Recruitment experience in the full-scale phase of the modification of diet in renal disease study

Recruitment Experience in the Full-Scale Phase of the Modification of Diet in Renal Disease Study John W. Kusek, PhD (Chair), Terry Coyne, MS, RD, Ann de Velasco, RN, Martin J. Drabik, BA, R. Allan Finlay, RN, Jennifer J. Gassman, MS, Sally Kiefer, RN, Sandra N. Powers, RD, Theodore I. Steinman, MD National Institutes of Health (J. W.K.); University of Pittsburgh (T. C.); University of Miami (A.D.V.); Cleveland Clinic Foundation (M.J.D., J.J.G.); University of Florida (R.A.F.); University of Southern California (S.K.); Vanderbilt University (S.N.P.); Brigham and Women's Hospital (T.I.S.) for The Modification of Diet in Renal Disease Study Group

ABSTRACT The Modification of Diet in Renal Disease (MDRD) Study is a randomized, multicenter clinical trial testing the effects of three different levels of dietary protein and p h o s p h o r u s intake a n d two levels of blood pressure control on the rate of loss of kidney function in persons with various chronic kidney diseases. During a 27-month recruitment period, 2507 persons w h o had objective evidence of impaired kidney function were screened at 15 centers. Eight h u n d r e d a n d forty m e n and w o m e n aged 18-70 with a glomerular filtration rate b e t w e e n 13 and 55 ml/min/1.73 m 2 were randomized. Medical record review was the primary means of identifying study participants at the beginning of recruitment. Later, use of mass media was instrumental in alerting both the public and the medical c o m m u n i t y of the need for MDRD Study participants. Overall, the most important sources of r a n d o m i z e d participants were referral by personal physician (45.4%) and relative/friend (5.6%), a n d self-referral after hearing about the trial from n e w s p a p e r s (23.9%) and television (5.2%). Review of medical records from defined patient populations was the source of 22.3% of the r a n d o m i z e d s t u d y participants. A total of 9.4% of the r a n d o m i z e d participants called a toll-free (800) telephone n u m b e r before contacting the centers. KEY WORDS: recruitment, renal disease, physician referral, randomized clinical trial

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Address reprint requests to: MDRD Data Coordinating Center, Desk P88, Department of Biostatistics and Epidemiology, The Cleveland Clinic Foundation, 9500 Euclid Avenue--One Clinic Center, Cleveland, Ohio 44195-5196. Address correspondence to: John W. Kusek, PhD, Division of Kidney, Urologic and Hematologic Diseases, National Institutes of Health, 5333 Westbard Avenue, Room 3A04, Bethesda, Maryland 20892. Received October 2, 1992; revised July 9, 1993. Presented in part at the Joint Meeting of the Society for Clinical Trials and the International Society for Clinical Biostatisticians, Brussels, Belgium, July 8-12, 1991.

0197-2456/93/$6.00

Controlled ClinicalTrials 14:538-557 (1993) © ElsevierScience Publishing Co., Inc. 1993 655 Avenue of the Americas, New York, New York 10010

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INTRODUCTION The Modification of Diet in Renal Disease (MDRD) Study is a multicenter, randomized clinical trial designed to test the effects of three levels of protein and phosphorus intake and two levels of blood pressure control on the rate of decline of kidney function among persons with various chronic kidney diseases. The results of the pilot study and the design and rationale for the full-scale study have been previously described in detail [1-3]. Recruitment for the MDRD Study offered numerous challenges due to several factors including the following: (1) The range of kidney function for eligibility was narrowly defined (glomerular filtration rate, or GFR, was 1355 ml/min/1.73 m2), (2) Serum creatinine concentration, used to screen patients, did not adequately reflect the level of kidney function as assessed by the GFR, (3) The prevalence of kidney disease in the general population is low and the prevalence of moderate (which constituted three fourths of the sample size in the present study) and advanced kidney impairment in the general population was unknown, (4) Nine of the 15 centers that were selected to conduct the full-scale study did not have recruitment experience from the pilot phase. In other clinical trials conducted to study the effects of low-protein diets on the course of chronic kidney disease, the means by which study participants were recruited was not documented. This information is important for planning future clinical trials of chronic kidney disease. The purpose of this paper is to describe the overall results of recruitment and the means by which participants in the full-scale phase of the MDRD Study were identified. METHODS Clinical Centers Fifteen clinical centers participated in the study. Boston, Massachusetts and Los Angeles, California each had two centers. The remaining centers were in Washington, D.C.; Iowa City, Iowa; Winston-Salem, North Carolina; Durham, North Carolina; Gainesville, Florida; Miami, Florida; Brooklyn, N e w York; San Antonio, Texas; Columbus, Ohio; Atlanta, Georgia; and Nashville, Tennessee. Screening, Baseline Visits, and Randomization Initial recruitment efforts were directed to identifying persons meeting the general eligibility criteria listed in Table 1. A more comprehensive list of eligibility and exclusion criteria can be found elsewhere [2]. Patients meeting the entry criteria and GFR measured at the first baseline visit (B0) near the range for randomization (13-55 ml/min/1.73 m 2) could be enrolled in a baseline, or run-in, period. The primary purpose of the baseline period was to determine eligibility for randomization. Other objectives were to (1) determine baseline measures for renal function, nutritional status, and blood pressure, (2) familiarize participants with diet and study procedures, (3) assess participants' ability to comply with study requirements prior to randomization, and (4) establish a rapport between the patient and the study team. Four visits (B0, B1, B2, and B3) were conducted during the baseline period (Table 2).

