1 Kidney International, Vol. 56, Suppl. 71 (1999), pp. S-222 S-226 Rationale and design of a trial improving outcome of type 2 diabetics on hemodialysis CHRISTOPH WANNER, VERA KRANE, GÜNTHER RUF, WINFRIED MÄRZ, and EBERHARD RITZ FOR DIE DEUTSCHE DIABETES DIALYSE STUDIE INVESTIGATORS Department of Medicine, Divisions of Nephrology and Clinical Chemistry, Universities of Freiburg, Heidelberg and Würzburg, and Gödecke/Parke Davis Freiburg, Germany Key words: atorvastatin, cholesterol, diabetes, triglycerides by the International Society of Nephrology Rationale and design of a trial improving outcome of type 2 diabetics on hemodialysis. Background. Non insulin-dependent diabetes mellitus dial- ysis patients have the highest cardiovascular mortality known in any group of patients. Mixed dyslipidemia with moderately elevated low-density lipoprotein (LDL) cholesterol and high levels of triglyceride-rich lipoproteins is common in this condition. It is not known, however, whether patients with type 2 diabetes on dialysis with this form of dyslipidemia derive bene- fit from lipid-lowering therapy. Recently, drugs have become available that potently lower triglyceride-rich, apob-containing lipoproteins and thus permit testing of this issue. This is the first trial to address specifically the issue of whether the excessive cardiovascular mortality of patients with type 2 diabetes on dialysis can be lowered by statins. Methods. The Die Deutsche Diabetes Dialyse Studie is a prospective randomized placebo-controlled trial that tests the hypothesis that atorvastatin, a hydroxymethyl-glutaryl coen- zyme A reductase inhibitor, decreases the rate of cardiovascular mortality and of nonfatal myocardial infarction in patients with type 2 diabetes who have been on hemodialysis treatment for no more than two years. The primary endpoint, cardiovascu- lar mortality, includes fatal myocardial infarction, sudden death, death during coronary intervention, death from heart failure, and other coronary causes. Secondary endpoints comprise overall mortality, nonfatal cardiovascular events, fatal and nonfatal cerebrovascular disease, and the mean percentage change in lipid profile from baseline. The trial enrolls 1200 men and women on hemodialysis for less than two years and with type 2 diabetes at 150 centers throughout Germany. Inclusion criteria are age of 18 to 80 years, low-density cholesterol of 80 to 190 mg/dl (2.1 to 4.9 mmol/liter), and triglyceride levels of less than 1000 mg/dl (11.4 mmol/liter). Patients are randomized to either inactive (placebo) or active (atorvastatin, 20 mg/day) drug therapy. The average duration of follow-up is more than 2.5 years. To protect against a lower than expected rate of events, the trial will be continued until a predetermined fixed number of endpoints occurs in the entire cohort so that the predefined power of the trial will be guaranteed. Conclusions. This trial was designed to demonstrate that lipid lowering with atorvastatin will improve life expectancy and quality of life in type 2 diabetics on hemodialysis. The resolution of this question is important because the genesis of vascular lesions in this condition is multifactorial and the precise role of dyslipidemia has not been defined. Cardiovascular and cerebrovascular events are the most important causes of death in diabetic patients on long-term dialysis therapy, accounting for 59% of overall mortality in this group . Approximately 12 to 19% of such deaths from cardiovascular causes are due to acute myocardial infarction, but 60% of patients die within one year after acute myocardial infarction . The causative role for plasma low-density lipoprotein (LDL) in the development of coronary artery disease has been well established in subjects without