Release Date:  November 18, 1998

RFA:  DK-98-019 (ORWH now participating, see NOT-DK-05-019)
                (Notice of limited competition for competing applications, see NOT-DK-05-016)


National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Environmental Health Sciences
National Heart, Lung, and Blood Institute
National Institute of Nursing Research
Office of Research on Women"s Health
Centers for Disease Control and Prevention

Letter of Intent Receipt Date:  February 10, 1999
Application Receipt Date:       March 24, 1999


The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the
National Institute of Environmental Health Sciences (NIEHS), the National Heart,
Lung, and Blood Institute (NHLBI), the National Institute of Nursing Research
(NINR), the Office of Research on Women"s Health (ORWH), and the Centers for
Disease Control and Prevention invite cooperative agreement applications for
investigators to design and implement a multicenter, randomized clinical trial
to study two primary research questions:  1)  Do interventions designed to
produce sustained weight loss in obese individuals with type 2 diabetes improve
health?  2)  How do the benefits and risks of interventions designed to produce
weight loss compare with the benefits and risks related to treatment of obesity-
related comorbid conditions in the absence of weight loss intervention?  The
Study of Health Outcomes of Weight-Loss (SHOW) is expected to recruit
approximately 6,000 patients over a three-year period with four additional years
of treatment and follow-up.  Midway during recruitment, an independent assessment
will be made to determine the feasibility of continuing the trial.

The NINR is interested in encouraging applications that include nurse researchers
as principal investigators or co-investigators.  The NINR also is interested in
the role of psychosocial variables on health outcomes in the SHOW trial
population and the relationship of these variables to physiologic outcomes.

NIEHS is interested in understanding if sustained weight loss impacts on the
response of individuals to environmental agents by providing support to research
grant applications responsive to this Request for Applications (RFA).  For
example, research on the effects, if any, of weight loss on the deposition of
environmental agents such as fat stored toxicants may be important in the context
of the SHOW trial.  In addition, research that addresses the effects of sustained
weight loss on the expression of enzymes involved in the metabolism of
environmental agents is also considered important.  Applicants to this RFA are
invited to address these issues in their applications.

The ORWH is interested in providing support to research grant applications
responsive to this RFA that specifically address research into sex and gender
related issues and the effects of hormonal status in the context of the SHOW
trial.  The ORWH also wishes to help ensure that there are adequate numbers of
women included, as well as representation from appropriate minority groups. 
Applicants to this RFA are invited to address these issues in their applications.

A separate request has been issued for a Data Coordinating Center for this trial
(RFA DK-98-020).


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 Request for Applications (RFA), Study
of Health Outcomes of Weight-Loss: Data Coordinating Center, is related to one
or more of the priority areas.  Potential applicants may obtain a copy of
"Healthy People 2000" at


Applications may be submitted by domestic 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.  Foreign institutions are not eligible for this award. 
Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.

The expertise appropriate for this research program includes knowledge of the
clinical and epidemiological aspects of obesity and type 2 diabetes, expertise
in the conduct of behavioral weight loss interventions in obese patients, and
experience in the conduct of multicenter clinical trials.

Institutions wishing to collaborate and function only as a 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, collaborations
with international sites are not acceptable.  An institution may apply for both
a Clinical Center and the Data Coordinating Center, however, separate
applications are required, and a specific plan of how the independent operation
(i.e., confidentiality of the study-wide data) of each unit will be maintained
is required in each application.


The administrative and funding mechanism to be used to undertake this project
will be the cooperative agreement (U01), which is an assistance mechanism rather
than an acquisition mechanism.  Under the cooperative agreement, the NIDDK"s
purpose is to support and/or stimulate the recipient"s activity by collaborating
and otherwise working jointly with the award recipient in a partnership 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. 
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."  Except as otherwise stated in this announcement, awards
will be administered under NIH grants policy as stated in the NIH Grants Policy

Applicants from institutions that 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.  If so, a letter of
agreement from either the GCRC program director or Principal Investigator should
be included with the application.

The total project period for an application submitted in response to this RFA
will be seven years.  Since the trial design is expected to require nine years
(including planning and close-out phases), it is anticipated that a second RFA
will be issued to support the continuation of the trial beyond seven years.  The
expected award date is September 30, 1999.  It is anticipated that the awards for
the Clinical Centers will average approximately $250,000 in direct costs per year
in Fiscal Year (FY) 1999, during the planning phase.  Direct costs at the
Clinical Centers are expected to gradually increase as the protocol is
implemented, to a maximum of approximately $810,000 per center (direct costs),
on average, by the end of recruitment.  In post-recruitment years, this level of
effort is anticipated to decline to approximately $660,000 in direct costs, in
keeping with reduced Clinical Center effort after recruitment has been completed
and after patients have entered the less intensive intervention associated with
maintenance of weight loss.  During the close-out year, costs are expected to
decrease to approximately $70,000 per center (direct costs), reflecting the shift
to analysis of data and reporting.


For FY 1999, during planning of the trial, $5.25 million (total costs) will be
committed to fund Clinical Center applications submitted in response to this RFA. 
It is anticipated that approximately 15 awards will be made for Clinical Centers.

NIDDK also has planned for the projected fiscal requirements of the study beyond
FY 1999, consistent with the direct costs of Clinical Centers as described above
and the projected budgets for the Data Coordinating Center (recruited under a
separate RFA, DK-98-020).

