POLYCYSTIC KIDNEY DISEASE CLINICAL TRIALS NETWORK Release Date: May 29, 2001 RFA: RFA-DK-01-029 (Reissued as RFA-DK-07-504 and RFA-DK-07-008) National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: October 16, 2001 Application Receipt Date: November 16, 2001 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 to establish a network to design and implement clinical trials to slow the progressive loss of renal function in polycystic kidney disease (PKD). The Network, consisting of a Data Coordinating Center (DCC) and Participating Clinical Centers (PCCs), will develop and execute both pilot and feasibility trials and a large randomized controlled clinical trial on blockade of the renin-angiotensin axis in patients with PKD. 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, Polycystic Kidney Disease Treatment Network , is related to one or more of the priority areas. Potential applicants may obtain a copy of Healthy People 2010 at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, for-profit and non-profit institutions, public and private organizations, such as universities, colleges, hospitals, units of State and local government, and eligible agencies of the Federal government. Foreign institutions are not eligible to apply. Racial/ethnic minorities, women, and persons with disabilities are encouraged to apply as Principal Investigators. An institution or organization may apply for both a Participating Clinical Center and a Data Coordinating Center. However, separate applications are required for each of these study components. The same person may not serve as the Principal Investigator of a PCC and the DCC, and other key staff cannot be shared by these study units. MECHANISM OF SUPPORT The administrative and funding instrument to be used for these awards will be the cooperative agreement (U01). The cooperative agreement is an assistance mechanism in which substantial NIDDK scientific and programmatic involvement is anticipated during the performance of the activity. Under the cooperative agreement, the NIDDK’s purpose is to support and encourage the recipient’s activities by working jointly with the awardees in a partnership role, but not to assume direction, prime responsibility, or dominance. Details of the responsibilities, relationships, and governance of a study funded under a cooperative agreement are described under the section entitled Terms and Conditions of Award. The total project period for applications submitted in response to this RFA is seven years. The anticipated award date is June 1, 2002. At this time, the NIDDK has not determined whether or how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE The NIDDK plans to make four awards for Participating Clinical Centers and one award for a Data Coordinating Center. Approximately $1,500,000 total cost (direct plus facilities and administrative costs) is expected to be available during year one of the study. In all subsequent years $3,000,000 will be available under this RFA. It is anticipated that the award for each Participating Clinical Center will be about $250,000 total cost in year one and $500,000 total cost in all subsequent years. The award for the Data Coordinating Center will be about $500,000 total cost in year one and approximately $1,000,000 total cost in all subsequent years of the program. The number of awards to be made is dependent on the receipt of a sufficient number of applications of high scientific merit and availability of funds. Although this program is provided for in the financial plans of the NIDDK, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES Background Polycystic kidney disease (PKD) is a serious, burdensome and costly disease. The cystic diseases are the fourth leading cause of chronic renal failure in the nation. Important advances in understanding the molecular basis of autosomal dominant PKD (ADPKD1 and ADPKD2) have generated intense interest, and have provided investigators with new research opportunities. Increased understanding of the underlying molecular processes that result in cyst formation and cyst growth is yielding improved animal models of disease. A number of agents are established to slow cyst growth in animal models, and these experimental strategies should yield potential new therapeutic approaches to the disease in man. Appropriate clinical interventions to ameliorate the course of PKD need to be developed and tested. Several previous studies have established that in PKD patients with renal insufficiency, glomerular filtration rate (GFR) declines rather rapidly. Nevertheless, through much of the course, GFR is relatively stable, and detectable decreases in GFR occur relatively late in the natural history of the disease. Current approaches to treatment of patients with PKD have not succeeded in slowing the progressive decline in GFR that frequently results in end- stage renal failure. Treatment of hypertension has not been definitively shown to retard loss of renal function in patients with PKD, and it is unclear whether target blood pressures should be lower in these patients than in the general population. A sizable body of data supports the effectiveness of converting enzyme inhibitors (CEI) in slowing the progression of other renal diseases, particularly those associated with proteinuria. These agents remain the most effective strategy to prevent or delay chronic renal failure, but the effectiveness of this class of agent in PKD is not clear. There is, however, biological evidence compatible with the hypothesis that interruption of the renin-angiotensin-aldosterone axis might have a protective effect in PKD. Some studies in animal models support this hypothesis. In polycystic kidneys from human patients, there is evidence for high tissue renin, and there is clinical evidence for activation of the renin-angiotensin axis in hypertensive patients with PKD. The results of randomized interventional clinical trials of CEI in PKD have been contradictory, although the total number of patients studied has been relatively small. Many nephrologists elect to use CEIs for blood pressure management, particularly in patients with PKD who also have some degree of proteinuria. In addition to converting enzyme inhibitors, other strategies to block this pathway include angiotensin receptor blockers and aldosterone antagonists, agents which potentially could be administered either alone or together with CEI. The NIDDK has recently funded the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) (RFA-DK-99-003) to determine whether changes in anatomic characteristics of the kidneys of patients with PKD will be useful in providing surrogate measures for disease progression. Although data from these studies are not presently available, preliminary findings from this group over the next several years might inform the designs of clinical trials in patients with PKD in the near future. B. Research Goals and Scope The goal of this research initiative is to identify strategies to slow the progressive loss of renal function in polycystic kidney disease (PKD). To achieve this goal, this initiative will establish the infrastructure to examine the effect of clinically practical