Headache, Migraine
Conditions
Brief summary
The purpose of this study is to evaluate the safety and efficacy of MK-6096 versus placebo for preventing migraines in participants with episodic migraine. After a 28-day Screening period during which baseline number of monthly migraine days was assessed, participants were randomized to receive MK-6096 or placebo for a 12-week Treatment Period. Participants who completed all 12 weeks of the Treatment Period received drug or placebo for an additional 2 weeks in the Run-out Period. Treatment assignment in the Run-out Period was determined at the initial randomization. In the Run-out Period, participants who received placebo in the Treatment Period continued to receive placebo and participants who received MK-6096 in the Treatment Period 2 received either MK-6096 or placebo in a 1:1 ratio. The hypothesis tested in the study is that MK-6096 10 mg is superior to placebo in reducing migraine frequency as measured by the mean change from baseline in monthly migraine days averaged over the 12- week treatment period.
Interventions
DRUGMK-6096
MK-6096, two 5 mg tablets (total 10 mg dose), orally, once daily
DRUGPlacebo
Placebo, 2 tablets, orally, once daily
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* History of migraine with or without aura for \>1 year and with ≥4 and ≤14 migraine days per month in the 3 months prior to study * Male, female not of reproductive potential, or female of reproductive potential who is not pregnant by pregnancy test and agrees to use acceptable contraception
Exclusion criteria
* Pregnancy, breast-feeding, or expecting to become pregnant * Planning to donate egg or sperm during the study or within 90 days after last dose of study medication * Basilar or hemiplegic migraine headache * \>50 years old at the age of migraine onset * ≥15 headache-days per month or medication taken for acute migraine or other headaches on more than 10 days per month in any of the three months prior to study * Migraine prophylactic medication (defined as medication taken daily to prevent migraines) taken in the 30 days prior to study * History of narcolepsy, cataplexy, circadian rhythm disorder, parasomnia, sleep related breathing disorder, restless legs syndrome, periodic limb movement disorder, excessive daytime sleepiness or difficulty sleeping due to a medical condition (e.g., asthma, gastroesophageal reflux disease, etc.) * Clinical, laboratory, or electrocardiogram (ECG) evidence of uncontrolled hypertension, uncontrolled diabetes, human immunodeficiency virus (HIV) disease, or significant pulmonary, renal, hepatic, endocrine, or other systemic disease * Myocardial infarction, unstable angina, coronary artery bypass surgery, or other revascularization procedure, stroke, or transient ischemic attack within 3 months of study * Other confounding pain syndromes (i.e., condition requiring daily use of opioids), psychiatric conditions such as uncontrolled major depression, dementia or significant neurological disorders other than migraine * Imminent risk of self-harm, based on clinical interview and responses on the Columbia Suicidality Severity Rating Scale (C-SSRS), or of harm to others. Exclude any prospective participant reporting suicidal ideation with intent, with or without a plan in the past 2 months or suicidal behavior in the past 6 months * History of malignancy ≤5 years prior to study, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer * History of hypersensitivity to more than two chemical classes of drugs, including prescription and over-the-counter medications * Recent history (within the past 1 year) or current evidence of drug or alcohol abuse or recreational use of illicit drugs or prescription medications * Donated blood products or has had phlebotomy of \>300 ml within 8 weeks of study, or intends to donate blood products or receive blood products within 30 days before study and throughout study * Consumption of 3 or more alcoholic drinks per day * Body Mass Index \>40 kg/m\^2 * History of transmeridian travel (across \>3 time zones) or shift work (defined as permanent night shift or rotating day/night shift work) within the past 2 weeks or anticipates needing to travel (across \>3 time zones) at any time during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Monthly Migraine Days | Baseline and average over Treatment Period (Weeks 0-12) | Participants recorded data in the electronic migraine headache diary in the evening approximately one hour before bed and prior to taking study medication during Screening and the Treatment Period. A migraine was defined as a headache with at least one associated symptom of aura, photophobia, phonophobia, nausea, or vomiting. Change in the mean monthly migraine days during Screening (Baseline) versus during the 12-week Treatment Period was assessed. A negative number indicates a reduction in mean monthly migraine days. |
