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)

The primary objective of this study is to demonstrate the superiority of **iptacopan** compared to placebo in reducing **proteinuria** at 6 months of treatment in patients with idiopathic immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN). Proteinuria is a critical marker of kidney damage, and its reduction is clinically significant as it may indicate improved renal function and potentially slow disease progression.

Secondary objectives include: - Demonstrating the superiority of iptacopan versus placebo in stabilizing estimated **Glomerular Filtration Rate (eGFR)** at 12 months. - Demonstrating the superiority of iptacopan versus placebo in the proportion of participants who achieved a composite renal endpoint at both 6 and 12 months. - Demonstrating the superiority of iptacopan compared to placebo in improvement of patient-reported fatigue. - Evaluating the safety and tolerability of iptacopan compared to placebo during the double-blind period. - Demonstrating the superiority of iptacopan compared to placebo in reducing proteinuria at 12 months of treatment.

The clinical trial involves a total of **77 participants** diagnosed with **Idiopathic Immune Complex Mediated Membranoproliferative Glomerulonephritis (IC-MPGN)**. The study population includes both male and female subjects, comprising adults aged 18 to 60 years and adolescents aged 12 to 17 years in non-EU countries and 16 to 17 years in EU countries. Participants were selected based on a confirmed diagnosis of idiopathic IC-MPGN via kidney biopsy within the specified timeframe prior to screening. All participants were required to have been on a maximally recommended or tolerated dose of renin-angiotensin system inhibitors (RASi) for at least 90 days before randomization. Additionally, the doses of other medications aimed at reducing proteinuria and controlling the disease, such as mycophenolic acids, corticosteroids, SGLT2 inhibitors, and mineralocorticoid receptor antagonists, needed to be stable for the same duration. The trial also mandated vaccinations against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae infections prior to the commencement of the study treatment. The trial population includes a vulnerable group, ensuring comprehensive safety and efficacy assessments of the investigational treatment.

The clinical trial is designed as a **randomized**, **double-blind**, parallel group, placebo-controlled study to evaluate the efficacy and safety of **iptacopan** in patients with **idiopathic immune complex mediated membranoproliferative glomerulonephritis** (IC-MPGN). The primary objective is to demonstrate the superiority of iptacopan compared to placebo in reducing proteinuria at six months of treatment. The trial is expected to run until May 31, 2028, with recruitment starting on August 1, 2023. Participants will be involved for a maximum treatment period of 18 months.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, diagnosis, and prior treatment regimens. Participants must have a confirmed diagnosis of IC-MPGN via kidney biopsy and stable doses of specific medications prior to randomization. Follow-up visits will occur at regular intervals to assess primary and secondary endpoints, including changes in proteinuria and estimated glomerular filtration rate (eGFR). The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary post-study care is arranged.

Participants are expected to adhere to the study protocol, including mandatory vaccinations against Neisseria meningitidis and Streptococcus pneumoniae prior to treatment initiation. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial will utilize hard gelatin capsules for both the active drug, iptacopan, and the placebo, administered orally. The study will ensure rigorous safety monitoring, including cardiovascular assessments in adolescent participants, to evaluate the potential effects of iptacopan on heart rate and blood pressure.

The clinical trial involves the administration of **IPTACOPAN HYDROCHLORIDE**, a chemical compound provided in the form of hard gelatin capsules. The active substance, **iptacopan hydrochloride**, is manufactured by Novartis Pharma AG. The pharmaceutical form is specified as hard gelatin capsules, and the medication is administered orally. The maximum daily dose is 400 mg, with a total treatment period extending up to 18 months. The dosing schedule is designed to ensure participant compliance, with regular monitoring to assess adherence to the prescribed regimen.

Another experimental medication used in the trial is **IPTACOPAN**, also provided in hard gelatin capsules. This formulation is specifically designed for pediatric use, although it is not limited to pediatric patients. The active substance, **iptacopan**, is chemically derived and also produced by Novartis Pharma AG. The administration route is oral, with a maximum daily dose of 400 mg, similar to the hydrochloride variant, and the treatment period is up to 18 months. Compliance with the dosing schedule is monitored throughout the trial to ensure accurate data collection and participant safety.

The study includes a placebo control, consisting of two types of placebo capsules. The first is a 0 mg hard gelatin capsule, size 0, serving as a placebo for the 200 mg dose of LNP023. The second is a 0 mg hard gelatin capsule, size 1, acting as a placebo for the 100 mg dose of LNP023. These placebo capsules are indistinguishable from the active medication in appearance and are administered orally. The use of placebo controls is integral to maintaining the double-blind nature of the study, ensuring unbiased assessment of the efficacy and safety of the experimental treatments.

The efficacy of iptacopan in the treatment of **idiopathic immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN)** will be assessed through a multicenter, randomized, double-blind, parallel group, placebo-controlled study. The primary endpoint for evaluating efficacy is the log-transformed ratio to baseline in the urine protein-to-creatinine ratio (UPCR) sampled from a 24-hour urine collection at 6 months. Secondary endpoints include changes from baseline in estimated glomerular filtration rate (eGFR) at 12 months, annualized total eGFR slope estimated over 12 months, and the log-transformed ratio to baseline in UPCR at 12 months. Additionally, changes from baseline to 12 months in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score will be measured.

Other secondary endpoints involve the occurrence of clinically significant vital signs, including mean sitting diastolic blood pressure, heart rate, electrocardiograms (ECG), and safety laboratory measurements, as well as adverse events (AEs) and study drug discontinuation due to an AE during the double-blind period. Cardiovascular safety surveillance will be performed only in adolescent patients, evaluating 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. The proportion of participants achieving the composite renal endpoint at 6 and 12 months will also be assessed.