| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult patient with mild to moderate essential hypertension and microalbuminuria. |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | M15 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020772 |
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| 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 |
| To demonstrate the difference in microalbuminuria (MAU) in form of urinary albumin excretion measured as urinary albumin/creatinine ratio (UACR) in the first morning urine after treatment with valsartan 320 mg/lisinopril 20 mg combination compared to lisinopril 40 mg monotherapy and to valsartan 320 mg monotherapy from baseline to Week 30 in hypertensive subjects with previously diagnosed MAU (baseline). |
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| E.2.2 | Secondary objectives of the trial |
1. To compare the effects of valsartan /lisinopril combination vs. monotherapy of each study drug on proportion of patients who return to normalization of urinary albumin excretion (week 30).
2. To evaluate the proportion of patients who proceed to macroalbuminuria at Week 30
3. To evaluate effects of valsartan, lisinopril and their combination on the reduction of MAU in patients who achieve the target blood pressure.
4. To compare the effects of valsartan, lisinopril and their combination on the proportion of patients, who achieve the target blood pressure and who return at Week 30 to normalization of UA excretion.
5. To compare the effects of valsartan, lisinopril and their combination on the change of creatinine clearance.
6. To evaluate the effects of valsartan, lisinopril and their combination on markers of vascular inflammation e. g. Hs-CRP, TNFalpha IL-6.
7. To evaluate safety and tolerability of valsartan, lisinopril and their combination.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
• Male or female subjects, age between 18-75 years inclusive.
• Patients with mild to moderate hypertension with a MSDBP >= 85 and < 110 mm Hg for non treated patients. Previously treated patients with MSDBP < 110 mm Hg. Treated is defined as having taken medication until < 2 days prior to Visit 1
• Positive urine spot test with Micral dipstick (detection of urinary albumin concentration >= 20 mg/l) at Visit 1 (day -21).
• Written informed consent to participate in the study prior to any study procedures.
• Confirmation of MAU determined in the first morning urine samples performed at Visit 2 (day -14) and Visit 3 (day -7). MAU is defined for male patients as UACR >= 2.5 mg/mmol and <= 25.0 mg/mmol and for female patients as UACR >= 3.5 mg/mmol and <= 35.0 mg/mmol at both visits.
• At Visit 4 all patients with mild to moderate hypertension with a MSDBP >= 85 mm Hg and < 110 mm Hg.
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| E.4 | Principal exclusion criteria |
1. Any kind of kidney disease, which is not primarily caused by diabetes or hypertension.
2. Any clinically relevant abnormality in kidney ultrasound, in the urine sediment or urine analysis with dipstick at Visit 1 (decision for exclusion due to clinically relevant abnormalities for protein, glucose and pH measured via dipstick is at discretion of the investigator).
3. Evidence of renal impairment as determined by any one of the following: Serum creatinine clearance < 30 ml/min as determined by Cockroft and Gault and/or serum creatinine > 1.25 x ULN at Visit 1, a history of dialysis, or a history of nephrotic syndrome.
4. Serum potassium values <3.5 mmol/l or >5.5 mmol/l at Visit 1
5. Any medical condition which might significantly alter the urinary excretion of albumin
6. Fluid depletion; the patient is to be instructed to drink at least 2 l/day, especially during the last day prior Visit 1-4, 9 and 12.
7. Unwillingness or inability to avoid extensive exercise (any sport activity lasting longer than 30 minutes) during the last day prior Visit 1-4, 9 and 12.
8. Active urinary infection
9. Vaginal discharge/fluor and/or vaginal infection
10. Active systemic infection and/or fever
11. Current obstruction of the urinary tract or difficulty in voiding due to mechanical as well as inflammatory conditions which is likely to require intervention during the course of the study or is regarded as clinically meaningful by the investigator
12. Severe hypertension defined as grade 3 of WHO classification; mean sitting diastolic blood pressure MSDBP >=110 mm Hg and/or mean sitting systolic blood pressure (MSSBP) >=180 mm Hg
13. Known history of hypotensive symptoms or orthostatic hypotension
14. Type 1 Diabetes mellitus
15. Uncontrolled treated Type 2 Diabetes mellitus with poor glucose control defined as HbA1c > 8.0 % at Visit 1
16. Inability to discontinue all prior anti-hypertensive medications safely for a period of 3 weeks, as required by the protocol
17. Administration of any agent indicated for the treatment of hypertension after the visit 1, permitted exception of those anti-hypertensive medications requiring tapering down commencing at Visit 1
18. Mandatory indication for any concomitant medication for coronary artery disease or any other disease that is not allowed during this study
19. Known or suspected contraindications as listed in the basic prescribing information, including history of allergy to ARBs and ACEIs, incl. consideration on contraindications of free add-on medication amlodipine and HCTZ
20. History of hypertensive encephalopathy, coronary artery bypass surgery, percutaneous transluminal angioplasty, transient ischemic cerebral attack, stroke or myocardial infarction during the last 12 months prior to Visit 1
21. Known Keith-Wagener grade III or IV hypertensive retinopathy
22. Evidence of a secondary form of hypertension, to include coarctation of the aorta, hyperaldosteronism, renal artery stenosis, or pheochromocytoma
23. History of heart failure
24. Second or third degree heart block without a pacemaker
25. Concomitant unstable angina pectoris
26. Concurrent potentially life threatening arrhythmia or symptomatic arrhythmia
27. Clinically significant valvular heart disease
28. Evidence of hepatic disease or cholestasis as determined by any one of the following: ALT or AST values 2 x ULN at visit 1, a history of hepatic encephalopathy, a history of esophageal varices, or a history of a portocaval shunt
29. Sodium value < 132 mmol/l at Visit 1
30. Female patients who are not either post-menopausal for one year or surgically sterile, and who are not using effective contraceptive methods such as oral contraceptives (stable regimen during the last 6 months), barrier method with spermicide or an intra-uterine device
31. Pregnant or lactating females
32. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of any drug (details see study protocol).
33. Any surgical or medical conditions which, at the discretion of the investigator, place the patient at higher risk from his/her participation in the study, or are likely to prevent the patient’s compliance for the study.
34. Any condition, which in the judgment of the investigator would jeopardize the evaluation of efficacy or safety
35. History of malignancy of any organ system, treated or untreated, within the past five years, with the exception of localized basal cell carcinoma of the skin.
36. Any previous history of a systemic autoimmune disease
37. History of drug or alcohol abuse within the last 2 years
38. History of non-compliance to medical regimens
39. Participation in any investigational drug trial within one month prior to Visit 1
40. Persons directly involved in the execution of this protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objective is to demonstrate the reduction in MAU in form of urinary albumin excretion measured as urinary albumin/creatinine ratio (UACR) in the first morning urine from baseline to Week 30 in hypertensive subjects with previously diagnosed MAU (baseline). The primary comparison is between the combination group of Valsartan 320 mg/Lisinopril 20 mg and the monogroups of Lisinopril 40 mg and Valsartan 320 mg.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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