Full Text DK-94-004 MORTALITY AND MORBIDITY IN HEMODIALYSIS PATIENTS: FULL-SCALE TRIAL NIH GUIDE, Volume 22, Number 45, December 17, 1993 RFA: DK-94-004 P.T. 34 Keywords: 0715133 Clinical Trial Cardiovascular Diseases Infectious Diseases/Agents National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: February 24, 1994 Application Receipt Date: March 22, 1994 PURPOSE The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), invites cooperative agreement applications from investigators to serve as a Clinical Center and/or Data Coordinating Center for the full-scale phase of the "Mortality and Morbidity in Hemodialysis Patients (MMHD)" Trial. The MMHD Trial is a prospective, multicenter, randomized, two-by-two factorial clinical trial of increased delivered hemodialysis as measured by the formula KT/V ((K is the dialyzer urea clearance (ml/min), t is the treatment time (min), V is the body urea distribution volume (ml)) and high-flux dialysis. The objectives of the study are to reduce mortality and morbidity in hemodialysis patients. Mortality due to all causes is the primary outcome. Secondary outcomes include rate of non-access (vascular) related hospital admissions, cardiovascular events including myocardial infarction, acute angina, and congestive heart failure, occurrence of severe infections, and decline in serum albumin. The protocol for the ongoing MMHD Pilot Study provides details on inclusion and exclusion criteria, baseline and follow-up procedures for participants, and overall organization of the trial. The protocol and sample size requirements were developed by awardees under a cooperative agreement mechanism with NIDDK assistance. It is recommended that applicants obtain a copy of the protocol, available upon request from DKUHD, to assist them in preparing their response to this RFA. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Health People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Mortality and Morbidity in Hemodialysis Patients: Full-Scale Trial, is related to the priority areas 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 Only U.S. organizations are eligible to apply. Domestic applications may not include international components. Applications may be submitted by for-profit and 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. Applications from minority and women investigators and minority institutions are encouraged. Applications from community-based hemodialysis centers alone, or in combination with academic institutions and/or academic affiliated hemodialysis units, are encouraged. The expertise appropriate for this research program for a Clinical Center includes a knowledge of the medical aspects of hemodialysis. Experience in carrying out clinical trials and clinical studies in hemodialysis patients is also important. Skills in management of multicenter clinical trials, establishing and maintaining a large data base, and analysis of complex data sets are appropriate for the Data Coordinating Center. An institution may apply for both a Clinical Center and Data Coordinating Center. However, a specific plan on how the independent operation (i.e., confidentiality of study-wide data) of each unit will be maintained is required. Two separate applications will be required from an institution applying for both a Clinical Center and Data Coordinating Center. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a cooperative agreement (U01), which is an assistance mechanism rather than an acquisition mechanism. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreement(s) are discussed later in this document under the section "Terms and Conditions of Award." FUNDS AVAILABLE The estimated funds (total costs) available for the first year of support for the entire program is approximately 3.65 million dollars. It is anticipated that one award for a Data Coordinating Center for approximately $650,000 (including direct and indirect costs) per year and 15 awards for Clinical Centers will be made. Funding for any single Clinical Center will be no more than $200,000 in total costs for each year. Although this program is provided for in the financial plans of the NIDDK, awards in response to this RFA are contingent on the availability of funds for this purpose. The total project period for applications submitted in response to the present RFA will be seven years. The anticipated award date is September 1994. At this time, the NIDDK anticipates that there will not be a renewed competition after seven years. RESEARCH OBJECTIVES Background I. Mortality The mortality rate of 23.4 percent per year among dialysis patients in the United States is among the highest in developed countries. The U.S. data reports exclude mortality occurring during the first three months of dialysis and probably underestimate the problem. This increased mortality, in fact, represents a trend that began in 1983 and has been steadily worsening since then. End-stage renal disease (ESRD) patients have from 1/4 to 1/5 the life expectancy of the U.S. general population; at age 40, the expected life of an ESRD patient is 8.8 years compared to 37.4 years for the U.S. general population of the same age. Factors implicated in the worsening mortality rates include the increasing age and number of co-morbid conditions among the hemodialysis population. The mean age of those enrolled into the ESRD registries has increased and 50 percent of new patients are now over 61 years of age. The U.S. also has the highest number of diabetics with ESRD compared to other national registries, and these patients are developing ESRD with more co-morbid conditions than just five years