interventions, such as single and combination drug regimens, on the outcomes of patients with PKD. This RFA solicits applications from investigator teams proposing to serve as either a Participating Clinical Center (PCC) or a Data Coordinating Center (DCC) in this research network. It is anticipated that the studies to be conducted by this consortium in this RFA will take place in four PCCs over a period of seven years. It is envisioned that each PCC will act as a referral center, with the capacity to enroll a total of approximately 500 patients with PKD. The data collection activities of the PCCs will be supported by a single DCC. The objectives of this RFA are to select a DCC and PCCs to: Recruit, evaluate, and follow sizable numbers of patients with PKD who will be appropriate for and willing to participate in interventional trials. Participate in pilot and feasibility studies and a full-scale interventional trial. Design the study protocols and write the manual of operations. Develop operational plans for the trial(s), including strategies for recruitment, screening, enrollment and adherence to study protocols. Develop a specimen bank and information data system from study samples and patient information. C. Study Design The design of the final research protocols for implementation by the PKD Clinical Trials Network will be developed during the Planning Phase by the Steering and Planning Committee, and will be subject to review by a Data and Safety Monitoring Board. The intent of this RFA is that the trial network should implement both a large multicenter trial examining the effect of renin-angiotensin blockade on progression of PKD and one or more pilot and feasibility studies examining innovative strategies for slowing the progression of PKD. The entire collaborative clinical trial network will function in several phases. Applicants for PCCs should present two research protocols in their applications: 1) A proposal for a large trial to examine the hypothesis that interruption of the renin-angiotensin-aldosterone axis offers clinical benefit to patients with polycystic kidney disease, and 2) A proposal for a pilot and feasibility study examining the effect of an innovative strategy for PKD treatment. For the large trial, applicants should propose a specific trial design, intervention, eligibility and exclusion criteria, and outcome measures. It is the intent of this RFA that this trial should ultimately provide pragmatic advice to clinicians caring for PKD patients, and that the trial should use an outcome measure that directly assesses clinical benefit. For example the study could assess whether the intervention delays the time to dialysis, doubling of serum creatinine or death. Since the PCC’s will be acting as referral centers and executing the trial in patients referred over a broad geographical area, simplicity of trial design will be important. Topics suitable for pilot and feasibility studies include, but are not limited to the following: The safety of new agents for treatment of PKD, The impact of blockade of the intensive blockade of the renin angiotensin axis on potassium homeostasis in patients with PKD and renal insufficiency, The impact of innovative interventions on surrogate markers for cyst growth or cyst growth assessed by imaging methods, The impact of innovative interventions on possible mechanisms of cystogenesis, such as loss of heterozygosity, The safety or effectiveness of potential interventions in special populations of patients with PKD. For each of the proposed clinical protocols, the PCC applicants should discuss the characteristics and number of potential participants that would be available from their own geographic region. Provision of recruitment data regarding previous studies in patients with PKD is encouraged. Provision should be made for meeting the appropriate representation of genders, minorities and children, as required for successful accomplishment of study goals. STUDY COMPONENTS 1. Participating Clinical Centers (PCCs) A PCC will be actively involved in the recruitment, evaluation, treatment, and follow-up of PKD patients as appropriate study subjects. It should consist of an interdisciplinary team of clinical investigators and appropriate personnel, such as a research coordinator and clerical staff. An application for a PCC should provide evidence that the investigators are capable of recruiting a sufficient number of participants for the proposed trials. Applicants for PCCs should describe the target population from which they expect to recruit PKD patients as study participants, and plans for recruitment of women, minorities, and children. PCCs will be required to submit study data to the DCC expeditiously. The PCC must work in concert with the DCC to implement procedures for uniform data collection, handling and transmittal of data, as well as data audits and other data quality control procedures as established by the study protocol(s). The Principal Investigator and co-investigators in each PCC should be skilled in collaborative clinical investigation. There should be evidence of strong institutional support for the PCC, including adequate space in which to conduct clinical activities and obtain research protocol data, and sufficient office space for staff. An organizational structure for the PCC should be set forth in the application delineating lines of authority and responsibility for dealing with problems in all general areas as well as a statement regarding willingness to follow commonly agreed upon protocols. The applicant should include a succinct discussion of previous relevant research efforts, including experience such as evaluating renal functional or radiologic parameters over time. The applicant should also discuss in detail the recruitment strategies to be employed to obtain the expected number of study participants, and approaches to attain high levels of adherence to interventions. In most cases, recruitment of large numbers of PKD patients will require agreements between the PCC and other health care providers. 2. Data Coordinating Center (DCC) The DCC will have primary responsibility for collecting, editing, storing, and analyzing data generated by the PCCs, and for establishing and implementing data auditing and quality control procedures for each aspect of the studies. The DCC will participate in trial design by providing needed biostatistical expertise. For example, the DCC will provide realistic estimates of the power and sample size of the clinical trials proposed during Phases I and II (see below). The DCC should establish a core facility for clinical specimen handling and analyses, and establish the informatics systems for data collection. The DCC will be responsible for the analysis of the clinical data generated by the PCCs. The DCC will coordinate banking of biologic samples at a repository to be established by the NIDDK. Sub-contracting of various aspects of the DCC to other institutions with special expertise may be included in the application. The DCC should be prepared to assume a key role in overseeing implementation of and adherence to the study protocol(s), and assuring quality control of the data