Non-diabetic Nephropathy
Conditions
Brief summary
The study is designed to primarily assess the effect of aliskiren on albuminuria in patients with non-diabetic nephropathy when treated with ramipril and volume intervention.
Interventions
DRUGAliskiren
Aliskiren 150 mg (Tablet)
Aliskiren 150 mg Matching Placebo (Tablet)
HCTZ 25mg (Capsule)
DRUGPlacebo to Hydrochlorothiazide (HCTZ)
HCTZ 25mg (Capsule) Matching Placebo
DRUGRamipril
Ramipril 10mg (Tablet)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female subjects, age 18 years and above * Patients with chronic kidney disease of non-diabetic origin * Glomerular filtration rate \>30 ml/min/1.73m2 * Patients with a history of hypertension and msSBP (mean systolic blood pressure) of \<160 mm Hg and msDBP (mean diastolic blood pressure) \<105 mm Hg at screening and baseline. * Subjects must have a body mass index (BMI) within the range of 18 and 35 kg/m2
Exclusion criteria
* Previously treated (within 3 months of screening) with aliskiren or a combination of aliskiren and ramipril. * Severe hypertension (msDBP ≥110 mmHg and msSBP ≥180 mmHg) * Pregnant or nursing (lactating) women, * A medical history of unstable coronary artery disease, myocardial infarction, coronary bypass surgery or cerebrovascular accident within the last six (6) months * Diabetes mellitus, Heart failure * High rate of renal function loss * History of severe hypersensitivity or contraindications to any of the medications or drugs belonging to the similar therapeutic class as the study drugs and the excipients. * History of liver disease, positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result * History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Aliskiren on Albuminuria as Measured by Urinary Albumin Excretion Rate (UAER) | 26 weeks | Two 24-hour collections of urine were to be made at each study visit. The arithmetic mean of the two collections were planned to be used in the calculation of summary statistics and the statistical analyses. |
| Effect of Aliskiren on Albuminuria as Measured by Creatinine Indexed Albumin | 26 weeks | Two 24-hour collections of urine were to be made at each study visit. The arithmetic mean of the two collections were planned to be used in the calculation of summary statistics and the statistical analyses. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Sitting Diastolic Blood Pressure (msDBP) | 26 weeks | At study entry, blood pressure (BP) was measured in both arms. If there was a clinically relevant difference in readings between arms (≥ 10 mmHg in systolic BP and/or ≥ 5 mmHg in diastolic BP), the arm with higher BP reading was used. If there was no clinically significant difference between arms, the non-dominant arm was used through out study. Diastolic blood pressure were assessed after the patient rested quietly in the sitting position for at least 3 minutes. For each sitting assessment, blood pressure was assessed at least 3 times. From these assessments, msDBP was calculated. All BP measurements were to be performed on the same arm. |
| Mean Glomerular Filtration Rate (GFR) as Measurement of Renal Function | 26 weeks | All patients had to visit the main center for renal function measurements. The measurements were performed using the constant infusion method with I-iothalamate (IOT) and I-hippuran. GFR was calculated as the urinary clearance of IOT. |
| Mean Effective Renal Plasma Flow (ERPF) as One of Hemodynamic Assessments | 26 weeks | — |
| Mean Extracellular Volume (ECV) as One of Hemodynamic Assessments | 26 weeks | — |
| Plasma Rennin Activity (PRA) | Baseline to week 26 | Blood biomarkers were obtained from blood samples in all patients at the time points such as baseline, week 6, week 12, week 18 and week 26. Plasma PRA is a direct measure of the formation of Ang I in the plasma. |
| Plasma Rennin Concentration (PRC) | Baseline to week 26 | Blood biomarkers were obtained from blood samples in all patients at the time points such as baseline, week 6, week 12, week 18 and week 26. PRC measures the concentration of immunoactive renin in the plasma. |
| Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril | 26 weeks | — |
| Percentage of Renal Filtration Fraction (RFF) as One of Hemodynamic Assessments | 26 weeks | — |
| Mean Sitting Systolic Blood Pressure (msSBP) | 26 weeks | At study entry, blood pressure (BP) was measured in both arms. If there was a clinically relevant difference in readings between arms (≥ 10 mmHg in systolic BP and/or ≥ 5 mmHg in diastolic BP), the arm with higher BP reading was used. If there was no clinically significant difference between arms, the non-dominant arm was used through out study. Systolic blood pressure were assessed after the patient rested quietly in the sitting position for at least 3 minutes. For each sitting assessment, blood pressure was assessed at least 3 times. From these assessments, msSBP was calculated. All BP measurements were to be performed on the same arm. |
Countries
Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ramipril (Ram) +HCTZ/Ram+Aliskiren (Ali)+HCTZ/Ram+Ali/Ram Period 1(Day 1 to end of week 6): 1 tablet ramipril 10 mg once daily (o.d.) + 2 tablets placebo to aliskiren 150mg o.d. + 1 capsule Hydrochlorothiazide (HCTZ) 25 mg o.d.
