Full Text DK-93-007

NON-INSULIN DEPENDENT DIABETES PRIMARY PREVENTION TRIAL

NIH Guide, Volume 22, Number 18, May 7, 1993

RFA:  DK-93-007  - (Reissued as RFA-DK-08-504)

P.T. 34

Keywords: 
  Diabetes 
  Clinical Trial 
  Disease Prevention+ 


National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Child Health and Human Development
Office of Research on Minority Health

Letter of Intent Receipt Date:  September 17, 1993
Application Receipt Date:  October 19, 1993

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), the National Institute of Child Health and Human Development
(NICHD), and the Office of Research on Minority Health (ORMH) invite
cooperative agreement applications for investigators to design and
implement a full-scale, multicenter, randomized clinical trial to
evaluate the efficacy of interventions designed to delay or prevent
onset of non-insulin dependent diabetes mellitus (NIDDM) in individuals
at increased risk for NIDDM.  Within the broad range of this NIDDK and
NICHD-sponsored initiative, ORMH is providing specific support for
research focussing on the sub-population of obese minority women with
a history of gestational diabetes.

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 RFA,
NIDDM Primary Prevention Trial, is related to the priority area of
diabetes and chronic disabling conditions.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock Number
017-001-00474-0 or Summary Report:  Stock Number 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325, telephone 202/783-3238.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by for-profit and non-profit domestic
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal government.  Minority individuals and
women are encouraged to submit as Principal Investigators. Applications
from minority institutions are especially encouraged.  Applications
from foreign institutions will not be considered.

The expertise appropriate for this research program includes a
knowledge of the clinical and epidemiological aspects of diabetes.

Institutions wishing to collaborate and function as a single Clinical
Center are required to submit one application.  In this regard,
applicants are encouraged to form collaborative arrangements with
investigators at minority institutions and/or minority investigators at
other institutions.  However, international collaborations are
unacceptable.

MECHANISM OF SUPPORT

The administrative and funding mechanism to be used to undertake this
program will be a cooperative agreement (U01), which is an assistance
mechanism, rather than an acquisition mechanism.  Under the cooperative
agreement, the NIH purpose is to support and/or stimulate the
recipient's activity by collaborating and otherwise working jointly
with the award recipient in a partner role, but it is not to assume
direction, prime responsibility, or a dominant role in the activity.
Details of the responsibilities, relationships and governance of this
study funded under a cooperative agreement are discussed under the
section "Terms and Conditions of Award."

FUNDS AVAILABLE

Support during the planning phase (Phase 1) of this trial for FY 1994
is expected to be approximately seven million dollars with total costs
per center of approximately $350,000.  It is anticipated that awards
for 15 to 20 new Clinical Centers will be made.  Additional centers
will be recruited through a follow-up RFA if necessary to achieve
adequate numbers of subjects.  During Phase 2 (full scale trial period)
it is expected that funding levels for each center will increase to
approximately $500,000 reflecting the start of the full scale trial.
During Phase 3 (close-out period) costs are expected to decrease to
approximately $100,000 in keeping with the reduction in clinical
personnel effort and the shift to close-out, analysis of data, and
reporting.  Cost for outcome measures should not be included
individually for each center.  These costs will be covered under the
Data Coordinating Center funding.

Although this program is provided for in the financial plans of the
NIDDK and the NICHD, awards in response to this RFA are contingent on
the availability of funds for this purpose.

The total project period for applications submitted in response to the
present RFA will be seven years due, in part, to the necessity to
screen large numbers of potential participants to identify individuals
with sufficient risk to answer the study question discussed below under
"RESEARCH OBJECTIVES".  The anticipated award date is July 1994.

At this time, the NIDDK anticipates that there will not be a renewed
competition after seven years.  If the NIDDK does not continue the
program, awardees may submit grant applications through the usual
investigator-initiated grants program.

RESEARCH OBJECTIVES

Background

A family history of diabetes, obesity, insulin resistance,
hyperinsulinemia, a history of gestational diabetes, and impaired
glucose tolerance (IGT) are risk factors for NIDDM (1).  Based on the
NHANES II survey data, IGT is present in 16 percent of adults aged 40
to 74 in the U.S. and in 23 percent of this age group who have a family
history of diabetes and body weight greater than 120 percent of
desirable weight (2).  Minority populations have even higher rates of
IGT (3).  For high risk individuals the rate of progression to NIDDM is
5 to 10 per cent per year (4).  Importantly, screening for IGT can
identify individuals at increased risk for development of NIDDM
(5,6,7).  There is currently no accepted standard of care for patients
with IGT. Screening for IGT, which is undiagnosed in most affected
individuals, is not widely recommended or practiced, nor are there
accepted interventions for patients with IGT.  No large scale,
randomized, prospective, controlled clinical trials have determined
whether or not progression of IGT to NIDDM can be prevented.

