MEDICATIONS TO TREAT ALCOHOL DEPENDENCE AND ALCOHOL-RELATED DISEASES Release Date: October 1, 2001 RFA: RFA-AA-02-005 National Institute on Alcohol Abuse and Alcoholism (http://www.niaaa.nih.gov/) Letter of Intent Receipt Date: January 13, 2002 Application Receipt Date: February 13, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS UP TO $250,000 PER YEAR. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is seeking research grant applications on the clinical use of medications for alcohol abuse/dependence and alcohol-related diseases. Investigation are needed on pharmacological agents that prevent or reduce alcohol intake by decreasing the alcohol craving/urge to drink and/or alleviating the negative symptoms associated with drinking (e.g., protracted withdrawal syndrome). Evaluations of pharmacological agents to clinically treat alcohol-induced diseases, such as alcoholic liver diseases, are also encouraged. In addition, applications can include the utilization of human laboratory paradigms to screen potential medications for subsequent Phase 2 and 3 trials as well as to determine the actions of the medications. All applications submitted in response to this RFA should be conducted in humans. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Medications to Clinically Treat Alcohol Dependence and Alcohol-Related Disease, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) and the NIAAA exploratory/developmental (R21) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for a research project grant (R01) application submitted in response to this RFA may not exceed 5 years. Exploratory/developmental grants (R21) are limited to 3 years for up to $100,000/year for direct costs. (See Program Announcement PA- 99-131, NIAAA Exploratory/Developmental Grant Program, http://grants.nih.gov/grants/guide/pa-files/PA-99-131.html, for a complete description of the R21 mechanism.) This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 2002. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the NIH. Complete and detailed instructions and information on Modular Grant applications have been incorporated into the PHS 398 (rev. 5/2001). Additional information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm FUNDS AVAILABLE The NIAAA intends to commit approximately $2,000,000 in FY 2002 to fund 6 to 10 new and/or competitive continuation grants in response to this RFA. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of NIAAA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Background During the past decade advances have been made in medications development to treat alcoholism (see comprehensive reviews by Garbutt et al., 1999; Swift, 1999; and Kranzler, 2000). The fruits of these efforts have been highlighted by the FDA approval of naltrexone, the first medication approved for alcoholism in the 50 years since the introduction of disulfiram. Advances have also been made in understanding the biological mechanisms underlying alcohol drinking behavior. For example, it is now known that multiple neurotransmitter, neuromodulator, and hormonal systems can alter alcohol intake and are either directly or indirectly involved in problematic drinking. These include opioid, serotonin, dopamine, gamma-aminobutyric acid (GABA), glutamate, neuropeptide Y, and hypothalamic-pituitary-adrenal (HPA) systems (Litten et al., 1996; Roberts and Koob, 1997; Johnson and Ait-Daoud, 2000). This recent knowledge has led to many biological targets for testing novel pharmacological agents. To date, the two most promising and successful medications are naltrexone and acamprosate. Two important clinical trials of naltrexone (Volpicelli et al., 1992 and O Malley et al., 1992) first demonstrated efficacy of naltrexone in alcohol dependent patients and contributed significantly to FDA approval of naltrexone. Although naltrexone is not a magic bullet for alcoholism treatment, it appears to have a moderate effect in reducing drinking, particularly reducing relapse to heavy drinking (Volpicelli et al., 1997; Anton et al., 1999; Morris et al., 2001; Heinala et al., 2001). Recent studies have suggested that patient compliance plays a significant role in the efficacy of naltrexone (Volpicelli et al., 1997; Chick et al., 2000). Several studies are currently being funded to address many issues surrounding the clinical use of naltrexone such as how long should patients receive naltrexone; what is the optimal dose; what types of alcoholics respond best; what is the optimal combination with behavioral/psychosocial interventions; and can the efficacy of naltrexone be improved by combining it with other medications. Finally, nalmefene, another opioid antagonist, has also demonstrated effectiveness in preventing relapse to heavy drinking in alcohol- dependent patients (Mason et al., 1999). Acamprosate has been studied extensively in Europe and is currently approved for alcoholism treatment in 37 countries. Sixteen controlled clinical trials have been conducted across 11 European countries involving more than 4,600 