Period 2 (Weeks 7 to 12): 1 tablet ramipril 10 mg o.d.+ 1 tablet aliskiren 150 mg in 1st week of period; thereafter, 2 tablets aliskiren 150mg o.d.+ 1 capsule HCTZ 25 mg o.d.
Period 3 (Weeks 13 to 18): 1 tablet ramipril 10 mg o.d. + 2 tablets aliskiren 150mg o.d. + 1 capsule placebo to HCTZ 25 mg o.d.
Period 4 (Weeks 19 to 26): 1 tablet ramipril 10 mg o.d. + 2 tablets placebo to aliskiren 150mg o.d. + 1 capsule placebo to HCTZ 25 mg o.d. | 4 |
| Ramipril (Ram) +HCTZ/Ram+Aliskiren (Ali)/Ram+Ali + HCTZ/Ram Period 1(Day 1 to end of week 6): 1 tablet ramipril 10 mg once daily (o.d.) + 2 tablets placebo to aliskiren 150mg o.d. + 1 capsule Hydrochlorothiazide (HCTZ) 25 mg o.d.
Period 2 (Weeks 7 to 12): 1 tablet ramipril 10 mg o.d.+ 1 tablet aliskiren 150 mg in 1st week of period; thereafter, 2 tablets aliskiren 150mg o.d.+ 1 capsule placebo to HCTZ 25 mg o.d.
Period 3 (Weeks 13 to 18): 1 tablet ramipril 10 mg o.d. + 2 tablets aliskiren 150mg o.d. + 1 capsule HCTZ 25 mg o.d.
Period 4 (Weeks 19 to 26): 1 tablet ramipril 10 mg o.d. + 2 tablets placebo to aliskiren 150mg o.d. + 1 capsule placebo to HCTZ 25 mg o.d. | 4 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 2 (Weeks 7 to 12) | Abnormal laboratory value(s) | 0 | 1 |
| Period 2 (Weeks 7 to 12) | Protocol Deviation | 1 | 0 |
Baseline characteristics
| Characteristic | Ramipril (Ram) +HCTZ/Ram+Aliskiren (Ali)+HCTZ/Ram+Ali/Ram | Ramipril (Ram) +HCTZ/Ram+Aliskiren (Ali)/Ram+Ali + HCTZ/Ram | Total |
|---|---|---|---|
| Age Continuous | 50.5 years STANDARD_DEVIATION 6.76 | 58.5 years STANDARD_DEVIATION 8.7 | 54.5 years STANDARD_DEVIATION 8.38 |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 8 | 5 / 7 | 3 / 7 | 4 / 6 |
| serious Total, serious adverse events | 0 / 8 | 0 / 7 | 0 / 7 | 0 / 6 |
Outcome results
Primary
Effect of Aliskiren on Albuminuria as Measured by Creatinine Indexed Albumin
Two 24-hour collections of urine were to be made at each study visit. The arithmetic mean of the two collections were planned to be used in the calculation of summary statistics and the statistical analyses.
Time frame: 26 weeks
Population: The study was terminated and consequentially was underpowered for adequate statistical analysis
Primary
Effect of Aliskiren on Albuminuria as Measured by Urinary Albumin Excretion Rate (UAER)
Two 24-hour collections of urine were to be made at each study visit. The arithmetic mean of the two collections were planned to be used in the calculation of summary statistics and the statistical analyses.
