Naltrexone for Alcoholism

(ABSTAIN Trial)

Overseen By Jazryn Nagum

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: Milky Kohno

Must not be taking: Psychotropics, Opioids

Disqualifiers: Neurological, Endocrine, Hepatic, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

Duration: 12 weeks

100 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you use psychotropic or opioid medications, or if you are on hormonal therapy other than contraceptives.

What data supports the effectiveness of the drug Naltrexone for treating alcoholism?

Research shows that Naltrexone can help reduce alcohol cravings and drinking, and lower relapse rates in people with alcohol dependence. It is more effective when combined with psychosocial support, and a long-acting injectable form may improve adherence and outcomes. ^{1 2 3 4 5}

Is naltrexone safe for humans?

Naltrexone, used for alcohol dependence, is generally safe but can have side effects. Injectable forms like Vivitrol have fewer side effects than oral versions and are less likely to cause liver issues. However, there is a potential risk of liver damage, especially in people with liver conditions, and concerns about overdose risk after stopping treatment. ^{1 3 6 7 8}

What makes the drug Naltrexone unique for treating alcoholism?

Naltrexone is unique for treating alcoholism because it works by blocking opioid receptors in the brain, which reduces the rewarding effects of alcohol and helps decrease cravings. Unlike some other treatments, it can be administered as a monthly injection (Vivitrol) or taken as a daily pill (ReVia, Depade), offering flexibility in how it is used. ^{9 10 11 12 13}

What is the purpose of this trial?

The goal of this clinical trial is to identify sex-specific biomarkers that confer greater susceptibility for Alcohol Use Disorder (AUD) and differentiate how treatment response varies by sex in people with Alcohol Use Disorder. The main questions it aims to answer are: * How does trauma affect emotion regulation, inflammation, and limbic function, and what are the sex-dependent effects of NTX (Naltrexone) on these aspects? * What is the mechanism of Naltrexone (NTX), and how does it potentially moderate reductions in alcohol use through changes in or interactions between emotion regulation, inflammation, or limbic system function? Participants will * Be consented and will undergo comprehensive screening for eligibility criteria * Complete behavioral assessments and neuropsychological assessments, as well as neurocognitive assessments and neuroimaging measures * Provide urine samples for a urine drug screen (UDS) and urine pregnancy test (for women), and have blood and a cheek swab collected and stored in the repository * Take a study drug once daily for 12 weeks and track drug usage and effects in a study journal * Undergo weekly assessment calls and bi-weekly medical follow-up safety exams Researchers will compare naltrexone to placebo in AUD to see if naltrexone is effective in reducing alcohol cravings and promoting abstinence. Researchers will also compare baseline measures between AUD and Healthy Controls.

Eligibility Criteria

This trial is for individuals with Alcohol Use Disorder (AUD) who are interested in how trauma and sex differences affect their condition. Participants will undergo various assessments, provide biological samples, take a daily study drug or placebo for 12 weeks, and attend regular follow-up exams.

Inclusion Criteria

Veteran enrolled in VHA healthcare

Alcohol Group: Must meet diagnosis for recent alcohol-use disorder (DSM-V)

Control Group: Must not meet DSM-V criteria for a use disorder other than nicotine

Exclusion Criteria

Current participation in an investigational drug study

MRI contraindications (e.g. metal in body)

Positive urine drug screen, except for nicotine and marijuana, on test days

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Participants complete behavioral, neuropsychological, and neurocognitive assessments, and provide biological samples

1-2 weeks

1 visit (in-person)

Treatment

Participants take a study drug (Naltrexone or placebo) once daily for 12 weeks, with weekly assessment calls and bi-weekly medical follow-up safety exams

12 weeks

6 visits (in-person), 6 calls (virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Naltrexone

Trial Overview The trial tests Naltrexone's effectiveness in reducing alcohol cravings and promoting abstinence in AUD patients. It explores the impact of trauma on emotion regulation, inflammation, brain function, and whether treatment effects differ between sexes.

Participant Groups

Group I: Alcohol Use Disorder (AUD) Experimental Treatment 1 Intervention

Drug: Naltrexone Half of the study participants with AUD will take an oral tablet of 50 mg naltrexone once daily for one week followed by 11 weeks of 100 mg naltrexone orally, once daily. Drug: Placebo oral tablet The other half of study participants will receive an identical looking placebo in tablet form and take the medication using an identical schedule as the real drug. Drug type will be randomized.

