A Study to Evaluate the Efficacy and Safety of Rituximab Versus Mycophenolate Mofetil (MMF) in Participants With Pemphigus Vulgaris (PV)
Condition: Pemphigus Vulgaris
MeSH terms: Pemphigus
Intervention: Mycophenolate Mofetil Placebo; Mycophenolate Mofetil; Rituximab; Rituximab Placebo
Intervention description: MMF matching placebo will be administered orally Q12H.; MMF will be administered at a starting dose of 500 milligrams (mg) Q12H and the dose will be titrated to achieve a goal of 1 gram (gm) Q12H.; Rituximab will be administered at a dose of 1000 mg via IV infusion.; Rituximab matching placebo will be administered via IV infusion.
Intervention MeSH terms: Mycophenolic Acid; Rituximab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 135.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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

          -  Agreement to avoid excessive exposure to sunlight during study participation

          -  Able to comply with the study protocol, in the investigator's judgment

        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

          -  Any concomitant condition that required treatment with oral or systemic
             corticosteroids within 12 weeks prior to randomization

          -  Treatment with intravenous (IV) immunoglobulin (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 complete excision of basal cell of the skin and squamous
             cell carcinoma of the skin that have been treated or 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-cluster of
             differentiation [CD] 20 [CD20], anti CD22, or anti-B-lymphocyte stimulator [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 participant's vaccination record and the need for immunization
             prior to study entry be carefully investigated

          -  Evidence of abnormal liver enzymes or hematology laboratory values

          -  Positive test results for hepatitis B surface antigen (HBsAg), hepatitis B core
             antibody (HBcAb), or hepatitis C virus (HCV) serology at screening