IN VIVO MEDICATION DEVELOPMENT FOR ALCOHOL-RELATED CONDITIONS Release Date: January 27, 1999 RFA: AA-99-004 P.T. National Institute on Alcohol Abuse and Alcoholism Letter of Intent Receipt Date: April 2, 1999 Application Receipt Date: April 28, 1999 PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) requests applications to develop and evaluate potential new medications for eventual clinical use in the treatment of alcoholism or alcohol-mediated medical consequences or to further develop and evaluate agents that already show clinical potential based on preclinical data. With the rapid advances in understanding how ethanol acts on the brain and behavior and on other organs of the body, an unprecedented opportunity exists to develop and evaluate new medications for eventual use in clinical trials. There are a number of alcohol-related phenomena that could be examined, including reduction in ethanol consumption, craving and relapse, signs and symptoms accompanying acute and protracted withdrawal, ethanol-induced cognitive dysfunction, intoxication, and various endpoints of organ damage. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA) is related to the priority area of alcohol abuse and alcoholism. Potential applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html. 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) award mechanism. Applicants may also submit Investigator-Initiated Interactive Research Project Grants (IRPG). Interactive Research Project Grants require the coordinated submission of related regular research project grant applications from investigators who wish to collaborate on research, but do not require extensive shared physical resources. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 5 years. This RFA is 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 30, 1999. FUNDS AVAILABLE The NIAAA intends to commit approximately $2,500,000 in FY 1999 to fund 8 to 10 new 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 the 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 applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES Background Neuroscience and behavioral research funded by NIAAA has led to significant advances in our understanding of how alcohol acts on the brain. Specific targets of alcohol in the brain are being characterized, and the adaptive mechanisms underlying the development of dependence on alcohol are beginning to be understood. New findings from several research groups are beginning to describe the configurations of the proteins of neurotransmitter receptors and ion channels necessary for alcohol's actions. In addition, amino acid sequences that are important in the actions of alcohol are being identified. For example, using site-directed mutagenesis, researchers have found sequences in the GABA receptor important for ethanol's action. Such studies will help in the design of new medications or the new use of already approved medications that can block the effects of alcohol on the brain. As research further defines the mechanisms underlying the development of alcohol dependence or other alcohol-related conditions, more effective pharmacotherapy can evolve from these findings by helping to identify compounds for possible clinical trials. Evidence of the benefits of this research is exemplified by the approval of naltrexone, the first drug approved by the Food and Drug Administration (FDA) for alcoholism treatment in almost 50 years. A similar approach can be used to develop new treatments for alcohol-induced tissue injury. For example, in the case of alcoholic liver disease, advances have been made in understanding some of the factors that contribute to the disease. Research has shown that TNF-alpha levels in plasma and liver are elevated in humans and animals affected with alcoholic liver disease. In animal models of alcoholic liver disease, administration of TNF-alpha antibodies attenuates liver injury and in TNF-alpha receptor-deficient mice, chronic ethanol feeding fails to elicit liver injury. Thus, attenuation of TNF-alpha levels may help to ameliorate alcoholic liver disease in humans. Potential compounds can arise from a number of sources. For example, researchers use many substances to elucidate mechanisms underlying the actions of alcohol. Some of them may have clinical potential if properly developed to the stage for controlled clinical trials. Prototypes could also come from existing libraries of compounds or from new ones based on some rational molecular design. Possible compounds can include those for use in other clinical conditions or diseases with potential for treating various aspects of alcohol-related conditions. In addition, through serendipitous findings, substances can reveal clinical potential. To proceed to clinical trials, appropriate in vivo efficacy and toxicological studies must be completed to allow for an application for an Investigational New Drug (IND) that would permit human testing. General Principles Any medication development program should be based on the clinical outcomes to be obtained from use of a medication. For example, in treating alcoholism, the distinction should be made among obtaining total abstinence from alcohol, decreased consumption, and reduced craving or relapse. The targeted outcome will determine the types of models and outcome measures used. (See below for areas of interest.) It is anticipated that the review process will include consideration of compound(s), appropriateness of the various models to test efficacy, and specificity and predictiveness of outcome measures. Validating the predictive ability of a compound could, when relevant, include the use of existing drugs for comparison purposes. Animal Models The use of animal models has been the hallmark of understanding how alcohol modifies behavior and biological mechanisms. These models have examined alcohol consumption, positive and negative reinforcement, dependence and withdrawal, craving and relapse and mimic alcohol-induced tissue injury. In developing and evaluating compounds of potential clinical value, some of the same paradigms may be used. However, rather than being research tools, they