Characteristics of Ongoing Clinical Trials for Alcohol Use Disorder Registered on ClinicalTrials.gov | Psychiatry and Behavioral Health | JAMA Psychiatry | JAMA Network
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Table 1.  Drugs Evaluated in 50 Ongoing Clinical Trials for Alcohol Use Disorder (AUD) Registered on ClinicalTrials.gov
Drugs Evaluated in 50 Ongoing Clinical Trials for Alcohol Use Disorder (AUD) Registered on ClinicalTrials.gov
Table 2.  Characteristics of 50 Ongoing Clinical Trials for Alcohol Use Disorder (AUD) Registered on ClinicalTrials.gov
Characteristics of 50 Ongoing Clinical Trials for Alcohol Use Disorder (AUD) Registered on ClinicalTrials.gov
1.
National Institute on Alcohol Abuse and Alcoholism. Strategic plan 2017-2021. Accessed January 1, 2019. https://www.niaaa.nih.gov/sites/default/files/StrategicPlan_NIAAA_optimized_2017-2020.pdf
2.
Litten  RZ, Falk  DE, Ryan  ML, Fertig  JB.  Discovery, development, and adoption of medications to treat alcohol use disorder: goals for the phases of medications development.   Alcohol Clin Exp Res. 2016;40(7):1368-1379. doi:10.1111/acer.13093PubMedGoogle ScholarCrossref
3.
US Food and Drug Administration. Alcoholism: developing drugs for treatment. Accessed January 1, 2019. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm433618.pdf
4.
Sobell  LC, Sobell  MB, Connors  GJ, Agrawal  S.  Assessing drinking outcomes in alcohol treatment efficacy studies: selecting a yardstick of success.   Alcohol Clin Exp Res. 2003;27(10):1661-1666. doi:10.1097/01.ALC.0000091227.26627.75PubMedGoogle ScholarCrossref
5.
Falk  DE, O’Malley  SS, Witkiewitz  K,  et al; Alcohol Clinical Trials Initiative (ACTIVE) Workgroup.  Evaluation of drinking risk levels as outcomes in alcohol pharmacotherapy trials: a secondary analysis of 3 randomized clinical trials.   JAMA Psychiatry. 2019;76(4):374-381. doi:10.1001/jamapsychiatry.2018.3079PubMedGoogle ScholarCrossref
6.
National Institute on Alcohol Abuse and Alcoholism. Division of medications development. Accessed January 1, 2019. https://www.niaaa.nih.gov/research/extramural-research/division-medications-development
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    Research Letter
    May 27, 2020

    Characteristics of Ongoing Clinical Trials for Alcohol Use Disorder Registered on ClinicalTrials.gov

    Author Affiliations
    • 1Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut
    • 2Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut
    • 3Section of General Internal Medicine, Yale School of Medicine, New Haven, Connecticut
    JAMA Psychiatry. 2020;77(10):1081-1084. doi:10.1001/jamapsychiatry.2020.1167

    In the US, 3 medications are approved by the US Food and Drug Administration (FDA) to treat alcohol use disorder (AUD): disulfiram, acamprosate, and naltrexone.1 However, fewer than 4% of people receive an FDA-approved treatment for AUD from a health care professional.1,2 In response, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) has outlined goals to support drug development, including trials focused on new and repurposed (ie, off-label) medications for AUD.1 Furthermore, the FDA recommends responder end points for trials, including abstinence or no heavy drinking days.3 Other end points, such as percentage of days heavy drinking and reductions in drinking risk level,4,5 have also been suggested. To inform these efforts, we evaluated the characteristics of ongoing clinical trials for AUD medications registered on ClinicalTrials.gov, including the medications, populations, and end points currently being studied.

