Single-Site Study of Naltrexone/Acetaminophen for the Acute Treatment of Migraine: A Phase 2 Randomized Trial

NCT05685225 | Withdrawn Phase 2 FDA Drug

• 1 other identifier: AT-06
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

• This two-stage clinical trial will assess a novel combination therapy for acute migraine. In Stage 1 (factorial), participants will receive the combination, each individual component, or placebo. In Stage 2 (dose-finding), they will test three doses of the combination. Before both stages, participants will complete a run-in period, documenting a migraine attack without study medication. They will then treat one migraine attack in each stage.
• 4 visits
• Requirements: Migraine Diagnosis. BMI below 34. Read, write, and speak English. No opioids, marijuana, benzodiazepines, or excessive alcohol.

Conditions

Migraine

Keywords

Naltrexone; Acetaminophen; Acute migraine; Low-dose naltrexone; Anxiety

Outcome Measures

Primary Outcomes (2)

• Proportion of subjects with acute migraine who achieved freedom from pain after dosing

  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

• Proportion of subjects with acute migraine who achieved freedom from migraine's Most Bothersome Symptoms (MBS) after dosing

  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 Outcomes (10)

• Proportion of subjects with acute migraine who achieved pain relief

  2 hours after dosing

• Proportion of subjects with acute migraine who achieved freedom from photophobia

  2 hours after dosing

• Proportion of subjects with acute migraine who achieved freedom from phonophobia

  2 hours after dosing

• Proportion of subjects with acute migraine who achieved freedom from nausea

  2 hours after dosing

• Proportion of subjects with acute migraine who achieved sustained pain relief from 2 to 24 hours

  2 to 24 hours

Other Outcomes (5)

• Hamilton Anxiety Rating Scale score

  Baseline (Randomization Visit) to 2 hours after dosing

• Hamilton Anxiety Rating Scale score

  Baseline (Randomization Visit) to 24 hours after dosing

• Self-reported overall sense of wellbeing

  2 hours after dosing

Study Arms (8)

Stage 1: Naltrexone/Acetaminophen

EXPERIMENTAL

One dose for a Qualifying Migraine Attack

Drug: Stage 1: Naltrexone/Acetaminophen

Stage 1: Naltrexone

ACTIVE COMPARATOR

One dose for a Qualifying Migraine Attack

Drug: Stage 1: Naltrexone

Satge 1: Acetaminophen

ACTIVE COMPARATOR

One dose for a Qualifying Migraine Attack

Drug: Stage 1: Acetaminophen

Stage 1: Placebo

PLACEBO COMPARATOR

One dose for a Qualifying Migraine Attack

Drug: Stage1: Placebo

Stage 2: Naltrexone/Acetaminophen-high dose

EXPERIMENTAL

One dose for a qualifying migraine attack

Drug: Stage 2: Naltrxone/Acetaminophen high dose

Stage 2: Naltrexone/Acetaminophen-medium dose

EXPERIMENTAL

One dose for a qualifying migraine attack

Drug: Stage 2: Naltrexone/Acetaminophen medium dose

Stage 2: Naltrexone/Acetaminophen-low dose

EXPERIMENTAL

One dose for a qualifying migraine attack

Drug: Stage 2: Naltrxone/Acetaminophen low dose

Stage 2: Placebo

PLACEBO COMPARATOR

One dose for a qualifying migraine attack

Drug: Stage 2: Placebo

Interventions

Stage 2: Naltrxone/Acetaminophen high dose DRUG

Combination high dose

Also known as: ALLOD-2

Stage 2: Naltrexone/Acetaminophen-high dose

Stage 2: Naltrexone/Acetaminophen medium dose DRUG

Combination medium dose

Also known as: ALLOD-2

Stage 2: Naltrexone/Acetaminophen-medium dose

Stage 2: Naltrxone/Acetaminophen low dose DRUG

Combination low dose

Also known as: ALLOD-2

Stage 2: Naltrexone/Acetaminophen-low dose

Stage 2: Placebo DRUG

Matching Placebo

Stage 2: Placebo

Stage 1: Naltrexone/Acetaminophen DRUG

Combination

Also known as: ALLOD-2

Stage 1: Naltrexone/Acetaminophen

Stage 1: Naltrexone DRUG

Naltrexone alone

Stage 1: Naltrexone

Stage 1: Acetaminophen DRUG

Acetaminophen alone

Satge 1: Acetaminophen

Stage1: Placebo DRUG

Matching placebo

Stage 1: Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 17 (ICHD-3).
• Migraine onset before age 50 years.
• Read, write, and speak English
• BMI Higher than 20 and Lower than 34
• 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.

