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Assumptions: Phase 1 extends from 1994 through Sep 30, 2001. After-AASK extends from February 1, 2002 through June 30, 2007. Of 1,094 originally randomized patients for the AASK trial, 263 were lost to death or dialysis by September 30, 2001. The AASK centers indicate that an additional 154 patients are lost to follow-up or unlikely to consent to After-AASK, leaving 677 active patients on September 30, 2001. For Phase 3, the numbers of events during AfterAASK were estimated by first fitting Weibul models to estimate event probabilities for each outcome as a function of baseline urine protein/creatinine and baseline GFR for patients in the ACE and Beta Blocker Groups. These models were then applied to the most recent urine October 1, 2002 52 protein/creatinine and GFR values to project future event rates for patients in all three treatment groups. Extensions of these models were used to account for the differences between the patient’s most recent serum creatinine value and their initial baseline serum creatinine when evaluating rates of doubling of serum creatinine from the original pre-randomization baseline serum creatinine for Phase 2 analyses. A 3% annual loss-to-follow-up was assumed for the period from October 1, 2001 though June 30, 2007.
Quality Assurance and Quality Control
Quality assurance focuses on steps taken prior to data collection to assure accuracy and minimize errors. Quality control focuses on steps taken after data are collected to examine quality, measure reproducibility and identify errors. Due to finite resources, quality assurance and control efforts must be concentrated on key procedures and measurements, typically, those related to the primary outcomes and exposures of interest.
Primary steps to assure high quality data are recruiting and retaining highly motivated staff, training (and retraining) of data collectors, and observing staff during mock or actual visits.
Local monitoring is vitally important and can identify and correct problems weeks or months before such problems become apparent on quality control reports. Specific activities that lead to high quality data collection and that standardize procedures within and across field centers include 1) preparation of a well-documented protocol and a manual of operations, 2) centralized training and certification of technicians, 3) proficiency requirements before initial certification of technicians, 4) requirements for a minimum number of procedures to maintain certification, 5) routine observation of technicians, and 6) routine calibration of equipment.
Quality Control The principal goals of quality control in a multi-center study such as the AASK Cohort study are to identify problems in data collection with sufficient time to institute appropriate corrections October 1, 2002 53 and to quantify the quality of data collected over the course of the study so as to provide information necessary to interpret study results. To accomplish the first goal, adequate data must be accumulated to enable valid analyses to be performed within a brief period after initiation of data collection. To accomplish the second goal, sufficient data must be compiled throughout the study to detect any drift or deterioration in data quality over time.
For quality control pertaining to field center operations, the coordinating center can provide considerable information from simple analyses. Bimonthly reports of such analyses should include 1) counts of completed tests, 2) distributions of test results by technician and center over time, 3) displays of reproducibility by technician and center, 4) counts of clinical events and of medical record retrieval, 5) distributions of lag time in data entry, 6) distribution of data entry errors, and 7) response time to queries from the coordinating center. Investigators and staff will review these reports carefully to identify areas of concern and take corrective action, if appropriate.
Overview The AASK Cohort will include 21 clinical centers, a coordinating center and several central laboratories. In addition to these centers, there will be several committees and subcommittees, comprised of AASK cohort investigators and staff, to provide guidance and oversight of the study. To minimize confusion and to take advantage of the existing infrastructure of AASK, the organizational structure will be similar to that of the AASK trial.
The following is a list of participating centers:
• The 21 AASK Clinical Centers from the AASK Trial - University of California at San Diego, Case Western Reserve University, Emory University, University of California at Los Angeles - Harbor Hospital, Howard University, Johns Hopkins University School of Public Health, Martin Luther King Medical Center, Medical University of South Carolina, Meharry Medical College, Harlem Hospital, Morehouse Medical College, Lenox Hill Hospital, Ohio State University, Rush Medical Center, University of Alabama, University of Florida, University of Miami, University of Michigan, University of Southern California, University of Texas - Southwest and Vanderbilt University. These centers will be responsible for retention of participants and collection of data.
• The AASK Coordinating Center at the Cleveland Clinic. This center will be responsible for coordinating all activities of the study, including subcommittee and committee activities;
preparation of the Manual of Operations; data collection and management procedures; data analyses; and preparation of study reports for the EAC, Steering Committee and NIDDK.
• The National Institute of Diabetes, Digestive and Kidney Diseases of the National Institutes of Health. The NIDDK will provide scientific, administrative and fiscal input into the conduct of the study.
• A Genetics Core Laboratory at Mount Sinai Hospital (NYC).
• A Cardiovascular Procedures Core Laboratory at Lenox Hill Hospital.
• Principal Investigators, Co-Investigators, Fellows, and Senior Staff from these centers will be eligible to present study data, participate in writing groups, and prepare manuscripts. In addition to the above centers, those pharmaceutical companies that provide substantive financial support for the AASK Cohort Study can attend Steering Committee meetings and can provide input on the study protocol and its amendments. These companies are not voting members of the Steering Committee.
Committees and Subcommittees The following are standing committees and subcommittees of the study. At the request of the Steering or Executive Committee, ad hoc groups will be formed to address specific, time-limited issues.
External Advisory Committee (EAC) - The EAC will advise the NIDDK and the AASK Cohort Steering Committee on matters related to the design and conduct of this study. During the study, the committee will serve as a Data Safety and Monitoring Board (DSMB) and will monitor data accrual, data analyses and participant safety.
Steering Committee - The Steering Committee is the governing body of the study. It will approve the protocol and all major amendments; will provide scientific guidance; will delegate responsibilities to the Executive Committee and Subcommittees; will review Subcommittee recommendations; and will resolve any disputes, such as authorship. Its voting members will include the Principal Investigators of each clinical center, the Principal Investigator of the Coordinating Center, and the Project Officer from NIDDK. The Steering Committee will meet August 1, 2002 56 at least annually and will vote on interim protocol changes, typically by FAX or email.
Executive Committee - The Executive Committee will act on behalf of the Steering Committee to oversee conduct of the study between Steering Committee meetings. Its members will include the Chair of study, Vice-Chair of the study, the NIH Project Officer, the DCC PI, and Chairs of each Standing Subcommittee. The Executive Committee will meet regularly by phone, typically monthly, to monitor conduct of the study, deliberate on major scientific and operations issues, and consider those items that might require Steering Committee approval. It will review all proposed publications, presentations and new substudies that have been initially reviewed by Publications and Ancillary Studies Committee.
Measurements/Quality Control Subcommittee - This subcommittee will recommend to the Steering Committee measures, processes, and procedures for assuring quality control of the study, including training, certification, quality control measures and procedures, and other activities directed at ensuring that data are valid and reliable.
Blood Pressure Management Subcommittee - This subcommittee will recommend to the Steering Committee the blood pressure goal; the approach toward use of antihypertensive medications;
and adherence measurements in the cohort study. During the Cohort, it will track blood pressure management at the centers.
Cardiovascular Outcomes Endpoint Subcommittee - This subcommittee will recommend to the Steering Committee the procedures for measurement of relevant cardiovascular variables including, but not limited to, echocardiography, ambulatory blood pressure monitoring and electrocardiography. It will be responsible for developing the Manual of Operations chapters related to these outcomes.
Publications/Ancillary Studies Subcommittee - This subcommittee will develop presentation and publications procedures; will assemble writing groups; will review new paper proposals; will monitor publication progress; will advise the Executive and Steering Committees on all matters related to publication and presentation of study results; and will review ancillary studies. This
Genetics Subcommittee - This subcommittee will propose genetic analyses to be done in the cohort, will track the accrual of specimens, and will evaluate new proposals related to family and/or genetic substudies.
Study Coordinators/Retention Subcommittee - This subcommittee, comprised of the Study Coordinators from each Clinical Center, will develop procedures to enhance retention of participants; will monitor the work load of staff; and will evaluate the impact of proposed data collection procedures.
Protocol Changes and Amendments
As a clinical trial, the AASK trial appropriately discouraged protocol changes. In contrast, the AASK cohort study is an observational study in which additional data collection, either new exposures or outcomes, are encouraged. These proposals should be proposed as substudies (to be done by all clinical centers) or ancillary studies (to be done by a few centers). Still, new data collection must be justified in terms of scientific importance, participant burden, and staff burden; fiscal implications will also be a major consideration. To facilitate review, investigators that propose substudies or ancillary studies must provide a synopsis of their proposal, typically 3-5 pages, that provides the hypothesis, background and methods, as well as a detailed description of the data collection procedure, frequency of collection, power analysis, participant burden, staff burden and budget, if appropriate.
Approval of new data collection items will require two or three steps, depending on the type of data collection proposed. First step: initially, the Publications and Ancillary Studies Subcommittee will review all proposals which request either collection of new data items or new analyses of stored specimens. Second step: if the PASC approves the study, the Executive Committee must then approve the request. Simple majorities of the PASC and the Executive August 1, 2002 58 Committee are required for the first and second steps. Third step (contingent upon the type of data collection): if the additional data collection substantially increases participant burden OR substantially increases staff burden OR substantially increases costs OR obtains sensitive information, the entire Steering Committee must approve the new data collection item. In this case, the vote will require a 3/4 majority of the Steering Committee.
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