Randomized Clinical Trial Comparing the Safety and Efficacy of Rituximab Versus Oral Cyclophosphamide in Severe Forms of Mucous Membrane Pemphigoid

NCT03295383 | Recruiting Phase 3 DMC

• 1 other identifier: 2015/208/HP
• Study Type: interventional
• Target: 130
• Locations: 1 country
• Sites: 27

Brief Summary

Mucous membrane pemphigoid (MMP) describes a group of chronic auto-immune bullous diseases (AIBD) of the basement membrane zone (BMZ), characterized by predominant or exclusive mucosal involvement, including oral, naso-pharyngeal, laryngo-tracheal, genital, oesophageal, anal and ocular mucous membranes. Circulating autoantibodies are directed against various antigens of the BMZ: BP180, laminin 332 and type 7 collagen. MMP is a rare disease with an incidence of 1.8 new cases/million inhabitants/year in France. Scar formation which is secondary to initial inflammation, is a characteristic feature of MMP, leading to major disability (e.g blindness and oesophageal, anal, vaginal stenosis) and life-threatening situations (e.g. laryngeal stenosis leading to respiratory failure). Dapsone is the first line treatment of mild/moderate forms of MMP. Dapsone is used both as initial treatment, and as maintenance therapy. However, severe forms of MMP can rapidly worsen leading to blindness, aphagia due to esophageal stenosis, respiratory failure due to tracheal or laryngeal stenosis, and urinary and sexual dysfunctions due to genital involvement. These patients are usually treated using immunosuppressive drugs. Indeed, corticosteroids (CS) are not recommended in MMP. Cyclophosphamide was considered as the most effective immunosuppressant in severe forms of MMP, before the use of rituximab, an anti-CD20 monoclonal antibody (MAb). Two series from our group have assessed the advantages and disadvantages of IV pulse and oral administration of cyclophosphamide in MMP. Oral administration seems more rapidly effective with 54% of complete remission (CR) after a median time of 24 weeks (16-52 weeks). The results of 41 patients with severe types of MMP (including a French series of 20 patients) treated with rituximab have been published. Rate of CR after one and two cycles were 66% and 90%, respectively. Clinical improvement was rapid, since a decrease in disease activity was observed after 4 weeks of treatment in 64% of patients. Our results and those of the literature suggest that rituximab might be more effective than cyclophosphamide, which has been considered as the gold standard of treatment in severe forms of disease, up to now.

Conditions

Severe Forms of Mucous Membrane Pemphigoid

Keywords

cyclophosphamide; Rituximab

Outcome Measures

Primary Outcomes (1)

• Proportion of patients achieving CR or Partial Remission (PR)

  Complete remission: absence of any inflammatory lesion, blister or erosion, and, absence of new fibrosing lesions, and/or absence of worsening of established fibrosing lesions Partial remission: presence of transient new inflammatory lesions, blisters or erosions that heal within one week without treatment and, absence of new fibrosing lesions, and/or absence of worsening of established fibrosing lesions. (Murrell D et al. 2015)

  Month 12

Secondary Outcomes (6)

• Mean evolution of MMP DAI activity score

  Month 24

• Mean evolution of MMP DAI activity score

  Month 6

• Evolution of MMP DAI activity score

  Month 12

• Number of flares / relapses

  Month 24

• Evolution of quality of life score (TAB QOL)

  Month 12

Study Arms (2)

Rituximab treatment

EXPERIMENTAL

Rituximab at a dose of 1000 mg (or matching placebo) will be administered by IV infusion on Day 1 and Day 15 whatever the patient's weight, with repeat maintenance rituximab (or matching placebo) administration on Day 182 and Day 197 cyclophosphamide placebo will be administered orally once daily

Drug: Rituximab 1g IV; Drug: Placebo Oral Tablet

Cyclophosphamide treatment

ACTIVE COMPARATOR

cyclophosphamide will be administered orally once daily at the following initial doses: patients younger than 75 years: 1.5 mg/kg/day, orally. patients older than 75 years: 1 mg/kg/day, orally. Rituximab placebo (NaCl 0.9 %) will be administered by IV infusion on Day 1 and Day 15 whatever the patient's weight, with repeat maintenance rituximab (or matching placebo) administration on Day 182 and Day 197

