Evaluation of Rituximab-Based Combination, Tocilizumab, and Tofacitinib in Granulomatosis with Polyangiitis Patients Unresponsive to Standard Therapy

The primary objective of this study is to identify the most promising therapeutic strategy for patients with an inadequate response to standard of care therapy in **granulomatosis with polyangiitis**. This involves evaluating the efficacy of three different salvage strategies to induce remission: a combination of **rituximab** with a conventional disease-modifying antirheumatic drug (cDMARD) such as **methotrexate**, **azathioprine**, or **mycophenolate mofetil** (preferably methotrexate); **tocilizumab**; or **tofacitinib**. This is clinically relevant as it aims to improve treatment outcomes for patients who do not respond adequately to existing therapies, potentially leading to better disease management and patient prognosis.

Secondary objectives include evaluating the safety profile through adverse events, assessing the corticosteroid dose, examining sequelae, and measuring functional disability and quality of life. Additionally, the study will assess patient-reported outcomes (PRO) and the evolution of ANCA titers in each salvage therapy group. These secondary objectives are crucial for understanding the broader impact of the therapies on patient health and well-being, beyond just the primary efficacy outcomes.

The clinical trial involves participants diagnosed with **granulomatosis with polyangiitis** (GPA) who have shown an inadequate response to standard care therapies, specifically combinations of glucocorticoids with cyclophosphamide and/or rituximab. The study population includes both male and female subjects aged 18 years and older, with active clinical manifestations attributable to GPA. Participants are required to have a stable dose of oral glucocorticoids and, if applicable, conventional disease-modifying antirheumatic drugs (cDMARDs) prior to enrollment. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria emphasize the ability to understand study requirements, provide informed consent, and comply with protocol procedures. Participants must also have an affiliation with a mode of social security. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of various **salvage therapies** for patients with granulomatosis with polyangiitis (GPA) who have shown an inadequate response to standard care therapies. This study is a randomized, double-blind, controlled trial with a primary objective to identify the most promising therapeutic strategy to induce remission. The trial will compare three different treatment strategies: a combination of **rituximab** with a conventional disease-modifying antirheumatic drug (cDMARD) such as **methotrexate**, **azathioprine**, or **mycophenolate mofetil**; **tocilizumab**; and **tofacitinib**. The trial is expected to last for a total duration of 52 weeks, with participant involvement spanning the same period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and previous treatment response. Following enrollment, participants will attend regular follow-up visits at weeks 12, 24, and 52 to assess treatment efficacy and safety. The primary endpoint is the proportion of patients achieving a response or remission at 12 weeks, as defined by the EULAR recommendations. Secondary endpoints include the assessment of response or remission at weeks 24 and 52, as well as patient-reported outcomes and adverse events.

Participants are expected to remain in the study for the full 52-week duration unless specific conditions necessitate early termination. These conditions include significant adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial aims to provide valuable insights into the management of GPA in patients who do not respond adequately to existing standard therapies.

**Rituximab** is administered as a **concentrate for solution for infusion**. The active substance, rituximab, is delivered intravenously. The maximum daily dose is 375 mg/m², with a total maximum dose of 3000 mg over a treatment period of up to 52 weeks. This medication is not formulated for pediatric use and is utilized as a comparator in the trial.

**Methotrexate** is provided as a **solution for injection/infusion**. The active substance, methotrexate, is administered via subcutaneous use. The maximum daily dose is 0.3 mg/kg, with a total maximum dose of 15.6 mg/kg over a 52-week period. Methotrexate is used as a comparator in the study and is not a pediatric formulation.

**Xeljanz** (tofacitinib) is available in **film-coated tablets** form. The active substance, tofacitinib, is administered orally. The maximum daily dose is 10 mg, with a total maximum dose of 3640 mg over a 52-week period. This medication is used as a test product in the trial and is not formulated for pediatric use.

**RoActemra** (tocilizumab) is provided as a **solution for injection in a pre-filled pen**. The active substance, tocilizumab, is administered via subcutaneous injection. The maximum daily dose is 162 mg, with a total maximum dose of 8424 mg over a 52-week period. RoActemra is used as a test product in the trial and is not a pediatric formulation.

**Azathioprine** is administered in **tablet** form. The active substance, azathioprine, is delivered orally. The maximum daily dose is 3 mg/kg, with a total maximum dose of 1092 mg/kg over a 52-week period. This medication is used as a comparator in the study and is not formulated for pediatric use.

**Mycophenolate mofetil** is available as a **coated tablet**. The active substance, mycophenolate mofetil, is administered orally. The maximum daily dose is 3 g, with a total maximum dose of 1092 g over a 52-week period. Mycophenolate mofetil is used as a comparator in the trial and is not a pediatric formulation.

The efficacy of the clinical trial will be assessed by evaluating the ability of different therapeutic strategies to induce remission in patients with **granulomatosis with polyangiitis** who have shown an inadequate response to standard care therapy. The primary endpoint is the proportion of patients achieving a response or remission at 12 weeks, as defined by the EULAR recommendations. Remission is characterized by the absence of disease activity attributable to active disease, while response is defined as a 50% reduction in disease activity.

Secondary endpoints include the proportion of patients with a response or remission at weeks 24 and 52, the difference between physician and patient global assessments of disease activity from baseline to weeks 12 and 52, and patient-reported outcomes (PRO) such as HAQ, SF-36, and VAA-PRO at weeks 12, 24, and 52. Additionally, the number of adverse events will be recorded according to the CTCAE toxicity grading system.

The trial will involve three different salvage strategies: a combination of rituximab with a conventional disease-modifying antirheumatic drug (cDMARD) such as methotrexate, azathioprine, or mycophenolate mofetil; tocilizumab; or tofacitinib. The efficacy parameters will be measured and collected at specified timepoints, including weeks 12, 24, and 52, using validated scales and patient-reported outcomes to ensure accurate and reliable data collection and analysis.