A Study of Treatment With NeoRecormon (Epoetin Beta) in Patients With Chronic Renal Anemia

A Randomized, Open-label Study of the Effect of NeoRecormon on Reduction of Cardiovascular Risk in Patients With Chronic Renal Anemia Who Are Not on Renal Replacement Therapy.

This study will evaluate whether anemia prevention with NeoRecormon has an additional impact on reducing cardiovascular risk over conventional anemia treatment in patients mostly with stage IV chronic kidney disease and renal anemia. The anticipated time on study treatment is 2+ years and the target sample size is 500+ individuals.

Study Overview

• Status: Completed
• Conditions: Anemia
• Intervention / Treatment: Drug: epoetin beta [NeoRecormon]; Drug: epoetin beta [NeoRecormon]

• Study Type: Interventional
• Enrollment (Actual): 605
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria, 4020
  • St Pölten, Austria, 3100
• Belgium
  • Bruxelles, Belgium, 1070
  • Bruxelles, Belgium, 1090
  • Edegem, Belgium, 2650
• Czech Republic
  • Brno, Czech Republic, 625 00
  • Havirov, Czech Republic, 736 01
  • Olomouc, Czech Republic, 775 20
  • Ostrava, Czech Republic, 708 52
• Denmark
  • Fredericia, Denmark, 7000
  • Herlev, Denmark, 2730
  • Holbaek, Denmark, 4300
  • Roskilde, Denmark, 4000
• Finland
  • Jyväskylä, Finland, 40620
  • Tampere, Finland, 33521
• France
  • Amiens, France, 80054
  • Angouleme, France, 16470
  • Bordeaux, France, 33000
  • Boulogne, France, 62321
  • Colmar, France, 68024
  • Lyon, France, 69437
  • Montpellier, France, 34295
  • Paris, France, 75743
  • Saint Brieuc, France, 22023
  • Troyes, France, 10003
  • Vandoeuvre-les-nancy, France, 54511
• Germany
  • Berlin, Germany, 13353
  • Villingen-schwenningen, Germany, 78054
  • Würzburg, Germany, 97072
• Greece
  • Athens, Greece, 115 27
  • Thessaloniki, Greece, 546 42
  • Veria, Greece, 59100
• Hong Kong
  • Hong Kong, Hong Kong
• Ireland
  • Dublin, Ireland, 9
• Italy
  • Bologna, Italy, 40138
  • Busto Arsizio, Italy, 21052
  • Cagliari, Italy, 09134
  • Cinisello Balsamo, Italy, 20092
  • Lecco, Italy, 23900
  • Napoli, Italy, 80131
  • Padova, Italy, 35128
  • Parma, Italy, 43100
  • Pavia, Italy, 27100
  • Roma, Italy, 00144
  • Roma, Italy, 00152
  • Roma, Italy, 00146
  • San Giovanni Rotondo, Italy, 71013
  • Trieste, Italy, 34125
  • Vimercate, Italy, 20059
• Mexico
  • Cuernavaca, Mexico, 62448
  • Tijuana, Mexico, 44650
• Norway
  • Oslo, Norway, 0407
• Poland
  • Gdansk, Poland, 80-211
  • Kielce, Poland, 25-736
  • Krakow, Poland, 31-501
  • Wroclaw, Poland, 50-417
• Portugal
  • Almada, Portugal, 2800
  • Carnaxide, Portugal, 2799-523
  • Lisboa, Portugal, 1800-083
  • Porto, Portugal, 4200-319
• Russian Federation
  • Moscow, Russian Federation
  • Moscow, Russian Federation, 123182
  • Moscow, Russian Federation, 125101
  • St Petersburg, Russian Federation, 195067
  • St Petersburg, Russian Federation, 197110
• Spain
  • Barcelona, Spain, 08035
  • Las Palmas de Gran Canaria, Spain, 35020
  • Madrid, Spain, 28046
  • Madrid, Spain, 28007
  • Valencia, Spain, 46009
• Sweden
  • Boras, Sweden, 50182
  • Helsingborg, Sweden, 25187
  • Jonkoping, Sweden, 55185
  • Karlstad, Sweden, 65185
  • Norrkoping, Sweden, 60182
  • Oerebro, Sweden, 70185
  • Stockholm, Sweden, 17176
  • Sundsvall, Sweden, 85186
• Taiwan
  • Taichung, Taiwan, 407
  • Tainan, Taiwan, 701
  • Taipei, Taiwan, 100
  • Taoyuan, Taiwan, 333
• Thailand
  • Bangkok, Thailand, 10700
  • Chiang Mai, Thailand, 50200
• Turkey
  • Ankara, Turkey, 06100
  • Istanbul, Turkey, 34390
  • Izmir, Turkey, 35100
• United Kingdom
  • Belfast, United Kingdom, BT9 7AB
  • London, United Kingdom, SE22 8PT
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
  • Salford, United Kingdom, M6 8HD
  • Southampton, United Kingdom, SO16 6YD
  • Surrey, United Kingdom, SM5 1AA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• adult patients >=18 years of age;
• chronic renal anemia;
• not receiving renal replacement therapy.

