Rituximab Maintenance Therapy versus Placebo in Patients with Stabilized Systemic Sclerosis–Associated Interstitial Lung Disease after Induction

The primary objective is to evaluate the efficacy of maintaining rituximab as a maintenance strategy in individuals with stabilized systemic sclerosis‑associated interstitial lung disease (systemic sclerosis‑ILD) following induction therapy, thereby assessing its potential to preserve lung function and prevent disease progression. Secondary objectives include:

• Assessment of the safety and tolerability profile of continued rituximab administration in this patient population.
• Evaluation of the broader efficacy impact of maintenance therapy on overall systemic sclerosis manifestations in addition to interstitial lung disease.
• Comparison of health‑related quality of life, functional disability, and patient‑reported outcomes between the rituximab and placebo groups.
• Estimation of the incremental cost‑utility of maintenance rituximab relative to placebo.

The trial enrolled adult patients (≥ 18 years) of both sexes who met the ACR/EULAR 2013 criteria for systemic sclerosis and had interstitial lung disease involving ≥ 10 % of lung parenchyma on HRCT. Participants had previously received rituximab induction (either two 1000 mg infusions two weeks apart or 375 mg/m² weekly for four weeks) and demonstrated stabilized disease, defined by absence of worsening respiratory symptoms, an absolute forced vital capacity decline of < 5 % predicted, a diffusing capacity for carbon monoxide decline of < 10 %, and no radiologic progression on HRCT. Additional requirements included completion of recommended vaccinations ≥ 4 weeks before baseline, provision of reliable contraception for women of child‑bearing potential, and affiliation with an accepted social security scheme. General health status was required to be stable, with no specific restrictions on diet or physical activity. The sponsor did not provide the total number of participants enrolled.

The study is a randomized, double‑blind, placebo‑controlled phase II/III trial evaluating maintenance therapy with rituximab versus intravenous sodium chloride in adults with stabilized systemic sclerosis–associated interstitial lung disease following an induction regimen. Participants undergo a screening visit to confirm eligibility, including pulmonary function testing, high‑resolution CT, and review of prior rituximab induction. Eligible subjects are randomized on Day 0 and receive the assigned infusion (rituximab 500 mg or placebo 250 ml) with subsequent maintenance infusions administered at Months 6, 12, and 18. Study visits at baseline, each infusion time point, and at 3‑month intervals for safety and efficacy assessments (spirometry, DLCO, 6‑minute walk test, HRCT, and patient‑reported outcomes) continue through the end‑of‑study visit at Month 18. The total participant involvement spans approximately 19 months, including the screening period. Early termination may occur if a participant experiences disease progression (e.g., ≥5 % decline in forced vital capacity or ≥10 % decline in DLCO), a serious adverse event related to study medication, withdrawal of informed consent, or significant protocol non‑compliance.

The investigational product is Truxima 500 mg concentrate for solution for infusion, containing the active monoclonal antibody rituximab. It is supplied as a solution for intravenous infusion and is administered at a dose of 500 mg per infusion. Infusions are performed according to the study’s predefined maintenance schedule, and each administration is documented in the infusion log to ensure adherence to the protocol.

The comparator is a placebo consisting of sodium chloride solution. The placebo is delivered as an intravenous infusion of 250 ml. It is administered using the same schedule and infusion procedures as the investigational product to maintain blinding, and infusion records are used to monitor participant compliance.

Efficacy will be evaluated primarily by the absolute change in FVC from baseline to Month 18 of randomization, measured using standardized spirometric techniques in accordance with international guidelines.

Secondary efficacy parameters include:

• Changes in FVC and diffusing capacity for carbon monoxide (DLCO) at 6, 12, and 18 months, assessed by spirometry and single‑breath DLCO testing.
• Progression‑free survival, defined as the composite of mortality, lung transplant, treatment failure, or a decline in FVC >10 % from baseline, evaluated at 6, 12, and 18 months.
• 6‑minute walk test distance measured at 6, 12, and 18 months using a validated protocol.
• Quantitative and qualitative changes in high‑resolution chest CT images at 6, 12, and 18 months.
• Scleroderma‑specific disease activity using the revised CRISS score and modified Rodnan skin score (mRSS) at 6, 12, and 18 months.
• Health‑related quality of life assessed by the St. George’s Respiratory Questionnaire, SF‑36, K‑BILD, HAQ‑DI, SHAQ, SSPRO, and ScleroID at 6, 12, and 18 months.
• Quality‑adjusted life years derived from EQ‑5D‑5L scores at 6, 12, and 18 months.
• Time to first respiratory‑related hospitalization, first acute ILD exacerbation, and overall survival, recorded throughout the trial.

All assessments will be performed at baseline and at the predefined study visits (Month 6, Month 12, and Month 18). Laboratory and imaging data will be collected centrally, and statistical analysis will compare the maintenance rituximab group with the placebo group using appropriate mixed‑effects models for repeated measures and time‑to‑event analyses for survival endpoints.