    Methods

    We searched ClinicalTrials.gov on August 28, 2019, to locate ongoing trials (with designations “not yet recruiting,” “recruiting,” “enrolling by invitation,” and “active, not recruiting”) of medications for patients with AUD or AUD and co-occurring conditions. The term alcohol was entered into the Other Terms search field to ensure the broadest number of trials were identified. For each eligible trial, we recorded interventions, co-occurring diseases, end points, and study characteristics. For each medication, we identified the drug class and FDA-approved indication(s). Lastly, we classified trials into trial phases and categories based on their target population and purpose, including medications for general AUD populations, for AUD subgroups, or for patients with AUD with co-occurring conditions. This study used public data and did not require ethics approval or informed consent. Analyses were performed using R version 3.4.0 (The R Foundation).

    Results

    We identified 50 trials focused on medications for AUD with or without co-occurring conditions (Table 1), of which 38 (76%) were phase 2 to 4 trials. The most common drug class studied was glutamate receptor antagonists (n = 12; 24%); 40 trials (80%) evaluated medications off-label for AUD and 3 (6%) evaluated medications without a current FDA indication (Table 2).

    While 25 trials (50%) assessed medications for general AUD populations, 17 trials (34%) were for patients with AUD with co-occurring conditions and 8 (16%) focused on AUD subpopulations (Table 2). The median (interquartile range) study duration was 12 (4-13) weeks, and the median (interquartile range) sample size was 123 (60-167) participants. Of the 38 phase 2 to 4 trials, 10 (26%) had FDA-recommended primary or secondary responder-based end points, and 9 (24%) measured percentage of days heavy drinking. Overall, 28 studies (56%) had support from NIAAA or the Department of Veterans Affairs.

    Discussion

    Our results show 50 ongoing trials registered on ClinicalTrials.gov are evaluating medications for treatment of AUD. Although a range of medications are investigated, most are repurposed, often for patients with AUD with co-occurring conditions. These trials are small and of short duration, and only one-quarter of phase 2 to 4 trials included FDA-recommended responder outcomes. These findings raise concerns about the future of AUD treatment, given seemingly limited testing of novel AUD medications by the pharmaceutical industry and a need for larger and longer trials. There may also be a growing preference for end points that focus on reduced alcohol intake, which can lead to improved health-related outcomes. Recently, there have been proposals to include a categorical drinking reduction measure as the primary end point for trials supporting FDA approval of medications.5

    This study has limitations. This study identified trials registered on ClinicalTrials.gov, and we may have missed early-phase trials not subject to registration requirements and evaluations conducted in other countries. Since our data were collected, additional trials may have been registered and ongoing trials may have been terminated, suspended, or completed. However, our evaluation of emerging research suggests that additional efforts may be necessary to fulfill NIAAA’s objective of identifying AUD medications.1 For instance, Request for Applications and regulatory incentives could encourage evaluations by investigators and industry.6 Furthermore, greater awareness and adoption of FDA-recommended responder end points can help ensure that trials provide insight regarding clinical benefit.

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    Article Information

    Accepted for Publication: March 24, 2020.

    Corresponding Author: Stephanie S. O’Malley, PhD, Department of Psychiatry, Yale School of Medicine, 34 Park St, New Haven, CT 06519 (stephanie.omalley@yale.edu).

    Published Online: May 27, 2020. doi:10.1001/jamapsychiatry.2020.1167

    Author Contributions: Drs Wallach and O’Malley had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Study concept and design: Wallach, O’Malley.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Wallach, O’Malley.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Wallach.

    Obtained funding: Krystal.

    Administrative, technical, or material support: Krystal.

    Study supervision: O’Malley.

