Effects of Aliskiren, Irbesartan, and the Combination in Hypertensive Patients With Type 2 Diabetes and Diabetic Nephropathy

A Randomized, Double-Blind, Parallel-Group, Cross-Over, 4-Period, 4 Treatment, Within-Subject Placebo-Controlled Study to Assess the Reno-Protective Effect of Renin Inhibition With Aliskiren as an Alternative to Irbesartan in Type 2 Patients With Incipient/Overt Diabetic Nephropathy

This study will assess the reno-protective effect of renin inhibition with aliskiren as an alternative to irbesartan in type 2 diabetes patients with incipient/overt diabetic nephropathy.

Antiproteinuric Effects of Aliskiren (Renin Inhibitor), Irbesartan (Angiotensin Receptor Antagonist) and the Combination in Hypertensive Patients With Type 2 Diabetes and Incipient/Overt Diabetic Nephropathy

Inclusion Criteria:

• Male and/or female subjects between the ages of 30-80 years with a diagnosis of type 2 diabetes (World Health Organization criteria)

• Body mass index (BMI) within the range of 20 and 32.

• Incipient or overt diabetic nephropathy (urinary albumin excretion ≥ 100 but ≤ 2000 mg/day).

• Glomerular filtration rate (GFR) ≥ 40 ml/min documented in the last 4 months prior to randomization

• To be eligible for randomization, patients must fulfill the following criteria:

  1. Patients on ongoing hypertensive therapy must have a blood pressure ≥ 135/85 mmHg but lower than 170/105 mmHg at Visit 2 (Day -1) AND patients must be on stable antihypertensive medications for at least 8 weeks prior to Visit 2 (run-in period).
  2. Newly diagnosed hypertensive patients must have a blood pressure ≥ 135/85 mmHg but lower than 170/105 mmHg at Visit 2 (Day -1).

• Patients must be on stable hypoglycemic medications for at least 8 weeks prior to Visit 2 (Day -1).

• Patients must be willing and medically able to discontinue all angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), aldosterone receptor antagonist and potassium sparing diuretic medications for the duration of the study.

• Female patients must be postmenopausal, have had a bilateral oophorectomy, or have been surgically sterilized or hysterectomized at least 6 months prior to screening.

• Oral body temperature within the range of 35.0-37.5 °C

• Able to provide written informed consent prior to study participation.

• Able to communicate well with the investigator and comply with the requirements of the study.

Exclusion Criteria:

• Severe hypertension, Grade 3 World Health Organization (WHO) classification (mean sitting diastolic blood pressure [MSDBP] ≥ 110 mmHg and/or mean sitting systolic blood pressure [MSSBP] ≤ 180 mmHg)

• Acetylsalicylic acid (ASA) treatment > 1 g/day or regular use of nonsteroidal anti-inflammatory drugs (NSAIDs)

• Kidney disease not caused by diabetes or hypertension

• Serum potassium < 3.5 or > 5.1 mEq/L

• GFR < 40 ml/min/1.73m2 as measured by the Modification of Diet in Renal Disease (MDRD) formula

• Serum albumin < 2.0 mg/dL

• History of hypertensive encephalopathy or cerebrovascular accident in the last 12 months prior to Visit 1

• Transient ischemic cerebral attack during the 6 months prior to Visit 1

• Current diagnosis of heart failure (New York Heart Association [NYHA] Class II-IV)

• History of myocardial infarction, unstable angina pectoris, coronary bypass surgery, or any percutaneous coronary intervention (PCI) during the 6 months prior to Visit 1

• Second or third degree heart block without a pacemaker

• Concurrent potentially life threatening arrhythmia or symptomatic arrhythmia

• Clinically significant valvular heart disease

• Type 1 diabetes mellitus

• Uncontrolled type II diabetes mellitus; hemoglobin subtype A1C (HbA1C) > 11%

• History of malignancy including leukemia and lymphoma (but not basal cell skin carcinoma) within the past five years

• Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulation.

• Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing.

• Significant illness within the two weeks prior to dosing.

• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs including, but not limited to, any of the following:

  • History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection
  • Currently active or previously active inflammatory bowel disease during the 12 months prior to Visit 1
  • Currently active gastritis, duodenal or gastric ulcers, or gastrointestinal/rectal bleeding during the 3 months prior to Visit 1.
  • Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase
  • Evidence of hepatic disease, a history of hepatic encephalopathy, a history of esophageal varices, or a history of portacaval shunt
  • Current treatment with cholestyramine or colestipol resins

• History of immunocompromise, including a positive test result.

• History of a positive hepatitis B surface antigen (HBsAg) or hepatitis C test result.

• History of drug or alcohol abuse within the 12 months prior to dosing.

• Persons directly involved in the execution of this protocol.

• Any condition that, in the opinion of the investigator or the Novartis medical monitor, would jeopardize the evaluation of efficacy or safety

• History of noncompliance to medical regimens or unwillingness to comply with the study protocol

• Known or suspected contraindications to the study medications, including history of allergy to ACE inhibitors and/or to thiazide diuretics or other sulfonamide derived drug

• Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study

• Use of any prescription drug or over-the-counter (OTC) medication which is prohibited by the protocol.

• Patients who previously participated in any aliskiren study.

Other protocol-defined inclusion/exclusion criteria may apply.