Although this program is provided for in the financial plans of the NIDDK and
other sponsoring institutions, the awards pursuant to this RFA are also
contingent upon the availability of funds and receipt of a sufficient number of
applications of outstanding scientific and technical merit.

NOTE:  Funds available under this RFA are intended to provide for costs of
performing various outcome measurements, such as carotid ultrasound scans, at the
Clinical Centers.  However, reading of ultrasound scans and other assessments of
laboratory and clinical measures will be done centrally through contracts
developed by the Data Coordinating Center.  Costs associated with the central
readings and laboratory tests will be covered under the Data Coordinating Center
funding and should not be included individually for each Clinical Center.


A. Background

Overweight and obesity now affect more than 50% of adult Americans, with 22.5%
classified as obese (BMI greater than or equal to 30) (Flegal et al, 1998).  This
major public health problem stems from the dramatic increase in obesity that has
occurred during the past ten years, a trend that continues.  Obesity is
associated with significant morbidity and mortality, and the direct and indirect
costs attributable to obesity are estimated to approach  $100 billion per year
in the U.S. (Wolf and Colditz, 1998). It is well established that the prevalence
of type 2 diabetes increases with increasing weight (National Diabetes Data
Group, 1995).  Data from NHANES III indicate that minority populations,
particularly African American and Mexican American women, are disproportionately
affected by obesity.  For example, 37.4% of non-Hispanic black women and 34.2%
of Mexican American women are obese (BMI greater than or equal to 30), compared
with 22.4% of Caucasian women.

Numerous studies show that short-term reductions in body weight improve obesity-
related risk factors, including dyslipidemia, hyperinsulinemia, hypertension, and
elevated plasma glucose (Maggio and Pi-Sunyer, 1997).  Consistent with these
observations, current public health policy recommends weight loss for obese
individuals (BMI greater than or equal to 30) and for overweight individuals (BMI
25.0þ29.9) with two or more comorbid conditions (NHLBI and NIDDK, 1998).  Despite
the compelling data for the benefits of short-term weight loss, there is little
information regarding the health effects of long-term intentional weight loss in
obese individuals.

Increasingly, critics in both the lay press (Johannes and Stecklow, 1998) and
professional literature (Kassirer and Angell, 1998) have questioned the safety,
efficacy, and desirability of recommending weight loss to obese individuals. 
This controversy has stemmed, in large part, from observational studies
suggesting that weight loss (Andres et al, 1993) or weight fluctuation
(Williamson, 1996) are associated with increased morbidity and mortality. 
However, such studies have a number of limitations, such as the inability to
distinguish intentional from unintentional weight loss and the possibility of
confounding due to effects of underlying illness or smoking status on weight
change.  One prospective 12-year study has examined the issue of intentional
weight loss in non-smokers by utilizing the American Cancer Society"s Cancer
Prevention Study (CPS-1) cohort (Williamson et al, 1995).  This study found that
intentional weight loss among overweight, never-smoking women aged 40-64 years
with obesity-related comorbidities was associated with increased longevity, but
that among overweight women with no preexisting illness, the association was

In April of 1997 the National Task Force on Prevention and Treatment of Obesity
convened a workshop with the support of the NIDDK, the National Heart, Lung and
Blood Institute, the National Institute on Aging, and the Centers for Disease
Control and Prevention to consider the need for and feasibility of a randomized
clinical trial to assess the long-term health effects of intentional weight loss
in obese persons (Yanovski et al, in press).  The workshop participants confirmed
the paucity of evidence demonstrating that intentional weight loss improves long-
term health outcomes and recommended that a well-designed randomized clinical
trial be undertaken to answer a number of important questions necessary for
development of a rational clinical and public health policy for management of
obese individuals.  Subjects with obesity-related comorbid conditions were felt
to be a useful target population, because the presence of comorbidities would
increase the event rate of the chosen outcome(s) in the control populations, thus
enhancing the feasibility of conducting a study to detect changes in health risk
and disease progression with weight loss.  Additional recommendations from the
workshop included: 1) the focus should be on health effects of weight loss,
rather than efficacy of specific interventions, 2) a range of outcomes should be
assessed, and 3) questions of public health importance, such as cost
effectiveness of weight loss intervention in comparison with treatment of
comorbidities in the absence of weight loss intervention, should be considered.

Individuals with type 2 diabetes are highly suitable as subjects for a trial of
the benefits and risks of intentional sustained weight loss.  Diabetes is a
common condition þ over six percent of individuals aged 45-64 have diagnosed
diabetes, primarily type 2 (National Diabetes Data Group, 1995).  Over one third
of all persons with type 2 diabetes are obese, and 70 percent are overweight
(National Diabetes Data Group, 1995).  Obesity in type 2 diabetes increases
mortality, exacerbates hyperglycemia, hyperinsulinemia and dyslipidemia, and also
causes increased insulin resistance (Maggio and Pi-Sunyer, 1997).  Weight loss
has been shown to improve glycemic control and other risk factors over the short
term in obese individuals with type 2 diabetes, but little information is
available on the long-term benefits of weight loss in this group.

