Diclofenac Dose Response Study

NCT06636227 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: HP-00109891
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

The development of efficacious medications for AUD remains a high research priority with current emphases on identifying novel molecular targets and efficiently screening new compounds. Pharmacological modulation of the kynurenine pathway (KP) represents a promising novel target for AUD. The KP is a complex enzymatic cascade with each step producing biologically active metabolites that are critically involved in diverse physiological and pathological processes. Chronic alcohol exposure produces dysregulation of the KP, particularly as evidenced by decreased levels of the neuroprotective metabolite kynurenic acid (KYNA) and increased levels of the neurotoxic metabolite quinolinic acid (QUIN). This metabolic shift is associated with various alcohol-related pathologies in animals and humans. Thus, a medication that targets the KP to restore KYNA and attenuate QUIN levels may be an effective treatment for AUD. The enzyme kynurenine 3- monooxygenase (KMO) is a major gatekeeper of the KP and resultant KYNA levels. KMO inhibition shifts the KP towards KYNA production in brain and away from QUIN production. Critically, KMO inhibition in rodents, through its increase in brain KYNA levels, decreases alcohol self-administration, preference, cue-reactivity, and relapse behaviors. However, KMO-inhibitors have not been tested in humans because of presumed lack of availability. Diclofenac is an FDA-approved Non-Steroidal Anti-Inflammatory Drug that was recently discovered to inhibit KMO activity. Consistent with KMO inhibition, diclofenac increases KYNA levels in the brain and periphery of rodents. However, it remains unknown whether diclofenac increases KYNA levels and affects alcohol-related behaviors in humans at approved, safe dosages. Investigators propose to conduct a human laboratory pilot study to test whether diclofenac can increase KYNA in individuals with AUD, and if so, which of 3 doses (50, 75, or 100 mg) most effectively increases KYNA. Individuals with AUD (n = 24) will complete four sessions where they receive diclofenac (50, 75, or 100 mg) or placebo. Investigators will examine increases in KYA levels and will also assess QUIN levels, alcohol craving, and negative mood.

Conditions

Alcohol-Related Disorders; Alcohol Use Disorder (AUD)

Keywords

Alcohol use disorder (AUD); Alcohol-Related Disorders; Alcoholism; Drinking Behavior; Substance-Related Disorders; Chemically-Induced Disorders

Outcome Measures

Primary Outcomes (1)

• Change in blood kynurenic acid (KYNA) levels

  To test whether diclofenac can increase blood kynurenic acid (KYNA) in individuals with Alcohol Use Disorder (AUD)

  From enrollment to the end of session 4 (approximately 5 weeks)

Study Arms (4)

Placebo

PLACEBO COMPARATOR

Placebo arm

Drug: Placebo control

Diclofenac 50mg

ACTIVE COMPARATOR

In this arm participants will receive 50mg of Diclofenac

Drug: Diclofenac 50mg

Diclofenac 75mg

ACTIVE COMPARATOR

In this arm participants will receive 75mg of Diclofenac

Drug: Diclofenac 75mg

Diclofenac 100mg

ACTIVE COMPARATOR

In this arm participants will receive 100mg of Diclofenac

Drug: Diclofenac 100mg

Interventions

Placebo control DRUG

Placebo control

Placebo

Diclofenac 100mg DRUG

Diclofenac 100mg

Diclofenac 100mg

Diclofenac 75mg DRUG

Diclofenac 75mg

Diclofenac 75mg

Diclofenac 50mg DRUG

Diclofenac 50mg

Diclofenac 50mg

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 21-65
• Meet DSM-5 diagnostic criteria for current AUD of any severity (Mild, Moderate, or Severe)
• In the 30-day period before enrollment, consume \> 14 and \> 7 standard drinks per week for men and women, respectively
• In the 30-day period before enrollment, engage in heavy drinking (5 or more drinks for men, 4 or more drinks for women) ≥ 5 times per month

You may not qualify if:

