E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
A chronic kidney disease due to complement activation |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The aim of this project is to assess aliskiren, a direct renin inhibitor, as a novel treatment to block complement activation in the kidneys and thereby attenuate renal disease and stabilize or improve kidney function and compare it to the currently used treatment with an angiotensin converting enzyme inhibitor (ACEi) in patients with the complement-mediated renal disease C3 glomerulopathy. The primary objective is to assess the effect and safety of aliskiren on reducing systemic and local complement activation as indicated by a reduction of serum C3 during a cross-over study and serum C3 and complement deposition in renal biopsies during an extension study in patients with C3 glomerulopathy as compared to the currently used treatment with enalapril (ACEi). |
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E.2.2 | Secondary objectives of the trial |
To assess the effect of aliskiren as compared to the currently used treatment with ACEi enalapril on: complement activation (such as serum C3a, C3d, C5a and related complement assays), proteinuria, kidney function, kidney biopsy findings, blood pressure, activation of the renin angiotensin system. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Children ≥ 6 years and adults. 2. Initial diagnosis of Dense Deposit Disease and C3 glomerulonephritis confirmed by kidney biopsy obtained not more than 2 years before the first dose of the study drug. 3. Either absence of treatment at the study start or ongoing treatment with aliskiren, ACEi, ARBs or immune suppressive medications (such as mycophenolate mofetil/MMF or corticosteroids) 4. Written informed consent has been given by: a. the patient’s legal guardians if the patient is less than 15 years old b. the patient and his/her legal guardians if the patient is ≥ 15 but < 18years old c. the patient if the patient is ≥ 18 years old
5. Female subjects of childbearing potential must: a. Understand that the study medication is expected to have a teratogenic risk b. Agree to use a highly effective contraception during study drug therapy. This applies unless the subject is less than 18 years of age, has not had sexual debut and commits to sexual abstinence confirmed by a pregnancy test on every study visit. c. Agree to have a pregnancy test before the start of study medication. This requirement also applies to women of childbearing age who practice complete and continued abstinence and adolescent girls after menarche. d. Agree to have a pregnancy test every 3rd month including at the end of study treatment, except in the case of confirmed tubal sterilization. This requirement also applies to women of childbearing age who practice complete and continued abstinence and adolescent girls after menarche. |
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E.4 | Principal exclusion criteria |
1. Known allergy to aliskiren or enalapril or substances contained in these preparations.
2. Angioedema caused by aliskiren or enalapril
3. Weight < 25 kg.
4. Glomerular filtration rate ≤ 50 ml/min/1.73 m2 (measured by iohexol clearance) in children and ≤ 30 ml/min/1.73 m2 in adults.
5. Rapid deterioration of kidney function during the latest year of the disease
5. Patients with a renal transplant.
6. Immune complex-mediated membranoproliferative glomerulonephritis (such as in HIV infection, hepatitis, SLE).
7. Females who breastfeed, are pregnant or planning to become pregnant during the study.
8. Co-morbidity such as malignancy, congestive heart failure, recent myocardial infarction.
9. Mental incapacity or language barriers to understand the contents of the study design.
10. Simultaneous use of another complement-antagonist (such as eculizumab). Eculizumab must be discontinued and complement activity normalized before the start of study drug.
11. Simultaneous use of aliskiren or enalapril with cyclosporine or nonsteroidal anti-inflammatory drugs (NSAID). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end-point assays include: Blood samples related to complement activation: C3.
Renal biopsies: complement deposition. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Start and every 3rd month for 3 years: C3 in blood samples.
Kidney biopsy: within 2 years of start and within 3 years of the start of the trial or at the end. |
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E.5.2 | Secondary end point(s) |
Blood samples related to complement activation: C3d, C3a, C5a, C5, TCC, C3 nephritic factor and related complement assays. Albumin level.
Urine samples: urine dipstick, albumin/creatinine ratio, angiotensinogen
Kidney function with iohexol clearance
Kidney biopsy: within 2 years of start and within the 3 years of the trial or at the end. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Blood samples: C3d, C3a, C5a, albumin, creatinine at start and every third month. Urine samples: urine dipstick, albumin/creatinine ratio, angiotensinogen at start and every third month. After 6, 12, 24 and 36 months also C5, properdin, soluble terminal complement complex, C3 nephritic factor, related complement assays.
Start and every 12 months: kidney function with iohexol clearance
Kidney biopsy: within 2 years of start and within the 3 years of the trial or at the end. |
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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 | No |
E.6.5 | Efficacy | No |
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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 | No |
E.8.7 | Trial has a data monitoring committee | Yes |
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 | 5 |
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 | 5 |