A Study to Evaluate the Efficacy and Safety of Rituximab Versus Mycophenolate Mofetil (MMF) in Participants With Pemphigus Vulgaris (PV)

NCT ID: NCT02383589

Last Updated: 2020-11-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 135 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-05-26
• Study Completion Date: 2019-10-29

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.

Conditions

Pemphigus Vulgaris

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Mycophenolate Mofetil

Intervention Type: DRUG

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 Placebo

Intervention Type: DRUG

Rituximab matching placebo will be administered via IV infusion.

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.

Group Type: EXPERIMENTAL

Mycophenolate Mofetil Placebo

Intervention Type: DRUG

MMF matching placebo will be administered orally Q12H.

Rituximab

Intervention Type: DRUG

Rituximab will be administered at a dose of 1000 mg via IV infusion.

Interventions

Mycophenolate Mofetil Placebo

MMF matching placebo will be administered orally Q12H.

Intervention Type: DRUG

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.

Intervention Type: DRUG

Rituximab

Rituximab will be administered at a dose of 1000 mg via IV infusion.

Intervention Type: DRUG

Rituximab Placebo

Rituximab matching placebo will be administered via IV infusion.

Intervention Type: DRUG

Other Intervention Names

MMF, CellCept; MabThera/Rituxan; MabThera/Rituxan

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: collaborator

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

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

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

Massachusetts General Hospital Dermatology

Boston, Massachusetts, United States

University of Minnesota

Minneapolis, Minnesota, United States

St Louis University Hospital

St Louis, Missouri, United States

Uni of NY and Roswell Cancer

Buffalo, New York, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Wake Forest Baptist Hospital Center for Dermatology Research

Winston-Salem, North Carolina, United States

Cleveland Clinic

Cleveland, Ohio, United States

Oregon Health Sciences Uni

Portland, Oregon, United States

Penn University

Philadelphia, Pennsylvania, United States

Hospital Italiano

Buenos Aires, , Argentina

Hospital Luis Lagomaggiore

Mendoza, , Argentina

Hospital Austral

Pilar, Pcia de Buenos Aires, , Argentina

Centro de Investigaciones Médicas - CIM

San Juan Bautista, , 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, São Paulo, Brazil

Santa Casa de São Paulo Hospital Central X

São Paulo, São Paulo, Brazil

Hospital das Clinicas - FMUSP

São Paulo, São Paulo, 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

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, , France

Klinik und Poliklinik für Dermatologie und Venerologie Universitätsklinikum Köln

Cologne, , Germany

University Hospital for Dermatology

Dresden, , Germany

Kompetenzzentrum Fragile Haut Klinik fur Dermatologie und Venerologie

Freiburg im Breisgau, , Germany

Universitätsklinikum Heidelberg

Heidelberg, , Germany

University Hospital Schleswig-Holstein

Lübeck, , Germany

Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR, Hautklinik und Poliklinik

Mainz, , Germany

University of Munster

Münster, , Germany

HaEmek MC

Afula, , Israel

Rambam Medical Centre; Dept. of Dermatology

Haifa, , Israel

Rabin Medical Centre; Dept. of Dermatology

Petah Tikva, , Israel

Sheba Medical Center

Ramat Gan, , Israel

Sourasky Medical Centre

Tel Aviv, , Israel

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, Italy

ASST DEGLI SPEDALI CIVILI DI BRESCIA; Clinica Dermatologica

Brescia, Lombardy, Italy

Clinica Universitaria de Navarra

Pamplona, Navarre, Spain

Hospital Clínic. Barcelona

Barcelona, , Spain

Hosp. G. U Gregorio Marañón

Madrid, , Spain

Hospital de la Victoria

Málaga, , Spain

Gülhane Military Medical Academy in Ankara

Ankara, , Turkey (Türkiye)

Akdeniz University Medical Faculty

Antalya, , Turkey (Türkiye)

Gaziantep University Medical Faculty Sahinbey Hospital

Gaziantep, , Turkey (Türkiye)

Bezm-i Alem University Medical Faculty

Istanbul, , Turkey (Türkiye)

Istanbul Uni Istanbul Medical Faculty

Istanbul, , Turkey (Türkiye)

Haydarpasa Numune Training and Research Hospital

Istanbul, , Turkey (Türkiye)

Marmara Uni

Istanbul, , Turkey (Türkiye)

Celal Bayar University Medical Faculty Hafsa Sultan Hospital

Manisa, , Turkey (Türkiye)

Karadeniz Teknik Üniversitesi Tıp Fakültesi Farabi Hastanesi

Trabzon, , Turkey (Türkiye)

Dnipropetrovsk State Medical Academy

Dnipropterovsk, , Ukraine

Territorial Medical Association "Dermatovenerologia"

Kyiv, , Ukraine

Countries

United States; Argentina; Australia; Brazil; Canada; France; Germany; Israel; Italy; Spain; Turkey (Türkiye); Ukraine

References

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.

Reference Type: DERIVED

PMID: 34097368 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2014-000382-41

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

WA29330

Identifier Type: -

Identifier Source: org_study_id