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

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ClinicalTrials.gov Identifier: NCT03295383
Recruitment Status : Not yet recruiting
First Posted : September 27, 2017
Last Update Posted : May 28, 2018
Sponsor:
Information provided by (Responsible Party):
University Hospital, Rouen

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.


Condition or disease Intervention/treatment Phase
Severe Forms of Mucous Membrane Pemphigoid Drug: Rituximab 1g IV Drug: Cyclophosphamide 50Mg Oral Tablet Drug: Placebo of Rituximab Drug: Placebo Oral Tablet Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Randomized Double Blind Double Dummy Control Trial Comparing the Safety and Efficacy of Rituximab Versus Oral Cyclophosphamide in Severe Forms of Mucous Membrane Pemphigoid
Estimated Study Start Date : August 2018
Estimated Primary Completion Date : November 2, 2022
Estimated Study Completion Date : November 2, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pemphigus

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




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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).

  5. 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)

  6. 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)



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03295383


Contacts
Contact: Pascal JOLY, Pr +3323288 ext 8059 pascal.joly@chu-rouen.fr
Contact: Julien BLOT +3323288 ext 8265 julien.blot@chu-rouen.fr

Locations
France
CHU Amiens Not yet recruiting
Amiens, France
Contact: Catherine Lok         
Principal Investigator: Catherine Lok         
CHU Angers
Angers, France
CH Argenteuil Not yet recruiting
Argenteuil, France
Contact: Emmanuel Mahe         
Principal Investigator: Emmanuel Mahe         
CHU Bordeaux Not yet recruiting
Bordeaux, France
Contact: Marie Beylot Barry         
Principal Investigator: Marie Beylot Barry         
Brest University Hospital
Brest, France
CHU Caen Not yet recruiting
Caen, France
Contact: Laurence Verneuil         
Principal Investigator: Laurence Verneuil         
CHU Clermont Ferrand
Clermont Ferrand, France
CHU Dijon Not yet recruiting
Dijon, France
Contact: Pierre Vabres         
Principal Investigator: Pierre Vabres         
CH Le Mans Not yet recruiting
Le Mans, France
Contact: Hervé Maillard         
Principal Investigator: Hervé Maillard         
CHU Lille Not yet recruiting
Lille, France
Contact: Emmanuel Delaporte         
Principal Investigator: Emmanuel Delaporte         
CHU de Limoges Not yet recruiting
Limoges, France
Contact: Christophe Bedane         
Principal Investigator: Christophe Bedane         
HCL Not yet recruiting
Lyon, France
Contact: Sébastien Debarbieux         
Principal Investigator: Sébastien Debarbieux         
Principal Investigator: Denis Jullien         
APHM La Timone Not yet recruiting
Marseille, France
Contact: Marie-Aleth Richard         
Principal Investigator: Marie-Aleth Richard         
CHU Montpellier
Montpellier, France
CHU Nantes Not yet recruiting
Nantes, France
Contact: Gaelle Querreux         
Principal Investigator: Gaelle Querreux         
CHU Nice Not yet recruiting
Nice, France
Contact: Jean-Philippe Lacour         
Principal Investigator: Jean-Philippe Lacour         
APHP Avicennes Not yet recruiting
Paris, France
Contact: Catherine Prost         
Principal Investigator: Catherine Prost         
APHP Bichat Not yet recruiting
Paris, France
Contact: Catherine Picard-Dahan         
Principal Investigator: Catherine Picard-Dahan         
APHP Cochin Not yet recruiting
Paris, France
Contact: Nicolas Dupin         
Principal Investigator: Nicolas Dupin         
APHP Henri Mondor Not yet recruiting
Paris, France
Contact: Oro Saskia         
Principal Investigator: Oro Saskia         
APHP Pitié Salpétrière Not yet recruiting
Paris, France
Contact: Stéphane Barete         
Principal Investigator: Stéphane Barete         
APHP Saint-Louis Not yet recruiting
Paris, France
Contact: Jean-David Bouaziz         
Principal Investigator: Jean-David Bouaziz         
CH Quimper Not yet recruiting
Quimper, France
Contact: Patrice Plantin         
Principal Investigator: Patrice Plantin         
CHU de Reims Not yet recruiting
Reims, France
Contact: Bernard Philippe         
Principal Investigator: Bernard Philippe         
CHU Rennes Not yet recruiting
Rennes, France
Contact: Alain Dupuy         
Principal Investigator: Alain Dupuy         
CHU saint-Etienne Not yet recruiting
Saint-Étienne, France
Contact: Bruno Labeille         
Principal Investigator: Bruno Labeille         
CHU Tours Not yet recruiting
Tours, France
Contact: Laurent Machet         
Principal Investigator: Laurent Machet         
Sponsors and Collaborators
University Hospital, Rouen
Investigators
Principal Investigator: Pascal JOLY, Pr Rouen University Hospital

Responsible Party: University Hospital, Rouen
ClinicalTrials.gov Identifier: NCT03295383     History of Changes
Other Study ID Numbers: 2015/208/HP
First Posted: September 27, 2017    Key Record Dates
Last Update Posted: May 28, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital, Rouen:
cyclophosphamide
Rituximab

Additional relevant MeSH terms:
Pemphigoid, Bullous
Pemphigoid, Benign Mucous Membrane
Skin Diseases, Vesiculobullous
Skin Diseases
Autoimmune Diseases
Immune System Diseases
Conjunctival Diseases
Eye Diseases
Cyclophosphamide
Rituximab
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists