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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT03295383
• Date of registration: 22/09/2017
• Prospective Registration: Yes
• Primary sponsor: University Hospital, Rouen
• Public title: Randomized Clinical Trial Comparing the Safety and Efficacy of Rituximab Versus Oral Cyclophosphamide in Severe Forms of Mucous Membrane Pemphigoid RITUX-MMP
• Scientific 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
• Date of first enrolment: July 11, 2019
• Target sample size: 130
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/show/NCT03295383
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Triple (Participant, Care Provider, Investigator).
• Phase: Phase 3

Countries of recruitment

France

Contacts

• Name: Pascal JOLY, Pr

• Name: Pascal JOLY, Pr
• Affiliation: Rouen University Hospital

Key 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.



Age minimum: 18 Years
Age maximum: 80 Years
Gender: All

Health Condition(s) or Problem(s) studied

Severe Forms of Mucous Membrane Pemphigoid

Intervention(s)

Drug: Placebo of Rituximab

Drug: Cyclophosphamide 50Mg Oral Tablet

Drug: Rituximab 1g IV

Drug: Placebo Oral Tablet

Primary Outcome(s)

Proportion of patients achieving CR or Partial Remission (PR) [Time Frame: Month 12]

Secondary Outcome(s)

Number of flares / relapses [Time Frame: Month 24]

Evolution of quality of life score (TAB QOL) [Time Frame: Month 12]

Evolution of quality of life score AB QOL [Time Frame: Month 12]

Evolution of MMP DAI activity score [Time Frame: Month 12]

Mean evolution of MMP DAI activity score [Time Frame: Month 24]

Mean evolution of MMP DAI activity score [Time Frame: Month 6]

Secondary ID(s)

2015/208/HP

Source(s) of Monetary Support

Please refer to primary and secondary sponsors