ALZHEIMER"S DISEASE PILOT CLINICAL TRIALS Release Date: January 14, 1999 PA NUMBER: PA-99-038 (Reissued as PAR-05-021) P.T. National Institute on Aging National Institute of Mental Health National Institute of Neurological Disorders and Stroke PURPOSE The National Institute on Aging (NIA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS) invite qualified investigators to submit research grant applications for pilot clinical drug trials directed toward the treatment of the cognitive and behavioral symptoms of Alzheimer"s Disease (AD). Data from pilot clinical studies are often required before proceeding to a full-scale clinical trial. The NIA, the NIMH, and the NINDS are interested in supporting exploratory studies required to obtain the necessary information to establish the basis for proceeding to a full-scale trial. The purpose of the Alzheimer"s Disease Pilot Clinical Trials initiative is to obtain preliminary data and conduct studies to support the rationale for a subsequent full-scale clinical drug trial of an intervention to slow, halt, or reverse the progressive decline in cognitive function and/or to modify the cognitive and behavioral symptoms in Alzheimer"s disease victims as well as to delay the onset of or prevent Alzheimer"s disease. Note: There is a companion Program Announcement available, the "Alzheimer"s Disease Clinical Trial Planning Grant" (PA-99-039). 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 PA, ALZHEIMER"S DISEASE PILOT CLINICAL TRIALS, is related to the priority area of chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202- 512-1800) or at http://www.crisny.org/health/us/health7.html. ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, 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 The mechanism of support for the Alzheimer"s Disease Pilot Clinical Trials initiative is the individual research project grant (R01). It is expected that most grants will not exceed $350,000 per year in direct costs for 3 years. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The award cannot be renewed. RESEARCH OBJECTIVES I. BACKGROUND Alzheimer"s disease (AD) is one of the most persistent and devastating dementing disorders of old age, because it eventually leads to a complete loss of memory and of the ability to function independently. It is estimated that up to four million people in the United States have AD in its various stages at an estimated cost to society of $90 billion per year, and it is projected that 14 million people could be victims of Alzheimer"s disease by the middle of the next century. The disease presents enormous problems not only to affected individual but also to their families and raises many complex social and economic issues for the country. AD provides a complex neurobiological puzzle. Its etiology is not known, and the pathobiological processes that underlie the steady progression of the clinical course of this disease are not yet completely understood. It is clear, however, that mechanisms of cell to cell communication are disrupted. These involve several different types of neurotransmitter, neuropeptide, and neuromodulator systems, neurochemical processes, protein trafficking, and elements of oxidative and cellular energy metabolism processes. The hallmark of the disease involves progressive cell dysfunction, cell loss, and the accumulation of a variety of abnormal protein and cytoskeletal abnormalities. It is still not known when and how the degenerative process begins. At present there are no generally safe and effective treatments for the cognitive and behavioral symptoms of AD. The few agents that are currently approved by the Food and Drug Administration have demonstrated only modest effects in modifying the disease symptoms for relatively short periods in subsets of patients, and none has shown an effect on disease progression. The majority of the compounds considered candidate drugs have generally been designed to affect the synthesis, release, or degradation of neurotransmitters. Most of the agents available thus far have been targeted towards the cholinergic system which is an especially vulnerable neural population in AD and cognitive function. The NIA, NIMH, NINDS and other NIH Institutes currently support extramural and intramural projects for the study of the epidemiology, etiology, diagnosis, and treatment of AD. Notwithstanding these efforts, the increasing numbers of affected individuals, the unknown etiology, the emotional, social, and economic costs to the victims, caregivers, and society, and the fact that there is no compound which can uniformly slow or reverse the progression of the disease or ameliorate the cognitive and behavioral symptoms, all require that the most creative scientific talents be mobilized to aggressively pursue a concerted effort to discover and test new treatments for Alzheimer"s disease. Although agents are still needed which can reliably ameliorate the cognitive and behavioral symptoms of the disease even for a short time (because such agents would provide needed relief, however brief, to the victims and their families), more efforts need to be focused on testing interventions which could potentially slow the disease progression, reverse the disease process, and delay the onset of or prevent AD entirely. II. RESEARCH OBJECTIVES AND SCOPE The objective of this solicitation is to stimulate pilot clinical drug trials to test interventions aimed at slowing, halting, or, if possible, reversing the progressive decline in cognitive function and modifying the cognitive and behavioral symptoms in Alzheimer"s disease victims as well as delaying the onset of or preventing AD. The goal is not to duplicate or compete with pharmaceutical companies but to encourage, complement, and accelerate the process of testing new, innovative, and effective treatments for cognitive impairment and behavioral symptoms in Alzheimer"s disease. The research project should directly address how the pilot grant will advance the design of a subsequent full-scale clinical trial. The application should also address the intrinsic scientific merit of the study conducted under the pilot grant, whether or not a full-scale trial is performed. The Alzheimer"s Disease Pilot Clinical Trials application may include: Studies to refine the intervention strategy (e.g. dosage, duration, delivery system) Studies to define and refine the target population and ensure protocol adherence and subject retention Collection of preliminary data for establishing measures of clinical efficacy and broader effectiveness (including primary and secondary outcome and assessment measures for both patients and caregivers) and safety. The objective of the Alzheimer"s Disease Pilot Clinical Trials initiative is to increase the quality of clinical research to evaluate interventions for the treatment or prevention of Alzheimer"s disease. To meet this objective the proposed pilot study must successfully incorporate creative and realistic solutions to difficult problems in clinical trials" research for the particular intervention being evaluated. SPECIFIC REQUIREMENTS TO BE ADDRESSED IN THE APPLICATION The scientific basis for the proposed intervention including discussion of current practice and alternative interventions. Impact of the proposed intervention on health care and quality of life. 3. Study Design and Procedures. a. Sequence of clinical studies, including the proposed pilot study, that will produce a definitive clinical trial. b. Translation of the clinical question into statistical hypotheses. c. Selection of outcome measure(s). d. Inclusion and exclusion criteria. e. Secondary questions (including capacity for post hoc analyses). f. Detailed protocol with standardized procedures that will be used for this pilot study. g. Ethical and safety issues and quality control procedures. 