Randomized Clinical Trial Comparing the Safety and Efficacy of Rituximab Versus Oral Cyclophosphamide in Severe Forms of Mucous Membrane Pemphigoid (RITUX-MMP)

October 23, 2019 updated by: University Hospital, Rouen

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Anticipated)

130

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • France
      • Amiens, France
        • Recruiting
        • CHU Amiens
        • Contact:
          • Catherine Lok
        • Principal Investigator:
          • Catherine Lok
      • Angers, France
        • Recruiting
        • Chu Angers
        • Contact:
          • Martine Avenel
        • Principal Investigator:
          • Martine Avenel
      • Argenteuil, France
        • Recruiting
        • CH Argenteuil
        • Contact:
          • Emmanuel MAHE
        • Principal Investigator:
          • Emmanuel Mahe
      • Bordeaux, France
        • Recruiting
        • CHU Bordeaux
        • Contact:
          • Marie Beylot Barry
        • Principal Investigator:
          • Marie Beylot Barry
      • Brest, France
        • Recruiting
        • Brest University Hospital
        • Contact:
          • Misery, Pr
      • Caen, France
        • Recruiting
        • CHU caen
        • Contact:
          • Laurence Verneuil
        • Principal Investigator:
          • Laurence Verneuil
      • Clermont Ferrand, France
        • Recruiting
        • CHU Clermont Ferrand
        • Contact:
          • Michel D'Incan
        • Principal Investigator:
          • Michel D'Incan
      • Dijon, France
        • Recruiting
        • CHU Dijon
        • Contact:
          • Pierre Vabres
        • Principal Investigator:
          • Pierre Vabres
      • Le Mans, France
        • Recruiting
        • CH Le Mans
        • Contact:
          • HERVE MAILLARD
      • Lille, France
        • Recruiting
        • CHU Lille
        • Contact:
          • Emmanuel Delaporte
        • Principal Investigator:
          • Emmanuel Delaporte
      • Limoges, France
        • Recruiting
        • CHU de Limoges
        • Contact:
          • Christophe BEDANE
        • Principal Investigator:
          • Christophe Bedane
      • Lyon, France
        • Recruiting
        • HCL
        • Contact:
          • Sébastien Debarbieux
        • Principal Investigator:
          • Sébastien Debarbieux
        • Principal Investigator:
          • Denis Jullien
      • Marseille, France
        • Recruiting
        • APHM La Timone
        • Contact:
          • Marie-Aleth RICHARD
        • Principal Investigator:
          • Marie-Aleth Richard
      • Montpellier, France
        • Recruiting
        • CHU Montpellier
        • Contact:
          • Olivier DEREURE
        • Principal Investigator:
          • Olivier Dereure
      • Nantes, France
        • Recruiting
        • CHU Nantes
        • Contact:
          • Gaelle Querreux
        • Principal Investigator:
          • Gaelle Querreux
      • Nice, France
        • Recruiting
        • CHU Nice
        • Contact:
          • Jean-Philippe Lacour
        • Principal Investigator:
          • Jean-Philippe Lacour
      • Paris, France
        • Recruiting
        • Aphp Cochin
        • Contact:
          • Nicolas Dupin
        • Principal Investigator:
          • Nicolas Dupin
      • Paris, France
        • Recruiting
        • APHP Avicennes
        • Contact:
          • Catherine PROST
        • Principal Investigator:
          • Catherine Prost
      • Paris, France
        • Recruiting
        • APHP Bichat
        • Contact:
          • Catherine Picard-Dahan
        • Principal Investigator:
          • Catherine Picard-Dahan
      • Paris, France
        • Recruiting
        • APHP Henri Mondor
        • Contact:
          • Oro Saskia
        • Principal Investigator:
          • Oro Saskia
      • Paris, France
        • Recruiting
        • Aphp Pitie Salpetriere
        • Contact:
          • Stéphane Barete
        • Principal Investigator:
          • Stéphane Barete
      • Paris, France
        • Recruiting
        • APHP Saint-Louis
        • Contact:
          • Jean-David BOUAZIZ
        • Principal Investigator:
          • Jean-David Bouaziz
      • Quimper, France
        • Recruiting
        • CH Quimper
        • Principal Investigator:
          • Patrice Plantin
      • Reims, France
        • Recruiting
        • CHU de Reims
        • Contact:
          • Bernard Philippe
        • Principal Investigator:
          • Bernard Philippe
      • Rennes, France
        • Recruiting
        • CHU Rennes
        • Contact:
          • Alain Dupuy
      • Saint-Étienne, France
        • Recruiting
        • CHU Saint-Etienne
        • Contact:
          • Bruno Labeille
        • Principal Investigator:
          • Bruno Labeille
      • Tours, France
        • Recruiting
        • Chu Tours
        • Contact:
          • Laurent Machet
        • Principal Investigator:
          • Laurent Machet

