Clinical trial NCT02383589: A Study to Evaluate the Efficacy and Safety of Rituximab Versus Mycophenolate Mofetil (MMF) in Participants With Pemphigus Vulgaris (PV)
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pemphigus Vulgaris
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: Genentech, Inc.
First posted: 2015-03-09
Enrollment: 135
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Percentage of Participants (Excluding Telemedicine [TM] Participants) Who Achieved Sustained Complete Remission, Evaluated by the Pemphigus Disease Area Index (PDAI) Activity Score
timeFrame: From Baseline up to 52 Weeks (up to clinical cut-off date (CCOD) of 28 November 2018)
Secondary outcomes:
measure: Cumulative Oral Corticosteroid Dose
timeFrame: From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
measure: Total Number of Protocol Defined Disease Flares
timeFrame: From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
measure: Time to Initial Sustained Complete Remission
timeFrame: From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
measure: Time to Protocol Defined Disease Flare
timeFrame: From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
measure: Change in Health-Related Quality of Life (HRQoL), as Measured by the Dermatology Life Quality Index (DLQI) Score
timeFrame: From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
measure: Percentage of Participants With Adverse Events, Serious Adverse Events, and Corticosteroid-Related Adverse Events
timeFrame: Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
measure: Percentage of Participants With Anti-Drug Antibodies (ADA)
timeFrame: Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
measure: Percentage of Participants With Immunoglobulin (Ig) Levels Below Lower Limit of Normal (LLN)
timeFrame: Baseline; Weeks 16, 24, 40 and 52; (end of treatment: up to Week 52) (up to CCOD of 28 November 2018)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Birmingham
state: Alabama
city: Tucson
country: United States
facility: University of Arizona Medical Research Office
state: Arizona
city: Sacramento
country: United States
facility: UC Davis Department of Dermatology
state: California
city: San Francisco
country: United States
facility: Univ of Calif-San Francisco
state: California
city: Torrance
country: United States
facility: Los Angeles Biomedical Research Institute
state: California
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital Dermatology
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: St Louis University Hospital
state: Missouri
city: Buffalo
country: United States
facility: Uni of NY and Roswell Cancer
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Hospital Center for Dermatology Research
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences Uni
state: Oregon
city: Philadelphia
country: United States
facility: Penn University
state: Pennsylvania
city: Buenos Aires
country: Argentina
facility: Hospital Italiano
city: Florencio Varela
country: Argentina
facility: Centro de Investigaciones Médicas - CIM
city: Mendoza
country: Argentina
facility: Hospital Luis Lagomaggiore
city: Pilar, Pcia De Buenos Aires
country: Argentina
facility: Hospital Austral
city: Kogarah, New South Wales
country: Australia
facility: St George Hospital
state: New South Wales
city: Woolloongabba
country: Australia
facility: Veracity Clinical Research
state: Queensland
city: Botucatu
country: Brazil
facility: Faculdade de Medicina de Botucatu - Hospital das Clínicas
state: SP
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas - FMUSP
state: SP
city: São Paulo
country: Brazil
facility: Santa Casa de São Paulo Hospital Central X
state: SP
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Surrey
country: Canada
facility: Guildford Dermatology
state: British Columbia
city: Markham
country: Canada
facility: Lynde Institute for Dermatology
state: Ontario
city: Bobigny
country: France
facility: Department of Dermatology Avicenne Hospital & University
city: CHU Hopitaux De Bordeaux
country: France
facility: CHU Hopitaux de Bordeaux
city: Lille
country: France
facility: Centre Hospitalier Régional Universitaire de Lille (CHRU) - Hôpital Claude Huriez
city: Lyon / Pierre Bénite
country: France
facility: Les Hospices Civils de Lyon Dermatologie inflammatoire et médecine interne
city: Reims
country: France
facility: CHU de Reims
city: Rennes
country: France
facility: CHU de Rennes - Hopital de Pontchaillo
city: Rouen
country: France
facility: CHU de Rouen - Hôpital Charles Nicolle
city: Saint Etienne
country: France
facility: CHU Saint Etienne - Hôpital Nord
city: Dresden
country: Germany
facility: University Hospital for Dermatology
city: Freiburg
country: Germany
facility: Kompetenzzentrum Fragile Haut Klinik fur Dermatologie und Venerologie
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Koeln
country: Germany
facility: Klinik und Poliklinik für Dermatologie und Venerologie Universitätsklinikum Köln
city: Lübeck
country: Germany
facility: University Hospital Schleswig-Holstein
city: Mainz
country: Germany
facility: Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR, Hautklinik und Poliklinik
city: Muenster
country: Germany
facility: University of Munster
city: Afula
country: Israel
facility: HaEmek MC
city: Haifa
country: Israel
facility: Rambam Medical Centre; Dept. of Dermatology
city: Petach Tikva
country: Israel
facility: Rabin Medical Centre; Dept. of Dermatology
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
city: Tel-Aviv
country: Israel
facility: Sourasky Medical Centre
city: Florence
country: Italy
facility: Ambulatorio di Malattie Rare e Immunopatologia Cutanea
state: Lazio
city: Parma
country: Italy
facility: Università di Parma Clinica Dermatologica
state: Lazio
city: Pavia
country: Italy
facility: U.O. Dermatologia Dipartimento Malattie Infettive Fondazione IRCCS Policlinico San Matteo
state: Lazio
city: Rome
country: Italy
facility: Centro Clinico per le genodermatosi Dipartimento di Dermatologia dell'Immacolata - IRCCS
state: Lazio
city: Turin
country: Italy
facility: S.C. Dermatologia 2 - Ambulatorio Malattie Rare
state: Lazio
city: Brescia
country: Italy
facility: ASST DEGLI SPEDALI CIVILI DI BRESCIA; Clinica Dermatologica
state: Lombardia
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Clínic. Barcelona
city: Madrid
country: Spain
facility: Hosp. G. U Gregorio Marañón
city: Malaga
country: Spain
facility: Hospital de la Victoria
city: Ankara
country: Turkey
facility: Gülhane Military Medical Academy in Ankara
city: Antalya
country: Turkey
facility: Akdeniz University Medical Faculty
city: Gaziantep
country: Turkey
facility: Gaziantep University Medical Faculty Sahinbey Hospital
city: Istanbul
country: Turkey
facility: Bezm-i Alem University Medical Faculty
city: Istanbul
country: Turkey
facility: Istanbul Uni Istanbul Medical Faculty
city: Istanbul
country: Turkey
facility: Haydarpasa Numune Training and Research Hospital
city: Istanbul
country: Turkey
facility: Marmara Uni
city: Manisa
country: Turkey
facility: Celal Bayar University Medical Faculty Hafsa Sultan Hospital
city: Trabzon
country: Turkey
facility: Karadeniz Teknik Üniversitesi Tıp Fakültesi Farabi Hastanesi
city: Dnipropterovsk
country: Ukraine
facility: Dnipropetrovsk State Medical Academy
city: Kyiv
country: Ukraine
facility: Territorial Medical Association "Dermatovenerologia"
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Werth VP, Joly P, Mimouni D, Maverakis E, Caux F, Lehane P, Gearhart L, Kapre A, Pordeli P, Chen DM; PEMPHIX Study Group. Rituximab versus Mycophenolate Mofetil in Patients with Pemphigus Vulgaris. N Engl J Med. 2021 Jun 17;384(24):2295-2305. doi: 10.1056/NEJMoa2028564. Epub 2021 May 19.