Macrovascular complications of type 2 diabetes are the major cause of morbidity
and mortality in individuals with type 2 diabetes, with coronary heart disease
(CHD) the leading cause of death.  Diabetic individuals have over twice the death
rate from coronary heart disease as individuals without diabetes (National
Diabetes Data Group, 1995).  A recent study in Finnish patients with type 2
diabetes demonstrates that the rate of CHD mortality in diabetic subjects with
no history of myocardial infarction is as high as that in nondiabetics with a
history of previous myocardial infarction (Haffner et el., 1998).  Obesity is
linked to cardiovascular risk factors and also is an independent predictor of
coronary atherosclerosis (Eckel, 1997).  In a multivariate simulation model,
simultaneous interventions for cardiovascular disease risk factors (smoking
cessation and correction of systolic blood pressure, cholesterol, and HDL
cholesterol to the non-diabetic reference range) are projected to eliminate only
half of the excess cardiovascular disease risk associated with type 2 diabetes
(Eastman and Keen, 1997).  Particular aspects of weight loss interventions, such
as changes in diet composition and/or physical activity, may have benefits with
respect to this residual cardiovascular disease risk that are independent of the
effects of weight loss on lipid levels and hypertension.

In addition to the long-term benefits and risks of intentional weight loss, the
efficacy of long-term weight loss interventions in sustaining weight loss is of
concern.  Recently, lifestyle interventions for weight loss have demonstrated the
ability to elicit sustained modest weight loss.  These interventions are capable
of producing a loss of 8 to 10 percent of initial body weight over a six-month
period, with gradual regain over several years.  In the Trial of Nonpharmacologic
Interventions in the Elderly (TONE), a mean weight loss of more than 4.5 kg at
30 months was reported in overweight older adults who received instruction in
diet, physical activity, and behavioral skills (Whelton et al, 1998).  Limited
data suggest that in some circumstances diabetic patients can succeed in
sustaining weight loss long-term.  In the Diabetes Treatment Study, a small
uncontrolled prospective trial in Northern Ireland, obese patients with recently
diagnosed diabetes were able to lose an average of 9 kg in 6 months and to
sustain this loss for up to 6 years, with 71% of patients able to control their
diabetes by diet alone at 6 years (Hadden et al, 1986).

Studies also have demonstrated that pharmacological treatment confers a modest,
but significant, increase in weight loss compared with that obtained by
behavioral treatment alone, and may assist in longer-term maintenance of weight
loss (National Task Force on Prevention and Treatment of Obesity, 1996, Sjostrom
et al, 1998, Hollander et al, 1998).  The availability of lifestyle interventions
that can sustain some degree of weight loss for an extended period, as well as
the potential use of pharmacological agents to help sustain weight loss, has
enhanced the feasibility of conducting a randomized clinical trial to address the
questions surrounding long-term weight loss, as recommended by the 1997 workshop.

The cost-effectiveness of weight loss interventions as a means of diminishing
obesity-related comorbid conditions in comparison to the cost-effectiveness of
treating comorbid conditions in the absence of weight loss has not been
systematically documented (Williamson et al, 1998).  A randomized clinical study
of interventions to produce sustained weight loss in diabetic patients compared
with community care of comorbid conditions offers an opportunity to
systematically assess the incremental cost-effectiveness of weight loss
interventions, as well as their efficacy in improving health.

B. Research Goal and Scope of the Activity

The goal of this RFA is to select Clinical Centers to participate in planning and
implementing a randomized, controlled, multicenter clinical trial in obese type
2 diabetic patients.  The trial will examine the effects of interventions
designed to produce sustained weight loss on a range of health outcomes.  The
primary outcome is anticipated to be differences in progression of
atherosclerosis.  This study also will examine the effects of the interventions
on cardiovascular and cerebrovascular event rates, cardiovascular and all-cause
mortality, cardiovascular risk factors, glycemic control, and other outcomes.

Several anticipated features of this study are cited below so that applicants
have a common understanding of factors necessary for the collaborative effort.

It is anticipated that two-thirds of the patients recruited to the study will be
randomly assigned to enrollment in weight loss interventions and one-third to
community care.  The SHOW trial is likely to have three arms, as follows:

1) Community Care -- Patients will receive medical care for their obesity and
obesity-related comorbid conditions (e.g., diabetes, hypertension, dyslipidemia)
from their primary care physician.  The primary care physician will be given
standard of care recommendations for treatment of obesity and comorbid conditions
(e.g., guidelines from the American Diabetes Association) and will be provided
with results of diagnostic tests carried out at study sites.

2) Intensive Lifestyle Intervention -- Patients will undergo a long-term
behavioral treatment program that includes dietary modification, increased
physical activity, and behavioral therapies designed to enhance weight loss and
weight maintenance.  This intervention is anticipated to be conducted in groups. 
Obesity-related comorbid conditions will be treated by the primary care physician
as in Group 1.

3) Intensive Lifestyle Intervention plus Weight-Loss Medication -- Medication
will be added to the intensive lifestyle intervention in an attempt to enhance
long-term weight maintenance.  Comorbid conditions will be treated by the primary
care physician as in Group 1.

Applicants may propose other designs (for instance, a two-arm design with the
potential for addition of obesity medications to the lifestyle intervention). 
In all cases, applicants should include a discussion of their rationale and
should address the pros and cons of utilizing obesity medications in the study.