4. Data Analysis. Specific methods to be used for data analysis. Adequacy of sample size to detect a treatment effect. The sample size for the pilot study may not be adequate to detect any but the largest treatment differences or statistical trends, however, the data from this study should provide a basis for providing sample size estimates for future trials. 5. Training and expertise of the investigators in Alzheimer"s disease and the proposed intervention as well as training and expertise in clinical trials in general. 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 have been 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 the following URL address: http://www.nih.gov/grants/guide/notice-files/not94-105.html Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may provide additional information concerning the policy. 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://www.nih.gov/grants/guide/notice-files/not98-024.html NOTE FOR APPLICATIONS FOCUSED ON AGING RESEARCH Applications received in response to this program announcement are expected to focus on scientific issues related to aging and to aging-related aspects of disease. In describing the plan to recruit human subjects, investigators may cite a focus on aging or on aging-related aspects of disease as the justification for why children will be excluded. In this regard applicants may use Justification 1, the research topic to be studied is irrelevant to children, from the policy announcement. NIA REQUIREMENTS FOR HUMAN INTERVENTION STUDIES NIA has specific requirements for human intervention studies that need to be addressed in the grant application. These requirements are directed toward protecting the safety of participants in intervention studies and assuring that trials are soundly conducted and analyzed. These requirements, "Implementation of Policies for Human Intervention Studies," have been published in the NIH Guide for Grants and Contracts, Vol. 25, No. 33, October 4, 1996, available at: http://www.nih.gov/grants/guide/notice-files/not96-237.html. In addition, NIH has recently indicated the NIH policy concerned with data and safety monitoring in the NIH Guide for Grants and Contracts for the week of June 12, 1998. The title is "NIH Policy for Data and Safety Monitoring," and the URL address is http://www.nih.gov/grants/guide/notice-files/not98-084.html. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: GrantsInfo@nih.gov. Applications are also available on the World Wide Web at http://www.nih.gov/grants/funding/phs398/phs398.html. The program announcement title and number must be typed on line 2 on the face page of the application form and the YES box must be marked. Submit the signed, original, single-sided application along with four exact, single-sided copies and four collated sets of appendix materials 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) In order to facilitate the review of applications, at the same time, mail or deliver one copy of the application to: Mary Nekola, Ph.D. Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2C212, MSC 9205 Bethesda, MD 20892-9205 Email: Mary_Nekola@nih.gov REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with the standard NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. 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. 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? 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? 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? 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)? 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, the "Specific Requirements To Be Addressed In The Application" will be evaluated, and the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research will be reviewed. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human subjects, the safety of the research environment, and conformance with the NIH Guidelines for the Inclusion of Women and Minorities as Subjects in Clinical Research and the NIA Guidelines for the Implementation of Policies for Human Intervention Studies. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review Availability of funds Program priority INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Neil S. Buckholtz, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Suite 3C307, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: Buckholn@exmur.nia.nih.gov Eugene J. Oliver, Ph.D. Division of Stroke, Trauma, and Neurodegenerative Disorders National Institute of Neurological Disorders and Stroke 7550 Wisconsin Avenue, Room 806 Bethesda, MD 20892 Telephone: (301) 496-5680 FAX: (301) 480-1080 Email: eollc@nih.gov George T. Niederehe, Ph.D. National Institute of Mental Health 5600 Fishers Lane, Room 10-75 Rockville, MD 20857 Telephone: (301) 443-1185 FAX: (301) 594-6784 Email: gniedere@mail.nih.gov Direct inquiries regarding fiscal matters to: Joseph Ellis Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: Joseph_Ellis@nih.gov Pat Driscoll Grants Management Branch National Institute of Neurological Disorders and Stroke 7550 Wisconsin Avenue, Room 1004 Bethesda, MD 20892 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: pd23n@nih.gov Diana S. Trunnell Grants Management Branch National Institute of Mental Health 5600 Fishers Lane, Room 7C-08 Rockville, MD 20857 Telephone: (301) 443-2805 FAX: (301) 443-6885 Email: Diana_Trunnell@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.866 (NIA), 93.242 (NIMH), and 93.853 (NINDS). 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 PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Note that there is a new publication of the NIH Grants Policy Statement published in the NIH Guide for Grants and Contracts on October 21, 1998 and available at http://www.nih.gov/grants/guide/notice-files/not98-146.html The PHS strongly encourages all grant and contract 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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