impairment of renal function, but the exact role of dyslipidemia in vascular disease of diabetic patients with renal failure remains to be defined. In diabetes, the pathogenesis of vascular lesions is likely to be more complex, and clarification of this point is therefore particularly important. Despite the burden of cardiac disease among patients on dialysis, there are currently no published data or no concepts to improve long-term survival or quality of life. There are several unanswered questions that are critical to knowing how to manage the plasma lipids of patients with or with- out diabetes and on long-term hemodialysis. Approxi- mately 8% of hemodialysis patients were prescribed a lipid-lowering medication , despite the fact that evi- dence-based data on this particular treatment and pa- tient group are still lacking. To elucidate this question, the Die Deutsche Diabetes Dialyse Studie was planned. MODERATELY ELEVATED PLASMA CHOLESTEROL LEVELS AND HYPERTRIGLYCERIDEMIA The causative role for plasma LDL in the development of coronary artery disease in subjects without impairment of kidney function is established. Lipid changes particu- larly hypertriglyceridemia with low HDL are a recog- nized hazard for cardiac survival in nonuremic patients as well . The role of dyslipidemia in diabetic patients with renal failure is yet not well defined, and only few data exist . Studies in nonrenal populations have con- S-222
2 Wanner et al: Die Deutsche Diabetes Dialyse Studie S-223 NONTRADITIONAL CARDIAC RISK FACTORS Smoking, hypertension, hyperhomocysteinemia, and high levels of fibrinogen and lipoprotein(a) originating from its genetically determined low molecular weight isoform were identified as independent risk factors in patients receiving hemodialysis (abstract; Kates et al, J Am Soc Nephrol 6:540, 1995) [11 15]. Furthermore, patients with activated acute phase response and elevated serum concentrations of interleukin 6, tumor necrosis factor-, and C-reactive protein are at high risk for cardiovascular complications [16, 17]. It is not currently known whether benefit from lipid lowering with an HMG-CoA reductase inhibitor will be potentiated or abrogated in the presence of several strong nontraditional uremia-related cardiac risk factors. STUDY DESIGN The overall goal of this prospective, randomized, pla- cebo-controlled trial is to determine whether lowering plasma cholesterol and triglycerides will decrease the primary endpoint, that is, the sum of cardiovascular death rate and nonfatal myocardial infarction in patients with type 2 diabetes on maintenance hemodialysis for less than two years. Cardiovascular mortality comprises fatal myocardial infarction, sudden death, death during coronary intervention, death from heart failure, and other coronary causes. Secondary endpoints comprise overall mortality, nonfatal cardiovascular events, fatal and nonfatal cerebrovascular events, total mortality, and mean percentage change in lipid profile from baseline. POPULATION Inclusion criteria are men and women with type 2 diabetes mellitus treated by maintenance hemodialysis for no more than two years in the age range 18 to 80 years. Exclusion criteria are serum LDL cholesterol of less than 80 or more than 190 mg/dl (less than 2.1 or more than 4.9 mmol/liter) and triglycerides of more than 1000 mg/dl (11.4 mmol/liter). Additional criteria are listed in Table 1. Table 1. Eligibility criteria for the 4D-Study centrated on the consequences and management of hypercholesterolemia resulting from elevated LDL levels. In contrast, the most important anomalies in uremia- associated dyslipidemia are an increase in serum levels of triglyceride, intermediate-density lipoprotein (IDL), cholesterol-rich very low-density lipoprotein (VLDL), apolipoprotein B (apob), and a decrease in serum levels of high-density lipoprotein (HDL) [7, 8]. In addition, hypertriglyceridemic diabetic patients on hemodialysis exhibit an enrichment of a highly atherogenic LDL subclass (small dense LDL) . From data published so far, it is expected that patients exhibit an LDL cholesterol in the range of 140 to 160 mg/dl and fasting serum triglycerides of 250 to 300 mg/dl [6, 10]. Inclusion criteria Men and women with type 2 diabetes on hemodialysis for no more than 24 months. Age years. Exclusion criteria Serum LDL cholesterol 80 or 190 mg/dl ( 2.1 or 4.9 mmol/ liter) Fasting serum triglycerides 1,000 mg/dl (11.4 mmol/liter) Symptomatic hepatobiliary cholestatic disease, Abnormal liver function with SGOT or SGPT 3 ULN. Positive test for HbsAg, HIV or known hepatitis C. Hematopoetic or systemic disease which is not related to end-stage renal failure, exclusive uremia-associated anemia. Non-amenorrhoeic women with child-bearing potential, who do not use a medical relevant contraception. Cardiovascular event (such as CABG, PTCA) congestive heart failure or myocardial infarction during the last 3 months. Previous unsuccessful kidney transplantation. Hypertension resistant to therapy (systolic blood pressure continuously 200 mg Hg or diastolic 110 mm Hg). Hypo- or hyperthyroidism (TSH beyond normal values). Excessive ethanol intake defined as 3 drinks per day (1 drink 45 ml/45% ethanol or equivalent). Prior sensitivity to HMG-CoA reductase inhibitors. Significant gastrointestinal disease or surgery, which may interfere with drug absorption, inclusive chronic pancreatitis with malabsorption. Participation in another drug trial during the last 30 days prior to randomization. Unwilling to consent. ULN is upper limit of normal. PRERANDOMIZATION PERIOD (SCREENING) The medical staff of the dialysis unit screens patients who are on regular hemodialysis treatment three times per week. If the dialysis physician is not the patient s personal physician, the latter is made aware of the implications of the study. Patients, who give informed consent will take part in a series of two qualifying visits. Docu- mented control of blood pressure is a prerequisite for entering the study. Specific dietary instructions are not given because patients on hemodialysis are already sub- ject to a restriction in food and fluid intake. The introduc- tion of a lipid-lowering diet might further add to the risk of malnutrition. All lipid-lowering agents must be stopped before the formal series of prerandomization visits are started. Serum lipids are measured by the core laboratory in fasting blood. Patients who have their dial- ysis sessions in the afternoon are allowed to have a standardized carbohydrate-containing breakfast at least six hours prior to blood sampling. Blood is drawn from the dialysis arteriovenous fistula prior to the start of the hemodialysis session and prior to the administration of heparin. The average lipid levels of two qualifying visits are used to determine patients eligibility. The patients lipid levels after randomization are not released to the patients, their physicians, or the investigators at the clini- cal centers. Clinical evaluation includes medical history, medication use, and physical examination.
