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

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

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

Study Overview

• Status: Completed
• Conditions: Migraine With or Without Aura
• Intervention / Treatment: Drug: Low-Dose Naltrexone and Acetaminophen Combination; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • North Miami, Florida, United States, 33181
      • Annette Toledano, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. The patient is a male or a female 18 years of age or older.
2. 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.
3. Migraine-associated nausea with ≥half of migraine attacks.
4. 5-8 migraine/probable migraine headache days on average per month in the three months prior to Visit 1 and during the Baseline Period.
5. The patient agrees to refrain from taking opiate medications from Visit 1 to 7 days after the last dose of the study drug.
6. 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.
7. 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.
8. The patient agrees to forgo any elective surgery for the duration of the study.
9. 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:

1. 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.
2. 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).
3. 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.
4. Confounding painful conditions, (e.g. fibromyalgia, chronic low back pain, complex regional pain syndrome, etc.).
5. 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.
6. 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).
7. The patient has a history within the previous 5 years of abuse of any drug, prescription, illicit, or alcohol.
8. 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.
9. The patient has known-allergy to any of the components of the investigational drug.
10. Participation in another study with an investigational drug within 30 days before Visit 1 or during the study.
11. Use of emergency care treatment more than 3 times in the previous 6 months.
12. The patient is in the opinion of the investigator, is unsuitable to participate in this study for any other reason.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Twice daily
Experimental: Low-Dose Naltrexone and Acetaminophen Combination	Drug: Low-Dose Naltrexone and Acetaminophen Combination; Twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Monthly Migraine Days (MMD) From Baseline to the Last 28 Days of Treatment Period.	Migraine with or without aura is defined according to the International Classification of Headache Disorders (ICHD)-3rd edition (beta version). 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 84-days double-blinded treatment period.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Participants With More Than 50% Improvement in the Mean Monthly Migraine Days (MMDs)	MMD stands for change in Monthly Migraine Days from 28-day baseline to the last 28 days of the double-blind treatment period	From the 28-day baseline period to the last 28 days of the 84-days double-blinded treatment period.
The Number of Participants With More Than 75% Improvement in the Mean Monthly Migraine Days (MMDs)		From the28-day baseline period to the last 28 days of the 84-day treatment period.
The Number of Participants With 100% Improvement in Mean MMD in the Last 28 Days Double-blinded Treatment Period.		From the 28-day baseline period to the last 28 days of the 84-day treatment period.
Mean Monthly Acute Migraine Medication Treatment Days Change From Baseline to Last 28 Days of Treatment		From the 28-day baseline period to the last 28 days of the 84-day treatment period.
The Change in HIT-6 From Baseline to Last 28 Days of Treatment	HIT-6 - headache impact test - was designed to provide a global measure of adverse headache impact. Score range is 36-78, Score ≥ 60 - a very severe impact on life, scored ≤ 49 little to no impact on life. The percent responders were calculated as follows: the change from baseline score divided by the score at the baseline minus 36.	From the 28-day baseline period to the last 28 days of the 84-day treatment period.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Change in Mean PIRS-20 From Baseline to Last 7 Days of Treatment.	Average of PIRS-20, (0-60 = higher with difficulty with sleep)	From baseline to month 3 of the treatment period.
The Number of Participants Who Had an Improvement in Patient Global Impression of Change (PGIC) at End of Treatment		From baseline to month 3 of the treatment period.
The Number of Participants Reporting Patients' Satisfaction Level		From baseline to month 3 of the treatment period.
Mean Monthly Migraine Hours Change From Baseline to Last 28 Days of Treatment		From baseline to month 3 of the treatment period.
Change in at Least Moderate Migraine Days in Treatment		From baseline to month 3 of the treatment period
The Number of Participants Who Achieved the Percentage of Response in at Least Moderate Migraine Days Baseline to Last 28 Days of Treatment		From baseline to month 3 of the treatment period.
Mean Severe Headache Days Change From Baseline to Last 28 Days of Treatment		From baseline to month 3 of the treatment period.

Collaborators and Investigators

• Sponsor: Allodynic Therapeutics, Inc
• Investigators: Principal Investigator: Annette Toledano, M.D., Allodynic Therapeutics, Inc

Study record dates

Study Major Dates

• Study Start (Actual): August 25, 2017
• Primary Completion (Actual): July 26, 2018
• Study Completion (Actual): July 28, 2018

Study Registration Dates

• First Submitted: June 16, 2017
• First Submitted That Met QC Criteria: June 20, 2017
• First Posted (Actual): June 21, 2017

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: March 17, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Migraine; Headache; Cytokines; Migraine Prevention; Innate Immune System; Cox-2
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Narcotic Antagonists; Alcohol Deterrents; Naltrexone; Acetaminophen
• Other Study ID Numbers: ANODYNE-3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No