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

The primary objective of this study is to demonstrate the **efficacy** of one or two dose regimens of HZN-825 compared to placebo in patients with **Diffuse Cutaneous Systemic Sclerosis**. This will be assessed by comparing the change in forced vital capacity (FVC) % predicted after 52 weeks of treatment. The clinical relevance of this objective lies in its potential to improve respiratory function, which is a critical concern in patients with this condition.

Secondary objectives include evaluating the effect of two dose regimens of HZN-825 versus placebo on various clinical and patient-reported outcomes after 52 weeks of treatment. These include the Health Assessment Questionnaire-Disability Index (HAQ-DI), Physician Global Assessment (MDGA), Patient Global Assessment (PTGA), and the Physical Effects and Physical Limitations subscales of the scleroderma skin patient-reported outcome (SSPRO-18). Additionally, the study will assess the modified Rodnan skin score (mRSS), the American College of Rheumatology-Composite Response Index in Systemic Sclerosis (ACR-CRISS), and ACR-CRISS-20. Safety and tolerability will be assessed based on adverse events, orthostatic hypotension, concomitant medication use, vital signs, 12-lead electrocardiogram (ECG), and clinical safety laboratory evaluations. The pharmacokinetics of HZN-825 will also be evaluated.

The clinical trial involves a total of **216 participants** diagnosed with **Diffuse Cutaneous Systemic Sclerosis**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants were selected based on specific criteria, including meeting the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for systemic sclerosis, with a total score of 9 or higher. The trial population is characterized by individuals with skin involvement proximal to the elbow and/or knee, classified under the diffuse cutaneous subset. Participants are required to have less than or equal to 72 months since the onset of the first systemic sclerosis manifestation, excluding Raynaud's phenomenon. The study also considers the suitability of the forearm skin for repeat biopsy in the first 110 subjects. Participants must have a modified Rodnan skin score (mRSS) of 15 or higher and a forced vital capacity (FVC) of 45% or more, as determined by spirometry at screening. The trial includes a vulnerable population, and participants are expected to comply with the treatment protocol and evaluations throughout the study duration.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy, safety, tolerability, and pharmacokinetics of HZN-825 in patients with **Diffuse Cutaneous Systemic Sclerosis**. The trial will involve a repeat-dose regimen and will be conducted across multiple centers. The primary objective is to assess the change in forced vital capacity (FVC) % predicted after 52 weeks of treatment with HZN-825 compared to placebo. The trial is expected to last until July 31, 2025, with recruitment having started on December 1, 2021.

Participants will be involved in the study for a maximum of 52 weeks. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, disease classification, and lung function, followed by regular follow-up visits to monitor treatment effects and safety. The end-of-study visit will occur at the conclusion of the 52-week treatment period. Participants will be required to provide written informed consent and meet specific inclusion criteria, such as being between 18 and 75 years old and having a modified Rodnan skin score (mRSS) of 15 or higher at screening.

Study visits will be structured to ensure comprehensive data collection and participant safety. The inclusion visit will involve detailed assessments to confirm eligibility, including spirometry to measure FVC. Follow-up visits will occur at regular intervals to monitor changes in FVC, health assessment questionnaire-disability index (HAQ-DI), and other secondary endpoints. The end-of-study visit will include final assessments to evaluate the overall impact of the treatment. Participants may be withdrawn from the study if they are unable to comply with the treatment protocol or if significant adverse events occur.

The trial will utilize a **tablet** formulation of the investigational product, Fipaxalparant, administered orally. The maximum daily dose is set at 600 mg, with the treatment period not exceeding 52 weeks. The study is categorized as a Phase 4 trial, indicating it is conducted after the product has been marketed to gather additional information on the drug's effect in a larger population. The trial's design ensures that neither the participants nor the investigators know which treatment the participants are receiving, maintaining the integrity of the double-blind methodology.

The clinical trial involves the administration of **Fipaxalparant**, an experimental medication, in the form of a tablet. The active substance in this medication is Fipaxalparant, also known by its synonyms SAR100842 and SAR-100842. The pharmaceutical form is a tablet, and the medication is administered orally. The maximum daily dose is 600 mg, with a total treatment period of 52 weeks. The medication is produced by Horizon Therapeutics Ireland DAC and is identified by the sponsor product code HZN-825. The trial aims to evaluate the efficacy, safety, tolerability, and pharmacokinetics of Fipaxalparant in patients with diffuse cutaneous systemic sclerosis.

In addition to the experimental medication, a **placebo** is used as a comparator treatment in this randomized, double-blind, placebo-controlled trial. The placebo is designed to match the experimental medication in appearance and administration route to maintain the study's blinding. The placebo is administered orally in the form of a film-coated tablet. The major ingredients of the placebo include mannitol, microcrystalline cellulose, magnesium stearate, polyvinyl alcohol, macrogol, titanium dioxide, and talc. The placebo serves as a control to assess the efficacy of Fipaxalparant by comparing changes in forced vital capacity (FVC) % predicted after 52 weeks of treatment.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints over a 52-week treatment period. The primary endpoint is the change in **forced vital capacity (FVC)** % predicted from baseline to Week 52. This parameter will be measured to determine the efficacy of HZN-825 compared to placebo in patients with diffuse cutaneous systemic sclerosis. Secondary endpoints include changes from baseline to Week 52 in several patient-reported and clinical outcomes: the Health Assessment Questionnaire-Disability Index (HAQ-DI), the Modified Rodnan Skin Score (mRSS), the Medical Doctor's Global Assessment (MDGA), the Patient's Global Assessment (PTGA), and the Physical Effects and Physical Limitations subscales of the Systemic Sclerosis Patient-Reported Outcome (SSPRO-18). Additionally, the proportion of subjects achieving a decrease in mRSS of at least 5 points and 25% from baseline at Week 52 will be evaluated. These assessments will be conducted using validated scales and spirometry, ensuring a comprehensive evaluation of the treatment's impact on disease progression and patient quality of life.