Kidney Disease, Chronic
Conditions
Brief summary
This randomized, single-blind, proof-of-concept study will investigate the protective effects of early treatment with Mircera in participants with chronic kidney disease on renal disease progression. Participants will be randomly assigned to receive 30 microgram (mcg) Mircera as subcutaneous injection once monthly or matching placebo. Depending on change of hemoglobin values, the dose of Mircera can be adjusted to 50 mcg or 75 mcg once monthly. The anticipated time on study treatment is 24 months.
Interventions
DRUGPlacebo
Placebo matching to Methoxy polyethylene glycol-epoetin beta subcutaneous injection once monthly up to 24 months.
DRUGMethoxy polyethylene glycol-epoetin beta
Methoxy polyethylene glycol-epoetin beta 30 microgram (mcg) subcutaneous injection once monthly up to 24 months with sequential dose adjustments to 50 mcg or 75 mcg depending on change of hemoglobin values of more than 1.0 gram (g)/ deciliter (dL).
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* For diabetic participants: Type 2 diabetes mellitus with glycated hemoglobin (HbA1c) greater than (\>) 7% or anti-diabetic treatment * For renal allograft recipients: Status at least 6 months post transplantation * Chronic kidney disease stage III * Urinary albumin-to-creatinine ratio less than (\<) 3000 milligram (mg)/gram (g) or total protein \<3000 mg/ 24 hour urine sample where applicable
Exclusion criteria
* Hemoglobin-level \< 11 or \> 14 g/deciliter (dL) * Average systolic blood pressure (SBP) \> 140 millimeter of mercury (mm Hg) or average diastolic blood pressure (DBP) \> 90 mm Hg * Initiation of angiotensin converting enzyme inhibitor, angiotensin 2 receptor blocker or aliskiren treatment less than 3 months before enrolment * Present and known iron deficiency * HbA1c \>9%
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Yearly Reduction Rate of Estimated Glomerular Filtration Rate (eGFR) Calculated by Modification of Diet in Renal Disease With 4 Variables (MDRD-4) | 24 months | The yearly reduction in eGFR was calculated using the MDRD-4 formula. This formula is based on age, sex, and serum creatinine and eGFR values are calculated as follows: GFR in milliliter per minute (mL/min) per 1.73 meter square (m\^2) = 175 x Serum Cr\^-1.154 x age\^-0.203 x 0.742 (if female). The yearly reduction rate (mL/min/1.73m\^2 / Year) is defined as -365.25 multiplied by Beta, where Beta is the slope parameter derived for each participants separately by simple linear regression of the change from baseline in participant's eGFR measurements (from Baseline to Visit 24) on the actual day of measurement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Month 24 | Baseline, Month 24 | Creatinine clearance was calculated according to the Cockcroft and Gault Formula. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is greater than or equal to (\>=) 90 mL/min. Change from baseline=CC at Week X minus CC at baseline where higher scores represented improved renal function. |
| Change From Baseline in Serum Creatinine Concentration at Month 24 | Baseline, Month 24 | Serum creatinine is an indicator of kidney function. Creatinine is a substance formed from the metabolism of creatine, commonly found in blood, urine, and muscle tissue. It is removed from the blood by the kidneys and excreted in urine. Normal adult blood levels of creatinine=45 to 90 micromoles per liter (mcmol/L) for females, 60 to 110 mcmol/L for males, however normal values are age-dependent. |
| Yearly Reduction Rate of Estimated Glomerular Filtration Rate (eGFR) Calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) | 24 months | The eGFR value calculated using the CKD-EPI equation. The formula used is based on age, sex, ethnicity, and serum creatinine and eGFR values are calculated as follows: GFR in mL/min per 1.73 m\^2 = 141 x min (SerumCr/k; 1)\^a x max(SerumCr/k; 1)\^(-1.209) x 0.993\^age x F x B, where k=0.7 for female (else=0.9); a=-0.329 for female (else=-0.411), F=1.018 for female (else=1), B=1.159 for black (else=1), min/max=minimum/maximum of listed values. The Yearly Reduction Rate (mL/min/1.73m\^2 / Year) is defined as -365.25 x Beta, where Beta is the slope parameter derived for each participant separately by simple linear regression of the change from baseline in participant's eGFR measurements (from Baseline to Visit 24) on the actual day of measurement. |
| Change From Baseline in Serum Cystatin C Concentration at Month 24 | Baseline, Month 24 | Cystatin C is a protein which is mainly used as a biomarker of kidney function. If kidney function and GFR decline, the blood levels of cystatin C rise. |
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | 24 months | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability or incapacity; and congenital anomaly. Percentage of participants with AEs included participants affected with both SAEs and non-SAEs. |
| Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Month 24 | Baseline, Month 24 | UACR is defined as the ratio: milligram of albumin per gram of creatinine. The presence of albumin in the urine (macroalbuminuria) is a marker of kidney disease. Albumin and creatinine concentrations were obtained from spot urine samples. |
Countries
Germany
Participant flow
Pre-assignment details
Total 241 participants were enrolled, 2 participants in the Mircera group and 4 participants in the placebo group did not receive medication.