3 S-224 Wanner et al: Die Deutsche Diabetes Dialyse Studie SERUM LIPID DETERMINATION On the day of collection, serum samples are shipped by surface mail to the core laboratory. Aliquots of plasma and serum are immediately frozen at 20 C for subsequent collection and analysis in ancillary studies. Eightyfive percent of samples arrive in the laboratory within 24 hours after collection and are analyzed in a blinded manner within 24 hours. Serum total cholesterol and triglyceride concentrations are measured using enzymatic methods and reagents provided by Roche Diagnostics (CHOD-PAP and GPO-PAP, respectively; Montclair, NJ, USA). VLDL cholesterol, LDL cholesterol, and HDL cholesterol are determined by electrophoresis in agarose gels and subsequent enzymatic staining for cholesterol using the rapid electrophoresis system (REP, HELENA Diagnostika GmbH, Hartheim, Germany). Unlike the Friedewald formula, this method produces accurate measurements of LDL cholesterol in samples with elevated triglyceride concentrations . RANDOMIZATION Randomization into the two treatment groups is stratified by the center so that a balance in therapy assignment is guaranteed within each of the participating centers. Patients are randomized by a randomization code prepared by the statistical coordinating center. The addition of other cholesterol-lowering drugs, such as fibric acid derivatives or cholestyramine, is not permitted in order to not enhance the risk of side-effects from interactions. CONTROL OF HYPERRESPONDERS If LDL cholesterol decreases to less than 50 mg/dl (1.3 mmol/liter), the dose of atorvastatin (or placebo) is decreased by 50%, and the response is reassessed within the next two consecutive visits. In case of dosage reduction in one treatment arm, an identical dosage adjustment in a randomly selected patient of the corresponding treatment group is made in order to maintain study blindness. MONITORING DURING THE TREATMENT PHASE The assessment of drug efficacy by blood sampling is obtained four weeks after randomization. Physical examinations, adverse event recording, compliance check, and a standard electrocardiogram are obtained in six-month intervals and at the end of the study. Compliance evaluation by the physician or the study nurse, if thought necessary, can be done three times per week during the hemodialysis sessions. Study end points and major noncardiovascu- lar events are recorded by the physician in charge. PROTOCOL OF DRUG THERAPY SAMPLE SIZE DETERMINATION AND Atorvastatin (20 mg once daily) or matching placebo DURATION OF THE TRIAL is administered. Patients are advised to take study drug at least two hours apart from phosphate binders, which The study is planned to have a 90% power to detect are usually ingested with meals. The expected effect of a 10% reduction in cardiovascular mortality at an alpha this dose of atorvastatin is to reduce plasma LDL cholesinterim analysis and one final analysis). The log-rank value of 0.05 (two-sided, adjusted for two preplanned terol by 44%, increase plasma HDL cholesterol by 12%, and decrease plasma triglyceride by 33% . Atorvathis test is used to compare the survival curves. To achieve statin increases the expression of LDL receptors, thus power, the protocol specifies that 1200 patients must accelerating the clearance of LDL from the circulation. be entered and followed until a fixed number of end It also decreases the rate of hepatic production of VLDL, points have occurred (unless the trial is stopped earlier the precursors of IDL and LDL. It is expected that the on the basis of an interim analysis). All statistical tests concentrations of the VLDL and IDL particles decrease. are done by intention-to-treat analysis. Exploratory eval- Atorvastatin is well tolerated, and adverse reactions are uation is also done by per-protocol analysis. The anticifew and are primarily mild. Clinical experience in pa- pated duration of follow-up will be more than four years. tients with impaired renal function is limited . Plasma The expected number of events will have occurred 2.5 protein binding of atorvastatin is 98 to 99%, and accumu- years after randomization. Recruitment is anticipated to lation in uremic patients has not been shown. last 1.5 years. The