Full Text DK-93-11 VANADIUM SALTS IN THE CLINICAL TREATMENT OF DIABETES MELLITUS NIH GUIDE, Volume 21, Number 42, November 20, 1992 RFA: DK-93-11 P.T. 34 Keywords: Diabetes Chemotherapeutic Agents Clinical Trial Metabolism Toxicology National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: February 18, 1993 Application Receipt Date: March 17, 1993 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites investigator-initiated research grant applications to study the effects of vanadium salts as potential therapeutic agents for the treatment of diabetes mellitus. A significant amount of prior research in experimental animals, isolated tissues, and cell preparations has strongly suggested that various forms of vanadium have a beneficial impact on the abnormal metabolic state associated with this disease. This solicitation intends to support preliminary studies of efficacy, dosimetry, and toxicity in human subjects with diabetes. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Vanadium Salts in the Clinical Treatment of Diabetes Mellitus, is related to the priority area of diabetes and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1). through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202/783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit or non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Minority individuals and women are encouraged to submit as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research grant (R01). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for applications submitted in response to the present RFA may not exceed two years. The anticipated award date is September 30, 1993. 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. In order to adhere to prudent principles of cost-containment, requested direct costs must not exceed $160,000 per year for any single application. Applications exceeding this limit will not be reviewed as part of this RFA. With respect to post-award administration, the current policies and requirements that govern the research grant programs of the NIH will prevail. FUNDS AVAILABLE A total of up to $500,000 in first year and $500,000 in the second year will be committed by the NIDDK to fund applications submitted in response to this RFA. The NIDDK plans to make one to three awards in FY 93 contingent on the receipt of highly meritorious applications in response to this solicitation. The award of grants pursuant to this RFA is contingent on the availability of funds for this purpose. RESEARCH OBJECTIVES Background The term "diabetes mellitus" encompasses a group of disorders characterized by abnormal metabolism of carbohydrates, lipids, and proteins. The classical clinical manifestations of diabetes include chronic elevations of blood glucose levels and a defined constellation of long-term sequelae. Two major forms of diabetes are recognized. Insulin-dependent diabetes mellitus (IDDM) is the result of the virtually total destruction of the insulin-producing beta cells of the pancreas, usually by an autoimmune process of still obscure pathogenesis. The existing treatment of this form of diabetes requires insulin replacement therapy. Non-insulin-dependent diabetes mellitus (NIDDM) appears to be the result of both significant resistance by the relevant tissues to the action of insulin and the coincident inability of the pancreatic beta cells to sufficiently compensate for this resistance by increasing secretion. Current treatment for this form of diabetes includes lifestyle modification (i.e., diet, exercise, weight loss) to ameliorate insulin resistance, oral hypoglycemic agents to stimulate insulin secretion and perhaps improve insulin resistance, and insulin replacement therapy, if necessary. Vanadium, a trace metal for a broad range of organisms, including humans, has been postulated to be a co-factor for a number of enzymatic processes. Salts of this element have been known for a decade to inhibit the action of a number of phosphatases in vitro. In particular, vanadate has been used frequently in laboratory settings with isolated tissues and cell cultures as a tool in biochemical studies of the mechanisms of insulin action and experimental insulin resistant states. This ion has shown insulinmimetic properties in preparations of muscle, liver, and adipose tissue as well as whole animals with various forms of diabetes. Non-diabetic laboratory animals appear to show much less response. Initial hypotheses to explain this property of vanadate centered around inhibition of tyrosine phosphatase activity associated with the membrane-bound insulin receptor. Although such inhibition occurs, this does not appear to adequately account for the actions of vanadate to induce insulin-like responses. Several research groups are presently exploring possible post-receptor mechanisms for a definitive answer to this question. Despite the lack of consensus on the precise biochemical mechanism of action for vanadate, it is clear that a broad array of cellular and physiologic processes are modified in an insulinmimetic pattern. These include glycemia, transmembrane glucose transport, glucose utilization, glycolysis, gluconeogenesis, glycogen metabolism, fatty acid and lipid metabolism, and bile acid metabolism in a number of different laboratory preparations and models of diabetes. The magnitude and universality (i.e., across tissues, across species, across diabetes type or model) of these effects are still being debated in the literature. In addition, vanadium can exist in a number of oxidation states (both cationic and anionic) and the state most relevant to insulin action is not established. Before embarking on human studies, it will be important to consider the known and potential toxicities of vanadium. There is a growing literature on the toxicology of this heavy metal which has been identified as a pollutant byproduct of coal combustion with significant health risks. Most of this work concerns the impact of pulmonary exposure through aerosols, but systemic effects after absorption have been documented