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1

Screening a n d Baseline Entry Eligibility Criteria Inclusion criteria • Age 18-70 • Evidence of chronic renal disease with: Increased serum creatinine Men: 1.4-7.0 mg/dl Women: 1.2-7.0 mg/dl or decreased creatinine clearance 16-70 ml/min/1.73 m 2 • Mean arterial blood pressure 4125 m m Hg Exclusion criteria • Insulin-dependent diabetes • Kidney transplant recipient

Table 2

Schedule of Participant M e a s u r e m e n t s D u r i n g Baseline Type of Data Counseling: Diet and Anthro- Blood Blood Blood Food Amino Month pometry Pressure GFR Urine Tests Pressure Record Acids ECG

Baseline 0 1 2 3

X X

Table 3

X X X X

X X

X X X X

X X

X X X X

X X X

X

Protein a n d P h o s p h o r u s C o n t e n t of Diets Protein (g/kg'/day)

Diets Study A: Usual Studies A and B: Low Study B: Very low

Phosphorus (mg/kg'/day)

1.30

16-20

0.575

5-10

0.28 plus keto acid mixture b

4-9

aStandard body weight [4]. b0.28 g/kg/day, Ross Laboratories, Columbus, Ohio.

T h o s e f o u n d ineligible d u r i n g baseline could be s c r e e n e d again a n d r e e n t e r e d into baseline evaluation if there w a s a c h a n g e in the criterion that p r e v i o u s l y h a d excluded t h e m . P e r s o n s w i t h a GFR level of 25-55 ml/min/1.73 m 2 at the B3 visit a n d e s t i m a t e d protein intake ~ 0 . 9 g/kg/day w e r e eligible for s t u d y A a n d rand o m i z a t i o n to either a l o w - p r o t e i n / p h o s p h o r u s or a usual p r o t e i n / p h o s p h o r u s diet, as indicated in Table 3. P e r s o n s w i t h a GFR level of 13-24 ml/min/1.73 m 2 at the B3 visit w e r e eligible for s t u d y B, regardless of their e s t i m a t e d

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541

protein intake. In study B, patients were randomized to either the low-protein/phosphorus diet or to a very low-protein diet (Table 3). Studies A and B were factorial design studies of diet and blood pressure. That is, within each diet group, study participants were also randomly assigned to either a low mean arterial pressure (MAP) goal or a moderate MAP goal. Each patient's blood pressure goal was also dependent on his or her age (Table 4). Recruitment Goals Based on variability of GFR measurements observed during the MDRD pilot study, the original calculated sample size needed for the full-scale study was 604 patients for study A (goal of 40 randomized per center) and 196 for study B (goal of 13 randomized per center) [2]. To achieve this, we set goals of 60 baseline patients per center in the study A GFR range and 17 baseline patients per center in the study B GFR range. During the course of the study, we observed lower-than-expected between-person variance in rates of decline in GFR in study A and higher-than-expected within-person variance in rates of decline in GFR in study B. These findings led the MDRD investigators to increase the sample size from 196 to 250 for study B and allowed the investigators to accept a decrease in sample size from 604 to 550 for study A. Recruitment goals were adjusted to allow the new sample size requirements to be met while maintaining each center's randomization goal of 53 per center for studies A and B combined. Recruitment Techniques During recruitment in the MDRD full-scale trial emphasis was placed on (1) using multiple recruitment techniques at all centers; (2) directly appealing to potentially eligible study participants by means of mass media with the aim of attracting persons to the study with GFR in the study A range; (3) evaluating the yield of randomized study participants identified from review of medical records from well-def'med patient populations; and (4) recruiting through medical channels, especially physicians. During the MDRD pilot study, 71% of the randomization goal was attained. The primary source of study participants in the pilot study was the clinical practices of the principal investigators [3], and most of the participants enrolled had GFRs in the range of study B. It was difficult for the centers to find patients with GFRs in the study A range (25-55 ml/min/1.73 m2). Based on this experience, multiple recruitment strategies were implemented during the full-scale study (Table 5). Table 4 Mean Arterial Blood Pressure (MAP) Goals a MAP Goal (mm Hg) Age in Years at Entry Moderate Low 18--60 ~107 ~92 t>61 ~113 ~98 "MAP = 2/3 diastolic + 1/3 systolic.

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J.W. Kusek et al. Table 5

Frequently Used Recruitment Techniques Systematic review of medical records Physician referral Mass media Review of laboratory test results (creatinine) and special medical reports (kidney biopsy)

As expected, many study B participants were referred by nephrologists. Because of the likelihood that persons with GFRs in the study A range would not yet be under the care of nephrologists, emphasis was placed on contacting internists, using hospital laboratory reports, and using the mass media. Television and radio interviews, public service announcements, and paid advertising in local newspapers were utilized by many centers to appeal directly to potentially eligible study participants. Recruitment materials were developed. These included a "Referring Physician's Booklet," a "Patient Information Pamphlet" (available from the MDRD Data Coordinating Center), and a professionally produced television public service announcement. Stand-up posters with tear-off flyers, as well as pads of flyers with a description of the study and the local center's telephone number, were provided to centers for placement in local pharmacies, physicians' offices and waiting rooms, and public locations. Other recruitment materials included feature articles in the print media and physician newsletters. A media distribution service periodically sent press releases about the study to newspapers and television and radio stations near the centers. One unique recruitment tool used in this study was the establishment of a toll-free (800) telephone number for persons to call if they wished to learn more about the study. Callers were referred to the nearest center to determine screening eligibility. When national publicity was used (e.g., through Cable News Network), we asked the (800) telephone number be provided. Recruitment through physician referrals was also emphasized. MDRD centers sent local physicians the "Referring Physician's Booklet" and a letter describing the purpose and design of the study and the need for study participants. Often physicians caring for a large number of patients received a follow-up telephone call from center staff, to further explain the study in hopes of gaining access to patient records for review and to stimulate direct referral of patients. With the consent of the facilities, medical records were reviewed at various outpatient clinics such as renal, diabetes, and hypertension clinics at participating MDRD centers, their affiliated hospitals, and other hospitals in the area. Medical record reviews were also used. During the pilot study, one center randomized 10 patients who had been found by reviewing 235 medical records, and many MDRD investigators believed that a systematic review of patient medical records would yield a substantial number of randomized participants in the full-scale trial. A systematic review was defined as review of the records or laboratory results from a defined population such as an outpatient clinic. During a systematic review, each record or result was reviewed and a chart review form indicating eligibility status for the screening visit was completed. (Forms were only required for patients meeting creatinine, age, diabetes, and kidney re-