Participants by arm
| Arm | Count |
|---|---|
| Mircera Methoxy polyethylene glycol-epoetin beta 30 mcg subcutaneous injection once monthly up to 24 months with sequential dose adjustments to 50 mcg or 75 mcg depending on change of hemoglobin values of more than 1.0 g/dL. | 115 |
| Placebo Placebo matching to Methoxy polyethylene glycol-epoetin beta subcutaneous injection once monthly up to 24 months. | 120 |
| Total | 235 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 7 |
| Overall Study | Blood pressure increase | 5 | 3 |
| Overall Study | Did not receive study medication | 2 | 4 |
| Overall Study | Hemoglobin decrease | 0 | 1 |
| Overall Study | Hemoglobin increase | 12 | 3 |
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Other | 4 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Skipping of CERA treatment at two visits | 3 | 0 |
| Overall Study | Treatment with prohibited medication | 4 | 5 |
| Overall Study | Withdrawal by Subject | 5 | 6 |
Baseline characteristics
| Characteristic | Mircera | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 63.37 years STANDARD_DEVIATION 12.26 | 62.97 years STANDARD_DEVIATION 14.3 | 63.17 years STANDARD_DEVIATION 13.31 |
| Sex: Female, Male Female | 44 Participants | 44 Participants | 88 Participants |
| Sex: Female, Male Male | 71 Participants | 76 Participants | 147 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 95 / 118 | 99 / 117 |
| serious Total, serious adverse events | 42 / 118 | 48 / 117 |
Outcome results
Primary
Yearly Reduction Rate of Estimated Glomerular Filtration Rate (eGFR) Calculated by Modification of Diet in Renal Disease With 4 Variables (MDRD-4)
The yearly reduction in eGFR was calculated using the MDRD-4 formula. This formula is based on age, sex, and serum creatinine and eGFR values are calculated as follows: GFR in milliliter per minute (mL/min) per 1.73 meter square (m\^2) = 175 x Serum Cr\^-1.154 x age\^-0.203 x 0.742 (if female). The yearly reduction rate (mL/min/1.73m\^2 / Year) is defined as -365.25 multiplied by Beta, where Beta is the slope parameter derived for each participants separately by simple linear regression of the change from baseline in participant's eGFR measurements (from Baseline to Visit 24) on the actual day of measurement.
Time frame: 24 months
Population: FAS included all randomized participants who received at least one dose of the study medication and provided any successive eGFR measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mircera | Yearly Reduction Rate of Estimated Glomerular Filtration Rate (eGFR) Calculated by Modification of Diet in Renal Disease With 4 Variables (MDRD-4) | 3.04 mL/min/1.73m^2/year |
| Placebo | Yearly Reduction Rate of Estimated Glomerular Filtration Rate (eGFR) Calculated by Modification of Diet in Renal Disease With 4 Variables (MDRD-4) | 0.82 mL/min/1.73m^2/year |
p-value: 0.65795% CI: [-0.35, 4.78]Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Month 24
Creatinine clearance was calculated according to the Cockcroft and Gault Formula. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is greater than or equal to (\>=) 90 mL/min. Change from baseline=CC at Week X minus CC at baseline where higher scores represented improved renal function.
Time frame: Baseline, Month 24
Population: FAS included all randomized participants who received at least one dose of the study medication and provided any successive eGFR measurement. Here, n=number of participants evaluable for each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mircera | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Month 24 | Baseline (n=115, 120) | 53.18 mL/min | Standard Deviation 15.95 |
| Mircera | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Month 24 | Change at Month 24 (n=67, 91) | -2.97 mL/min | Standard Deviation 10.52 |
| Placebo | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Month 24 | Baseline (n=115, 120) | 52.48 mL/min | Standard Deviation 16.04 |
| Placebo | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Month 24 | Change at Month 24 (n=67, 91) | -2.08 mL/min | Standard Deviation 9.72 |
Secondary
Change From Baseline in Serum Creatinine Concentration at Month 24
Serum creatinine is an indicator of kidney function. Creatinine is a substance formed from the metabolism of creatine, commonly found in blood, urine, and muscle tissue. It is removed from the blood by the kidneys and excreted in urine. Normal adult blood levels of creatinine=45 to 90 micromoles per liter (mcmol/L) for females, 60 to 110 mcmol/L for males, however normal values are age-dependent.
