Efficacy and Safety of Rituximab Versus Cyclophosphamide in Severe Mucous Membrane Pemphigoid: A Randomized, Double-Blind, Double-Dummy Controlled Trial
- Trial ID
- 2024-514885-38-00
- Protocol
- 2015/208/HP
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **superiority** of rituximab compared to cyclophosphamide, when used in combination with dapsone, in achieving complete remission (CR) or partial remission (PR) of disease activity at Month 12 in patients with severe forms of mucous membrane pemphigoid (MMP). This is clinically relevant as achieving remission can significantly improve patient outcomes and quality of life in this severe autoimmune condition.
Secondary objectives include:
- Comparing the efficacy of rituximab and cyclophosphamide over the study period (M6, M12, M18, M24) on disease activity, post-inflammatory fibrosis, and scarring using the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI). Additionally, assessing the rate of major MMP complications, relapse rates from the end of immunosuppressive therapy to the study's conclusion, and the rate of patients requiring interventional procedures for scarring sequelae. Quality of life will be evaluated using the ABQOL and TAQOL scales.
- Comparing the tolerance of rituximab and cyclophosphamide, focusing on side effects.
- Conducting a biological assessment.
Participants
The clinical trial involves participants diagnosed with **severe forms of mucous membrane pemphigoid** (MMP), a condition characterized by blisters or erosions affecting mucous membranes. The study population includes both male and female subjects aged between 18 and 85 years. Participants are selected based on specific clinical features and diagnostic criteria, including the presence of sight-threatening ocular disease or potentially life-threatening stenosis in the laryngeal, tracheal, or esophageal regions. The trial population is composed of individuals who are able to comply with the study protocol and have updated vaccinations. Lifestyle considerations include the requirement for participants to avoid excessive sunlight exposure during the study. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, ensuring that all participants have read and understood the informed consent and are affiliated with a social security category.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, double-dummy controlled study to evaluate the safety and efficacy of **rituximab** versus oral **cyclophosphamide** in patients with severe forms of mucous membrane pemphigoid. The trial aims to assess the superiority of rituximab in achieving complete or partial remission of disease activity at Month 12. The study is expected to run from July 2019 to January 2026, with a maximum treatment period of 12 months for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including age, diagnosis, and disease severity. Following the screening, participants will be randomized to receive either rituximab or cyclophosphamide, with additional treatments such as dapsone as part of the combination therapy. The trial includes regular follow-up visits to monitor disease activity, treatment efficacy, and safety, with assessments conducted at baseline, Month 3, Month 6, Month 12, Month 18, and Month 24. The end-of-study visit will evaluate the long-term outcomes and any adverse events experienced during the trial.
The expected length of participant involvement is up to 24 months, including the treatment and follow-up periods. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant. The primary endpoint is the proportion of patients achieving complete or partial remission at Month 12, while secondary endpoints include the evolution of disease activity scores, quality of life assessments, and the prevention of post-inflammatory fibrosis and scarring.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Rituximab**, marketed as MabThera, is the primary experimental medication. It is provided as a 500 mg concentrate for solution for infusion. The pharmaceutical form is a solution for infusion, and it is administered intravenously. The maximum daily dose is 500 mg, with a total maximum dose of 2000 mg over a treatment period of up to 12 months. Rituximab is a protein-based substance, specifically classified under the ATC code L01XC02. Participant compliance with the dosing schedule will be monitored throughout the trial.
**Cyclophosphamide**, marketed as ENDOXAN 50 mg, is used as a comparator treatment in the study. It is available in the form of a coated tablet and is administered orally. The active substance is anhydrous cyclophosphamide, a chemical compound classified under the ATC code L01AA01. The maximum daily dose is 128.5 mg, with a total maximum dose of 1784400 mg over a 12-month period. Compliance with the oral administration schedule will be closely monitored to ensure adherence to the treatment protocol.
**Lactose** is utilized as a placebo in the trial. It is provided in tablet form and administered orally. The maximum daily dose is 128.5 mg, with a total maximum dose of 1784400 mg over the course of the study. Lactose serves as a chemically inert substance to maintain the double-blind nature of the trial. Participant adherence to the placebo regimen will be monitored to ensure the integrity of the study results.
