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Evaluation of a Renin Inhibitor, Aliskiren, Compared to Enalapril, in C3 Glomerulopathy

Primary Purpose

C3 Glomerulopathy, Membranoproliferative Glomerulonephritis, Complement Abnormality

Status
Recruiting
Phase
Phase 2
Locations
Sweden
Study Type
Interventional
Intervention
Aliskiren
Enalapril
Sponsored by
Region Skane
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for C3 Glomerulopathy

Eligibility Criteria

6 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • Sahlgrenska Hospital
  • Region Skåne Skåne UniversitetssjukhusRecruiting
  • Karolinska Hospital
  • Akademiska sjukhuset

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Aliskiren treatment

Enalapril treatment

Arm Description

Patients will be randomized to tablet treatment with aliskiren (target daily dose) 150-300 mg once daily or every other day (depending on weight) for 6 months. After 6 months the patients will be switched to tablet treatment with enalapril (target daily dose 7.5-20 mg once or twice a day) for the coming 2,5 years.

Patients will be randomized to tablet treatment with enalapril (target daily dose 7.5-20 mg once or twice a day) for 6 months. After 6 months the patients will be switched to tablet treatment with aliskiren (target daily dose) 150-300 mg once daily or every other day (depending on weight) for the coming 2,5 years.

Outcomes

Primary Outcome Measures

C3 levels in serum
To assess the effect and safety of aliskiren as compared to enalapril on reducing systemic complement activation as assayed by C3 levels in serum.
Complement deposition in kidneys
To quantify complement deposition in kidney biopsies from patients with C3 glomerulopathy using immunohistological staining

Secondary Outcome Measures

C3a in serum
To assess the effect of aliskiren compared to currently used treatment with the ACEi enalapril on C3a in serum
C3dg in plasma
To assess the effect of aliskiren compared to currently used treatment with the ACEi enalapril on C3dg in plasma
C5a in serum
To assess the effect of aliskiren compared to currently used treatment with the ACEi enalapril on C5a in serum
Glomerular basement membrane thickness
To assess the effect of aliskiren compared to currently used treatment with the ACEi enalapril on glomerular basement membrane thickness assessed by electron microscopy measurement
Proteinuria
To assess the effect of aliskiren compared to currently used treatment with the ACEi enalapril on protein levels in urine measured as the ratio between albumin/creatinine in urine

Full Information

First Posted
November 14, 2019
Last Updated
March 28, 2023
Sponsor
Region Skane
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1. Study Identification

Unique Protocol Identification Number
NCT04183101
Brief Title
Evaluation of a Renin Inhibitor, Aliskiren, Compared to Enalapril, in C3 Glomerulopathy
Official Title
Phase 2, Multicenter, Randomized, Open-label, Controlled, 2-arm Cross-over Study to Evaluate the Clinical Efficacy of a Renin Inhibitor, Aliskiren, Compared to an Angiotensin Converting Enzyme Inhibitor, Enalapril, in C3 Glomerulopathy
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 1, 2020 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Region Skane

