Full Text HL-97-013 CLINICAL RESEARCH ON COOLEY'S ANEMIA NIH GUIDE, Volume 26, Number 25, August 1, 1997 RFA NUMBER: HL-97-013 P.T. Keywords: National Heart, Lung, and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: October 15, 1997 Application Receipt Date: January 8, 1998 PURPOSE The Blood Diseases Program of the Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute (NHLBI), and the Hematology Program of the Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), invite grant applications for support of research efforts to improve the clinical management of patients with Cooley's anemia (beta-thalassemia). The focus of this initiative is to support clinically-related or translational research. Areas of particular importance include studies on improved methods for the non-invasive measurement of tissue iron burden, alternative approaches to iron chelation therapy, and pharmacologic enhancement of fetal hemoglobin. 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), Clinical Research on Cooley's Anemia, is related to the priority area of maternal and infant health, and diabetes and chronic disabling diseases. 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 202-512-1800). 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 or 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. Domestic applications may include foreign components. FOREIGN INSTITUTIONS: Awards under this announcement may be made to foreign institutions provided the application (1) is of high scientific merit and (2) offers a special opportunity for furthering research programs through the use of unusual talents, resources, populations, or conditions in other countries which are not readily available in the United States or which augment existing U.S. resources. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. MECHANISM OF SUPPORT This RFA will use the NIH Research Project grant (R01) mechanism of support. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Applicants, including those from foreign institutions, may request up to five years of support. It is anticipated that support for this program will begin in July 1998. Administrative adjustments in project period and/or amount may be required at the time of the award. This RFA is a one-time solicitation. Successful applicants, upon completion of their entire project period (up to five years) may submit an unsolicited competing renewal application which will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. FUNDS AVAILABLE Awarding of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. Approximately seven awards will be made. The NHLBI is planning for five grants at a total cost of $2,000,000 for the first year of support for this initiative. The NIDDK will award approximately two grants and has budgeted $800,000 for the first year of support. The specific number of grants to be funded will depend on the merit and scope of the applications received and on the availability of funds. Applicants may request up to a 3 percent inflationary increase per year. Increases above this amount must be specifically justified. CONSORTIUM ARRANGEMENTS If a grant application includes research activities that involve institutions other than the grantee institution, the program is considered a consortium effort. A consortium application should be prepared so that the scientific, fiscal, and administrative considerations are explained fully. The published policy governing consortia is available in the business offices of institutions that are eligible for Federal grants-in-aid. Consult the latest published policy governing consortia before developing the application. If clarification of the policy is needed, please contact Ms. Jane R. Davis (see below). RESEARCH OBJECTIVES Background Cooley's anemia (also called beta-thalassemia major or thalassemia major) and its clinical management has been the subject of an extensive review (1). Cooley's anemia is a genetic blood disease that results in an inadequate production of hemoglobin, the essential oxygen-carrying substance in blood. This causes severe anemia that begins shortly after birth. As a group, thalassemic disorders are one of the most common single-gene genetic diseases worldwide. In the United States, thalassemia mainly affects specific ethnic groups, including people of Mediterranean, Middle Eastern, African, Southeast Asian, Chinese, and Asiatic Indian origin. Individuals affected with Cooley's anemia require frequent and lifelong blood transfusions to sustain life. Because there are no natural means for the body to eliminate iron, the iron contained in the transfused red blood cells builds up over many years and eventually becomes toxic to tissues and organ systems. This excess iron must be removed from Cooley's anemia patients or they may not survive beyond the second decade of life. To accomplish this, patients must use the iron-binding or chelating drug, deferoxamine, that is administered for about 10 hours every day by pumping it through a needle inserted either under the skin or intravenously. Before the introduction of transfusion and chelation therapy, life expectancy