Evaluation of Ianalumab Efficacy, Safety, and Tolerability in Diffuse Cutaneous Systemic Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Multicenter Study

The primary objective of this study is to demonstrate the superiority of **ianalumab** compared to placebo in achieving a 3/5 Revised Composite Response Index in Systemic Sclerosis 25 (rCRISS25) response at Week 52. This is clinically relevant as it aims to establish the efficacy of ianalumab in improving clinical outcomes for patients with diffuse cutaneous systemic sclerosis, a condition characterized by skin thickening and organ involvement, which can significantly impact quality of life and overall prognosis.

Secondary objectives include:

• Demonstrating the superiority of ianalumab over placebo in the change from baseline in percent-predicted forced vital capacity (FVC%) at Week 52, which is important for assessing lung function improvement.
• Evaluating the change from baseline in the modified Rodnan Skin Score (mRSS) at Week 52, a measure of skin involvement severity.
• Assessing the change from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 52, which evaluates the impact on daily living activities.
• Assessing the pharmacokinetics of ianalumab to understand its absorption, distribution, metabolism, and excretion.
• Evaluating the immunogenicity of ianalumab to determine the potential for immune response generation.
• Assessing the overall safety and tolerability of ianalumab to ensure its suitability for long-term use in patients.

The clinical trial involves a total of **138 participants** diagnosed with **diffuse cutaneous systemic sclerosis (dcSSc)**. The study population comprises both male and female subjects aged between 18 and 70 years. Participants were selected based on specific criteria, including a confirmed diagnosis of systemic sclerosis according to the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria and a disease duration of 60 months or less. The trial includes individuals with active disease, as indicated by various clinical parameters such as modified Rodnan skin score (mRSS) and the presence of interstitial lung disease. Participants must also test positive for specific autoantibodies, with a limitation on those positive only for anti-nuclear antibody. The trial population includes a vulnerable group, reflecting the serious nature of the condition under investigation. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, parallel group, placebo-controlled** study to evaluate the efficacy, safety, and tolerability of **ianalumab** in participants with **diffuse cutaneous systemic sclerosis**. The primary objective is to demonstrate the superiority of ianalumab compared to placebo in achieving a 3/5 Revised Composite Response Index in Systemic Sclerosis 25 (rCRISS25) response at Week 52. The trial is expected to commence recruitment on July 31, 2024, and conclude by July 15, 2030, with a total duration of approximately six years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, disease duration, and specific clinical markers. Following successful screening, participants will be randomized to receive either ianalumab or placebo. The trial includes regular follow-up visits to monitor treatment response, safety, and any adverse events. These visits will assess changes from baseline in various parameters, including Forced Vital Capacity (FVC) percentage, modified Rodnan Skin Score (mRSS), and Health Assessment Questionnaire-Disability Index (HAQ-DI). The end-of-study visit will occur at Week 52, marking the completion of the treatment phase and the primary endpoint assessment.

The expected length of participant involvement is 104 weeks, encompassing both the treatment and follow-up periods. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent by the participant. The trial will adhere to rigorous methodological standards to ensure the reliability and validity of the findings, contributing valuable insights into the management of diffuse cutaneous systemic sclerosis.

The clinical trial involves the administration of **VAY736**, a solution for infusion containing the active substance **ianalumab**. This investigational drug is provided in a pharmaceutical form suitable for **subcutaneous use**. The maximum treatment period for VAY736 is 104 weeks. The dosing schedule and specific dosage amounts are not detailed in the provided data. Participant compliance will be monitored throughout the study to ensure adherence to the dosing regimen.

**TENOFOVIR ALAFENAMIDE** is included in the trial as an auxiliary treatment. It is an antiviral agent administered orally in the form of PHF00082MIG. The maximum treatment period for this medication is 104 weeks. The specific dosage and frequency of administration are not specified in the data provided. Compliance with the dosing schedule will be monitored to ensure participant adherence.

Another auxiliary treatment in the trial is **TENOFOVIR DISOPROXIL**, combined with **emtricitabine**. This antiviral combination is also administered orally in the form of PHF00082MIG, with a maximum treatment period of 104 weeks. The data does not specify the exact dosage or frequency of administration. Participant compliance will be monitored to ensure adherence to the prescribed regimen.

**ENTECAVIR** is included as an auxiliary antiviral treatment, administered orally in the form of PHF00082MIG. The maximum treatment period for entecavir is 104 weeks. The specific dosage and frequency of administration are not detailed in the provided data. Compliance monitoring will be conducted to ensure participant adherence to the dosing schedule.

The trial also includes a **placebo** comparator, specifically a placebo to VAY736, provided as a 150 mg/1 mL solution for injection in a pre-filled syringe. The placebo is used to maintain the double-blind nature of the study, ensuring unbiased assessment of the investigational drug's efficacy and safety. The route of administration and dosing schedule for the placebo are not specified in the data provided.

The efficacy of ianalumab in participants with diffuse cutaneous systemic sclerosis will be assessed using the primary endpoint of achieving a 3/5 Revised Composite Response Index in Systemic Sclerosis 25 (**rCRISS25**) response at Week 52. Secondary endpoints include changes from baseline in Forced Vital Capacity (FVC) percentage predicted, modified Rodnan Skin Score (mRSS), and Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 52. Additionally, ianalumab concentrations in serum during the treatment and follow-up period, as well as the incidence and titer of anti-drug antibodies (ADAs) in serum over time, will be evaluated. Safety evaluations will include monitoring adverse events, laboratory parameters, and vital signs. These assessments will be conducted at specified timepoints throughout the trial to ensure comprehensive data collection and analysis.