become evaluative tools. The efficacy of a compound is determined, in part, by the outcome measures selected. Appropriate care should be taken in selecting the appropriate outcome measures, including consideration of eventual FDA approval of human trials. Human Testing Early human screening of potential compounds is a critical element in the drug development process. Before embarking on costly Phase III clinical trials, it is vital to know whether medications that look efficacious and safe in animal models are also relevant to alcohol-related human behaviors and conditions. Applications are also sought to develop/enhance the use of a limited number of humans for early-stage testing of new clinical entities and/or existing compounds for treatment of alcohol-related behaviors and medical conditions. The development plan for both animals and humans should include: (1) specification and rationale for the component(s) of the alcohol-related phenomena being targeted, e.g., initiation of alcohol consumption, positive reinforcement, negative reinforcement, relapse reduction, craving for alcohol, improvement in cognitive deficits caused by excessive drinking. (2) Theoretical basis and detailed methodology for laboratory studies. (3) Rationale and relevance of surrogate markers/outcome measures to clinical features of the selected alcohol phenomenon. (4) Rationale and putative mechanism of action by which the proposed compound(s) to be evaluated might alter the targeted alcohol phenomenon. (5) Clear and definitive strategy for rejecting/further advancing a compound's development. In the case of human studies, full safety and toxicity profiles for proposed compound(s) are needed to adequately justify introduction of test compounds into human subjects. Areas Of Interest Agents that Modulate/Suppress the Desire to Drink Over the past 5 years, significant progress has been made with medications that diminish the desire to drink (sometimes referred to as "anticraving" medications). This progress has been highlighted by the recent FDA-approval of the opioid antagonist naltrexone. In two landmark studies, alcohol- dependent patients were treated with naltrexone for 3 months and experienced higher sobriety rates, fewer days drinking, and lower craving for alcohol than did placebo-treated subjects. In particular, naltrexone-treated subjects who sampled alcohol drank less alcohol than those who had received placebo. With psychosocial intervention, naltrexone-treated subjects who received a supportive therapy emphasizing abstinence enjoyed higher rates of sobriety. If drinking was initiated, those treated with naltrexone and coping-skill training were more successful in avoiding a return to heavy drinking. In addition to opioid antagonists, other types of agents appear promising. One of these is acamprosate (calcium acetylhomotaurinate) and has been studied extensively in Europe and appears efficacious in reducing alcohol consumption and relapse, with no major adverse effects reported. Although the mechanism underlying acamprosate's effect is still being investigated, it appears that acamprosate interacts with the GABA system and excitatory amino acids such as glutamate. With the paucity of medications to reduce the desire to drink, a high priority is for the development of new compounds in this area. Agents to Treat the Protracted Withdrawal Syndrome The protracted withdrawal syndrome, also known as protracted abstinence, late withdrawal, or "dry drunk," is in the very early stages of research. Pharmacological treatment has been hampered by the lack of agreement on distinctive signs and symptoms and the duration of the syndrome. Some of the purported symptoms include anxiety, irritability, hostility, depression, insomnia, fatigue, and craving. Recent research has suggested that the kindling effect may contribute to symptoms of protracted withdrawal, thereby leading to alcohol craving and relapse. Research is needed to determine the efficacy of medications in preventing kindling and reducing the symptoms associated with it. It is likely that some of these medications may overlap with pharmacological agents described above in reducing the desire to drink. Agents Used to Treat Acute Alcohol Withdrawal Acute alcohol withdrawal is characterized by a highly variable range of signs and symptoms. These include relatively mild signs and symptoms such as sweating, tachycardia, hypertension, tremors, and anxiety to more serious consequences including seizures and delirium tremens. Its etiology has been hypothesized to involve perturbation of one or more neuronal and hormonal systems, including noradrenergic hyperactivity, alterations in gamma- aminobutyric acid (GABA)-benzodiazepine receptors, elevated activity of the hypothalamic-pituitary-adrenal axis, and changes in the N-methyl-D-aspartate (NMDA) glutamate receptors. For more than two decades, benzodiazepines have been the most widely used medication for pharmacological management of alcohol withdrawal. They are effective in preventing delirium tremens and have consistently been demonstrated to assuage many signs and symptoms of withdrawal. Although the most recent studies have focused on benzodiazepine dosing strategies, benzodiazepines still have adverse effects including acute memory difficulties, drowsiness, lethargy, and acute cognitive problems that may complicate treatment and recovery. Carbamazepine has also been shown to be effective for treating alcohol withdrawal. Other medications are being explored in the management of withdrawal symptoms, including GABAergic agents, NMDA antagonists, dopaminergic agents, calcium channel antagonists, and nitrous oxide. Their effectiveness in the clinic has not been established. Another research topic under active investigation is alcohol withdrawal "kindling" or sensitization. Kindling studies suggest that the severity of withdrawal symptoms increases as a function of the number of previous alcohol withdrawals, an observation that has been reported in both animals and humans. If kindling plays an important role in the intensity of withdrawal symptoms, especially after repeated withdrawals, new therapeutic