In addition, obesity and gestational diabetes (GDM), an apparently
temporary condition of pregnancy, are important independent risk
factors for the subsequent development of NIDDM.  African, Hispanic,
and Native American women have significantly increased prevalence of
both of these conditions.  It appears that excessive weight gain during
pregnancy may play a role in the appearance of GDM and the documented
lack of weight loss to pre-pregnancy levels following delivery may
conspire to magnify the risk of future NIDDM in these groups of
minority women.

Insulin resistance is the earliest abnormality detected in individuals
who will develop NIDDM and appears to be genetically determined (8).
However, it is not known whether reversing insulin resistance will
prevent or delay onset of NIDDM.  Insulin resistance can be reduced
through weight reduction and exercise (9).  Corresponding to these
findings, epidemiologic data indicate an association between exercise
frequency and significant lowering of risk for NIDDM (10,11).  Results
of a study performed in Sweden suggest that moderate weight reduction
of two to four percent of initial weight and increased maximal oxygen
uptake of 10 to 14 percent can be maintained for a period of five
years.  This was found to be associated with improvement in glucose
tolerance, blood pressure, lipids, hyperinsulinemia, and reduced
mortality (12).  Sustained intervention appears to be necessary to
achieve these lifestyle changes (13), but importantly, such changes
have the potential to slow the deterioration of glucose tolerance in
IGT, thereby delaying the onset of diabetes.

Pharmacologic agents also can potentially prevent or delay onset of
NIDDM.  Biguanides are suggested to reduce insulin resistance and
improve glycemia and hyperinsulinemia, while sulfonylurea agents appear
to improve glycemia by increasing insulin secretion and through
extra-pancreatic effects.  Data in the literature are inconclusive with
respect to the ability of these agents to prevent or delay onset of
NIDDM.  One study using the biguanide metformin showed no effect on
prevention or delay of onset (14).  In contrast, studies with
sulfonylureas have shown decreased rates of diabetes and of mortality
in patients treated with modest doses for IGT (15,16) but are
inconclusive.  Nonetheless, these interventions could slow the
deterioration of glucose tolerance in patients with IGT.  In so doing,
diabetic complications, including atherosclerosis, may also be delayed
reducing morbidity and mortality due to diabetes.

Methods are available for potentially reducing insulin resistance and
improving glucose tolerance.  Based on this and the high rates of IGT
in the United States, the NIDDK has determined that a randomized
controlled clinical trial is necessary.  Such a trial would define the
effectiveness of interventions for delaying or preventing NIDDM in high
risk persons with impaired glucose tolerance.  Since the estimated
population prevalence of undiagnosed NIDDM is six percent screening for
IGT will detect individuals with previously undiagnosed NIDDM, most of
whom do not have fasting hyperglycemia (2).  In addition, the NIDDK
considers that those with newly diagnosed NIDDM should be treated in a
randomized, prospective fashion to determine whether early detection
and treatment of NIDDM can reverse the disease process or have
favorable effects on the deterioration of glucose tolerance that is
characteristic of NIDDM.  The NIDDK also believes that obese minority
women with a history of GDM constitute an excellent interventional
target to establish whether the expected high rate of NIDDM in this
population can be altered.

Goal of the Activity

The purpose of this RFA is to initiate a collaborative study of
interventions to prevent NIDDM in people with IGT or a history of GDM
and to prevent the worsening of glucose tolerance in people with newly
diagnosed NIDDM.  The study will determine whether onset of NIDDM can
be delayed and whether interventions in newly diagnosed NIDDM can
favorably influence glucose tolerance and progression to fasting
hyperglycemia.

The objectives of this RFA are to select centers to:

o  Participate in a full-scale trial.

o  Design the study protocol and write the manual of operations.

o  Develop operational plans for the trial in close collaboration with
the communities they serve.  These plans must include racially and
ethnically sensitive strategies for recruitment, screening, enrollment
and adherence to the study protocol.

The collaborative protocol will be developed by a Steering Committee
composed of the awardees, the Chairperson, the Principal Investigator
of the Data Coordinating Center, and the  NIDDK Project Coordinator.
The protocol and manual of operations will be subject to review by an
uninvolved expert group (Policy and Data Monitoring Committee), and the
NIDDK.  The study will move into its operational phase only with the
concurrence of the awardees, the Policy and Data Monitoring Committee,
and the Institute.

