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Rituximab versus oral cyclophosphamide for severe mucous membrane pemphigoid

Randomized Double Blind Double Dummy Control Trial Comparing the Safety and Efficacy of Rituximab Versus Oral Cyclophosphamide in Severe Forms of Mucous Membrane Pemphigoid

Phase 3 Interventional University Hospital, Rouen · NCT03295383

This trial will test whether rituximab or oral cyclophosphamide works better and is safer for adults with severe mucous membrane pemphigoid.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment130 (estimated)
Ages18 Years to 80 Years
SexAll
SponsorUniversity Hospital, Rouen Academic / other
Drugs / interventionsrituximab, cyclophosphamide
Locations27 sites (Amiens and 26 other locations)
Trial IDNCT03295383 on ClinicalTrials.gov

What this trial studies

This randomized phase 3 trial compares rituximab (1 g IV) with oral cyclophosphamide (50 mg) using matched placebos to maintain blinding. Participants are assigned to one of the two treatment arms and followed for safety, disease control, and prevention of mucosal scarring and functional loss. Eligible adults (18–80 years) have severe mucous membrane pemphigoid confirmed by clinical features and immunopathology per international consensus. The multicenter French study is led by the University Hospital of Rouen and aims to generate comparative evidence to guide treatment choices for this rare disabling disease.

Who should consider this trial

Good fit: Adults aged 18–80 with newly or previously diagnosed severe mucous membrane pemphigoid who meet international clinical and laboratory (DIF/histology) diagnostic criteria are eligible.

Not a fit: Patients with mild or predominantly cutaneous pemphigoid, those outside the 18–80 age range, or those who do not meet the diagnostic criteria are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, the trial could identify a safer and more effective therapy that reduces scarring and prevents blindness or stenosis from severe MMP.

How similar studies have performed: Rituximab has shown promise in case series and small nonrandomized cohorts for pemphigoid and cyclophosphamide is a long-used option, but randomized head-to-head comparisons have been limited.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

1. 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.
2. 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
3. Patient having read and understood the information letter and signed the Informed Consent Form
4. 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.
5. 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.
6. Patient agreement to avoid excessive exposure to sunlight during study participation
7. Patient able to comply with the study protocol, in the investigator's judgment
8. Patient affiliated with, or beneficiary of a social security category

Exclusion Criteria:

1. Patient \< 18 years old or \> 80 years old
2. Non-consenting patient or patient who cannot be followed regularly
3. Patients with only MMP sequelae (stenosis, fibrosis, without inflammation or disease activity)
4. Patients with Brunsting Perry pemphigoid and exclusive skin lesions without mucosal involvement
5. Karnofsky index \< 50% (see Appendix 3)
6. Unstable angina or advanced ischemic cardiopathy (extensive myocardial infarction within the last 3 months or post-infarction heart failure)
7. Severe heart failure (NYHA Class III or IV) or severe uncontrolled cardiac disease
8. Uncontrolled cardiac rhythm disorders
9. Severe bronchial obstruction
10. 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.
11. Anemia (haemoglobin \< 10 g/ dL ), neutropenia (\<1000/mm3), lymphopenia (\<900/mm3), thrombopenia (\<100 000/mm3)
12. Positive test results for hepatitis B surface antigen (HBsAg), hepatitis B core, antibody (HBcAb), or hepatitis C virus (HCV) serology at screening
13. Liver insufficiency, major renal insufficiency (creatinin clearance ≤ 30 ml/min)
14. Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 24 weeks prior to screening
15. Patients with positive blood test for HIV
16. Inherited or acquired severe immune deficiency
17. Known active infection of any kind (excluding fungal infections of nail), or recent episode of infection, which has required oral antibiotic treatment within 2 weeks prior to enrollment in the trial
18. Infection having required hospitalization, or IV antibiotic treatment within 4 weeks prior to enrollment
19. 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
20. 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
21. Any concomitant condition that required treatment with oral or systemic corticosteroids within 12 weeks prior to randomization
22. Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery.
23. Patients having received immunosuppressive treatment (such as cyclosporine, mycophenolate mofetil, azathioprine), or any other treatment that might potentially be active on MMP lesions (anti-TNF) within 4 weeks prior to baseline.
24. Treatment with intravenous immunoglobulins, plasmapheresis, or other similar procedure within 8 weeks prior to randomization
25. Previous treatment of MMP with one of the test products: cyclophosphamide or rituximab
26. Previous treatment with a B cell-targeted therapy other than rituximab (e.g., anti-CD20, anti-CD22, or anti-BLyS)
27. Treatment with a live or attenuated vaccine within 28 days prior to randomization
28. Contraindication to MABTHERA 500 mg concentrate for solution for infusion
29. Contraindication to ENDOXAN 50 mg, tablets
30. Contraindication to methylprednisolone marketed as 120 mg powder for injectable solution pharmaceutical form
31. Contraindication to paracetamol marketed as 10 mg/ml solution for infusion pharmaceutical form
32. Contraindication to hydroxyzine marketed as 100 mg / 2 ml injectable solution pharmaceutical form
33. Contraindication to sodium chloride marketed as 0,9% sodium chloride solution for infusion pharmaceutical form
34. Contraindication to glucose marketed as 5% glucose solution for infusion pharmaceutical form
35. Lactose intolerance
36. Lack of peripheral venous access
37. 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.
38. 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
39. Participation in another interventional clinical trial within 28 days prior to randomization and during the study
40. Person deprived of liberty by administrative or judicial decision or placed under judicial protection (guardianship or supervision)

Where this trial is running

Amiens and 26 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Severe Forms of Mucous Membrane PemphigoidcyclophosphamideRituximab
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.