alcohol dependent patients. The studies have consistently shown that individuals treated with acamprosate are more likely to complete treatment, have longer times to their first drink, have greater abstinence rates, and demonstrate longer cumulative abstinence durations than placebo-treated patients (Mason and Ownby, 2000). A 21-site trial of acamprosate has recently been completed in the US with 601 alcohol dependent patients. Results of this trial will be submitted to the FDA as part of a New Drug Application to obtain US approval. Acamprosate’s mechanism of action has yet to be definitively identified, although several studies suggest that it may modulate activity of the glutamate system (Littleton, 1995; Spanagel and Zieglgansberger, 1997). The serotonergic system has also been implicated in drinking behavior. The serontonin3 (5-HT3) receptor has been shown to regulate release of dopamine in the mesolimbic area, particularly in the nucleus accumbens. Ondansetron, a 5- HT3 antagonist, has been demonstrated to reduce desire to drink in humans and to augment stimulant and sedative effects of alcohol (Johnson, 1993; Swift et al., 1996). A 12-week dosage trial of ondansetron has recently been completed in early onset alcoholics and late onset alcoholics (Johnson et al., 2000b). Ondansetron reduced frequency and quantity of alcohol consumption in early onset alcoholics, but not in the late onset alcoholics. Interestingly, a preliminary study combining ondansetron and naltrexone showed that the combination reduced alcohol craving and enhanced drinking outcome to a greater extent than had each demonstrated alone (Johnson et al., 2000a; Ait-Daoud et al., 2001). Results of selective serotonin reuptake inhibitors (SSRIs) in human alcohol trials have been inconsistent (Pettinati, 1996, Kranzler, 2000). Recent data, however, suggest that subpopulations of alcohol dependent patients respond differentially to the SSRIs. For example, Kranzler et al. (1996) and Pettinati et al. (2000) showed that higher-risk/severity type B alcoholics had less favorable treatment outcome to SSRIs than lower-risk/severity type A alcoholics. Cornelius and colleagues (1997) found that fluoxetine reduced depressive symptoms and alcohol intake in severe inpatient populations of alcoholics with major depression and suicide risk. In contrast, Pettinati et al. (2001) and McGrath (1998) reported that fluoxetine and sertraline were no better than placebo in improving depression and reducing drinking in a less severe population of depressed alcoholics. Since all the medications discussed above produce small to medium effects to reduce or prevent drinking, developing and evaluating new and more potent medications remain a high priority. Several promising pharmacological agents could lead to clinical testing. These include, but are not limited to, memantine, a non-competitive NMDA antagonist (Holter et al., 1996); kudzu and its purified active components (e.g., puerarin) (Keung and Vallee, 1993; Lin et al., 1996); corticotropin-releasing factor (CRF) antagonists (Bell et al., 1998; Le et al., 2000; Richter et al., 2000); opioid subtype receptor antagonists such as delta2 antagonist naltriben (June et al., 1999); 6-beta naltrexol, an active metabolite of naltrexone (Rukstalis et al., 2000); synthetic neurosteroids (Morrow et al., 1999); 1-aminocyclopropanecarboxylic acid (ACPC), a NMDA partial agonist (Stromberg et al., 1999); and FG 5974 (and its analogues), a 5-HT1A agonist/5-HT2A antagonist (Roberts et al., 1998). Finally, progress has been made in elucidating the mechanisms of alcohol- induced organ damage. In particular, several primary factors underlying the pathogensis of alcoholic liver disease have been identified including cytokines and reactive oxygen species (ROS) (Tsukamoto and Lu, 2001). For example, the administration of antibodies against the proinflammatory tumor necrosis factor (TNF)-? attenuated alcohol-induced liver injury in rats (Iimuro et al., 1997). A later study showed an absence of alcohol liver injury in knockout mice missing the TNF receptor 1 (Yin et al., 1999). ROS are generated by the metabolism of alcohol and can also cause damage to the liver (Tsukamoto and Lu, 2001). ROS are quickly inactivated by antioxidants, such as glutathione and vitamins A and E. Antioxidants, such as S-adenosyl-L- methionine (SAMe), have also been shown to reduce alcohol-induced liver injury in animals. Potential new treatments of alcoholic liver disease include antioxidants, such as SAMe and vitamin E; as well as other types of agents including phosphatidylcholine, a phospholipid; pirfenidone, a new broad- spectrum anti-fibrotic agent; and metformin, an insulin-sensitizing agent (Lieber, 2001; Miric et al., 2001; Tsukamoto and Lu, 2001). Specific Areas of Interest NIAAA is committed to the development and assessment of pharmacological agents to treat alcohol use disorders as well as the more prevalent and severe medical conditions associated with chronic drinking. Pharmacological agents of interest for human