Group II: Healthy Controls Active Control 1 Intervention

Baseline measures will be taken but controls will not continue to the drug trial.

Naltrexone is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Vivitrol for:

• Alcohol dependence
• Opioid use disorder

Approved in European Union as Naltrexone for:

• Opioid dependence
• Alcohol dependence

Approved in Canada as Vivitrol for:

• Opioid use disorder
• Alcohol dependence

Who Is Running the Clinical Trial?

Milky Kohno

Lead Sponsor

Trials

1

Recruited

100+

Portland VA Medical Center

Collaborator

Trials

44

Recruited

7,800+

Findings from Research

A systematic review of 49 trials found that only 14% of studies on naltrexone for alcohol dependence had high adherence assurance, which may explain the variability in treatment efficacy observed.

The study revealed a significant correlation between adherence levels and treatment outcomes, suggesting that improving adherence monitoring could enhance the effectiveness of naltrexone in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adherence monitoring in naltrexone pharmacotherapy trials: a systematic review. Swift, R., Oslin, DW., Alexander, M., et al.[2022]

A systematic review of 29 randomized placebo-controlled trials involving 5997 alcohol-dependent patients found that naltrexone significantly reduces heavy drinking in 70% of the studies, highlighting its efficacy in this area.

However, naltrexone showed less effectiveness in promoting abstinence, with only 36% of trials demonstrating an advantage over placebo, suggesting that its primary benefit lies in reducing excessive drinking rather than achieving complete sobriety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The status of naltrexone in the treatment of alcohol dependence: specific effects on heavy drinking. Pettinati, HM., O'Brien, CP., Rabinowitz, AR., et al.[2013]

The FDA-approved extended-release injectable formulation of naltrexone (Vivitrol) offers a promising alternative to daily oral medication for alcohol dependence, potentially improving adherence and treatment outcomes.

When combined with psychosocial support, long-acting naltrexone has shown significant improvements in drinking outcomes, particularly for patients who are abstinent at the start of treatment, suggesting its efficacy in managing alcohol dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-acting injectable naltrexone for the treatment of alcohol dependence. Mannelli, P., Peindl, K., Masand, PS., et al.[2013]

In a study involving 99 men, naltrexone treatment significantly reduced alcohol cravings and drinking, and led to lower relapse rates compared to placebo, indicating its efficacy in treating alcohol dependence.

Naltrexone is considered a safe and effective adjunct to psychosocial interventions for alcohol dependence, with better outcomes observed in patients who consistently attended all treatment visits, suggesting that adherence to the treatment program enhances its effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naltrexone in the treatment of alcoholism: a clinical review. O'Brien, CP., Volpicelli, LA., Volpicelli, JR.[2019]

In a study of 603 participants from the COMBINE Study, family history of alcoholism (FHA) was linked to increased alcohol consumption per drinking occasion, indicating that individuals with a stronger FHA may drink more when they do drink.

While naltrexone showed a significant effect on reducing heavy drinking days over time, the study found that FHA did not significantly influence the effectiveness of naltrexone, suggesting that other factors may be more important in determining treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does family history of alcoholism moderate naltrexone's effects on alcohol use? Capone, C., Kahler, CW., Swift, RM., et al.[2019]

Injectable formulations of naltrexone, such as Vivitrex/Vivitrol and Naltrel, show promise in treating alcohol dependence with potentially fewer side effects compared to oral naltrexone, which has limitations like a small treatment effect size and plasma level fluctuations.

Vivitrex/Vivitrol has been effective in reducing heavy drinking in alcohol-dependent males, while Naltrel has been shown to promote abstinence and reduce relapse rates, indicating that these depot formulations may offer improved therapeutic options for alcohol dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naltrexone long-acting formulation in the treatment of alcohol dependence. Johnson, BA.[2021]

A study involving 250 opioid-dependent patients, many of whom had chronic hepatitis C virus (HCV) and HIV, found that intramuscular extended-release naltrexone (XR-NTX) did not significantly increase liver enzyme levels compared to a placebo, indicating its safety in this population.

Even though some patients experienced elevated liver enzymes, these levels improved over time, and no specific symptoms were linked to these elevations, suggesting that XR-NTX can be safely administered to patients with mild to moderate chronic HCV and/or HIV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatic safety of injectable extended-release naltrexone in patients with chronic hepatitis C and HIV infection. Mitchell, MC., Memisoglu, A., Silverman, BL.[2019]

A review of 263 cases related to Vivitrol (extended-release naltrexone) found that 84.6% of fatal overdoses occurred within two months after the last injection, highlighting a critical period for overdose risk.

The study suggests that there may be a link between Vivitrol discontinuation and increased overdose risk, indicating the need for further investigation and monitoring during this time frame.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of Case Narratives from Fatal Overdoses Associated with Injectable Naltrexone for Opioid Dependence. Saucier, R., Wolfe, D., Dasgupta, N.[2019]

In a 12-week study involving 30 patients with stable plaque psoriasis, both calcipotriol and calcitriol combined with NBUVB phototherapy significantly reduced symptoms like erythema and scaling, showing effectiveness as treatments.

Calcipotriol was found to be more effective than calcitriol, leading to quicker plaque clearance and a lower relapse rate, while also requiring fewer NBUVB treatment sessions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative evaluation of efficacy and safety of calcipotriol versus calcitriol ointment, both in combination with narrow-band ultraviolet B phototherapy in the treatment of stable plaque psoriasis. Chakraborty, D., Aggarwal, K.[2023]

Falecalcitriol, a vitamin D analogue designed to avoid metabolism by CYP24A1, has been used since 2001 to treat secondary hyperparathyroidism, demonstrating its efficacy in managing this condition.

The 23-hydroxy metabolite of falecalcitriol retains biological activity and is resistant to further metabolism, which may enhance its therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent developments for introducing a hexafluoroisopropanol unit into the Vitamin D side chain. Kawagoe, F., Sugiyama, T., Uesugi, M., et al.[2019]

The study identified a novel VDR agonist, 22S-butyl-20-epi-25,26,27-trinorvitamin D derivative 5, which induces a unique structure in the vitamin D receptor's ligand-binding pocket, enhancing its potency.

In contrast, the compound 4 with the natural configuration at C(20) acts as a potent VDR antagonist, creating a new cavity in the receptor structure, marking the first instance of a VDR antagonist altering the canonical pocket architecture.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new class of vitamin D analogues that induce structural rearrangement of the ligand-binding pocket of the receptor. Inaba, Y., Yoshimoto, N., Sakamaki, Y., et al.[2019]

Gemini analogs of calcitriol, like BXL0124, are more effective agonists of the vitamin D receptor (VDR) than calcitriol, showing enhanced biological activity due to a structural rearrangement that allows for better binding.

BXL0124 demonstrated superior anti-cancer properties, specifically in inhibiting breast cancer cell growth and reducing tumor volume compared to its counterpart BXL0097, indicating its potential as a more potent therapeutic agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structural analysis and biological activities of BXL0124, a gemini analog of vitamin D. Belorusova, AY., Suh, N., Lee, HJ., et al.[2018]

The active form of vitamin D(3), calcitriol, has been shown to inhibit the growth and spread of prostate and liver cancer cells, suggesting its potential use in cancer therapy.

Newly developed vitamin D analogs, such as MART-10 and MART-11, show promise as effective cancer treatments with reduced risk of hypercalcemia, making them safer alternatives for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potent 19-norvitamin D analogs for prostate and liver cancer therapy. Kittaka, A., Yoshida, A., Chiang, KC., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Adherence monitoring in naltrexone pharmacotherapy trials: a systematic review. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

The status of naltrexone in the treatment of alcohol dependence: specific effects on heavy drinking. [2013]

3. England pubmed.ncbi.nlm.nih.gov

Long-acting injectable naltrexone for the treatment of alcohol dependence. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Naltrexone in the treatment of alcoholism: a clinical review. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Does family history of alcoholism moderate naltrexone's effects on alcohol use? [2019]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Naltrexone long-acting formulation in the treatment of alcohol dependence. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Hepatic safety of injectable extended-release naltrexone in patients with chronic hepatitis C and HIV infection. [2019]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Review of Case Narratives from Fatal Overdoses Associated with Injectable Naltrexone for Opioid Dependence. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Comparative evaluation of efficacy and safety of calcipotriol versus calcitriol ointment, both in combination with narrow-band ultraviolet B phototherapy in the treatment of stable plaque psoriasis. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Recent developments for introducing a hexafluoroisopropanol unit into the Vitamin D side chain. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

A new class of vitamin D analogues that induce structural rearrangement of the ligand-binding pocket of the receptor. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Structural analysis and biological activities of BXL0124, a gemini analog of vitamin D. [2018]

13. England pubmed.ncbi.nlm.nih.gov

Potent 19-norvitamin D analogs for prostate and liver cancer therapy. [2021]