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

NCT02383589 | Completed Phase 3 Results

• 2 other identifiers: WA293302014-000382-41
• Study Type: interventional
• Target: 135
• Locations: 12 countries
• Sites: 68

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• 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)

• Time to Initial Sustained Complete Remission

  From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)

• Time to Protocol Defined Disease Flare

  From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)

• 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)

Study Arms (2)

Mycophenolate Mofetil (MMF)

ACTIVE COMPARATOR

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.

Drug: Mycophenolate Mofetil; Drug: Rituximab Placebo

Rituximab (RTX)

EXPERIMENTAL

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.

Drug: Mycophenolate Mofetil Placebo; Drug: Rituximab

Interventions

Mycophenolate Mofetil Placebo DRUG

MMF matching placebo will be administered orally Q12H.

Rituximab (RTX)

Mycophenolate Mofetil 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.

Also known as: MMF, CellCept

Mycophenolate Mofetil (MMF)

Rituximab DRUG

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

Also known as: MabThera/Rituxan

Rituximab (RTX)

Rituximab Placebo DRUG

Rituximab matching placebo will be administered via IV infusion.

Also known as: MabThera/Rituxan

Mycophenolate Mofetil (MMF)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead
• Genentech, Inc.: collaborator

Study Sites (68)

University of Alabama Birmingham

Birmingham, Alabama, 35294, United States

Location

University of Arizona Medical Research Office

Tucson, Arizona, 85724, United States

Location

UC Davis Department of Dermatology

Sacramento, California, 95816, United States

Location

Univ of Calif-San Francisco

San Francisco, California, 94115, United States

Location

Los Angeles Biomedical Research Institute

Torrance, California, 90502, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Massachusetts General Hospital Dermatology

Boston, Massachusetts, 02114, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

St Louis University Hospital

St Louis, Missouri, 63104, United States

Location

Uni of NY and Roswell Cancer

Buffalo, New York, 14203, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Wake Forest Baptist Hospital Center for Dermatology Research

Winston-Salem, North Carolina, 27104, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Oregon Health Sciences Uni

Portland, Oregon, 97239, United States

Location

Penn University

Philadelphia, Pennsylvania, 19104, United States

Location

Hospital Italiano

Buenos Aires, C1181ACH, Argentina

Location

Hospital Luis Lagomaggiore

Mendoza, 5500, Argentina

Location

Hospital Austral

Pilar, Pcia de Buenos Aires, 1500, Argentina

Location

Centro de Investigaciones Médicas - CIM

San Juan Bautista, 1888, Argentina

Location

St George Hospital

Kogarah, New South Wales, New South Wales, 2217, Australia

Location

Veracity Clinical Research

Woolloongabba, Queensland, 4102, Australia

Location

Faculdade de Medicina de Botucatu - Hospital das Clínicas

Botucatu, São Paulo, 18618-970, Brazil

Location

Santa Casa de São Paulo Hospital Central X

São Paulo, São Paulo, 01221-020, Brazil

Location

Hospital das Clinicas - FMUSP

São Paulo, São Paulo, 05403-000, Brazil

Location

University of Alberta

Edmonton, Alberta, T6G 2G3, Canada

Location

Guildford Dermatology

Surrey, British Columbia, V3R 6A7, Canada

Location

Lynde Institute for Dermatology

Markham, Ontario, L3P 1X2, Canada

Location

Department of Dermatology Avicenne Hospital & University

Bobigny, 93000, France

Location

CHU Hopitaux de Bordeaux

CHU Hopitaux de Bordeaux, 33000, France

Location

Centre Hospitalier Régional Universitaire de Lille (CHRU) - Hôpital Claude Huriez

