| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • Investigate the antiproteinuric effect of increasing dose administration of Aliskiren versus Aliskiren matching placebo |
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| E.2.2 | Secondary objectives of the trial |
• Assess the effect on Glomerular Filtration Rate (GFR) of multiple dose administration of Aliskiren.
• Assess the effect on blood pressure of multiple dose administration of Aliskiren.
• To investigate whether there is a change on biomarkers of inflammation and cardiovascular risk.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Male and/or female patients from 30-80 years of age.
2. Type 2 diabetes (defined using WHO criteria)
3. Incipient or overt nephropathy (urinary albumin excretion ≥100 but ≤ 2000 mg/day). Investigator should make an effort to have two subgroups (incipient and overt nephropathy) as balanced as possible, but at least 6 patients in each subgroup.
4. GFR ≥40ml per minute (either documented in the 4 months prior to the screening visit or assessed at randomization [Day -1, Period 1])
5. To be eligible for randomization, patients must fulfill the following criteria:
a) Patients on ongoing hypertensive therapy must have a blood pressure ≥ 135/85 mm Hg but lower than 170/105 mm Hg at Visit 3 (Day -1, Period 1) AND patients must be on stable antihypertensive medications for at least 8 weeks prior to Visit 2 (Run-in period)
b) Newly diagnosed hypertensive patients must have a blood pressure ≥ 135/85 mm Hg but lower than 170/105 mm Hg at Visit 3 (Day -1, Period 1)
6. Female patients must be postmenopausal (i.e. must have had no regular menstrual bleeding for at least 2 years prior to inclusion) or must have had a bilateral oophorectomy or must have been surgically sterilized or hysterectomized at least 6 months prior to screening. Menopause will be confirmed by a plasma 17β-estradiol concentration of <20 pg/mL and a plasma FSH level of >40 IU/L. Surgical sterilization procedures or hysterectomy must be supported with clinical documentation made available to the sponsor
7. Oral body temperature within the range 35.0-37.5 °C
8. Able to provide written informed consent prior to study participation.
Subject information and consent forms generated by the investigator must be approved by the sponsor prior to submission to the Ethics Committee (EC)/Institutional Review Board (IRB). A copy of the subject information and consent forms approved by the EC/IRB must be forwarded to the sponsor prior to study initiation.
9. Able to communicate well with the investigator and comply with the requirements of the study.
10. Patients must be willing and medically able to discontinue anti-hypertensive treatment or any other medication which is prohibited in the study protocol.
11. Patients must be on stable hypoglycemic medications for at least 8 weeks prior to visit 1 (Screening visit)
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| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria during screening or baseline evaluations will be excluded from entry into or continuation in the study:
1. Use of any prescription drug or over-the-counter (OTC) medication which is prohibited by the protocol.
2. Severe Hypertension Grade 3 WHO classification (MSDBP ≥110 mmHg and/or MSSBP ≥180 mmHg)
3. ASA treatment >1g/day or regular use of NSAIDs
4. Kidney disease not caused by diabetes or hypertension
5. Serum potassium < 3.5 or > 5.1 mEq/L
6. GFR < 40 ml/min/1.73m2 as measured by the MDRD formula
7. Serum albumin < 2.0mg/dL
8. Hypertensive encephalopathy at any time prior to Visit 1.
Cerebrovascular accident at any time in the last 12 motnts prior to Visit 1
9. Transient ischemic cerebral attack during the 6 months prior to Visit 1
10. Current diagnosis of heart failure (NYHA Class II-IV)
11. History of myocardial infarction, unstable angina pectoris, coronary bypass surgery, or any percutaneous coronary intervention (PCI) during the 6 months prior to Visit 1
12. Second or third degree heart block without a pacemaker
13. Concurrent potentially life threatening arrhythmia or symptomatic arrhythmia
14. Clinically significant valvular heart disease
15. Type 1 diabetes mellitus
16. Uncontrolled Type II diabetes mellitus (HbA1C >11 %)
17. History of malignancy including leukemia and lymphoma (but not basal cell skin carcinoma) within the past five years
18. Pregnant or nursing women
19. Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulation.
20. Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing.
21. Significant illness within the two weeks prior to dosing.
22. 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 as determined by any one of the following: SGOT/AST or SGPT/ALT values exceeding 2 x ULN at Visit 1, and Gamma GT x 3 ULN at Visit 1 a history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt
• Current treatment with cholestyramine or cholestipol resins
23. History of immunocompromise, including a positive HIV (ELISA and Western blot) test result.
24. History of a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.
25. History of drug or alcohol abuse within the 12 months prior to dosing.
26. Persons directly involved in the execution of this protocol.
27. Any condition that in the opinion of the investigator or the Novartis medical monitor would jeopardize the evaluation of efficacy or safety
28. History of noncompliance to medical regimens or unwillingness to comply with the study protocol
29. 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
30. 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
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Pharmacodynamic assessment of the change in albuminuria following increasing dose administration of Aliskiren |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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