TREATMENT OF HAART-ASSOCIATED METABOLIC CHANGES IN PATIENTS WITH HIV INFECTION Release Date: July 17, 2001 RFA: RFA-DK-02-006 National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov) National Heart, Lung and Blood Institute (http://www.nhlbi.nih.gov) Letter of Intent Receipt Date: February 21, 2002 Application Receipt Date: March 21, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. USE THE MODULAR BUDGET INSTRUCTIONS THAT BEGIN ON PAGE 13 IN THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.pdf. PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart, Lung and Blood Institute (NHLBI) seek applications to develop and test strategies for treating the metabolic complications associated with anti-retroviral drug therapy in patients with HIV infection. In recent years, the advent of highly active anti-retroviral therapy (HAART) has dramatically improved the survival of patients infected with HIV. Despite the benefits of the new anti-retroviral therapies, HAART has been associated with a variety of metabolic complications -- including dyslipidemia, insulin resistance and abnormal distribution of body fat (lipodystrophy) -- all of which are major risk factors for the development of other serious diseases, such as diabetes and cardiovascular disease. Of particular concern for many patients has been the problem of lipodystrophy, characterized by increased deposition of fat in the abdomen and trunk, and/or loss of fat in the face and extremities. Distress over these often disfiguring changes has caused some patients to stop taking anti-viral medications. This RFA solicits clinical studies to 1) test the efficacy, in patients infected with HIV, of agents currently approved for the treatment of dyslipidemia, insulin resistance or diabetes, and osteoporosis, and 2) develop and test novel treatment approaches to HAART-associated metabolic changes, including lipodystrophy. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Treatment of HAART-Associated Metabolic Changes in Patients with HIV, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) and the Exploratory/Development Research Grant (R21) award mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an R01 application submitted in response to this PA may not exceed 5 years. The R21 awards are to demonstrate feasibility and to obtain preliminary data testing innovative ideas that represent clear departure from ongoing research interests. These grants are intended to 1) provide initial support for new investigators, 2) allow exploration of possible innovative new directions for established investigators, and 3) stimulate investigators from other areas to lend their expertise to research within the scope of this solicitation. Applicants for the R21 must limit their requests to $150,000 direct costs per year and are limited to two years. These R21 grants will not be renewable, continuation of projects developed under this program will be through the regular research grant (R01) program. Applicants from institutions which have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2002. FUNDS AVAILABLE For fiscal year 2002, the NIDDK intends to commit approximately $2 million and the NHLBI intends to commit approximately $500,000 to fund 4-10 grants in response to this RFA. An applicant may request a project period of up to 5 years for R01s and up to two years for R21s. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NIDDK and the NHLBI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES Background In recent years, the advent of highly active anti-retroviral therapy (HAART) has dramatically improved the survival of patients with HIV infection. Despite the clear benefits of the new anti-retroviral therapies, HAART has been associated with a variety of metabolic complications -- including dyslipidemia, insulin resistance and abnormal distribution of body fat (lipodystrophy). These metabolic abnormalities represent major risk factors for the development of other serious diseases, such as diabetes and cardiovascular disease. Even more recently, reports of clinically significant osteopenia have been emerging in HAART-treated patients. Initial attention focused on protease inhibitors as the cause of these metabolic complications, however, the protease inhibitors are frequently used in combination with nucleoside and non-nucleoside reverse transcriptase inhibitors, making it difficult to pinpoint the offending agent. In addition, metabolic complications have emerged in patients who are not being treated with protease inhibitors. Lipodystrophy, characterized by increased deposition of fat (lipohypertrophy) in the abdomen and trunk, and/or loss of fat (lipoatrophy) in the face and extremities, appears to occur commonly in patients on HAART. Currently, it is not clear whether abdominal lipohypertrophy is simply accompanied by peripheral lipoatrophy, or whether these changes constitute two separate entities. The lipodystrophic changes have been a particular issue for many affected individuals. In addition to concerns over potential long-term health implications of these body composition changes, distress over these often disfiguring changes has caused some patients to stop taking anti- viral medications. HAART has also been increasingly associated with hyperinsulinemia and impaired glucose tolerance, to date, frank diabetes has been reportedly less frequently. However, concern about eventual progression to diabetes is real, particularly in those patients who also have accumulation of abdominal (particularly visceral) fat. Patients receiving HAART frequently develop hypertriglyceridemia, which can be extreme, as well as hypercholesterolemia. Elevated total and LDL-cholesterol levels, which occur following the institution of HAART, may be superimposed on low HDL-cholesterol levels, which have been described in HIV-infected patients prior to initiating any therapy. In non-HIV-infected individuals, co-existence of dyslipidemia and insulin resistance/diabetes confers additive risk for the development of atherosclerotic heart disease, making these HAART-associated side effects a serious potential public health concern. Recently, an increasing number of case reports, as well as several small clinical studies, have documented the development of osteoporosis and osteopenia, often associated with fractures, in patients on HAART. Large epidemiologic studies are currently ongoing to better describe the metabolic changes associated with HAART and understand whether particular drugs, or classes of drugs, are the etiologic agent(s) of these changes. In addition, a large research effort is aimed at understanding the molecular mechanism(s) by which anti-retroviral drugs might lead to these metabolic abnormalities. A long-term goal of such research might be the development of new, highly active anti-HIV drugs that lack