collected. The DCC will be expected to provide appropriate biostatistical, data management, and administrative expertise. The DCC will be expected to provide the NIDDK with a well documented data set after the termination of the studies supported by this RFA. The DCC also will be expected to generate appropriately detailed reports to the Steering and Planning Committee (see below) and to the Data Safety and Monitoring Committee (see below) at regular intervals, and will be responsible for the logistics and planning of the meeting of these committees and their subcommittees. Applicants for the DCC should provide a detailed description of prior experience in multicenter clinical studies. Study Phases The program will be carried out in three phases over a seven-year period. Phase I (Months 1-6): Protocol Development. Work to be performed during this phase includes the development of the interventional protocols, including procedures and forms for data collection, by the Steering and Planning Committee. A manual of operations including well-defined procedures for the studies and for the training and certification of clinical personnel in study procedures will be written. Parameters to be assessed in Central Laboratories will be outlined. The Data Coordinating Center will begin computer programming to establish the database for the study. The collaborative protocols for the trial(s) will be developed by the Steering Committee (composed of the awardees and the NIDDK Project Scientists). Prior to implementation of any trial(s), the protocol(s) and Manual of Operations will be reviewed, and must be approved by the Data Safety and Monitoring Committee (see below). Any pilot and feasibility study, and the long-term study will move into operational phase (Phase II) only with the concurrence of the Data Safety and Monitoring Committee and the NIDDK. During this phase, outlay of funds will be primarily for appropriate levels of salary support for investigators to develop the trial protocol(s) and Manual of Operations, and for travel to the Steering and Planning Committee meetings. Phase II (Months 7-78): Recruitment of Study Participants/Initiation of Pilot and Feasibility Studies and Therapeutic Interventional Trial(s)/Follow-up Assessments/Development of Further Interventions. At the beginning of this period, training of study staff will begin, to ensure uniform protocols and provide certification for study procedures. Over this period potentially eligible participants will be identified, invited to the PCCs for baseline assessment, and those found eligible will be asked to enter the appropriate trial(s). During this phase the full component of personnel will be included in the budget. Concurrent with recruitment, follow-up of all study participants will be conducted in a standardized fashion over regular intervals. Further interventions will be developed as necessary during this phase, as an ongoing process, as determined by the results of pilot and feasibility studies. The Data Safety and Monitoring Committee will review the progress of recruitment yearly, review interim outcomes and recommend to the NIDDK whether the trial(s) should continue, and will review subsequent trials proposed by the Steering and Planning Committee during this Phase. The major activity during the first half of this phase will be the recruitment, assessment, enrollment and retention of patients in the trial(s). Preparation of manuscripts describing recruitment of the subjects, baseline demographic and clinical characteristics of the participants, and the cross-sectional relationships between level of renal function and other parameters, including clinical, demographic, radiographic, and laboratory measurements will begin to be developed in the first half of this phase. The major activity during the latter part of this phase will be manuscript preparation and follow-up clinic visits. Follow-up and data collection on study participants will continue throughout this phase, as determined by the study protocol(s). Manuscripts will be prepared and submitted for publication on the interim findings from the study, and the results of completed pilot and feasibility studies or interventional trials. The last follow-up visit of study participants will be scheduled during the final two months of this phase. Phase III (Months 79-84): Final Data Analysis and Close-out of the PCCs and the DCC. During the final six months of the program, the activities include final data analyses and preparation of manuscripts on the findings from the trials. The Participating Clinical Centers, the Data Coordinating Center, and all central facilities will be closed-out in the last two months of this phase of the study. Study Organization Participating Clinical Centers The Participating Clinical Center investigators will have direct responsibility for developing the study protocol(s) and uniform data collection forms, identifying potentially eligible study participants, assessing their eligibility to participate in the clinical trials, conducting baseline and follow-up visits, obtaining blood, urine, and other biological samples, performing renal functional and other measurements, collecting data, and transmitting it in a timely fashion to the Data Coordinating Center. They, along with staff from the Data Coordinating Center and the various central laboratories, will also be responsible for making presentations at scientific meetings, and for writing and publishing manuscripts on the findings of their studies. Data Coordinating Center The Data Coordinating Center will be responsible for assisting the PCC investigators, through the Steering and Planning Committee, in developing the trial protocol(s) during Phases I and II. The Data Coordinating Center will create data collection forms based on input from the Steering and Planning Committee. The Data Coordinating Center will be responsible for establishing a database to accommodate data sent by the Participating Clinical Centers, developing a web-based data communication system, assessing data quality and completeness throughout the study, and providing general assistance to the Participating Clinical Centers to maintain long-term participation of the study subjects and their adherence to the study protocols. Adherence of the participants will be monitored and reported by the DCC at regular intervals during the trial(s) to the PCCs and to the Data Safety and Monitoring Committee. The Data Coordinating Center will also perform analyses as suggested by the Participating Clinical Centers, as well as propose original analyses to the collaborative group for their consideration. The Data Coordinating Center will prepare periodic reports on the progress of the study, including data quality control, and interim and final results to the Steering and Planning Committee, the NIDDK and the Data Safety and Monitoring Committee. The DCC will be responsible for coordinating transfer of biologic samples to a repository to be established by the NIDDK. The Data Coordinating Center will be responsible for arranging meetings and conference calls of the Steering and Planning Committee, meetings of the Data Safety and Monitoring Committee, and