for patients with Cooley's anemia was two or three years. Today, the picture is considerably brighter with some patients living into their thirties and beyond. Survival and quality of life depend upon the absence or control of transfusion complications such as infectious diseases (mainly hepatitis and AIDS) and the adequate removal of excess iron. In spite of the increased survival and quality of life, the current treatment modalities are inadequate. Iron-chelation therapy is extremely demanding, and many patients experience considerable discomfort from administration of the drug. In fact, the therapy is so burdensome that many adolescents and teenagers have refused to continue. The prognosis for these noncompliant patients is quite poor. In addition to the physical and psychological burden of therapy, the financial burden on the family is substantial. The cost of transfusions and iron-chelation therapy amounts to about $30,000 per year per patient, and it has been estimated that the total annual Cooley's anemia-related costs may be as much as $100,000 per year per patient. The search for an improved chelator continues. A variety of compounds have been produced and examined as potential oral iron- chelating agents. One of these, deferiprone (1,2-dimethyl-3- hydroxypyridin-4-one, also known as L1, CP20, and DMHP) has been administered to patients in other countries, but some patients have developed neutropenia or agranulocytosis. The magnitude of the risk of agranulocytosis is being evaluated in a multicenter clinical trial in the U.S. and other countries. No published data, however, are available on the long-term efficacy of deferiprone. A recent prospective evaluation of this orally active chelator (2) has suggested that deferiprone may induce decreases in hepatic iron, but continued use does not result in sufficiently diminished levels of hepatic iron, despite the continued urinary excretion of iron in these patients. This implies that deferiprone may be chelating a pool of iron that may not be readily accessible to deferoxamine and that perhaps therapy utilizing a combination of these two chelators may be clinically superior to a single agent. Experts would still argue that deferiprone alone may be quite efficacious in the prevention, rather than the reversal, of iron overload in young children. There is an urgent need to undertake further studies to firmly establish whether this promising oral iron chelator has a role in the management of iron overload in transfusion-dependent anemias. Other iron chelators are being investigated. A single bolus injection of a long-acting form of deferoxamine linked to a polymeric backbone of hydroxyethyl starch has been reported to induce a urinary iron excretion equal to that excreted after several days of deferoxamine infusions. This approach should be investigated further. Results of animal studies have shown that a new, water soluble, synthetic hexadentate chelator (IRC11) having a higher affinity for iron(III) than deferoxamine, but much less toxic, may be useful in the treatment of transfusional iron overload (4). Progress in our ability to reverse the ontogenic switch from fetal to adult hemoglobin, thereby reactivating the expression of the dormant gamma-globin gene, has increased in the past decade. This holds promise that a new, effective form of therapy for thalassemic patients may soon be available. Three classes of drugs, (a) cytotoxic drugs, (b) hematopoietic growth factors and cytokines, and (c) fatty acids, have been shown to enhance fetal hemoglobin production, but their effects have been minimal. However, there are encouraging suggestions that the effects of these drugs may be additive (5). Clinical studies are needed to test the effectiveness and safety of combinations of these drugs and other new hemoglobin switching agents as they are identified. The importance of the accurate assessment of body iron in patients with thalassemia major has been emphasized by advances in understanding the quantitative relationship between iron burden and clinical outcome. The current gold standard for quantifying tissue iron burden still relies on the chemical analysis of liver biopsy specimens. None of the less invasive clinically available methods of evaluating body iron (serum ferritin concentration, transferrin saturation, or urinary iron excretion after administration of a chelating agent) is sufficiently accurate to permit optimal management of iron-chelation therapy. Magnetic susceptometry measurement of hepatic iron using the Superconducting Quantum Interference Device (SQUID) can provide accurate measurements. However, perhaps due to the liquid helium operating temperature and the large size, only two such instruments are available worldwide. Potential approaches to improving the measurement of body iron include refinements in the assay of serum ferritin (such as the measurement of ferritin iron, glycosylated ferritin, H- or L- subunits, and other methods), advances in the quantitative use of magnetic resonance imaging (MRI), and improvement in the availability of magnetic susceptibility by development