ago. Particularly important co-morbid conditions include cardiovascular diseases, diabetes, and malnutrition. The increasing age and co-morbidity reflect, in part, the high acceptance rate into dialysis programs (151/million/year in 1987). In addition, the high transplant rate (37/million/year in 1987) and the preferential acceptance of younger patients and those with fewer co-morbid conditions for renal transplantation contributes to the demographic characteristics and high mortality of patients remaining on hemodialysis. Finally, racial differences are also evident, as black patients appear to develop ESRD at a higher rate than white patients. II. Adequacy of Dialysis The optimal KT/V for hemodialysis has not been determined. The current recommended KT/V of 1.0, based on the results of the National Cooperative Dialysis Study, corresponds to a urea clearance of only 10 ml/min, which is still far below the normal renal urea clearance of 70-95 ml/min. A report from the United States Renal Data System indicates that prescribed KT/V is greater than 1.0 in only 47 percent of patients in the U.S. Furthermore, mean delivered KT/V, estimated by two different formulas, was only 0.72 and 0.90, respectively. Explanations for the low values for KT/V include inadequate delivery by equipment and staff, and patient non-compliance. These considerations suggest that the high mortality of hemodialysis patients in the U.S. may be related to inadequate dialysis, as judged by KT/V. Of particular importance is the recent recognition that delivery of dialysis above a KT/V of 1.0 may improve survival. However, many of these studies are either retrospective or non-randomized prospective studies, and considerable uncertainty still exists about the optimum level of dialysis. Thus a randomized, controlled clinical trial is necessary to determine whether higher than usually delivered hemodialysis therapy (as measured by KT/V) is beneficial in reducing mortality and morbidity. III. High-Flux Membranes The clinical effects of hemodialysis membranes has also received considerable attention. Conventional cellulosic membranes most frequently used for routine hemodialysis, remove an insignificant fraction of substances with molecular weight over approximately 2,000 daltons. In contrast, the normal kidney excretes and/or catabolizes substances, particularly proteins, with molecular weights up to approximately 60,000 daltons. While high-flux membranes differ in their sieving capacity and ability to adsorb large molecules, those clinically available can remove molecules efficiently of at least the molecular weight of beta-2 microglobulin. Some membranes may even remove substances of molecular weight of 60,000 daltons. In all cases these properties are much closer to those of the intact kidney and very different from conventional membranes. A recent retrospective study showed that patients treated with high-flux dialysis experienced a 76 percent reduction in relative risk of death as compared with patients treated with conventional dialysis. The rate of hospital admissions, however, was not statistically significant. The influence of high-flux membranes on patient mortality and morbidity deserves study in a randomized, controlled clinical trial. MMHD Pilot Study In 1991 the NIDDK released the RFA, "Reduction in Mortality and Morbidity among Hemodialysis Patients: Pilot Study." Four Clinical Centers, one Data Coordinating Center, and one Intervention Coordinating Center were selected to develop the study protocol and carry out a pilot study. The Pilot Study protocol was developed from October 1992 through October 1993. The pilot phase is planned as an extended (6 month, March - August 1994) run-in period during which a small number of patients (N=32) will be randomized, treated and followed-up. It is anticipated that the full-scale trial will begin in September 1994. Goal of the Activity The goal of this RFA is to initiate a collaborative full-scale trial to test whether hemodialysis with an increased KT/V and high-flux dialysis significantly reduces mortality and morbidity among patients receiving this form of therapy. It is also important to evaluate whether these interventions are safe and acceptable to patients. Currently, the protocol stipulates that patients will be randomized to either a KT/V of 1.3-1.5 or a KT/V of 0.9-1.1, calculated from two-pool, variable volume, two-point urea kinetic modeling. Patients will also be randomized to high-flux membranes or low-flux dialysis membranes. High-flux membranes include the following: polysulfone, acrylonitrile (AN69), polymethylmethylacrylate (PMMA), or polyamide. Low flux membranes include cuprophane. To achieve uniformity, standards of care have been defined for several aspects of dialysis therapy and common medical problems of hemodialysis patients. Highest priority will be devoted to maintenance of acceptable blood urea nitrogen, protein, and energy intake; fluid management and estimation of dry weight; treatment of hypertension; dialysis duration (time) and standardization of water and dialysis purity. Standards of care are also defined for the vascular access; anemia; calcium, phosphorus, hyperparathyroidism and bone disease; hyperlipidemia; diabetes; and general health maintenance. Scope of the Activity Nine hundred study participants, recruited by fifteen clinical centers, will be required for the full-scale trial. Thus each Clinical Center is expected to randomize at least 60 study participants during an 18-month initial period of recruitment. In addition, for each study participant who either dies, receives a renal transplant, transfers to a