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 78 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Rituximab treatment

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
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
Drug: Placebo Oral Tablet
cyclophosphamide placebo will be administered orally once daily
Active Comparator: Cyclophosphamide treatment

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

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.
Drug: Placebo of Rituximab
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of patients achieving CR or Partial Remission (PR)
Time Frame: Month 12
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mean evolution of MMP DAI activity score
Time Frame: Month 24
MMP DAI score is a scoring system who include 2 sub scores: the MMP DAI activity score which assesses disease activity (mucous membrane and skin erosions and blisters), and the MMP DAI damage score, which assesses disease damage (mucous membrane and skin scaring and pigmentation). These 2 "activity" and "damage" sub scores enable distinction between active erosions and blisters from post inflammatory changes and scarring from resolving lesions.
Month 24
Mean evolution of MMP DAI activity score
Time Frame: Month 6
MMP DAI score is a scoring system who include 2 sub scores: the MMP DAI activity score which assesses disease activity (mucous membrane and skin erosions and blisters), and the MMP DAI damage score, which assesses disease damage (mucous membrane and skin scaring and pigmentation). These 2 "activity" and "damage" sub scores enable distinction between active erosions and blisters from post inflammatory changes and scarring from resolving lesions.
Month 6
Evolution of MMP DAI activity score
Time Frame: Month 12
MMP DAI score is a scoring system who include 2 sub scores: the MMP DAI activity score which assesses disease activity (mucous membrane and skin erosions and blisters), and the MMP DAI damage score, which assesses disease damage (mucous membrane and skin scaring and pigmentation). These 2 "activity" and "damage" sub scores enable distinction between active erosions and blisters from post inflammatory changes and scarring from resolving lesions.
Month 12
Number of flares / relapses
Time Frame: Month 24
relapse / flare is defined as "the reappearance of at least 3 new lesions a month (blisters, erosions) that do not heal within one week, or the extension of established lesions in a patient who has achieved disease control." (Murrell D et al. 2015).
Month 24
Evolution of quality of life score (TAB QOL)
Time Frame: Month 12
ABQOL score is a quality of life questionnaires specifically developed for patients with autoimmune blistering disorders to assess quality of life (ABQOL)
Month 12
Evolution of quality of life score AB QOL
Time Frame: Month 12
TAB QOL score is a quality of life questionnaires specifically developed for patients with autoimmune blistering disorders to assess evolution under treatment (TAB QOL)
Month 12

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Rouen

Investigators

  • Principal Investigator: Pascal JOLY, Pr, Rouen University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 11, 2019

Primary Completion (Anticipated)

November 2, 2022

Study Completion (Anticipated)

November 2, 2023

Study Registration Dates

First Submitted

September 22, 2017

First Submitted That Met QC Criteria

September 22, 2017

First Posted (Actual)

September 27, 2017

Study Record Updates

Last Update Posted (Actual)

October 25, 2019

Last Update Submitted That Met QC Criteria

October 23, 2019

Last Verified

October 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2015/208/HP

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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