Phase II Randomized Double‑Blind Placebo‑Controlled Study of Intravenous Obinutuzumab in Patients with Diffuse Systemic Sclerosis

The primary objective is to assess whether treatment with obinutuzumab reduces skin and lung fibrosis in patients with diffuse Systemic sclerosis as measured by the revised Composite Response Index in SSc at 360 days post‑randomisation, thereby evaluating therapeutic efficacy. Secondary objectives include:

• Evaluation of safety and tolerability of obinutuzumab in this population.
• Comparison of disease activity between the obinutuzumab and placebo groups at days 90, 180, 270, and 360.
• Assessment of patient‑reported quality of life and functional disability at baseline and the same time points.
• Economic analyses comprising cost‑utility and cost‑effectiveness assessments.

The trial enrolled adult patients (≥18 years) of both sexes who had newly diagnosed or active diffuse systemic sclerosis at screening. Participants were required to meet the 2013 ACR/EULAR classification criteria for systemic sclerosis and to have a diffuse disease pattern as defined by Leroy et al. Disease duration had to be less than eight years or show activity according to the EUSTAR score, and the modified Rodnan skin score needed to be between 10 and 35 units. Stable use of mycophenolate or methotrexate for at least two months was allowed, and anti‑fibrotic therapy such as nintedanib could be continued. Women of childbearing potential required a negative pregnancy test and reliable contraception. Written informed consent and affiliation with a social security scheme were also required. The sponsor did not provide information on the total number of participants.

OBINUSS is a prospective, multicenter, phase II, randomized, double‑blind, placebo‑controlled trial evaluating the safety and efficacy of obinutuzumab in patients with newly diagnosed or active diffuse systemic sclerosis; the overall study timeline extends from September 2026 to January 2030. Eligible adults (≥18 years) with disease duration <8 years, a modified Rodnan skin score between 10 and 35, and stable background immunosuppression are screened at an initial visit to confirm inclusion criteria, including a negative pregnancy test for women of child‑bearing potential. After randomisation, participants receive a single intravenous infusion of 1000 mg Gazyvaro or matching placebo, followed by scheduled study visits at days 90, 180, 270 and 360 to assess skin and lung fibrosis using the revised Composite Response Index in Systemic Sclerosis (CRISS), safety parameters, and patient‑reported outcomes. The primary efficacy assessment occurs at day 360, with secondary evaluations at days 180 and 270. Participant involvement therefore spans approximately 12 months from randomisation to the end‑of‑study visit. Early discontinuation may occur in the event of severe adverse events, pregnancy, withdrawal of informed consent, or failure to comply with protocol‑required assessments.

The investigational product is Gazyvaro 1,000 mg concentrate for solution for infusion, containing the monoclonal antibody obinutuzumab. It is supplied as a sterile solution for infusion and is administered intravenously at a dose of 1,000 mg per infusion. The infusion is performed in accordance with the study dosing schedule, which specifies the timing and number of administrations for each participant.

The control arm receives a matching placebo consisting of 0.9 % sodium chloride solution (NaCl 0.9 %). The placebo is prepared to mimic the volume, appearance, and infusion rate of the active product and is administered intravenously using the same schedule as the investigational medication.

All infusions are delivered by qualified clinical personnel in a controlled setting. Dosing schedules are recorded in the study case report forms, and compliance is monitored through infusion logs, electronic medication administration records, and periodic review of protocol adherence. Adverse events and infusion-related reactions are documented throughout the treatment period to ensure participant safety and data integrity.

Efficacy will be evaluated primarily by the proportion of participants achieving a ≥20% improvement from baseline in the revised Composite Response Index in systemic sclerosis (CRISS) on at least three of the five core set measures at 360 days post‑randomisation. Secondary efficacy assessments will include the proportion of patients attaining the same CRISS20 response at days 180 and 270, as well as the distribution of 30% to 100% improvements in the core set measures at days 180, 270, and 360. Changes in the overall CRISS score will be calculated at days 180, 270, and 360. Physician‑ and patient‑reported visual analogue scales will be recorded at the same time points.

Patient‑reported outcomes and health‑related quality of life will be measured using validated instruments: the SF‑36 and EQ‑5D‑5L at baseline (day 0) and on days 90, 180, 270, and 360; the HAQ‑DI and SHAQ at the same intervals; and disease‑specific questionnaires including SSPRO, ScleroID, SGRQ, KBILD, the Saint‑Georges Respiratory Hospital Questionnaire, and the King‑Brief Interstitial Lung Disease questionnaire. All assessments will be performed according to the study schedule, and data will be analysed using predefined statistical methods to compare the obinutuzumab and placebo groups.