FEASIBILITY PROJECTS TO TEST STRATEGIES FOR PREVENTING OR SLOWING THE PROGRESSION OF DIABETIC NEPHROPATHY Release Date: September 17, 2001 RFA: RFA-DK-02-025 National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov) Letter of Intent Receipt Date: January 17, 2002 Application Receipt Date: February 14, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) seeks applications for studies to test new strategies for prevention or treatment of diabetic nephropathy. Through large scale interventional trials, it has been established that blockade of the renin-angiotensin system (RAS) and good glycemic control both slow progression of diabetic nephropathy. Nonetheless, many patients with diabetes develop progressive renal disease in spite of adequate management of these factors, and new strategies, both to prevent disease and to slow its progression, are needed urgently. This RFA invites clinical research applications for trials using novel agents or drug combinations in patients to prevent the appearance or slow the progression of diabetic nephropathy. The goal of this initiative is to evaluate therapies that might potentially be taken to large, phase III interventional trials. In the pilot phase studies supported by this RFA, use of urine protein measurements, either albumin or total protein, as a surrogate marker for disease progression is appropriate. Applicants should note that a companion RFA DK-02-016 Surrogate Endpoints for Diabetic Microvascular Complications invites applications to improve surrogate endpoints in clinical trials for diabetes complications. It is assumed that, unless contraindicated, proteinuric subjects in the control and trial groups will be treated with RAS blockade as the current standard of care, and that the studies will examine either addition of alternate agents or incremental effects of RAS blockade. Enrollment strategies should emphasize a patient population in young- to mid-adulthood and strong representation of patients with type 1 diabetes mellitus. If indicated, assessment of the impact of the intervention on retinopathy or neuropathy could be incorporated into a trial design. 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 RFA, Feasibility Projects to Test Strategies For Preventing or Slowing the Progression of Diabetic Nephropathy, is related to the priority area of diabetes and chronic disabling conditions. 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) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 2 years or $500,000 direct costs in any year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions). Applications with requested budgets up to $250,000 per budget year must use the modular grants format. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the NIH. Complete and detailed instructions and information on Modular Grant applications have been incorporated into the PHS 398 (rev. 5/2001). Additional information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE For fiscal year 2002, the NIDDK intends to commit approximately $2 million to fund up to six new grants in response to this RFA. An applicant may request a project period of up to two years. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NIDDK 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. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Background In the United States, diabetes is the leading cause of new cases of end stage renal disease. Identification of patients at risk for the development of diabetic nephropathy, with the hope of early intervention, is a public health priority. Patients with type 1 diabetes mellitus have a 20 to 40% lifetime risk of developing renal failure. Low levels of albumin excretion in the urine (microalbuminuria) are established as a strong risk factor for later development of diabetic nephropathy. Overt proteinuria is the next manifestation and usually precedes notable reductions in glomerular filtration rate. However, the predictive value of microalbuminuria for the progression to overt nephropathy is not precise. Thus, it might be desirable to intervene in patients with normal albumin excretion, if patients at high risk for the development of nephropathy could be identified. Growth factors and their receptors have been implicated in the development of nephropathy, and some studies indicate that urinary excretion of TGF-beta and other potential mediators of renal disease might be early markers of nephropathy. Other potential mediators of progressive renal disease, such as advanced glycation end products and their receptors, tissue inhibitors of metalloproteinases, cytokines and chemokines and their receptors, and members of intracellular signaling cascades have been identified, but few studies have attempted inhibition of their actions. Several trials have established the efficacy of angiotensin converting enzyme inhibitors (ACEIs) in slowing the progression of diabetic nephropathy to end-stage renal disease. Initial results have suggested that angiotensin receptor blockers (ARBs) might also have utility in prevention of diabetic nephropathy or amelioration of its course. Addition of spironolactone to treatment of patients with cardiovascular disease has been shown to improve outcomes. Relatively few data are available regarding the risks and benefits associated with treatment with combinations of ACEIs and ARBs, or with combinations of these agents and spironolactone in patients with diabetic nephropathy. In addition, little is known regarding the effect of treatment of anemia and the effects of treatment with erythropoietin and iron on outcomes in patients with diabetic nephropathy with renal insufficiency. Objectives and Scope This RFA invites clinical research applications to develop approaches for clinical trials of novel therapies for patients with diabetic nephropathy, and to conduct preliminary pilot and feasibility trials of such therapies. The overall goal of this RFA is to evaluate therapies that might potentially be taken to large, phase III interventional trials, and to ensure that adequate preliminary data is available to design such trials. Appropriate topics for investigation under this RFA would include: Studies to identify novel agents to add to standard therapy of diabetic nephropathy, Studies of strategies to prevent the development of microalbuminuria, Studies to evaluate the effects and safety of combination therapy directed against the renin-angiotensin-aldosterone axis, Studies comparing the effectiveness of different strategies for RAS blockade, Studies to gather preliminary information regarding potential interactions of therapy directed toward diabetic nephropathy with the treatment of anemia, and Studies to gather preliminary information regarding effect sizes to be expected from such interventions. Investigators can budget assessment of disease markers into budgets for these projects. However, if extensive evaluation of novel disease markers is anticipated, applicants are encouraged to submit a separate application focusing on the surrogate endpoints for the proposed trial, as outlined in RFA-DK-02-016 Surrogate Endpoints for Diabetic Microvascular Complications . 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. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS All investigators proposing research involving human subjects should read the policy that was published in the NIH Guide for Grants and Contracts, June 5, 2000 (Revised August 25, 2000), and is available at the following URL address http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. 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. 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 January 17, 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: Francisco O. Calvo, Ph.D. 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.html are to be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable PDF format. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. SPECIFIC 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.html is to be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. 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: Francisco O. Calvo, Ph.D. 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 appropriate national advisory council or board. 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. Since these applications are to support studies of two years duration, they are to be designed primarily as pilot studies to obtain preliminary data to be used in more definitive, larger future studies. o 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? o 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? o 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? 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)? o 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 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: January 17, 2002 Application Receipt Date: February 14, 2002 Peer Review Date: August 2002 Council Review: September 2002 Earliest Anticipated Start Date: September 30, 2002 AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review, o Availability of funds, o Program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Thomas Hostetter, M.D. Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Rm. 625 Bethesda MD 20892-5458 Telephone: (301) 594-8864 FAX: (301) 480-3510 E-mail: th192u@nih.gov Direct inquiries regarding fiscal matters to: Teresa Farris Marquette Grants Management Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 728 MSC Bethesda, MD 20892-5458 Telephone: (301) 594-7628 FAX: (301) 480-3504 E-mail: tf102y@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.849. Awards are made under authorization of sections 301 and 405 of the Public Health Service Act as amended (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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