Long-term Safety and Tolerability Evaluation of Open-label Iptacopan in Adult Patients with Primary IgA Nephropathy: A Rollover Extension Program

The primary objective of this study is to evaluate the long-term **safety** and **tolerability** of open-label iptacopan in adult participants with primary **IgA nephropathy** who have completed a Novartis-sponsored iptacopan parent study. This is clinically relevant as it aims to ensure that iptacopan, a potential therapeutic agent, can be safely administered over an extended period, which is crucial for chronic conditions like IgA nephropathy.

The secondary objective is to characterize the clinical benefit, specifically the efficacy, of iptacopan in eligible participants receiving open-label iptacopan. Understanding the efficacy of iptacopan will provide insights into its potential therapeutic benefits and inform future treatment strategies for patients with IgA nephropathy.

The clinical trial involves a total of **440 participants** diagnosed with **IgA Nephropathy**, a condition characterized by the deposition of immunoglobulin A in the kidneys. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their completion of prior related trials and their ability to benefit from the open-label treatment of iptacopan, as determined by the investigator's clinical judgment. All participants are required to be on a stable dose of ACE inhibitors or angiotensin receptor blockers, unless contraindicated. The trial also includes individuals from vulnerable populations, ensuring a comprehensive evaluation of the treatment's safety and tolerability across diverse groups. Participants must have an estimated glomerular filtration rate (eGFR) of at least 20 mL/min/1.73m², calculated using the CKD-EPI formula or a modified MDRD formula, depending on specific ethnic groups and local practice guidelines. Additionally, prior vaccinations against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae must be up to date. The selection process ensures that participants are well-informed and capable of complying with the study requirements.

The clinical trial is designed to evaluate the long-term safety and tolerability of **iptacopan** in adult participants with primary **IgA nephropathy** who have completed a prior Novartis-sponsored study. This is a multicenter, open-label, Phase IIIb trial, which integrates elements of both Phase III and Phase IV studies. The trial employs a **randomized**, **controlled** design, ensuring that participants are assigned to treatment groups in a manner that minimizes bias. The trial is expected to span approximately 12 years, with an estimated end date in September 2033.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as completion of a parent trial and specific health parameters, including an eGFR of at least 20 mL/min/1.73m². Following the screening, participants will receive **iptacopan** at a dose of 200 mg twice daily, administered in the form of hard gelatin capsules. The study includes regular follow-up visits to monitor safety and efficacy endpoints, such as adverse events, laboratory parameters, and changes in eGFR. The end-of-study visit will conclude the participant's involvement, assessing the overall impact of the treatment.

The expected duration of participant involvement is up to 96 weeks, with conditions for early termination including significant adverse events or non-compliance with study protocols. Participants must maintain a stable dose of ACE inhibitors or **angiotensin II receptor blockers (ARBs)** as per KDIGO guidelines, unless contraindicated. The trial's primary endpoints focus on safety and tolerability, while secondary endpoints include changes in eGFR and urinary protein-to-creatinine ratio. This structured approach ensures comprehensive data collection to assess the long-term effects of **iptacopan** in this patient population.

The clinical trial involves the administration of **Iptacopan**, an experimental medication, which is provided in the form of hard gelatin capsules. The active substance in Iptacopan is chemically derived and is identified by the sponsor product code LNP023. The maximum daily dose of Iptacopan is 400 mg, administered orally. The treatment period for participants is up to 96 weeks. Iptacopan is being evaluated for its long-term safety and tolerability in adult participants with primary IgA nephropathy who have completed a prior Novartis-sponsored study. Participant compliance with the dosing regimen will be monitored throughout the trial.

In addition to Iptacopan, the study includes the use of **Angiotensin II Receptor Blockers (ARBs), Combinations**. These are auxiliary treatments administered orally, with a chemical origin. The pharmaceutical form and specific dosage for these ARBs are not specified, and they are used as part of the standard care in the trial. The maximum treatment period for these auxiliary medications is also 96 weeks.

Another auxiliary treatment in the study is **Angiotensin II Receptor Blockers (ARBs), Plain**. Similar to the combination ARBs, these are administered orally and are of chemical origin. The pharmaceutical form and dosage details are not provided, and they are used to support the primary treatment with Iptacopan. The treatment duration is consistent with the other medications, extending up to 96 weeks.

The trial also includes **ACE Inhibitors, Plain** as an auxiliary treatment. These inhibitors are administered orally and are chemically derived. The pharmaceutical form and dosage are unspecified, and they are used to complement the primary treatment regimen. The maximum treatment period for these inhibitors is 96 weeks.

Lastly, **ACE Inhibitors, Combinations** are included as auxiliary treatments. These are administered orally, with a chemical origin, and are identified by the pharmaceutical form code PHF00082MIG. The specific dosage is not detailed, and they are used alongside the primary treatment. The treatment period for these inhibitors is also up to 96 weeks.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints focus on safety and tolerability, including adverse events (AEs), serious adverse events (SAEs), safety laboratory parameters, and vital signs. These parameters will be systematically collected and analyzed to ensure a comprehensive evaluation of the treatment's safety profile.

Secondary endpoints will include the **annualized total eGFR slope**, change from baseline in eGFR, and log-transformed ratio to baseline in urine protein-to-creatinine ratio (UPCR) and urine albumin-to-creatinine ratio (UACR). These endpoints are critical for assessing the treatment's impact on kidney function over time. The measurements will be conducted at specified intervals throughout the trial to monitor changes and trends in these parameters.