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

Pemphigus Vulgaris Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02383589
• Other study ID #: WA29330
• Secondary ID: 2014-000382-41
• Status: Completed
• Phase: Phase 3
• 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
• 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

Related Conditions & MeSH terms

• Pemphigus
• Pemphigus Vulgaris

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)