**Glucose** is also used as a placebo in the trial, provided as a solution for infusion. It is administered intravenously, with a maximum daily dose of 500 mg and a total maximum dose of 2000 mg over the 12-month treatment period. As with lactose, glucose is chemically inert and is used to maintain the double-blind design of the study. Monitoring of participant compliance with the glucose infusion schedule will be conducted to ensure accurate data collection.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints related to the treatment of severe forms of **mucous membrane pemphigoid** (MMP). The primary endpoint is the proportion of patients achieving complete remission (CR) or partial remission (PR) at Month 12. CR is defined as the absence of any inflammatory lesion, blister, or erosion, and the absence of new fibrosing lesions or worsening of established fibrosing lesions. PR is characterized by the presence of transient new inflammatory lesions, blisters, or erosions that heal within one week without treatment, along with the absence of new fibrosing lesions or worsening of established fibrosing lesions.
Secondary endpoints include several measures of efficacy on disease activity and prevention of post-inflammatory fibrosis and scarring. These include the mean evolution of the MMP Disease Activity Index (DAI) activity score from Week 0 to Week 104, time to achieve CR or PR, cumulative duration of periods of CR or PR, number of flares or relapses, and time to disease flare or relapse. Quality of life will be assessed at baseline, Month 3, Month 6, Month 12, Month 18, and Month 24 using the AB QOL and TAB QOL scores, which are specifically developed for patients with autoimmune blistering diseases. Additionally, the mean evolution of the MMP DAI damage score will be evaluated, including ocular involvement assessed by ophthalmologists using the MMPDAI eye subsection score, the rate of patients developing new laryngeal, tracheal, or oesophageal stenosis, and the proportion of patients with new scarring sequelae necessitating an invasive procedure from Week 0 to Week 104.
Biological assessments will include the decrease of serum antibodies directed against different target antigens of the basement membrane zone (BMZ) involved in MMP, such as BP180, laminin 332, and type 7 collagen, measured by ELISA assays. The affinity of corresponding auto-antibodies and the evolution of the number of BPAG2-specific peripheral blood B lymphocytes will be measured by ELISPOT assay in both treatment groups. These assessments will provide comprehensive data on the efficacy of the treatments being compared in this trial.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female patients aged ≥18 years old and ≤ 85 years old with a newly diagnosed or previously diagnosed severe MMP diagnosed according to the International MMP Consensus (Chan 2002) on the following criteria: Clinical features: Blisters or erosions predominantly affecting any or all mucous membranes (oral, nasal, pharyngeal, laryngeal, anal, genital, or esophageal,) with or without clinically observable scarring. Ocular involvement includes conjunctival inflammation, shortening of fornices, symblepharon, ankyloblepharon, entropion, trichiasis and corneal neovascularisation. Patients with skin involvement must not have more than 2 out of the 4 clinical criteria for bullous pemphigoid (BP) proposed by the French group (Vaillant L et al,1998; Joly P et al. 2004) Direct Immunofluorescence (DIF): Linear deposits of IgG, IgA and/or C3 on the BMZ by DIF of patient's skin or mucous membrane NB: Patients with pure ocular involvement can be included despite a negative DIF performed on the oral mucosa and despite the absence of suggestive histological picture if ophtalmologists consider the clinical ocular features are typical of MMP and that performing a biopsy on an inflammatory conjunctiva is risky. Histology: Sub epithelial blister with or without significant leukocyte infiltrate by standard histology of skin or mucosal lesions, when the skin or mucosal biopsy is possible and appropriate.
- MMP is defined as "severe" in patients with: Sight-threatening ocular disease, and/or Potentially life-threatening laryngeal, tracheal or oesophageal stenosis, and/or Involvement of a mucosal site where there is a risk of scarring stenosis (larynx, trachea, esophagus, anus, foreskin, vagina…) and/or DocuSign Envelope ID: 50295166-4E99-49C6-987F-578D0A3FC8AE XML File Identifier: aaTJ0TmguGQxRA0B9cisw43tfaI= Page 15/39 More than one mucosal site involved and/or Mucosal involvement (including exclusive but severe oral involvement defined as an oral MMP DAI score > 10), and/or Skin or oral involvement, which have not achieved control of disease activity despite a one month treatment with dapsone at the maximum dose tolerated or by salazopyrine in patents intolerant to dapsone or having a contra indication to dapsone. or for patients with sightthreatening ocular disease, and/or potentially life-threatening laryngeal, tracheal or oesophageal stenosis, without previous treatment by dapsone
- Patient having read and understood the information letter and signed the Informed Consent Form
- Patient with updated vaccinations. It is recommended that a patient's vaccination record and the need for immunization prior to study entry be carefully investigated.
- For women who are not postmenopausal (≥12 months of non− therapy-induced amenorrhoea) or surgically sterile (absence of ovaries and/or uterus) and who do not plan on having children anymore: 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. 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.
