 or Visit 2. Vital sign measurements that exceed these limits may be repeated only once

    5.02 An ECG with clinically significant abnormalities at screening as determined by the investigator

    5.03 QTcF > 450 msec for males and QTcF > 470 msec for females at Visit 1 based on the ECG report of the central reviewer

    5.04 Clinically significant laboratory values (see protocol section 5.2)

    5.05 Positive result on the urine drug screen at Visit 1 unless explained by concomitant medication use

    5.06 History of acute hepatitis within 6 months of screening ; or chronic hepatitis; or a positive result on anti-hepatitis A IgM antibody, hepatitis B surface antigen, anti–hepatitis C antibody or anti-hepatitis E IgM antibody testing at screening

    6.01 Employed by or is an immediate family member of one of the investigators, study staff, or sponsor

    6.02 Participant has a condition or is in a situation which in the investigator's opinion may put the participant at significant risk, may confound the study results, or may interfere significantly with the participant’s participation in the study

    6.03 Any medical or other reasons that, in the investigator’s opinion, might indicate that the participant is unsuitable for the study
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in mean monthly migraine days across the 12-week treatment period.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From baseline to Week 12. Baseline is defined as the number of migraine days during the last 28 days of the baseline phase (ie, Day -28 to -1)
    E.5.2Secondary end point(s)
    Change from baseline in mean monthly headache days across the 12-week treatment period.

    Change from baseline in mean monthly acute medication use days across the 12-week treatment period.

    Achievement of at least a 50% reduction in mean monthly migraine days across the 12-week treatment period.

    Change from baseline in MSQ v2.1 Role Function-Restrictive domain score at Week 12

    Change from baseline in the HIT-6 total score at Week 12
    E.5.2.1Timepoint(s) of evaluation of this end point
    From baseline to Week 12. Baseline is defined as the number of migraine days during the last 28 days of the baseline phase (ie, Day -28 to -1)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability of atogepant will also be evaluated
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA66
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    Czech Republic
    Denmark
    France
    Germany
    Hungary
    Italy
    Netherlands
    Poland
    Russian Federation
    Spain
    Sweden
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the date of the last visit of the last participant in the study.

    A participant is considered to have completed the study if he/she has not been terminated early and has completed all phases of the study including the last scheduled procedure shown in the schedule of activities.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days8
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days8
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 63
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 564
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state72
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 430
    F.4.2.2In the whole clinical trial 627
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    No study intervention will be administered after the end of the study.

    Following the end of study, the participant may be treated as per usual practice and standard of care or referred to the participant’s treating physician/general practitioner for further medical care at the investigator’s discretion.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-07-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-24
    P. End of Trial
    P.End of Trial StatusOngoing
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