Evaluation of Personalized Maintenance Therapy Using Anti-Desmoglein Antibodies Versus Standard Rituximab and Corticosteroids in Pemphigus Patients

Trial ID: 2024-514886-21-00
Protocol: 2020/0424/HP
Sponsor: Centre Hospitalier Universitaire Rouen

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Diseases & Conditions

Pemphigus

Objectives

The primary objective of this study is to assess the **superiority** of a personalized treatment strategy in reducing the 4-year relapse rate in patients with **pemphigus** diseases, specifically Pemphigus Vulgaris and Pemphigus Foliaceus. This strategy involves maintenance infusions of rituximab, administered only to patients identified as having a high relapse risk. Identification is based on initial disease severity, assessed by the Pemphigus Disease Area Index (PDAI) score, and the evolution of serum antidesmoglein antibodies as biomarkers of disease activity. This approach is compared to the current treatment regimen recommended in the French guidelines. The clinical relevance of this objective lies in potentially improving long-term disease management and reducing relapse rates, which can significantly impact patient outcomes and quality of life.

Secondary objectives include: - Demonstrating that the personalized treatment strategy increases the time before the first flare/relapse and the time in remission. - Evaluating the possibility of using a reduced dose of rituximab (1 g) for maintenance infusions instead of the standard 2 g dose, thereby reducing the total quantity of rituximab prescribed. - Assessing the clinical and biological tolerability of the treatment strategy. - Avoiding corticosteroids-related adverse events and improving patients' quality of life. - Describing and comparing the evolution of anti-Dsg1 and anti-Dsg3 autoantibodies according to treatment strategies. - Assessing the number of patient-years and the number needed to treat (NNT) to avoid one clinical relapse/flare per patient-year. - Evaluating the cost-effectiveness of the new strategy, expressed as the cost to avoid one relapse/flare, and estimating the global budgetary impact of this strategy.

Participants

The clinical trial involves participants diagnosed with **pemphigus diseases**, specifically Pemphigus Vulgaris (PV) and Pemphigus Foliaceus (PF). The study population includes both male and female subjects aged between 18 and 80 years. Participants are required to have a confirmed diagnosis of PV or PF, characterized by histological features of acantholysis and specific immunofluorescence findings. The trial targets individuals with moderate-to-severely active disease, as indicated by a PDAI score greater than 15. Participants must be able to receive standard-of-care treatments, including corticosteroids and rituximab, and must be vaccinated against Covid-19 prior to study entry. The trial includes a vulnerable population, and participants must be affiliated with a social security plan. Lifestyle considerations include adherence to specific contraceptive measures for both men and women during and after the treatment period. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of a personalized maintenance therapy for **pemphigus** diseases, specifically **Pemphigus Vulgaris** and **Pemphigus Foliaceus**, compared to the standard treatment regimen involving **rituximab** and corticosteroids. This is a Phase IV, randomized, double-blind, controlled trial. The trial aims to assess the superiority of a personalized treatment strategy in reducing the 4-year relapse rate by utilizing maintenance infusions of rituximab based on the evolution of serum antidesmoglein antibodies as biomarkers of disease activity. The trial is expected to commence recruitment on September 2, 2024, and conclude by March 2, 2032.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease diagnosis, and ability to comply with the study protocol. The inclusion criteria require participants to be between 18 and 80 years old, have a confirmed diagnosis of pemphigus with moderate-to-severely active disease, and be able to receive standard-of-care treatment. Participants must also be vaccinated against Covid-19 and meet specific contraceptive requirements if applicable. The screening visit will involve assessments such as histological examination and direct immunofluorescence to confirm the diagnosis.

Following the inclusion visit, participants will be randomized into either the personalized treatment group or the standard treatment group. The trial will include regular follow-up visits to monitor disease activity, treatment response, and any adverse events. These visits will ensure adherence to the treatment protocol and allow for adjustments based on the participant's condition. The end-of-study visit will occur at the conclusion of the participant's involvement, which is expected to last up to 45 days for the treatment period, with additional follow-up as necessary.

Participants may be withdrawn from the study early if they experience significant adverse events, are unable to comply with the study protocol, or if the investigator deems it in the participant's best interest. The trial's primary endpoint is to evaluate the reduction in the 4-year relapse rate, while secondary endpoints will assess other clinical outcomes related to the treatment's efficacy and safety. The study will utilize **MabThera 500 mg concentrate for solution for infusion**, administered intravenously, with a maximum daily dose of 1000 mg and a total dose not exceeding 8000 mg over the treatment period.