Lille, 59037, France

Location

Les Hospices Civils de Lyon Dermatologie inflammatoire et médecine interne

Lyon / Pierre Bénite, 69495, France

Location

CHU de Reims

Reims, 51100, France

Location

CHU de Rennes - Hopital de Pontchaillo

Rennes, 35033, France

Location

CHU de Rouen - Hôpital Charles Nicolle

Rouen, 76031, France

Location

CHU Saint Etienne - Hôpital Nord

Saint-Etienne, 42055, France

Location

Klinik und Poliklinik für Dermatologie und Venerologie Universitätsklinikum Köln

Cologne, 50937, Germany

Location

University Hospital for Dermatology

Dresden, 01304, Germany

Location

Kompetenzzentrum Fragile Haut Klinik fur Dermatologie und Venerologie

Freiburg im Breisgau, 79104, Germany

Location

Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

Location

University Hospital Schleswig-Holstein

Lübeck, 23538, Germany

Location

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

Mainz, 55131, Germany

Location

University of Munster

Münster, 48149, Germany

Location

HaEmek MC

Afula, 18341, Israel

Location

Rambam Medical Centre; Dept. of Dermatology

Haifa, 31096, Israel

Location

Rabin Medical Centre; Dept. of Dermatology

Petah Tikva, 49100, Israel

Location

Sheba Medical Center

Ramat Gan, 5262100, Israel

Location

Sourasky Medical Centre

Tel Aviv, 6423906, Israel

Location

Ambulatorio di Malattie Rare e Immunopatologia Cutanea

Florence, Lazio, 50125, Italy

Location

Università di Parma Clinica Dermatologica

Parma, Lazio, Italy

Location

U.O. Dermatologia Dipartimento Malattie Infettive Fondazione IRCCS Policlinico San Matteo

Pavia, Lazio, 27100, Italy

Location

Centro Clinico per le genodermatosi Dipartimento di Dermatologia dell'Immacolata - IRCCS

Rome, Lazio, 00167, Italy

Location

S.C. Dermatologia 2 - Ambulatorio Malattie Rare

Turin, Lazio, 10126, Italy

Location

ASST DEGLI SPEDALI CIVILI DI BRESCIA; Clinica Dermatologica

Brescia, Lombardy, 25123, Italy

Location

Clinica Universitaria de Navarra

Pamplona, Navarre, 31008, Spain

Location

Hospital Clínic. Barcelona

Barcelona, 08036, Spain

Location

Hosp. G. U Gregorio Marañón

Madrid, 28007, Spain

Location

Hospital de la Victoria

Málaga, 29010, Spain

Location

Gülhane Military Medical Academy in Ankara

Ankara, Turkey (Türkiye)

Location

Akdeniz University Medical Faculty

Antalya, 07059, Turkey (Türkiye)

Location

Gaziantep University Medical Faculty Sahinbey Hospital

Gaziantep, Turkey (Türkiye)

Location

Bezm-i Alem University Medical Faculty

Istanbul, 34093, Turkey (Türkiye)

Location

Istanbul Uni Istanbul Medical Faculty

Istanbul, 34093, Turkey (Türkiye)

Location

Haydarpasa Numune Training and Research Hospital

Istanbul, 34668, Turkey (Türkiye)

Location

Marmara Uni

Istanbul, Turkey (Türkiye)

Location

Celal Bayar University Medical Faculty Hafsa Sultan Hospital

Manisa, 45040, Turkey (Türkiye)

Location

Karadeniz Teknik Üniversitesi Tıp Fakültesi Farabi Hastanesi

Trabzon, Turkey (Türkiye)

Location

Dnipropetrovsk State Medical Academy

Dnipropterovsk, Ukraine

Location

Territorial Medical Association "Dermatovenerologia"

Kyiv, 01032, Ukraine

Location

Related Publications (1)

• 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.

  PMID: 34097368 DERIVED

MeSH Terms

Conditions

Pemphigus

Interventions

Mycophenolic Acid; Rituximab

Condition Hierarchy (Ancestors)

Skin Diseases, Vesiculobullous; Skin Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 4, 2015
• First Posted: March 9, 2015
• Study Start: May 26, 2015
• Primary Completion: November 28, 2018
• Study Completion: October 29, 2019
• Last Updated: November 10, 2020
• Results First Posted: January 18, 2020

Record last verified: 2020-10

Locations

BR (3); UA (2); CA (3); AR (4); FR (8); DE (7); AU (2); IL (5); US (15); IT (6); ES (4); TU (9)