these adverse metabolic consequences. In the meantime, it is essential to develop strategies to improve lipid levels, insulin sensitivity and body fat distribution, and to minimize bone loss, in order to enhance patient compliance and decrease the risk for future disease. The safety and efficacy of lipid lowering drugs or diabetes medications have not been extensively studied in patients infected with HIV and/or receiving HAART. It is not known whether adverse drug interactions might affect efficacy and safety, or whether the underlying infection with HIV (or other opportunistic) infections, might affect treatment success. For example, the metabolism and clearance of some statins may be affected by concomitant use of protease inhibitors. Some available drugs (e.g., metformin, thiazolidinediones) will be contraindicated because of co-existing renal or liver disease in patients with AIDS. In addition, attention must be paid to other risk factors for diabetes and cardiovascular disease, such as smoking, physical inactivity, diet and hypertension. Objectives and Scope This RFA solicits clinical studies to 1) test the efficacy, in patients infected with HIV, of agents currently approved for the treatment of dyslipidemia, insulin resistance or diabetes, and osteoporosis/osteopenia, and 2) develop and test novel treatment approaches to the metabolic consequences of anti-HIV therapy, including lipodystrophy. Appropriate topics for investigation under this RFA would include but are not limited to: o Studies to examine the effects of currently available pharmacotherapies for the treatment of insulin resistance or diabetes, hypercholesterolemia and/or hypertriglyceridemia, and osteoporosis in the metabolic syndromes associated with HAART, o Studies to identify potential drug interactions between HAART and current pharmacotherapies for the treatment of insulin resistance or diabetes, hypercholesterolemia and/or hypertriglyceridemia, and osteoporosis, o Studies to test agents that affect fat deposition and/or metabolism for the treatment of HAART-associated lipodystrophy, o Studies to identify and test new therapies to prevent or reverse the metabolic complications associated with HAART, o Studies to evaluate the efficacy of diet and exercise alone, or in combination with medication, in reversing dyslipidemia and insulin resistance/diabetes in patients on HAART, o Studies to evaluate whether switching anti-HIV drugs is an effective approach to the treatment of metabolic changes. SPECIAL REQUIREMENTS Upon initiation of this program, the NIDDK and the NHLBI plan to hold annual meetings to encourage exchange of information among investigators who participate in this program. A goal of these meetings would be to foster collaborative efforts among program grantees, including the sharing of resources to enhance productivity. Applicants must budget for travel funds that will allow principal investigators and other key research scientists to participate in these one-day meetings in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in such meetings. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. LETTER OF INTENT Prospective applicants are asked to submit, by February 21, 2002, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIDDK staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.pdf is to be used in applying for these grants. This version of PHS 398 is available in an interactive, searchable PDF format. Although applicants are strongly encouraged to begin using the 5/2001 revision of the PHS 398 as soon as possible, the NIH will continue to accept applications prepared using the 4/1998 revision until January 9, 2002. Beginning January 10, 2002, however, the NIH will return applications that are not submitted on the 5/2001 version. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. STEP-BY-STEP INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.pdf is to be used in applying for these grants, with the modifications noted below. Applicants are permitted, however, to use the 4/1998 revision of the PHS 398 for scheduled application receipt dates until January 9, 2002. If you are preparing an application using the 4/1998 version, please refer to the step-by-step instructions for Modular Grants available at http://grants.nih.gov/grants/funding/modular/modular.htm. The RFA label available in the PHS 398 (rev. 5/2001) application form (http://grants.nih.gov/grants/funding/phs398/labels.pdf) must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. 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: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Applications must be received by the application receipt date listed in the heading of the RFA. If an application is received after that date, it will be returned to the applicant without review. Supplemental documents containing significant revision or additions will not be accepted, unless applicants are notified by the Scientific Review Administrator. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications previously reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the NIDDK and the NHLBI Advisory Councils. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o Adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration to the proposed research. o The adequacy of the proposed protection of humans, animals, or the environment, to the extent that they may be adversely affected by the project proposed in the application. o Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries which are not readily available in the United States or which provide augmentation of existing U.S. resources. Schedule Letter of Intent Receipt Date: February 21, 2002 Application Receipt Date: March 21, 2002 Peer Review Date: July 2002 Council Review: September 2002 Earliest Anticipated Start Date: September 30, 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit as determined by peer review, o Availability of funds, o Programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Barbara Linder, M.D, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 699 MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-0021 FAX: (301) 480-3503 E-mail: bl99n@nih.gov Deborah Applebaum-Bowden, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10184, MSC 7956 Bethesda, MD 20892-7956 Telephone: (301) 435-0550 FAX: 301/480-2858 Email: da40q@nih.gov Direct inquiries regarding fiscal matters to: Charlette Kenley Division of Extramural Activities Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 723 MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8847 FAX: (301) 480-3504 E-mail: ck128k@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847 and 93.837. Awards are 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 NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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