A Clinical Study to Evaluate Renal Hemodynamic Responses to Aliskiren in Patients With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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The study objective was to assess the effect of single and multiple doses of aliskiren on renal plasma flow, glomerular filtration rate and to compare the effects of single and multiple doses of aliskiren versus captopril or irbesartan on renal blood flow, glomerular filtration rate, and retinal blood flow in patients with type 2 diabetes mellitus.

Official Title
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An Open-label, Randomized, Parallel-group Study to Evaluate the Acute and Steady-state Renal Hemodynamic Responses to Aliskiren in Patients With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Aliskiren
* Drug: Irbesartan
* Drug: Captopril


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hypertensive, male and females of non-child bearing potential patients, with type 2 diabetes mellitus (T2DM) (diagnosed at least 8 weeks before Screening), with or without renal impairment; estimated glomerular filtration rate (eGFR) ≥ 40 mL/min/1.73 m^2, documented at least 3 months before the study start, aged 18-75 years with a minimum body weight of 50 kg and having an appropriate intravenous access as determined by the study staff, able to communicate well were enrolled in the study. Patients must be on a stable dose of hypoglycemic medications for at least 8 weeks prior to the study. Patients must be medically able to discontinue anti- hypertensive medications for the duration of the study. Exclusion Criteria: Patients with type 1 diabetes mellitus or uncontrolled T2DM (HbA1C> 11%), eGFR <40 mL/min/1.73 m^2 (calculated by the Modification of Diet in Renal Disease (MDRD) formula), renal disease not caused by diabetes or hypertension, serum potassium < 3.5 or > 5.1 mEq/L, heart failure (New York Heart Association (NYHA) Class II-IV) or history of acute/decompensated heart failure within the 6 months prior to dosing, history of myocardial infarction, unstable angina pectoris, coronary bypass surgery, or any percutaneous coronary intervention (PCI) during the 6 months prior to the baseline visit, history of malignancy including leukemia and lymphoma within past five years, hypertensive encephalopathy any time in the past or cerebrovascular accident within the 6 months prior to the baseline visit, or with history of drug or alcohol abuse within the 12 months prior to dosing were excluded from the study. Patients with glaucoma, or prior ocular surgery. Patients with renal disease not caused by diabetes or hypertension. Patients with history of clinically significant drug or atopic allergy, acute or chronic respiratory disease, history of malignancy, or history of myocardial infarction, unstable angina pectoris, coronary bypass surgery, or any coronary intervention (percutaneous coronary intervention; PCI) during the 6 months prior to the study. Patients who had used any prescription drugs which may affect the renin-angiotensin-aldosterone system or with known effect on renal hemodynamics within 2 weeks prior to dosing and during the study, over-the-counter (OTC) medication within two (2) weeks prior to dosing, Any surgical or medical condition which may jeopardize the patient in case of participation in the study. Participation in any clinical investigation within 4 weeks prior to the study. Donation or loss of 400 mL or more of blood within 8 weeks prior to the study. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aliskiren<br>On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received aliskiren 300 mg tablets orally once a day for 14 days. | Drug: Aliskiren<br>* Aliskiren 300 mg tablets<br>* Other names: SPP100;Drug: Captopril<br>* Captopril 25 mg tablet<br>|
| Active Comparator: Irbesartan<br>On Day 1 participants received a single oral dose of 25 mg captopril. Starting on Day 2 participants received irbesartan 300 mg tablets orally once a day for 14 days. | Drug: Irbesartan<br>* Irbesartan 300 mg tablets<br>Drug: Captopril<br>* Captopril 25 mg tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Renal Plasma Flow (RPF) After a Single Dose of Aliskiren or Irbesartan | Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. The measure of the single dose effect (SDE) for aliskiren and irbesartan was calculated as Day 2 peak - Day 2 baseline RPF. Baseline RPF was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak RPF was obtained using a moving average concept. | Day 2: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose. | 
| Change From Baseline to Steady State Trough in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan | Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. This multiple dose effect at steady state (MDE_SS) was calculated as Day 15 baseline - Day 2 baseline. Baseline RPF was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. | Day 2 and Day 15 at Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) . | 
| Change From Baseline to Steady State Peak in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan | Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. This maximum multiple dose effect (MDE_Max) was calculated as Day 15 peak - Day 2 baseline. Baseline RPF was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak RPF was obtained using a moving average concept. | Day 2: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and Day 15: 1, 2, 3, 4 and 5 hours post-dose. | 
