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

  • STATUS
    Recruiting
  • End date
    Nov 2, 2023
  • participants needed
    130
  • sponsor
    University Hospital, Rouen
Updated on 23 January 2021

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.

Details
Condition Severe Forms of Mucous Membrane Pemphigoid
Treatment Placebo Oral Tablet, Placebo of Rituximab, Rituximab 1g IV, Cyclophosphamide 50Mg Oral Tablet
Clinical Study IdentifierNCT03295383
SponsorUniversity Hospital, Rouen
Last Modified on23 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 18 yrs and 80 yrs?
Gender: Male or Female
Do you have any of these conditions: Do you have Severe Forms of Mucous Membrane Pemphigoid??
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
\. 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 > 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
Inherited or acquired severe immune deficiency
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
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 condition that required treatment with oral or systemic corticosteroids within 12 weeks prior to randomization
Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery
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
Treatment with intravenous immunoglobulins, plasmapheresis, or other similar procedure within 8 weeks prior to randomization
Previous treatment of MMP with one of the test products: cyclophosphamide or rituximab
Previous treatment with a B cell-targeted therapy other than rituximab (e.g., anti-CD20, anti-CD22, or anti-BLyS)
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 hydroxyzine marketed as 100 mg / 2 ml 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 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
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)
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