will perform other administrative functions necessary to coordinate the efficient operation of the PKD Clinical Trials Network. The Data Coordinating Center will establish, via subcontracts, Central Laboratories and other necessary adjuncts to the study, as necessitated by the study protocol(s). The DCC will be expected to provide the NIDDK with data in a uniform, usable platform throughout the course of the studies and after the termination of the studies supported by this RFA. Steering and Planning Committee The primary governing body of the study will be the Steering and Planning Committee, comprised of each of the Principal Investigators of the Participating Clinical Centers and the Principal Investigator of the Data Coordinating Center, the Chairperson of the Steering and Planning Committee, and the NIDDK Project Scientists (described in detail under Terms and Conditions). The Steering and Planning Committee will develop policies for the study pertaining to access to patient data and specimens, ancillary studies, performance standards, and publications and presentations. They will meet initially to develop the study protocol(s) and subsequently to discuss the progress of the study and to consider problems arising during its conduct. The Steering and Planning Committee may establish subcommittees on such topics as recruitment, quality control, and publications and ancillary studies. Small working groups may be established to prepare manuscripts and presentations. Data Safety and Monitoring Committee An independent group of experts in areas such as nephrology, epidemiology, radiology, ethics, and biostatistics who are not otherwise involved in the study, as well as lay persons, will be recruited by the NIDDK to evaluate the proposed protocol(s) and review periodically the progress of the study (described in detail under Terms and Conditions). Project Scientists The NIDDK will identify two Project Scientists for the study. The Project Scientists will assist the Steering and Planning Committee and the Data Safety and Monitoring Committee in carrying out the study (described in detail under Terms and Conditions). SPECIAL REQUIREMENTS Terms and Conditions of Award The following terms and conditions will be incorporated into the award statement and provided to each Principal Investigator as well as to the institutional officials at the time of the award. These terms are in addition to, not in lieu of, otherwise applicable Office of Management and Budget (OMB) administrative guidelines, HHS Grant Administration Regulations at 45 CFR Part 74 and 92, and other HHS and NIH Grants Administration policy statements. The administrative and funding instrument used for this program is the cooperative agreement (U01), an assistance mechanism (rather than an acquisition mechanism), in which substantial NIH scientific and/or programmatic involvement with awardees is anticipated during the performance of the activity. Under the cooperative agreement, the NIH’s 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, primary responsibility, or a dominant role in the activity. Consistent with the cooperative agreement concept, the dominant role and prime responsibility for the planned activity reside with the awardees for the project as a whole, although specific tasks and activities in carrying out the activity will be shared among the awardees and NIDDK Project Scientists. Responsibilities of the Participating Clinical Centers: The Participating Clinical Centers will have primary responsibility for developing the study protocol(s), recruiting a sufficient number of study participants, maintaining high rates of follow-up and data collection, ensuring adherence to the study protocol(s) on the part of the investigative team and the subjects, obtaining data of high quality, transmitting it accurately and expeditiously to the DCC, and interpreting, presenting, and publishing findings from the study. A PCC will work collaboratively with the other PCCs and the DCC, and will follow study protocols. Responsibilities of the Data Coordinating Center: The Data Coordinating Center will assist in protocol development and preparation of scientific publications. The Data Coordinating Center has the major responsibility of creating a database and data collection systems for the Clinical Centers, providing ongoing evaluation of data quality and performance monitoring of the PCCs, and performing statistical analyses of the data. The DCC will be expected to provide the NIDDK with data in a uniform, usable platform throughout the course of the studies and after the termination of the studies supported by this RFA. The DCC will coordinate transfer of biologic samples to a repository to be established by the NIDDK. In addition, the Data Coordinating Center will supply logistical support for the meetings of the Steering Committee and the Data Safety and Monitoring Committee. (1) Awardees Rights and Responsibilities Awardees will have substantial and lead responsibilities in all tasks and activities. These include protocol development, enrollment of study participants, data collection, data quality control, management of the trial(s), final data analyses and interpretation, and preparation of publications. The awardees agree to work cooperatively with the other PCCs and agree to follow the common protocol(s) developed by the Steering and Planning Committee. The awardees agree also to transmit the study data in a timely manner according to study protocol(s) to the Data Coordinating Center for combination and analysis. Awardees will retain custody of and have primary rights to their data developed under these awards for the duration of the awards, subject to Government (e.g., NIDDK, NIH, or PHS) rights or access consistent with current HHS and NIH policies. (2) NIDDK Staff Responsibilities The NIDDK will name two Project Scientists from within the Division of Kidney, Urologic and Hematologic Diseases whose function will be to assist the Steering and Planning Committee in carrying out the study. The Project Scientists will have experience in nephrology and the development and conduct of multi-center clinical trials. The Project Scientists will have substantial scientific-programmatic involvement in assisting protocol development, quality control, interim data analysis, final data analysis and interpretation, preparation of publications, and will provide assistance in coordination and performance monitoring. The NIDDK Project Scientists will have voting membership on the Steering and Planning Committee (constituting a single vote). One of the NIDDK Project Scientists will also serve as Executive Secretary of the Data Safety and Monitoring Committee. The NIDDK reserves the right to terminate or curtail the study (or an individual award) in the event of difficulties in recruiting participants to the study, maintaining high rates of follow-up and data collection/completion of participants tests, in timely data reporting, achieving high levels of data quality, maintaining adherence to the study protocol(s), working cooperatively or other major breaches of the protocol(s), or human subject or ethical issues that may dictate a premature