Evaluation of a Renin Inhibitor, Aliskiren, Compared to Enalapril, in C3 Glomerulopathy
Evaluation of a Renin Inhibitor, Aliskiren, Compared to Enalapril, in C3 Glomerulopathy
The aim of this cross-over trial 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
 the angiotensin converting enzyme inhibitor, enalapril, in patients with the
 complement-mediated renal disease C3 glomerulopathy. Patients will be randomized to one or
 the other treatment for the first 6 months and then switch to the other treament for the
 following 2.5 years. Treatment will continue for altogether 3 years for each patient.
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 the cross-over
 study and serum C3 and complement deposition in renal biopsies during the extension study in
 patients with C3 glomerulopathy as compared to the currently used treatment with the
 angiotensin converting enzyme inhibitor (ACEi) enalapril.

 Secondary objectives are to assess the effect of aliskiren as compared to the currently used
 treatment with the ACEi enalapril on: complement activation (such as serum C3a, C3dg, C5a and
 related complement assays), proteinuria, kidney function, kidney biopsy findings, blood
 pressure, activation of the renin angiotensin system.

 Aliskiren will be administered orally in tablet form at 150 -300 mg/daily (maximal dose 300
 mg). Enalapril 2.5-20 mg/daily (maximal dose 20 mg). These drugs may be administered once or
 twice.

 The investigators estimate an inclusion of maximum 15 patients for start of treatment with
 aliskiren and maximum 15 patients for start of treatment with enalapril. Suitable patients
 will be chosen from those patients who:

 1. Do not have severe renal failure. Pediatric patients will be included if they have a
 glomerular filtration rate ≥ 50 ml/min/1.73m2, adults ≥ 30 ml/min/1.73m2.

 2. Children, above the age of 6 years of age and adults.

 3. Patients treated with aliskiren will be compared to patients treated with the ACE
 inhibitor enalapril as monotherapy. Use of ACE inhibitor as a nephroprotective therapy
 will increase renin levels without blocking its effect. Thus, the investigators will
 compare patients on aliskiren with those on enalapril to investigate if ACE inhibition
 as monotherapy has a negative effect on complement activation in comparison to direct
 renin inhibition.

 4. Patients treated with immune suppressive medications at the start (such as mycophenolate
 mofetil (MMF) or corticosteroids) will be compared to patients treated with MMF or
 steroids plus aliskiren or enalapril.

 All suitable patients who fulfill inclusion criteria and who submitted written informed
 consent (patient or patient's legal guardians) will have undergone a renal biopsy at the most
 2 years before inclusion or at inclusion and will be randomized for treatment with aliskiren
 or enalapril. After 6 months patients on aliskiren will switch to enalapril and vice versa,
 patients on enalapril will switch to aliskiren treatment. Patients will be followed
 routinely, every 3rd month, regarding renal function (creatinine, urea, estimated glomerular
 filtration rate), albumin (blood and urine), renin levels and complement activation assays in
 blood samples (C3, C3dg, C5, properdin, soluble terminal complement complex, C3a, C5a, C3
 nephritic factor and other complement assays). The follow-up period, a total of 3 years from
 the start, will be carried out by the patient's own nephrologist and will not differ from the
 clinical follow-up offered patients not participating in the study. After 1-3 years (when
 medically indicated but at the most 3 years after start), a repeat renal biopsy will be
 performed to validate the effect of treatment on renal morphology. Renal biopsies, both the
 initial and the repeat biopsy, will be evaluated for complement deposition and glomerular
 basement membrane thickness.
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,
 angiotensin converting enzyme inhibitors, angiotensin receptor blockers or immune
 suppressive medications (such as mycophenolate mofetil/MMF or corticosteroids)

 4. Written informed consent has been given by:

 1. the patient's legal guardians if the patient is less than 15 years old

 2. the patient and his/her legal guardians if the patient is ≥ 15 but < 18 years old

 3. the patient, if the patient is ≥ 18 years old

 5. Female subjects of childbearing potential must:

 1. Understand that the study medication is expected to have a teratogenic risk

 2. Agree to use a highly effective contraceptive 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. Either of the following methods of contraception may be used:

 -  Combined (estrogen and progesterone) hormonal contraception associated with
 inhibition of ovulation: oral, intravaginal or transdermal

 -  Progestogen-only hormonal contraception associated with inhibition of
 ovulation: oral, injectable or implantable

 -  Intrauterine device

 -  Intrauterine hormone-releasing system

 -  Bilateral tubal occlusion

 -  Vasectomized partner

 -  Sexual abstinence

 -  Male or female condom with or without spermicide

 -  Cap, diaphragm or sponge with spermicide

 3. 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.

 4. 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.

 Exclusion Criteria:

 1. Known allergy to aliskiren, ACEi 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

 6. Patients with a renal transplant

 7. Immune complex-mediated membranoproliferative glomerulonephritis (such as in HIV
 infection, hepatitis, SLE)

 8. Females who breastfeed, are pregnant or planning to become pregnant during the study.

 9. Co-morbidity such as malignancy, congestive heart failure, recent myocardial
 infarction.

 10. Mental incapacity or language barriers to understand the contents of the study design.

 11. Simultaneous use of another complement-antagonist (such as eculizumab). Eculizumab
 must be discontinued and complement activity normalized before the start of study
 drug.

 12. Simultaneous use of aliskiren or enalapril with cyclosporine or nonsteroidal
 anti-inflammatory drugs (NSAID).