nonparticipating center, or switches to home dialysis or peritoneal dialysis prior to the final year of the study, the Clinical Center is required to recruit a new study participant into the study (so-called "recruit to replace" strategy). Thus a total clinic population of at least 60 randomized study participants will be maintained throughout the period of follow-up. The full-scale study will consist of three phases: (1) an 18-month period of recruitment; (2) a 60-month period of intervention and follow-up and (3) six months for data analysis, close-out of the Clinical Centers, and reporting of results. Unless otherwise noted in this RFA, applicants should prepare their applications using patient eligibility criteria set forth in the MMHD Pilot Study protocol. Major entry and exclusion characteristics are briefly described as follows. The study participants in this trial will be males and females of all races; age greater than 18 years old and less than 75 years old; on in-center hemodialysis three times a week; and on hemodialysis for more than three months. Selected exclusion criteria include patients currently in an acute or chronic care hospital; an interdialytic 24-hour urine collection with a urea clearance greater than 3 ml/min (required if patient has been on dialysis less than two years or urine output greater than 400 ml/day); pregnant; scheduled living related donor renal transplant within the period of the study; current malignancies requiring active chemotherapy or radiation therapy and severe congestive heart failure. Each applicant should demonstrate the ability to follow an established study protocol and manual of operations. Applicants must also demonstrate the ability to recruit and randomize the required number of study participants, be able to implement the various study procedures, and maintain high rates of follow-up during the course of the trial. It will be particularly important to minimize the number of patients transferring to hemodialysis units not under the direct supervision of the Clinical Center medical staff. Applicants must also specify the hemodialysis membrane reuse procedure(s) employed in those units from which patients will be recruited. Study Outline Investigators should develop their applications for the full-scale trial based on the inclusion and exclusion criteria and the general design of the pilot study as outlined in this RFA and the Pilot Study Protocol. It is expected that investigators will carry out the already developed protocol, however, modifications to this protocol are expected. Study Components 1. Clinical Centers A Clinical Center is an institution that is actively involved in the recruitment, evaluation, treatment, and follow-up of study participants. It should consist of an interdisciplinary team of clinical investigators and appropriate personnel, such as a research coordinator, dietitian/data collector, dialysis technician, and clerical staff. Applications for Clinical Centers should provide evidence that the investigators are capable of randomizing at least 60 participants into the study during the 18-month period of recruitment and an ability to "recruit to replace" as described under Scope of Activity. Applicants for the Clinical Centers should describe the target population from which they expect to randomize the required number of study participants. Clinical Centers will be required to submit protocol data expeditiously. The Principal Investigator and Co-Investigators in each Clinical Center should be skilled in collaborative clinical investigation and hemodialysis. There should be evidence of strong institutional support for the Clinical Center, including adequate space in which to conduct clinic activities and office space for staff. An organizational structure for the Clinical Center should be set forth in the application delineating lines of authority and responsibility for dealing with problems in all general areas as well as stated willingness to follow the stated common protocol. The applicant should include a succinct discussion of previous relevant investigational efforts. The applicant also should discuss in detail the recruitment strategies to procure the expected number of randomized participants, approaches to attain high levels of adherence to the intervention, and high rates of follow-up. 2. Central Functions The Data Coordinating Center will have primary responsibility for collecting, editing, storing, and analyzing data generated by the Clinical Centers. This includes data collection for dietary intake of protein and calories. It should be prepared to assume a key role in overseeing implementation and adherence to the protocol, and assuring quality control. The Data Coordinating Center will be expected to provide appropriate biostatistical, data management, and coordination expertise. The Data Coordinating Center also will be expected to provide appropriate detailed reports to the Steering Committee and to the External Advisory Committee at regular intervals and will be responsible for the logistics and planning of meetings of these committees and their subcommittees. Applicants for the Data Coordinating Center should provide a detailed description of prior experience in multicenter studies. 3. Steering Committee The primary governing body of the study will be the Steering Committee comprised of each of the Principal Investigators of the Clinical Centers and the Data Coordinating Center, the Chairperson of the Steering Committee, and the NIDDK Project Coordinator (described in detail under Terms and Conditions). 