of instruments utilizing "high-temperature" (liquid nitrogen) superconducting materials. Approaches that would be useful for measuring cardiac iron levels are of particular importance. Transfusion therapy continues to be the centerpiece of the management of thalassemia. The advantages of regular transfusion of red cells are well established and include improved growth and development, decreased enlargement of the liver and spleen, increased longevity and a vastly improved overall well-being. At the same time, transfusions continue to be the source of toxic iron deposits in vital organs. In addition, patients with thalassemia major are at a particularly high risk of contracting transfusion-transmitted diseases because of their lifelong dependence on blood transfusions. The optimal hemoglobin level at which to maintain patients with thalassemia remains uncertain, and new methods for determining the relationship between hemoglobin level and suppression of bone marrow erythropoietic activity may help clinicians adjust the hemoglobin level to achieve the desired results of transfusion therapy while limiting the number of donor exposures and the amount of newly accumulated iron. Alternative approaches to conventional transfusion therapy, including erythrocytapheresis, have been suggested as methods for decreasing the amount of transfusional iron accumulation but currently remain unproven. Clinical studies are needed to improve the safety and effectiveness of transfusion therapy and to develop alternative methods of blood transfusion to reduce the degree of iron loading. This initiative is intended to stimulate the submission of grant applications which address important clinical issues in the management of Cooley's anemia. GRANT APPLICATIONS MUST INCLUDE STUDIES DIRECTLY INVOLVING PATIENTS, either for an intervention protocol or for the development and testing of diagnostic technologies such as noninvasive measurement of tissue iron concentration. Areas of particular importance include, but are not limited to, the following: 1) Clinical studies of more effective iron chelators, new modes of administration of existing chelators, and combinations of chelators. Such studies must include measurement of patient compliance with drug therapy and accurate assessment of changes in body iron stores. 2) Research on improved technology for the non-invasive measurement of tissue iron deposits. 3) Clinical studies of fetal hemoglobin enhancing drugs and combinations of these agents. 4) Clinical studies to improve the safety and effectiveness of transfusion therapy and to develop alternative methods of blood transfusion to reduce the degree of iron loading. The demographics of beta-thalassemia in the United States have been changing because of the large increases in the Asian population in the last ten years. Therefore, applicants are encouraged to include patients with hemoglobin E beta-thalassemia, hemoglobin H, and hemoglobin H-Constant Spring genotypes if their inclusion would not diminish the scientific merit of the proposed clinical study. References (1) "Thalassemia Management I," Seminars in Hematology, P Beris, Ed., Vol 32, No 4 (October), 1995 and "Thalassemia Management II," Seminars in Hematology, P Beris, Ed., Vol 33, No 1 (January), 1996. (2) Olivieri NF, Long-term follow-up of body iron in patients with thalassemia major during therapy with the orally active iron chelator deferiprone (L1). BLOOD 88 (Suppl. 1):1229a, 1996. (3) Olivieri NF, Nisbet-Brown E, Srichairatanakool S, Dragsten P, Hallaway P, Hedlund B, Porter JB. Studies of iron excretion and non- transferrin-bound plasma iron (NTBPI) following a single infusion of hydroxyethyl starch-deferoxamine (HES-DFO): A new approach to iron chelation therapy. BLOOD 88 (Suppl. 1):1228a, 1996). (4) Hershko C, Rivkin G, Link G, Simhon E, Cyjon RL, Klein JY. IRC11, a new synthetic chelator with selective interaction with catabolic red blood cell iron. BLOOD 88 (Suppl. 1):1951a, 1996. (5) Olivieri NF, Rees DC, Ginder GD, Thein SL, Waye JS, Chang L, Brittenham GM, Dover GJ, Weatherall DJ. First report of long-term elimination of red cell transfusions in thalassemia major through augmentation of fetal hemoglobin with sodium phenylbutyrate (SPB) and hydroxyurea (HU). BLOOD 88 (Suppl. 1):1227a, 1996. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI and the NIDDK will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. In the budget for the grant application, applicants should request travel funds for a 1-day meeting each year, most likely to be held in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in these 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 subpopulations 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 new 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 have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide to Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by October 15, 1997, 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 staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent may also be helpful to the applicant since it may alert NHLBI staff to the possibility