A Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Rituximab Versus Mycophenolate Mofetil in Patients With Pemphigus Vulgaris

• Register: EUCTR
• Last refreshed on: 25 November 2019
• Main ID: EUCTR2014-000382-41-DE
• Date of registration: 09/12/2014
• Prospective Registration: Yes
• Primary sponsor: F. Hoffmann-La Roche Ltd
• Public title: A Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Rituximab Versus Mycophenolate Mofetil in Patients With Pemphigus Vulgaris
• Scientific title: A randomized, double-blind, double-dummy active-comparator, multicenter study to evaluate the efficacy and safety of rituximab versus MMF in patients with pemphigus vulgaris - PEMPHIX
• Date of first enrolment: 06/03/2015
• Target sample size: 132
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-000382-41
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Canada, France, Germany, Israel, Italy, Spain, Turkey, Ukraine, United States

Contacts

• Name: Trial Information Support Line-TISL
• Affiliation: F. Hoffmann-La Roche Ltd

• Name: Trial Information Support Line-TISL
• Affiliation: F. Hoffmann-La Roche Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
• Age 18-75 years
• Signed Informed Consent Form
• First confirmed diagnosis of PV within the previous 24 months, based on the presence of: histological features of acantholysis via skin or mucosal biopsy and one of the following: tissue-bound IgG antibodies by direct immunofluorescence on the surface of affected epithelium or serological detection of serum Dsg3 autoantibodies against epithelial cell surface either by indirect immunofluorescence microscopy or by enzyme-linked immunosorbent assay
• Presence of moderate to severely active disease, defined as overall PDAI activity score of = 15
• Receiving standard-of-care corticosteroids consisting of 60-120 mg/day PO prednisone or equivalent (1.0 - 1.5 mg/kg/day) and, in the judgment of the investigator, expected to benefit from the addition of immunosuppressive therapy
• For women who are not postmenopausal (= 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use two effective 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.
Examples of contraceptive methods with a failure rate of < 1% per year(highly effective contraceptive methods) include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices.
• For men (including those who have undergone a vasectomy): 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.
In addition to male contraception, agreement to advise female partners of childbearing potential to use highly effective contraception during the study and for at least 12 months after the last dose of study treatment
• Agreement to avoid excessive exposure to sunlight during study participation
• Able to comply with the study protocol, in the investigator’s judgment
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 100
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 32

Exclusion criteria:
Diagnosis of pemphigus foliaceus or evidence of paraneoplastic pemphigus or other non-PV autoimmune blistering disease
• History of a severe allergic or anaphylactic reaction to humanized or murine monoclonal antibodies, or known hypersensitivity to any component of rituximab
• Known hypersensitivity or contraindication to MMF, mycophenolic acid, polysorbate, or oral corticosteroids
• Lack of peripheral venous access
• Pregnant or lactating, or intending to become pregnant during the study Women who are not postmenopausal (= 12 months of non-therapy-induced amenorrhea) or surgically sterile must have two negative result with a sensitivity of = 25 mIU/mL: one from a serum pregnancy test at Day -8 to Day -10 of screening and another from an urine pregnancy test at Day 1 prior to randomization.
• Participated in another interventional clinical trial within 28 days prior to randomization
• Use of any investigational agent within 28 days or 5 elimination half-lives prior to randomization (whichever is the longer)
• Significant cardiovascular or pulmonary disease (including obstructive pulmonary disease)
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
• Treatment with IV Ig, plasmapheresis, or other similar procedure within 8 weeks prior to randomization
• Treatment with immunosuppressive medications (e.g., azathioprine, MMF) within 1 week prior to randomization
• Treatment with cyclophosphamide within 12 weeks prior to randomization
• History of or currently active primary or secondary immunodeficiency, including known history of HIV infection and other severe Immunodeficiency blood disorders
• Known active infection of any kind (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV anti-infectives within 4 weeks prior to screening, or completion of oral anti-infectives within 2 weeks prior to randomization; entry into this study may be reconsidered once the infection has fully resolved.
•History of or current cancer, including solid tumors, hematologic malignancies, and carcinoma in situ (except basal cell carcinoma and squamous cell carcinoma of the skin that have been excised and cured.)
•Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 24 weeks prior to screening
•Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery
•Treatment with rituximab or a B cell-targeted therapy (e.g., anti-CD20, anti CD22, or anti-BLyS) within 12 months prior to randomization
•Treatment with a live or attenuated vaccine within 28 days prior to randomization; it is recommended that a patient?s vaccination record and the need for immunization prior to study entry be carefully investigated.
•Evidence of abnormal liver (AST, ALT) and pancreatic (amylase) enzymes or