    Conflict of Interest Disclosures: Dr Wallach has received research support through Yale University from the Laura and John Arnold Foundation and the US Food and Drug Administration (grant U01FD00593) outside the submitted work. Dr Krystal has received grants from the National Institute on Alcohol Abuse and Alcoholism during the conduct of the study; grants from the National Institute of Mental Health, National Center to Advance Translational Science, Research Triangle Institute, US Department of Veterans Affairs, and US Department of Defense; personal fees for consulting from Arkin Holdings, AstraZeneca, Axon Advisors, Biogen, Biomedisyn, Bionomics, Boehringer Ingelheim, COMPASS Pathways, Concert Pharmaceuticals, Epiodyne, EpiVario, Heptares Therapeutics, Janssen Research & Development, L.E.K. Consulting, Otsuka America Pharmaceutical, Perception Neuroscience Holdings, Pfizer Neuroscience, SK Life Science, Spring Care, Sunovion Pharmaceuticals, Takeda, and Taisho Pharmaceutical; and nonfinancial research support from AstraZeneca, Novartis, and Pfizer outside the submitted work; serves on an advisory board of BiOasis Technologies, Biohaven Pharmaceuticals, BioXcel Therapeutics, BlackThorn Therapeutics, Cadent Therapeutics, Cerevel Therapeutics, EpiVario, Eisai, Lohocla Research, Novartis, and PsychoGenics; is on the board of directors of Inheris Biopharma; has stock in Biohaven Pharmaceuticals, Sage Pharmaceuticals, and Spring Care; has stock options with Biohaven Pharmaceuticals, BlackThorn Therapeutics, EpiVario, and Terran Life Sciences; is the Editor of Biological Psychiatry; and holds US patent Nos. 5,447,948; 8,778,979; and 9592207; US patent applications 15/379,013 and 61/973/961; USPTO docket Nos. Y0087.70116US00 and 62/719,935; and US provisional patent application No. 62/444,552. Dr Ross has received grants from the US Food and Drug Administration, Johnson & Johnson, Medical Device Innovation Consortium, Agency for Healthcare Research and Quality, National Heart, Lung, and Blood Institute, Laura and John Arnold Foundation, US Centers for Medicare & Medicaid Services, Blue Cross Blue Shield Association, and Medtronic outside the submitted work. Dr O’Malley has received grants and contracts from the National Institute on Alcohol Abuse and Alcoholism during the conduct of the study; grants from the National Institute on Drug Abuse and US Food and Drug Administration Center for Tobacco Products; personal fees from Alkermes, Opiant Pharmaceuticals, Mitsubishi Tanabe Pharma, and Indivior; and nonfinancial support from Amygdala Neurosciences, AstraZeneca, Novartis, and Pfizer outside the submitted work; is a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative (ACTIVE) supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Ethypharm, Indivior, Lundbeck, Mitsubishi Tanabe Pharma, and Otsuka America Pharmaceutical; and is a data and safety monitoring board member for the NIDA Clinical Trials Network (Emmes Corporation).

    Funding/Support: Supported in part by grant P50AA012870 from the National Institute on Alcohol Abuse and Alcoholism.

    Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

    References
    1.
    National Institute on Alcohol Abuse and Alcoholism. Strategic plan 2017-2021. Accessed January 1, 2019. https://www.niaaa.nih.gov/sites/default/files/StrategicPlan_NIAAA_optimized_2017-2020.pdf
    2.
    Litten  RZ, Falk  DE, Ryan  ML, Fertig  JB.  Discovery, development, and adoption of medications to treat alcohol use disorder: goals for the phases of medications development.   Alcohol Clin Exp Res. 2016;40(7):1368-1379. doi:10.1111/acer.13093PubMedGoogle ScholarCrossref
    3.
    US Food and Drug Administration. Alcoholism: developing drugs for treatment. Accessed January 1, 2019. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm433618.pdf
    4.
    Sobell  LC, Sobell  MB, Connors  GJ, Agrawal  S.  Assessing drinking outcomes in alcohol treatment efficacy studies: selecting a yardstick of success.   Alcohol Clin Exp Res. 2003;27(10):1661-1666. doi:10.1097/01.ALC.0000091227.26627.75PubMedGoogle ScholarCrossref
    5.
    Falk  DE, O’Malley  SS, Witkiewitz  K,  et al; Alcohol Clinical Trials Initiative (ACTIVE) Workgroup.  Evaluation of drinking risk levels as outcomes in alcohol pharmacotherapy trials: a secondary analysis of 3 randomized clinical trials.   JAMA Psychiatry. 2019;76(4):374-381. doi:10.1001/jamapsychiatry.2018.3079PubMedGoogle ScholarCrossref
    6.
    National Institute on Alcohol Abuse and Alcoholism. Division of medications development. Accessed January 1, 2019. https://www.niaaa.nih.gov/research/extramural-research/division-medications-development
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