Treatment

The clinical trial involves the use of **MabThera**, a pharmaceutical product containing the active substance **rituximab**. MabThera is formulated as a **concentrate for solution for infusion** and is administered via **intravenous use**. The product is provided in a dosage of 500 mg per vial, with a maximum daily dose of 1000 mg and a total maximum dose of 8000 mg over the course of the treatment. The maximum treatment period is 45 days. Rituximab, the active substance, is a protein of non-human origin, specifically classified under the ATC code L01XC02. The product is manufactured by Roche Registration GmbH and is not a pediatric formulation.

In this trial, the experimental treatment involves a personalized maintenance therapy strategy, which is based on the evolution of anti-desmoglein antibodies as biomarkers of subclinical activity in patients with **pemphigus**. This strategy is compared to the standard treatment regimen, which includes rituximab in combination with corticosteroids. The objective is to assess the superiority of the personalized treatment in reducing the 4-year relapse rate in patients identified as having a high risk of relapse, based on initial disease severity and biomarker evolution.

Efficacy

Efficacy in this clinical trial will be assessed by evaluating the reduction in the 4-year relapse rate of **pemphigus** in patients receiving a personalized treatment strategy compared to the standard treatment regimen. The primary endpoint involves the use of serum anti-desmoglein antibodies as biomarkers to monitor disease activity and predict relapse risk. The personalized treatment strategy includes maintenance infusions of **rituximab** for patients identified with a high relapse risk based on initial disease severity, assessed by the Pemphigus Disease Area Index (PDAI) score, and the evolution of serum anti-desmoglein antibodies. The trial aims to demonstrate the superiority of this personalized approach over the current standard treatment, which includes rituximab and corticosteroids, as outlined in the French guidelines. Efficacy assessments will be conducted at specified intervals throughout the trial duration, with data collection and analysis performed using validated scales and laboratory tests to ensure accuracy and reliability of the results.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥ 18 and ≤ 80 years
Signed Informed Consent Form (or from the family in case of impossibility of patient’s consent).
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
Presence of moderate-to-severely active disease, defined by an overall PDAI score> 15
Patient able to receive the standard-of-care consisting of corticosteroids (prednisone 1 mg/kg/day PO) and rituximab
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 or 20) before study entry.
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 <1% per year, during the treatment period and for at least 12 months after the last dose of study treatment. They must have a negative result from a blood beta-HCG test within 1 week prior to randomization Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Barrier methods must always be supplemented with the use of a spermicide.
For men: Surgical sterility or agreement to remain abstinent or use a condom during the treatment period and for at least 12 months after the last dose of study treatment and agreement to refrain from donating sperm during this same period. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
Able to comply with the study protocol, in the investigator’s judgment
Patient affiliated with, or beneficiary of a social security (national health insurance) plan

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Exclusion Criteria

Non-consenting patient or patient who cannot be followed regularly.
Diagnosis of paraneoplastic pemphigus or other non-PV or PF autoimmune blistering disease
Contraindication to rituximab marketed as 500 mg concentrate for solution for infusion
Contraindication to prednisone marketed as 20 mg scored tablet pharmaceutical form
Contraindication to methylprednisolone marketed as 120 mg powder for injectable solution pharmaceutical form
Contraindication to paracetamol marketed as 10 mg/mL solution for infusion pharmaceutical form
Contraindication to dexchlorpheniramine maleate marketed as 5 mg/1mL injectable solution pharmaceutical form
Lack of peripheral venous access
Pregnant or lactating women
Significant cardiovascular or pulmonary disease (including o bstructive pulmonary disease)
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
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)
Treatment with IV Ig, plasmapheresis, or other similar procedure (immunoadsorption) within 8 weeks prior to randomization
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
Treatment with cyclophosphamide within 12 weeks prior to randomization
Patients with positive blood test for HIV
Inherited or acquired severe immune deficiency
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
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 )
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
Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 24 weeks prior to screening
Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery
Treatment with rituximab or a B cell−targeted therapy (e.g., anti-CD20, anti-CD22, or anti-BLyS) within 12 months prior to randomization
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 entry be carefully investigated.
Major biological abnormality which in the investigator’s judgment, would preclude patient participation
Positive test results for hepatitis B surface antigen (HBsAg),HBe antigen, positive hepatitis B DNA, or hepatitis C virus(HCV) serology at screening
Participation in another interventional clinical trial within 28 days prior to randomization and during the study
Person deprived of liberty by administrative or judicial decision or placed under judicial protection (guardianship or supervision)