Exclusion Criteria:

• women who are pregnant or lactating;
• previous treatment with erythropoietin or other erythropoietic substance;
• blood transfusion within the last 3 months;
• need for dialysis expected in the next 6 months;
• administration of another investigational drug within 30 days preceding study start, or during the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early Epoetin Beta Therapy; Participants received immediate epoetin beta therapy starting at 2000 IU, subcutaneously once weekly up to four years to reach a target Hb level of 13-15 g/dL; with an individual Hb increase of at least 2 g/dL within approximately 3 months.	Drug: epoetin beta [NeoRecormon]; Participants in the early treatment group immediately started epoetin beta treatment to reach a target Hb level of 13-15 g/dL at the end of the correction phase.; Drug: epoetin beta [NeoRecormon]; Participants in the late treatment Group started epoetin beta treatment once a decline in Hb level to <10.5 g/dL had occurred.
Active Comparator: Late Epoetin Beta Therapy; Participants received epoetin beta treatment starting at 2000 IU, subcutaneously once weekly up to four years only when a decline in Hb levels to <10.5 g/dL had occurred in order to reach a target Hb of 10.5-11.5 g/dL.	Drug: epoetin beta [NeoRecormon]; Participants in the early treatment group immediately started epoetin beta treatment to reach a target Hb level of 13-15 g/dL at the end of the correction phase.; Drug: epoetin beta [NeoRecormon]; Participants in the late treatment Group started epoetin beta treatment once a decline in Hb level to <10.5 g/dL had occurred.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Time to First Cardiovascular Event	The cardiovascular event was defined as any of the following: angina pectoris leading to hospitalization for at least 24 hours or prolongation of hospitalization, acute heart failure, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, sudden death, transient cerebral ischemic attack (TIA), peripheral vascular disease (amputation, necrosis), cardiac arrhythmias leading to hospitalization for at least 24 hours or prolongation of hospitalization. The time to occurrence of a cardiovascular event was determined as the time from randomization until any of the above listed events whichever occurred first. The first event per participant was used for the analysis. Only events confirmed by the Endpoint Committee were considered for analysis.	Up to 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Time to Death Due to Cardiovascular Events	Time to death due to cardiovascular events is the time determined between randomization and death due to cardiovascular events.	Up to 4 years
Number of Participants Who Died Due to Cardiovascular Events	The cardiovascular event was defined as any of the following: angina pectoris leading to hospitalization for at least 24 hours or prolongation of hospitalization, acute heart failure, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, sudden death, transient cerebral ischemic attack (TIA), peripheral vascular disease (amputation, necrosis), cardiac arrhythmias leading to hospitalization for at least 24 hours or prolongation of hospitalization.	Up to 4 years
Median Time to Death Due to All Causes	Time to death due to all causes is the time determined between randomization and death due to all causes.	Up to 4 years
Number of Participants Who Died Due to All Causes	Number of participants who died due to all causes are presented in table below.	Up to 4 years
Number of Participants Experiencing Worsening of New York Heart Association (NYHA) Class (CL) of Chronic Heart Failure From Baseline (BL)	The NYHA functional classification assesses the severity of symptoms of chronic heart failure and is comprised of four classes. Class I is defined as no limitation of physical activity, Class II is defined as slight limitation of physical activity, Class III is defined as marked limitation of physical activity, and Class IV is defined as unable to carry on any physical activity without discomfort. Shifts of participants from CL 0, CL I, CL II, CL III, CL IV at Baseline (Day 1) to CL 0, CL I, CL II, CL III, CL IV during the study period was determined and presented.	Up to 4 years
Median Time to First Cardiovascular Intervention	Time to first cardiovascular intervention is the time between randomization and first intervention determined for all cardiovascular interventions after randomization. Cardiovascular interventions considered were: angioplasty with or without stents/atherectomy, coronary artery bypass surgery, cardioverter defibrillator (CD) cardioversion/defibrillation, temporary pacemaker, permanent pacemaker and implantable cardioverter defibrillator (ICD) implantation.	Up to 4 years
Total Number of Cardiovascular Intervention	Cardiovascular intervention was defined by a clinical review of all concomitant treatments. The cardiovascular interventions considered were: angioplasty with or without stents/atherectomy, coronary artery bypass surgery, cardioverter defibrillator (CD) cardioversion/defibrillation, temporary pacemaker, permanent pacemaker and implantable cardioverter defibrillator (ICD) implantation. The total number of cardiovascular intervention was determined and presented by each cohort.	Up to 4 years
Median Time to First Hospitalization Due to Cardiovascular Events	Time to first hospitalization due to cardiovascular events is defined as the time determined between randomization and first hospitalization due to cardiovascular events.	Up to 4 years