| Percentage of Participants With One or More Adverse Events | Treatment Period: Weeks 0-12; Run-out Period: Weeks 13-14 | An adverse event was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the sponsor's product, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the sponsor's product, is also an adverse event. Statistical analysis compared the Treatment Period arms only. |
| Percentage of Participants Discontinued From Study Medication Due to an Adverse Event | Treatment Period: Weeks 0-12; Run-out Period: Weeks 13-14 | An adverse event was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the sponsor's product, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the sponsor's product, is also an adverse event. Statistical analysis compared the Treatment Period arms only. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Monthly Headache Days | Baseline and average over Treatment Period (Weeks 0-12) | Participants recorded data in the electronic migraine headache diary in the evening approximately one hour before bed and prior to taking study medication during Screening and the Treatment Period. A headache was defined as headache pain of at least 30 minutes duration or for any duration for which headache treatment was administered. Change in the mean monthly headache days during Screening (Baseline) versus during the 12-week Treatment Period was assessed. A negative number indicates a reduction in mean monthly headache days. |
| Percentage of Participants With at Least a 50% Reduction From Baseline in Monthly Migraine Days | Baseline and average over Treatment Period (Weeks 0-12) | Participants recorded data in the electronic migraine headache diary in the evening approximately one hour before bed and prior to taking study medication during Screening and the Treatment Period. A migraine was defined as a headache with at least one associated symptom of aura, photophobia, phonophobia, nausea, or vomiting. Percentage of participants with at least 50% reduction in the monthly migraine days during the 12-week Treatment Period versus during Screening (Baseline) was analyzed using a generalized linear mixed effects model. |
| Percentage of Participants With at Least a 30% Reduction From Baseline in Monthly Migraine Days | Baseline and average over Treatment Period (Weeks 0-12) | Participants recorded data in the electronic migraine headache diary in the evening approximately one hour before bed and prior to taking study medication during Screening and the Treatment Period. A migraine was defined as a headache with at least one associated symptom of aura, photophobia, phonophobia, nausea, or vomiting. Percentage of participants with at least 30% reduction in the monthly migraine days during Screening (Baseline) versus during the 12-week Treatment Period was analyzed using a generalized linear mixed effects model. |
Participant flow
Pre-assignment details
A total of 423 participants were screened. Of these, 237 participants completed screening and met the eligibility criteria, including the required number of migraine days during the Screening period.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Period: MK-6096 Participants received double-blind MK-6096, two 5 mg tablets (10 mg dose), orally, once daily for 12 weeks in the Treatment Period | 120 |
| Treatment Period: Placebo Participants received double-blind placebo, two tablets, orally, once daily for 12 weeks in the Treatment Period | 117 |
| Total | 237 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Run-out Period | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 |
| Run-out Period | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 |
| Treatment Period | Adverse Event | 8 | 4 | 0 | 0 | 0 |
| Treatment Period | Lack of Efficacy | 3 | 0 | 0 | 0 | 0 |
| Treatment Period | Lost to Follow-up | 2 | 3 | 0 | 0 | 0 |
| Treatment Period | Physician Decision | 1 | 0 | 0 | 0 | 0 |
| Treatment Period | Protocol Violation | 1 | 2 | 0 | 0 | 0 |
| Treatment Period | Randomized not treated | 0 | 2 | 0 | 0 | 0 |
| Treatment Period | Withdrawal by Subject | 8 | 5 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Treatment Period: MK-6096 | Treatment Period: Placebo | Total |
|---|---|---|---|
| Age, Continuous | 42.5 Years STANDARD_DEVIATION 10.7 | 41.9 Years STANDARD_DEVIATION 11.3 | 42.2 Years STANDARD_DEVIATION 11 |
| Sex: Female, Male Female | 102 Participants | 99 Participants | 201 Participants |
| Sex: Female, Male Male | 18 Participants | 18 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 26 / 120 | 10 / 115 | 1 / 50 | 4 / 47 | 1 / 101 |
| serious Total, serious adverse events | 0 / 120 | 0 / 115 | 0 / 50 | 0 / 47 | 0 / 101 |
Outcome results
Primary
Mean Change From Baseline in Monthly Migraine Days
Participants recorded data in the electronic migraine headache diary in the evening approximately one hour before bed and prior to taking study medication during Screening and the Treatment Period. A migraine was defined as a headache with at least one associated symptom of aura, photophobia, phonophobia, nausea, or vomiting. Change in the mean monthly migraine days during Screening (Baseline) versus during the 12-week Treatment Period was assessed. A negative number indicates a reduction in mean monthly migraine days.
