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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis
ClinicalTrials.gov Identifier:
NCT00660309
First received: April 11, 2008
Last updated: August 27, 2012
Last verified: August 2012
  Purpose

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.


Condition Intervention Phase
Type 2 Diabetes Mellitus
Drug: Aliskiren
Drug: Irbesartan
Drug: Captopril
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Change From Baseline in Renal Plasma Flow (RPF) After a Single Dose of Aliskiren or Irbesartan [ Time Frame: Day 2: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose. ] [ Designated as safety issue: No ]

    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.


  • Change From Baseline to Steady State Trough in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan [ Time Frame: Day 2 and Day 15 at Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) . ] [ Designated as safety issue: No ]

    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.


  • Change From Baseline to Steady State Peak in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan [ Time Frame: 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. ] [ Designated as safety issue: No ]

    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.


  • Change From Single Dose Peak to Steady State Peak in Renal Plasma Flow (RPF) After Aliskiren or Irbesartan [ Time Frame: Day 2 and Day 15: 1, 2, 3, 4 and 5 hours post-dose. ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • Change From Baseline in Renal Plasma Flow (RPF) After a Single Dose of Captopril [ Time Frame: Day 1: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose. ] [ Designated as safety issue: No ]

    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.


  • Change From Baseline in Glomerular Filtration Rate (GFR) After a Single Dose of Captopril [ Time Frame: Day 1: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose. ] [ Designated as safety issue: No ]

    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.


  • Change From Baseline in Glomerular Filtration Rate (GFR) After a Single Dose of Aliskiren or Irbesartan [ Time Frame: Day 2: Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) and 1, 2, 3, 4 and 5 hours post-dose. ] [ Designated as safety issue: No ]

    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.


  • Change From Baseline to Steady State Trough in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan [ Time Frame: Day 2 and Day 15 at Baseline (10 minutes and 5 minutes pre-treatment and 0 hours) . ] [ Designated as safety issue: No ]

    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.


  • Change From Baseline to Steady State Peak in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan [ Time Frame: 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. ] [ Designated as safety issue: No ]

    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.


  • Change From Single Dose Peak to Steady State Peak in Glomerular Filtration Rate (GFR) After Aliskiren or Irbesartan [ Time Frame: Day 2 and Day 15: 1, 2, 3, 4 and 5 hours post-dose. ] [ Designated as safety issue: No ]

    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.


  • Change in Plasma Renin Concentration (PRC) After Captopril, Aliskiren or Irbesartan [ Time Frame: Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15. ] [ Designated as safety issue: No ]

    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.


  • Change in Plasma Pro-renin Concentration After Captopril, Aliskiren or Irbesartan [ Time Frame: Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15. ] [ Designated as safety issue: No ]

    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.


  • Change in Plasma Renin Activity (PRA) After Captopril, Aliskiren or Irbesartan [ Time Frame: Predose and 5 hours post dose on Days 1, 2 and 15. ] [ Designated as safety issue: No ]

    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.


  • Change in Plasma Angiotensin I After Captopril, Aliskiren or Irbesartan [ Time Frame: Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15. ] [ Designated as safety issue: No ]

    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.


  • Change in Plasma Angiotensin II After Captopril, Aliskiren or Irbesartan [ Time Frame: Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15. ] [ Designated as safety issue: No ]

    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.


  • Change in Serum Aldosterone After Captopril, Aliskiren or Irbesartan [ Time Frame: Predose (Baseline) and 5 hours post dose on Days 1, 2 and 15. ] [ Designated as safety issue: No ]

    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.


  • Change From Baseline in Retinal Blood Flow After Aliskiren or Irbesartan [ Time Frame: Baseline (Day 1), Day 2 and Day 15. ] [ Designated as safety issue: No ]

    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



Enrollment: 45
Study Start Date: April 2008
Study Completion Date: December 2009
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Aliskiren
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
Aliskiren 300 mg tablets
Other Name: SPP100
Drug: Captopril
Captopril 25 mg tablet
Active Comparator: Irbesartan
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
Irbesartan 300 mg tablets
Drug: Captopril
Captopril 25 mg tablet

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00660309

Locations
United States, Massachusetts
Novartis Investigator Site
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Novartis
Investigators
Principal Investigator: Novartis Novartis investigator site
  More Information

No publications provided by Novartis

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis
ClinicalTrials.gov Identifier: NCT00660309     History of Changes
Other Study ID Numbers: CSPP100A2329
Study First Received: April 11, 2008
Results First Received: July 20, 2012
Last Updated: August 27, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
Type 2 diabetes mellitus
renal disease
hypertension
renal blood flow
retinal blood flow
aliskiren
irbesartan
captopril

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Irbesartan
Captopril
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 18, 2014