Pemphigus diseases (Pemphigus Vulgaris - PV and Pemphigus Foliaceus (PF). MedDRA version: 20.1 Level: PT Classification code 10067776 Term: Ocular pemphigoid System Organ Class: 10015919 - Eye disorders MedDRA version: 20.0 Level: PT Classification code 10034277 Term: Pemphigoid System Organ Class: 10040785 - Skin and subcutaneous tissue disorders MedDRA version: 21.1 Level: LLT Classification code 10057052 Term: Cicatricial pemphigoid System Organ Class: 10040785 - Skin and subcutaneous tiss
Conditions
Interventions
Trade Name: Rituximab (MABTHERA and BIOSIMILARS)
Product Name: RITUXIMAB
Pharmaceutical Form: Solution for injection/infusion
Sponsors
CHU de Rouen
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1) Age = 18 and = 80 years 2) Signed Informed Consent Form (or from the family in case of impossibility of patient’s consent). 3) Confirmed newly diagnosed PV or PF, based on the presence of the following: histological features of acantholysis on skin or mucosal biopsy, and deposition of IgG, complement component 3, or both on the keratinocyte membrane detected by direct immunofluorescence on affected skin or mucosa 4) Presence of moderate-to-severely active disease, defined by an overall PDAI score> 1554 5) Patient able to receive the standard-of-care consisting of corticosteroids (prednisone 1 mg/kg/day PO) and rituximab 6) Patients must be vaccinated against Covid-19 before study entry. It is recommended that patients are vaccinated against influenza and pneumococcus and have their first injection (Prevenar 13) before study entry. 7) For women who are not postmenopausal (menopausal: = 12 months of non-therapy-induced amenorrhoea) or not sterile: agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of =65 years) yes F.1.3.1 Number of subjects for this age range 100
Exclusion criteria
Exclusion criteria: 1) Non-consenting patient or patient who cannot be followed regularly. 2) Diagnosis of paraneoplastic pemphigus or other non-PV or PF autoimmune blistering disease 3) Contraindication to rituximab marketed as 500 mg concentrate for solution for infusion 4) Contraindication to prednisone marketed as 20 mg scored tablet pharmaceutical form 5) Contraindication to methylprednisolone marketed as 120 mg powder for injectable solution pharmaceutical form 6) Contraindication to paracetamol marketed as 10 mg/mL solution for infusion pharmaceutical form 7) Contraindication to dexchlorpheniramine maleate marketed as 5 mg/1mL injectable solution pharmaceutical form 8) Lack of peripheral venous access 9) Pregnant or lactating women 10) Significant cardiovascular or pulmonary disease (including o bstructive pulmonary disease) 11) Uncontrolled concomitant disease that, in the investigator’s judgment, would preclude patient participation, including but not limited to nervous system, renal, hepatic, endocrine, or gastrointestinal disorders 12) Any concomitant condition that required treatment with oral or systemic corticosteroids within 12 weeks prior to randomization- excluding transitory treatments (such as a corticosteroid therapy prescribed for a few days for an acute infection), and chronic corticosteroid treatments with a prednisone / prednisolone dose =20 mg/day, (these latter patients remain eligible for study entry) 13) Treatment with IV Ig, plasmapheresis, or other similar procedure (immunoadsorption) within 8 weeks prior to randomization 14) Patients having received immunosuppressive treatment (such as cyclosporine, mycophenolate mofetil, azathioprine given at an effective dose for any other condition than Pemphigus, or any other treatment that might potentially be active on Pemphigus lesions (anti-TNF) within 4 weeks prior to baseline 15) Treatment with cyclophosphamide within 12 weeks prior to randomization 16) Patients with positive blood test for HIV 17) Inherited or acquired severe immune deficiency 18) Severe active infection (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV anti-infectives within 4 weeks prior to screening. Entry into this study may be reconsidered once the infection has fully resolved. 19) Patients with a currently treated cancer, including solid tumors, hematologic malignancies, and carcinoma (except basal cell of the skin and squamous cell carcinoma of the skin which are small and localized and can be easily cured with a standard excision ) 20) Patients with a past history ( < 5 years) of cancer, including solid tumors, hematologic malignancies, and carcinoma (except complete excision of basal cell carcinoma and squamous cell carcinoma of the skin that have been excised and cured) NB: Patients whose cancer is cured and do not have anti-cancer treatment anymore must be referred to an oncologist before entry in the study 21) Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 24 weeks prior to screening 22) Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery 23) Treatment with rituximab or a B cell-targeted therapy (e.g., anti-CD20, anti-CD22, or anti-BLyS) within 12 months prior to randomization 24) Treatment with a live or attenuated vaccine within 28 days prior to randomization. It is recommended that a patient’s vaccination record and the need for immunization prior to study entr
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the superiority of a personalized treatment strategy (based on maintenance infusions of rituximab proposed only in pemphigus patients with a high relapse risk who are identified using the initial disease severity (assessed by the PDAI score), and the evolution of serum anti-desmoglein (Dsg) Abs as biomarkers of disease activity), in reducing the 4-year relapse rate as compared with the current treatment regimen proposed in the French guidelines.;Secondary Objective: -To demonstrate that this maintenance treatment proposed in patients with subclinical serological pemphigus activity: -avoids re-treatment of relapsing patients with systemic corticosteroids -permits the use of 1 g of rituximab for maintenance infusions instead of a 2 g dose (which is recommended in patients with a clinical relapse to achieve disease control) -is well tolerated -improves patients’ quality of life, - To assess the number of patient-years and number needed to treat (NNT) with the personalized treatment strategy to avoid one clinical relapse/flares by patient-year. - To assess the cost-effectiveness of this new strategy, expressed as the cost to avoid one relapse/flare and estimate the global budgetary impact of this new strategy.;Primary end point(s): Number of relapses/ flares by patient-year. A relapse is defined according to the pemphigus consensus statement, by the appearance of 3 or more new lesions a month that do not heal spontaneously within 1 week, or by the extension of established lesions, in a patient who has achieved disease control. ;Timepoint(s) of evaluation of this end point: 532 patients-years | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Cumulative duration of complete remission during the study • Time to disease flare/ relapse. • Cumulative dose of oral corticosteroids by patient-year over the study period • Cumulative dose of rituximab by patient-year • Number of maintenance infusions of 2 g of rituximab per patient-year • Number of patients-years of additional rituximab infusions to avoid one relapse by year (Number needed to treat, NNT). • Quality of life, using the: Auto Immune Bullous Quality of Life (ABQOL) and Treatment related Auto Immune Bullous Quality of Life (TABQOL) bullous specific QOL questionnaires, the French version of which we recently validated. • Change from baseline in anti-Dsg1 and anti-Dsg3 autoantibodies • Tolerance (occurrence of treatment-related adverse events and severe adverse events) • Cost-effectiveness and budgetary impact analysis (see Medico-economic analysis section below). • Safety outcome measures include, but are not limited to, the following: Nature, frequency, and severity of adverse events, including serious adverse events and adverse events leading to discontinuation Vital signs and clinical laboratory test results (including complete blood count and blood chemistry) Circulating B cells, T cells, and other leukocytes Plasma Ig levels (total Ig, IgG, IgM, and IgA) Corticosteroid-related adverse events in relation to corticosteroid exposure ;Timepoint(s) of evaluation of this end point: 532 patients-years | — |
Countries
France
Contacts
Public ContactVALLIN
CHU de Rouen
Outcome results
None listed