Scope of the Activity

It is expected that the study will take place in fifteen to twenty
Clinical Centers over a period of seven years. The clinical centers
will randomize an approximate average  of 200 study participants per
center over a 12 month period of recruitment.  The entire collaborative
clinical trial will consist of the following three phases:

Phase 1 (12 months):  Planning phase, collaborative development of the
protocol and manual of operations which includes procedures for data
collection and pretesting of these procedures.  There must also be
included in the manual well-defined procedures for the training and
certification of clinic personnel in study procedures.

Phase 2 (60 months):  Conduct of the full-scale collaborative clinical
trial including patient recruitment and followup.

Phase 3 (12 months): Close out, analysis of data, and reporting of
results.

Each applicant should propose the study design he or she believes best
addresses the objectives of this project and is most appropriate for
their patient population.  The goal of the NIDDK and the NICHD is to
have approximately 50 per cent of the subject population comprised of
minorities.  The study population mix at any one center may vary from
this overall goal based on local demography.  The overall study
population may include, but is not limited to, Caucasians, Native
Americans and Alaskan Natives, Blacks, Hispanics, and Asian/Pacific
Islanders.  In addition, applicants are encouraged, if a suitable
population base exists, to include a cohort of obese women with a
history of GDM.  Applicants should provide a detailed justification for
whatever strategy is proposed for subject selection as well as an
estimate of the number of subjects in the source population and an
estimate of the necessary time and effort needed for recruitment.
Issues of racial and subgroup analysis will be dealt with by the
Steering Committee.

It is not the intent of this RFA to solicit elaborately detailed
research plans for the conduct of the trial since the final protocols
will be collaboratively developed by the investigators and the NIDDK
during the planning phase (Phase 1) of the study described later under
"Study Phases".

SPECIAL REQUIREMENTS

To promote the development of a collaborative program among the award
recipients, the following minimum number of issues should be addressed:

o  The rationale and criteria for subject selection, as well as plans
for and documentation of the ability to recruit sufficient numbers of
study participants;

o  Documentation of specific competence and previous experience of the
professional, technical, and administrative staff in the operation of
a Clinical Center in the proposed study;

o  Documentation of experience in the treatment of persons with
diabetes;

o  The willingness of the applicant to work cooperatively with the
other Clinical and Data Coordinating Centers; and

o  The willingness to follow the common protocols that will be
collaboratively developed in Phase 1.

Personnel

The participating members of the study team should include or have
access to:

o  Diabetologists to enroll and maintain the patients in this study and
coordinate the activities of the medical team.  The diabetologists used
in this study must have faculty appointments.

o  Nurse/Clinic Coordinator who can provide full-time attention to
clinic administration and management, including logistical aspects of
patient follow-up and data transmittal in addition to participating in
management of patients;

o  Behavioral scientists to conduct standardized neuropsychological
testing and psychological evaluations and to provide consultation to
other clinic staff in the selection and management of the study
subjects;

o  Exercise trainer\therapist to conduct the exercise related aspects
of this trial

o  Nutritionists-dieticians and nurse educators to perform the
educational aspects of the Protocol and provide diabetes care; and

o  clerical and technical support.

Study Organization

1.  Study Outline.  The applicant's study design should include a
detailed proposal of eligibility requirements including patient age,
gender, and racial/ethnic background for study participation.  In
addition, exclusion criteria should be specified.  Consideration should
be given to screening individuals in the population at higher risk for
NIDDM, such as those with obesity and a family history of diabetes.
The procedure for screening for IGT should be provided in the
application.  The screening procedure should be designed to identify
individuals at highest risk for progression to NIDDM and to minimize
inclusion of individuals with transient IGT.

It has been documented that women with a history of GDM are also at
particularly high risk for the subsequent development of NIDDM.  Thus,
in addition to the NIDDK, the OMP is particularly interested in
addressing this minority women's health issue.  Applicants are
therefore encouraged to include a GDM cohort in their study population
where a suitable population base exists.