Time frame: Baseline and average over Treatment Period (Weeks 0-12)
Population: The population analyzed included participants who received at least one dose of double-blind study treatment and had at least one evaluable endpoint measurement, including those with only a baseline measurement. This outcome measure applied only to the Treatment Period and was not analyzed for the Run-out Period.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Period: MK-6096 | Mean Change From Baseline in Monthly Migraine Days | Baseline | 8.2 Days/month | Standard Error 0.1 |
| Treatment Period: MK-6096 | Mean Change From Baseline in Monthly Migraine Days | Change from Baseline | -1.7 Days/month | Standard Error 0.3 |
| Treatment Period: Placebo | Mean Change From Baseline in Monthly Migraine Days | Baseline | 8.2 Days/month | Standard Error 0.1 |
| Treatment Period: Placebo | Mean Change From Baseline in Monthly Migraine Days | Change from Baseline | -1.3 Days/month | Standard Error 0.3 |
p-value: 0.3315395% CI: [-1.3, 0.4]Constrained Longitudinal Analysis (cLDA)
Primary
Percentage of Participants Discontinued From Study Medication Due to an Adverse Event
An adverse event was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the sponsor's product, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the sponsor's product, is also an adverse event. Statistical analysis compared the Treatment Period arms only.
Time frame: Treatment Period: Weeks 0-12; Run-out Period: Weeks 13-14
Population: The population analyzed included all randomized participants who received at least one dose of double-blind study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Period: MK-6096 | Percentage of Participants Discontinued From Study Medication Due to an Adverse Event | 6.7 Percentage of participants |
| Treatment Period: Placebo | Percentage of Participants Discontinued From Study Medication Due to an Adverse Event | 4.3 Percentage of participants |
| Run-out Period: MK-6096 / MK-6096 | Percentage of Participants Discontinued From Study Medication Due to an Adverse Event | 0.0 Percentage of participants |
| Run-out Period: MK-6096 / Placebo | Percentage of Participants Discontinued From Study Medication Due to an Adverse Event | 0.0 Percentage of participants |
| Run-out Period: Placebo / Placebo | Percentage of Participants Discontinued From Study Medication Due to an Adverse Event | 0.0 Percentage of participants |
95% CI: [-4, 8.9]
Primary
Percentage of Participants With One or More Adverse Events
An adverse event was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the sponsor's product, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the sponsor's product, is also an adverse event. Statistical analysis compared the Treatment Period arms only.
Time frame: Treatment Period: Weeks 0-12; Run-out Period: Weeks 13-14
Population: The population analyzed included all randomized participants who received at least one dose of double-blind study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Period: MK-6096 | Percentage of Participants With One or More Adverse Events | 46.7 Percentage of participants |
| Treatment Period: Placebo | Percentage of Participants With One or More Adverse Events | 37.4 Percentage of participants |
| Run-out Period: MK-6096 / MK-6096 | Percentage of Participants With One or More Adverse Events | 10.0 Percentage of participants |
| Run-out Period: MK-6096 / Placebo | Percentage of Participants With One or More Adverse Events | 17.0 Percentage of participants |
| Run-out Period: Placebo / Placebo | Percentage of Participants With One or More Adverse Events | 7.9 Percentage of participants |
95% CI: [-3.4, 21.6]
Secondary
Mean Change From Baseline in Monthly Headache Days
Participants recorded data in the electronic migraine headache diary in the evening approximately one hour before bed and prior to taking study medication during Screening and the Treatment Period. A headache was defined as headache pain of at least 30 minutes duration or for any duration for which headache treatment was administered. Change in the mean monthly headache days during Screening (Baseline) versus during the 12-week Treatment Period was assessed. A negative number indicates a reduction in mean monthly headache days.