You may not qualify if:

• Pregnant or nursing women or those planning a pregnancy.
• Used opioids (including methadone and buprenorphine), barbiturate-containing medications, muscle relaxants, or benzodiazepines within 3 months prior to screening.
• Used any recreational drugs in the past 3 months.
• 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.
• Uncontrolled cardiovascular or cerebrovascular disease or a history of heart failure, atrial fibrillation, or myocardial infarction.
• Uncontrolled hypertension (systolic/diastolic blood pressure ˃ 140/90 mmHg) or diabetes.
• Immediate family members or same household members participating in the study.
• Site personnel, their friends, and family.
• Abnormal laboratory or ECG results.
• Aspartate transaminase (AST/SGOT), alanine transaminase (ALT/SGPT), or alkaline Phosphatase ≥ 1.5 x Upper Limit of Normal (ULN). creatinine ≥ 1.5 x ULN.
• BBB or intraventricular conduction defect with a QRS duration ≥ 150 msec. ST-T wave abnormalities.
• Hemoglobin \< 10 g/dL
• Neutrophil count ≤ 1000/μL
• Cholesterol ≥ 300 mg/dL

Sponsors & Collaborators

• Allodynic Therapeutics, Inc: lead

Study Sites (1)

Keystone Clinical Research

North Miami, Florida, 33181, United States

Location

Related Publications (43)

• Lipton RB, Baggish JS, Stewart WF, Codispoti JR, Fu M. Efficacy and safety of acetaminophen in the treatment of migraine: results of a randomized, double-blind, placebo-controlled, population-based study. Arch Intern Med. 2000 Dec 11-25;160(22):3486-92. doi: 10.1001/archinte.160.22.3486.

  PMID: 11112243 BACKGROUND

• Wieseler J, Ellis A, McFadden A, Stone K, Brown K, Cady S, Bastos LF, Sprunger D, Rezvani N, Johnson K, Rice KC, Maier SF, Watkins LR. Supradural inflammatory soup in awake and freely moving rats induces facial allodynia that is blocked by putative immune modulators. Brain Res. 2017 Jun 1;1664:87-94. doi: 10.1016/j.brainres.2017.03.011. Epub 2017 Mar 16.

  PMID: 28322750 BACKGROUND

• Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies. Headache. 2015 Jan;55(1):3-20. doi: 10.1111/head.12499.

  PMID: 25600718 BACKGROUND

• Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, Patel SJ, Crysdale NY, Harrison JA, Maier SF, Rice KC, Watkins LR. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). Eur J Neurosci. 2008 Jul;28(1):20-9. doi: 10.1111/j.1460-9568.2008.06321.x.

  PMID: 18662331 BACKGROUND

• Nicotra L, Loram LC, Watkins LR, Hutchinson MR. Toll-like receptors in chronic pain. Exp Neurol. 2012 Apr;234(2):316-29. doi: 10.1016/j.expneurol.2011.09.038. Epub 2011 Oct 6.

  PMID: 22001158 BACKGROUND

• Ellis A, Wieseler J, Favret J, Johnson KW, Rice KC, Maier SF, Falci S, Watkins LR. Systemic administration of propentofylline, ibudilast, and (+)-naltrexone each reverses mechanical allodynia in a novel rat model of central neuropathic pain. J Pain. 2014 Apr;15(4):407-21. doi: 10.1016/j.jpain.2013.12.007. Epub 2014 Jan 9.

  PMID: 24412802 BACKGROUND

• Lewis SS, Loram LC, Hutchinson MR, Li CM, Zhang Y, Maier SF, Huang Y, Rice KC, Watkins LR. (+)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats. J Pain. 2012 May;13(5):498-506. doi: 10.1016/j.jpain.2012.02.005. Epub 2012 Apr 20.

  PMID: 22520687 BACKGROUND

• Wang X, Zhang Y, Peng Y, Hutchinson MR, Rice KC, Yin H, Watkins LR. Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4. Br J Pharmacol. 2016 Mar;173(5):856-69. doi: 10.1111/bph.13394. Epub 2016 Feb 4.

  PMID: 26603732 BACKGROUND

• Selfridge BR, Wang X, Zhang Y, Yin H, Grace PM, Watkins LR, Jacobson AE, Rice KC. Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists. J Med Chem. 2015 Jun 25;58(12):5038-52. doi: 10.1021/acs.jmedchem.5b00426. Epub 2015 Jun 5.

  PMID: 26010811 BACKGROUND

• Roberts ID, Krajbich I, Way BM. Acetaminophen influences social and economic trust. Sci Rep. 2019 Mar 11;9(1):4060. doi: 10.1038/s41598-019-40093-9.

  PMID: 30858394 BACKGROUND

• Dewall CN, Macdonald G, Webster GD, Masten CL, Baumeister RF, Powell C, Combs D, Schurtz DR, Stillman TF, Tice DM, Eisenberger NI. Acetaminophen reduces social pain: behavioral and neural evidence. Psychol Sci. 2010 Jul;21(7):931-7. doi: 10.1177/0956797610374741. Epub 2010 Jun 14.

