FEASIBILITY PROJECTS TO TEST STRATEGIES FOR PREVENTING OR SLOWING THE
PROGRESSION OF DIABETIC NEPHROPATHY
Release Date: September 17, 2001
RFA: RFA-DK-02-025
National Institute of Diabetes and Digestive and Kidney Diseases
(http://www.niddk.nih.gov)
Letter of Intent Receipt Date: January 17, 2002
Application Receipt Date: February 14, 2002
THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING
LESS THAN $250,000 PER YEAR IN ALL YEARS. 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 of Diabetes and Digestive and Kidney Diseases
(NIDDK) seeks applications for studies to test new strategies for
prevention or treatment of diabetic nephropathy. Through large scale
interventional trials, it has been established that blockade of the
renin-angiotensin system (RAS) and good glycemic control both slow
progression of diabetic nephropathy. Nonetheless, many patients with
diabetes develop progressive renal disease in spite of adequate
management of these factors, and new strategies, both to prevent
disease and to slow its progression, are needed urgently.
This RFA invites clinical research applications for trials using novel
agents or drug combinations in patients to prevent the appearance or
slow the progression of diabetic nephropathy. The goal of this
initiative is to evaluate therapies that might potentially be taken to
large, phase III interventional trials. In the pilot phase studies
supported by this RFA, use of urine protein measurements, either
albumin or total protein, as a surrogate marker for disease progression
is appropriate. Applicants should note that a companion RFA DK-02-016
Surrogate Endpoints for Diabetic Microvascular Complications invites
applications to improve surrogate endpoints in clinical trials for
diabetes complications. It is assumed that, unless contraindicated,
proteinuric subjects in the control and trial groups will be treated
with RAS blockade as the current standard of care, and that the studies
will examine either addition of alternate agents or incremental effects
of RAS blockade. Enrollment strategies should emphasize a patient
population in young- to mid-adulthood and strong representation of
patients with type 1 diabetes mellitus. If indicated, assessment of the
impact of the intervention on retinopathy or neuropathy could be
incorporated into a trial design.
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 RFA,
Feasibility Projects to Test Strategies For Preventing or Slowing the
Progression of Diabetic Nephropathy, is related to the priority area
of diabetes and chronic disabling conditions. 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
nonprofit 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. 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 2 years or $500,000 direct costs
in any year. (Applications that request more than $250,000 direct costs
in any year must follow the traditional PHS 398 application
instructions). Applications with requested budgets up to $250,000 per
budget year must use the modular grants format.
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
For fiscal year 2002, the NIDDK intends to commit approximately $2
million to fund up to six new grants in response to this RFA. An
applicant may request a project period of up to two years. 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 NIDDK 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. At this time, it is not known if this RFA will be
reissued.
RESEARCH OBJECTIVES
Background
In the United States, diabetes is the leading cause of new cases of end
stage renal disease. Identification of patients at risk for the
development of diabetic nephropathy, with the hope of early
intervention, is a public health priority.
Patients with type 1 diabetes mellitus have a 20 to 40% lifetime risk
of developing renal failure. Low levels of albumin excretion in the
urine (microalbuminuria) are established as a strong risk factor for
later development of diabetic nephropathy. Overt proteinuria is the
next manifestation and usually precedes notable reductions in
glomerular filtration rate.
However, the predictive value of microalbuminuria for the progression
to overt nephropathy is not precise. Thus, it might be desirable to
intervene in patients with normal albumin excretion, if patients at
high risk for the development of nephropathy could be identified.
Growth factors and their receptors have been implicated in the
development of nephropathy, and some studies indicate that urinary
excretion of TGF-beta and other potential mediators of renal disease
might be early markers of nephropathy. Other potential mediators of
progressive renal disease, such as advanced glycation end products and
their receptors, tissue inhibitors of metalloproteinases, cytokines and
chemokines and their receptors, and members of intracellular signaling
cascades have been identified, but few studies have attempted
inhibition of their actions.
Several trials have established the efficacy of angiotensin converting
enzyme inhibitors (ACEIs) in slowing the progression of diabetic
nephropathy to end-stage renal disease. Initial results have suggested
that angiotensin receptor blockers (ARBs) might also have utility in
prevention of diabetic nephropathy or amelioration of its course.