Because maintenance of weight loss for extended periods of time has been
difficult to achieve, applicants may propose a subrandomization of study
participants to more than one approach to weight loss maintenance.  Applicants
incorporating such a substudy should address the rationale for alternative
maintenance strategies to be tested, specific aims, design, and assessment

Primary outcome: The SHOW trial is intended to be of sufficient size and duration
to detect differences in the rate of progression of atherosclerosis.  Applicants
are invited to submit applications utilizing the development or progression of
atherosclerosis, as assessed by quantitative carotid B-mode ultrasound, as the
primary outcome of this study.  NOTE:  If an applicant wishes to propose an
alternative primary cardiovascular outcome, this should be accompanied by a
detailed justification, including discussion of projected progression or event
rates for the proposed outcome, sample sizes, statistical assumptions underlying
the design, and potential advantages and disadvantages.

Secondary outcomes:  This study also will examine the effects of the
interventions on cardiovascular and cerebrovascular event rates, cardiovascular
and all-cause mortality, and cardiovascular risk factors, as well as glycemic

Other outcomes of interest include, but are not limited to: costs and cost-
effectiveness of the interventions, health-related psychosocial measures (e.g.,
health-related quality of life, social support, self-efficacy), changes in body
fat and body fat distribution, diabetes-specific microvascular outcomes,
musculoskeletal outcomes, such as bone density, change in use of medications,
fitness measures, such as cardiovascular fitness and flexibility, and development
of gallbladder disease.  It is the intention of the NIDDK to study these and
other possible outcomes as funds permit.  Applicants are invited to identify
their highest priorities for other outcome measures that can reasonably be
budgeted within the resources available, and to include these additional high-
priority outcome measures in their study designs and budgets.

Other questions of clinical and public health importance about which this trial
may provide information include:  1) To what extent can weight loss be sustained
over the long term in persons with type-2 diabetes using the best currently
available non-surgical interventions?  2) Does weight fluctuation impact on the
outcomes listed above?  3) Is there a difference in the effectiveness or benefit
of the intervention(s) by age, sex, or ethnicity?

C.  Study Phases

Phase 1 (Planning phase, approximately 12 months):  This phase will encompass
collaborative development of the protocol and the manual of operations by a
Steering Committee composed of the Principal Investigators of the Clinical
Centers, the Chairperson of the study, the Principal Investigator of the Data
Coordinating Center, and the NIDDK Project Coordinator.  The Steering Committee-
approved protocol and manual of operations will be subject to review by an NIDDK-
appointed expert group, the Data Safety and Monitoring Board, that will serve to
advise the Institute on subject safety, data quality and other issues.  The study
will move into its operational phase only following the recommendation of the
Data Safety and Monitoring Board and the final approval of the NIDDK.

Phase 2 (Recruitment phase, 36 months): The protocol for the study will be
initiated in Phase Two.  Clinical Centers will recruit and randomize 6,000
participants over this period, implement the protocol according to the manual of
operations, collect the outcome data specified in the protocol, and provide study
data to the Data Coordinating Center.  Clinical Centers also will be responsible
for collecting and shipping patient specimens to central facilities for

Midway in Phase 2, the NIDDK will assess the feasibility of continuing the trial. 
Criteria that will influence the decision to continue enrollment or to terminate
the trial include: 1) Ability of at least one weight-loss intervention to achieve
and sustain a clinically meaningful weight difference from the community care arm
(clinically meaningful weight difference will be defined by the Steering
Committee as part of the trial design), and 2) Satisfactory recruitment and
retention of participants.

Phase 3 (Treatment and Follow-up phase, 48 months):  Clinical Centers will no
longer recruit patients, but will continue to implement the protocol, collect
outcome data, ship specimens, and provide study data to the Data Coordinating
Center during this period.  All patients will continue to be studied throughout
Phase 3 (average duration of intervention 5.5 years, range 4-7 years).

Phase 4 (Close-out phase, 12 months):  The final phase of the study will be for
close-out of Clinical Center activities, final data analysis, and reporting of


A.  Participation in a Collaborative Program

To promote the development of a collaborative program among the awardees, the
applicant should present evidence of experience in working cooperatively with
other Clinical and Data Coordinating Centers and of ability to follow common
protocols that are collaboratively developed.  Clinical Centers also will be
expected to communicate with the Data Coordinating Center and the NIDDK Project
Coordinator on a regular basis.

All centers in the SHOW trial must agree to implement the protocol and manual of
operations that will be developed cooperatively during Phase 1 and agree to
electronically transmit all study data in a timely fashion to a central Data
Coordinating Center for combination and analysis.  An explicit statement of
willingness to participate in a collaborative program should be included in the

B.  Personnel

The application must describe the expertise of key scientific, technical and
administrative personnel and include a mechanism for replacing key professional
or technical personnel should the need arise.  Overall, the staff of a Clinical
Center should include expertise in nutrition/nutrition education, exercise
training/therapy, and behavioral science.  The study team is anticipated to
include members who perform in roles similar to those cited below.  Members may
be full or part-time and may serve in more than one capacity, as appropriate. 
The following suggested roles are intended to be illustrative, not prescriptive:

o  Principal Investigator to provide overall scientific guidance.

o  Project Coordinator who can provide full-time attention to administration and
management of the trial.

o  Recruitment coordinator to develop recruitment strategies, oversee recruitment
efforts, and serve as initial liaison between the potential subjects and the
research team.

o  Individuals to perform the educational and group intervention aspects of the
protocol, including nutrition education, exercise training, and behavioral

o  Physician(s) with expertise in the clinical management of obesity and diabetes
to help enroll and maintain the patients in this study and to oversee the use of
weight-loss medication.

o  Individual(s) such as research nurse(s) or other allied health professional(s)
to assist in case management and data collection procedures (e.g.,
electrocardiograms, phlebotomy, and patient assessments).

o  Individual(s) for clerical and technical support, including administrative
tasks, data entry, laboratory sample handling, assistance with recruitment and
other tasks.

