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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02383589
Other study ID # WA29330
Secondary ID 2014-000382-41
Status Completed
Phase Phase 3
First received
Last updated
Start date May 26, 2015
Est. completion date October 29, 2019

Study information

Verified date October 2020
Source Hoffmann-La Roche
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


Recruitment information / eligibility

Status Completed
Enrollment 135
Est. completion date October 29, 2019
Est. primary completion date November 28, 2018
Accepts healthy volunteers No
Gender All
Age group 18 Years to 75 Years
Eligibility 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

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Mycophenolate Mofetil Placebo
MMF matching placebo will be administered orally Q12H.
Mycophenolate Mofetil
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
Rituximab will be administered at a dose of 1000 mg via IV infusion.
Rituximab Placebo
Rituximab matching placebo will be administered via IV infusion.

Locations

Country Name City State
Argentina 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
Australia St George Hospital Kogarah, New South Wales New South Wales
Australia Veracity Clinical Research Woolloongabba Queensland
Brazil 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
Canada University of Alberta Edmonton Alberta
Canada Lynde Institute for Dermatology Markham Ontario
Canada Guildford Dermatology Surrey British Columbia
France 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 Les Hospices Civils de Lyon Dermatologie inflammatoire et médecine interne Lyon / Pierre Bénite
France CHU de Reims Reims
France CHU de Rennes - Hopital de Pontchaillo Rennes
France CHU de Rouen - Hôpital Charles Nicolle Rouen
France CHU Saint Etienne - Hôpital Nord Saint Etienne
Germany University Hospital for Dermatology Dresden
Germany 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
Israel 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
Italy ASST DEGLI SPEDALI CIVILI DI BRESCIA; Clinica Dermatologica Brescia Lombardia
Italy Ambulatorio di Malattie Rare e Immunopatologia Cutanea Florence Lazio
Italy Università di Parma Clinica Dermatologica Parma 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
Spain Hospital Clínic. Barcelona Barcelona
Spain Hosp. G. U Gregorio Marañón Madrid
Spain Hospital de la Victoria Malaga
Spain Clinica Universitaria de Navarra Pamplona Navarra
Turkey Gülhane Military Medical Academy in Ankara Ankara
Turkey Akdeniz University Medical Faculty Antalya
Turkey Gaziantep University Medical Faculty Sahinbey Hospital Gaziantep
Turkey Bezm-i Alem University Medical Faculty Istanbul
Turkey Haydarpasa Numune Training and Research Hospital Istanbul
Turkey Istanbul Uni Istanbul Medical Faculty Istanbul
Turkey Marmara Uni Istanbul
Turkey Celal Bayar University Medical Faculty Hafsa Sultan Hospital Manisa
Turkey Karadeniz Teknik Üniversitesi Tip Fakültesi Farabi Hastanesi Trabzon
Ukraine Dnipropetrovsk State Medical Academy Dnipropterovsk
Ukraine Territorial Medical Association "Dermatovenerologia" Kyiv
United States University of Alabama Birmingham Birmingham Alabama
United States Massachusetts General Hospital Dermatology Boston Massachusetts
United States Uni of NY and Roswell Cancer Buffalo New York
United States Northwestern University Chicago Illinois
United States Cleveland Clinic Cleveland Ohio
United States University of Minnesota Minneapolis Minnesota
United States Icahn School of Medicine at Mount Sinai New York New York
United States Penn University Philadelphia Pennsylvania
United States Oregon Health Sciences Uni Portland Oregon
United States UC Davis Department of Dermatology Sacramento California
United States St Louis University Hospital Saint Louis Missouri
United States Univ of Calif-San Francisco San Francisco California
United States Los Angeles Biomedical Research Institute Torrance California
United States University of Arizona Medical Research Office Tucson Arizona
United States Wake Forest Baptist Hospital Center for Dermatology Research Winston-Salem North Carolina

Sponsors (2)

Lead Sponsor Collaborator
Hoffmann-La Roche Genentech, Inc.

Countries where clinical trial is conducted

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

Outcome

Type Measure Description Time frame Safety issue
Primary 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 Cumulative Oral Corticosteroid Dose From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
Secondary Total Number of Protocol Defined Disease Flares 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. From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
Secondary Time to Initial Sustained Complete Remission From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
Secondary Time to Protocol Defined Disease Flare 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. From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
Secondary Change in Health-Related Quality of Life (HRQoL), as Measured by the Dermatology Life Quality Index (DLQI) Score 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. From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
Secondary Percentage of Participants With Adverse Events, Serious Adverse Events, and Corticosteroid-Related Adverse Events 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. Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
Secondary Percentage of Participants With Anti-Drug Antibodies (ADA) 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. Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
Secondary 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)
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