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cipient criteria noted in Table 1.) A chart review form was also completed for patients referred directly (usually by mass media or direct physician referral) to the MDRD Study rather than located through systematic chart reviews. So that we could later assess the utility of medical record review as a source of study participants, center staff noted on the chart review form whether the partidpant was found through direct referral or another nonsystematic scheme, or through systematic medical record review. Several centers tried to locate potential study participants by reviewing computerized laboratory data for serum creatinine. Centers also obtained pathologists' lists of patients who had had kidney biopsies performed at their institutions; this was a particularly rich source of potential participants in some centers. For all three sources of patient records (chart reviews, laboratory data reviews, and biopsy record reviews), the MDRD Study team asked physicians for permission to contact their patients by letter and/or telephone. Study principal investigators and other physicians participated in recruitment by contacting private physicians within their institutions and community to promote patient referrals. Study physicians also participated in television/radio interviews and news stories. They informed local medical societies about the goals of the trial through presentations and printed material. They used grand rounds, other meetings of physicians, and presentations to special groups (e.g., patients with polycystic kidney disease) to provide additional publicity for recruitment.

Data Collection Information regarding referral sources of potential study participants was collected at several points in the recruitment process. For each person who called the toll-free (800) number, the operator completed a form that included the following question: "Where did the caller hear about study 800 number?" Possible responses included relative/friend, personal physician, study brochure, newspaper, radio, television, and other. The chart review form asked whether the patient's chart came from a nephrology clinic, private nephrology office, other physician's office, HMO, or laboratory; for those found during a nonsystematic review, the center could respond instead that the patient was specifically referred by physician, self-referred, and other. During the first baseline visit, we again asked, "Where did the person first hear about the study?" and asked whether the person had called the toll-free number prior to being in contact with the center.

Data Monitoring The Data Coordinating Center monitored and reported progress in recruitment. The total and clinic-specific results of recruitment were reported to investigators on a monthly basis at first and then on a weekly basis by electronic mail. Summaries included the total number of screening visits, number enrolled in baseline by GFR level, exclusion/dropout rate during baseline, anti number of participants randomized by each center. Referral source at screening visit and the rate of randomization by referral source was

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J.W. Kusek et al. maintained centrally and locally to determine the most efficient and successful recruitment strategies.

RESULTS Review of Medical Records A total of 4300 medical records were reviewed; 2060 were from a defined patient population and designated as systematic reviews, and 2225 were classified as nonsystematic, with 15 reviews unidentified as to type. Of the patients designated as identified during systematic reviews, 45.9% were from nephrology clinics (Table 6). Of the patients designated identified from nonsystematically record reviews, 45% were considered self-referred from study publicity. Participants identified during systematic chart review had a lower rate of eligibility for a screening visit (30.3% versus 84.6%), a lower rate of entry into baseline (21.9% versus 60.2%), and a lower percentage of participants randomized (9.1% versus 29.3%), compared to those identified in other, nonsystematic ways. Reasons for exclusion from a screening visit (as determined by chart review) or exclusion from entering baseline (as determined by a screening visit) are listed in Table 7.

Referrals from Toll-Free Telephone Number The toll-free (800) telephone number generated 1944 referrals to the centers over 27 months. During the first full year of recruitment (1989), there were 725 referrals. In the second year, 1001 persons were referred to the centers, an increase of 38%. The remaining referrals were made prior to 1989 (94) and during the last 3 months of recruitment (124). The total number of referrals to individual centers varied from 54 to 287. Newspaper (34.3%) and television (14.5%) were the major sources of knowledge about the toll-free number.

Table 6

Referral Sources for Medical Records a Type of Review

Referral Source Nephrology clinic Private nephrology office Other physician's office HMO Laboratory Referred by physician Self-referred Other Total "Source of 15 records were missing.

Systematic Number (%) 945 (45.9%) 278 (13.5%) 202 (9.8%) 41 (2.0%) 52 (2.5%) 21 (1.0%) 20 (1.0%) 501 (24.3%) 2060 (100.0%)

Nonsystematic Number (%) 225 (10.1%) 219 (9.8%) 72 (3.2%) 10 (0.4%) 13 (0.6%) 375 (16.8%) 1002 (45.0%) 308 (13.8%) 2225 (100.0%)

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Table 7 Reasons for Exclusion at Screening Visit and Baseline Visits for Systematic and Nonsystematic Medical Record Reviews Sytematic Review Urinary tract obstruction Renal artery stenosis Staghorn calculi Cystinuria Serious medical condition Drugs Compliance doubtful In another study Pregnant or lactating Urinary retention Allergy to iothalamate Urine protein I>10 g/day Serum albumin <3.0 g/dl Body weight Other MAP >125 mm Hg Creatinine out of range Total exclusions Total patients