| Change From Single Dose Peak to Steady State Peak in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan | Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) was calculated as Day 15 peak - Day 2 peak. Peak RPF was obtained using a moving average concept. | Day 2 and Day 15: 1, 2, 3, 4 and 5 hours post-dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Renal Plasma Flow (RPF) After a Single Dose of Captopril | Renal plasma flow (RPF) was measured by the clearance of para-aminohippurate (PAH) by autoanalyzer methods. The measure of the single dose effect (SDE) for captopril was calculated as Day 1 peak - Day 1 baseline RPF. Baseline RPF was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak RPF was obtained using a moving average concept. | Day 1: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose. | 
| Change From Baseline in Glomerular Filtration Rate (GFR) After a Single Dose of Captopril | Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. The measure of the single dose effect (SDE) for captopril was calculated as Day 1 peak - Day 1 baseline GFR. Baseline GFR was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak GFR was obtained using a moving average concept. | Day 1: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose. | 
| Change From Baseline in Glomerular Filtration Rate (GFR) After a Single Dose of Aliskiren or Irbesartan | Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. The measure of the single dose effect (SDE) for aliskiren and irbesartan was calculated as Day 2 peak - Day 2 baseline GFR. Baseline GFR was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak GFR was obtained using a moving average concept. | Day 2: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose. | 
| Change From Baseline to Steady State Trough in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan | Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. This multiple dose effect at steady state (MDE_SS) was calculated as Day 15 baseline - Day 2 baseline GFR. Baseline GFR was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. | Day 2 and Day 15 at Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) . | 
| Change From Baseline to Steady State Peak in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan | Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. This maximum multiple dose effect (MDE_Max) was calculated as Day 15 peak - Day 2 baseline GFR. Baseline GFR was determined as the median of the -10 minute, -5 minute predose and predose (0 hour) values. Peak GFR was obtained using a moving average concept. | Day 2: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and Day 15: 1, 2, 3, 4 and 5 hours post-dose. | 
| Change From Single Dose Peak to Steady State Peak in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan | Glomerular filtration rate (GFR) was measured by the clearance of inulin by autoanalyzer methods. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) was calculated as Day 15 peak - Day 2 peak GFR. Peak GFR was obtained using a moving average concept. | Day 2 and Day 15: 1, 2, 3, 4 and 5 hours post-dose. | 
| Change in Plasma Renin Concentration (PRC) After Captopril, Aliskiren or Irbesartan | The following plasma renin concentration effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour. | Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15. | 
| Change in Plasma Pro-renin Concentration After Captopril, Aliskiren or Irbesartan | The following plasma pro-renin concentration effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour. | Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15. | 
| Change in Plasma Renin Activity (PRA) After Captopril, Aliskiren or Irbesartan | PRA was measured by the trapping method and the following effects assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 baseline / Day 2 baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour. | Predose and 5 hours post dose on Days 1, 2 and 15. | 
| Change in Plasma Angiotensin I After Captopril, Aliskiren or Irbesartan | The following angiotensin I effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour. | Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15. | 
| Change in Plasma Angiotensin II After Captopril, Aliskiren or Irbesartan | The following angiotensin II effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour. | Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15. | 
| Change in Serum Aldosterone After Captopril, Aliskiren or Irbesartan | The following serum aldosterone effects were assessed: The single dose effect (SDE) for captopril, expressed as the ratio to pre-dose measurement on Day 1, = Day 1, 5 hour / Day 1 Baseline. SDE for aliskiren and irbesartan = Day 2, 5 hour / Day 2 Baseline. Steady state trough effect (multiple dose effect at steady state; MDE_SS) = Day 15 Baseline / Day 2 Baseline. Steady State peak effect (maximum multiple dose effect; MDE_Max) = Day 15, 5 hour / Day 2 Baseline. Accumulation of peak effect from single dose to multiple dose (MDE_Acc) = Day 15, 5 hour / Day 2, 5 hour. | Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15. | 
| Change From Baseline in Retinal Blood Flow After Aliskiren or Irbesartan | Retinal blood flow was assessed using the laser Doppler technique. The blood flow in the superior temporal retinal artery in one of the eyes of each study participant was determined. The Single dose effect of aliskiren or irbesartan was measured as the change/difference between Day 2 and baseline measurements. The Multiple dose effect of aliskiren or irbesartan wsas measured as the change/difference between Day 15 and Day 2 measurements | Baseline (Day 1), Day 2 and Day 15. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes mellitus, renal disease, hypertension, renal blood flow, retinal blood flow, aliskiren, irbesartan, captopril