Multi-Center Study of Naltrexone-Acetaminophen in Acute Migraine, With an Exploratory Analysis of Co-occurring Anxiety

Study Overview
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Brief Summary
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Naltrexone has a dual function as an opioid receptor antagonist and a Toll-Like Receptor-4 (TLR4) antagonist. While primarily approved in a 50 mg tablet for treating opioid and alcohol addiction by blocking opioid receptors, naltrexone's TLR4-blocking effect is also significant. This action reduces the levels of pro-inflammatory cytokines responsible for pain generation, primarily in the trigeminal ganglion and dorsal root ganglia. These sites play a key role in the effectiveness of naltrexone as a pain-alleviating agent. Acetaminophen is the active ingredient in Tylenol, an over-the-counter non-opioid analgesic and antipyretic agent. Both naltrexone and acetaminophen have demonstrated effectiveness in the treatment of acute migraine, physical pain, and emotional pain. However, while naltrexone has demonstrated potential in animal and human studies, confirmatory clinical trials for pain treatment in humans are still lacking. Additionally, it is important to note that around 50% of migraine patients experience co-occurring anxiety. Therefore, this study aims to assess the effectiveness of naltrexone-acetaminophen in treating migraine and co-occurring anxiety compared to each drug alone and placebo. The sponsor has conducted four clinical studies showing promising results of naltrexone-acetaminophen in treating migraine, chronic low-back pain, and emotional pain.

Detailed Description
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This study evaluating naltrexone-acetaminophen in acute migraine and co-occurring anxiety in adults lasts between 1.2 to 3.5 months (depending on when a migraine attack is treated during the treatment period). The study includes the following key events: Screening Visit (Day 1). 30-day Run-In Period (Days 1-30). Randomization Visit (Days 31-37). Treatment Period (Days 31-97): up to 60 days to treat a migraine at home. End-of-Study Visit (Days 36 -106): 3 to 7 days after treatment.

Official Title
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A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Full-Factorial, Parallel-Group Study Evaluating Safety and Efficacy of Naltrexone-Acetaminophen Combination in Acute Migraine Treatment in Adults, With Exploratory Focus on Co-Occurring Anxiety

Conditions
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Migraine, Episodic Migraine, Migraine, Classic, Migraine With Aura, Migraine Without Aura