Nonsystematic Review

At Screen

At Baseline

At Screen

At Baseline

20 56 8 4 463 117 178 11 3 11 4 3 5 9 9 0 0 901 801

1 1 0 0 4 7 82 0 0 0 4 0 7 0 0 7 73 186 136

1 5 2 1 26 12 16 2 0 4 5 1 0 0 0 0 0 83 71

1 3 0 0 12 6 311 0 1 3 9 0 20 0 0 20 318 704 450

Screening Visits Recruitment experience from screening through randomization is shown in Fig. 1. The screening period began in January 1989 and continued through March 1991, with a total of 2741 screening visits conducted over the 27-month period. These visits included persons who entered baseline, dropped out during that period for various reasons (N = 142), and were screened again to reenter baseline, and persons who were screened twice (N = 9) before their first entry into baseline. Of the remaining 2590 visits, 83 were rescreenings (second or third) of individuals previously found ineligible prior to entering baseline. Hence, a total of 2507 individuals were screened. Approximately three fourths (77%) of the potential study participants who completed the screening visit were found to be eligible for the first baseline visit. The total number of persons attending screening visits varied nearly threefold among the centers (range 86-241).

Baseline Experience A baseline 0 (B0) GFR measurement was obtained on a total of 1785 persons (Fig. 1). (Figure I includes only the most recent entry into baseline for patients who entered baseline, dropped out, and were reentered.) Of the 1785 patients, 1325 (74.2%) fell within the MDRD Study GFR range (13-55 ml/min/1.73 m2). Eighty-two participants (4.6%) had a B0 GFR below 13 ml/min/1.73 m 2, and 378 (21.2%) had a B0 GFR greater than 55 ml/min/1.73 m 2. Enrollment into baseline for studies A and B by calendar quarter of re-

Figure 1 Flow diagram of recruitment in the MDRD Study.

321

1,161

Number of Baseline 3 visits conducted

j

1,095

1,935

Number of persons who dropped out or were excluded after B3 visit

774

Number of persons who dropped out or were excluded prior to B3

,,.._

Number of Baseline 0 GFR'., performed (N=1,935 among 1,785 persons)

Number of persons who dropped out or were excluded at any time during Baseline

152

Number of persons who re-entered Baseline

2,741

Number of Screening Visits (N=2,741 among 2,507 persons)

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Recruitment in the MDRD Study

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Figure 2 Baseline enrolloment and randomization by calendar quarter of recruitment: study A. cruitment is shown in Figs. 2 a n d 3. One hundred thirty-five study A participants were to be enrolled into baseline each quarter. This goal was not met except during the last quarter of recruitment. Forty-five study B participants were to be enrolled in baseline each quarter. This goal was met easily (Fig. 3) during the first four quarters, and admission of study B participants into baseline then decreased, since there were already nearly enough participants to meet the original randomization goal of 196. When the need for an increase in study B sample size was announced after 24 months of recruitment, entry into baseline for study B increased. Among 1935 entries into the baseline period, including the multiple entries of those who reentered baseline, 774 potential participants dropped out or were excluded from baseline prior to the B3 visit and 321 after the B3 visit, for a total of 1095 exclusions (Fig. 1). As noted in Table 8, the major reason for dropping out before the B3 visit was B0 GFR too high; the most frequently cited reason for exclusion after the B3 visit was estimated protein intake too low (study A only). The exclusion or dropout rates among those in the studies A and B range were 41.7 and 47%, respectively.

548

J.W. Kusek et el.

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Table 8

Reasons for D r o p p i n g Out/Exclusions D u r i n g Baseline a Reasons

Before Baseline 3 Visit

After Baseline 3 Visit

GFR too high GFR too low Estimated protein intake < 0.9---study A Doubtful compliance Patient request/won't consent Study team preference Medical conditions Unusual diet preferences Other

328 105 31 97 215 69 42 Not available 65

82 50 111 37 30 21 3 12 28

aA potential study participant may have had more than one reason for exclusion, but for persons excluded on the basis of B3 GFR too high or too low, only that reason was counted.

Randomization D u r i n g the 29-month r a n d o m i z a t i o n period (April 1989 t h r o u g h A u g u s t 1991), 585 s t u d y A a n d 255 s t u d y B participants were r a n d o m i z e d . These 840 r a n d o m i z a t i o n s were the result of 4300 chart reviews a n d 2057 s u b s e q u e n t screening visits. W h e n screening efficiency is defined as the n u m b e r of per-

549

Recruitment in the MDRD Study

sons randomized/the number of individual persons seen at screening visits, we had an overall screening efficiency of 33.5%. This ranged from 24.0-62.8% among the centers depending on the prescreening criteria established at individual centers. The 3-month goal for study A randomization (N = 90) was rarely achieved (Fig. 2). In contrast to the study A randomization goal attainment, but in agreement with study B baseline goal attainment, the quarterly study B randomization goal (N = 20) was easily achieved during the calendar quarters when clinics were being encouraged to enroll study B participants (Fig. 3). The cumulative number of randomized participants for study A was well below the original goal throughout the recruitment period (Fig. 4). With extension of the recruitment period and the decrease in study A sample size requirement, we eventually exceeded the revised goal of 550 and approached the original goal of 604 (Fig. 4). In contrast, the cumulative number of randomized study participants for study B largely exceeded goal throughout most of the recruitment period (Fig. 5). All but one center met or exceeded its recruitment goals for study A and study B combined. There was no difference in recruitment goal attainment between the centers who had participated in the MDRD pilot study and those who had not. Of the randomized participants, 22.3% came from systematic medical record review. Major sources of all randomized participants included personal physician referral (45.4%), relative/friend referral (5.6%), and self-referral after hearing about the study from newspaper (23.9%) and television (5.2%). Sources of referral for randomized participants in study A and study B were similar. A total of 9.4% of the randomized participants had called the toll-free number prior to their contact with the centers.

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Figure 5 Cumulative number of randomized participants: study B. DISCUSSION With the recruitment period extended for 6 months, recruitment in the full-scale phase of the MDRD Study was successfully completed, despite significantly higher numbers of patients excluded during baseline for both studies A and B than had been observed in the pilot study. The success of recruitment in the full-scale study can be attributed to a number of factors, including the use of multiple recruitment strategies, increased use of mass media, and an organized approach to and monitoring of recruitment during this phase of the study. Study-wide and clinic-specific goals were established early in the recruitment period, and site visits, conference calls, and periodic meetings of recruitment coordinators emphasized the importance of meeting recruitment goals and the need to implement multiple recruitment strategies. Particular emphasis was placed on finding participants for study A because of the difficulty in identifying these patients and because of the need for a larger number of study A participants compared to study B. Recruitment activities were supplemented with study-wide efforts to obtain free national promotion. MDRD investigators were successful in obtaining notices in national publications including USA Today and Prevention magazine, which listed the toll-free (800) number. National publicity, coupled with the toll-free telephone number, may be an efficient and cost-effective recruitment tool for future clinical trials of renal disease and deserves further evaluation. This is the first detailed report of recruitment for a clinical trial on kidney disease. Recently the results of several trials that studied the effects of lowprotein diets on the decline of kidney function were reported [5-8]. Among three small single-center trials, the source of participants in two trials was the outpatient renal clinic [5,7], and in the other trial [6], the source was not

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stated. In a multicenter trial, the Northern Italian Cooperative Study Group [8], over 400 study participants were recruited from 21 nephrology units. None of these reports, however, provides detailed information about h o w recruitment was accomplished. As previously noted, the recruitment period in the MDRD Study was extended by 6 months. In a review of 13 population-based studies and randomized clinical trials supported by the National Heart, Lung, and Blood Institute, 11 studies extended recruitment and 2 studies completed projected recruitment within their planned recruitment period [9]. The ratio of our actual versus planned recruitment time of 1.29 is similar to the average ratio of 1.32 for the 13 studies noted above. There is little standardization in reporting results of recruitment in clinical trials. However, one measure of success that has been proposed [9] is recruitment efficiency, or the ratio of the observed to the expected numbers of person-weeks accumulated during the recruitment period. For the MDRD Study, the overall recruitment efficiency was 80% (71.8% for study A and 102% for study B). The MDRD recruitment efficiency is similar to the recruitment efficiencies for the Multiple Risk Factor Intervention Trial, the Aspirin Myocardial Infarction Study (AMIS), and the Beta Blocker Heart Attack Trial of 81, 83, and 82%, respectively [9]. However, the overall favorable ratio observed in the MDRD Study was due to the high rate of randomization for study B early in recruitment. Caution should be exercised in comparing recruitment efficiencies in this manner for clinical trials because differences in demands on staff time and resources available may vary considerably among studies [9]. Physician referrals accounted for nearly half of the randomized study participants. These referrals were often the result of center staff contacting physicians by letter and/or telephone to review patient charts so as to identify persons eligible for screening. In some cases, patients responded to publicity about the study and contacted their physicians to seek more information. Physician referrals have been cited as sources of study participants in other clinical trials. The contribution of these referrals to the total number of randomized participants has been shown to be minimal in some studies [10-12], and uncertain [13] or poor in others [14]. Little is known about the factors that may influence physicians to refer patients to clinical trials [15]. However, we believe that our success in obtaining physician referrals is attributed to simplifying the referral process by directly contacting potential study participants and clearly delineating the goals of the study. In our study, referrals may have been more easily attained since no standard course of treatment is available for these patients. The clinic staff went to physicians' offices to review medical records and undertook the burden of contacting potential study participants with physician permission. Each patient was provided with a clear and understandable description of the study so that a discussion about the possible benefits of joining the study might be initiated with his or her physician. Moreover, private physicians were provided the results of laboratory tests conducted on their patients. In addition, as previously noted, physicians were provided a handbook describing the study in detail, which served to make them better advocates for their patients.

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J.w. Kusek et al. The MDRD Study indicates that recruitment by mass media is a feasible strategy for attracting participants to a clinical trial of chronic kidney disease. Nearly 30% of the self-referred randomized study participants identified mass media (i.e., television, newspaper, and radio) as their source of information about the study. A series of press releases were disseminated via a media distribution service. Although we were unable to quantitate the effect of the press releases, they added to the background of publicity generated locally by center staff. Contrary to our original belief, however, the proportion of randomized participants who identified mass media as their primary source of information about the trial did not differ significantly by study group. Systematic review of medical records, primarily in nephrology clinics, was considered by many MDRD recruitment coordinators to be a time-consuming recruitment technique. However, systematic review of hospital/clinic medical records provided a modest but steady flow of potential participants at some centers early on in the recruitment period before other techniques were implemented. Chart or medical record review has been used sparingly as a recruitment technique in other clinical trials seemingly because of the effort required to implement this strategy and the low return of eligible study participants [16,17]. However, over 40% of the randomized study participants were from hospital record review in the AMIS [18], and, as previously noted, over 22% of randomized MDRD participants came from systematic review of medical records. While the major sources of randomized participants were physician referrals and medical record reviews, it appears that a direct appeal for volunteers by both local and national mass media was instrumental in stimulating prospective participants to discuss the study with their physician or to call the toll-free number. Media efforts may have stimulated interest within the medical community to refer patients as well. Based on our experience in the full-scale MDRD trial, the following general recommendations are made regarding recruitment: 1. The day-to-day activities of recruitment are best handled by a recruitment coordinator. 2. Recruitment goals must be established prior to starting the trial. 3. Local physicians should be informed about the goals of the study. Such education may make physicians more receptive to support their patients' participation in the trial or to refer patients for screening. 4. Adequate resources must be provided to support recruitment, especially for implementation of certain recruitment strategies (i.e., use of mass media including newspaper advertising and production of a television public service announcement). 5. Multiple recruitment techniques are often necessary to achieve recruitment goals in a timely fashion. 6. Frequent communication among recruitment coordinators, including conference calls and workshops, is essential to the dissemination of successful recruitment techniques and the promotion of study-wide competition. 7. Periodic reporting of center-specific recruitment results by the Data Coordinating Center provides incentive to improve performance. 8. Depending on the manpower available and the disease/condition under