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
Detailed Description
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: 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. Children, above the age of 6 years of age and adults. 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
C3 Glomerulopathy, Membranoproliferative Glomerulonephritis, Complement Abnormality, Dense Deposit Disease, C3 Glomerulonephritis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Model Description
Phase 2, multicenter, randomized, open-label, controlled, 2-arm cross-over study to evaluate the clinical efficacy and safety of a renin inhibitor, aliskiren, compared to an angiotensin converting enzyme inhibitor, enalapril, in children and adults with C3 glomerulopathy
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Aliskiren treatment
Arm Type
Experimental
Arm Description
Patients will be randomized to tablet treatment with aliskiren (target daily dose) 150-300 mg once daily or every other day (depending on weight) for 6 months. After 6 months the patients will be switched to tablet treatment with enalapril (target daily dose 7.5-20 mg once or twice a day) for the coming 2,5 years.
Arm Title
Enalapril treatment
Arm Type
Active Comparator
Arm Description
Patients will be randomized to tablet treatment with enalapril (target daily dose 7.5-20 mg once or twice a day) for 6 months. After 6 months the patients will be switched to tablet treatment with aliskiren (target daily dose) 150-300 mg once daily or every other day (depending on weight) for the coming 2,5 years.
Intervention Type
Drug
Intervention Name(s)
Aliskiren
Other Intervention Name(s)
Enalapril
Intervention Description
Patients will be randomized to start treatment with aliskiren tablet 150 mg every other day up to 300 mg daily depending on weight. After 6 months switch to enalapril 2.5-20 mg daily and continue with that 2.5 years.
Intervention Type
Drug
Intervention Name(s)
Enalapril
Other Intervention Name(s)
Aliskiren
Intervention Description
Patients will be randomized to start with enalapril 2.5-20 mg daily depending on weight. After 6 months switch to aliskiren tablet 150 mg every other day up to 300 mg daily depending on weight and continue with this treatment for 2.5 years.
Primary Outcome Measure Information:
Title
C3 levels in serum
Description
To assess the effect and safety of aliskiren as compared to enalapril on reducing systemic complement activation as assayed by C3 levels in serum.
Time Frame
3 years
Title
Complement deposition in kidneys
Description
To quantify complement deposition in kidney biopsies from patients with C3 glomerulopathy using immunohistological staining
Time Frame
3 years
Secondary Outcome Measure Information:
Title
C3a in serum
Description
To assess the effect of aliskiren compared to currently used treatment with the ACEi enalapril on C3a in serum
Time Frame
3 years
Title
C3dg in plasma
Description
To assess the effect of aliskiren compared to currently used treatment with the ACEi enalapril on C3dg in plasma
Time Frame
3 years
Title
C5a in serum
Description
To assess the effect of aliskiren compared to currently used treatment with the ACEi enalapril on C5a in serum
Time Frame
3 years
Title
Glomerular basement membrane thickness
Description
To assess the effect of aliskiren compared to currently used treatment with the ACEi enalapril on glomerular basement membrane thickness assessed by electron microscopy measurement
Time Frame
3 years
Title
Proteinuria
Description
To assess the effect of aliskiren compared to currently used treatment with the ACEi enalapril on protein levels in urine measured as the ratio between albumin/creatinine in urine
Time Frame
3 years
Other Pre-specified Outcome Measures:
Title
Renal function
Description
To assess the effect of aliskiren compared to currently used treatment with the ACEi enalapril on kidney function measured as iohexol clearance glomerular filtration rate
Time Frame
3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Children ≥ 6 years and adults. 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. 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) Written informed consent has been given by: the patient's legal guardians if the patient is less than 15 years old the patient and his/her legal guardians if the patient is ≥ 15 but < 18 years old the patient, if the patient is ≥ 18 years old Female subjects of childbearing potential must: Understand that the study medication is expected to have a teratogenic risk 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 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. 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: Known allergy to aliskiren, ACEi or substances contained in these preparations. Angioedema caused by aliskiren or enalapril Weight < 25 kg Glomerular filtration rate ≤ 50 ml/min/1.73 m2 (measured by iohexol clearance) in children and ≤ 30 ml/min/1.73 m2 in adults. Rapid deterioration of kidney function during the latest year of the disease Patients with a renal transplant Immune complex-mediated membranoproliferative glomerulonephritis (such as in HIV infection, hepatitis, SLE) Females who breastfeed, are pregnant or planning to become pregnant during the study. Co-morbidity such as malignancy, congestive heart failure, recent myocardial infarction. Mental incapacity or language barriers to understand the contents of the study design. Simultaneous use of another complement-antagonist (such as eculizumab). Eculizumab must be discontinued and complement activity normalized before the start of study drug. Simultaneous use of aliskiren or enalapril with cyclosporine or nonsteroidal anti-inflammatory drugs (NSAID).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Diana Karpman, MD PhD
Phone
+46-46-2220747
Email
diana.karpman@med.lu.se
First Name & Middle Initial & Last Name or Official Title & Degree
Zivile Bekassy, MD PhD
Email
zivile.bekassy@med.lu.se
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Diana Karpman
Organizational Affiliation
Region Skåne
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sahlgrenska Hospital
City
Gothenburg
Country
Sweden
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gregor Guron, MD PhD
Email
gregor.guron@vgregion.se
Facility Name
Region Skåne Skåne Universitetssjukhus
City
Lund
ZIP/Postal Code
22184
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Diana Karpman, MD PhD
Phone
+46462220747
Email
diana.karpman@med.lu.se
First Name & Middle Initial & Last Name & Degree
Zivile Bekassy, MD PhD
Email
zivile.bekassy@med.lu.se
Facility Name
Karolinska Hospital
City
Stockholm
Country
Sweden
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peter Barany, MD PhD
Email
peter.barany@sll.se
Facility Name
Akademiska sjukhuset
City
Uppsala
Country
Sweden
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hans Furuland, MD PhD
Phone
+4618-6110000
Ext
14052
Email
hans.furuland@medsci.uu.se

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The study and de-identified data will be shared with study coordinators at various sites
IPD Sharing Time Frame
5 years from the start, two years of inclusion until the inclusion of the last patient
IPD Sharing Access Criteria
Data will be presented at meetings and by de-identified emails
Citations:
PubMed Identifier
29884545
Citation
Bekassy ZD, Kristoffersson AC, Rebetz J, Tati R, Olin AI, Karpman D. Aliskiren inhibits renin-mediated complement activation. Kidney Int. 2018 Oct;94(4):689-700. doi: 10.1016/j.kint.2018.04.004. Epub 2018 Jun 5.
Results Reference
background
PubMed Identifier
30692664
Citation
Smith RJH, Appel GB, Blom AM, Cook HT, D'Agati VD, Fakhouri F, Fremeaux-Bacchi V, Jozsi M, Kavanagh D, Lambris JD, Noris M, Pickering MC, Remuzzi G, de Cordoba SR, Sethi S, Van der Vlag J, Zipfel PF, Nester CM. C3 glomerulopathy - understanding a rare complement-driven renal disease. Nat Rev Nephrol. 2019 Mar;15(3):129-143. doi: 10.1038/s41581-018-0107-2.
Results Reference
background
PubMed Identifier
10792600
Citation
Taal MW, Brenner BM. Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int. 2000 May;57(5):1803-17. doi: 10.1046/j.1523-1755.2000.00031.x.
Results Reference
background

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Evaluation of a Renin Inhibitor, Aliskiren, Compared to Enalapril, in C3 Glomerulopathy

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