Apremilast for Alcoholism

Overseen By Sabrina Coppola

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Yale University

Must not be taking: Psychoactive drugs, Cytochrome P450 inducers

Disqualifiers: Significant medical conditions, Substance use disorder, Pregnancy, Mental illness, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 15 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a medication called apremilast (Otezla) to determine its effectiveness for individuals with Alcohol Use Disorders (AUD). Researchers aim to discover if apremilast can reduce alcohol consumption in adults who drink heavily. Participants must have struggled with AUD for at least the past six months and regularly consume more than the recommended number of drinks per week. The trial targets individuals who can take oral medications and are willing to adhere closely to the study's procedures. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain drugs that may influence study outcomes, like disulfiram, naltrexone, acamprosate, or anticonvulsants. Past 30-day use of psychoactive drugs may be allowed at the study doctor's discretion.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it excludes those using drugs that may influence study outcomes, like disulfiram, naltrexone, acamprosate, and anticonvulsants. It's best to discuss your current medications with the study team to see if they might affect your eligibility.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that apremilast is usually well-tolerated. Studies have found it has fewer serious side effects compared to other similar treatments. Even at higher doses, it appears safe for most people. While some side effects can occur, they are often mild. The FDA has already approved apremilast for other conditions, indicating its safety for humans. However, using it for new purposes might lead to different results. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Apremilast is unique because it offers a new approach to treating alcoholism by targeting the inflammatory pathways that might be involved in addiction behaviors. Unlike traditional treatments for alcoholism, which often focus on counseling, support groups, or medications like disulfiram and naltrexone that reduce cravings or cause unpleasant effects when alcohol is consumed, Apremilast is an oral medication that works by inhibiting an enzyme called phosphodiesterase 4 (PDE4). This enzyme plays a role in inflammation and immune responses, which can be linked to the brain's reward system. Researchers are excited about Apremilast because it could address the underlying biological mechanisms of addiction, potentially leading to better outcomes for people struggling with alcoholism.

What evidence suggests that apremilast might be an effective treatment for alcoholism?

Research has shown that apremilast, which participants in this trial will receive, might help people with Alcohol Use Disorders (AUD) reduce their drinking. In one study, participants taking apremilast cut their drinking by more than half, from an average of five drinks a day. Another study found that apremilast reduced drinking in individuals not actively seeking treatment. Tests on animals also demonstrated that apremilast lowered alcohol consumption and alleviated problems related to drinking. These findings suggest that apremilast could be a promising method to help people with AUD reduce their alcohol use. ^{1 2 3 4 6}

Who Is on the Research Team?

Sherry McKee, PhD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for adults aged 21-65 with Alcohol Use Disorders (AUD) who meet specific drinking criteria. Participants must be able to handle responsibilities the day after a session, comply with study procedures, take oral medications, and provide informed consent. It's not suitable for those unable to fulfill these requirements.

Inclusion Criteria

I can read and write in English.

I can take pills and will follow the medication plan.

I have signed and understand the consent form.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Titration

Titration to steady state medication levels over 6 days

6 days

Daily visits (in-person)

Treatment

Participants receive apremilast (60mg/day) and complete laboratory and cue-reactivity sessions

15 days

Multiple visits (in-person)

Follow-up

Participants are contacted to assess any side effects from discontinuing medication

2 weeks

1 contact (virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Apremilast

Trial Overview

The trial is testing Apremilast (60mg/day) as a potential treatment for AUD in both women and men. The goal is to collect preliminary data on its effectiveness and safety for individuals struggling with alcohol consumption issues.

How Is the Trial Designed?

Group I: Apremilast Experimental Treatment 1 Intervention

Apremilast (60mg/day). Administered orally twice daily at 8:00 AM and 8:00 PM while titrating to the full dose. Titration schedule: Day 1 10mg AM; Day 2 10mg AM, 10mg PM; Day 3 10mg AM, 20mg PM; Day 4 20mg AM, 20mg PM; Day 5 20mg AM, 30mg PM; Day 6 30mg AM, 30mg PM. Once at steady state, administration is orally twice daily at 8:00 AM (30mg) and 8:00 PM (30mg).