  PMID: 20548058 BACKGROUND

• Wardle MC, Bershad AK, de Wit H. Naltrexone alters the processing of social and emotional stimuli in healthy adults. Soc Neurosci. 2016 Dec;11(6):579-91. doi: 10.1080/17470919.2015.1136355. Epub 2016 Jan 22.

  PMID: 26710657 BACKGROUND

• Devlen J. Anxiety and depression in migraine. J R Soc Med. 1994 Jun;87(6):338-41.

  PMID: 8046705 BACKGROUND

• Buse DC, Reed ML, Fanning KM, Bostic R, Dodick DW, Schwedt TJ, Munjal S, Singh P, Lipton RB. Comorbid and co-occurring conditions in migraine and associated risk of increasing headache pain intensity and headache frequency: results of the migraine in America symptoms and treatment (MAST) study. J Headache Pain. 2020 Mar 2;21(1):23. doi: 10.1186/s10194-020-1084-y.

  PMID: 32122324 BACKGROUND

• Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018 Jan;38(1):1-211. doi: 10.1177/0333102417738202. No abstract available.

  PMID: 29368949 BACKGROUND

• Edmeads J, Findlay H, Tugwell P, Pryse-Phillips W, Nelson RF, Murray TJ. Impact of migraine and tension-type headache on life-style, consulting behaviour, and medication use: a Canadian population survey. Can J Neurol Sci. 1993 May;20(2):131-7. doi: 10.1017/s0317167100047697.

  PMID: 8334575 BACKGROUND

• Kwilasz AJ, Todd LS, Duran-Malle JC, Schrama AEW, Mitten EH, Larson TA, Clements MA, Harris KM, Litwiler ST, Wang X, Van Dam AM, Maier SF, Rice KC, Watkins LR, Barrientos RM. Experimental autoimmune encephalopathy (EAE)-induced hippocampal neuroinflammation and memory deficits are prevented with the non-opioid TLR2/TLR4 antagonist (+)-naltrexone. Behav Brain Res. 2021 Jan 1;396:112896. doi: 10.1016/j.bbr.2020.112896. Epub 2020 Sep 6.

  PMID: 32905811 BACKGROUND

• Kato J, Svensson CI. Role of extracellular damage-associated molecular pattern molecules (DAMPs) as mediators of persistent pain. Prog Mol Biol Transl Sci. 2015;131:251-79. doi: 10.1016/bs.pmbts.2014.11.014. Epub 2015 Jan 30.

  PMID: 25744676 BACKGROUND

• Parkitny L, Younger J. Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia. Biomedicines. 2017 Apr 18;5(2):16. doi: 10.3390/biomedicines5020016.

  PMID: 28536359 BACKGROUND

• Su M, Ran Y, He Z, Zhang M, Hu G, Tang W, Zhao D, Yu S. Inhibition of toll-like receptor 4 alleviates hyperalgesia induced by acute dural inflammation in experimental migraine. Mol Pain. 2018 Jan-Dec;14:1744806918754612. doi: 10.1177/1744806918754612. Epub 2018 Jan 8.

  PMID: 29310498 BACKGROUND

• Gudala K, Bansal D, Vatte R, Ghai B, Schifano F, Boya C. High Prevalence of Neuropathic Pain Component in Patients with Low Back Pain: Evidence from Meta-Analysis. Pain Physician. 2017 Jul;20(5):343-352.

  PMID: 28727698 BACKGROUND

• Cant R, Dalgleish AG, Allen RL. Naltrexone Inhibits IL-6 and TNFalpha Production in Human Immune Cell Subsets following Stimulation with Ligands for Intracellular Toll-Like Receptors. Front Immunol. 2017 Jul 11;8:809. doi: 10.3389/fimmu.2017.00809. eCollection 2017.

  PMID: 28744288 BACKGROUND

• Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther. 2005 Jan-Feb;12(1):46-55. doi: 10.1097/00045391-200501000-00008.

  PMID: 15662292 BACKGROUND

• Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res. 2002 Feb;52(2):69-77. doi: 10.1016/s0022-3999(01)00296-3.

  PMID: 11832252 BACKGROUND

• HAMILTON M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50-5. doi: 10.1111/j.2044-8341.1959.tb00467.x. No abstract available.

  PMID: 13638508 BACKGROUND

• Bihari B. Bernard Bihari, MD: low-dose naltrexone for normalizing immune system function. Altern Ther Health Med. 2013 Mar-Apr;19(2):56-65. No abstract available.

  PMID: 23594453 BACKGROUND

• Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009 May-Jun;10(4):663-72. doi: 10.1111/j.1526-4637.2009.00613.x. Epub 2009 Apr 22.