Addition of spironolactone to treatment of patients with cardiovascular
disease has been shown to improve outcomes. Relatively few data are
available regarding the risks and benefits associated with treatment
with combinations of ACEIs and ARBs, or with combinations of these
agents and spironolactone in patients with diabetic nephropathy. In
addition, little is known regarding the effect of treatment of anemia
and the effects of treatment with erythropoietin and iron on outcomes
in patients with diabetic nephropathy with renal insufficiency.
Objectives and Scope
This RFA invites clinical research applications to develop approaches
for clinical trials of novel therapies for patients with diabetic
nephropathy, and to conduct preliminary pilot and feasibility trials of
such therapies. The overall goal of this RFA is to evaluate therapies
that might potentially be taken to large, phase III interventional
trials, and to ensure that adequate preliminary data is available to
design such trials.
Appropriate topics for investigation under this RFA would include:
Studies to identify novel agents to add to standard therapy of diabetic
nephropathy,
Studies of strategies to prevent the development of microalbuminuria,
Studies to evaluate the effects and safety of combination therapy
directed against the renin-angiotensin-aldosterone axis,
Studies comparing the effectiveness of different strategies for RAS
blockade,
Studies to gather preliminary information regarding potential
interactions of therapy directed toward diabetic nephropathy with the
treatment of anemia, and
Studies to gather preliminary information regarding effect sizes to be
expected from such interventions.
Investigators can budget assessment of disease markers into budgets for
these projects. However, if extensive evaluation of novel disease
markers is anticipated, applicants are encouraged to submit a separate
application focusing on the surrogate endpoints for the proposed trial,
as outlined in RFA-DK-02-016 Surrogate Endpoints for Diabetic
Microvascular Complications .
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 may also 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 IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS
All investigators proposing research involving human subjects should
read the policy that was published in the NIH Guide for Grants and
Contracts, June 5, 2000 (Revised August 25, 2000), and is available at
the following URL address
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
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, by January 17, 2002, 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 NIDDK staff to estimate the potential review
workload and plan the review.
The letter of intent is to be sent to:
Francisco O. Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone: (301) 594-8885
FAX: (301) 480-3505
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. This version of the PHS 398 is
available in an interactive, searchable PDF format. 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 time of submission, two additional copies of the application must be sent to:
Francisco O. Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Applications must be received by the application receipt date listed in
the heading of the RFA. If an application is received after that date,
it will be returned to the applicant without review. Supplemental
documents containing significant revision or additions will not be
accepted, unless applicants are notified by the Scientific Review
Administrator.
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 previously
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 NIDDK. Incomplete and/or non-responsive
applications will be returned to the applicant without further
consideration.
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 NIDDK 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 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.
Since these applications are to support studies of two years duration,
they are to be designed primarily as pilot studies to obtain
preliminary data to be used in more definitive, larger future studies.
o 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?
o 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?
o Innovation: Does the project employ novel concepts, approaches, or
methods? Are the aims original and innovative? Does the project
challenge existing paradigms or develop new methodologies or
technologies?
o 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)?
o 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 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 to the
proposed research.
o The adequacy of the proposed protection of humans or the
environment, to the extent that they may be adversely affected by the
project proposed in the application.
o Availability of special opportunities for furthering research
programs through the use of unusual talent resources, populations, or
environmental conditions in other countries which are not readily
available in the United States or which provide augmentation of
existing U.S. resources.
Schedule
Letter of Intent Receipt Date: January 17, 2002
Application Receipt Date: February 14, 2002
Peer Review Date: August 2002
Council Review: September 2002
Earliest Anticipated Start Date: September 30, 2002
AWARD CRITERIA
Applications will compete for available funds with all other approved
applications. The following will be considered in making funding
decisions:
o Quality of the proposed project as determined by peer review,
o Availability of funds,
o 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:
Thomas Hostetter, M.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Rm. 625
Bethesda MD 20892-5458
Telephone: (301) 594-8864
FAX: (301) 480-3510
E-mail: th192u@nih.gov
Direct inquiries regarding fiscal matters to:
Teresa Farris Marquette
Grants Management Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 728 MSC
Bethesda, MD 20892-5458
Telephone: (301) 594-7628
FAX: (301) 480-3504
E-mail: tf102y@nih.gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance
No. 93.849. Awards are made under authorization of sections 301 and 405
of the Public Health Service Act as amended (42 USC 241 and 285) 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 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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