• Currently in treatment, a history of treatment within the 30 days before enrollment, or currently seeking immediate treatment for AUD
• Current (last 12 months) DSM-5 diagnosis of SUD for any psychoactive substances other than alcohol, nicotine, and cannabis (cannabis use disorder, mild severity allowed; moderate and severe excluded)
• Currently prescribed a psychotropic medication for the treatment of schizophrenia spectrum and other psychotic disorders, bipolar and related disorders
• Lifetime DSM-5 diagnosis of schizophrenia spectrum and other psychotic disorders and bipolar and related disorders
• Positive urine toxicology screen for the following substances: cocaine, opiates, amphetamines, methamphetamine, phencyclidine, barbiturates, benzodiazepine, methadone, and tricyclic antidepressants
• Self-reported current daily use of opioids (including prescribed)
• If female: pregnant, nursing, or with reproductive potential who refuses to use reliable methods of birth control throughout the study
• Serious alcohol withdrawal symptoms as indicated by a score ≥ 10 on the Clinical Institute Withdrawal Assessment for Alcohol-Revised
• Any lifetime history of 1) serious GI conditions, including ulcer disease, gastrointestinal bleeding, and clinically significant gastritis, or, 2) serious cardiovascular conditions, including heart failure, myocardial infarction, stroke, pulmonary embolism, blood clots, deep vein thrombosis, or clotting disorder, 3) liver disease or impaired liver function, and 4) renal disease or insufficiency
• Current uncontrolled hypertension
• AST and ALT \> four times the upper limit of the normal range, or albumin, GFR, BUN, or creatinine 15% \> the upper limit of the normal range
• Clinically significant ECG findings, including clinically significant arrhythmia, atrioventricular block, prolonged QTc interval, or enlarged or hypertrophic heart
• Attempted suicide in the past 3 years and/or serious suicidal intention or plan within the past year
• Currently on prescription medication that contraindicates use of diclofenac, including but not necessarily limited to: oral corticosteroids, anticoagulants, lithium, warfarin, aspirin (daily use), methotrexate, cyclosporine, ACE-inhibitors, diuretics like furosemide and thiazides, and any medication that significantly influences CYP2C9 enzyme activity (e.g., rifampin, voriconazole).
• Previously known hypersensitivity, including gastroenteritis, asthma, and allergic-type reactions, to any NSAID and/or aspirin

Sponsors & Collaborators

• University of Maryland, Baltimore: lead

Study Sites (1)

Maryland Psychiatric Research Center

Catonsville, Maryland, 21248, United States

RECRUITING

Related Publications (7)

• Rover S, Cesura AM, Huguenin P, Kettler R, Szente A. Synthesis and biochemical evaluation of N-(4-phenylthiazol-2-yl)benzenesulfonamides as high-affinity inhibitors of kynurenine 3-hydroxylase. J Med Chem. 1997 Dec 19;40(26):4378-85. doi: 10.1021/jm970467t.

  PMID: 9435907 BACKGROUND

• Leclercq S, Schwarz M, Delzenne NM, Starkel P, de Timary P. Alterations of kynurenine pathway in alcohol use disorder and abstinence: a link with gut microbiota, peripheral inflammation and psychological symptoms. Transl Psychiatry. 2021 Oct 1;11(1):503. doi: 10.1038/s41398-021-01610-5.

  PMID: 34599147 BACKGROUND

• Vengeliene V, Cannella N, Takahashi T, Spanagel R. Metabolic shift of the kynurenine pathway impairs alcohol and cocaine seeking and relapse. Psychopharmacology (Berl). 2016 Sep;233(18):3449-59. doi: 10.1007/s00213-016-4384-9. Epub 2016 Jul 30.

  PMID: 27475106 BACKGROUND

• Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci. 2012 Jul;13(7):465-77. doi: 10.1038/nrn3257.

  PMID: 22678511 BACKGROUND

• Litten RZ, Falk DE, Ryan ML, Fertig J, Leggio L. Advances in Pharmacotherapy Development: Human Clinical Studies. Handb Exp Pharmacol. 2018;248:579-613. doi: 10.1007/164_2017_79.

  PMID: 29294197 BACKGROUND

• Maisel NC, Blodgett JC, Wilbourne PL, Humphreys K, Finney JW. Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful? Addiction. 2013 Feb;108(2):275-93. doi: 10.1111/j.1360-0443.2012.04054.x. Epub 2012 Oct 17.

  PMID: 23075288 BACKGROUND

• Skinner MD, Lahmek P, Pham H, Aubin HJ. Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PLoS One. 2014 Feb 10;9(2):e87366. doi: 10.1371/journal.pone.0087366. eCollection 2014.

  PMID: 24520330 BACKGROUND

MeSH Terms

Conditions

Alcoholism; Alcohol-Related Disorders; Drinking Behavior; Substance-Related Disorders; Chemically-Induced Disorders

Interventions

Diclofenac

Condition Hierarchy (Ancestors)

Mental Disorders; Behavior

Intervention Hierarchy (Ancestors)

Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals

Central Study Contacts

Mathew Glassman, MS

CONTACT

410-402-6411; mglassman@som.umaryland.edu

Neil Batra, BS

CONTACT

410-402-6803; nbatra@som.umaryland.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: This is a double-blind, placebo-controlled, randomized, cross-over study in which individuals with AUD (n=24) complete four sessions where they receive diclofenac (50 mg, 75 mg, or 100 mg) or placebo. Eligible participants will be randomized to receive the three doses of diclofenac and placebo in a randomized, double-blind fashion. Because the study is completely within subject, there are no groups or group assignment. There are no control subjects.

Study Record Dates

• First Submitted: October 3, 2024
• First Posted: October 10, 2024
• Study Start: December 1, 2024
• Primary Completion (Estimated): May 31, 2026
• Study Completion (Estimated): August 31, 2026
• Last Updated: February 9, 2026

Record last verified: 2026-02

Locations

US (1)