termination. (3) Collaborative Responsibilities The Steering and Planning Committee, composed of each of the Principal Investigators of the PCCs, the Principal Investigator of the DCC, the NIDDK Project Scientists, and the Chairperson of the Steering and Planning Committee, will be the main governing board of the study. The Committee will have the primary responsibility for developing the study protocol(s), facilitating the conduct of participant follow-up and testing, monitoring completeness of data collection adherence to protocol(s), and timely transmission to the Data Coordinating Center, and reporting the study results. It will also be responsible for establishing study policies in such areas as access to patient data and specimens, ancillary studies, publications and presentations, and performance standards. Each member of the Steering and Planning Committee will have one vote (NIDDK will have one vote), and all major scientific decisions will be determined by a majority vote of the Steering and Planning Committee. A Chairperson will be chosen by the NIDDK from among the Steering and Planning Committee members (but not one of the NIDDK Project Scientists) or alternatively, from among experts in such fields as nephrology, or clinical trials design, who are not participating directly in the study. An independent Data Safety and Monitoring Committee (DSMC), selected by the Director, NIDDK, will review periodically the progress of the study to ensure patient safety during the conduct of the trial(s). This group will include experts in the relevant medical, epidemiological, radiological, statistical, and ethics fields, as well as lay representatives, who are not otherwise involved in the study. The DSMC will review the study protocol(s) as developed during Phases I and II, and will evaluate results, monitor data quality, participant safety, and provide operational and policy advice to the Steering and Planning Committee and to the NIDDK regarding the status of the study. One of the NIDDK Project Scientists will serve as Executive Secretary of the Data Safety and Monitoring Committee. The members of the DSMC will review the PKD Clinical Trials Network’s progress and will report to the NIDDK at least once each year, or more often if necessary. (4) Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award) between recipients and the NIDDK may be brought to arbitration. An arbitration panel will be composed of three members, one selected by the Steering and Planning Committee (with the NIDDK member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NIDDK, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee’s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16. 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 is provided 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 1003-43). Eleven 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 is 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 the 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. 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 also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLS) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit, by October 16, 2001, a letter of intent that includes a descriptive title of the proposed research, name, address, and telephone number of the Principal Investigator, identities of other key personnel and participating institutions, and 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 it contains allows the NIDDK staff to estimate the potential review workload and 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, Digestive, and Kidney Diseases 6707 Democracy Boulevard, Room 752 Room 752, MSC 5452 Bethesda, Maryland 20892-5452 (for courier service use 20817) Telephone: (301) 594-8885 Fax: (301) 480-3505 Email: fc15y@nih.gov APPLICATION PROCEDURES Applications must be submitted on the standard research grant application form PHS 398 (rev. 4/98). See "Budget Preparation by Year section below for additional instructions. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, Maryland 20892-7910, telephone (301) 710-0267, E-mail: GrantsInfo@nih.gov. The RFA label available in the form PHS 398 must be affixed to the bottom of the face page. 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. For purposes of identification and processing, item 2 of the face page of the application must be marked YES and the RFA number and the words Polycystic Kidney Disease Clinical Trials Network must be typed in. The RFA label and line 2 of the application should both indicate the RFA number. The RFA label must be affixed to the bottom of the face page. 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. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in PDF format. 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 the time of submission, two additional copies of the application and appendices must be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes, Digestive, and Kidney Diseases 6707 Democracy Boulevard, Room 752 Room 752 MSC 5452 Bethesda, Maryland 20892-5452 (For express/courier service, use 20817) Applications must be received by November 16, 2001. If an application is received after this date it will be returned to the applicant without review. 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 a substantial revision of an application already reviewed, but such an application must follow the guidance in the PHS 398 applications instructions for the preparation of revised applications, including an introduction addressing the previous critique. The page limitations for applications responding to this RFA will be those outlined in the current PHS 398 application kit (25 pages for the Research Plan, sections A-D). Within the 25 page limit, a guideline for pilot and feasibility studies is two pages, and four pages for the full scale interventional trial. Information to be Included in Application Details of Participation in Proposed Study Protocol(s): Applicants for both the DCC and the PCC should present two research protocols in their applications: 1) A proposal for a large trial to examine the hypothesis that interruption of the renin-angiotensin- aldosterone axis offers clinical benefit to patients with polycystic kidney disease, 2) A proposal for a pilot and feasibility study examining the effect of an innovative strategy for PKD treatment. The laboratory and medical tests, questionnaires, and other data collection and the frequency of assessment during follow-up must be specified. Applicants for the PCC should provide detailed information regarding the size of the potential pool of PKD patients who will be willing to come to the PCC to participate in screening visits to assess study eligibility, and a reasonable projection of the proportion of patients screened and found eligible that would be willing to commit to participation in pilot and feasibility trials and a long-term trial as described in this RFA. A detailed description of the PKD patients targeted for intervention as well as a comprehensive plan to recruit patients must be provided. Realistic rates of study drop-outs and outmigration should be proposed. Efforts to maintain follow-up