Evaluation of Iptacopan (LNP023) Efficacy in Achieving Sustained Remission in Patients with Active ANCA-Associated Vasculitis: A Randomized Controlled Trial

The primary objective of this study is to evaluate the effect of **iptacopan** in achieving sustained remission in patients with active antineutrophilic cytoplasmic antibody (ANCA) associated vasculitis, compared to the standard of care (SOC). This is clinically relevant as achieving sustained remission is crucial for improving long-term outcomes and quality of life in patients with this condition.

Secondary objectives include:

• Assessing the time to remission through Week 24, which is important for understanding the speed of therapeutic response.
• Evaluating the effect of iptacopan on disease relapse, which is critical for determining the long-term efficacy and stability of the treatment.
• Assessing the effect of iptacopan on renal function, as renal involvement is a significant concern in ANCA-associated vasculitis and can impact patient prognosis.

The clinical trial involves a total of **34 participants** diagnosed with **active antineutrophilic cytoplasmic antibody (ANCA) associated vasculitis**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including a positive antibody test for anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies, and a diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) as per the 2022 ACR/EULAR classification criteria. The trial population is characterized by individuals requiring treatment with rituximab (RTX) and glucocorticoids (GC), as determined by the investigator's judgment. The study does not specify particular lifestyle considerations such as diet or physical activity. The inclusion of a vulnerable population is noted, although specific details are not provided.

The clinical trial is designed to evaluate the efficacy of **iptacopan** in patients with active antineutrophilic cytoplasmic antibody (ANCA) associated vasculitis. This is a randomized, controlled, phase 4 study with a double-blind methodology to ensure unbiased results. Participants will be randomly assigned to receive either iptacopan or a placebo, both administered in the form of hard gelatin capsules. The trial aims to assess the effect of iptacopan in achieving sustained remission compared to the standard of care over a period of 48 weeks.

The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as a positive antibody test for anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies and a diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Following successful screening, participants will undergo randomization and begin the treatment phase. Study visits will be scheduled at regular intervals to monitor the participants' health, assess the primary endpoint of sustained remission through Week 48, and evaluate secondary endpoints, including time to reach a Birmingham Vasculitis Activity Score (BVAS) of zero and changes in estimated glomerular filtration rate (eGFR).

The expected duration of participant involvement is approximately 48 weeks, with the trial estimated to conclude by August 2027. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to adhere to the study protocol, or withdraw consent. The end-of-study visit will involve a comprehensive assessment to gather final data on the efficacy and safety of the treatment. This trial is not categorized as low intervention, reflecting its comprehensive design and the need for rigorous monitoring to ensure participant safety and data integrity.

The clinical trial involves the administration of **Iptacopan**, a chemical compound with the active substance name **Iptacopan**. It is provided in the form of hard gelatin capsules. The pharmaceutical form is specified as hard gelatin capsules, and the route of administration is oral. The maximum daily dose is 400 mg, with a total maximum dose of 134.40 mg over a treatment period of up to 48 weeks. The capsules are manufactured by Novartis Pharma AG. The chemical name of the active substance is 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid, also known by synonyms such as NVP-LNP023-NX and LNP-023.

The study also includes a **placebo** control, which is a 0 mg hard gelatin capsule, size 0, designed to match the appearance of the Iptacopan capsules. The placebo is administered orally, following the same schedule as the experimental treatment, to ensure blinding and maintain the integrity of the study. The placebo serves as a comparator to evaluate the efficacy of Iptacopan in achieving sustained remission in patients with active ANCA-associated vasculitis. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed by evaluating the effect of **iptacopan** in achieving sustained remission in patients with active ANCA-associated vasculitis. The primary endpoint for efficacy is defined as sustained remission through Week 48, characterized by complete remission at Week 24 without major relapse up to Week 48. Secondary endpoints include the time to reach a Birmingham Vasculitis Activity Score (BVAS) of 0, time to major relapse through Week 48, and changes in estimated glomerular filtration rate (eGFR) using the CKD-EI formula, urinary protein excretion, and hematuria over the 48-week period.

Data collection will occur at specified timepoints, including Week 24 and Week 48, to assess these endpoints. The BVAS will be utilized as a validated scale to measure disease activity, while laboratory tests will be conducted to evaluate eGFR, urinary protein excretion, and hematuria. These assessments will provide comprehensive data on the efficacy of **iptacopan** compared to the standard of care in achieving and maintaining disease remission in the study population.