Interventions may include diet, exercise, and pharmacologic agents in
a randomized, placebo controlled, factorial design.  Individuals with
newly diagnosed NIDDM identified in the screening process should be
included in the randomization scheme.  Methods to monitor patient
adherence to the trial protocol must be clearly defined.  Proposed
methods for management of cardiovascular risk factors, including
hypertension, dyslipidemia, and smoking cessation in all subjects
should be included.  For IGT or for women with a history of GDM,
outcome measures should be chosen to address the efficacy and adverse
effects of interventions on deterioration of glucose tolerance and
progression to NIDDM.  For newly diagnosed diabetes, outcome measures
should address the efficacy and adverse effects of interventions to
prevent deterioration of glucose tolerance and progression of
hyperglycemia.  Outcome measures should include sequential evaluation
of metabolic status.

All centers must agree to implement the protocol and manual of
operations that will be developed cooperatively by the Steering
Committee during Phase 1 and agree to transmit all study data to a
central Data Coordinating Center for combination and analysis.

The recruitment of a Data Coordinating Center will be accomplished by
means of a separate RFA (DK-93-008).

2.  Study Components

a.  Clinical Centers.  A Clinical Center is an institution that is
actively involved in the recruitment, evaluation, treatment, and
follow-up of study participants.  It should consist of a core team of
researchers, including Principal Investigator, full-time study
coordinator, nutritionist, behaviorist, exercise therapist\trainer and
clerical staff.  Applications for Clinical Centers should provide
evidence that the center will be capable of screening for IGT and NIDDM
and, if applicable, have access to a patient base of women with a
history of GDM.  It will be the goal of each center to randomize
approximately 200 participants into the study during the 12 month
period of recruitment.

Clinical Centers should describe their experience in recruiting and
studying patients with diabetes including those with a history of GDM
or other conditions, and in minimizing losses of patients to follow-up
during long-term clinical studies.  There should be evidence of strong
institutional support for the Clinical Center, including documentation
of adequate space in which to conduct clinic activities and office
space for staff.  Applicants from institutions that have a General
Clinical Research Center (GCRC) funded by the NIH National Center for
Research Resources are strongly encouraged to use this facility and to
identify the GCRC as a resource for conducting the proposed study. If
so, a letter of agreement from either the GCRC Program Director or
Principal Investigator should be included with the application.

An organizational structure for the Clinical Center should be provided
in the application delineating lines of authority and responsibility
for dealing with problems in all general areas.  In addition, a
statement of agreement to follow the common protocol agreed upon in
Phase 1 should be included.

The applicant should include a succinct discussion of previous relevant
investigational efforts.  The applicant also should discuss in detail
the important design considerations for a clinical trial to investigate
primary prevention of NIDDM, intervention in newly diagnosed NIDDM, and
treatment of cardiovascular risk factors in study participants, and
suggest solutions to likely problems.  Clinical Centers will be
required to submit protocol data expeditiously to a central Data
Coordinating Center.  The Principal Investigator and treatment team in
each Clinical Center should be skilled in diabetes management and
collaborative clinical investigation.

b.  Steering Committee.  The primary governing body of the study will
be the Steering Committee comprised of each of the Principal
Investigators of the Clinical Centers and the Data Coordinating Center
and The NIDDK Project Coordinator (described in detail under Terms and
Conditions).

c.  Data Coordinating Center.  A Data Coordinating Center recruited
through a separate RFA (DK-93-008) will participate with the Clinical
Centers and Institute staff during the entire clinical trial.  The Data
Coordinating Center will have primary responsibility for the
biostatistical analyses and data management aspects of the trial.  It
will also manage through subcontracts the central laboratory and
clinical support aspects of this trial.  The Data Coordinating Center
will perform interim analyses as needed to monitor the course of the
trial as well as analyses needed for final reporting.  Preparation of
interim and final reports, however, will be collaborative undertakings
by all participating Centers, the Data Coordinating Center, and the
NIDDK.

d.  Policy and Data Monitoring Committee.  An independent committee
supported by the NIDDK and composed of experts in relevant medical,
psychological, statistical, operational, and bioethical fields who are
not otherwise involved in the study will be established to review
periodically the progress of the study (described in detail under Terms
and Conditions).

e.  Project Coordinator.  The NIDDK will name the Director, Special
Programs from within the Division of Diabetes, Endocrinology, and
Metabolic Diseases to be the Project Coordinator.  The Project
Coordinator's function will be to assist the Steering Committee and
Policy and Data Monitoring Committee in carrying out the study
(described in detail under Terms and Conditions).

Study Phases

After the protocol is completed by the study group during the planning
phase (Phase 1), it will be reviewed by the Policy and Data Monitoring
Committee and the NIDDK.  Progression to Phase 2 is dependent on the
favorable recommendation of the protocol by the Policy and Data
Monitoring Committee and the concurrence of the NIDDK.