laboratory testing and Phase 2, 3, and 4 clinical testing can be categorized by function as follows: - Agents to decrease craving or urge to drink; - Agents to attenuate negative symptoms of alcoholism (e.g.,"protracted withdrawal" symptoms); - Agents to diminish drinking by alleviating co-occurring psychiatric pathology and other drug use; - Agents to treat alcohol-associated liver disease and other end-organ diseases, such as pancreatitis, cardiomyopathy, and bone disease. Many important clinical priorities and issues exist for these classes of pharmacological agents and are identified, but not limited, to the following: - New and existing pharmacological agents (already having IND status) and combination of those agents, need to be identified and evaluated in conjunction with behavioral therapies for alcoholism treatment. Optimal dosing regimens and length of treatment need to be established. Although NIAAA has supported projects on the efficacy of the opioid antagonist naltrexone, the therapeutic potential of other pharmacological agents in the opioid class is a current research priority. In addition to opioid antagonists, the therapeutic potential of other types of agents needs to be assessed. Among these are agents that interact with the serotonergic, dopaminergic, glutamatergic, GABAergic, and HPA systems as well as herbal preparations. - Development of pharmacological agents to attenuate negative symptoms of chronic drinking, sometimes referred to as the "protracted withdrawal" syndrome. Research on potential pharmacological treatment of this phenomenon has been quite limited, due to failure to specify cardinal symptoms associated with sustained sobriety by alcoholics. Research is needed to establish operational definitions of this event as is research on agents to reduce relapse. - Pharmacological agents need to be identified and their efficacy evaluated in special populations previously understudied in medication trials. Examples of such populations of interest are alcohol abusing/dependent individuals in the criminal justice system, health professions, adolescents and the elderly. - Development of pharmacological agents to treat alcoholics with comorbid psychopathology such as bipolar disorder, schizophrenia, and anxiety disorders including social phobia and post-traumatic stress disorder. The co-occurrence of psychiatric problems among alcoholics in treatment is frequent. Comorbidity, however, is generally associated with a poorer treatment prognosis as well as high dropout rates and poor compliance. Research needs to include assessment of changes in the comorbid psychopathology as well as changes in drinking outcomes. - Development of medications to treat alcoholic liver diseases and other alcohol-related, end-organ diseases. These may include agents that inactivate excess ROS or alter the production or clearance of cytokines. In reducing the high mortality from alcoholic hepatitis and cirrhosis, potential medications that prevent necrosis/inflammation and avert or reverse the progression of fibrosis are of high priority. Other potential agents include those that are effective in treating alcohol-induced portal hypertension, pancreatitis, and bone disease. - Factors influencing clinical efficacy of medications to treat alcohol abuse and dependence can be identified using human laboratory behavioral pharmacology paradigms. Prior to beginning phase 2 clinical trials potential medications can be screened in the laboratory to determine the following: 1) the medication’s impact to reduce craving for alcohol and/or to diminish the negative symptoms of drinking; 2) likelihood of adverse events, especially in the presence of alcohol; 3) pharmacokinetics for medication combinations; and 4) optimal dosing regimens. Studies are sought which develop and expand use of these human laboratory paradigms. Supported pharmacological investigations should include use of appropriate control groups, adequate sample sizes, and employment of proper statistical analyses. In evaluating the efficacy of all pharmacological agents, it is important to identify subtypes of alcoholics particularly amenable to pharmacological treatment as well as to explore integration of pharmacotherapy with behavioral and verbal therapies. In addition, the experimental treatments should be carefully described, and diagnostic and outcome instruments should reflect state-of-the-art alcoholism assessment. While early clinical studies may employ highly homogeneous samples in a single setting, it is desirable in later-stage research to have greater heterogeneity in samples and sites. Efficacy studies also need to measure compliance with the pharmacological intervention and adequately verify self-reports. Finally, after completion of the active treatment of the clinical trial, it is recommended that subjects be followed-up for at least six months. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. DATA AND SAFETY MONITORING PLAN As of the October 2000 receipt date, applicants must supply a general description of the Data and Safety Monitoring Plan for ALL clinical trials; this must be included in the application http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html The degree of monitoring should be commensurate with risk. NIH Policy for Data and Safety Monitoring requires establishment of formal Data and Safety Monitoring Boards for multi-site clinical trials involving interventions that entail potential risk to the participants. The absence of this information will negatively affect your priority score. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIAAA staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: RFA-AA-02-005 Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-4375 FAX: (301) 443-6077 by the letter of intent receipt date listed. APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in applying for these grants and will be accepted at the standard application deadlines (http://grants.nih.gov/grants/dates.htm) as indicated in the application kit. This version of the PHS 398 is available in an interactive, searchable PDF format. The NIH will return applications that are not submitted on the 5/2001 version. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Extramural Project Review Branch RFA: AA02-005 National Institute on Alcohol Abuse and Alcoholism 6000 Executive Blvd, Suite 409, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20852 (for express/courier service) Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by NIAAA. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAAA in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory Council on Alcohol Abuse and Alcoholism. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans or the environment, to the extent they may be adversely affected by the project proposed in the application. o The adequacy of the proposed plan to share data, if appropriate. Schedule: Letter of Intent Receipt Date: January 13, 2002 Application Receipt Date: February 13, 2002 Peer Review Date: April-May 2002 Council Review: August 2002 Earliest Anticipated Start Date: September 29, 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Joanne B. Fertig, Ph.D. Division of Clinical and Prevention Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard MSC 7003, Suite 505 Bethesda, MD 20892-7003 Rockville, MD 20852 (for express mail/courier) Telephone: (301) 443-0635 FAX: (301) 443-8774 Email: jfertig@willco.niaaa.nih.gov Direct inquiries regarding fiscal matters to: Judy Fox Simons Grants Management Branch National Institute on Alcohol Abuse and Alcoholism Willco Building, Suite 505 6000 executive Blvd. (MSC-7003) Bethesda, MD 20892-7003 (For express mail use: Rockville, MD 20852) Telephone: (301) 443-2434 Email: jsimons@willco.niaaa.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.273. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. REFERENCES Ait-Daoud, N., Johnson, B.A., Prihoda, T.J., and Hargita, I.D. (2001) Combining odansetron and naltrexone reduces craving among biologically predisposed alcoholics: Preliminary clinical evidence. Psychopharmacology 154:23-27. Anton, R.F., Moak, D.H., Waid, L.R., Latham, P.K., Malcolm, R.J. and Dias, J.K. (1999) Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: Results of a placebo-controlled trial. American Journal of Psychiatry 156:1758-1764. Bell, S.M., Reynolds, J.G., Thiele, T.E., Gan, J., Figlewicz, D.P., and Woods, S.C. (1998) Effects of third intracerebroventricular injections of corticotropin-releasing factor (CRF) on ethanol drinking and food intake. Psychopharmacology 139:128-135. Chick, J., Anton, R., Checinski, K., Croop, R., Drummond, D.C., Farmer, R., Labriola, D., Marshall, J., Moncrieff, J., Morgan, M.Y., Peters, T., and Ritson, B. (2000) A multicentre, randomized, double-blind, placebo-controlled trial of naltrexone in the treatment of alcohol dependence or abuse. The Journal of Alcohol and Alcoholism 35:587-593. Cornelius, J.R., Salloum, I.M., Ehler, J.G., Jarrett, P.J., Cornelius, M.D., Perel, J.M., Thase, M.E., and Black, A. (1997) Fluoxetine in depressed alcoholics: A double-blind, placebo-controlled trial. Archives of General Psychiatry 54:700-705. Garbutt, J.C., West, S.L., Carey, T.S., Lohr, K.N., and Crews, F.T. (1999) Pharmacological treatment of alcohol dependence: A review of the evidence. Journal of the American Medical Association 281:1318-1325. Heinala, P., Alho, J., Kiianmaa, K., Lonnqvist, J., Kuoppasalmi, K., and Sinclair, J.D. (2001) Targeted use of naltrexone without prior detoxification in the treatment of alcohol dependence: A factorial double-blind, placebo- controlled trial. Journal of Clinical Psychopharmacology 21:287-292. Holter, S.M., Danysz, W., and Spanagel, R. (1996) Evidence for alcohol anti- craving properties of memantine. European Journal of Pharmacology 314:R1-R2. Iimuro, Y., Gallucci, R.M., Luster, M.I., Kono, H., and Thurman, R.G. (1997) Antibodies to tumor necrosis factor alpha attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology 26: 1530-1537. 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