trial is scheduled to end in March CONTROL OF ELEVATED LOW-DENSITY LIPOPROTEIN AND TRIGLYCERIDES ANALYSIS OF DATA Outcome variables The primary outcome variable is the combined endpoint of nonfatal myocardial infarction and cardiovascu- lar death (fatal myocardial infarction, sudden death, con- gestive heart failure, death attributable to a diagnostic or therapeutic procedure involving the coronary arterial The core laboratory monitors the lipid levels of the patients and adjusts the dosage. Some patients may demonstrate LDL cholesterol levels during follow-up that exceed the upper limit. If LDL cholesterol is more than 190 mg/dl on two consecutive measurements, the patient is offered to leave the protocol for active treatment.
4 Wanner et al: Die Deutsche Diabetes Dialyse Studie S-225 circulation, death from other coronary causes). The sec- at the various dialysis facilities and committee members ondary outcome variables are total mortality, nonfatal work without any reimbursement. cardiovascular events (initial or repeated coronary angio- Reprint requests to Christoph Wanner, M.D., Department of Mediplasty or coronary artery bypass surgery), fatal and non- cine, Division of Nephrology, University Clinic, Josef-Schneider-Str. 2, fatal cerebrovascular events, and changes in serum lipids Würzburg, Germany. relative to baseline. REFERENCES ANALYSIS 1. USRDS Annual Data Report. VI. Causes of death. Am J Kidney When evaluating the main target criterion, the com- Dis 32(Suppl 1):S81 S88, 1998 peting risk of dying from noncardiovascular causes will 2. USRDS Annual Data Report. IV. Medication use among dial- ysis patients in the DMMS. Am J Kidney Dis 32(Suppl 1):S38 S49, be taken into account by applying cumulative incidence 1998 functions. They will be assessed for both therapy groups 3. Herzog CA, Ma JZ, Collins AJ: Poor long-term survival after according to the method of Aalen and Johansen . acute myocardial infarction among patients on long-term dialysis. N Engl J Med 339: , 1998 The relative risk with an accompanying 95% confidence 4. Deleted in proof. interval will be assessed using a Cox regression model, 5. Uusitupa MIJ, Niskanen LK, Siitonen OM, Voutilanainen E, although adjustments will be made in an additional analrelation to general risk factors, insulin level, and abnormalities in Pyörälä K: 5-year incidence of atherosclerotic vascular disease in ysis of the most important baseline variables, which have lipoprotein composition in non-insulin-diabetic and nondiabetic an influence on the occurrence of the observed events. subjects. Circulation 82:27 86, 1990 The log rank test will be used to compare the survival 6. Tschöpe W, Koch M, Thomas B, Ritz E: Serum lipids predict cardiac death in diabetic patients on maintenance hemodialysis. curves of the treatment and control groups. Two interim Nephron 64: , 1993 analyses will be conducted because previous subgroup 7. Attmann P-O, Alaupovic P, Gustavson A: Serum apolipoprotein analysis of patients with diabetes mellitus in the 4S  profile of patients with chronic renal failure. Kidney Int 32: , 1987 and CARE clinical trials revealed positive treatment ef- 8. Shoij T, Nishizawa Y, Kawagishi T, Kawasaki K, Taniwaki H, fects of simvastatin and pravastatin at this point in time, Tabata T, Inoue T, Morii H: Intermediate-density lipoprotein as respectively. Several subgroups have been prespecified an independent risk factor for aortic atherosclerosis in hemodialy- sis patients. J Am Soc Nephrol 9: , 1998 to analyze effects of dialysis treatment modalities: the 9. Quaschning T, Schömig M, Keller M, Thiery J, Nauck M, type of dialyzer membrane material, dialysis dose, and Schollmeyer P, Wanner C, Krämer-Guth A: NIDDM and hyperconcurrent medications. triglyceridemia impair