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study, s y s t e m a t i c r e v i e w of medical records m a y be a significant source of s t u d y participants. A pilot s t u d y of this r e c r u i t m e n t a p p r o a c h m a y be justified. Supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health through cooperative agreements: U01 DK34495, U01 DK34513, U01 DK37072, U01 DK23416, U01 DK39819, U01 DK34534, U01 DK39368, U01 DK39481, U01 DK39366, U01 DK39486, U01 DK39485, U01 DIC39479,U01 DK39488, U01 DK39367, U01 DK39480, U01 DK35073, U01 DK40509, and the Health Care Financing Administration. The authors thank Jeffrey Probstfield, MD of the Fred Hutchinson Cancer Center (Seattle, Washington) for providing valuable advice throughout the recruitment period. A special thanks is given to Ken Manske (Gresham, Oregon) for developing the concept and coordinating the production of recruitment flyers and stand-up posters. The creativity and resourcefulness of MDRD recruitment coordinators, study dietitians, and other center staff is also acknowledged.

REFERENCES 1. Klahr S: The Modification of Diet in Renal Disease Study. N Engl J Med 320:864866, 1989 2. The Modification of Diet in Renal Disease Study Group (Prepared by Beck GJ, Berg RL, Coggins CH, Gassman JJ, Hunsicker LG, Schlucter MD, Williams GW): Design and statistical issues of the Modification of Diet in Renal Disease Trial. Controlled Clin Trials 12:566-585, 1991 3. The Modification of Diet in Renal Disease Study Group: The Modification of Diet in Renal Disease (MDRD) Study: design, methods and results from the feasibility study. Am J Kidney Dis 20:18-33, 1992 4. Frischano, AR: Anthropomehic Standards for the Assessment of Growth and Nutritional Status. Ann Arbor, University of Michigan Press, 1990 5. Williams PS, Stevens ME, Fass G, Irons L, Bone JM: Failure of dietary protein and phosphate restriction to retard the rate of progression of chronic renal failure: a prospective, randomized, controlled trial. Q J Med 294:837-855, 1991 6. Zeller K, Whittaker E, Sullivan L, Raskin P, Jacobson HR: Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Engl ] Med 324:78-84, 1991 7. Ihle BU, Becket GJ, Whilworth JA, Charlwood KA, Kincaid-Smith PS: The effect of protein restriction on the progression of renal insufficiency. N Engl J Med 321:1773-1777, 1989 8. Locatelli F, Alberti D, Graziani G, Buccianti G, Redaelli B, Giangrande A, The Northern Italian Cooperative Study Group: Prospective, randomized, multicentre trial of effect of protein restriction on progression of chronic renal insufficiency. Lancet 337:1299-1304, 1991 9. Probstfield JL, Wittes JT, Hunninghake DB: Recruitment in NHLBI populationbased studies and randomized clinical trials: data analysis and survey results. Controlled Clin Trials 8 (suppl):141S-149S, 1987 10. Vogt TM, Ireland CC, Black D, Camel G, Hughes G: Recruitment of elderly volunteers for a multicenter clincal trial: the SHEP pilot study. Controlled Clin Trials 7:118-133, 1986 11. The Lipid Research Clinics Program: Participant recruitment to the Coronary Primary Prevention Trial. J Chron Dis 6:451-465, 1983 12. Buchwald H, Matts JP, Hansen BJ, Long JM, Fitch LL, and the POSCH Group: Program on surgical control of the hyperlipidemias (POSCH): recruitment experience. Controlled Clin Trials 8 (suppl):94S-104S, 1987

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J.W. Kusek et al. 13. Tangrea J, Edwards B, Hartman A, Taylor P, Peck G, Salasche S, Menon P, Winton G, Mellette R, Guill M, Robinson J, Guin J, Stoll H, and the ISO-BCC Study Group: Isoretinoin-basal cell carcinoma prevention trial. Controlled Clin Trials 11:433-450, 1990 14. Tilley BC, Peterson EL, Kleerekoper M, Phillips E, Nelson DA, Shorck MA: Designing clinical trials of treatment of osteoporosis: recruitment and follow-up. Calcif Tissue Int 47:327-331, 1990 15. Friedman, MA: Patient accrual to clinical trials. Cancer Treat Rep 71:557-558, 1987 16. Petrovitch H, Byington R, Bailey G, Borhani P, Carmody S, Goodwin L, Harrington J, Johnson HA, Johnson P, Jones M, Levin J, Sugars C, Probstfield JL: Systolic Hypertension in the Elderly Program (SHEP) part 2: screening and recruitment. Hypertension 17 (suppl):II-16-II-23, 1991 17. Hunninghake DB, Blaszkowski TP (Eds): Proceedings of the workshop on the recruitment experience in NHLBI-sponsored clinical trials. Controlled Clin Trials 8 (suppl):1S-149S, 1987 18. Schoenberger JA: Recruitment experience in the Aspirin Myocardial Infarction Study. Controlled Clin Trials 8 (suppl):74S-78S, 1987