Intervention / Treatment
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* Drug: Naltrexone-Acetaminophen
* Drug: Naltrexone
* Drug: Acetaminophen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ages 18 to 75 years, inclusive At least 1-year of history of migraine with or without aura as defined by the International Classification of Headache Disorders 3rd edition (ICHD-3) Migraine onset before age 50 years No use of opioids (including methadone and buprenorphine) from 6 months before the study, during the study, and for 7 days after taking the study medication No use barbiturate-containing medications, muscle relaxants, benzodiazepines, or marijuana from 6 months before the study and during the study, BMI equal to or lower than 36 kg/m2. Exclusion Criteria: Pregnant or nursing women or those planning a pregnancy. Use of opioids in the past 6 months. Use of medications to treat headaches more than 10 days per month in any of the past 3 months. Use of barbiturate-containing medications, muscle relaxants, benzodiazepines, or marijuana in the past 6 months. Positive results for cocaine, marijuana, opiates, methamphetamines, and oxycodone in a urine drug screen. Symptoms consistent with chronic migraine, cranial neuropathy, and other pain syndromes. Headaches lasting more than 2 days in the past 3 months. More than one emergency care treatment for migraine in the past 12 months. BMI equal to or greater than 37 kg/m2. Uncontrolled cardiovascular or cerebrovascular disease or a recent history of heart failure, atrial fibrillation, or myocardial infarction. Uncontrolled hypertension or diabetes. Current diagnosis of major depression, schizophrenia, dementia, significant neurological disorders, or other pain syndromes. Gastric or small intestinal surgery or malabsorption and hepatic disease. Significant hematologic, endocrine, pulmonary, renal, or gastrointestinal disease or history of malignancy in the past 5 years. History of alcohol or drug abuse or current cannabis use in the past 12 months. Known allergy to naltrexone or acetaminophen. Participation in another clinical trial. Immediate family members or same household members participating in the study. Site personnel, their friends, and family. Paid referral fees are not allowed. Abnormal laboratory or ECG results such as bundle branch block, liver or kidney function tests, hemoglobin level, neutrophil count, cholesterol, or triglycerides.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Interventional Model Description: Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Full-Factorial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Naltrexone-Acetaminophen<br>Subjects take a single dose for a Qualifying Migraine | Drug: Naltrexone-Acetaminophen<br>* Combination<br>* Other names: ALLOD-2;|
| Active Comparator: Naltrexone<br>Subjects take a single dose for a Qualifying Migraine | Drug: Naltrexone<br>* Naltrexone alone<br>|
| Active Comparator: Acetaminophen<br>Subjects take a single dose for a Qualifying Migraine | Drug: Acetaminophen<br>* Acetaminophen alone<br>|
| Placebo Comparator: Placebo<br>Subjects take a single dose for a Qualifying Migraine | Drug: Placebo<br>* Matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of subjects with acute migraine who achieved freedom from pain 2 hours after dosing with naltrexone-acetaminophen compared to the placebo. | Freedom from pain is defined as the absence of headache pain from moderate or severe pain at baseline, without the use of rescue medication. The pain is measured on a 4-point scale, with 0 indicating no pain, 1 for mild pain, 2 for moderate pain, and 3 for severe pain. | 2 hours after dosing | 
| The proportion of subjects with acute migraine who achieved freedom from migraine's Most Bothersome Symptoms (MBS) 2 hours after dosing with naltrexone-acetaminophen compared to the placebo | MBS freedom is defined as the absence of the identified Most Bothersome Symptom (MBS), which can be nausea, photophobia, or phonophobia. The MBS is measured on a binary scale, either absent or present. | 2 hours after dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of subjects with acute migraine who achieved pain relief compared to placebo | Pain relief is defined as a reduction in headache pain severity from moderate or severe to mild or no headache pain. | 2 hours after dosing | 
| The proportion of subjects with acute migraine who achieved freedom from photophobia | Freedom from photophobia is defined as absence of photophobia | 2 hours after dosing | 
| The proportion of subjects with acute migraine who achieved freedom from phonophobia | Freedom from phonophobia is defined as absence of phonophobia | 2 hours after dosing | 
| The proportion of subjects with acute migraine who achieved freedom from nausea | Freedom from nausea is defined as absence of nausea | 2 hours after dosing | 
| The proportion of subjects with acute migraine who achieved sustained pain relief from 2 to 24 hours | Sustained pain relief is defined as the absence of headache pain of moderate or severe intensity without the use of rescue medication. | 2 to 24 hours | 
| The proportion of subjects with acute migraine who achieved sustained pain freedom from 2 to 24 hours | Sustained pain freedom is defined as the absence of any headache pain of any intensity without the use of rescue medication. | 2 to 24 hours | 
| Functional disability at 2 hours | Functional disability refers to the inability to perform activities of daily living or work tasks to a normal level due to physical, mental, or sensory impairments. It is measured on a scale of 0 to 3, where 0 indicates normal function and 3 indicates the need for bedrest due to severe impairment. | 2 hours after dosing | 
| Functional disability at 24 hours | Functional disability refers to the inability to perform activities of daily living or work tasks to a normal level due to physical, mental, or sensory impairments. It is measured on a scale of 0 to 3, where 0 indicates normal function and 3 indicates the need for bedrest due to severe impairment. | 24 hours after dosing | 
| Use of rescue medications within 24 hours | Rescue medication use refers to the use of an additional medication to treat the current migraine. | within 24 hours | 
| Pain relapse within 48 hours | Pain relapse refers to the reappearance of headache pain of any severity when the subject had been free of pain 2 hours after dosing. | within 48 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Naltrexone, Acetaminophen, Acute migraine, Low-dose naltrexone, Anxiety