Time frame: Baseline, Month 24
Population: FAS included all randomized participants who received at least one dose of the study medication and provided any successive eGFR measurement. Here, n=number of participants evaluable for each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mircera | Change From Baseline in Serum Creatinine Concentration at Month 24 | Change at Month 24 (n=68, 91) | 7.04 mcmol/L | Standard Deviation 27.23 |
| Mircera | Change From Baseline in Serum Creatinine Concentration at Month 24 | Baseline (n=115, 120) | 147.8 mcmol/L | Standard Deviation 31.71 |
| Placebo | Change From Baseline in Serum Creatinine Concentration at Month 24 | Baseline (n=115, 120) | 149.3 mcmol/L | Standard Deviation 35.67 |
| Placebo | Change From Baseline in Serum Creatinine Concentration at Month 24 | Change at Month 24 (n=68, 91) | 4.04 mcmol/L | Standard Deviation 30.99 |
Secondary
Change From Baseline in Serum Cystatin C Concentration at Month 24
Cystatin C is a protein which is mainly used as a biomarker of kidney function. If kidney function and GFR decline, the blood levels of cystatin C rise.
Time frame: Baseline, Month 24
Population: FAS included all randomized participants who received at least one dose of the study medication and provided any successive eGFR measurement. Here, n=number of participants evaluable for each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mircera | Change From Baseline in Serum Cystatin C Concentration at Month 24 | Baseline (n=115, 120) | 1.79 mg/L | Standard Deviation 0.39 |
| Mircera | Change From Baseline in Serum Cystatin C Concentration at Month 24 | Change at Month 24 (n=67, 91) | 0.10 mg/L | Standard Deviation 0.29 |
| Placebo | Change From Baseline in Serum Cystatin C Concentration at Month 24 | Baseline (n=115, 120) | 1.76 mg/L | Standard Deviation 0.46 |
| Placebo | Change From Baseline in Serum Cystatin C Concentration at Month 24 | Change at Month 24 (n=67, 91) | 0.02 mg/L | Standard Deviation 0.33 |
Secondary
Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Month 24
UACR is defined as the ratio: milligram of albumin per gram of creatinine. The presence of albumin in the urine (macroalbuminuria) is a marker of kidney disease. Albumin and creatinine concentrations were obtained from spot urine samples.
Time frame: Baseline, Month 24
Population: FAS included all randomized participants who received at least one dose of the study medication and provided any successive eGFR measurement. Number of Participants Analyzed (N) = number of participants evaluable and available with valid data for this outcome measure. Here, n=number of participants evaluable for each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mircera | Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Month 24 | Baseline (n=110, 107) | 261.1 mg/g | Standard Deviation 564 |
| Mircera | Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Month 24 | Change at Month 24 (n=43, 53) | 173.8 mg/g | Standard Deviation 573.3 |
| Placebo | Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Month 24 | Change at Month 24 (n=43, 53) | 70.59 mg/g | Standard Deviation 546.8 |
| Placebo | Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Month 24 | Baseline (n=110, 107) | 237.3 mg/g | Standard Deviation 699.6 |
Secondary
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability or incapacity; and congenital anomaly. Percentage of participants with AEs included participants affected with both SAEs and non-SAEs.
Time frame: 24 months
Population: The Safety Analysis Set (SAF) included all participants who received at least one dose of study medication. Analysis for SAF was performed according to the study medication actually received (as treated population). Number of participants analyzed=participants evaluable for this measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mircera | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 35.6 percentage of participants |
| Mircera | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 84.7 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 41.0 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 86.3 percentage of participants |
Secondary
Yearly Reduction Rate of Estimated Glomerular Filtration Rate (eGFR) Calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
The eGFR value calculated using the CKD-EPI equation. The formula used is based on age, sex, ethnicity, and serum creatinine and eGFR values are calculated as follows: GFR in mL/min per 1.73 m\^2 = 141 x min (SerumCr/k; 1)\^a x max(SerumCr/k; 1)\^(-1.209) x 0.993\^age x F x B, where k=0.7 for female (else=0.9); a=-0.329 for female (else=-0.411), F=1.018 for female (else=1), B=1.159 for black (else=1), min/max=minimum/maximum of listed values. The Yearly Reduction Rate (mL/min/1.73m\^2 / Year) is defined as -365.25 x Beta, where Beta is the slope parameter derived for each participant separately by simple linear regression of the change from baseline in participant's eGFR measurements (from Baseline to Visit 24) on the actual day of measurement.
Time frame: 24 months
Population: FAS included all randomized participants who received at least one dose of the study medication and provided any successive eGFR measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mircera | Yearly Reduction Rate of Estimated Glomerular Filtration Rate (eGFR) Calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) | 3.02 mL/min/1.73m^2/year |
| Placebo | Yearly Reduction Rate of Estimated Glomerular Filtration Rate (eGFR) Calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) | 0.78 mL/min/1.73m^2/year |
p-value: 0.70995% CI: [-0.54, 5.01]Wilcoxon (Mann-Whitney)