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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