The Preventive Treatment of Migraine With Low-Dose Naltrexone and Acetaminophen Combination

Study Overview
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Brief Summary
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The Preventive Treatment of Migraine with Low-Dose Naltrexone and Acetaminophen Combination: A Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial with an Open-Label Extension for None-Responders

Official Title
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Randomized, Double-Blind, Study to Assess Low-Dose Naltrexone and Acetaminophen Combination in the Prevention of Episodic Migraine in Adults

Conditions
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Migraine With or Without Aura

Intervention / Treatment
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* Drug: Low-Dose Naltrexone and Acetaminophen Combination
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient is a male or a female 18 years of age or older. History of migraine with or without aura according to the International Classification of Headache Disorders (ICHD)-3rd edition (beta version) for at least one-year with onset of migraine prior to 50 years of age. Migraine-associated nausea with ≥half of migraine attacks. 5-8 migraine/probable migraine headache days on average per month in the three months prior to Visit 1 and during the Baseline Period. The patient agrees to refrain from taking opiate medications from Visit 1 to 7 days after the last dose of the study drug. The patient is able to complete study questionnaires, comply with the study requirements and restrictions, and willing to provide written informed consent and authorize HIPAA. The patient has been taking a stable dose of a medication with migraine prevention potential for at least 3 month prior to the screening visit and agrees to not start, stop, or change dosage of any medication with migraine prevention potential during the study period. (E.g., beta-blockers, calcium channel blockers, tricyclic antidepressants, anticonvulsants, selective serotonin re-uptake inhibitors (SSRIs), serotonin-norepinephrine re-uptake inhibitors (SNRIs), magnesium or riboflavin supplements at high doses, herbal preparations (e.g. feverfew or St. john's wort)), Botulinum toxin must be discontinued one year prior to Visit 1. The patient agrees to forgo any elective surgery for the duration of the study. The female patient who is premenopausal or postmenopausal less than 1 year, or have not had surgical sterilization (i.e., tubal ligation, partial or complete hysterectomy) must have a negative urine pregnancy test, be non-lactating, and commit to using 2 methods of adequate and reliable contraception throughout the study and for 28 days after taking the last dose of the study drug (e.g., barrier with additional spermicidal, intra-uterine device, hormonal contraception). Male patients must be surgically sterile or commit to the use of 2 different methods of birth control during the study and for 28 days after the study. Exclusion Criteria: Usage of acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) ≥15 days/month, or ergotamine and triptans >10 days/month, or opioids and barbiturates >2 days/month in the 3 months prior to Visit 1 or during the Baseline Period. Tension-type-like, and/or migraine-like headache on ≥15 days per month in the 3 months prior to Visit 1 or during the Baseline Period. Diagnosis of chronic migraine, cluster headache or neurologically complicated migraine (hemiplegic, basilar, retinal, ophthalmoplegic migraine). Regular use of the following medications for any reason: acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), antipsychotic drugs, monoamine oxidase inhibitors, benzodiazepines, sleep medications, muscle relaxants, anti-emetic medications, blood thinning medications (e.g., warfarin or heparin), cannabinoids, or botulinum toxin to head and neck regions. Low-dose aspirin for cardiovascular disease prophylaxis is permitted. Confounding painful conditions, (e.g. fibromyalgia, chronic low back pain, complex regional pain syndrome, etc.). Diagnosis of any concurrent medical or psychiatric condition; this includes, chronic unstable debilitating diseases such as Parkinson's disease, multiple sclerosis, cancer, significant renal impairment, significant hepatic impairment, etc. The patient has a history or diagnosis of moderate-to-severe hepatic or renal impairment (>2 × the upper limit of normal [ULN] for alanine transaminase or aspartate transaminase. ≥1.5 × ULN for alkaline Phosphatase, bilirubin, BUN, or creatinine). (Patients with elevated bilirubin level due to Gilbert's syndrome are allowed). The patient has a history within the previous 5 years of abuse of any drug, prescription, illicit, or alcohol. The Female patient is pregnant, actively trying to become pregnant, or breast-feeding. The Male patient is not practicing 2 different methods of birth control with their partner during the study, and for 28 days after the investigational drug last dose or will not remain abstinent during the study, and for 28 days after the last dose. The patient has known-allergy to any of the components of the investigational drug. Participation in another study with an investigational drug within 30 days before Visit 1 or during the study. Use of emergency care treatment more than 3 times in the previous 6 months. The patient is in the opinion of the investigator, is unsuitable to participate in this study for any other reason.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low-Dose Naltrexone and Acetaminophen Combination<br> | Drug: Low-Dose Naltrexone and Acetaminophen Combination<br>* Twice daily<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the mean number of migraine/probable migraine headache days. | (Migraine with or without aura is defined according to the International Classification of Headache Disorders (ICHD)-3rd edition (beta version). Probable migraine, is defined according to the ICHD - 3 (beta version) criteria, as attacks fulfilling all but one of criteria A-D for migraine with or without aura, where criteria B is headache attacks lasting 4-72 hours (untreated or unsuccessfully treated). Migraine/probable migraine headaches must be moderate or severe and lasting ≥30 minutes. When the patient falls asleep during migraine and wakes up without it, duration of the attack is reckoned until the time of awakening). | From the 28-day baseline period to the last 28 days of the 12-week treatment period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the mean number of headache days. | (Headache days are defined as none-migraine headache days plus migraine headache days). | From the 28-day baseline period to the last 28 days of the 12-week treatment period. | 
| Proportion of patients with 50% or more reduction in migraine/probable migraine headache days. |  | From the28-day baseline period to the last 28 days of the12-week treatment period. | 
| Change from baseline in the mean migraine severity. | (Measured on the 4-point (0-3) rating scale, (0=none, 1=mild, 2=moderate, 3=severe)). | From the 28-day baseline period to the last 28 days of the 12-week treatment period. | 
| Change from baseline in the mean migraine duration. |  | From the 28-day baseline period to the last 28 days of the12-week treatment period. | 
| Change from baseline in the mean nausea severity. | (Measured on the 4-point (0-3) rating scale, (0=none, 1=mild, 2=moderate, 3=severe)). | From the 28-day baseline period to the last 28 days of the12-week treatment period. | 
| Change from baseline in the mean number of acute migraine medications intake days. |  | From the 28-day baseline period to the last 28 days of the 12-week treatment period. | 
| Proportion of patients satisfied or extremely satisfied with migraine prevention. |  | Week 12. | 
| Change from baseline in the mean migraine disability assessment scale (MIDAS) |  | From baseline to week 12 of the treatment period. | 
| Change from baseline in the mean headache impact test (HIT-6). |  | From the 28-day baseline period to the last 28 days of the 12-week treatment period. | 
| Change from baseline in the mean Pittsburgh Insomnia Rating Scale-20 (PIRS-20). |  | From baseline to week 12 of the treatment period. | 
| Comparison of the proportion of patients who experienced adverse events. |  | A 12-week treatment period. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Innate Immune System, Cytokines, Cox-2, Headache, Migraine, Migraine Prevention