in the kidney, bone, and blood cells. The oxidative state of vanadium may relate to toxicity, with some ions being less detrimental. Therefore, clinical studies of any vanadium compound with regard to diabetes will need to carefully monitor for incipient toxicity. Scope The objective of this RFA is to stimulate investigator-initiated research designed to provide feasibility data on the clinical utility of vanadium-containing compounds for the treatment of diabetes mellitus in humans. Therefore, all applications in response to this RFA must primarily concern the clinical study of patients with this disease (NIDDM and/or IDDM) and may include normal (non-diabetic) volunteers as appropriate to the experimental design. Relevant research topics listed below are examples and should not be construed as required or limiting. Responsive applications to this solicitation include: o placebo controlled, double-blind comparisons of alternative treatments with vanadium salts for diabetes mellitus o assessment of metabolic effects of vanadium salts in human subjects including dose-response relationships o studies of therapeutic combinations including vanadium salts o toxicologic assessments of oral vanadium salts in humans with diabetes STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues must be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 (rev. 9/91) in Sections 1-4 of the Research Plan and summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States' racial/ethnic minority population (i.e., Native Americans [including American Indians or Alaskan natives], Asian/Pacific islanders, blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of disease, disorders or conditions, included, but not limited to, clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the Unites States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Potential applicants are strongly encouraged to submit a letter of intent by February 18, 1993. The letter of intent is to include: (1) name of the Principal Investigator/program director, and principal collaborators, (2) descriptive title of the potential application, (3) identification of the organization(s) involved, and (4) 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 to avoid conflict of interest in the review. The letter of intent is to be sent to:, Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 605 Bethesda, MD 20892 Telephone: (301) 496-7083 FAX: (301) 402-1277 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone 301/496-7441; and from the NIDDK program administrator named below. The RFA label found in the form PHS 398 application kit must be affixed to the bottom of the face page of the original completed application form. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title, "Vanadium and Clinical Diabetes," and number, "DK-93-11," must be typed on line 2a of the face page of the application form, and the YES box must be marked. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center of Research Resources may wish to identify the Center as a resource for conducting the proposed research. If so, a letter of agreement from the GCRC Program Director should be included in the application material. Applications must be received by March 17, 1993. If an application is received after this date, it will be returned to the applicant without review. Submit a signed original of the application, including the Checklist, and three signed photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must also be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Westwood Building, Room 605 Bethesda, MD 20892 The Division of Research Grants (DRG) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of the applications already reviewed, but such application must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the DRG and responsiveness by the NIDDK. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, NIDDK staff will contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited application at the next review cycle. Applications may be triaged by an NIDDK peer review group on the basis of relative competitiveness. The NIDDK will withdraw from further competition those applications judged to be non-competitive for award and notify the applicant Principal Investigator and Institutional official. Those applications judged to be competitive will undergo further scientific merit review. Those applications that are complete and responsive will be evaluated in accordance with the criteria stated below for scientific/technical merit by an appropriate peer review group convened by the NIDDK. The second level of review will be provided by the National Diabetes and Digestive and Kidney Diseases Advisory Council. Review criteria for RFAs are generally the same as those for unsolicited research grant applications. o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA The anticipated date of award is September 30, 1993. 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 Programmatic priorities of the NIDDK INQUIRIES Inquiries regarding programmatic issues related to this announcement may be directed to: Joan T. Harmon, Ph.D. Executive Director, Diabetes Research Program Diabetes Programs Branch, DDEM National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 622 Bethesda, MD 20892 Telephone: (301) 496-7731 FAX: (301) 480-0383 Inquiries regarding fiscal matters may be directed to: Betty Bailey Grants Management Specialist Grants Management Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 649 Bethesda, MD 20892 Telephone: (301) 496-7467 FAX: (301) 496-9721 Schedule: Letter of Intent: February 18, 1993 Application Receipt Date: March 17,1993 Initial Review: June/July 1993 NIDDK Advisory Council Review: September 1993 Anticipated Award Date: September 30, 1993 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847. Awards are made under the authority of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and federal regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. .
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