C.  Study Outline

The applicants should discuss the important design considerations for a clinical
trial to investigate the health consequences of sustained intentional weight loss
in obese patients with type 2 diabetes.  Solutions should be suggested for likely
problems.  The applicant"s study design should propose eligibility requirements
for study participation, including patient age, gender, and racial/ethnic
background.  In addition, exclusion criteria should be specified, along with a
rationale.  Applicants should provide a justification for the subject selection
criteria, including discussion of statistical considerations, an estimate of the
number of subjects in the source population, and projected necessary time for

The overall ethnic and racial composition of the recruited patient populations
is expected to reflect the prevalence rates of diabetes in the U.S.  Based on
NHANES III data, for adults aged 20 years or older with type 2 diabetes, 74.4%
are non-Hispanic White, 15.0% are non-Hispanic Black, 5.8% are Mexican-American,
and 4.8% are other race-ethnic groups.  The study population mix at any one
center may vary from this overall distribution based on local demography.  The
overall study population may include, but is not limited to, Caucasians, Native
Americans and Alaskan Natives, African Americans, Hispanics, and Asian or Pacific
Islanders.  Issues related to oversampling of minority populations should be
considered in developing the design.  Applicants should provide a 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.  Plans should include racially
and ethnically sensitive strategies for recruitment, screening, and enrollment
to the study protocol.

Each applicant should propose the study design he or she believes best addresses
the objectives of this project as described in the RESEARCH OBJECTIVES and is
most appropriate to the proposed patient population. The potential differential
effectiveness of lifestyle interventions with respect to racial/ethnic background
of study participants should be discussed.  It is anticipated that applicants
will propose group lifestyle interventions rather than individual interventions
for reasons of efficacy and cost-effectiveness.  Many other aspects of proposed
lifestyle interventions are anticipated to be similar to those of the Diabetes
Prevention Program (DPP).  The protocol for the DPP will be available on the SHOW
website at: as a
resource for applicants.  Proposals should address potential modifications of the
DPP lifestyle intervention program needed to suit the population of subjects
proposed by the applicant.  Alternatively, if the DPP model is not considered to
be adaptable to their patient populations, applicants may propose other lifestyle
intervention programs.  NOTE: Inclusion and exclusion criteria and recruitment
and screening strategies are expected to differ from the DPP.

Applicants also should discuss their concepts for the use of obesity medications
in the trial, (e.g., whether medications should be used in a separate arm of the
trial, which drugs should be considered, whether a single drug should be selected
or a choice of drugs should be utilized, and potential problems concerning the
use of obesity medications, as well as proposed solutions).

In addition to the primary and secondary outcome measures listed Under RESEARCH
OBJECTIVES, which should be included in the study design, applicants should
indicate other outcome measures proposed for assessment (e.g., computed
tomography scans for assessment of body composition, dual energy absorptiometry
studies of bone density, quality of life assessments), identifying those they
consider the highest priority that can be accommodated within the funds

Methods to monitor and encourage patient adherence to the trial protocol should
be clearly defined.  Plans for collection and handling of data and samples should
be discussed.  Part of the proposed study design also should address the means
for communicating results of patient laboratory tests and guidelines for
treatment of comorbidities to primary care physicians.

NOTE:  It is not the intent of this RFA to solicit elaborately detailed
operational 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.

D.  Study Components

1) Clinical Centers.  Clinical Centers in the SHOW trial will be expected to:

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

o  Develop operational plans for the Recruitment phase and the Treatment and
Follow-up phase of the trial in close collaboration with the communities they

o  Participate in a full-scale clinical trial.

o  Participate in ancillary studies of trial subjects, as appropriate.

A Clinical Center is an institution that is actively involved in the recruitment,
evaluation, treatment, and follow-up of study participants.  For this trial it
will consist of a core team of researchers who are skilled in delivery of
behavioral/lifestyle interventions for obesity and have experience in
collaborative clinical investigation.  This expertise should be clearly

Clinical Centers should describe their experience in recruiting and studying
obese patients, and in minimizing losses of patients to follow-up during long-
term clinical studies.  Clinical Centers also should document prior involvement
in multi-center clinical trials and success in recruiting from minority

Applicants should provide evidence that the Clinical Center will be capable of
recruiting a sufficient number of obese type 2 diabetic patients with the
proposed inclusion criteria.  The NIDDK expects that the average number of
patients per center will be approximately 400, of whom two-thirds will receive
a lifestyle intervention.

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.  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.

