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 301/435-0714, 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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