To prospectively test for superiority of 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
ID
Source
Brief title
Condition
- Headaches
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change from Baseline (CFB) in mean monthly migraine days across the 12-week
treatment period.
Secondary outcome
- Achievement of at least a 50% reduction in mean monthly migraine days across
the 12-week treatment period.
- CFB in mean monthly headache days across the 12 week treatment period.
- CFB in mean monthly acute medication use days across the 12-week treatment
period.
- CFB in MSQ v2.1 Role Function-Restrictive domain score at Week 12
- CFB in mean monthly Physical Impairment domain score of the AIM-D across the
12 week treatment period
- CFB in the HIT-6 total score at Week 12
Background summary
Migraine affects 18% of women and 6% of men in the United States with peak
prevalence occurring between the ages of 25 to 55 years. Approximately
one-third of these migraineurs have 3 or more migraine headaches per month, and
over half report severe impairment or the need for bed rest. Prevalence is
similar in Europe, with migraine headache affecting on average 17.6% of women
and 8% of men. As of 2016, migraine is the second leading cause of disability
worldwide.
Migraine is typically characterized by attacks of throbbing, unilateral
headache of moderate or severe pain intensity, associated with nausea,
vomiting, and/or sensitivity to light (photophobia) and sound (phonophobia). In
about 25% of individuals, the migraine headache is preceded by focal
neurological dysfunction (aura). Improving diagnosis and optimizing treatments
for migraine have been recognized as critically important to overcoming current
barriers to reduce the global burden of migraine.
Because there are no biological markers for migraine, diagnosis is based on
clinical history, exam, and the exclusion of other headache disorders.
Physicians apply clinical criteria to guide diagnoses and subsequent treatment.
Episodic migraine (EM) can be divided into low frequency (LFEM) and high
frequency episodic migraine (HFEM) depending on the headache days suffered per
month (GBD 2017).
Episodic migraine (EM) is a syndrome diagnosis applied to patients with
migraine (with or without aura) who have 1 to 14 headache days per month.
Chronic migraine is a specific ICHD-3diagnosis applied to a subset of patients
with >=15 headache days per month.
This study will include participants with episodic migraine who had failed 2-4
classes of prior oral prophylactic medications. The rationale for targeting
this population is 2-fold. Firstly, patients on currently available oral
prophylactic medications may experience poor tolerability; secondly, many of
these treatments have shown insufficient efficacy (did not sufficiently reduce
either severity or frequency) of migraine for many patients.
The consequences of the limitations in current oral prophylactic migraine
treatments amount to both poor adherence and reluctance to initiate
prophylactic treatment. In fact, recent studies have indicated that
approximately half of migraine patients discontinued their initial oral
migraine prophylactic treatment within 60 days, which might be explained by
poor tolerability or lack of efficacy.
Moreover, in a US-based retrospective database study it was concluded that
approximately 70% of patients who begin migraine prophylaxis with
antidepressants, antiepileptics, or beta-blockers are no longer taking these
medications at 6 months. Of those patients who continue to take a prophylactic
medication, many still have substantial disease burden.
Therefore, the proposed population for Study 3101-304-002 reflects clinical
practice. There is severe unmet need in patients that have failed multiple
migraine prophylactic oral medications, and these patients are currently often
relying on ineffective treatments and many suffer from intolerability to
currently available medications
Study objective
To prospectively test for superiority of 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
Study design
A global, multicenter, randomized, double-blind, placebo-controlled, parallel
group study in participants with episodic migraine who have previously failed 2
to 4 classes of oral medications for the prophylaxis of migraine
Intervention
Patient participation will begin with a 4-week screening/baseline period.
Participants who complete the 4-week screening/baseline period and meet all
entry criteria will be randomized to the doubleblind treatment period of the
study at Visit 2 (Randomization Visit). The double-blind treatment period will
last 12 weeks, with a subsequent safety follow-up period of 4 additional weeks.
Total duration of study participation for one participant is approximately 20
weeks.
Study burden and risks
The study will include a total of 8 visits and will be up to 20 weeks in
duration. Subjects are expected to undergo procedures/assessments as described
in the section 1.3 of the study protocol, which include: Physical exam, vital
signs, demographic and medical history; ECG; eDiary: reporting information on
symptoms/signs of disease, (i.e. headache duration, frequency, characteristics,
symptoms, acute medication use, etc.); Blood and urine tests (including urine
drug screening); Completion of questionnaire and answering questions from the
study team; Pregnancy tests in women of childbearing potential; Female
patients: no breastfeeding allowed. Effective methods of birth control must be
used from the time of signing the ICF, throughout the entire study; Male
patients: due to the potential risk of the effect on the sperm appropriate
method of contraception must be used starting at screening and throughout the
entire study.