  PMID: 19453963 BACKGROUND

• Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013 Feb;65(2):529-38. doi: 10.1002/art.37734.

  PMID: 23359310 BACKGROUND

• Smith JP, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS. Low-dose naltrexone therapy improves active Crohn's disease. Am J Gastroenterol. 2007 Apr;102(4):820-8. doi: 10.1111/j.1572-0241.2007.01045.x. Epub 2007 Jan 11.

  PMID: 17222320 BACKGROUND

• Cree BA, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. 2010 Aug;68(2):145-50. doi: 10.1002/ana.22006.

  PMID: 20695007 BACKGROUND

• Chopra P, Cooper MS. Treatment of Complex Regional Pain Syndrome (CRPS) using low dose naltrexone (LDN). J Neuroimmune Pharmacol. 2013 Jun;8(3):470-6. doi: 10.1007/s11481-013-9451-y. Epub 2013 Apr 2.

  PMID: 23546884 BACKGROUND

• Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002 Jan 16;287(3):337-44. doi: 10.1001/jama.287.3.337.

  PMID: 11790213 BACKGROUND

• Krenzelok EP, Royal MA. Confusion: acetaminophen dosing changes based on NO evidence in adults. Drugs R D. 2012 Jun 1;12(2):45-8. doi: 10.2165/11633010-000000000-00000.

  PMID: 22530736 BACKGROUND

• Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. Br J Clin Pharmacol. 1980 Oct;10 Suppl 2(Suppl 2):291S-298S. doi: 10.1111/j.1365-2125.1980.tb01812.x.

  PMID: 7002186 BACKGROUND

• Aurora SK, Papapetropoulos S, Kori SH, Kedar A, Abell TL. Gastric stasis in migraineurs: etiology, characteristics, and clinical and therapeutic implications. Cephalalgia. 2013 Apr;33(6):408-15. doi: 10.1177/0333102412473371. Epub 2013 Mar 5.

  PMID: 23463252 BACKGROUND

• Alstadhaug K, Salvesen R, Bekkelund S. 24-hour distribution of migraine attacks. Headache. 2008 Jan;48(1):95-100. doi: 10.1111/j.1526-4610.2007.00779.x.

  PMID: 18184291 BACKGROUND

• Pascual J. Clinical benefits of early triptan therapy for migraine. Headache. 2002 Jan;42 Suppl 1:10-7. doi: 10.1046/j.1526-4610.2002.0420s1010.x.

  PMID: 11966859 BACKGROUND

• Burch RC, Loder S, Loder E, Smitherman TA. The prevalence and burden of migraine and severe headache in the United States: updated statistics from government health surveillance studies. Headache. 2015 Jan;55(1):21-34. doi: 10.1111/head.12482.

  PMID: 25600719 BACKGROUND

• Lipton RB, Scher AI, Kolodner K, Liberman J, Steiner TJ, Stewart WF. Migraine in the United States: epidemiology and patterns of health care use. Neurology. 2002 Mar 26;58(6):885-94. doi: 10.1212/wnl.58.6.885.

  PMID: 11914403 BACKGROUND

• Brandes JL. Global trends in migraine care: results from the MAZE survey. CNS Drugs. 2002;16 Suppl 1:13-8. doi: 10.2165/00023210-200216001-00003.

  PMID: 12196035 BACKGROUND

• Buse DC, Rupnow MF, Lipton RB. Assessing and managing all aspects of migraine: migraine attacks, migraine-related functional impairment, common comorbidities, and quality of life. Mayo Clin Proc. 2009 May;84(5):422-35. doi: 10.1016/S0025-6196(11)60561-2.

  PMID: 19411439 BACKGROUND

• Lipton RB, Hamelsky SW, Dayno JM. What do patients with migraine want from acute migraine treatment? Headache. 2002 Jan;42 Suppl 1:3-9. doi: 10.1046/j.1526-4610.2002.0420s1003.x.

  PMID: 11966858 BACKGROUND

• Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache. 2008 Sep;48(8):1157-68. doi: 10.1111/j.1526-4610.2008.01217.x.

  PMID: 18808500 BACKGROUND

MeSH Terms

Conditions

Migraine Disorders; Anxiety Disorders

Interventions

Acetaminophen

Condition Hierarchy (Ancestors)

Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines

Study Officials

• Annette C Toledano, MD

  Allodynic Therapeutics, Inc

  STUDY DIRECTOR

• Natalia Belikova, MD PhD

  Keystone Clinical Research

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Randomized, Double-Blind, Placebo-Controlled, Parallel-Group

Study Record Dates

• First Submitted: December 27, 2022
• First Posted: January 17, 2023
• Study Start: January 31, 2025
• Primary Completion: December 2, 2025
• Study Completion: December 2, 2025
• Last Updated: December 8, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)