Duration of Hospitalization for Cardiovascular Events	The duration of hospitalization was the total number of days that a participant was hospitalized due to cardiovascular events. Participants with no hospitalization were excluded from analysis.	Up to 4 years
Mean Change From Baseline in Left Ventricular Mass Index (LVMI)	LVMI is determined by echocardiogram. LVMI indexed to body surface area (gram/square meter) estimated by LV cavity dimension and wall thickness at end-diastole. The change was calculated as week value minus baseline value.	Baseline, Week 12, Week 24, Week 36, and Week 48
Mean Change From Baseline in Left Ventricular Ejection Fraction (LVEF) and Fractional Myocardial Shortening (FS)	LVEF is a marker of left ventricular systolic function and determined by echocardiogram. It is expressed as the ratio of left ventricular stroke volume (LVSV) to left ventricular end-diastolic volume (LVEDV), and is measured as a percentage. FS is used as an estimate of myocardial contractility and determined by echocardiogram and measures as a percentage. The change for LVEF and FS was calculated as Week value minus baseline value.	Baseline, Week 12, Week 24, Week 36, and Week 48
Mean Change From Baseline in Left Ventricular Volume (LV Volume )	Left Ventricular Volume is the estimated of left ventricular end-diastolic volume (LVEDv) and left ventricular end-systolic volume (LVESV) determined by Echocardiogram. The change was calculated as week value minus baseline value.	Baseline, Week 12, Week 24, Week 36, and Week 48
Mean Values of Echocardiography Parameters	Mean values of Echocardiography (ECHO) Parameters: Left Ventricular End Diastolic Diameter (LVEDD), Left Ventricular Posterior Wall Thickness (LVPWT), IV Septal Wall Thickness (IVSWT), LV End Systolic Diameter (LVESD), LV Relative wall thickness (LVRWT) at Baseline, Year 1, Year 2, Year 3 and Year 4 were presented.	Baseline, Year 1, Year 2, Year 3, and Year 4
Mean Values of Body Surface Area	The body surface area (BSA) was determined by Echocardiogram. Absolute mean values of Echocardiography (ECHO) Parameter: Body surface area (BSA) at Baseline, Year 1, Year 2, Year 3 and Year 4 were calculated and presented.	Baseline, Year 1, Year 2, Year 3, and Year 4.
Mean Change From Baseline in the Scores of Each of The Eight Health Scales of Quality of Life Based on Short Form-36 (SF-36) Questionnaire	The Quality of life was assessed on the basis of a change from baseline in the scores of each of the eight health scales in the SF-36 questionnaire. The SF-36 is a standardized survey evaluating 8 domains (consisting of 2 components; physical and mental) of functional health and well-being: physical and social functioning, physical and emotional role (role-physical, role-emotional) limitations, bodily pain, general health (GH), vitality, mental health. The score for a section is an average of the individual question scores, which are scaled from 0 (worst level of functioning) to 100 (100=best level of functioning). The least squares mean (LSM) change from baseline was determined by Analysis of covariance (ANCOVA) model and presented for each of the eight health scale.	Baseline, Year 1, and Year 2
Number of Participants on Blood Pressure/Anti-Hypertensive Treatment According to Class Of Drugs	Anti-hypertensive is defined as class of drugs that are used to treat hypertension. Numbers (No.) of participants treated with at least one hypertensive medication/Treatment (Tt) according to class of drugs were reported.	Up to 4 years
Number of Participants With Marked Laboratory Abnormalities	Marked abnormality of laboratory parameters is defined as the value which is outside the defined reference range of that respective parameter. Values above and below the given reference range were determined as High or Low range values of the laboratory parameter. Roche's standard reference ranges for laboratory test parameters were used for the analysis. The laboratory parameters with marked abnormality are platelets (reference range is 150-350 10^9 cells/liter [L]), creatinine (reference range is 0-133 micromole per liter), albumin (reference range is 35.0-55 g/L), phosphate (reference range is 0.84-1.45 millimole per liter [mmol /L]) and potassium (reference range is 3.4-4.8 mmol /L).	Baseline, every 3 months up to 4 years

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Locatelli F, Eckardt KU, Macdougall IC, Tsakiris D, Clyne N, Burger HU, Scherhag A, Drueke TB; Cardiovascular Risk Reduction in Early Anaemia Trial with Epoetin Beta investigators and coordinators. Value of N-terminal brain natriuretic peptide as a prognostic marker in patients with CKD: results from the CREATE study. Curr Med Res Opin. 2010 Nov;26(11):2543-52. doi: 10.1185/03007995.2010.516237. Epub 2010 Sep 17.
• Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A; CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006 Nov 16;355(20):2071-84. doi: 10.1056/NEJMoa062276.

Study record dates

Study Major Dates

• Study Start: July 1, 2000
• Primary Completion (Actual): October 1, 2004
• Study Completion (Actual): December 1, 2004

Study Registration Dates

• First Submitted: May 3, 2006
• First Submitted That Met QC Criteria: May 3, 2006
• First Posted (Estimate): May 4, 2006

Study Record Updates

• Last Update Posted (Estimate): June 29, 2016
• Last Update Submitted That Met QC Criteria: May 27, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Anemia; Hematinics; Epoetin Alfa
• Other Study ID Numbers: BA16169