The following risks were the most common side effects in a study of patients
with migraine receiving atogepant or placebo (medically inactive substance)
daily for 12 weeks: nausea, common cold, constipation, urinary tract infection,
fatigue, increased creatine phosphokinase
The risks involved in taking this study medication have been carefully assessed
by previous testing done in animal and human studies. Overall, the risks are
considered to be acceptable although some risks are unforeseeable. In addition
to the risks listed above, there may be some infrequent and unforeseeable risks
associated with the use of atogepant. Atogepant is investigational, when taken
alone or in combination with other medications, so there may be other risks
that are unknown.
Older drugs in this class have been associated with an increased risk of liver
problems. However, atogepant is a new drug that has been designed specifically
to minimise this risk. Based on previous studies with this drug, no safety
issues related to taking atogepant and liver problems have been detected.
Placebo Risks: If the study subject is in the group which is assigned placebo,
study subject*s symptoms of migraine may not improve or may worsen. Even if the
study subject is in the group that gets the active drug during the study, the
symptoms may not improve or may worsen.
Blood Sample Risks: Subjects may feel a slight needle prick when blood is
drawn. Some participants may have a slight bruise that will go away within a
few days. Sometimes, participants feel light headed or feel dizzy. Other rare
complications associated with the blood sample collection include: infections,
nerve lesions, accidental arterial puncture (when the needle pierces an artery
instead of a vein) and bleeding, inflammation of vein, and dizziness.
Electrocardiogram (ECG) Risks: The ECG procedure may cause minimal discomfort
and skin irritation during or after the attachment/removal of the leads (and
adhesive).
Allergic Reaction Risks: As with taking any treatment, there is a risk of
allergic reaction. Some symptoms of allergic reactions are: Rash; Wheezing and
difficulty breathing; Dizziness and fainting; Swelling around the mouth, throat
or eyes; A fast pulse; Sweating.
This study will include participants with episodic migraine who had failed 2-4
classes of prior oral prophylactic medications. The rationale for targeting
this population is 2-fold. Firstly, patients on currently available oral
prophylactic medications may experience poor tolerability; secondly, many of
these treatments have shown insufficient efficacy (did not sufficiently reduce
either severity or frequency) of migraine for many patients.
The consequences of the limitations in current oral prophylactic migraine
treatments amount to both poor adherence and reluctance to initiate
prophylactic treatment. In fact, recent studies have indicated that
approximately half of migraine patients discontinued their initial oral
migraine prophylactic treatment within 60 days, which might be explained by
poor tolerability or lack of efficacy.
Moreover, in a US-based retrospective database study it was concluded that
approximately 70% of patients who begin migraine prophylaxis with
antidepressants, antiepileptics, or beta-blockers are no longer taking these
medications at 6 months. Of those patients who continue to take a prophylactic
medication, many still have substantial disease burden.
Therefore, the proposed population for Study 3101-304-002 reflects clinical
practice. There is severe unmet need in patients that have failed multiple
migraine prophylactic oral medications, and these patients are currently often
relying on ineffective treatments and many suffer from intolerability to
currently available medications
Knollstrasse -
Ludwigshafen 67061
DE
Knollstrasse -
Ludwigshafen 67061
DE
Listed location countries
Age
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 both criteria below (ie, a and b). 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 at least one treatment from the list below:
i. Propranolol OR metoprolol;
ii. Topiramate;
iii. Flunarizine;
iv. Amitriptyline
3.01 Male participants willing to minimize the risk of inducing pregnancy as
detailed below:
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 and
refrain from donating sperm during this period.
Female participants willing to minimize the risk of inducing pregnancy as
detailed below:
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.
Exclusion criteria
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 nonpharmacological 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 barbiturate-containing or opioid-containing analgesics > 2
days/month, triptans or ergots >= 10 days/month, or simple analgesics (eg,
aspirin, NSAIDs, acetaminophen) >= 15 days/month in the 3 months prior to Visit
1 per investigator*s judgment, or during the baseline period.
(Note: barbiturate-containing analgesics are excluded 30 days prior to
screening, during the screening/baseline period, and for the duration of the
study. Opioid-containing analgesics are excluded during the screening/baseline
period and throughout the study, however, episodic use of opioids for purposes
not related to migraine or headache, eg, surgery, is not exclusionary.)
3.04 Previous exposure to:
• Atogepant
• Injectable monoclonal antibodies blocking the CGRP pathway within the last 6
months prior to Visit 1
• Any other 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-003448-58-NL |
| ClinicalTrials.gov | NCT04740827 |
| CCMO | NL72795.056.20 |