APPENDIX: PHASE III ACKNOWLEDGMENTS Participants in the MDRD Study are the following:

National Institute of Diabetes and Digestive and Kidney Diseases: Gary E. Striker, M.D., John W. Kusek, Ph.D.,* and Lawrence Y. Agodoa, M.D. Health Care Financing Administration: Arne Anderson Chairman of the Steering Committee: Saulo Klahr, M.D. Vice-Chairman of the Steering Committee Andrew S. Levey, M.D. Clinical Centers:

Bowman Gray School of Medicine, Winston-Salem, North Carolina: Vardaman M, Buckalew, M.D.,** John M. Burkart, M.D., Curt D. Furberg, M.D., John Felts, M.D., Michael Moore, M.D., Michael Rocco, M.D., Sharon Warren, R.N., Barbara Bearden, B.S.N., R.N., Carolyn Starkey, R.N., Therese A. Dolecek, Ph.D., R.D., Jody Harvey, M.Ed., R.D., Diane Poole, M.S., R.D., Susann Dahlquist, R.D., Linda Doroshenko, M.S., R.D., Kathleen Bradham, M.S., R.D., Debbie West, M.S., R.D., Jan Agostino, B.S., Barbara Baker, and Kim Hairston

Brigham and Women's Hospital/Beth Israel Hospital, Boston, Massachusetts: J. Michael Lazarus, M.D.,** Theodore I. Steinman, M.D., Julian L. Seifter, M.D., Margaret A. Desmond, B.S., R.N., Michelle A. Fiorenzo, B.S., R.N., Anne T. Chiavacci, M.S., R.D., Thalia Metalides, M.S., M.B.A., R.D., Debra Korzec-Ramirez, M.S., R.D., Sandra Lee Gould, M.A., and Vivian Pickett *MDRDProgram Director. **Principal Investigator.

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Brookdale Hospital Medical Center, Brooklyn, New York: Jerome G. Porush, M.D.,** Pierre F. Faubert, M.D., Samuel Spitalewitz, M.D., Jessy S. Faubert, M.S.W., ACSW, Gail S. Zimmer, M.S., R.D., Debra L. Saum, M.S., R.D., Marie Block, M.T., Jan-Yves Woel, B.S., and Mary F. Rose Duke University School of Medicine, Durham, North Carolina: Vincent W. Dennis, M.D.,** (through 8/92) Steve J. Schwab, M.D.,** Sharon A. Minda, B.S.N., R.N., Susan M. Condon, M.S., R.D., Beth F. Jenks, M.S., R.D., and Georgianne Gedon, B.A., R.N. Emory University, Atlanta, Georgia: William E. Mitch, M.D.,** Bradley J. Maroni, M.D., Brian K. England, M.D., J. Michael Soucie, B.S., M.P.H., Margaret F. Pedersen, R.D., L.D., Lillie Akpele, M.S., R.D., L.D., Patti Callahan, B.S.N., R.N., and Betsy Hall, R.N. George Washington University, Washington, D.C.: Juan P. Bosch, M.D.,**Violet Q. Habwe, M.D., Betsy Culbertson, P.A.C., Mary Stack-Dunne, M.P.H., R.N., Mary Hankey, M.S., R.D., Susan Leah O'Neill, R.D., Kimberly Witzmann, B.A., Cliff Goldman, B.S., Deneane Boyle, R.D., and Lucille M. Salmon Harbor-UCLA Medical Center, Torrance, California: Joel D. Kopple, M.D.,** Sharon G. Adler, M.D., Raimund Hirschberg, M.D., Janet DiChiro, M.S., R.D., Kristie Snider, R.D., Wendy Devine, M.P.H., R.D., Susan McKay, R.N., Jeanine M. McDonald, B.S., Judith Carter, L.V.N., and Wanda J. Nelson New England Medical Center~Massachusetts General Hospital, Boston, Massachusetts: Andrew S. Levey, M.D.,** Cecil H. Coggins, M.D., Johanna T. Dwyer, D.Sc., R.D., Margaret L. McLaughlin, M.D., Joseph Gronich, M.D., Andrew J. King, M.D., Carol Stollar, M.Ed., R.D., Deborah Raizman, M.P.H., R.D., Lorraine Castaldo, R.D., Denise DeSimone, R.D., Ann Efstathion, M.S., R.D., Kristen Yonkers, M.S., R.D., Jennifer A. Fine, M.S., R.D., Nancy Huggins, B.S., R.N., Alice Martin, B.S.N., R.N., Susan Baldi, R.N., Christopher Moleske, B.A., and David Furlong, B.Sc. Ohio State University, Columbus, Ohio: Lee A. Hebert, M.D.,** N. Stanley Nahman, Jr., M.D., Virginia Driver, B.S.N., R.N., Mary Jo Cosio, R.N., Judith A. Hartman, R.D., Cynthia S. Levy, M.S., R.D., Denise Londergan, M.P.H., R.D., Margaret GiUigan, R.D., Tobitha J. Beckman, R.N., Judy Miller, R.N., C.R.C., and Elizabeth Smith University of Florida, Gainesville, Florida: C. Craig Tisher, M.D.,** John C. Peterson, M.D., Charles S. Wingo, M.D., R. Allan Finlay, R.N., Elizabeth S. Parris, R.D., L.D., Gary Ivey, M.T., Patricia Gregory, M.A., R.D., L.D., Renee Hoffinger, R.D., L.D., Donna Garcia, R.D., L.D., and Chanda Preston Univers'ity of Iowa Hospitals and Clinics, Iowa City, Iowa: Lawrence G. Hunsicker, M.D.,** John A. Bertolatus, M.D., Victoria Lim, M.D., Linda Snetselaar, Ph.D., R.D., L.D., Byron Welch, M.D., Lisa L.