Time frame: Baseline and average over Treatment Period (Weeks 0-12)
Population: The population analyzed included participants who received at least one dose of double-blind study treatment and had at least one evaluable endpoint measurement, including those with only a baseline measurement. This outcome measure applied only to the Treatment Period and was not analyzed for the Run-out Period.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Period: MK-6096 | Mean Change From Baseline in Monthly Headache Days | Baseline | 9.6 Days/month | Standard Error 0.2 |
| Treatment Period: MK-6096 | Mean Change From Baseline in Monthly Headache Days | Change from Baseline | -1.7 Days/month | Standard Error 0.3 |
| Treatment Period: Placebo | Mean Change From Baseline in Monthly Headache Days | Baseline | 9.6 Days/month | Standard Error 0.2 |
| Treatment Period: Placebo | Mean Change From Baseline in Monthly Headache Days | Change from Baseline | -1.2 Days/month | Standard Error 0.3 |
p-value: 0.2400895% CI: [-1.4, 0.4]Constrained Longitudinal Analysis (cLDA)
Secondary
Percentage of Participants With at Least a 30% Reduction From Baseline in Monthly Migraine Days
Participants recorded data in the electronic migraine headache diary in the evening approximately one hour before bed and prior to taking study medication during Screening and the Treatment Period. A migraine was defined as a headache with at least one associated symptom of aura, photophobia, phonophobia, nausea, or vomiting. Percentage of participants with at least 30% reduction in the monthly migraine days during Screening (Baseline) versus during the 12-week Treatment Period was analyzed using a generalized linear mixed effects model.
Time frame: Baseline and average over Treatment Period (Weeks 0-12)
Population: The population analyzed included participants who received at least one dose of double-blind study treatment and had at least one evaluable endpoint measurement, including those with only a baseline measurement. This outcome measure applied only to the Treatment Period and was not analyzed for the Run-out Period.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Treatment Period: MK-6096 | Percentage of Participants With at Least a 30% Reduction From Baseline in Monthly Migraine Days | 40.7 Percentage of participants | 95% Confidence Interval 0.3 |
| Treatment Period: Placebo | Percentage of Participants With at Least a 30% Reduction From Baseline in Monthly Migraine Days | 40.5 Percentage of participants | 95% Confidence Interval 0.3 |
p-value: 0.973795% CI: [0.7, 1.5]Generalized linear mixed effects model
Secondary
Percentage of Participants With at Least a 50% Reduction From Baseline in Monthly Migraine Days
Participants recorded data in the electronic migraine headache diary in the evening approximately one hour before bed and prior to taking study medication during Screening and the Treatment Period. A migraine was defined as a headache with at least one associated symptom of aura, photophobia, phonophobia, nausea, or vomiting. Percentage of participants with at least 50% reduction in the monthly migraine days during the 12-week Treatment Period versus during Screening (Baseline) was analyzed using a generalized linear mixed effects model.
Time frame: Baseline and average over Treatment Period (Weeks 0-12)
Population: The population analyzed included participants who received at least one dose of double-blind study treatment and had at least one evaluable endpoint measurement, including those with only a baseline measurement. This outcome measure applied only to the Treatment Period and was not analyzed for the Run-out Period.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Treatment Period: MK-6096 | Percentage of Participants With at Least a 50% Reduction From Baseline in Monthly Migraine Days | 24.7 Percentage of participants | 95% Confidence Interval 0.3 |
| Treatment Period: Placebo | Percentage of Participants With at Least a 50% Reduction From Baseline in Monthly Migraine Days | 21.1 Percentage of participants | 95% Confidence Interval 0.3 |
p-value: 0.4309395% CI: [0.7, 2]Generalized linear mixed effects model