lipoprotein metabolism in chronic hemodi- alysis patients. J Am Soc Nephrol 10: , Koch M, Kutkuhn B, Grabensee B, Ritz E: Apolipoprotein A, fibrinogen, age, and history of stroke are predictors of death in APPROVAL FOR HUMAN dialysed diabetic patients: A prospective study in 412 subjects. SUBJECTS RESEARCH Nephrol Dial Transplant 12: , Becker BN, Himmelfarb J, Henrich WL, Hakim RM: Reassessing This trial has been approved by the Institutional Re- the cardiac risk profile in chronic hemodialysis patients: A hypotheview Boards of the Universities of Würzburg and Heidel- sis on the role of oxidant stress and other non-traditional cardiac berg and by all Review Boards responsible for the partic- risk factors. J Am Soc Nephrol 8: , Cressmann MD, Heyka RJ, Paganini EP, O Neil J, Skibinski ipating centers located at the Landesärztekammer of the CI, Hoff HF: Lipoprotein(a) is an independent risk factor for 16 Länder throughout Germany. cardiovascular disease in hemodialysis patients. Circulation 86: , Koch M, Kuthuhn B, Trenkwalder E, Bach D, Grabensee B, TRIAL ORGANIZATION Dieplinger H, Kronenberg F: Apolipoprotein B, fibrinogen, HDL cholesterol, and apolipoprotein(a) phenotypes predict coronary Out of a total of 902 known dialysis centers all over artery disease in hemodialysis patients. J Am Soc Nephrol 8:1889 Germany, 150 dialysis centers will participate. The contract 1898, Kronenberg F: Homocysteine, lipoprotein(a) and fibrinogen: Metresearch organization (CRO), Kendle (Munich, Germany), abolic risk factors for cardiovascular complications of chronic renal supports the trial headquarters regarding the recruitment disease. Curr Opin Nephrol Hypertens 7: , 1998 of study sites, is responsible for the safety reporting, and 15. Wu M-S, Yu C-C, Yang C-W, Wu C-H, Haung J-Y, Hong J-J, Chiang C-YF, Huang C-C, Leu M-L: Poor pre-dialysis glycaemic conducts the monitoring and the clinical data managecontrol is a predictor of mortality in type II diabetic patients on ment of the Die Deutsche Diabetes Dialyse Studie ac- maintenance haemodialysis. Nephrol Dial Transplant 12:2105 cording to the ICH-Good Clinical Practice Standard. 2110, Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C: Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 55: , 1999 SPONSOR 17. Bologa RM, Levine DM, Parker TS, Cheigh JS, Serur D, Stenzel KH, Rubin AL: Interleukin-6 predicts hypoalbuminemia, hy- Gödecke/Parke-Davis (Freiburg, Germany) provides study medication and the grant for study management. pocholesterolemia, and mortality in hemodialysis patients. Am J Kidney Dis 32: , 1998 Neither sponsor nor CRO has any access to unblinded 18. Nauck M, Winkler K, März W, Wieland H: Quantitative determination of high-, low- and very low-density lipoprotein and data from the core laboratory or end points. Physicians lipo-
5 S-226 Wanner et al: Die Deutsche Diabetes Dialyse Studie protein(a) by agarose gel electrophoresis and enzymatic choles- Klinik, Manfred Pollok, Michael Grahl, Tobias Marsen; Krefeld Klinikum, terol staining. Clin Chem 41: , 1995 Dieter Bach, Frank Porzelt; Lahr, Iris Lubrich-Birkner, Tina 19. Nawrocki JW, Weiss SR, Davison MH, Sprecher DL, Schwartz Fader, Marianne Schnell; Leipzig KfH, Hans-Eberhardt Stein, Kathleen SL, Lupien PJ, Jones PH, Haber HE, Black DM: Reduction of Proboszcz; Lingen/Ems, Hans-Joachim Schurek, Margret Eich, LDL cholesterol by 25% to 60% in patients with primary hypercho- Ewald Jansen; Lohr KfH, Ulf Grunewald, Erich Lang; Lüdenscheid lesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Klinikum, Helmut Kingreen, Richard Staube, Marlies Kirstein; Magde- Arterioscler Thromb Vasc Biol 15: , 1995 burg KfH, Hans-Peter Bosselmann, Sabine Kötte; Mannheim, Andreas 20. Stern RH, Yang BB, Horton M, Moore S, Abel RB, Olson