Time frame: 26 weeks
Population: The study was terminated and consequentially was underpowered for adequate statistical analysis
Secondary
Mean Effective Renal Plasma Flow (ERPF) as One of Hemodynamic Assessments
Time frame: 26 weeks
Population: The study was terminated and consequentially was underpowered for adequate statistical analysis
Secondary
Mean Extracellular Volume (ECV) as One of Hemodynamic Assessments
Time frame: 26 weeks
Population: The study was terminated and consequentially was underpowered for adequate statistical analysis
Secondary
Mean Glomerular Filtration Rate (GFR) as Measurement of Renal Function
All patients had to visit the main center for renal function measurements. The measurements were performed using the constant infusion method with I-iothalamate (IOT) and I-hippuran. GFR was calculated as the urinary clearance of IOT.
Time frame: 26 weeks
Population: The study was terminated and consequentially was underpowered for adequate statistical analysis
Secondary
Mean Sitting Diastolic Blood Pressure (msDBP)
At study entry, blood pressure (BP) was measured in both arms. If there was a clinically relevant difference in readings between arms (≥ 10 mmHg in systolic BP and/or ≥ 5 mmHg in diastolic BP), the arm with higher BP reading was used. If there was no clinically significant difference between arms, the non-dominant arm was used through out study. Diastolic blood pressure were assessed after the patient rested quietly in the sitting position for at least 3 minutes. For each sitting assessment, blood pressure was assessed at least 3 times. From these assessments, msDBP was calculated. All BP measurements were to be performed on the same arm.
Time frame: 26 weeks
Population: The study was terminated and consequentially was underpowered for adequate statistical analysis
Secondary
Mean Sitting Systolic Blood Pressure (msSBP)
At study entry, blood pressure (BP) was measured in both arms. If there was a clinically relevant difference in readings between arms (≥ 10 mmHg in systolic BP and/or ≥ 5 mmHg in diastolic BP), the arm with higher BP reading was used. If there was no clinically significant difference between arms, the non-dominant arm was used through out study. Systolic blood pressure were assessed after the patient rested quietly in the sitting position for at least 3 minutes. For each sitting assessment, blood pressure was assessed at least 3 times. From these assessments, msSBP was calculated. All BP measurements were to be performed on the same arm.
Time frame: 26 weeks
Population: The study was terminated and consequentially was underpowered for adequate statistical analysis
Secondary
Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril
Time frame: 26 weeks
Population: The safety analysis set consisted of all patients who received at least one study drug and had no major protocol deviations that could have impacted safety data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramipril +HCTZ | Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril | patients with adverse events | 7 Participants |
| Ramipril +HCTZ | Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril | patients with death | 0 Participants |
| Ramipril +HCTZ | Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril | patients with serious adverse events | 0 Participants |
| Ramipril+Aliskiren + HCTZ | Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril | patients with adverse events | 5 Participants |
| Ramipril+Aliskiren + HCTZ | Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril | patients with death | 0 Participants |
| Ramipril+Aliskiren + HCTZ | Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril | patients with serious adverse events | 0 Participants |
| Ramipril+Aliskiren | Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril | patients with serious adverse events | 0 Participants |
| Ramipril+Aliskiren | Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril | patients with adverse events | 3 Participants |
| Ramipril+Aliskiren | Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril | patients with death | 0 Participants |
| Ramipril | Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril | patients with adverse events | 4 Participants |
| Ramipril | Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril | patients with death | 0 Participants |
| Ramipril | Number of Participants With Adverse Events, Serious Adverse Events and Death as Assessment of Safety and Tolerability of Aliskiren Added to Ramipril | patients with serious adverse events | 0 Participants |
Secondary
Percentage of Renal Filtration Fraction (RFF) as One of Hemodynamic Assessments
Time frame: 26 weeks
Population: The study was terminated and consequentially was underpowered for adequate statistical analysis
Secondary
Plasma Rennin Activity (PRA)
Blood biomarkers were obtained from blood samples in all patients at the time points such as baseline, week 6, week 12, week 18 and week 26. Plasma PRA is a direct measure of the formation of Ang I in the plasma.
Time frame: Baseline to week 26
Population: The study was terminated and consequentially was underpowered for adequate statistical analysis
Secondary
Plasma Rennin Concentration (PRC)
Blood biomarkers were obtained from blood samples in all patients at the time points such as baseline, week 6, week 12, week 18 and week 26. PRC measures the concentration of immunoactive renin in the plasma.
Time frame: Baseline to week 26
Population: The study was terminated and consequentially was underpowered for adequate statistical analysis