of study participants must also be described. Applicants must consider the sample size proposed in this RFA in light of their previous research and clinical activities. In addition to trial protocols, applications for the DCC should include plans for data collection, and overall quality control of the study. The applicant should indicate willingness to take the lead in determining effect sizes and proposing power analyses for studies considered by the consortium. An administrative plan to coordinate the activities of the Central Laboratories, including quality control and data transmission to the Data Coordinating Center must be included in the application. The experience of the DCC in developing and maintaining web-based data collection systems for large-scale, multi- center studies, including clinical trials should be documented. Plans for transferring biologic samples to a repository to be established by the NIDDK should be outlined. A description of anticipated problems in carrying out this study and their proposed solutions must be included in the application. Institutional Support: There should be evidence of strong institutional support for the study, including adequate space in which to conduct participant evaluations and follow-up (PCCs) and data analysis/management (DCC) activities. A PCC application should delineate facilities available for assessment of renal functional and radiologic parameters in a large group of study participants. An organizational structure for the study should be set forth in the application, delineating lines of authority and responsibility for dealing with anticipated problems in all general areas as well as stated willingness to follow the commonly agreed-upon protocol(s). Previous Experience: The applicant should include a succinct discussion of previous relevant research efforts in multi-center clinical trials, and any relevant experience/success in working collaboratively with investigators outside their own research institution. Experience in the recruitment and retention of participants for long-term studies should be described. Expertise in renal functional assessments and radiologic evaluation of patients with renal disease should be included. Previous participation in studies of racial and ethnic minority populations should be included. Suggested Personnel Requirements: The application must describe the expertise of key scientific, technical and administrative personnel and include a mechanism for replacing key professional or technical personnel should the need arise. For the Participating Clinical Centers, expertise in nephrology and clinical trials is required. Personnel may be full-time or part-time and may serve in more than one capacity, as appropriate. A suggested Participating Clinical Center study team might include, besides a Principal Investigator, a co- investigator (M.D. or Ph.D.), a radiologist, study coordinators, GFR technician, appointment scheduler/administrative assistant and data entry clerk. Personnel required for the Data Coordinating Center must include expertise in biostatistics, epidemiology, data management, computer programming and database development. Experience in the use of web-based data collection systems in a multi-center study setting is also necessary. Inclusion of consultants as necessary is possible. Budget Preparation by Year Applicants for the Participating Clinical Centers and the Data Coordinating Center must include an adequately justified year-by-year budget, reflecting the major changes in proposed activities as the study progress through its various phases. Budgets should reflect the number of patients proposed for the pilot and feasibility studies and the long-term interventional trial. Note: The PHS Form 398 will be used for each proposed year (12 months each) in accordance with the project objectives proposed specified above in the "Information to be Included in Application" section. The PHS Form accommodates up to 5 years in composite budget information, however as prescribed in the "Application Procedures" section the applicant shall include the 6th and 7th year composite budget information as required congruent with the individual year 6 and 7 budgetary information. The applicants shall not submit budget information in modular format and cost projections should adequately correspond to the scope of research proposed. Phase I (First 6 months of Year 1). The budget will be for development of the protocol(s) by the Participating Clinical Centers in collaboration with the Data Coordinating Center. The Data Coordinating Center will establish the database necessary to accommodate the data transmitted by the PCCs. A web-based technology for data transmission will be established in Phase I that will be efficient, and will protect study participant privacy. The Data Coordinating Center will identify and establish subcontracts with Central Laboratories and other support centers as necessitated by the study protocol(s). It is expected that the Data Coordinating Center will purchase all the necessary hardware and software for data transmission from the PCCs for their use in the study. The proposed study protocol(s) will also be reviewed by the Data Safety and Monitoring Committee and must be approved prior to implementation. The travel budget for Phase I should be estimated based on travel for two key investigators to attend two-day, monthly meetings of the Steering and Planning Committee in the Washington, D. C. area. The first meeting will be held June 4 and 5, 2002. Phase II (Months 7-78). The budget for the Participating Clinical Centers should reflect the level of effort necessary to recruit the entire study groups, implement the interventions, and perform baseline and follow-up studies. Follow-up data will be collected by the PCCs. A guideline is to devote approximately 25% of resources in Phase II to pilot and feasibility studies and 75% to the long-term interventional trial. Trials may be developed during this phase based on findings of earlier pilot and feasibility studies. The major activities in this phase are enrollment, follow-up and assessment of study participants. Initially, data analysis of the recruitment experience and baseline characteristics of the study participants will be undertaken. The first manuscripts will focus on cross-sectional findings. Subsequently, manuscripts will deal with interim findings and results of the pilot and feasibility studies. Data analysis will be conducted and papers addressing the secondary goals of the studies will also be prepared. Costs should be included for any specialized studies of renal function (such as GFR measurement) and for other necessary parameters consistent with pilot and feasibility studies or large interventional trials. In- clinic visit follow-up of the study participants will be terminated during the last several months of Phase II. The Data Coordinating Center will receive and store the data transmitted by the Participating Clinical Centers, assess its completeness, provide feedback to the PCCs regarding data quality, and prepare progress reports for the Steering and Planning Committee and the Data Safety and Monitoring Committee on