of an application being unresponsive to the goals of the RFA. In such an instance, the applicant would be notified before preparing the application. The letter of intent is to be mailed, or faxed, to: Dr. C. James Scheirer Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 E-mail: James_Scheirer@NIH.GOV APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone: 301-710-0267, E-mail: ASKNIH@odrockm1.od.nih.gov; and from the program staff listed under INQUIRIES. The RFA label found in the PHS 398 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 2a of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application and three signed, photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to Dr. C. James Scheirer, at the address given above in the section on LETTER OF INTENT. Applications must be received by January 8, 1998. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) 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. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and for responsiveness by the NHLBI. Incomplete applications will be returned to the applicant without further consideration. If NHLBI staff find that the application is not responsive to the RFA, it will be returned 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 in accordance with NIH peer review procedures. As part of the initial merit review, all applications will undergo a peer review streamlining process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory Councils of the NHLBI and the NIDDK. A written critique will be provided for all applications, including those that are not discussed and not scored. The NIH will withdraw from further competition those applications that were unscored and the applicant Principal Investigator and institutional official will be notified. The personnel category will be reviewed for appropriate staffing based on the requested percent effort and any changes requested in future years. The total budget request will be reviewed for consistency with the proposed methods and specific aims. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the recommended scope of the project. 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 the GCRC program director could be included with the application. Peer 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 judging the likelihood that the proposed research will have a substantial impact on the pursuit of these goals and those of the RFA, the reviewers will address each of the listed criteria, and consider them in assigning the overall priority score, weighting them as they feel appropriate for each application. Please note that your grant application may not need to be strong in all categories to be judged likely to have a 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 the 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 proposed study 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 performed 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 applicant institutional support? The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other applications submitted in response to this RFA. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priority. Schedule Letter of Intent Receipt Date: October 15, 1997 Application Receipt Date: January 8, 1998 Initial Review: March 1998 Review by NHLBI and NIDDK Advisory Councils: May 1998 Anticipated Award Date: July 1, 1998 INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding scientific and programmatic issues to either of the Program staff below. However, for specific questions regarding the responsiveness of the planned research grant application to the goals of this RFA, please contact the NHLBI Program Administrator. Dr. Helena O. Mishoe Blood Diseases Program Division of Blood Diseases and Resources, NHLBI 6701 Rockledge Drive, Room 10156 Bethesda, MD 20892-7950 Telephone: (301) 435-0050 FAX: (301) 480-0868 E-mail: helena.mishoe@nih.gov or Dr. David G. Badman Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-13C MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7717 FAX: (301) 480-3510 E-mail: David_Badman@nih.gov Direct inquiries regarding fiscal matters to: Ms. Jane R. Davis Grants Management Office National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0166 FAX: (301) 480-3310 E-mail: jane_davis@nih.gov or Aretina Perry-Jones Division of Extramural Activities, NIDDK 45 Center Drive, Room 6AN-38B, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8862 FAX: (301) 480-3504 E-mail: PerryA@extra.niddk.nih.gov AUTHORITY AND REGULATIONS The programs of the Division of Blood Diseases and Resources, NHLBI, and the Division of Kidney, Urologic and Hematologic Diseases, NIDDK are described in the Catalog of Federal Domestic Assistance Nos. 93.839 and 93.849, respectively. Awards are made under the authority of the Public Health Service (PHS) Act, Section 301 (42 USC 241) and administered under PHS grant policies and Federal regulations, most specifically 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. 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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