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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
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.

Conditions
-----------------
Anemia

Intervention / Treatment
-----------------
* Drug: epoetin beta [NeoRecormon]
* Drug: epoetin beta [NeoRecormon]


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early Epoetin Beta Therapy<br>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]<br>* 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.<br>|
| Active Comparator: Late Epoetin Beta Therapy<br>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]<br>* Participants in the late treatment Group started epoetin beta treatment once a decline in Hb level to <10.5 g/dL had occurred.<br>|

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 |