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
Overview
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 135
- Locations
- 68
- Primary Endpoint
- Percentage of Participants (Excluding Telemedicine [TM] Participants) Who Achieved Sustained Complete Remission, Evaluated by the Pemphigus Disease Area Index (PDAI) Activity Score
Overview
Brief Summary
This is a Phase III, randomized, double-blind, double-dummy, active-comparator, parallel-arm, multicenter study to evaluate the efficacy and safety of rituximab compared with MMF in participants with moderate-to-severely active PV requiring 60-120 milligrams per day (mg/day) oral prednisone or equivalent. Participants must have a confirmed diagnosis of PV within the previous 24 months (by skin or mucosal biopsy and immunohistochemistry) and evidence of active disease at screening.
Approximately 135 participants will be enrolled at up to 60 centers worldwide. Participants will be randomized in a 1:1 ratio to receive either rituximab plus MMF placebo or rituximab placebo plus MMF. Randomization will be stratified by duration of illness.
The study will consist of three periods: a screening period of up to 28 days, a 52-week double-blind treatment period, and a 48-week safety follow up period that begins at the time of study treatment completion or discontinuation.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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 immunoglobulin G (IgG) antibodies by direct immunofluorescence on the surface of affected epithelium or serological detection of serum desmoglein-3 (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 greater than or equal to (\>/=)15
- •Receiving standard-of-care corticosteroids consisting of 60-120 mg/day oral prednisone or equivalent 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 less than (\<) 1 percent (%) 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 participant. 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 participant
- •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
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 results with a sensitivity of \>/=25 milli-international units per milliliter (mIU/mL): one from a serum pregnancy test at Day -8 to Day -10 of screening and another from a 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 participant participation, including but not limited to nervous system, renal, hepatic, endocrine, malignant, or gastrointestinal disorders
Arms & Interventions
Mycophenolate Mofetil (MMF)
Participants will receive MMF orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants will also receive rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria have been met.
Intervention: Mycophenolate Mofetil (Drug)
Mycophenolate Mofetil (MMF)
Participants will receive MMF orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants will also receive rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria have been met.
Intervention: Rituximab Placebo (Drug)
Rituximab (RTX)
Participants will receive rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria have been met. Participants will also receive MMF matching placebo orally twice daily Q12H from Day 1 to Week 52.
Intervention: Mycophenolate Mofetil Placebo (Drug)
Rituximab (RTX)
Participants will receive rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria have been met. Participants will also receive MMF matching placebo orally twice daily Q12H from Day 1 to Week 52.
Intervention: Rituximab (Drug)
Outcomes
Primary Outcomes
Percentage of Participants (Excluding Telemedicine [TM] Participants) Who Achieved Sustained Complete Remission, Evaluated by the Pemphigus Disease Area Index (PDAI) Activity Score
Time Frame: From Baseline up to 52 Weeks (up to clinical cut-off date (CCOD) of 28 November 2018)
Secondary Outcomes
- Time to Protocol Defined Disease Flare(From Baseline up to 52 Weeks (up to CCOD of 28 November 2018))
- Change in Health-Related Quality of Life (HRQoL), as Measured by the Dermatology Life Quality Index (DLQI) Score(From Baseline up to 52 Weeks (up to CCOD of 28 November 2018))
- Percentage of Participants With Immunoglobulin (Ig) Levels Below Lower Limit of Normal (LLN)(Baseline; Weeks 16, 24, 40 and 52; (end of treatment: up to Week 52) (up to CCOD of 28 November 2018))
- Percentage of Participants With Adverse Events, Serious Adverse Events, and Corticosteroid-Related Adverse Events(Baseline up to 52 Weeks (up to CCOD of 28 November 2018))
- Time to Initial Sustained Complete Remission(From Baseline up to 52 Weeks (up to CCOD of 28 November 2018))
- Percentage of Participants With Anti-Drug Antibodies (ADA)(Baseline up to 52 Weeks (up to CCOD of 28 November 2018))
- Cumulative Oral Corticosteroid Dose(From Baseline up to 52 Weeks (up to CCOD of 28 November 2018))
- Total Number of Protocol Defined Disease Flares(From Baseline up to 52 Weeks (up to CCOD of 28 November 2018))