4. External Advisory Committee An independent committee supported by the NIDDK and composed of experts in nephrology, hemodialysis, biostatistics, clinical trials, and bioethics who are not otherwise involved in the study will be established to review periodically the progress of the study (described in detail under Terms and Conditions). 5. Project Coordinator The Clinical Trials Program Director, Division of Kidney, Urologic and Hematologic Diseases will be the Project Coordinator for the full-scale trial. The Project Coordinator will assist the Steering Committee and External Advisory Committee in carrying out the study (described in detail under Terms and Conditions). Study Phases The randomized full-scale clinical trial will include fifteen Clinical Centers and one Data Coordinating Center for a period of 84 months. It will have the following three phases: 1. Participant Recruitment: 18 months 2. Intervention and Follow-up: 60 months 3. Study Close-Out and Data Analysis: 6 months It is expected that each Clinical Center will randomize 60 participants during an initial 18-month period and "recruit to replace" thereafter. Follow-up procedures will be carried out over a period of 60-months (It is important to note, however, that as participants are randomized, intervention and follow-up will begin immediately). A six-month period is planned for close-out of Clinical Centers, data analysis, and reporting of results. It is expected that all data will be submitted centrally and that access to data and publications will be by the mechanism(s) defined in the protocol. The External Advisory Committee, appointed by the NIDDK, will review progress at least semi-annually and provide advice to the Institute. Guidelines for Budget Preparation by Study Phases Each applicant for a Clinical Center and for the Data Coordinating Center should submit an adequately justified yearly budget for the entire anticipated project period of 84 months. The budgets for each budget period of the study should be clearly delineated. The following information is provided to assist applicants in the preparation of budgets. Detailed budgets will vary according to policies of the applicant and specific needs identified in the response to this announcement. Budget Period Time Period Activity* #1 9/30/94 through 9/29/95 Recruitment, Intervention and Follow-Up #2 9/30/95 through 9/29/96 Recruitment, Intervention and Follow-Up #3 9/30/96 through 9/29/97 Intervention & Follow-Up #4 9/30/97 through 9/29/98 Intervention & Follow-Up #5 9/30/98 through 9/29/99 Intervention & Follow-Up #6 9/30/99 through 9/29/2000 Intervention & Follow-Up #7 9/30/2000 thru 9/29/2001 6 months of Intervention & Follow-Up and 6 months of Close-Out of Clinical Centers/Data Analysis and Reporting of Results *An initial recruitment period of 18 months is delineated to obtain a sample size of 900 among 15 Clinical Centers. However, intervention and follow-up will begin immediately after randomization. In addition, "recruitment to replace" will begin during budget period #1 and continue through 12/31/99, or the mid-point of budget period #6. For a Clinical Center, the budget should request support for the minimum number of full-and/or part-time staff to successfully carry out the trial. A Clinical Center could include a Principal Investigator, Co-Investigator, study coordinator, dietitian/data collector, lead dialysis technician, and data entry clerk. Support for travel for two key investigators to attend quarterly meetings of the Steering Committee should also be included within the budget. Steering Committee meetings will be held in the Washington, D.C. area. Travel for centralized training of the study coordinator, dietitian, lead dialysis technician and data entry clerk must also be budgeted (assume central training to be held in the Washington, DC area). For applications for the Data Coordinating Center, the budget should also include the time and effort of key personnel needed to conduct the trial and the required number and cost of computers to be used at the Clinical Centers for distributed data entry. Travel to the Washington, DC area for External Advisory Committee meetings (two per year), Steering Committee meetings (three per year), site visits (four in year 1 and six in year 2) is also to be included in the budget. The Data Coordinating Center should also budget for travel for the Chairperson of the Steering and Planning Committee (three meetings per year). Terms and Conditions of Award The administrative and funding instrument to be used for this program will be a cooperative agreement (U01), an "assistance" mechanism" (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the Institute Project Coordinator. These special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74, and other HHS, PHS, and NIH grant administration policy statements. 1. Awardee Activities The tasks or activities in which awardees will have substantial and lead responsibilities include protocol revision, patient recruitment and follow-up, data collection, quality control, final data analysis and interpretation, and preparation of publications. The awardee agrees to follow the common protocol and manual of operations developed for the Pilot Study and as amended. The awardees also agree to transmit all study data to a central Data Coordinating Center for combination and analysis. 