A Study to Evaluate the Efficacy and Safety of Rituximab Versus Mycophenolate Mofetil (MMF) in Participants With Pemphigus Vulgaris (PV)
- Conditions
- Pemphigus Vulgaris
- Interventions
- Registration Number
- NCT02383589
- Lead Sponsor
- Hoffmann-La Roche
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 135
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Mycophenolate Mofetil (MMF) Rituximab Placebo 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. Rituximab (RTX) Mycophenolate Mofetil Placebo 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. Mycophenolate Mofetil (MMF) Mycophenolate Mofetil 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. Rituximab (RTX) Rituximab 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.
- Primary Outcome Measures
Name Time Method Percentage of Participants (Excluding Telemedicine [TM] Participants) Who Achieved Sustained Complete Remission, Evaluated by the Pemphigus Disease Area Index (PDAI) Activity Score From Baseline up to 52 Weeks (up to clinical cut-off date (CCOD) of 28 November 2018)
- Secondary Outcome Measures
Name Time Method Time to Protocol Defined Disease Flare From Baseline up to 52 Weeks (up to CCOD of 28 November 2018) Disease flare is defined as the appearance of three or more new lesions a month that do not heal spontaneously within 1 week or by the extension of established lesions in a participant who has achieved disease control.
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) Total DLQI scores range from 0 to 30 with higher DLQI scores reflecting greater impairment in a participant's health-related quality of life. The DLQI score is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. The measure type mean is the estimated mean from adjusted MMRM.
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) An adverse event is any untoward medical occurrence in a participant to whom a medicinal product is administered and which does not necessarily have a causal relationship with this treatment. A serious adverse event is an adverse event that results in death or is life-threatening or requires/prolongs hospitalization or results in persistent/significant disability/incapacity or congenital abnormality/birth defect. Adverse events of Grade 3 of higher are severe and life-threatening adverse events CS-related adverse events - causality as determined by the investigator.
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) Participants with treatment-induced and treatment-enhanced anti-drug antibodies. The clinical relevance of anti-rituximab antibody formation in RITUXAN treated pemphigus vulgaris (PV) participants is unclear.
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) Disease flare is defined as appearance of three or more new lesions a month that do not heal spontaneously within 1 week, or by the extension of established lesions, in a participant who has achieved disease control.
Trial Locations
- Locations (68)
Gülhane Military Medical Academy in Ankara
🇹🇷Ankara, Turkey
Hospital de la Victoria
🇪🇸Malaga, Spain
Dnipropetrovsk State Medical Academy
🇺🇦Dnipropterovsk, Ukraine
Gaziantep University Medical Faculty Sahinbey Hospital
🇹🇷Gaziantep, Turkey
Celal Bayar University Medical Faculty Hafsa Sultan Hospital
🇹🇷Manisa, Turkey
Bezm-i Alem University Medical Faculty
🇹🇷Istanbul, Turkey
Akdeniz University Medical Faculty
🇹🇷Antalya, Turkey
Haydarpasa Numune Training and Research Hospital
🇹🇷Istanbul, Turkey
Marmara Uni
🇹🇷Istanbul, Turkey
Territorial Medical Association "Dermatovenerologia"
🇺🇦Kyiv, Ukraine
Hosp. G. U Gregorio Marañón
🇪🇸Madrid, Spain
Istanbul Uni Istanbul Medical Faculty
🇹🇷Istanbul, Turkey
Hospital Clínic. Barcelona
