Release Date:  July 27, 2001

RFA:  RFA-DK-01-032

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute Of Neurological Disorders and Stroke
National Institute of Child Health and Human Development
National Institute of Nursing Research
Juvenile Diabetes Research Foundation International

Letter of Intent Receipt Date:  October 17, 2001
Application Receipt Date:       November 21, 2001



The National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK), the National Institute of Neurological Disorders and Stroke 
(NINDS), the National Institute of Child Health and Human Development 
(NICHD), the National Institute of Nursing Research (NINR) and the 
Juvenile Diabetes Research Foundation International (JDRF) solicit 
applications for clinical studies designed to enhance understanding and 
prevention of hypoglycemia in patients with diabetes. Large clinical 
trials have demonstrated the efficacy of intensified glucose control in 
the prevention of the long-term complications of diabetes. However, 
episodes of severe hypoglycemia may complicate intensified treatment 
and are often a major obstacle to the achievement of euglycemia in many 
patients. This RFA solicits clinical studies to 1) define and 
characterize hypoglycemia in diabetic individuals and 2) develop new 
approaches to prevent the development of hypoglycemia or to ameliorate 
its effects in individuals with diabetes.

A separate RFA (DK 01-031) solicits basic and clinical research 
specifically addressing the problem of hypoglycemia unawareness. An 
additional related RFA (NS-02-008) solicits basic research on the 
effects of hypoglycemia on cerebral metabolism and neural cell function 
and survival.


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 Request for 
Applications (RFA), New Approaches to Prevent Hypoglycemia in Patients 
with Diabetes, is related to the priority area of diabetes and chronic 
disabling conditions.  Potential applicants may obtain a copy of 
"Healthy People 2010" at


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.


This RFA will use the National Institutes of Health (NIH) research 
project grant (R01) and the Exploratory/Development Research Grant 
(R21) award mechanisms. Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.  
The total project period for an R01 application submitted in response 
to this RFA may not exceed 5 years. 

The R21 awards are to demonstrate feasibility and to obtain preliminary 
data testing innovative ideas that represent clear departure from 
ongoing research interests. These grants are intended to 1) provide 
initial support for new investigators, 2) allow exploration of possible 
innovative new directions for established investigators, and 3) 
stimulate investigators from other areas to lend their expertise to 
research within the scope of this solicitation. Applicants for the R21 
must limit their requests to $125,000 direct costs per year and are 
limited to two years. These R21 grants will not be renewable, 
continuation of projects developed under this program will be through 
the regular research grant (R01) program.

Applicants from institutions which have a General Clinical Research 
Center (GCRC) funded by the NIH National Center for Research Resources 
may wish to identify the GCRC as a resource for conducting the proposed 
research.   In such a case, a letter of agreement from either the GCRC 
program director or principal investigator should be included with the 

This RFA is a 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 July 2002.


The NIDDK, the NINDS, the NICHD and the NINR intend to commit 
approximately $3.25 million in FY 2002 to fund 4 to 8 grants in 
response to this RFA. The JDRF intends to commit up to $500,000 in 
additional funds to co-fund research project grants that are both 
scientifically meritorious and fit within the mission and research 
emphasis areas of the JDRF (see, for more 
information). All awards will be issued by the NIDDK, the NINDS, the 
NICHD and the NINR. 

An R01 applicant may request a project period of up to 5 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, the NINDS, the NICHD, the NINR and the 
JDRF 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.  



The Diabetes Control and Complications Trial (DCCT), for type 1 
diabetes, and the United Kingdom Prospective Diabetes Study (UKPDS), 
for type 2 diabetes, established the importance of intensified diabetes 
control in dramatically reducing the devastating complications that 
result from poorly controlled diabetes. However, with current treatment 
modalities, tight control remains an unattainable goal for many people 
with diabetes. For example, in the DCCT, fewer than 5% of individuals 
receiving intensified treatment maintained normal hemoglobin A1c 

To achieve glycemic control, many patients must walk a tightrope, 
balancing euglycemia against the danger of low blood glucose. Indeed, 
for many individuals with diabetes, episodes of severe hypoglycemia are 
the major obstacle to the achievement of euglycemia and the prevention 
of long-term complications. Hypoglycemia is frightening to patients and 
their families. In fact, for some individuals or their families, fear 
of hypoglycemia may outweigh concern over long-term complications of 
diabetes, leading to inadequate glycemic control. Fear of hypoglycemia 
is well-founded, as low blood glucose levels impart significant 
morbidity and mortality. Two to 4 per cent of deaths among individuals 
with type 1 diabetes have been attributed to hypoglycemia. Acutely, 
diminished brain function during a hypoglycemic episode poses potential 
physical danger to the patient. In addition, recurrent hypoglycemia may 
impose long-lasting damaging effects on the brain, resulting in 
impairment of memory or other cognitive functions. This is especially a 
concern in the early childhood years when the nervous system is still 

Recurrent hypoglycemia may also impair the body’s defense mechanisms 
against hypoglycemia, creating a vicious cycle for the patient. A major 
problem in many individuals with diabetes is a progressive decay in the 
counterregulatory response over time, resulting in “hypoglycemia 
unawareness.”  The individual fails to become aware of hypoglycemia and 
does not initiate appropriate responses. This can result in prolonged 
hypoglycemia, with consequent brain injury, seizure or loss of 
consciousness. Children and the elderly may be particularly vulnerable 
to the development of hypoglycemia and to its deleterious effects. 
Young children cannot reliably report or interpret symptoms of 
hypoglycemia. In older individuals, decline of beta adrenergic function 
with age, coupled with other medical problems (e.g., mild renal 
impairment which could alter drug metabolism), may predispose to the 
risk of hypoglycemia and hypoglycemia unawareness. Unrecognized 
hypoglycemia could contribute to subtle declines in mental function 
that might simply be attributed to “dementia.”

Hypoglycemia occurs because of a mismatch between insulin dose, food 
intake and energy expenditure. Despite vigilant blood sugar monitoring 
and adherence to treatment regimens, euglycemia often cannot be 
achieved safely (i.e., without the occurrence of hypoglycemia), because 
current treatment modalities do not mimic normal, physiologically 
regulated insulin secretion.

To address this critical problem in diabetes, the Juvenile Diabetes 
Research Foundation International, the American Diabetes Association 
(ADA), the NIDDK, the NINDS, the NICHD and NASA cosponsored a workshop 
on Hypoglycemia and the Brain on Sept. 7-8, 2000. Participants in the 
workshop identified a number of knowledge gaps requiring future 
research (  Basic 
research is needed to enhance understanding of the hypothalamic and 
peripheral control mechanisms that counteract hypoglycemia, and the 
pathogenic mechanisms involved in loss of counterregulatory control. In 
addition, clinical studies are needed to better define the scope of the 
problem and develop new prevention and treatment approaches. As a first 
step toward addressing the problem of hypoglycemia in diabetes, the 
NIDDK, the NINDS, the NICHD, the NINR and the JDRF have issued this 

Scope and Objectives

This RFA solicits clinical studies to 1) define the scope and nature of 
hypoglycemia in individuals with diabetes, and 2) develop and test 
strategies to prevent the development of hypoglycemia in patients with 
diabetes, or to ameliorate its effects. Recent scientific advances, 
including the availability of continuous glucose monitoring, 
potentially open up new avenues of exploration. The NINR is 
particularly interested in applications from qualified nurse 
investigators that focus on reduction of hypoglycemia through the use 
of advanced technologies, such as the use of insulin pumps in children 
and adolescents. 

While this RFA focuses on clinical studies of hypoglycemia, a separate 
RFA (DK 01-031) solicits basic and clinical research specifically 
addressing the problem of hypoglycemia unawareness. An additional 
related RFA (NS-02-008) solicits basic research on the effects of 
hypoglycemia on cerebral metabolism and neural cell function and 

Appropriate topics for investigation under this RFA would include but 
are not limited to: 

o Studies to determine the prevalence of hypoglycemia in patients with 
diabetes, with a focus on delineating differences among various age 
groups (e.g., children, adults, the elderly),

o Studies to delineate the role of age, gender, race/ethnicity, 
socioeconomic status and other factors in the risk of hypoglycemia, 

o Studies to identify factors, including method of treatment, exercise, 
nutrition, or duration of diabetes, which affect risk of hypoglycemia,

o Studies to establish normative data for blood glucose levels, 
particularly in children, throughout a 24-hour period,

o Studies to determine whether there are changes in counterregulatory 
mechanisms with age,

o Studies to determine whether intensive glucose control during 
pregnancy has adverse effects on the developing fetus,

o Studies to determine whether alternative fuels (e.g., ketones) can 
provide a buffer against hypoglycemia, 

o Studies to assess the reliability and utility of continuous glucose 
sensors in detecting falling blood glucose levels and in preventing 
severe hypoglycemia,

o Studies to determine whether the occurrence of hypoglycemia can be 
minimized by altering the timing of drug delivery or by drugs with 
altered kinetics,

o Studies to determine whether different treatment regimens for 
diabetes affect counterregulatory mechanisms,

o Studies to evaluate whether there are differences in 
counterregulation between individuals with type 1 and type 2 diabetes,

o Studies to develop and test strategies for minimizing the risk of 
hypoglycemia with intensive glucose management.