the progress of the trial(s). The budget should include costs associated with necessary Central Laboratories and with transfer and maintenance of biologic samples in a repository to be established by the NIDDK. This phase of the program will require meeting approximately every four months in the Washington, D.C., area. The travel budget for Phase II should be estimated based on travel for the Principal Investigator and the Study Coordinator as well as any other key personnel for both the Participating Clinical Centers and the Data Coordinating Center. Travel for key staff at the Participating Clinical Centers and the Data Coordinating Center should be budgeted each year for centralized training and recertification of PCC staff. Central training will occur annually and key staff should be budgeted to travel to the Washington, D. C. area. For a PCC, the budget should request support for the minimum number of full and/or part-time staff to successfully carry out the proposed studies. PCC personnel could include a Principal Investigator, co- investigator(s), study coordinators, GFR technician, appointment scheduler/administrative assistant, and data entry clerk. The PCC should budget for renal functional and radiologic assessments, as well as other clinical laboratory measurements to be obtained over the course of the trials. For applications for the Data Coordinating Center, the budget should include the time and effort of key personnel for database management, programming, data analysis, and administrative functions to support the collaborative group. The budget should also include subcontracts for Central Laboratory and facilities and costs associated with maintenance of biologic samples in a repository to be established by the NIDDK. Travel by Data Coordinating Center staff to Washington, D.C., and coordination for a meeting with the Data Safety and Monitoring Committee should be planned and budgeted for annually by the DCC. Phase III (Months 79-84). Final Data Analysis and Close-out of the Participating Clinical Centers, the Data Coordinating Center, and Central Laboratories. The major activities during this Phase include final data analysis of the trial(s). Manuscripts describing these findings will be prepared and submitted to peer-reviewed scientific journals for publication. The Participating Clinical Centers, the Data Coordinating Center and the Central Laboratories will be closed-out during the last two months of this phase of the program. Two meetings of the Steering and Planning Committee and one meeting of the Data Safety and Monitoring Committee will be held in Phase III. The following is a list of yearly major activities to assist in the preparation of budgets for each of the five years of the program. Year 1 (Months 1-6): Develop the study protocol and data collection forms for the collaborative studies by means of meetings every month. The database will be established by the Data Coordinating Center. A web-based data transmission system will also be developed by the Data Coordinating Center. Central Laboratories will be identified and established by the Data Coordinating Center. Recruitment plans will be developed by the PCCs. Computer hardware and software will be purchased by the Data Coordinating Center for use by the PCCs. Year 1 (Months 6-12): The Participating Clinical Centers begin recruitment and screening of study participants, and beginning implementing interventions. Participant follow-up assessment begins. New trials are proposed. Database development is continued by the Data Coordinating Center. The Central Laboratories will begin functioning. Year 2-6 (Months 13-78): Recruitment of study participants continues. Participant follow-up assessment by the PCCs continues. Reports on recruitment rates, data quality, and baseline characteristics of study participants will be prepared by the Data Coordinating Center. Plans for data analysis on the recruitment experience and baseline findings are established by the Data Coordinating Center. Reports on data quality, and follow-up studies will be generated by the Data Coordinating Center during Years 3-6. Manuscripts describing the recruitment experience, baseline clinical and demographic characteristics of the participants, and initial results of pilot and feasibility trials will be prepared based on analyses from the Data Coordinating Center. Manuscripts describing other findings from the study will be prepared based on data analyses from the Data Coordinating Center. New trials will be proposed and implemented in the earlier parts of this Phase based on the findings of initial studies. The PCCs and the Data Coordinating Center, and whenever appropriate the Central Laboratories, will participate in special studies. Year 7 (First 6 months): Participant follow-up assessment by PCCs continues. Data analysis and manuscripts will be prepared addressing findings of the various trials. Plans will be established for study close-out. Year 7 (Last 6 months): Final follow-up clinic visits are conducted. Plans will be established for final data analyses by the Data Coordinating Center and Clinical Centers. Final data analyses will be performed and major reports and manuscripts prepared. The Data Coordinating Center, the PCCs and the Central Laboratories will be closed-out. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and for 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, a process will be used by the initial review group in which 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 of review by the National Diabetes and Digestive and Kidney Disease Advisory Council. Review Criteria Applicants are encouraged to submit and describe their own ideas about how best to meet the goals of the cooperative study as outlined in this RFA, and are expected to address issues identified under INFORMATION TO BE INCLUDED IN APPLICATIONS. In the written comments, reviewers will be asked to discuss the following aspects of the application. This will apply to all elements, including the proposed long-term interventional trial and the pilot and feasibility studies, 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. Review Criteria for Participating Clinical Centers 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? Approach: Does the applicant propose sound approaches to achieve the aims of the RFA? Is the potential pool of study participants available to the investigator outlined clearly? Have realistic estimates been made regarding the number of participants who will prove to be eligible for the studies? Among persons found eligible during screening, have realistic participation rates been applied to meet the sample size goals stated in the RFA? Has the racial, ethnic, and gender composition of the proposed study participants been adequately described, and plans described for appropriate analyses? Has information on the distribution of renal function of the population targeted for recruitment been discussed? What plans have been presented to ensure the high rates of follow-up and high rates of adherence mandated by the study protocol? What steps are planned for data quality control? The applicant must provide plans to ensure the