2. NIDDK Activities The NIDDK Project Coordinator is the Clinical Trials Program Director, Division of Kidney, Urologic and Hematologic Diseases whose function will be to assist the Steering Committee and External Advisory Committee in carrying out the trial. The NIDDK Project Coordinator will assist in quality control, interim data analysis, safety monitoring, and final data analysis and interpretation, preparation of publications, and coordination and performance monitoring. The NIDDK Project Coordinator will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The NIDDK reserves the right to terminate or curtail the study (or an individual award) in the event of a substantial shortfall in participant recruitment, follow-up, data reporting, quality control or other major breach in the program. Early termination may also occur due to adverse effects of the interventions and reaching study endpoints. If the NIDDK does not agree with the protocol approved by the Steering Committee, the arbitration process described elsewhere should be used to resolve the differences between the parties. 3. Cooperative Activities A Steering Committee, composed of the principal investigator of each Clinical Center, the principal investigator of the Data Coordinating Center, the NIDDK Project Coordinator and the Chairperson of the Steering Committee will be the main governing board of the study and will have primary responsibility for facilitating the conduct, monitoring interim measures of trial progress, and reporting trial results. The chairperson, who will be someone other than the NIDDK staff member, will be selected by the Steering Committee from among their members, or alternatively, from among experts in the fields of nephrology or clinical trials who are not participating directly in the trial. Subcommittees will be established by the Steering Committee, as it deems appropriate; the NIDDK Project Coordinator will serve on subcommittees as he/she deems appropriate. Any changes to the collaborative protocol will be developed by the Steering Committee. Data will be submitted centrally to the Data Coordinating Center. Protocols will define rules regarding access to data and publications. An independent External Advisory Committee, to be appointed by the NIDDK, will review progress at least annually and report to the Institute. It is anticipated that awardees will have lead responsibilities in all joint tasks and activities. The NIDDK Project Coordinator will have voting membership on the Steering Committee, and as appropriate, its subcommittees. Awardees will be required to accept and implement the common protocol and procedures approved by the Steering Committee. 4. Governance The primary governing body of the study will be the Steering Committee. Each member of the Steering Committee will have one vote. It is anticipated that the Steering Committee will meet on a quarterly basis during the course of the trial, or more often if deemed necessary. Subcommittees of the Steering Committee may be established as necessary and will meet as necessary. The NIDDK Project Coordinator or in and the Data Coordinating Center will be represented on each subcommittee. An independent External Advisory Committee supported by the NIDDK and composed of experts in relevant medical, statistical and bioethical fields who are not otherwise involved in the study will be established to review periodically the progress of the study. The committee will oversee participant safety, evaluate results, monitor data quality, and provide operational and policy advice to the Steering Committee and the NIDDK regarding the status of the study. The Principal Investigator of the Data Coordinating Center, the NIDDK Project Coordinator, and the Director of the Division of Kidney, Urologic and Hematologic Diseases may participate as ex-officio, non-voting members of this Committee. Committee members will be appointed by the NIDDK in consultation with members of the Steering Committee. The NIDDK will provide an executive secretary for the External Advisory Committee. 5. Arbitration Any disagreement that may arise in scientific-programmatic matters between award recipients and NIDDK may be brought to arbitration. An arbitration panel will be composed of three members---one selected by the Steering Committee (with NIDDK member not voting) or by the individual awardees in the event of an individual disagreement, a second member selected by NIDDK and the third member selected by the two prior members. This special arbitration procedure in no way affects the awardees' right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, Subpart D. The special terms of award (1-5) described above are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR parts 74 and 92, and other HHS, PHS, and NIH grant policy statements. 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 will be 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 Item 4 (Research Design and Methods) of the Research Plan AND summarized in Item 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 populations; 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 epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders, or conditions, including 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. If the required information is not contained within the application, the application will be returned without review. 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 will be 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 Prospective applicants are asked, but not required, to submit a letter of intent. This letter is to include the name, telephone number, and mailing address of the Principal Investigator, the names of key personnel, the name of the applicant institution, and the number and title of this RFA. Such a letter of is not binding and it will not enter into the review of any application subsequently submitted nor is it a requirement for application. Letters of intent are requested solely for planning purposes. The information contained in these letters is helpful in planning for review of applications. It allows NIDDK staff to estimate the potential review workload and to avoid possible conflicts of interest in the review. The NIDDK staff will not provide responses to such letters. Letters of intent are to be received no later than February 24, 1994 and are to be addressed to: Dr. Robert D. Hammond Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 406 Bethesda, MD 20892 APPLICATIONS PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these awards. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone 301/710-0267; and from the NIH program administrators named below. Use the conventional format for research project grant applications and ensure that the points identified in the "Review Criteria" section below are fulfilled. To identify the application as a response to the RFA, Check "YES" on item 2a of page 1 of the application and enter the title "Mortality and Morbidity in Hemodialysis Patients: Full Scale Study" and enter the RFA number DK-94-004 in the space provided. The RFA label available in the PHS 398 (rev. 9/91) application form must be affixed to the bottom of the face page of the original completed application form. Failure to use the label could result in delayed processing of the application such that it may not reach the review committee in time for review. Send or deliver the completed, signed application and three complete photocopies to the following office, making sure that the original application with the RFA label attached is on top to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Send two additional copies of the application to Dr. Hammond at the address listed under LETTER OF INTENT. It is important to send these two copies at the same time as the original and three copies are sent to the Division of Research Grants, otherwise the NIDDK cannot guarantee that the application will be reviewed in competition for the RFA. Applications must be received by March 22, 1994. An application not received by this date will be returned to the applicant. REVIEW CONSIDERATIONS Upon receipt, the Division of Research Grants (DRG) will review the application for completeness. Applications will be reviewed by NIDDK staff for responsiveness to the objectives of this RFA. If an application is judged to be incomplete or unresponsive, it will be returned to the applicant. If the number of applications is large compared to the number of awards to be made, the NIDDK will conduct a preliminary scientific peer review and will withdraw from further competition those applications that are not judged to be competitive for award. The NIDDK will notify the applicant and institutional official of this action. Those applications judged to be both competitive and responsive will be evaluated further according to the review criteria stated below for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities, NIDDK. Subsequently, they will be reviewed by the National Diabetes and Digestive and Kidney Diseases Advisory Council. Review Criteria The Initial Review Groups evaluates the merit of each grant application on the meeting agenda according to specific criteria. The principal criteria for the initial review of research project grant applications, as required in the PHS Scientific Peer Review Regulations, include: 1. scientific, technical, or medical significance and originality of the proposed research; 2. appropriateness and adequacy of the experimental approach and methodology to be used; 3. qualifications of the principal investigator and staff in the area of the research; 4. the principal investigator's experience and record in previous research activity; 5. reasonable availability of resources; 6. reasonableness and adequacy of justification of the proposed budget and duration of support; and 7. adequacy of the proposed means for protecting against adverse effects upon humans, vertebrate animals, or the environment. The evaluation of applications for both Clinical Centers and the Data Coordinating Center will be based primarily on the scientific merit of the proposed study. If an institution wishes to apply both as a Clinical Center and Data Coordinating Center, separate applications must be prepared. Specific criteria for review of applications will be as follows: For Clinical Centers: 1. Documentation of the specific competence and previous experience of professional, technical, and administrative staff pertinent to the operation of a Clinical Center in the proposed Clinical Trial. Evaluation will include the following: familiarity with and experience in recruiting participants in a randomized trial; handling laboratory specimens; working in collaboration with other investigators under a common protocol; ability to implement study procedures in hemodialysis units from which patients are to be recruited and meticulous and expeditious handling of study data. 2. Documentation of access to hemodialysis patient population(s) from which a substantial number of trial participants can be recruited in sufficient numbers to meet the goals specified in the RFA. 3. Understanding and awareness of the scientific, ethical, and practical issues underlying the proposed trial and appropriateness of plans to deal with them. 4. Responsible budgeting, and staffing and distribution of available resources appropriate for the work proposed. 5. Adequacy of the proposed facility and space. 6. Evidence of the degree of institutional commitment and support for the proposed program, including the relative position of the proposed project staff within the applicant's organizational structure. 