strategies may be suggested. Agents to Improve Cognitive Dysfunction There is a very significant need to develop treatments for the prevention and amelioration of the cognitive disturbances and structural brain damage associated with alcohol consumption. Among excessive drinkers, there is a wide spectrum of cognitive disturbances associated with chronic ethanol consumption, ranging from mild cognitive disturbances such as reduced attentional and visuospatial abilities to severe amnesia, dementia and psychosis. Thus, medications to improve cognitive function in alcoholics, particularly in alcoholic dementia and Korsakoff's psychosis, would lead to enrichment in quality of life of alcoholics as well as reduction in costs of long-term institutionalization. Recent studies have suggested some medications can improve memory to a clinically meaningful degree in some patients with alcohol-induced amnesia. Unfortunately, very little research has been conducted on developing pharmacological cognitive enhancers or neuroprotective agents, a topic of major concern. Agents Used to Induce Sobriety in Intoxicated Individuals The search for a single effective amethystic agent (alcohol antagonist) has to-date been unsuccessful, perhaps due to alcohol's diverse effects on body systems. Continued research in this area is important since a significant number of people die each year from alcohol overdose. Development of medications to induce sobriety quickly and safely is particularly needed to assist treatment in emergency room settings. Since death often comes from respiratory arrest, medications blocking the effects of alcohol on respiration should be emphasized. Agents Used to Treat Alcohol-Induced Organ/Tissue Damage Organ/tissue damage is a major medical consequence of chronic alcohol abuse. Medications are needed to prevent, alleviate, or counteract alcohol-induced tissue injury. Diseases include alcohol-induced hepatitis, hypertension, cardiomyopathy, and pancreatitis. Several approaches have been taken in the treatment of alcoholic liver disease. A major effort is exploring the role of oxidative stress. To this end, investigators are testing the effectiveness of the antioxidants vitamin A and E and precursors of glutathione, and other nutritional supplements, such as phosphatidylcholine and S-adenosylmethionine. Further studies are required to test the efficacy of various antioxidants for the treatment and prevention of alcoholic liver disease. In addition, research on gene therapy for alcoholic liver disease is being encouraged. An example of this approach is to increase in the liver the amount of superoxide dismutase, an enzyme that metabolizes free radicals. Reducing the activity of TNF-alpha in the liver would be another approach to treating alcoholic liver disease. Approaches could include developing TNF- alpha antibodies or antisense nucleotides or reducing other proinflammatory cytokines such as IL-1 and IL-6. 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 subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided 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 "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: https://grants.nih.gov/grants/guide/notice-files/not94-105.html. 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: https://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. 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 avoid conflict of interest in the review. The letter of intent is to be sent to the program staff listed under INQUIRIES by the letter of intent receipt date listed in the heading of this RFA. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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. 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: Chief, Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, 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 the NIAAA. 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, a process may be used by the initial review group in which applications 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, e.g. clinical outcome? 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? Are the compounds, the models, and the relevance of the outcome measures appropriately justified? (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, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. Schedule Letter of Intent Receipt Date: April 2, 1999 Application Receipt Date: April 28, 1999 Peer Review Date: July 1999 Council Review: September 1999 Earliest Anticipated Start Date: September 30, 1999 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; and o programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues involving animal studies to: Walter A. Hunt, Ph.D. Division of Basic Research National Institute of Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402, MSC 7003 Bethesda, MD 20892 Telephone: (301) 443-4225 FAX: (301) 594-0673 Email: whunt@willco.niaaa.nih.gov Direct inquiries regarding programmatic issues involving human studies to: Joanne Fertig, Ph.D. Division of Clinical and Prevention Research National Institute of Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 505, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-0635 FAX: (301) 443-8774 Email: jfertig@willco.niaaa.nih.gov Direct inquiries regarding fiscal matters to: Linda Hilley Grants Management Branch National Institute of Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 504, MSC-7003 Bethesda, MD 20892-7003 Telephone: (301) 443-4704 FAX: (301) 443-3891 Email: lhilley@willco.niaaa.nih.gov Applications from small businesses under the SBIR Program are also encouraged under the Small Business Innovative Research (SBIR) Program announcement. SBIR grant application guidelines and application receipt deadline dates can be found at https://grants.nih.gov/grants/funding/sbir.htm. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.273. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under NIH grant policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 or Part 92, as applicable. 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.
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