2)  Data Coordinating Center.  A Data Coordinating Center recruited through a
separate RFA (DK-98-020) 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 also will manage the central laboratory and clinical
support aspects of this trial through subcontracts.  Preparation of interim and
final reports will be collaborative undertakings by all participating Centers,
the Data Coordinating Center, and the NIDDK.

3)  Steering Committee.  The primary governing body of the study will be the
Steering Committee, which will have responsibility for overall study design and
policy decisions (described in more detail under Terms and Conditions).

4)  Executive Committee.  An Executive Committee also will be convened to
facilitate the monitoring and conduct of the study between meetings of the
Steering Committee (described in more detail under Terms and Conditions).

5) Data Safety and Monitoring Board.  An independent committee will be
established by the Director, NIDDK, to review the progress of the study on a
regular basis (described in more detail under Terms and Conditions).

6) NIDDK Project Coordinator.  The NIDDK will name an NIDDK Project Coordinator
whose function will be to assist the other components as appropriate in all
aspects of the study (described in more detail under Terms and Conditions).

E.  Budget Preparation by Year

Applicants should submit adequately justified budgets for each 12-month period
of the trial, reflecting the major changes in proposed activities projected to
occur as the trial progresses through its phases.

During Phase 1 (Year 1), the budget will be for development of the protocol and
manual of operations, staff recruitment and training, and staff certification. 
The travel budget for Phase 1 should be estimated on the basis of eight meetings
at regular intervals during the first year of award.

During Phase 2 (Years 2,3 and 4), the budget should reflect subject recruitment
and randomization, implementation of the proposed interventions, collection of
outcome data proposed by the applicant, and provision of study data to the Data
Coordinating Center.  Phase 2 budgets should include three meetings per year.

During Phase 3 (Years 5,6,7 and 8), the budget should reflect the end of
recruitment and the continued implementation of the proposed interventions,
collection of proposed outcome data, and provision of study data to the Data
Coordinating Center.  Phase 3 budgets should include three meetings per year.

The Phase 4 budget (Year 9) will be concerned with study close-out, analysis of
study data, and reporting of results.  Phase 4 budgets should include two


o  Detailed budget estimates for years in Phases 2, 3, and 4 should be based on
the applicant"s proposed plan.  Actual budgets for these phases will be based on
the final protocol developed collaboratively during Phase 1.

o  It is the intention of the NIDDK that the Data Coordinating Center will
establish central resource units for the standardized assessment of key
laboratory and clinical parameters.  These costs will be included in the Data
Coordinating Center funding and should not be budgeted by the Clinical Centers. 
However, Clinical Centers should budget for performance of carotid B-mode
ultrasound scans at the research rate (or budget for an alternative
cardiovascular primary outcome measure, if an alternative has been proposed in
the study outline).  Clinical Center budgets should also include costs of
performing other proposed outcome measures (e.g., computed tomography scans,
exercise tolerance tests, dual x-ray absorptiometry), reflecting the assumption
that central facilities will provide for standardized readings where possible.

o  Budgets should allow travel and lodging costs for approximately four persons,
including the Principal Investigator, to attend Steering Committee and
Subcommittee meetings.  Since actual meeting locations have not been selected,
each meeting may be assumed to cost $1500 per person for budget purposes.  It is
anticipated that about one-third of the meetings will be held in Bethesda, MD.

F. Terms and Conditions of Award

The following special terms of award (1-5) 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 and NIH grant
administration policies.

1)  Collaborative Responsibilities.  The administrative and funding mechanism to
be used to undertake this project will be the cooperative agreement (U01), which
is an assistance mechanism (rather than an acquisition mechanism) in which
substantial NIH scientific and/or programmatic involvement with the awardee is
anticipated during the performance of the activity.  Under the cooperative
agreement, the NIDDK 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, the
Data Coordinating Center, and the NIDDK Project Coordinator.

2)  Awardee Rights and Responsibilities.  The tasks or activities in which
awardees for the Clinical Centers and the Data Coordinating Center of the SHOW
trial will have substantial and lead responsibilities include protocol
development, patient recruitment and follow-up, data collection, quality control,
final data analysis and interpretation, and preparation of publications.  The
awardee agrees to work cooperatively with the other Clinical Centers and the Data
Coordinating Center and agrees to follow the common protocol and manual of
operations developed in Phase 1 of the study by the Steering Committee.

Awardees will retain custody of and have primary rights to their data developed
under these awards, subject to Government policies regarding rights of access.

3)  NIDDK Responsibilities.  The NIDDK will name the Director, Obesity Special
Projects, Division of Digestive Diseases and Nutrition, NIDDK, to be the NIDDK
Project Coordinator.  The Project Coordinator"s function will be to provide
technical assistance to the Steering Committee, Executive Committee, Data Safety
and Monitoring Board, and other subcommittees in carrying out the study,
including 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, the Executive Committee, and, as
appropriate, other subcommittees of the Steering Committee.  The NIDDK Project
Coordinator also will serve as executive secretary of the independent Data Safety
and Monitoring Board.

Other NIDDK scientists may, as appropriate, serve on study committees and work
with awardees on issues coming before the Steering Committee or its
subcommittees.  However, in all cases, the NIDDK will have only a single vote on
study committees, either of the whole or on subcommittees.  In addition, the
NIDDK may invite non-voting representatives from other sponsoring Institutes and
agencies, as appropriate.