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

Approved in United States as Otezla for:

• Psoriatic arthritis
• Plaque psoriasis
• Behçet’s disease

Approved in European Union as Otezla for:

• Psoriatic arthritis
• Plaque psoriasis
• Behçet’s disease

Approved in Canada as Otezla for:

• Psoriatic arthritis
• Plaque psoriasis

Approved in Japan as Otezla for:

• Psoriatic arthritis
• Plaque psoriasis

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Collaborator

Trials

865

Recruited

1,091,000+

Office of Research on Women's Health (ORWH)

Collaborator

Trials

34

Recruited

36,300+

Published Research Related to This Trial

In a study involving 212 patients with new-onset seizures and 206 untreated controls, adverse event reporting did not significantly differ between those starting low-dose antiepileptic drugs (AEDs) and those not receiving treatment, suggesting that low-dose AEDs may not increase the risk of adverse effects compared to no treatment.

Factors such as depression, female gender, and a history of seizures were linked to higher adverse event reporting, indicating that addressing these variables could enhance the tolerability of epilepsy treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse antiepileptic drug effects in new-onset seizures: a case-control study. Perucca, P., Jacoby, A., Marson, AG., et al.[2022]

The definition of an adverse drug event (ADE) should be tailored to the specific purpose of the evaluation, with stricter definitions needed for scientific studies and more flexible ones for clinical use.

Postmarketing safety data for drugs is limited at launch, but can be supplemented through systems like the FDA's Spontaneous Reporting System and targeted research projects, emphasizing the importance of robust epidemiological evidence for regulatory actions like drug recalls.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug events: identification and attribution. Rogers, AS.[2022]

In a study involving 604 patients with alcohol dependence, nalmefene significantly reduced heavy drinking days by an average of 2.3 days and total alcohol consumption by 11.0 grams per day compared to placebo over 24 weeks.

While nalmefene showed clinical benefits and improvements in liver enzymes, it also had a higher incidence of mild to moderate adverse events compared to placebo, although serious adverse events were similar between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extending the treatment options in alcohol dependence: a randomized controlled study of as-needed nalmefene. Mann, K., Bladström, A., Torup, L., et al.[2022]

In a 12-week study involving 378 adults with alcohol dependence, those taking nalmefene as needed significantly reduced their heavy drinking days by an average of 13.1 days per month, demonstrating its efficacy in lowering alcohol consumption.

The treatment was well tolerated, with common side effects including nausea (18.3%) and dizziness (17.7%), indicating that nalmefene can be a safe option for managing alcohol dependence in primary care settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nalmefene, Given as Needed, in the Routine Treatment of Patients with Alcohol Dependence: An Interventional, Open-Label Study in Primary Care. Castera, P., Stewart, E., Großkopf, J., et al.[2019]

Naltrexone significantly reduced ethanol consumption in Wistar rats at a dose of 0.1 mg/kg, confirming its effectiveness in reducing alcohol use.

Acamprosate did not show significant effects on ethanol consumption when used alone, and combining it with naltrexone did not enhance the reduction in alcohol intake, suggesting that using these medications together may not provide additional benefits over using them separately.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of acamprosate and naltrexone, alone or in combination, on ethanol consumption. Stromberg, MF., Mackler, SA., Volpicelli, JR., et al.[2019]

Apremilast is an orally administered drug that effectively inhibits phosphodiesterase 4 (PDE4) and has been approved for treating active psoriatic arthritis and moderate to severe plaque psoriasis, highlighting its efficacy in managing these conditions.

The drug is noted for its excellent safety profile and ease of prescription, making it a favorable option for dermatologists, and it is increasingly being explored for off-label uses in other inflammatory skin conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apremilast in Psoriasis and Beyond: Big Hopes on a Small Molecule. Afra, TP., Razmi, TM., Dogra, S.[2020]

Pharmacological therapy for alcohol use disorders should be tailored to individual needs, focusing on three treatment phases: withdrawal to abstinence, abstinence and relapse prevention, and reduction of alcohol consumption.

In addition to approved medications, some off-label drugs show promise in treating alcohol use disorders and warrant further investigation, highlighting the importance of a personalized, multidisciplinary approach to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological treatments in alcohol use disorders: state of art and new perspectives. Guglielmo, R., Ioime, L., Solaroli, S., et al.[2018]

Nalmefene, a newly approved opioid antagonist, is designed to reduce alcohol consumption rather than support complete abstinence, which marks a shift in treatment strategies for alcoholism.

Clinical studies indicate that nalmefene acts on both µ-opioid receptors and kappa receptors, potentially offering a novel approach to managing alcohol intake in patients who struggle with relapses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Nalmefene: a novel pharmacotherapeutic option for alcoholism]. Soyka, M.[2021]

The proposed three-part framework for analyzing adverse events includes phases for documenting incidents, conducting in-depth reviews, and assessing the association between exposure and adverse events, which can enhance product safety.