Drug: Cyclophosphamide 50Mg Oral Tablet; Drug: Placebo of Rituximab

Interventions

Rituximab 1g IV DRUG

Rituximab at a dose of 1000 mg will be administered by IV infusion on Day 1 and Day 15 whatever the patient's weight, with repeat maintenance rituximab (or matching placebo) administration on Day 182 and Day 197

Rituximab treatment

Cyclophosphamide 50Mg Oral Tablet DRUG

cyclophosphamide will be administered orally once daily at the following initial doses: * patients younger than 75 years: 1.5 mg/kg/day, orally. * patients older than 75 years: 1 mg/kg/day, orally.

Cyclophosphamide treatment

Placebo of Rituximab DRUG

Rituximab placebo will be administered by IV infusion on Day 1 and Day 15 whatever the patient's weight, with repeat maintenance rituximab administration on Day 182 and Day 197

Cyclophosphamide treatment

Placebo Oral Tablet DRUG

cyclophosphamide placebo will be administered orally once daily

Rituximab treatment

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients aged ≥18 years old and ≤ 80 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 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 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 involvement, which have not achieved control of disease activity despite a one month treatment with dapsone at the maximum dose tolerated or for patients with sight-threatening 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

You may not qualify if:

• Patient \< 18 years old or \> 80 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% (see Appendix 3)
• 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 10 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.
• Anemia (haemoglobin \< 10 g/ dL ), neutropenia (\<1000/mm3), lymphopenia (\<900/mm3), thrombopenia (\<100 000/mm3)
• Positive test results for hepatitis B surface antigen (HBsAg), hepatitis B core, antibody (HBcAb), or hepatitis C virus (HCV) 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

Sponsors & Collaborators

• University Hospital, Rouen: lead

Study Sites (27)

CHU Amiens

Amiens, France

RECRUITING

CHU Angers

Angers, France

RECRUITING

CH Argenteuil

Argenteuil, France

RECRUITING

CHU Bordeaux

Bordeaux, France

RECRUITING

Brest University Hospital

Brest, France

RECRUITING

CHU Caen

Caen, France

RECRUITING

CHU Clermont Ferrand

Clermont-Ferrand, France

RECRUITING

CHU Dijon

Dijon, France

RECRUITING

CH Le Mans

Le Mans, France

RECRUITING

CHU Lille

Lille, France

RECRUITING

CHU de Limoges

Limoges, France

RECRUITING

HCL

Lyon, France

RECRUITING

APHM La Timone

Marseille, France

RECRUITING

CHU Montpellier

Montpellier, France

RECRUITING

CHU Nantes

Nantes, France

RECRUITING

CHU Nice

Nice, France

RECRUITING

APHP Avicennes

Paris, France

RECRUITING

APHP Bichat

Paris, France

RECRUITING

APHP Cochin

Paris, France

RECRUITING

APHP Henri Mondor

Paris, France

RECRUITING

APHP Pitié Salpétrière

Paris, France

RECRUITING

APHP Saint-Louis

Paris, France

RECRUITING

CH Quimper

Quimper, France

RECRUITING

CHU de Reims

Reims, France

RECRUITING

CHU Rennes

Rennes, France

RECRUITING

CHU saint-Etienne

Saint-Etienne, France

RECRUITING

CHU Tours

Tours, France

RECRUITING

MeSH Terms

Interventions

Rituximab; Cyclophosphamide; Tablets

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Dosage Forms; Pharmaceutical Preparations

Study Officials

• Pascal JOLY, Pr

  University Hospital, Rouen

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Pascal JOLY, Pr

CONTACT

+3323288; pascal.joly@chu-rouen.fr

Julien BLOT

CONTACT

+3323288; julien.blot@chu-rouen.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 22, 2017
• First Posted: September 27, 2017
• Study Start: July 11, 2019
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027
• Last Updated: February 18, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

FR (27)