SC: Schwarzbeck, Martina Wolf; Marktheidenfeld, Peter Hans-Joachim Renal dysfunction does not alter the pharmacokinetics or LDL Kulzer, Sibylle Götz; Mettmann, Michael Koch, Barbara Esmyol; cholesterol reduction of Atorvastatin. J Clin Pharmacol 37:816 München KfH, Johannes Mann, Barbara Felgenträger, Ruth Weßling; 819, 1997 München KfH, Achim Weise, Jürgen Eberhard Scherberich, Manfred 21. Aalen OO, Johansen S: An empirical transition matrix for nonhomogeneous Dlugosch; Neumarkt KfH, Rolf Pilgrim, Josef Wopperer, Bettina Ro- Markov chains based on censored observations. Scand sener, Brunhilde Katzmeier; Neusäß KfH, Iradj Nemann, Michael J Stat 5: , 1997 Sachse; Nienburg, Eckhard Tielke, Klaus Eckert; Oberhausen Johan- 22. Pyörälä K, Pedersen TR, Kjekshus J, Faergeman O, Olsson niter Krankenhaus, Peter Ausserehl, Natascha Virnich; Offenbach AG, Thorgeirsson G: Cholesterol lowering with simvastatin improves Klinikum, Gerd Schäfer, Stephanie Graf-Lingnau; Offenburg, Klaussubgroup prognosis of diabetic patients with coronary heart disease: A Peter Stoll, Christina Weiß-Hollerbach, Erich Keller, Christa Hein; Old- analysis of the Scandinavian Simvastatin Survival Study enburg KfH, Hans-Robert Kertelge, Monika Wiesner, Karin Müller; (4S). Diabetes Care 20: , 1997 Paderborn PHV, Peter Schilken, Nicme Eickel; Passau Klinikum/KfH, Jürgen Zehner, Richard Flamensbeck, Thomas Martan; Pfarrkirchen, APPENDIX Michael Adler, Gabriele Schannen, Petra Brandmeier; Pforzheim, Heinrich Kütemeyer, Andrea Dittrich; Pirmasens, Walter Krämer, Dr Clinical Centers*: Amberg Kuratorium für Dialyze und Trans- Walker, Stefan Winzenhörlein, Renate Siehler; Plauen KfH/Auerbach, plantation (KfH), Nikolaus Luz, Monika Wendl-Brandt; Ansbach/Bad Volkmar Gläser, Harald Seidel, Olaf Siegel, Hannelore Fritsch, Mech- Windsheim, Klaus Bittner, Rüdiger Götz, Anette Hartmann; Aschaf- thild Männel; Regensburg KfH, Rainer Müller, Robert Lieb, Irmgard fenburg, Peter Dragoun; Bozena Kamieniak, Bad Hersfeld KfH, Peter Tutsch; Regensburg St. Josef Krankenhaus/KfH, Peter Roch, Angela Thon, Kerstin Dammer, Simone Pommerenke; Bad Kissingen, Gün- Lang; Reinbek, Peter Färber, Anja Hopf; Reutlingen, Eugen Hübel, ther Schönweiß, Anja Winter; Bad Nauheim KfH, Thomas Meyer, Gaby Dunschen-Weimar; Rostock, Roland Erwin Winkler, Birgit Angelika Berners; Bayreuth KfH, Detlef Seybold, Bernhard Riedl, Pietsch; Rosenheim KfH, Lothar Musselmann, Andreas Thieler, Ger- Christine Rösch; Berlin KfH, Hans-Gernot Asmus, Manfred Pluer, thie Leiner, Uschi Kassner, Elfriede Weiß; Saarbrücken, Anton Hümp- Berenic Ziesak; Berlin-Buch Klinikum, Friedrich Luft, Sylvia Gott- fner, Silke Taubold-Franck; Schweinfurt KfH, Wolfgang Rebstöck, schalk; Berlin KfH, Wolfgang Pommer, Björn Schwarzenberger, Mar- Christian Keilholz; Stade, Enrique Fernandez Redo, Kai Meßtorff, ion Albrecht; Bottrop KfH, André Voßkühler, Maria Lusch; Bremen, Mechthild Rosowski; Stuttgart PHV, Tilman Kirschner, Uta Bubeck, Rolf Ebbinghaus, Andrea Tetzel; Chemnitz KfH, Lutz Wagner, Ursula Birgit Freyer-Loeckle; Stuttgart Katharinenhospital, Christoph Ol- Hofmann, Langer Sabine; Coburg KfH, Hans Hennemann, Gudrun bricht, Antje Helbing; Trier Krankenhaus Barmherzige Brüder, Wolf Bauer; Darmstadt KfH, Jürgen Geyer, Linde Otto, Kerstin Kärgel; H. Boesken, Martin Weisgerber; Tutzing Krankenhaus, Hendrik Dob- Daun/Eifel Dialyze Trainingszentrum (DTZ), Fuat Bozkurt, Holger belstein, Werner Härtl, Marc Haydenreich, Beate Breutterer, Ralf Bicker; Deggendorf Klinikum/KfH, Andreas Weikl, Max Goller; Dessau Viersen, Michael Körfers; Ulm/Ehingen KfH, Rosemarie Krämer, Die- KfH, Rita Rösch, Britta Kuhle; Dortmund, Andreas Wiemeyer, Mech- ter Bundschuh, Ingo Wetter, Buzena Arth, Eva Kley, Svitlana Höb; thild Dellwig; Dresden, Sybille