severe forms of mucous membrane pemphigoid MedDRA version: 20.1 Level: PT Classification code 10067776 Term: Ocular pemphigoid System Organ Class: 10015919 - Eye disorders MedDRA version: 20.0 Level: PT Classification code 10034277 Term: Pemphigoid System Organ Class: 10040785 - Skin and subcutaneous tissue disorders MedDRA version: 21.1 Level: LLT Classification code 10057052 Term: Cicatricial pemphigoid System Organ Class: 10040785 - Skin and subcutaneous tissue disorders
Conditions
Interventions
Trade Name: MABTHERA
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: e
Sponsors
CHU-Hôpitaux de Rouen
Eligibility
Sex/Gender
All
Inclusion 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 pa
Exclusion criteria
Exclusion criteria: 1. Patient 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. Anaemia (haemoglogin < 10 g/ dL ), neutropoenia (<1000/mm3), lymphopoenia (<900/mm3), thrombopoenia (<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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the superiority of rituximab compared to cyclophosphamide used in combination therapy with dapsone, to achieve CR or partial remission (PR) (corresponding in clinical practice to “almost Complete Remission”) of disease activity at Month 12, in patients with severe forms of MMP;Secondary Objective: 1-To compare the efficacy of rituximab and cyclophosphamide during the study (M6, M12, M18, M24) on: - Disease activity, - post inflammatory fibrosis and scarring from resolving lesions using a specific scoring system published by a panel of international experts: the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI) - Rate of patients with major MMP complications such as: stenosis of the oesophagus, larynx or trachea or major eye impairment. -Rate of relapse/flare of MMP from the end of immunosuppressive therapy (Month 12) to the end of the study (Month 24). -Rate of patients with scarring sequelae necessitating an interventional procedure - Quality of life using the ABQOL and TAQOL 2- To compare the tolerance of rituximab and cyclophosphamide (side effects) 3- Biological assessment ;Primary end point(s): Proportion of patients achieving complete remission (CR) or Partial Remission (PR) at Month12, defined as “CR: absence of any inflammatory lesion, blister or erosion, and, absence of new fibrosing lesions, and/or absence of worsening of established fibrosing lesions PR: presence of transient new inflammattory 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 (from slightly modified MMP International Consensus Statement definition). ;Timepoint(s) of evaluation of this end point: M12 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Efficacy on disease activity: - Mean evolution of MMP DAI activity score from Week 0 to Week 104 - Time to achieve CR or PR - Cumulative duration of periods of CR or PR during the study - Number of flares / relapses during the study. - Time to disease flare/relapse - Quality of life measured at baseline, M3, M6, M12, M18 and M24 by the AB QOL and TAB QOL scores, which are quality of life questionnaires specifically developed for patients with autoimmune blistering diseases. • Efficacy on prevention of post inflammatory fibrosis and scarring from resolving lesions: - Mean evolution of the MMP DAI damage score from Week 0 to Week 104 including: - Ocular involvement assessed by ophthalmologists using the MMPDAI eye subsection score. - Rate of patients developing new laryngeal, tracheal or oesophageal stenosis. - Proportion of patients with new scarring sequelae necessitating an invasive procedure from Week 0 to Week 104. • -Tolerance: - Number of Serious Adverse Event, (SAEs) including fatal, Non-Serious Adverse Event, SAEs leading to drug discontinuation/withdrawal of the patient from the study (using Common Terminology Criteria for Adverse Events (CTCAE and MeDRA terminology), - Number and causes of death during the study • -Biological assessment -Decrease of serum antibodies directed against the different target antigens of BMZ involved in MMP (BP180, laminin 332, type 7 collagen) by ELISA assays - Affinity of corresponding auto-antibodies; - Evolution of the number of BPAG2- specific peripheral blood B lymphocytes measured by ELISPOT assay, in both treatment groups. ;Timepoint(s) of evaluation of this end point: M6, M12, M18, M24 | — |
Countries
France
Contacts
Public ContactBLOT
CHU-Hôpitaux de Rouen
Outcome results
None listed