The NIDDK 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 or (c) failure
to achieve and sustain a clinically meaningful difference in weight loss between
the control and at least one weight loss intervention, or (d) substantial
shortfall in recruitment and/or retention of subjects.

4) Governance.

a) The Steering Committee, comprised of each of the Principal Investigators of
the Clinical Centers, the Principal Investigator of the Data Coordinating Center,
the NIDDK Project Coordinator, and the Study Chairperson, will have primary
responsibility for developing common clinical protocols, facilitating the conduct
and monitoring of the studies, and reporting the study results.  Each member of
the Steering Committee will have one vote, and all major scientific decisions
will be determined by majority vote of the Steering Committee.  A Chairperson
will be chosen from among the Steering Committee members (but not the Project
Coordinator or Data Coordinating Center director), or alternatively, from among
experts in the field of obesity clinical research who are not participating
directly in the study.  Subcommittees appointed by the Steering Committee and
comprised of Principal Investigators and appropriate staff from the Clinical
Centers and the Data Coordinating Center will be involved in design of the
protocol and the manual of operations, and in ongoing functions of the trial,
such as review of ancillary studies and preparation of publications.  Not all
Clinical Centers will necessarily be represented on all subcommittees.

b) An Executive Committee comprised of the Study Chairperson, the Principal
Investigator of the Data Coordinating Center and the NIDDK Project Coordinator
also will be convened to effect management decisions required between Steering
Committee meetings, as needed for efficient progress of the trial.  The Executive
Committee will report its actions to the Steering Committee on a regular basis. 
Meetings of the Executive Committee will generally be held in the Washington,
D.C. metropolitan area or by conference call.

c) An independent Data Safety and Monitoring Board will be appointed by the
Director, NIDDK, to review periodically the progress of the SHOW trial.  It will
be comprised of experts in relevant medical, psychological, statistical,
operational, and bioethical fields who are not otherwise involved in the study. 
The Data Safety and Monitoring Board will oversee participant safety, evaluate
results, monitor data quality, and provide operational and policy advice to the
Steering Committee and to 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 Digestive Diseases and Nutrition
(or representative) may participate as ex-officio, non-voting members of the
Board. The NIDDK Project Coordinator will serve as executive secretary of the
Data Safety and Monitoring Board.  The Data Safety and Monitoring Board will
review progress and report to the NIDDK at least once per year.

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 the NIDDK member not voting) or by the individual
awardees in the event of an individual disagreement, a second member selected by
NIDDK, and a third member selected by the preceding two members.  These special
arbitration procedures in no way affect the awardee"s 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.


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 is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research," which was published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11,
March 18, 1994, available on the web at:

Investigators may also obtain copies from these sources or from the program staff
or contact person listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.


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.

However, the NIDDK has determined that the SHOW trial does not require inclusion
of children for the following reasons.  One of the trial arms will likely include
weight-loss medications that have not been studied in individuals under the age
of 18 years for any length of time.  Because the risks of taking these
medications have not been assessed in phase II studies in children or
adolescents, it is not known if the risks of medication use outweigh any
potential benefits.  Thus, for pediatric subjects, the proposed study has greater
than minimal risk without the prospect of direct benefit.  Further, since the
cardiovascular disease endpoints that are the primary focus of this study will
not be evident in young individuals, the study does not present an opportunity
to prevent a serious problem affecting the health or welfare of children. 
Therefore, this research cannot be approved for subjects under the age of 18
years on the basis of federal regulation 45-CFR-46 Subpart D.


Prospective applicants are asked to submit, by February 10, 1999, 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 avoid conflict of interest in the

The letter of intent is to be sent to:

Ann A. Hagan, Ph.D.
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8885
FAX:  (301) 480-3505


The research grant application form PHS 398 (rev. 5/95) is to be used in applying
for these grants.  These forms are available at most institutional offices of
sponsored research and from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone 301/710-0267, email:

The RFA label available in the PHS 398 (rev. 5/95) application form must be
affixed to the bottom of the face page of the application.  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.

Applicants must describe plans to accommodate the stated program requirements,
criteria, and staff involvement.  Applicants must address points discussed in the

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

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:

Ann A. Hagan, Ph.D.
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F, MSC 6600
Bethesda, MD  20892-6600

Applications must be received by March 24, 1999.  If an application is received
after that date, it will be returned to the applicant without 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.  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, a process will be used by the initial review group in which
applications receive a written critique and undergo a process in which only those
applications deemed to have the highest scientific merit will be discussed,
assigned a priority score, and receive a second level review by the National
Diabetes and Digestive and Kidney Diseases Advisory Council.

Review Criteria

Applicants are encouraged to submit and describe their own ideas about how best
to meet the goals of the cooperative study a outlined in this RFA, and are
expected to address the points discussed under SPECIAL REQUIREMENTS.  In the
written comments reviewers will be asked to evaluate 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.

o  Significance:  Does this study address an important problem?  If the aims of
the applications are achieved, how will scientific knowledge be advanced?  What
will be the effect of these studies on the concepts or methods that drive this

o  Approach: Are the conceptual framework, design, and methods adequately
developed, well integrated, and appropriate to the aims of the project?  Does the
applicant acknowledge potential problem areas and consider alternative tactics?

