A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Full-Factorial Study Evaluating Naltrexone-Acetaminophen Combination in Acute Migraine Treatment in Adults, With Exploratory Focus on Co-Occurring Anxiety

A-06

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.

2024-07-01

2026-07-01

2026-07-01

Not yet recruiting

Early phase I

300

Inclusion Criteria: 1. Male or female ages 18 to 75 years, inclusive. 2. At least 1-year of history of migraine with or without aura as defined by the International Classification of Headache Disorders 3rd edition 17 (ICHD-3). 3. Migraine onset before age 50 years. 4. Migraine episodes typically last 4 to 72 hours if untreated or treated unsuccessfully and are separated by at least 48 hours of no headache pain in each of the previous 3 months. 5. 2 to 8 migraine days and 10 or fewer headache days per month in the previous 3 months. 6. Have not used opioids (including methadone and buprenorphine) for 12 months before the study (except for a maximum of 3 days post-surgery, provided the last dose occurred at least 7 days before study entry). Able to avoid them during study, and for 7 days after taking the study medication. 7. Have not used barbiturate-containing medications, muscle relaxants, benzodiazepines, or marijuana for 12 months before and are able to avoid them during the study. 8. BMI equal to or lower than 36 kg/m2. 9. Subjects on standard migraine preventive medications must have been taking a stable dose for the past 3 months and must continue taking them during the study. These medications include beta-blockers, tricyclic antidepressants, topiramate, valproic acid, botulinum toxin, and CGRP (calcitonin gene-related peptide). 10. Able to provide written informed consent, authorize HIPAA, complete the study questionnaires, and comply with the study requirements and restrictions. 11. Must own a smartphone and agree to use the timer stopwatch application. 12. The female subject who is premenopausal or postmenopausal less than one 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 two methods of adequate and reliable contraception throughout the study and for 28 days after taking the last dose of the study medication (e.g., barrier with an additional spermicidal, intra- uterine device, hormonal contraception). Male subjects must be surgically sterile (the procedure occurred greater than 6 months before the Screening Visit) or commit to using two different birth control methods during the study and for 28 days after the last dose of the study medication. Exclusion Criteria: 1. Pregnant or nursing women or those planning a pregnancy. 2. Use of opioids, including methadone and buprenorphine, in the past 12 months, except for a maximum of 3 days post-surgery, provided the last dose occurred at least 7 days before study entry. 3. A positive urine drug screen for cocaine, marijuana, opiates, methamphetamines, and oxycodone at the Screening Visit. 4. Use of medications to treat headaches more than 10 days per month in the past 3 months or use of any pain medication for other pain syndromes for more than 10 days per month. 5. Use of barbiturate-containing medications, muscle relaxants, benzodiazepines, or marijuana within 12 months prior to screening. 6. Symptoms consistent with chronic migraine or medication overuse headache. 7. Symptoms consistent with neurologically complicated migraine, cluster headaches, or new persistent daily headache. History of retinal migraine, basilar migraine, or hemiplegic migraine. 8. Headaches lasting more than 2 days in a row in the last year. 9. More than one emergency care treatment for migraine in the past 12 months. 10. Use of more than one preventive migraine medication (beta-blockers, tricyclic antidepressants, topiramate, valproic acid, botulinum toxin, and CGRPs). 11. BMI equal to or greater than 37 kg/m2. 12. Uncontrolled cardiovascular or cerebrovascular disease or a history of heart failure, atrial fibrillation, or myocardial infarction. 13. Uncontrolled hypertension (systolic/diastolic blood pressure ˃ 140/90 mmHg) or diabetes. 14. Major psychiatric conditions (major depression, schizophrenia, psychosis, bipolar affective disorder, or suicide risk). Significant neurological (dementia, Parkinson's, or seizures). 15. A history of gastric or small intestinal surgery (including gastric bypass, gastric banding, gastric sleeve, gastric balloon, etc.) or a disease that causes malabsorption. Hepatic disease, known or suspected, (hepatitis B or C). 16. Any clinically significant symptoms or conditions, cardiac, pulmonary, metabolic, hematologic renal, hepatic, or gastrointestinal conditions or history of such conditions that, in the opinion of the investigator might interfere with study assessments or safety of participant. history of malignancy in the past 5 years. 17. History of alcohol or drug abuse in the past 12 months. 18. Current use of prescription anti-coagulant (Pradaxa, Coumadin, Eliquis, Xarelto). 19. Known allergy to naltrexone or acetaminophen. 20. Participation in another clinical trial while in this study. 21. Immediate family members or same household members participating in the study. 22. Site personnel, their friends, and family. Paid referral fees are prohibited. 23. Subjects who have previously participated in studies involving this Investigational Product 24. Abnormal laboratory or ECG results. 1. Aspartate transaminase (AST/SGOT), alanine transaminase (ALT/SGPT), or alkaline Phosphatase ≥ 1.5 x Upper Limit of Normal (ULN). creatinine ≥ 1.5 x ULN. 2. BBB or intraventricular conduction defect with a QRS duration ≥ 150 msec. ST-T wave abnormalities. 3. Hemoglobin \< 10 g/dL 4. Neutrophil count ≤ 1000/μL 5. Cholesterol ≥ 300 mg/dL 6. Triglycerides ≥ 500 mg/dL

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2024-03-19