Randomized double blind double dummy control trial comparing the safety and efficacy of rituximab versus oral cyclophosphamide in severe forms of mucous membrane pemphigoid - (RITUX-MMP)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire Rouen

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

Trial duration

11 Jul 2019 → ongoing

Decision date (initial)

2024-10-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-514885-38-00

EudraCT number

2016-004666-26

ClinicalTrials.gov

NCT03295383

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Diagnosis, Efficacy, Safety

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 objectives 3

1. 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 DocuSign Envelope ID: 50295166-4E99-49C6-987F-578D0A3FC8AE XML File Identifier: aaTJ0TmguGQxRA0B9cisw43tfaI= Page 14/39 procedure - Quality of life using the ABQOL and TAQOL
2. 2- To compare the tolerance of rituximab and cyclophosphamide (side effects)
3. 3- Biological assessment

Conditions and MedDRA coding

severe forms of mucous membrane pemphigoid

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 1. Male or female patients aged ≥18 years old and ≤ 85 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 NB: Patients with pure ocular involvement can be included despite a negative DIF performed on the oral mucosa and despite the absence of suggestive histological picture if ophtalmologists consider the clinical ocular features are typical of MMP and that performing a biopsy on an inflammatory conjunctiva is risky.  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. 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 DocuSign Envelope ID: 50295166-4E99-49C6-987F-578D0A3FC8AE XML File Identifier: aaTJ0TmguGQxRA0B9cisw43tfaI= Page 15/39  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 or oral involvement, which have not achieved control of disease activity despite a one month treatment with dapsone at the maximum dose tolerated or by salazopyrine in patents intolerant to dapsone or having a contra indication to dapsone. or for patients with sightthreatening ocular disease, and/or  potentially life-threatening laryngeal, tracheal or oesophageal stenosis, without previous treatment by dapsone
3. 3. Patient having read and understood the information letter and signed the Informed Consent Form
4. 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. 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. 6. Patient agreement to avoid excessive exposure to sunlight during study participation
7. 7. Patient able to comply with the study protocol, in the investigator's judgment
8. 8. Patient affiliated with, or beneficiary of a social security category

Exclusion criteria 40

1. 1. Patient < 18 years old or > 85 years old
2. 2. Non-consenting patient or patient who cannot be followed regularly
3. 3. Patients with only MMP sequelae (stenosis, fibrosis, without inflammation or disease activity)
4. 4. Patients with Brunsting Perry pemphigoid and exclusive skin lesions without mucosal involvement
5. 5. Karnofsky index < 50%
6. 6. Unstable angina or advanced ischemic cardiopathy (extensive myocardial infarction within the last 3 months or post-infarction heart failure)
7. 7. Severe heart failure (NYHA Class III or IV) or severe uncontrolled cardiac disease
8. 8. Uncontrolled cardiac rhythm disorders
9. 9. Severe bronchial obstruction
10. 10. Past history of malignant disease in the previous 5 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. 11. Anaemia (haemoglogin < 10 g/ dL ), neutropoenia (<1000/mm3), Persistent lymphopoenia (<800/mm3), thrombopoenia (<100 000/mm3)
12. 12. Positive test results for hepatitis B surface antigen , hepatitis B core, antibody , or hepatitis C virus serology at screening
13. 13. Liver insufficiency, major renal insufficiency (creatinin clearance ≤ 30 ml/min)
14. 14. Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 24 weeks prior to screening
15. 15. Patients with positive blood test for HIV
16. 16. Inherited or acquired severe immune deficiency
17. 17. Current active systemic infection which has required oral antibiotic treatment within 2 weeks prior to randomization
18. 18. Infection having required hospitalization, or IV antibiotic treatment within 4 weeks prior to enrollment
19. 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. 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. 21. Any concomitant chronic condition that required prolonged treatment with oral or systemic corticosteroids with a prednisone / prednisolone dose >20 mg/day
22. 22. Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery.
23. 23. Patients having received immunosuppressive treatment (such as cyclosporine, mycophenolate mofetil, azathioprine) given at an effective dose for any other condition than MMP, or any other treatment that might potentially be active on MMP lesions (anti-TNF) within 4 weeks prior to baseline
24. 24. Treatment with intravenous immunoglobulins, plasmapheresis, or other similar procedure within 8 weeks prior to randomization
25. 25. Recent treatment: with cyclophosphamide (<2 months) or rituximab (<6 months)
26. 26. Previous treatment with a B cell−targeted therapy other than rituximab (e.g., anti-CD20, anti-CD22, or anti-BLyS) during the last 6 months
27. 27. Treatment with a live or attenuated vaccine within 28 days prior to randomization
28. 28. Contraindication to MABTHERA 500 mg concentrate for solution for infusion
29. 29. Contraindication to ENDOXAN 50 mg, tablets
30. 30. Contraindication to methylprednisolone marketed as 120 mg powder for injectable solution pharmaceutical form
31. 31. Contraindication to paracetamol marketed as 10 mg/ml solution for infusion pharmaceutical form
32. 32. Contraindication to dexchlorphéniramine maleate marketed as 5 mg/ injectable solution pharmaceutical form
33. 33. Contraindication to sodium chloride marketed as 0,9% sodium chloride solution for infusion pharmaceutical form
34. 34. Contraindication to glucose marketed as 5% glucose solution for infusion pharmaceutical form
35. 35. Lactose and/or sucrose intolerance
36. 36. Lack of peripheral venous access
37. 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. 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 or Cyclophosphamide
39. 39. Participation in another interventional clinical trial within 28 days prior to randomization and during the study
40. 40. Person deprived of liberty by administrative or judicial decision or placed under judicial protection (guardianship or supervision)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 4

1. • 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.
2. • 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.
3. • -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
4. • -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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire Rouen

Sponsor organisation

Centre Hospitalier Universitaire Rouen

Address

1 Rue De Germont, Bp 96031 Bp 96031

City

Rouen Cedex

Postcode

76031

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire Rouen

Contact name

David MALLET

Public contact point

Organisation

Centre Hospitalier Universitaire Rouen

Contact name

David MALLET

Locations

1 EU/EEA country · 28 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications