A Comparative Study of Rituximab and Cyclophosphamide Versus Rituximab Monotherapy in Patients with ANCA-Associated Vasculitis

The primary objective of this study is to determine the number of rituximab (RTX) infusions required to maintain clinical remission over a period of two years in patients with ANCA Vasculitis. This is clinically relevant as it aims to optimize treatment regimens, potentially reducing the frequency of infusions and associated healthcare costs while maintaining disease control. Secondary objectives include:

• Assessing measurements for minimal residual autoimmunity (MRA), such as time to ANCA seronegativity, proportion of seronegativity, time to ANCA return, proportion of ANCA return, duration of B-cell depletion, and the composition of the memory B-cell and plasma cell populations.
• Investigating the potential association between MRA and disease flares.
• Evaluating the occurrence of severe adverse events, cost-effectiveness, and quality of life.

The clinical trial involves participants diagnosed with ANCA Vasculitis, specifically granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), as defined by the Chapel-Hill Consensus Conference. The study population includes both male and female subjects aged 18 years and older, with either newly-diagnosed or relapsed disease characterized by the involvement of at least one major organ such as the kidney, lung, heart, or nervous system. Participants are required to have a positive test for anti-PR3 or anti-MPO, either current or historical. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria ensure that participants are willing and able to provide written informed consent and comply with the study protocol. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the clinical and immunological effects of rituximab with cyclophosphamide compared to rituximab alone in patients with ANCA vasculitis. This is a randomized, double-blind, controlled trial with an estimated duration of eight years, from May 2019 to June 2027. The primary objective is to determine the number of rituximab infusions required to maintain clinical remission over a two-year period. Participants will be randomly assigned to receive either rituximab alone or in combination with cyclophosphamide, with both treatments administered intravenously. The trial will include several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a clinical diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, age of at least 18 years, and a positive test for anti-PR3 or anti-MPO. Participants must also provide written informed consent. Following the screening, participants will undergo regular follow-up visits to monitor treatment efficacy and safety, assess B-cell depletion, and evaluate ANCA status using ELISA tests. The end-of-study visit will conclude the trial, assessing the overall clinical outcomes and safety parameters. Participant involvement is expected to last up to two years, with the possibility of early termination if adverse events occur or if the participant withdraws consent. The trial will also assess secondary endpoints, including the time to ANCA negativity, duration of B-cell depletion, and quality of life measures. Safety will be monitored according to WHO toxicity criteria, and any infectious events will be recorded. The trial is categorized as a phase-IV intervention study, focusing on the long-term effects and safety of the treatment regimens in a real-world setting.

The clinical trial involves the administration of Truxima, a rituximab-based medication, which is provided in two different concentrations: 100 mg and 500 mg. Both formulations are presented as a concentrate for solution for infusion. The pharmaceutical form is a solution for infusion, and the route of administration is intravenous. The maximum daily dose for each formulation is 1000 mg, with a total maximum dose of 2000 mg over a treatment period of up to 2 months. The active substance, rituximab, is a protein of non-human origin, and the product is manufactured by Celltrion Healthcare Hungary Kft. The trial aims to evaluate the number of rituximab infusions required to maintain clinical remission over a 2-year period in patients with ANCA-associated vasculitis (AAV). In addition to rituximab, the trial also includes the administration of Cyclophosphamide, which is provided as a 500 mg powder for solution for injection or infusion. This medication is also administered intravenously, with a maximum daily dose of 500 mg and a total maximum dose of 3000 mg over a treatment period of up to 12 months. Cyclophosphamide is a chemical-based active substance, and the product is manufactured by Sandoz Ltd. This medication serves as a comparator in the study, allowing for the evaluation of the combined effects of rituximab and cyclophosphamide compared to rituximab alone. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment regimen. The study does not include any placebo or other non-experimental treatments. The primary objective is to assess the clinical and immunological effects of rituximab with cyclophosphamide compared to rituximab alone in maintaining remission in AAV patients.

The efficacy of the clinical trial titled "Evaluating, clinical and immunological effects of rituximab with cyclophosphamide compared to rituximab alone in AAV patients (The ENDURRANCE-1 Study)" will be assessed using both primary and secondary endpoints. The primary endpoint focuses on comparing the number of rituximab (RTX) retreatment infusions required to maintain clinical remission over a period of two years, based on B-cell status and ANCA status, in both treatment arms. This will provide insight into the effectiveness of the treatment regimens in sustaining remission in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Secondary endpoints include several parameters: the time to achieve an ANCA negative test using a high-quality ELISA, the time to ANCA return defined by seroconversion or a doubling of ANCA serum levels, and the duration of B-cell depletion as measured by standard flow cytometry. Additionally, safety parameters will be assessed, including adverse events according to WHO toxicity criteria and the recording of infectious events. Patient-reported outcomes will be evaluated to assess quality of life using AAV-PRO and SNOT22 scores. Clinical disease activity will also be monitored as described in the study protocol. These assessments will be conducted at specified intervals throughout the trial to ensure comprehensive evaluation of the treatment efficacy.