STUDY OF HEALTH OUTCOMES OF WEIGHT-LOSS (SHOW) 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) P.T. 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 PURPOSE 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). 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 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 http://www.crisny.org/health/us/health7.html. ELIGIBILITY REQUIREMENTS 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. MECHANISM OF SUPPORT 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 Statement. 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. FUNDS AVAILABLE 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. RESEARCH OBJECTIVES 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 25.0 29.9) 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 ambiguous. 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 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 features. 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 control. 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 evaluation. 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 results. SPECIAL REQUIREMENTS 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 application. 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 treatment. 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 recruitment. 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: http://www.niddk.nih.gov/fund/fund.htm 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 available. 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 serve. 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 documented. 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 populations. 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 meetings. NOTE: 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. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification 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: http://www.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html 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. NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. 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. LETTER OF INTENT 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 review. 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 APPLICATION PROCEDURES 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: GrantsInfo@nih.gov. 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 SPECIAL REQUIREMENTS section of this RFA. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At time of submission, two additional copies of the application must be sent to: 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, 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 field? 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 efforts. 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 environment. Schedule 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 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 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 http://www.niddk.nih.gov/fund/fund.htm 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 applications. 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 Email: HarrisonB@extra.niddk.nih.gov 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 Email: galvin@niehs.nih.gov 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 Email: robin_hill@nih.gov 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 Email: nell_armstrong@nih.gov 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 Email: DixonN@extra.niddk.nih.gov AUTHORITY AND REGULATIONS 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. References Andres R, Muller DC, and Sorkin JD. Long-term effects of change in body weight on all-cause mortality: A review. Ann Int Med 1993 119 (7 pt 2): 737-43. Eastman RC and Keen H. The impact of cardiovascular disease on people with diabetes: the potential for prevention. Lancet 1997, 350: S129-32. Eckel R, American Heart Association Science Advisory: Obesity and Heart Disease. Circulation 1996, 96(9): 3248-50. Flegal KM, Carroll MD, Kuczmarski RJ, and Johnson CL. Overweight and Obesity in the United States: prevalence and trends, 1960-1994. Int J of Obesity 1998, 22: 3947. Hadden DR, Blair ALT, Wilson EZ, et al. Natural history of diabetes presenting age 40-69 years: a prospective study of the influence of intensive dietary therapy. Quart J Med 1986, 59: 579-98. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from Coronary Heart Disease in Subjects with Type 2 Diabetes and in Nondiabetic Subjects with and without Prior Myocardial Infarction. N Eng J Med 1998, 339(4): 229-34. Hollander PA, Elbein SC, Hirsch IB, et al. Role of Orlistat in the Treatment of Obese Patients with Type 2 Diabetes. Diabetes Care 1998, 21(8): 1288-1294. Johannes L and Stecklow S. Dire Warnings About Obesity Rely on a Slippery Statistic. Wall Street Journal, Feb. 9,1998. Kassirer J and Angell, M. Losing Weight An Ill-Fated New Year"s Resolution. N Eng J Med 1998, 338(1): 52-4. Maggio CA and Pi-Sunyer FX. The Prevention and Treatment of Obesity. Diabetes Care 1997, 20(11): 1744-1766. National Diabetes Data Group. Diabetes in America 2nd edition 1995, National Institutes of Health Publication Number 95-1469, Chapter 19 and Appendix 7.11. NHLBI and NIDDK. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. 1998. Available at http://www.nhlbi.nih.gov/nhlbi/cardio/obes/prof/guidelns/ob_home.htm National Task Force on Prevention and Treatment of Obesity. Long-term Pharmacotherapy in the Management of Obesity. JAMA 1996, 276(23): 1907-1915. Sjostrom, L, Rissanen A, Andersen T, et al. Randomized placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet 1998, 352: 167-72. Whelton PK, Appel LJ, Espeland MA, et al. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). JAMA. 1998, 279: 839- 46. Williamson DF, Pamuk E, Thun M, et al. Prospective Study of Intentional Weight Loss and Mortality in Never-Smoking Overweight US White Women Aged 40-64 Years. Am J Epidemiol 1995, 141(12): 1128-41. Williamson DF. Weight Cycling and Mortality: How do the Epidemiologists Explain the Role of Intentional Weight Loss? J Amer Coll Nutr 1996: 15(1): 6-13. Williamson DF, Venkat Narayan KM, and Teutsch SM. The Economic Impact of Obesity in the United States: Whither? Obesity Research 1998, 6(2): 173-5. Wolf AM, Colditz GA. Current estimates of the economic cost of obesity in the United States. Obesity Research 1998, 6: 97-106. Yanovski, SZ, Bain RP and Williamson, DF. Report of the NIH-CDC workshop on the feasibility of conducting a randomized clinical trial to evaluate the long-term health impact of intentional weight loss in obese persons. Am J Clin Nutr, in press.

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