The protocol for the study will be implemented in Phase 2.  It is
anticipated that the Clinical Centers will recruit and randomize
participants, implement the protocol according to the manual of
operations, collect the outcome data specified in the protocol, and
provide all study data to the Data Coordinating Center.  Twelve months
will be allowed for subject recruitment and randomization.  Clinical
Centers will be responsible for collecting and shipping patient
specimens and other study data to designated Central Resource Units.

The final phase (Phase 3) of the study will be for close-out of
Clinical Center activities, final data analysis, and reporting of
results.  Phase 3 will be for a period of 12 months.

Budget Preparation by Study Phase

Each applicant for a Clinical Center should submit adequately justified
budgets for the entire anticipated project period of 84 months.  The
budgets for each phase of the study should be clearly delineated.
Detailed budgets will vary according to policies of the applicant
institution and specific needs identified in the response to this
announcement.  Applicants should prepare individual budgets for each of
the three planned phases of the study.

The Phase 1 budget period will be for development of the protocol and
manual of operations, staff training and certification.  The Phase 2
period will be for 60 months.  Separate budgets for each 12-month
budget period in Phase 2 should be submitted.  Activities in this
second phase will include subject recruitment, randomization,
treatment, and clinical assessment of randomized study participants.
The Phase 3 period will be for 12 months.  This budget period will be
concerned with study close-out, analysis of study data, and reporting
of results.

Phase 1 activities will require phasing-in of staff within six-months
prior to initiating recruitment.  Budgets should allow for
approximately three persons, including the Principal Investigator, to
attend Steering Committee and Subcommittee meetings.  The detailed
budget for this phase should be estimated on the basis of monthly
meetings during Phase 1.  Phase 2 budgets should include travel funds
for three evenly spaced meetings per year during Phase 2.  Phase 3 will
involve two meetings over the  twelve-month interval.  Each meeting
should be assumed to be for two days at a cost of $1000 per person.

Detailed budget estimates for Phase 2 and 3 should be based on the
applicant's proposed plan.  Budgets for both Phases 2 and 3 will be
modified based on the final protocol developed collaboratively during
Phase 1.

Terms and Conditions of Award

1.  Cooperative Activities.  The administrative and funding mechanism
to be used to undertake this project will be cooperative agreements
(U01), which is an assistance mechanism, rather than and acquisition
mechanism.  Under the cooperative agreement, the NIDDK and NICHD
purpose is to support and/or stimulate the recipient's activity by
collaborating and otherwise working jointly with the award recipient in
a partner role, but it is not to assume direction, prime
responsibility, or a dominant role in the activity.  Consistent with
this concept, the tasks and activities in carrying out the studies will
be shared among the awardees and the NIDDK Project Coordinator.

2.  Awardee Activities.  Awardees will have substantial and lead
responsibilities in all tasks and activities.  These include protocol
development, patient recruitment and follow-up, data collection,
quality control, final data analysis and interpretation, preparation of
publications.  The awardee agrees to work cooperatively with the other
Clinical and Data Coordinating Centers and agrees to follow the common
protocol and manual of operations developed in Phase 1 of the study by
the Steering Committee.  The awardee also agrees to transmit all study
data to a central Data Coordinating Center for combination and
analysis.

Awardees will retain custody of and have primary rights to their data
developed under these awards, subject to Government, e.g., NIDDK, NIH,
or PHS, rights or access consistent with current HHS, PHS, and NIH
policies.

3.  NIDDK Activities.  It is the intention of the NIDDK that central
resource units for the standardized assessment of key laboratory and
clinical parameters will be established and utilized by all
participating Clinical Centers.  These central resources will function
and be supported under the Data Coordinating Center award.

The NIDDK will name a Project Coordinator from within the Division of
Diabetes, Endocrinology, and Metabolic Diseases whose function will be
to assist the Steering Committee and Policy and Data Monitoring
Committee in carrying out the study.  The Project Coordinator will be
a voting member of all key study group committees. The Project
Coordinator will serve as executive secretary of the independent Policy
and Data Monitoring Committee. The NIDDK Project Coordinator will
assist in quality control, interim data and safety monitoring, final
data analysis and interpretation, preparation of publications, and
coordination and performance monitoring.

The NIDDK Project Coordinator will have voting membership on the
Steering Committee, and as appropriate, its subcommittees.

The NIDDK and NICHD reserves the right to terminate or curtail the
study (or an individual award) in the event of (a) a major breach in
the protocol or substantial changes in the agreed-upon protocol with
which the Institute does not agree or (b) human subject ethical issues
that may dictate a premature termination.

