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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Region Skane

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20], Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]

Trial duration

1 Jan 2020 → 24 Oct 2025

Decision date (initial)

2024-07-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

ALF medel · Knut and Alice Wallenberg Wallenberg clinical scholar · Maggie Stephens foundation · Swedish Research Council · Swedish Kidney foundation · Skåne Center of Excellence in Health · Crafoord foundation · Region Skåne’s research and development funds

External identifiers

EU CT number

2024-515892-36-00

EudraCT number

2019-001440-22

ClinicalTrials.gov

NCT04183101

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

The overall 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 to currently used treatment with the
ACEi enalapril in patients with the complement-mediated renal disease C3 glomerulopathy.
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 ACEi enalapril.

Secondary objectives 1

1. To assess the effect of aliskiren as compared to the currently used treatment with the 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.

Conditions and MedDRA coding

C3 glomerulopathy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

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 < 18 years 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 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 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.

Exclusion criteria 12

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 antiinflammatory drugs (NSAID).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Serum C3 during the cross-over study.
2. Serum C3 and complement deposition in renal biopsies during the extension study.

Secondary endpoints 6

1. Complement activation (such as serum C3a, C3d, C5a and other complement assays)
2. Proteinuria
3. Kidney function
4. Kidney biopsy findings
5. Blood pressure
6. Activation of the renin-angiotensin system

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Region Skane

Sponsor organisation

Region Skane

Address

Dockplatsen 26, Malmo S:t Petri Malmo S:t Petri

City

Malmo

Postcode

211 74

Country

Sweden

Scientific contact point

Organisation

Region Skane

Contact name

Diana Karpman

Public contact point

Organisation

Region Skane

Contact name

Diana Karpman

Locations

1 EU/EEA country · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications