Evaluation of Anifrolumab Efficacy and Safety in Systemic Sclerosis: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to demonstrate the **superiority** of anifrolumab compared to placebo, with or without standard therapy, on measures of signs, symptoms, and impacts associated with **Systemic Sclerosis (SSc)**. This is clinically relevant as it aims to establish anifrolumab as a more effective treatment option for managing the complex manifestations of SSc, potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Demonstrating the superiority of anifrolumab over placebo in SSc participants, with or without standard therapy, on lung function in participants with SSc-associated **interstitial lung disease (ILD)** and on skin thickness.
• Assessing the effect of anifrolumab compared with placebo on each component of the measures of signs, symptoms, and impacts associated with SSc, ILD progression as quantified by CT, skin-specific health-related quality of life (HRQOL) assessment, and lung function in participants with SSc and SSc-associated ILD.
• Evaluating the **pharmacokinetics**, **pharmacodynamics**, and **immunogenicity** of subcutaneous anifrolumab.

The clinical trial involves a total of **194 participants** diagnosed with **Systemic Sclerosis (SSc)**, including both limited and diffuse cutaneous subsets. The study population comprises adult patients aged between 18 and 70 years, inclusive of both **male and female** subjects. Participants were selected based on specific criteria, including a confirmed classification of SSc according to the 2013 ACR/EULAR criteria, and a disease duration of 6 years or less from the first non-Raynaud’s phenomenon manifestation. The trial includes individuals with stable background therapies such as hydroxychloroquine, methotrexate, and other immunosuppressive agents. Participants are required to have uninvolved skin at injection sites and a body weight of 145 kg or less. The study also considers lifestyle factors, such as the ability to maintain stable background therapies. The trial population includes a vulnerable population, ensuring a comprehensive assessment of the treatment's efficacy across diverse patient profiles.

The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the safety and efficacy of **anifrolumab** compared to placebo in participants with **systemic sclerosis**. The trial will involve male and female participants aged 18 to 70 years, with a focus on those presenting with limited or diffuse cutaneous subsets of the disease. The study aims to demonstrate the superiority of anifrolumab over placebo, with or without standard therapy, by assessing various measures of signs, symptoms, and impacts associated with systemic sclerosis. The trial is expected to run until December 31, 2027, with recruitment having commenced on June 29, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease classification, and skin condition at injection sites. Following randomization, participants will receive either anifrolumab or placebo via subcutaneous injection. The trial will include regular follow-up visits to monitor safety, efficacy, and any adverse events. These visits will assess primary endpoints, such as the proportion of participants achieving a Revised Composite Response Index in Systemic Sclerosis-25 (Revised-CRISS-25) response, and secondary endpoints, including changes in pulmonary function and skin scores. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of the treatment's long-term safety and tolerability.

The expected length of participant involvement is up to 104 weeks, depending on the treatment arm. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The trial will ensure that all participants are monitored closely to maintain the integrity of the study and the safety of the participants.

The clinical trial involves the administration of **Anifrolumab**, a **solution for injection** developed by AstraZeneca AB. Anifrolumab is a protein-based therapeutic agent classified under the category "Protein - Other." The pharmaceutical form of Anifrolumab is a solution intended for **subcutaneous use**. The dosing regimen for Anifrolumab is specified in milligrams per milliliter (mg/ml), although the exact dosage and frequency are not detailed in the provided data. The maximum treatment period for Anifrolumab is 52 weeks. The administration of Anifrolumab is facilitated by a single-use, disposable system designed to deliver the labeled dose subcutaneously while incorporating a safety mechanism to minimize accidental needle sticks during disposal.

The study also includes a **placebo** group, referred to as Anifrolumab Placebo. The placebo is used as a comparator treatment to evaluate the efficacy and safety of Anifrolumab. The placebo does not contain any active substance and is administered in a manner consistent with the experimental treatment to maintain the double-blind nature of the trial. The placebo's pharmaceutical form and route of administration are not specified in the data provided.

The efficacy of Anifrolumab in the treatment of **Systemic Sclerosis (SSc)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of participants achieving a Revised Composite Response Index in Systemic Sclerosis-25 (Revised-CRISS-25) response. This composite endpoint defines a responder as a participant who shows improvement in at least two components, such as a ≥5% increase in percent predicted forced vital capacity (ppFVC) or a ≥25% decrease in the Modified Rodnan Skin Score (mRSS), Health Assessment Questionnaire Disability Index (HAQ-DI), Patient Global Assessment (PtGA), or Clinician Global Assessment (CGA). Additionally, there should be no significant SSc-related events as defined in the study protocol.

Secondary endpoints include treatment-related differences in mean change from baseline in pulmonary function and mRSS, the proportion achieving Revised-CRISS-25 components, and the progression of interstitial lung disease. Patient-reported outcomes will be evaluated using the Scleroderma Skin patient-reported outcome measure. The study will also assess the pharmacokinetics, pharmacodynamics, and immunogenicity of subcutaneous Anifrolumab, as well as its safety and tolerability with or without standard therapy in participants with SSc. These assessments will be conducted at various time points throughout the study, with specific intervals for data collection and analysis as outlined in the trial protocol.