4.  Governance.  The primary governing body of the study will be the
Steering Committee comprised of each of the Principal Investigators of
the Clinical Centers and the Data Coordinating Center and the NIDDK
Project Coordinator.  The Steering Committee has primary responsibility
for developing common clinical protocols, facilitating the conduct and
monitoring of the studies, and reporting the study results.  Topics for
the protocols will be proposed and prioritized by the steering
Committee.  Each member of the Steering Committee will have one vote.
A chairperson will be appointed by the voting members of the Steering
Committee from among the Steering Committee members but not the Project
Coordinator, or alternatively, from among experts in the field of
diabetes and clinical trials who are not participating directly in the
study.

It is anticipated that the Steering Committee will meet on a monthly
basis during protocol development (Phase 1), three times a year in
Phase 2, and two times in Phase 3.  Subcommittees of the Steering
Committee may be established as necessary and will meet as necessary.
The NIDDK Project Coordinator or designee and the Data Coordinating
Center will be represented on each subcommittee.

An independent Policy and Data Monitoring Committee supported by the
NIDDK and composed of experts in relevant medical, psychological,
statistical, operational, and bioethical fields who are not otherwise
involved in the study will be established to review periodically the
progress of the study.  The committee will oversee participant safety,
evaluate results, monitor data quality, and provide operational and
policy advice to the Steering Committee and the NIDDK regarding the
status of the study.  The Principal Investigator of the Data
Coordinating Center, the NIDDK Project Coordinator, and the Director of
the Division of Diabetes, Endocrinology and Metabolism may participate
as ex-officio, non-voting members of this Committee.  Committee members
will be appointed by the Director, NIDDK in consultation with members
of the Steering Committee.  The NIDDK named Project Coordinator will
serve as executive secretary of the Policy and Data Monitoring
Committee.

5.  Arbitration.  Any disagreement that may arise in
scientific-programmatic matters between award recipients and NIDDK may
be brought to arbitration.  An arbitration panel will be composed of
three members - one selected by the Steering Committee (with NIDDK
member not voting) or by the individual awardees in the event of an
individual disagreement, a second member selected by NIDDK and the
third member selected by the preceding two members.  This special
arbitration procedure in no way affects the awardees' right to appeal
an adverse action that is otherwise appealable in accordance with the
PHS regulations at 42 CFR part 50, subpart D and HHS regulations at 45
CFR part 16.

The special terms of award (1-5) described above are in addition to and
not in lieu of otherwise applicable OMB administrative guidelines, HHS
Grant Administration Regulations at 45 CFR parts 74 and 92, and other
HHS, PHS, and NIH grant administration policy statements.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women in
study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis must be placed on the need for inclusion of minorities
and women in studies of diseases, disorders and conditions which
disproportionately affect them.  This policy is intended to apply to
males and females of all ages.  If women or minorities are excluded or
inadequately represented in clinical research, particularly in proposed
population-based studies, a clear compelling rationale must be
provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research design
and sample size appropriate for the scientific objectives of the study.
This information must be included in the form PHS 398 (rev. 9/91) in
Item 4 (Research Design and Methods) of the Research Plan AND
summarized in Item 5, Human Subjects.  Applicants are urged to assess
carefully the feasibility of including the broadest possible
representation of minority groups.  However, NIH recognizes that it may
not be feasible or appropriate in all research projects to include
representation of the full array of United States racial/ethnic
minority populations; i.e., Native Americans [including American
Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks,
Hispanics.

The rationale for studies on single minority population
groups should be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology, prevention
[and preventive strategies], diagnosis, or treatment of diseases,
disorders or conditions, including, but not limited to, clinical
trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

If the required information is not contained within the application,
the application will be returned without review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and reflected in assigning
the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.

LETTER OF INTENT

Prospective applicants are asked, but not required, to submit a letter
of intent.  This letter is to include the name, telephone number and
mailing address of the Principal Investigator, the names of other key
personnel, the name of the applicant institution, and the number and
title of this RFA.  Such a letter of intent is not binding and it will
not enter into the review of any application subsequently submitted nor
is it a requirement for application.  Letters of intent are requested
solely for planning purposes.  The information contained in these
letters is helpful in planning for the review of applications.  It
allows NIDDK staff to estimate the potential review workload and to
avoid possible conflicts of interest in the review.  The NIDDK staff
will not provide responses to such letters.