Letter of Authorization

Applicants should submit a brief letter to the NIDDK indicating whether 
or not they wish their application to be considered for funding by the 
JDRF. While applicants may request that their applications be 
considered only by the NIH and not by the JDRF, it is necessary that 
the record indicate the applicant"s consideration of this opportunity. 
For those applicants who wish to have the JDRF consider their 
application, all materials relating to the application will be promptly 
forwarded to that organization and the summary statements for such 
applications will be shared with the JDRF when available. This separate 
letter of authorization may be submitted with the Letter of Intent (see 


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 

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 
(, a 
complete copy of the updated Guidelines are available at  
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.


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:  

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.


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.


NIH policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  This policy announcement is found 
in the NIH Guide for Grants and Contracts Announcement dated June 5, 
2000, at the following website:


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:       

Applicants may wish to place data collected under this RFA (PA) 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.


Prospective applicants are asked to submit, by 10/17/01, 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:

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


The PHS 398 research grant application instructions and forms (rev. 
5/2001) available at are to be used 
in applying for these grants. This version of the PHS 398 is available 
in an interactive, searchable PDF format. Although applicants are 
strongly encouraged to begin using the 5/2001 revision of the PHS 398 
as soon as possible, the NIH will continue to accept applications 
prepared using the 4/1998 revision until January 9, 2002. Beginning 
January 10, 2002, however, the NIH will return applications that are 
not submitted on the 5/2001 version.  For further assistance contact 
GrantsInfo, Telephone 301/710-0267, Email:


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 is to be used 
in applying for these grants, with modular budget instructions provided 
in Section C of the application instructions.  Applicants are 
permitted, however, to use the 4/1998 revision of the PHS 398 for 
scheduled application receipt dates until January 9, 2002.  If you are 
preparing an application using the 4/1998 version, please refer to the 
step-by-step instructions for Modular Grants available at  Additional 
information about Modular Grants is also available on this site.

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:

Submit a signed, typewritten original of the application, including the 
Checklist, and five signed, photocopies, in one package to:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

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 

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.


Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NIDDK.  If the application is not responsive 
to the RFA, NIDDK or CSR staff may contact the applicant to determine 
whether to return the application to the applicant or submit it for 
review in the 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 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 NIDDK, the NINDS, the 
NICHD and the NINR Advisory Councils.

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?  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?

(3) 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 

(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  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, animals, 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.


Letter of Intent Receipt Date:    October 17, 2001
Application Receipt Date:         November 21, 2001
Peer Review Date:                 March 2002
Council Review:                   May 2002
Earliest Anticipated Start Date:  July 1, 2002


Award criteria that will be used to make award decisions include:

o Scientific merit as determined by peer review,
o Availability of funds,
o Programmatic priorities.


Inquiries concerning this RFA are encouraged.  The opportunity to 
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Barbara Linder, M.D, Ph.D. 
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 699 MSC 5460
Bethesda, MD 20892-5460
Telephone:  (301) 594-0021
FAX:  (301) 480-3503

Toby Behar, Ph.D.
Neural Environment
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd., Rm. 2114A
Bethesda, MD 20892-9521
Telephone: (301) 496-1431
FAX: (301) 480-2424

Gilman D. Grave, M.D.
Chief, Endocrinology, Nutrition, and Growth Branch
National Institute of Child Health and Human Development
6100 Executive Blvd., Room 4B11A, MSC 7510
Bethesda, MD 20892-7510
Telephone: (301) 496-5593
FAX: (301) 480-9791

Nell Armstrong, Ph.D., R.N.
National Institute of  Nursing Research
Building 45, Room 3AN12
Bethesda, MD 20892—6300
Telephone, (301) 594-5973
FAX: (301) 480-8260

Direct inquiries regarding fiscal matters to:

Charlette Kenley
Division of Extramural Activities
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases 
6707 Democracy Boulevard, Rm. 640 MSC 5456
Bethesda, MD 20892-5456
Telephone:  (301) 594-8847 
FAX:  (301) 480-3504

Mary Graham
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd., Rm. 3290
Bethesda, MD 20892
Telephone: (301) 496-9231
FAX: (301) 402-0219

Mary Daley
Grants Management Branch 
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17E, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-1305
FAX:  (301) 402-0915

Robert L. Tarwater
Office of Grants and Contracts Management
National Institute of Nursing Research
Building 45, Room 3AN12
Bethesda, MD 20892-6300
Telephone: (301) 594-2807
FAX: (310) 480-8260


This program is described in the Catalog of Federal Domestic Assistance 
No. 93.847, 93.853, 93.865 and 93.361.  Awards are made under 
authorization of Sections 301 and 405 of the Public Health Service Act 
as amended (42 USC 241 and 284) 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 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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