Hans, Ina Herrmann; Detmold Patienmut Reichel, Monika Dentlinger; Waldshut, Rainer Liebig, Günter Viersen, Michael Körfers, Erik Lahoda; Villingen-Schwenningen, Hel- tenheimversorgung (PHV), Hans-Jürgen Knieß, Dagmar Schippmann, Volker Weishaupt; Donauwörth KfH, Werner Bihlmeier, Andreas Kind; Waren DTZ, Kristin Nöhring, Margret Hübbe; Weiden KfH, Baumann, Claudia Kuhr, Margit Rehm-Kächler; Duisburg Marien Hos- Werner Deininger, Michael Brunner, Karin Schönberger, Rosi Schödl; Westerburg, Hans-Georg Dehnert, Petra Kunz; Wiesbaden KfH, Arpital, Wilhelm Kreußer, Hannelore Grunow; Duisburg, Karsten Jüstel, nold Röckel, U. Hohenstatt; Wiesbaden HSK Klinikum, Christian Johannes Wagner, Michael Komarek; Düsseldorf, Bruno Hartmann, Piper, Michael Schmidt, Siegfried Dell; Wuppertal, Shigeo Kashiwagi, Werner Kleophas, Mechthild Kolbe; Eberswalde Klinikum, Sabine Kathrein Wirtz, Heinberg; Stendal, Reiner Krainz, Ralf Kühn, Janette Ludewig, Gabriele Grabarz; Emmering DTZ, Marion Ring; Emsdet- Kattengell, Doreen Widiger; Wuppertal, Harald Messner, M. Hessmann; ten, Peter Tillmann, Christian Hansen, Anneliese Johannesmann; Er- Wentdorf, Gotthard Feyerabend, Klaus Zapf, Elke Lehmann; Würzfurt Klinikum/KfH, Heinrich Thieler, Beatrice Kaschke; Frankfurt burg KfH, Udo Bernhard Bahner, Ursula Buschmann, Roswitha Meyer, KfH, Alexei N. Mazur; Freiburg DTZ, Gunnar Schaeffer, Petra Pie- Elisabeth Beck-Faulhaber; Würzburg, Lothar Schramm, Claudia Schön; chatzek; Freiburg, Thomas Watter, Silvia Burkhardt; Friedrichshafen, Zeitz, Karl Enke, Anja Meister. Peter Piazolo, Eleonora Becker; Fulda KfH, Winfried Fassbinder, Ma- *centers active as of November 1998 ria Heimes, Rita Selzer; Fürth KfH, Beatrix Büschges-Seraphin, Contract research organization (CRO): Kendle, Munich, Stefan Reich- Christa Hein; Gießen, Volker Wizemann, Helga Schweitzer; Hagen muth (Project Manager), Sabine Laukamp (Manager Datamanagement). KfH, Friedrich Josef Lazarus, A. Coldik; Halle KfH, Bernd Osten, Trial headquarters: Clinical Coordinating Center, University of Ilona Klatt; Hannoversch-Münden, Eduard Quellhorst, Andreas Solf, Würzburg, Division of Nephrology, Christoph Wanner, Vera Krane Reinhard Vogler, Volker Müller; Heidelberg, Gudrun Bommer, Tina (Clinical Manager), Susanne Schubert. Gödecke/Parke Davis, Frei- Kessler-Back; Heilbronn, Gabriele Kunowski, Karlheinz Hofmann; burg, Günther Ruf, Hans Groth, Barbara Rauer (Project Manager). Hof Klinikum/KfH, Herbert Militzer, Andreas Riegel, Birgit Rister; Central laboratories: Lipid and safety core laboratory: University of Homburg/Saar Uni-Klinik, Werner Riegel, Herbert Tharrach, Ruth Freiburg, Winfried März, Heinrich Wieland. ECG-monitoring board: Jörg, Sabine Thomas; Igersheim, Volker Wunderle, Corina Hammel; University of Würzburg, Malte Meesmann, Peter Schanzenbächer. Iserlohn, Johannes Bunia, Horst Beinghaus; Jena KfH, Sabine Schnei- Committees: Safety Board: Martin Wehling, Erich Keller, Michael der, Katrin Hachenburg, Mandy Köhler; Karlsruhe, Rainer Betzinger, Schumacher. Event Committee: Johannes Mann, Jürgen Bommer, Peter Ulrike Hogg, Nicole Schult; Karlsruhe, Hans Georg Röder, Gerhard Schanzenbächer. Advisory Board: Ulrich Frei, Heiner Greten, Friedrich Hock, Dorothea Bohnenstengel; Kassel KfH, Hans Joachim Tönnis, Luft, Karl-Wilhelm Kühn, Heinrich Kütemeyer. Steering Committee: Frank Deuermaier; Kaufbeuren, Christoph Ballé, Doris Poller; Kiel, Joachim Albrecht, Uwe Bartsch; Kitzingen KfH, Kurt Georg Bausewein, Manuela Fischer; Köln KfH, Michael Nebel, Marlies Paus; Köln Uni- Christoph Wanner, Eberhard Ritz (under the auspices of the Deutsche Arbeitsgemeinschaft für klinische Nephrologie and the Deutsche Dialysegesellschaft niedergelassener Ärzte e.v.).
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