Since the final study design will be developed collaboratively by the Steering
Committee for the trial, the peer review group will focus on evidence that the
applicant has carefully thought about the issues involved and possesses the
knowledge necessary to contribute meaningfully to the final design, including
understanding of the scientific, ethical, and practical issues underlying the
proposed study.

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)? 

For the SHOW trial, review under this criterion will focus on the following
questions: Is there documentation of the scientific competence and previous
experience of the Principal Investigator relevant to the operation of a Clinical
Center in the proposed study.  Is there evidence of successful collaborative
interactions with other investigators under a common protocol in a multi-center
clinical trial?

o  Environment: Does the scientific environment in which the work will be done
contribute to the probability of success?  Is there evidence of institutional
support and commitment for the proposed program?

Review of applications for Clinical Center awards also will be based on the
following specific criteria:

o  Scientific and technical merit of the proposed approach to managing the
requirements of the study as outlined in the RFA.

o  Staff Qualifications:  Specific competence and previous experience of
professional, technical, and administrative staff relevant to the operation of
a Clinical Center in the proposed study.  Documented expertise in the design,
delivery, and monitoring of intensive behavioral/lifestyle interventions for the
treatment of obesity.  Demonstrated knowledge of clinical and epidemiological
aspects of obesity and type 2 diabetes appropriate for this study.

o  Recruitment Capability:  Evidence of successful experience in recruitment and
retention of research subjects in multicenter clinical trials, especially
experience in the recruitment of obese and/or diabetic persons. Evidence of
ability to ability to recruit, enroll, and maintain minority subjects in a
randomized trial or other clinical studies at the proposed center.  This includes
documentation of access to an adequate patient population from which to recruit
400 eligible patients over a three-year period.

o  Resources:  Documented adequacy of the proposed facility, space, and resources
for the work proposed.  This includes evidence of an appropriate organizational
structure and institutional support.

o  Data and Sample Management:  Adequacy of plans to ensure accurate collection
and timely transmission of study data and patient samples.  Documented experience
in meticulous and expeditious handling of laboratory specimens and study data.

o  Knowledge of Problems:  Demonstrable knowledge of the potential problems
associated with the conduct of this study and possible solutions.

o  Cooperative Experience: Evidence of prior experience in working
collaboratively in carrying out a developed study protocol.  Evidence of
willingness to work cooperatively in this study.

o  Collaborations between Centers: For those applications that propose
collaborative efforts between two applicants to form a single Clinical Center,
additional factors to be considered would include the advantages of the
collaboration in terms of cost, recruitment, or facilities, the commitment of the
participants to the collaboration, and the adequacy of plans to coordinate

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their subgroups
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 in relation to the
proposed research

o  The adequacy of the proposed protection for humans or the environment, to the
extent they may be adversely affected by the project proposed in the application. 
The initial review group will also examine the safety of the research


Letter of Intent Receipt Date:    February 10, 1999
Application Receipt Date:         March 24, 1999
Peer Review Date:                 June-July 1999
Council Review:                   September 8-9, 1999
Earliest Anticipated Start Date:  September 30, 1999


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

o  Scientific and technical merit of the proposed Clinical Center
o  Availability of funds
o  Availability of appropriate study populations, including racial and ethnic
balance among the populations to be accessed by the potential awardees
o  Geographical distribution of the applicant organizations
o  Program balance, including, in this instance, sufficient compatibility of
features to make a successful collaborative program a reasonable likelihood.
o  Cost


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

A website on the NIDDK homepage containing information pertaining to this RFA is
located at

Answers to frequently asked questions and other information updates concerning
this RFA and the companion RFA for the Data Coordinating Center (DK-98-020) will
be posted on the site as they are developed.  Applicants are highly encouraged
to visit this website on a regular basis in the course of preparing their

Direct inquiries regarding programmatic issues that are not addressed at the
website to:

Barbara Harrison, M.S.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN-18C, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8858
FAX:  (301) 480-8300

Michael J. Galvin, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, EC-23
111 T.W. Alexander Drive, EC-23 (for express/courier service)
Research Triangle Park, NC  27709
Telephone:  (910) 541-7825
FAX:  (919) 541-5064

Robin Hill, Ph.D.
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 8122, MSC-7936
Bethesda, MD  20892-7936
Telephone:  (301) 435-0407
FAX:  (301) 480-1773

Nell Armstrong, Ph.D., RN
Division of Extramural Activities
National Institute of Nursing Research
45 Center Drive, Room 3AN-12, MSC 6300
Bethesda, MD  20892-6300
Telephone:  (301) 594-5973
FAX:  (301) 480-8260

Direct inquiries regarding fiscal and administrative matters to:

Nancy Dixon
Division of Extramural Activities
National Institute od Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN-44C, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8854
FAX:  (301) 480-4237


This program is described in the Catalog of Federal Domestic Assistance No.
93.847 and 93.848.  Awards are made under authorization of the Public Health
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-
158, 42 USC 241 and 285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health Systems
Agency review.

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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on all-cause mortality: A review.  Ann Int Med 1993 119 (7 pt 2): 737-43.

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diabetes:  the potential for prevention.  Lancet 1997, 350: S129-32.

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Circulation 1996, 96(9): 3248-50.

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the United States:  prevalence and trends, 1960-1994.  Int J of Obesity 1998, 22:

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