- Patient agreement to avoid excessive exposure to sunlight during study participation
- Patient able to comply with the study protocol, in the investigator's judgment
- Patient affiliated with, or beneficiary of a social security category
Exclusion Criteria
- Patient < 18 years old or > 85 years old
- Non-consenting patient or patient who cannot be followed regularly
- Patients with only MMP sequelae (stenosis, fibrosis, without inflammation or disease activity)
- Patients with Brunsting Perry pemphigoid and exclusive skin lesions without mucosal involvement
- Karnofsky index < 50%
- Unstable angina or advanced ischemic cardiopathy (extensive myocardial infarction within the last 3 months or post-infarction heart failure)
- Severe heart failure (NYHA Class III or IV) or severe uncontrolled cardiac disease
- Uncontrolled cardiac rhythm disorders
- Severe bronchial obstruction
- Past history of malignant disease in the previous 5 years, or current progressive malignant disease, except basal cell carcinoma, and squamous cell carcinoma of the skin that have been treated or excised and cured, in situ cervix carcinoma, or any situation in which the oncologist in charge of the patient considers that risk of evolution of severe localisation(s) of MMP is higher than oncologic risk of cyclophosphamide and rituximab.
- Anaemia (haemoglogin < 10 g/ dL ), neutropoenia (<1000/mm3), Persistent lymphopoenia (<800/mm3), thrombopoenia (<100 000/mm3)
- Positive test results for hepatitis B surface antigen , hepatitis B core, antibody , or hepatitis C virus serology at screening
- Liver insufficiency, major renal insufficiency (creatinin clearance ≤ 30 ml/min)
- Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 24 weeks prior to screening
- Patients with positive blood test for HIV
- Inherited or acquired severe immune deficiency
- Current active systemic infection which has required oral antibiotic treatment within 2 weeks prior to randomization
- Infection having required hospitalization, or IV antibiotic treatment within 4 weeks prior to enrollment
- Past history of severe infection such as fasciitis, osteomyelitis septic arthritis during the year prior to enrollment. Entry into this study may be reconsidered once the infection has fully resolved
- Evidence of any new or uncontrolled concomitant disease that, in the investigator's judgment, would preclude patient participation, including but not limited to nervous system, renal, hepatic, endocrine, malignant, or gastrointestinal disorders
- Any concomitant chronic condition that required prolonged treatment with oral or systemic corticosteroids with a prednisone / prednisolone dose >20 mg/day
- Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery.
- Patients having received immunosuppressive treatment (such as cyclosporine, mycophenolate mofetil, azathioprine) given at an effective dose for any other condition than MMP, or any other treatment that might potentially be active on MMP lesions (anti-TNF) within 4 weeks prior to baseline
- Treatment with intravenous immunoglobulins, plasmapheresis, or other similar procedure within 8 weeks prior to randomization
- Recent treatment: with cyclophosphamide (<2 months) or rituximab (<6 months)
- Previous treatment with a B cell−targeted therapy other than rituximab (e.g., anti-CD20, anti-CD22, or anti-BLyS) during the last 6 months
- Treatment with a live or attenuated vaccine within 28 days prior to randomization
- Contraindication to MABTHERA 500 mg concentrate for solution for infusion
- Contraindication to ENDOXAN 50 mg, tablets
- 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 dexchlorphéniramine maleate marketed as 5 mg/ injectable solution pharmaceutical form
- Contraindication to sodium chloride marketed as 0,9% sodium chloride solution for infusion pharmaceutical form
- Contraindication to glucose marketed as 5% glucose solution for infusion pharmaceutical form
- Lactose and/or sucrose intolerance
- Lack of peripheral venous access
- Women pregnant or lactating, or intending to become pregnant during and for 12 months following the study. Women who are not postmenopausal (≥ 12 months of non−therapy-induced amenorrhea) or surgically sterile must have a negative result from a serum pregnancy test within 1 week prior to randomization.
- Patients who plan on having children (due to the risk of amenorrhoea/azoospermia related to cyclophosphamide) and due to the long retention time of rituximab in B cells depleted patients, women of childbearing potential should use effective contraceptive methods during and for 12 months following treatment with MABTHERA or Cyclophosphamide
- 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)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 11 Jul 2019 | 130 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
GLUCOSE | Placebo | — | INTRAVENOUS | 500 | 12 | SUB13981MIG |
LACTOSE | Placebo | — | ORAL USE | 128.5 | 12 | SUB14317MIG |
ENDOXAN 50 mg, comprimé enrobé | Comparator | COMPRIMÉ ENROBÉ | ORAL USE | 128.5 | 12 | PRD350176 |
MabThera 500 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 500 | 12 | PRD2154043 |