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J.W. Kusek et al. Brooks, M.A., R.D., L.D., Donna L. Hollinger, M.S., R.D., L.D., Ilona Lichty, R.D., L.D., Dru K. Mueller, M.S., R.D., L.D., Sheryl Eastin, B.S.N., R.N., Anskje Tanna, R.N., Julie Steele, B.G.S., and Keila Rieck University of Miami~Jackson Memorial Hospital Medical Center, Miami, Florida: Jacques J. Bourgoignie, M.D.,** David Roth, M.D., Dollie F. Green, M.D., Carmen Ortiz de Valderrama, M.D., Donna Merrill, R.N., Ann de Velasco, R.N., Margaret Garcon, R.D., Cesiah Rojas, R.D., Mary Zaragoza, and Sonia Barton University of Southern California, Los Angeles, California: Shaul G. Massry, M.D.,** Mohammad Akmal, M.D., George Fadda, M.D., M. Smorgorzerski, M.D., Sally Kiefer, R.N., Sally Rauch, M.S., R.D., Maureen Eyerman, M.S., R.D., and Laura Kigawa, R.D. University of Texas Health Science Center at San Antonio, San Antonio, Texas: Meyer D. Lifschitz, M.D.,** Charles R. Nolan, III, M.D., Steven Gouge, M.D., George Bakris, M.D., Eleanor Young, Ph.D., Christine Armes, R.D., Cary Warner, R.D., Arlene Tansey, R.N., M. Olga Flores, B.S., and Catherine S. Delea, B.A. Vanderbilt University Medical Center, Nashville, Tennessee: Paul E. Teschan, M.D.,** Raymond M. Hakim, M.D., Julia A. Breyer, M.D., Gerald Schulman, M.D., Nancy L. Rogers, M.S., Sandra N. Powers, R.D., Sandra McLeroy, M.S., R.D., Shelley Fischer, B.S., R.D., Myrna Deere, M.T. (A.S.C.P.), and Evelyn M. Cutler, B.S. Data Coordinating Center: The Cleveland Clinic Foundation, Cleveland, Ohio: Gerald J. Beck, Ph.D.,** George W. Williams, Ph.D.*** (through 5/91), Jennifer J. Gassman, M.S., Tom Greene, Ph.D., Mark D. Schluchter, Ph.D., Richard L. Berg, M.S., Mary Brown, Lee Chu, M.S., Martin J. Drabik, B.A., Kathy J. Fatica, B.S., Karen E. Lambdin, Judith R. Leatherman, B.S., Joseph A. McPherson, B.S., Venita Midcalf, B.A., Betty Moore, DeAnn M. Swinderman, Lillian Webb, and Kimberly A. Yanchar, A.A.B. Nutrition Coordinating Center: Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania: Arlene W. Caggiula, Ph.D., R.D.,** N. Carole Milas, M.S., R.D., Monica E. Yamamoto, Dr.P.H., R.D., William P. Amoroso, M.P.H., Frani M. Averbach, M.P.H., R.D., Terry Coyne, M.S., R.D., Bonnie Gillis, M.S., R.D., Fran L. Jones, M.P.H., Emil A. Maurer, B.S., Rebecca J. Meehan, B.S., JoAnn A. Naujelis, B.S., Marian B. Olson, M.S., Laura K. Scherch, M.S., R.D., and Elaine Stano, R.D. Consultants: W. Cameron Chumlea, Ph.D. and Rena R. Wing, Ph.D. Central Amino Acid Laboratory: University of Iowa, Iowa City, Iowa: Lewis D. Stegink, Ph.D.** and Marvin C. Brummel, M.S. Central Biochemistry Laboratory: The Cleveland Clinic Foundation, Cleveland, Ohio:

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Frederick Van Lente, Ph.D.,** Joan A. Waletzky, M.S., Linda M. Erdei, M.T. (ASCP) SC., Cynthia A. South, M.L.T. (ASCP), Colleen Spagnola, M.L.T. (ASCP), and Cathy O'Laughlin, M.L.T. (ASCP). Central ECG Laboratory: The Cleveland Clinic Foundation, Cleveland, Ohio: William L. Proudfit, M.D.** and Donald A. Underwood, M.D. Central GFR Laboratory: The Cleveland Clinic Foundation, Cleveland, Ohio: Phillip M. Hall, M.D.,** Henry A. Rolin, M.T. (ASCP), M.S., and Diane S. Pexa, M.T. (ASCP) Drug Distribution Center: The Cleveland Clinic Foundation, Cleveland, Ohio: Edward Jones, Pharm.D.** and Margaret Basch, R.Ph. Executive Advisory Committee: Professor Giuseppe D'Amico, John H. Dirks, M.D., Jared Grantham, M.D., Alfred E. Harper, Ph.D., M.D., Keith Peters, M.D., Jay H. Stein, M.D., Edmund D. Pellegrino, M.D., and Professor Charles van Ypersele External Monitoring Committee: Bryan D. Myers, M.D. (Chairman), James E. Grizzle, Ph.D., C. Morton Hawkins, M.P.H., Sc.D., Malcolm A. Holliday, M.D., Daniel Rudman, M.D., Donald S. Young, M.D., Ph.D., Vernon Young, Ph.D., and Robert Luke, M.D., Paul Whelton, M.D., Raymond Bain, Ph.D. Consultants: Robert M. Kaplan, Ph.D. and Robert P. Byington, Ph.D.