🇪🇸Barcelona, Spain
Karadeniz Teknik Üniversitesi Tıp Fakültesi Farabi Hastanesi
🇹🇷Trabzon, Turkey
University of Alabama Birmingham
🇺🇸Birmingham, Alabama, United States
University of Arizona Medical Research Office
🇺🇸Tucson, Arizona, United States
UC Davis Department of Dermatology
🇺🇸Sacramento, California, United States
Massachusetts General Hospital Dermatology
🇺🇸Boston, Massachusetts, United States
Univ of Calif-San Francisco
🇺🇸San Francisco, California, United States
Los Angeles Biomedical Research Institute
🇺🇸Torrance, California, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Uni of NY and Roswell Cancer
🇺🇸Buffalo, New York, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
St Louis University Hospital
🇺🇸Saint Louis, Missouri, United States
Wake Forest Baptist Hospital Center for Dermatology Research
🇺🇸Winston-Salem, North Carolina, United States
Oregon Health Sciences Uni
🇺🇸Portland, Oregon, United States
Hospital Italiano
🇦🇷Buenos Aires, Argentina
Centro de Investigaciones Médicas - CIM
🇦🇷Florencio Varela, Argentina
Hospital Luis Lagomaggiore
🇦🇷Mendoza, Argentina
Hospital Austral
🇦🇷Pilar, Pcia De Buenos Aires, Argentina
St George Hospital
🇦🇺Kogarah, New South Wales, New South Wales, Australia
Veracity Clinical Research
🇦🇺Woolloongabba, Queensland, Australia
Faculdade de Medicina de Botucatu - Hospital das Clínicas
🇧🇷Botucatu, SP, Brazil
Hospital das Clinicas - FMUSP
🇧🇷Sao Paulo, SP, Brazil
Santa Casa de São Paulo Hospital Central X
🇧🇷São Paulo, SP, Brazil
University of Alberta
🇨🇦Edmonton, Alberta, Canada
Guildford Dermatology
🇨🇦Surrey, British Columbia, Canada
Lynde Institute for Dermatology
🇨🇦Markham, Ontario, Canada
Department of Dermatology Avicenne Hospital & University
🇫🇷Bobigny, France
CHU Hopitaux de Bordeaux
🇫🇷CHU Hopitaux De Bordeaux, France
Centre Hospitalier Régional Universitaire de Lille (CHRU) - Hôpital Claude Huriez
🇫🇷Lille, France
CHU de Reims
🇫🇷Reims, France
CHU de Rennes - Hopital de Pontchaillo
🇫🇷Rennes, France
CHU Saint Etienne - Hôpital Nord
🇫🇷Saint Etienne, France
Les Hospices Civils de Lyon Dermatologie inflammatoire et médecine interne
🇫🇷Lyon / Pierre Bénite, France
CHU de Rouen - Hôpital Charles Nicolle
🇫🇷Rouen, France
Kompetenzzentrum Fragile Haut Klinik fur Dermatologie und Venerologie
🇩🇪Freiburg, Germany
Universitätsklinikum Heidelberg
🇩🇪Heidelberg, Germany
Klinik und Poliklinik für Dermatologie und Venerologie Universitätsklinikum Köln
🇩🇪Koeln, Germany
University Hospital Schleswig-Holstein
🇩🇪Lübeck, Germany
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR, Hautklinik und Poliklinik
🇩🇪Mainz, Germany
University of Munster
🇩🇪Muenster, Germany
HaEmek MC
🇮🇱Afula, Israel
Rambam Medical Centre; Dept. of Dermatology
🇮🇱Haifa, Israel
Rabin Medical Centre; Dept. of Dermatology
🇮🇱Petach Tikva, Israel
Sheba Medical Center
🇮🇱Ramat Gan, Israel
Sourasky Medical Centre
🇮🇱Tel-Aviv, Israel
Università di Parma Clinica Dermatologica
🇮🇹Parma, Lazio, Italy
Ambulatorio di Malattie Rare e Immunopatologia Cutanea
🇮🇹Florence, Lazio, Italy
U.O. Dermatologia Dipartimento Malattie Infettive Fondazione IRCCS Policlinico San Matteo
🇮🇹Pavia, Lazio, Italy
Centro Clinico per le genodermatosi Dipartimento di Dermatologia dell'Immacolata - IRCCS
🇮🇹Rome, Lazio, Italy
S.C. Dermatologia 2 - Ambulatorio Malattie Rare
🇮🇹Turin, Lazio, Italy
ASST DEGLI SPEDALI CIVILI DI BRESCIA; Clinica Dermatologica
🇮🇹Brescia, Lombardia, Italy
Clinica Universitaria de Navarra
🇪🇸Pamplona, Navarra, Spain
University Hospital for Dermatology
🇩🇪Dresden, Germany
Icahn School of Medicine at Mount Sinai
🇺🇸New York, New York, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Penn University
🇺🇸Philadelphia, Pennsylvania, United States