Letters of intent are to be received no later than September 17, 1993,
and are to be addressed to:

Robert D. Hammond, Ph.D.
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892
Telephone:  (301) 594-7515
FAX:  (301) 594-7503

APPLICATION PROCEDURES

Submit applications on form PHS 398 (rev. 9/91), the application form
for NIH research project grants.  This form is available in the
applicant institution's office of sponsored research and may be
obtained from the Office of Grants Inquiries, Division of Research
Grants, National Institutes of Health, Westwood Building, Room 449,
Bethesda, MD 20892, telephone (301) 594-7250.

Use the conventional format for research project grant applications and
ensure that the points identified in the SPECIAL REQUIREMENTS section
above and in "Review Criteria" section below are fulfilled.  To
identify the application as a response to the RFA, Check "YES" on item
2a of page 1 of the application and enter the title "NIDDM Primary
Prevention Trial" and enter the RFA number DK-93-007 in the space
provided.

The RFA label available in the form PHS 398 application kit must be
affixed to the bottom of the face page of the original completed
application form.  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.

Send or deliver the completed, signed application and three complete
photocopies to the following office, making sure that the original
application with the RFA label attached is on top to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Send two additional copies of the application to Dr. Hammond at the
address listed under LETTER OF INTENT.  It is important to send these
two copies at the same time as the original and three copies are sent
to the Division of Research Grants, otherwise the NIDDK cannot
guarantee that the application will be reviewed in competition for the
RFA.

Applications must be received by October 19, 1993.  An application not
received by this date will be returned to the applicant.

REVIEW CONSIDERATIONS

Upon receipt, the Division of Research Grants (DRG) will review the
application for completeness.  Applications will be reviewed by NIDDK
staff for responsiveness to the objectives of this RFA.  If an
application is judged incomplete or unresponsive, it will be returned
to the applicant.

If the number of applications is large compared to the number of awards
to be made, the NIDDK will conduct a preliminary scientific peer review
and will withdraw from further competition those applications that are
not competitive for award.  The NIDDK will notify the applicant and
institutional official of this action.  Those applications judged to be
both competitive and responsive will be evaluated further according to
the review criteria stated below for scientific and technical merit by
an appropriate peer review group convened by the Division of Extramural
Activities, NIDDK.  Subsequently, they will be reviewed by the National
Diabetes and Digestive and Kidney Diseases Advisory Council and the
National Advisory Child Health and Human Development Council.

Review Criteria

Specific criteria for review of applications will be as follows:

o  The scientific merit of the proposed study design to address the
objectives of the RFA.  This includes criteria for subject selection,
plans for recruitment of subjects, proposed follow-up assessments and
schedule for data collection during follow-up (in tabular form),
proposed diagnostic and therapeutic modalities, and techniques for
monitoring and maintaining continued contact with subjects during the
course of the study.

o  Documentation of the specific competence and previous experience of
professional, technical, and administrative staff pertinent to the
operation of a Clinical Center in the proposed study.  Evaluation
criteria will include the following:  familiarity with and experience
in recruiting research subjects, especially, the ability to access,
enroll and maintain minority subjects in a randomized trial or other
clinical studies; working in collaboration with other investigators
under a common protocol; and experience with careful and expeditious
handling of study data.

o  Documentation of experience in the treatment of persons with
diabetes.  This includes documentation of a sufficient patient
population from which to recruit in order to meet the individual
Clinical Center goal for number of randomized study participants
(guidelines including examples of appropriate format for presenting
this information should be requested from the NIDDK project coordinator
indicated below).

o  Understanding and awareness of the scientific, ethical, and
practical issues underlying the proposed study and appropriateness of
plans to address them.

o  Appropriateness of the budget for the work proposed.

o  Adequacy of the proposed facility and space, including floor plans
of proposed space.

o  Evidence of substantive institutional commitment and support for the
proposed program.

o  A willingness to work cooperatively with other centers in a manner
summarized in the RFA.

Seminar for Prospective Applicants

A special technical assistance workshop will be offered to assist
potential applicants, especially those with limited experience with the
NIH application process.  The purpose of this seminar is to give
background information and respond to any questions about the
preparation of an application in response to this RFA.  The workshop
will be held in the Washington, DC metropolitan area approximately one
month after the publication of this announcement.  The NIH cannot
support individuals who wish to attend the conference, but the
conference will be open to any individual or organization who wishes to
attend.  Interested persons may contact Dr. Sanford A. Garfield, at the
address listed under INQUIRIES, for further information.