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Pemphigus Vulgaris (PV)
MedDRA version: 20.0 Level: LLT Classification code 10052802 Term: Pemphigus vulgaris System Organ Class: 100000004858

Therapeutic area: Diseases [C] - Skin and Connective Tissue Diseases [C17]

Intervention(s)

Trade Name: MABTHERA®
Product Name: Rituximab
Product Code: RO0452294/V02
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Current Sponsor code: RO 0452294
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 500mg/50ml-
Pharmaceutical form of the placebo: Concentrate for solution for infusion
Route of administration of the placebo: Intravenous use

Trade Name: CELLCEPT®
Product Name: Mycophenolate mofetil
Product Code: RO1061443/F02
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Mycophenolate mofetil
CAS Number: 128794-94-5
Current Sponsor code: RO1061443/F02
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: - To evaluate the efficacy of rituximab compared with MMF in achieving sustained complete remission, evaluated by the Pemphigus Disease Area Index (PDAI; see Section 3.4.1.1), and assessed at Week 52 in patients with moderate-to-severely active PV
- To evaluate the safety of rituximab compared with MMF with a focus on adverse events and safety laboratory values.

Primary end point(s): Efficacy:
Proportion of patients (excluding telemedicine patients)who achieve a sustained complete remission without experiencing an event that constitutes treatment failure, as measured at Week 52. Sustained complete remission is defined as achieving healing of lesions with no new active lesions (i.e., PDAI activity score of 0) while on 0 mg/day prednisone or equivalent, and maintaining this response for a total of at least 16 consecutive weeks, during the 52-week treatment period.

Secondary Objective: • To evaluate the efficacy of rituximab compared with MMF, as measured by the time to disease flare the duration of sustained complete remission, the total number of disease flares during the treatment period, and the time to initial sustained complete remission
• To assess corticosteroid exposure over 52 wks
• To assess the effect of rituximab compared with MMF on health-related quality of life (HRQoL), as measured by the Dermatology Life Quality Index
• To assess the effect of rituximab compared with MMF on patients’ impression of PV symptoms, as measured by the Patient Global Impression of Change questionnaire
• To assess the effect of rituximab compared with MMF on clinician impression of patients’ PV symptoms, as measured by the Clinician Global Impression of Change questionnaire
• To evaluate corticosteroid-related adverse events in relation to corticosteroid exposure

Timepoint(s) of evaluation of this end point: Week 52

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 1-8: From baseline to Week 52
9-14: From baseline to Week 52 and upon study completion or early withdrawal #9, 11, 12 and 13 during the 48-week safety follow up period

Secondary end point(s): Efficacy:
1. Time to disease flare
2. Duration of sustained complete remission
3. Total number of diseases flares during the treatment period
4. Cumulative oral corticosteroid dose (prednisone or equivalent) over the treatment period
5. Time to sustained complete remission
6. Change in health-related quality of life (HRQoL), as measured by the Dermatology Life Quality Index (DLQI) score from baseline to Week 52
7. Patients' impression of change in PV symptoms as measured by the
Patients' Global Impression of Change (PGIC) score during the treatment
period
8. Clinician impression of change in patients’ PV symptoms as measured by the Clinician Global Impression of Change (CGIC) score during the treatment period

Safety:
9. Frequency of adverse events, including serious adverse events and adverse events leading to discontinuation
10. Vital signs and clinical laboratory test results (including complete blood count and blood chemistry)
11. Incidence of human anti-chimeric antibody (HACA)
12. Circulating B cells, T cells, natural killer (NK) cells, plasma cells, and other leukocytes
13. Plasma Ig levels (total Ig, IgG, IgM, and IgA)
14 Corticosteroid-related adverse events in relation to coticosteroid exposure

Secondary ID(s)

WA29330

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd

Ethics review

Status: Approved
Approval date:
Contact: