A multicenter, randomized, double-blind, parallel group, placebo-controlled study to evaluate the efficacy and safety of iptacopan (LNP023) in idiopathic immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

2 Oct 2023 → ongoing

Decision date (initial)

2023-09-13

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Therapy, Efficacy

To demonstrate the superiority of iptacopan compared to placebo in reducing proteinuria at 6 months of treatment

Secondary objectives 6

1. To demonstrate the superiority of iptacopan vs. placebo in stabilizing estimated Glomerular Filtration Rate (eGFR) at 12 months.
2. To demonstrate the superiority of iptacopan vs. placebo in the proportion of participants who achieved a composite renal endpoint at 12 months
3. To demonstrate the superiority of iptacopan compared to placebo in improvement of patient-reported fatigue.
4. To evaluate the safety and tolerability of iptacopan compared to placebo during the double-blind period.
5. To demonstrate the superiority of iptacopan compared to placebo in reducing proteinuria at 12 months of treatment.
6. To demonstrate the superiority of iptacopan vs. placebo in the proportion of participants who achieved a composite renal endpoint at 6 months.

Conditions and MedDRA coding

Idiopathic Immune Complex Mediated Membranoproliferative Glomerulonephritis (IC-MPGN)

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002705-PIP05-23

Plan to share IPD

Yes

IPD plan description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Male and female adult (aged at least 18 years to ≤ 60 years) and adolescent (12-17 years in non-EU countries and 16-17 years in EU countries, at screening) patients
2. Diagnosis of idiopathic IC-MPGN as confirmed by kidney biopsy within 12 months prior to screening in adults and within 3 years of screening in adolescents (a biopsy report, review and confirmation by the Investigator is required). If such a biopsy is not available in an adult participant, this must be obtained during screening/run-in period (performed and assessed locally for adults only).
3. Prior to randomization, all participants must have been on a maximally recommended or tolerated dose of RASi (e.g. an ACEI or ARB) for at least 90 days (or as according to local guidelines). The doses of other drugs administered to reduce proteinuria and control the disease including mycophenolic acids (MPAs – mycophenolate mofetil or mycophenolate sodium), corticosteroids, SGLT2 inhibitors and mineralocorticoid receptor antagonists should be stable for at least 90 days prior to randomization
4. UPCR > 1.0 g/g (> 113 mg/mmol) sampled from the first moving void urine sample at Day -75 and Day -15
5. Estimated GFR (using the chronic kidney disease [CKD]-EPI formula for adult participants and modified Schwartz formula for adolescents aged 12 to 17 years) or measured GFR > 30 ml/min.1.73m2 at screening and Day -15.
6. Mandatory vaccination against Neisseria meningitidis and Streptococcus pneumoniae infection prior to the start of study treatment. If the participants has not been previously vaccinated, or if a booster is required, the vaccine should be given according to local regulations at least 2 weeks prior to the first administration of study treatment. If the study treatment has to start earlier than 2 weeks post vaccination, prophylaxis antibiotic treatment should be initiated in accordance with local standard of care.
7. If not previously vaccinated, or if a booster is required, vaccination against Haemophilus influenzae infections should be given, if available and according to local regulations, at least 2weeks prior to the first study treatment administration.

Exclusion criteria 10

1. Participants who have undergone cell or solid organ transplantation, including kidney transplantation.
2. Participants diagnosed with secondary IC-MPGN including but not limited to any of the following conditions: • Deposition of antigen-antibody immune complexes as a result of any chronic infections, include o Hepatitis C virus (HCV) including HCV-associated mixed cryoglobulinemia, hepatitis B virus (HBV); o Bacterial-endocarditis, infected ventriculo-atrial shunt, visceral abscesses, leprosy, meningococcal meningitis; chronic bacterial infections o Protozoa/other infections- malaria, schistosomiasis, mycoplasma, leishmaniasis, filariasis, histoplasmosis • Renal deposition of immune complexes as a result of a systemic autoimmune disease: o Systemic lupus erythematosus (SLE) o Sjogren syndrome o Rheumatoid arthritis o Mixed connective tissue disease, etc. • Deposition of monoclonal immunoglobulins because of a monoclonal gammopathy due to plasma cell or B cell disorders. Monoclonal gammopathy of undetermined significance (MGUS) confirmed by the measurement of serum free light chains or other investigation as per local standard of care • Fibrillary glomerulonephritis
3. Rapidly progressive crescentic glomerulonephritis defined as a 50% decline in the eGFR within 3 months with kidney biopsy findings of glomerular crescent formation seen in at least 50% of glomeruli on the most recent biospy
4. Kidney biopsy showing interstitial fibrosis/tubular atrophy (IF/TA) or more than 50%.
5. Participants with an active systemic bacterial, viral or fungal infection within 14 days prior to study treatment administration or the presence of fever > 380C (100.40F) within 7 days prior to study treatment administration.
6. A history of recurrent invasive infections caused by encapsulated organisms, e.g., Neisseria meningitis and Streptococcus pneumoniae
7. The use of inhibitors of complement factors (e.g., Factor B, Factor D, complement 3 (C3) inhibitors, anti-Complement 5 (C5) antibodies, C5a receptor antagonists) within 3 months or 5 half-lives after stopping this medication, whichever is longer, prior to the Screening visit.
8. The use of immunosuppressants (except MPAs), cyclophosphamide or systemic prednisone at a dose >7.5 mg/day (or equivalent for a similar corticosteroid medication) within 90 days of study drug administration
9. The use of MPAs is not permitted within 90 days prior to randomization in India, as per the local health authority requirement.
10. Acute post-infectious glomerulonephritis at screening, based upon the opinion of the investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Log-transformed ratio to baseline in UPCR (sampled from a 24-hour urine collection) at 6 months.

Secondary endpoints 7

1. Change from baseline in eGFR at 12 months. Annualized total eGFR slope estimated over 12 months.
2. Log-transformed ratio to baseline in UPCR (sampled from a 24-hour urine collection) at 12 months.
3. Change from baseline to 12 months in the Functional Assessment of chronic Illness Therapy-Fatigue (FACIT-Fatigue) score.
4. Occurrence of clinically significant vital signs (mean sitting diastolic blood pressure [msSBP], heart rate, electrocardiograms (ECG), and safety laboratory measurements, as well as adverse events (AEs), AEs of special interest, and study drug discontinuation due to an AE (or any safety issue) during the double-blind period of the study.
5. Additional cardiovascular safety surveillance-performed only in adolescent patients includes the evaluation of iptacopan’s potential effects on heart rate, systolic and diastolic blood pressures, cardiac function, and a cardiac biomarker throughout the double-blind and open label treatment periods.
6. Proportion of participants who achieved the composite renal endpoint at 6 months
7. Proportion of participants who achieved the composite renal endpoint at 12 months.

Investigational products

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

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel Town

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 20

Locations

10 EU/EEA countries · 52 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 120 files

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

Application history

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