By standardizing the evaluation of adverse events through this framework, companies can better manage risks and improve consumer products based on reliable data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-market surveillance of consumer products: Framework for adverse event management. Kingston, R., Sioris, K., Gualtieri, J., et al.[2022]

In a phase 3 study involving Japanese patients with alcohol dependence, nalmefene significantly reduced heavy drinking days and total alcohol consumption, particularly in patients under 65 years old, with no family history of problem drinking, and who started drinking at age 25 or older.

The study identified specific patient characteristics that may enhance the effectiveness of nalmefene, suggesting that those who are non-smokers and have favorable drinking histories are more likely to benefit from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical moderators of response to nalmefene in a randomized-controlled trial for alcohol dependence: An exploratory analysis. Hashimoto, N., Habu, H., Takao, S., et al.[2022]

Current clinical trials have not identified any safe alternatives to traditional treatments like benzodiazepines for severe alcohol withdrawal syndrome, despite ongoing research into anticonvulsants over the past 40 years.

Topiramate and valproate show promise for reducing alcohol consumption and treating alcohol dependence in patients with bipolar disorder, but further well-controlled studies with longer durations are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Anticonvulsants in the treatment of alcoholism]. Bonnet, U., Schäfer, M., Richter, C., et al.[2014]

Ondansetron was found to be effective in treating early-onset alcoholics (72% of Type B subjects) but not late-onset alcoholics, highlighting the importance of age of onset in predicting treatment response.

The study suggests that the early- vs. late-onset classification is a better predictor of ondansetron efficacy than the Type A/B classification, indicating that neurobiological differences related to the age of onset may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prediction of serotonergic treatment efficacy using age of onset and Type A/B typologies of alcoholism. Roache, JD., Wang, Y., Ait-Daoud, N., et al.[2022]

The Lithuanian version of the Liverpool Adverse Events Profile (LT-LAEP) is a reliable tool for assessing adverse effects of antiseizure medications in people with epilepsy, showing high internal consistency and test-retest reliability.

Key factors influencing higher LT-LAEP scores include being female, experiencing more frequent seizures, and having higher levels of anxiety and depression, rather than the total amount of medication taken.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability of antiseizure medicines using Lithuanian version of the Liverpool Adverse Events Profile. Jasionis, A., Jasionytė, G., Mameniškienė, R.[2021]

A new standardized strategy for reporting adverse events (AEs) and serious adverse events (SAEs) in substance use disorder (SUD) clinical trials was developed, which aims to reduce the reporting burden while maintaining safety monitoring.

In a review of 17 SUD trials involving 6737 participants, the new strategy showed a significant reduction in irrelevant safety event reporting, leading to a more consistent safety assessment system tailored to the risks associated with specific trial interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategies for safety reporting in substance abuse trials. Lindblad, R., Campanella, M., Styers, D., et al.[2013]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10014105/

Preclinical and clinical evidence for suppression of alcohol ...

Importantly, apremilast (90 mg/d) reduced excessive drinking in non–treatment-seeking individuals with AUD in a double-blind, placebo-controlled ...

2.

news.ohsu.edu

news.ohsu.edu/2023/02/21/pill-for-skin-disease-also-curbs-excessive-drinking

Pill for skin disease also curbs excessive drinking

On average, the people who received the medication, called apremilast, reduced their alcohol intake by more than half — from five drinks per day ...

3.

insight.jci.org

insight.jci.org/articles/view/189732

Apremilast reduces co-occurring alcohol drinking and ...

Apremilast reduced alcohol drinking in both strains of rats. Apremilast reduced mechanical allodynia immediately after drinking, persisting into early and late ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT07029529

Dose-response Study of Apremilast in Women and Men ...

For this protocol, the investigators plan to collect data to evaluate apremilast (60mg/day or 90mg/day) vs placebo in adults with Alcohol Use Disorders ...

5.

biorxiv.org

biorxiv.org/content/10.1101/2021.05.13.444033.full

The FDA-approved drug apremilast suppresses alcohol ...

When given orally prior to the last day of drinking, apremilast (20 mg/kg) was shown to decrease ethanol intake in non-dependent (air control) ...

6.

rheumatologyadvisor.com

rheumatologyadvisor.com/news/additional-adverse-events-identified-with-apremilast-use/

Additional Adverse Events Identified With Apremilast Use

Additional safety signals have been identified with apremilast, with some adverse events specific to certain patient populations.