7. Willingness to work cooperatively with other centers in the manner summarized in the RFA. 8. Willingness to carry out a developed study protocol. Of particular importance is the ability to send patient samples (including samples routinely collected during hemodialysis) to a Central Biochemistry Laboratory for testing, and implementation of the interventions described in the protocol. For the Data Coordinating Center: 1. Documentation of the specific competence and previous experience of professional, technical, and administrative staff pertinent to the operation of a Data Coordinating Center for a collaborative clinical trial, as well as available, on-site medical consultation, and the time these professionals will devote to the project. Prior experience in similar studies in the collection of data and patient specimens from multiple clinical sites, as well as experience in monitoring the quality and timeliness of such data, must be demonstrated. 2. Ability to collect, maintain, and analyze dietary data including protein and calorie intake of study participants. Centralized training of Clinical Center staff in this data collection is also required. 3. Suitability of proposed data management and data analysis plans. 4. Ability to design, implement and maintain a distributed data entry system for the Clinical Centers. 5. The approach to and likelihood of soliciting cooperation from the participating clinical centers and exercising appropriate leadership in matters of study design and protocol revision, and data acquisition, management, and analysis. 6. Appropriateness of the budget for the work proposed. 7. The adequacy of the proposed facility, technical hardware, and space. 8. The organizational and administrative structure of the proposed program. 9. Evidence of the degree of commitment and support of the organization/institution for the proposed program, including the relative position of the proposed project staff within the applicant's organizational structure. AWARD CRITERIA Applications recommended by the National Diabetes and Digestive and Kidney Diseases Advisory Council will be considered for award based upon (a) scientific and technical merit; (b) program balance, including in this instance, sufficient compatibility of features to make a successful collaborative program a reasonable likelihood; and (c) availability of funds. Schedule The timetable for receipt, peer review, and funding of this RFA is as follows: Letter of Intent Receipt Date: February 24, 1994 Application Receipt Date: March 22, 1994 Initial Review: June 1994 NIDDK Advisory Council Review: September 1994 Anticipated Award Date: September 30, 1994 INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Applicants are encouraged to request a copy of the pilot study protocol. Direct inquiries regarding programmatic issues to: John W. Kusek, Ph.D. Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 3A04 Bethesda, MD 20892 Telephone: (301) 594-7522 FAX: (301) 594-7501 Inquiries regarding fiscal matters may be directed to: Nancy C. Dixon Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 649B Bethesda, MD 20892 Telephone: (301) 594-7543 FAX: (301) 594-7594 AUTHORITY AND REGULATIONS This program is described in the catalog of Federal Domestic Assistance No. 93.849-Kidney, Urologic and Hematologic Diseases Research. 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 52 and 45 CFR Part 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. References 1. Rettig, RA and Levinsky, NG (editors). Kidney Failure and the Federal Government. Institute of Medicine. National Academy Press. Washington, D.C. 1991. 2. U.S. Renal Data System, USRDS 1993 Annual Data Report, The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, March 1993. 3. Hull, AR and Parker T. Introduction and Summary. Proceedings from the Morbidity, Mortality and Prescription of Dialysis Symposium, Dallas, TX, September 15-17, 1989. American Journal of Kidney Diseases 15:375-383, 1990. 4. Collins AJ, Hanson, G, Umen et al. Changing risk factor demographics in end-stage renal disease patients entering hemodialysis and the impact of long-term mortality. American Journal of Kidney Diseases 15:422-432, 1990. 5. Gotch, FA, Yarian S and Keen, M. A kinetic survey of US hemodialysis prescriptions. American Journal of Kidney Diseases 15:511-515, 1990. 6. Hornberger JC, Chernew M, Petersen J, and Garber AM. A multivariate analysis of mortality and hospital admissions with high-flux dialysis. Journal of the American Society of Nephrology 3:1227-1237, 1992. 7. Hakim, RM. Clinical implications of hemodialysis membrane biocompatibility. Kidney International 44:484- 494, 1993. 8 Hakim RM, Depner TA, Parker TF. Adequacy of hemodialysis. American Journal of Kidney Diseases 20:107- 123, 1992. 9. Collins A., Liao M, Umen A, Hanson G, Keshaviah P. Diabetic (DM) hemodialysis (HD) patients (PTS) treated with a high KT/V have a lower risk of death than standard KT/V (Abstract). Journal of the American Society of Nephrology 2:318, 1991. 10. Lowrie EG and Laird NM (editors). Cooperative Dialysis Study. Kidney International 23:(supplement) S-1-S-122, 1983. 11. Held PJ, Port FK, Garcia J, Gaylin DS, Levin NW, Agodoa L. U.S. Renal Data System: Hemodialysis prescription in the U.S.: Results from USRDS case mix study (abstract). Journal of the American Society of Nephrology 2:328, 1991. 12. Protocol for the Mortality and Morbidity in Hemodialysis Patients Multicenter Clinical Trial. Division of Kidney, Urologic and Hematologic Diseases, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. 1993. .
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