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

Migraine Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05685225
• Other study ID #: A-06
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: July 1, 2024
• Est. completion date: July 1, 2026

Study information

• Verified date: December 2023
• Source: Allodynic Therapeutics, Inc
• Contact: Annette C Toledano, MD
• Phone: 3058956808
• Email: ctg[@]allodynic.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 300
• Est. completion date: July 1, 2026
• Est. primary completion date: July 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Migraine
• Migraine Disorders

Intervention

Drug:
• Naltrexone-Acetaminophen
Combination
• Naltrexone
Naltrexone alone
• Acetaminophen
Acetaminophen alone
• Placebo
Matching placebo

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Allodynic Therapeutics, Inc

References & Publications (43)

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* Note: There are 43 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Hamilton Anxiety Rating Scale score	The Hamilton Anxiety Rating Scale is a validated assessment tool for measuring anxiety symptoms. The scale consists of fourteen items designed to assess the severity of anxiety on a scale of zero to four, with four being the most severe.	Baseline (Randomization Visit) to 2 hours after dosing
Other	Self-reported hurt feelings score	Self-reported hurt feelings on a 4-point scale: (0=Not at all, 1=Slightly, 2=Moderate, 3=Extremely).	2 hours after dosing
Other	Self-reported tense feelings score	Self-reported tense feelings on a 4-point scale: (0=Not at all, 1=Slightly, 2=Moderate, 3=Extremely).	2 hours after dosing
Other	Self-reported overall sense of wellbeing	Self-reported overall sense of wellbeing (physical and emotional) is a subjective measurement that reflects an individual's perception of their physical and emotional health. It is typically assessed on a 4-point scale, ranging from 0 (Poor) to 3 (Superb), with 1 (Okay) and 2 (Good) representing intermediate levels of wellbeing. This measurement considers factors such as physical pain, positive emotions, life satisfaction, stress management, and the absence of negative emotions like depression and anxiety.	2 hours after dosing
Other	Sustained pain freedom for naltrexone-acetaminophen versus naltrexone	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
Other	Sustained pain freedom for naltrexone-acetaminophen versus Acetaminophen	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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