With nearly 18 million people in the United States with an alcohol use disorder and an annual total economic cost of $235 billion, there is a clear need for more interventions to treat alcohol use disorders. More treatment options can help minimize the negative consequences felt by dependent individuals, their families, workplaces, and society as a whole. One aspect of treatment, in addition to well-known methods such as mutual-help groups and individual therapy, is the use of medications. Several medications are approved by the FDA for treating alcoholism and others show promise.

The drug development process, however, is extremely lengthy (approximately 13 years from discovery to market) and very expensive. To help encourage the development of medications to treat alcoholism, NIAAA founded the Clinical Investigations Group (NCIG) in 2007 to test the safety and effectiveness of promising medications in proof-of-concept Phase II clinical trials that bridges the gap between preclinical studies and Phase III clinical trials involving larger groups of participants. Additionally, NCIG hopes to serve as a model for pharmaceutical companies by improving the methodology to best detect a treatment’s effect with minimal cost and time.

When considering medications to evaluate in the NCIG program, program staff look for signs of efficacy shown in prior research, such as a reduction in drinking or craving for alcohol or other subjective effects. Candidate medications include those already marketed for the treatment of other diseases or disorders as well as new compounds currently in development by pharmaceutical companies. When a compound shows signs of efficacy, staff then work collaboratively with the pharmaceutical industry to increase the likelihood that the drug will be made available to patients.

NCIG has successfully completed 5 Phase II, randomized, placebo-controlled multi-site clinical trials since the program’s inception in 2007:

1. Quetiapine, an atypical antipsychotic medication used in treating psychiatric disorders, was examined in 224 very heavy-drinking alcohol-dependent individuals. Quetiapine significantly reduced depressive symptoms and improved sleep compared to placebo, but had no signifcant effect on drinking outcomes ⁽¹⁾.

2. Levetiracetam XR (Keppra XR®), an antiseizure drug, was tested in 130 very heavy-drinking alcohol dependent individuals. Levetiracetam XR decreased the number of alcohol-related consequences compared to placebo, but had no significant effect on drinking or other outcomes ⁽²⁾.

3. Varenicline (Chantix®), a smoking cessation medication, was evaluated in 200 alcohol-dependent individuals. Varenicline significantly reduced alcohol consumption and craving, making it a potentially viable option for the treatment of alcohol dependence ⁽³⁾.

4. ABT-436, a novel arginine vasopressin (AVP) type 1B receptor (V1B) antagonist developed by the pharmaceutical company, AbbVie, was evaluated in 148 alcohol dependent individuals. ABT-436 significantly increased the percentage of days abstinent compared to placebo ⁽⁴⁾.

5. Gabapentin enacarbil extended-release (HORIZANT®), a gabapentin prodrug formulation, was tested in 346 individuals with at least moderate alcohol use disorder. HORIZANT® had no effect on alcohol consumption, alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms ⁽⁵⁾.

Most of these NCIG databases are available to researchers per request and approval. Please click here to view the available databases and to apply for access.

NCIG encourages proposals from pharmaceutical companies with promising compounds for the treatment of alcohol use disorder. The pharmaceutical industry’s response to the NCIG program has been positive. Numerous major pharmaceutical companies have contacted NIAAA with potential compounds for testing via the NCIG program, including AbbVie, with whom NCIG is currently conducting a clinical trial on a new molecular entity. The continued review of data from already conducted NCIG trials provides an opportunity to enhance and improve the methodology for conducting these trials as efficiently and productively as possible. Data from NCIG trials gives additional insights about evaluating future studies that will hopefully improve the evidence base for treating patients with alcohol use disorders. In addition, as more drugs with different neural targets are tested, further insights will be gained into the mechanisms underlying the development and maintenance of alcohol use disorders.

NIAAA’s objective for NCIG has been to make more drugs available to physicians to treat alcohol use disorders. Through NCIG, NIAAA seeks to encourage pharmaceutical companies to consider testing compounds for treating alcohol dependence at an early stage of the development.

The NCIG team is composed NIAAA staff from the Medications Development Branch (MDB) within the Division of Treatment and Recovery (DTR) and the Office of the Director:

Raye Z. Litten, Ph.D. (Project Officer)
Joanne Fertig, Ph.D. (Principal Investigator)
Daniel E. Falk, Ph.D. (Principal Investigator)
Megan Ryan, M.B.A. (Clinical Trials Operations and Technology Innovation Officer)

For more information on NCIG, contact:
Raye Z. Litten, Ph.D.
(301) 443-0636
rlitten@mail.nih.gov

REFERENCES:

1. Litten, R.Z., Fertig, J.B., Falk, D.E., Ryan, M.L., et al. (2012). A phase 2, double-blind, placebo-controlled trial to assess the efficacy of quetiapine fumarate sustained release for the treatment of alcohol dependency in very heavy drinkers.  Alcoholism:  Clinical and Experimental Research, 36(3), 406-16. doi: 10.1111/j.1530-0277.2011.01649.  PMID: 21950727
 

2. Fertig J.B., Ryan, M.L., Falk, D.E., Litten, R.Z., et al. (2012). A phase 2, double-blind, placebo-controlled trial to assess the efficacy of leviteracetam extended release for alcohol dependence.  Alcoholism: Clinical and Experimental Research, 36(8), 1421-30. doi: 10.1111/j.1530-0277.2011.01716.  PMID: 22324516
 

3. Litten, R.Z., Ryan M.L., Fertig, J.B., Falk, D.E., et.al. (2013). A double-blind, placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence. Journal of Addiction Medicine, 7(4), 277-86. doi:10.1097/ADM.0b013e31829623f4.  PMID: 23728065

4. Ryan, M.L., Falk, D.E., Fertig, J.B., Rendenbach-Mueller, B., Katz, D.A., Tracy, K.A., Strain, E.C., Dunn, K.E., Kampman, K., Mahoney, E., Ciraulo, D.A., Sickles-Colaneri, L., Ait-Daoud, N., Johnson, B.A., Ransom, J., Scott, C., Koob, G.F., & Litten, R.Z. (2017). A phase 2, double-blind, placebo-controlled randomized trial assessing the efficacy of ABT-436, a novel V1b receptor antagonist, for alcohol dependence. Neuropsychopharmacology. 2017 Apr;42(5):1012-1023. doi: 10.1038/npp.2016.214. PMID: 27658483.

5. Falk, D.E., Ryan, M.L., Fertig, J.B., Devine, E.G., Cruz, R., Brown, E.S., Burns, H., Salloum, I.M., Newport, D.J., Mendelson, J., Galloway, G., Kampman, K., Brooks, C., Green, A.I., Brunette, M.F., Rosenthal, R.N., Dunn, K.E., Strain, E.C., Ray, L., Shoptaw, S., … National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group (NCIG) Study Group (2019). Gabapentin enacarbil extended-release for alcohol use disorder: a randomized, double-blind, placebo-controlled, multisite trial assessing efficacy and safety. Alcoholism: Clinical and Experimental Research, 43(1), 158–169. doi: 10.1111/acer.13917. PMID: 30403402.