Comparison of treatment efficacy in the patients with Systemic sclerOsis: dapagliFlozin vs. Tocilizumab – a randomized head to head study

This study compares the efficacy of dapagliflozin and tocilizumab in the treatment of patients with systemic sclerosis after 12 months of therapy. The primary objective addresses a clinically relevant need to evaluate comparative effectiveness between these two therapeutic agents in managing this autoimmune connective tissue disorder characterized by fibrosis and vascular abnormalities.

The secondary objectives include:

• Evaluation of whether treatment with dapagliflozin is more effective than treatment with tocilizumab in patients with systemic sclerosis after 12 months of therapy.

• Assessment of the impact of dapagliflozin compared to tocilizumab on image of vessels in capillaroscopic examination in patients with systemic sclerosis after 12 months of therapy.

• Assessment of the impact of dapagliflozin compared to tocilizumab on cardiac functional and morphological parameters in patients with systemic sclerosis after 12 months of therapy.

• Assessment of the impact of dapagliflozin compared to tocilizumab on lung aeration parameters in patients with systemic sclerosis after 12 months of therapy.

• Assessment of the impact of dapagliflozin compared to tocilizumab on kidney function in patients with systemic sclerosis after 12 months of therapy.

• Assessment of the impact of dapagliflozin compared to tocilizumab on levels of proinflammatory cytokines in patients with systemic sclerosis after 12 months of therapy.

• Comparison of affection of the treatment on the quality of life of patients with systemic sclerosis after 12 months of therapy.

• Assessment of the safety of therapies used during the study.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consisted of **adult participants** aged over 18 years, including both **male and female subjects**. Participants were diagnosed with **systemic sclerosis** according to the 2023 ACR/EULAR criteria, specifically the **diffuse cutaneous systemic sclerosis** (dcSSc) form with skin involvement proximal to the **metacarpophalangeal joints** and/or the trunk. The trial targeted individuals in the early or intermediate fibrotic phase, with disease duration of 5 years or less from the first **non-Raynaud's symptom**. Participants presented with active **skin fibrosis**, defined by a **Modified Rodnan Skin Score** (mRSS) ranging from 15 to 40 points. Those receiving prior systemic sclerosis pharmacotherapy, such as **mycophenolate mofetil**, **methotrexate**, or **phosphodiesterase-5 inhibitors**, were required to maintain stable treatment for at least 4 weeks before enrollment. Laboratory parameters included adequate **absolute neutrophil count**, **platelet count**, and **hemoglobin** levels, along with negative results for **QuantiFERON**, **HBsAg**, **anti-HIV**, and **anti-HCV** tests. Women of childbearing potential and men with partners of reproductive potential were required to use effective contraception during treatment and for at least 3 months following the last dose of the investigational medicinal product.

This is a randomized, head-to-head clinical trial evaluating the efficacy of **dapagliflozin** compared to **tocilizumab** in patients with **systemic sclerosis**. The study is designed as a Phase IV trial with a comparative treatment approach. The primary objective is to compare the efficacy of dapagliflozin and tocilizumab in the treatment of patients with systemic sclerosis after 12 months of therapy. The trial employs a non-inferiority design for the primary endpoint, assessing changes in disease severity using the **modified Rodnan Skin Score** (mRSS), with the assumption that the difference in improvement between study arms does not exceed 3 points. Secondary objectives include superiority testing of dapagliflozin over tocilizumab, evaluation of **capillaroscopic** findings, assessment of cardiac parameters through **magnetic resonance imaging** and **echocardiography**, analysis of pulmonary morphological parameters via **high-resolution computed tomography** (HRCT), evaluation of renal function parameters including **eGFR** and **albuminuria**, measurement of **proinflammatory cytokine** concentrations, quality of life assessments using standardized questionnaires, and comprehensive safety evaluation through adverse event monitoring.

The investigational medicinal products include **Forxiga** 10 mg film-coated tablets containing dapagliflozin administered orally at a maximum daily dose of 10 mg, and **RoActemra** 20 mg/mL concentrate for solution for infusion containing tocilizumab administered by **intravenous infusion** at a maximum daily dose of 800 mg. Placebo for dapagliflozin is also utilized in the study design. **Sodium chloride** 0.9% solution for infusion serves as a diluent, administered intravenously at a maximum daily dose of 100 mL. The maximum treatment period for all investigational products is 12 months.

Eligible participants include adults over 18 years of age with a diagnosis of systemic sclerosis according to the 2023 ACR/EULAR criteria, specifically presenting with **diffuse cutaneous systemic sclerosis** (dcSSc) involving skin proximal to the **metacarpophalangeal joints** and/or the trunk. Disease duration must be 5 years or less from the first non-Raynaud's symptom to ensure inclusion of patients in the early or intermediate fibrotic phase. Active skin fibrosis must be present, defined as an mRSS of 15 to 40 points at screening, corresponding to the active fibrotic phase with the highest likelihood of reversibility. Participants must have stable systemic sclerosis pharmacotherapy for at least 4 weeks prior to inclusion if applicable. Laboratory requirements include **absolute neutrophil count** of at least 2 × 10⁹/L, **platelet count** of at least 100 × 10³/μL, **hemoglobin** of at least 8.0 g/dL, and negative results for QuantiFERON, **HBsAg**, anti-HIV, and anti-HCV. Women of childbearing potential and men with partners of reproductive potential must consent to use effective contraception during treatment and for at least 3 months after the last dose of investigational medicinal product.

The screening visit (W1) establishes baseline eligibility and disease parameters. During the 12-month treatment period, participants receive either dapagliflozin or tocilizumab according to randomization assignment. Follow-up visits are conducted at regular intervals to monitor efficacy parameters, safety, and disease progression. The end-of-study visit occurs at 12 months, at which time all primary and secondary endpoints are assessed. Total participant involvement spans approximately 12 months from randomization to study completion. The estimated recruitment start date is March 2026, with an estimated study end date of July 2029.

Conditions that may lead to early termination from the study include withdrawal of informed consent, occurrence of serious adverse events requiring discontinuation of investigational medicinal product, protocol violations, investigator decision based on safety concerns, pregnancy, or loss to follow-up. Safety assessment throughout the study includes comprehensive analysis of the occurrence and characteristics of adverse events and serious adverse events in both treatment arms.

The experimental medication **Forxiga** contains **dapagliflozin** as the active substance and is supplied as **film-coated tablets** with a strength of 10 mg. The maximum daily dose is **10 mg** administered via the **oral route**. The maximum total dose per administration is 10 mg. The maximum treatment period is **12 months**. The investigational medicinal product will be repackaged into new primary packaging, labelled for clinical trial use, subjected to batch control and qualified person release.

The **comparator treatment** **RoActemra** contains **tocilizumab** as the active substance, which is a protein of biological origin. The product is supplied as a **concentrate for solution for infusion** at a concentration of 20 mg/mL. The maximum daily dose is **800 mg** administered via **intravenous infusion**. The maximum total dose per administration is 800 mg. The maximum treatment period is 12 months.

**Sodium chloride** 0.9% solution (NATRIUM CHLORATUM 0.9% FRESENIUS) is used as a **placebo** and as a vehicle for infusion preparation. The product is supplied as a **solution for infusion** at a concentration of 9 mg/mL. The maximum volume per administration is **100 mL** administered via **intravenous infusion**. The maximum total volume per administration is 100 mL. The maximum treatment period is 12 months.

A **placebo** matching dapagliflozin is included in the study design to maintain blinding in the treatment arms. The placebo formulation is administered via the oral route to match the active comparator administration schedule.

The primary efficacy endpoint will be evaluated by assessing the change in disease severity using the modified Rodnan Skin Score (mRSS) after 12 months of therapy in both treatment arms. The non-inferiority analysis will determine whether the difference in improvement, measured as reduction in mRSS, between the study arms does not exceed 3 points. Secondary efficacy endpoints will include the change in the systemic sclerosis severity score after 12 months of therapy, with a superiority analysis examining whether the difference in improvement between the study arms exceeds 3 points in favor of dapagliflozin. Additional secondary endpoints will assess capillaroscopic examination results according to the Cutolo scale, cardiac functional and morphological parameters evaluated by magnetic resonance imaging (MRI) and echocardiography, morphological parameters of lung aeration on high-resolution computed tomography (HRCT) of the chest, renal function parameters including eGFR and albuminuria, and proinflammatory cytokine concentrations, all measured after 12 months of therapy. Quality of life and psychological outcomes will be evaluated using a questionnaire developed by prof. Wioletta Tuszyńska-Bogucka, PhD, along with standardized instruments including the SF-36 Questionnaire, Pol-SScQoL Questionnaire, the Stress Assessment Questionnaire (KOS), the Goldberg General Health Questionnaire (GHQ) in the Polish adaptation, the PHQ-9 Depression Scale, and the GAD-7 (Generalized Anxiety Disorder 7-item Scale) after 12 months of therapy.