AWARD CRITERIA

The anticipated date of award is July 1, 1994.  Applications will
compete for available funds with all other approved applications
submitted in response to this RFA.  The following will be considered in
making funding decisions:

o  Quality of the proposed work as determined by peer review.
o  Availability of funds
o  Geographical balance among all applications considered for funding
under this RFA.
o  Racial and ethnic balance among the populations to be accessed by
the potential awardees.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues and address the letter
of intent to:

Sanford Garfield, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 626
Bethesda, MD  20892
Telephone:  (301) 594-7535
FAX:  (301) 594-9011

Dr. Gilman D. Grave
Endocrinology, Nutrition and Growth Branch
National Institute of Child Health and Human Development
6100 Building, Room 4B11
Bethesda, MD  20892
Telephone:  (301) 496-5593
FAX:  (301) 402-2085

Inquiries regarding fiscal matters should be directed to:

Ms. Linda Stecklein
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649B
Bethesda, MD  20892
Telephone:  (301) 594-7543
FAX:  (301) 594-7594

Schedule

Letter of Intent Receipt Date:  September 17 ,1993
Application Receipt Date:       October 19, 1993
Initial Review:                 February/March 1994
NIDDK/NICHD Council Review:     May/June 1994
Anticipated Award Date:         July 1994

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 93.847.  Awards are made under the authority 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 Part 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.

References

1.  National Diabetes Data Group:  Classification and diagnosis of
diabetes mellitus and other categories of glucose intolerance.
Diabetes 28:1039-57, 1979

2.  Harris MI, Hadden WC, Knowler WC, Bennett PH. Prevalence of
diabetes and impaired glucose tolerance and plasma glucose levels in
U.S. population aged 20-74 yr. Diabetes 36:523-534;1987

3.  Harris MI Epidemiological correlates of NIDDM in Hispanics, Whites,
and Blacks in the U.S. population. Diabetes Care 14:639-648:1991

4.  Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH.
The natural history of impaired glucose tolerance in the Pima Indians.
New Engl J Med 319:1500- 1506;1988

5.  Yudkin JS, Alberti KGMM, Mclarty DG, Swai ABM Impaired glucose
tolerance. Brit Med J 301:397-402;1990

6.  Eriksson KF, Lindgarde F, Impaired glucose tolerance in a
middle-aged male urban population: a new approach for identifying high
risk cases. Diabetologia 33:526- 531;1990

7.  Harris MI, Hadden WC, Knowler WC, Bennett PH: International
criteria for the diagnosis of diabetes and impaired glucose tolerance.
Diabetes Care 8:562-67, 1985

8.  Lillioja S, Mott DM, Zawadzki JK, Young AA, Abbott WGH, Knowler WC,
Bennett PH, Moll P, Bogardus C.  In vivo insulin action is a familial
characteristic in nondiabetic Pima Indians.  Diabetes 36:1329;1987

9.  Horton ES. Exercise and decreased risk of NIDDM. N Engl J Med
325:197;1991 (editorial)

10.  Helmrich SP, Ragland DR, Leung RW, Paffenbarger RS. Physical
activity and reduced occurrence of non-insulin- dependent diabetes
mellitus.  N Engl J Med 325:147;1991

11.  Manson JE, Nathan DM, Krowlewski AS, Stampfer MJ, Willett WC,
Hennekens CH. A prospective study of exercise and incidence of diabetes
among US male physicians.  JAMA 268:63;1992

12.  Eriksson KF, Lindgarde F.  Prevention of Type 2
(non-insulin-dependent) diabetes mellitus by diet and physical
exercise:  The 6-year Malmo feasibility study. Diabetologia
34:891-898;1991

13.  Page RCL, Harnden KE, Cook JTE, Turner RC.  Can life-styles of
subjects with impaired glucose tolerance be changed?  A feasibility
study.  Diabetic Medicine 9:562-566;1992

14.  Jarrett RJ, Keen H, Fuller H, McCartney M. Worsening to diabetes
in men with impaired glucose tolerance ("Borderline Diabetes").
Diabetologia 16:25- 30;1979

15.  Sartor G, Schersten B, Carlstrom S, Melander A, Norden A, Persson
G. Ten-year follow-up of subjects with impaired glucose tolerance.
Diabetes 29:41;1980

16.  Melander A, Bitzen P-O, Sartor G, Schersten B, Wahlin-Boll E.
Will sulfonylurea treatment of impaired glucose tolerance delay
development and complications of NIDDM?  Diabetes Care 13:53-58;1990

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