complete, reliable, and timely transmission of study data to the Data Coordinating Center. Knowledge of the possible problems associated with the conduct of multi-center trials and any potential issues of importance in this study should be described. Investigators: Is the Principal 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? Are the Principal Investigator and her/his co- investigators experienced in collaborating with other investigators in a multi-center study? Are the investigators willing to participate in establishing and conducting a common protocol? Does the Principal Investigator and the proposed study team possess experience in recruiting participants to pilot and feasibility studies and to long- term interventional studies? Does the Principal Investigator and the proposed study team possess experience in clinical trial design to ensure meaningful participation in Phases I and II of the PKD Clinical Trials Network? Is there sufficient diversity in the proposed study team to allow the PKD Clinical Trials Network to propose a variety of clinically meaningful trials in Phases I and II? Necessary Expertise: Documented experience in nephrology, and specifically in the field of polycystic kidney disease, and clinical trial methodology is required. Experience in renal functional and radiologic assessments is highly desirable. Staff Qualifications: Documented specific competence and relevant experience of professional, technical, and administrative staff pertinent to the operation of a Participating Clinical Center are required. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Documented adequacy of the proposed facility and space is necessary. Is there evidence of institutional support and commitment for the proposed program? Access to Large Number of Eligible Patients and Ability to Recruit Large Numbers of Patients in Clinical Trials: Evidence of the ability to access large numbers of appropriate patients from which potential study participants will be recruited is necessary. Documentation must be provided on the ability to contact patients identified in order to invite them to more detailed, clinical assessments of their eligibility to participate in the trial(s). Provisions must be made to ensure subject confidentiality and ethical standards. Recruitment of Women and Minority Participants: Has the applicant described in detail the distribution of minority participants to be recruited? Is the racial and ethnic composition of the proposed recruited population similar to the U.S. PKD patient population? Review Criteria for a Data Coordinating Center: Significance: Does the study address an important problem? If the aims of the applications 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? Approach: Does the applicant acknowledge potential problem areas and consider alternative tactics in the implementation and performance of the trials necessary to achieve the goals of this RFA? What is the approach to handle missing follow-up data and patient non-adherence? Experience in developing protocols, developing web-based technology for data collection, establishing and maintaining large databases for data from the Participating Clinical Centers, plans for analysis of the combined data, and efforts to ensure high quality data collection, and ensuring study participant adherence and confidentiality will be evaluated. Investigators: Is the Principal 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? Are the Principal Investigator and her/his co- investigators experienced in collaborating with other investigators in a multi-center study? Documented experience in epidemiology, clinical trial methodology and biostatistics is required. Does the applicant have expertise in longitudinal data analysis, including renal functional and radiologic measurements? The level of expertise of consultants in nephrology will be considered. Experience in database development, data management, and statistical analysis is required. The ability of the investigators from the Data Coordinating Center to take the lead in developing a cooperative relationship among the Participating Clinical Centers and the Central Laboratories, and to exercise appropriate leadership in matters of study design, data acquisition, data management, data quality, data analysis, repository function, and administration and coordination of Steering and Planning Committee meetings will be considered. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Documented adequacy of the proposed facility and space is necessary. Is there evidence of institutional support and commitment for the proposed program? In addition to the above criteria, in accordance with NIH policy, all applications will be reviewed with respect to the following. The reasonableness of the proposed budget for each year of the program. The adequacy of the proposed protection for humans and the environment, to the extent they may be adversely affected by the studies described in this RFA. The scientific review group will also examine the safety of the research environment. Schedule Letter of Intent Receipt Date: October 16, 2001 Application Receipt Date: November 16, 2001 Special Review Committee: April 2002 NDDK Advisory Council: May, 2002 Anticipated Award Date: June, 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Ability to assess eligibility of, enroll, and maintain patients in clinical trials of interventions appropriate for PKD. o Scientific merit as determined by peer review o Availability of funds o Cost o The size and gender, racial and ethnic composition of the proposed patient study populations. o Geographic distribution of the Participating Clinical Centers INQUIRIES Written and telephone inquiries concerning this RFA are strongly encouraged. The opportunity to clarify any issues or questions form potential applicants is welcome. For information relating to the NIDDK, programmatic inquiries may be made to: John Kusek, PhD, or Paul L. Kimmel, M.D. Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Room 617 MSC 5458 6707 Democracy Boulevard Bethesda, Maryland 20892-5458 (for express or courier service use 20817) Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: Dr. Kusek jk61x@nih.gov Dr. Kimmel pk77g@nih.gov Fiscal and administrative inquiries may be directed to: Ms. Teresa Farris Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Room 728 MSC 5456 6707 Democracy Boulevard Bethesda, Maryland 20892-5456 (for express/courier service use 20817) Telephone: (301) 594-7682 FAX: (301) 480-3504 Email: tf102y@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.849 and 93.864. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410), as amended by Public Law 99-158, 42 USC 241 and 285) and administered under Public Health Service grants policies and Federal Regulations 42 CFR 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 Public Health Service strongly encourages all grant and contract recipients to provide a smoke-free work place 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 Public Health Service mission to protect and advance the physical and mental health of the American people.

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