Efficacy and Safety of Ofatumumab in Treatment of Pemphigus Vulgaris

OPV116910: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Investigate the Efficacy and Safety of Ofatumumab Injection for Subcutaneous Use in Subjects With Pemphigus Vulgaris

Pemphigus vulgaris (PV) is a rare, chronic, debilitating, and potentially life-threatening autoimmune disorder that is characterized by mucocutaneous blisters. Ofatumumab is a novel monoclonal antibody (mAb) that specifically binds to the human CD20 antigen, which is expressed only in B lymphocytes.

The purpose of this study was to evaluate the efficacy, tolerability, and safety of ofatumumab injection for subcutaneous use (ofatumumab SC) 20 milligrams (mg) administered once in every 4 weeks, (with an additional 20 mg loading dose [i.e. 40 mg total] at both Week 0 and Week 4) in subjects with PV. It was anticipated that with sustained B-cell depletion in the presence of ofatumumab SC, and the resultant reduction of pathogenic anti Dsg (desmoglein) autoantibodies in PV, that clinical remission of the disease would result.

Study Overview

• Status: Terminated
• Conditions: Pemphigus Vulgaris
• Intervention / Treatment: Biological: Ofatumumab; Biological: Placebo

Detailed Description

Novartis terminated the development of the PV program and this study was terminated for non-safety reasons

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • East Melbourne, Victoria, Australia, 3002
      • Novartis Investigational site
    • Melbourne, Victoria, Australia, 3050
      • Novartis Investigational site
• Greece
  • Thessalonica, Greece, 54643
    • Novartis Investigational site
• Israel
  • Ramat-Gan, Israel, 52621
    • Novartis Investigational site
  • Tel Aviv, Israel, 64239
    • Novartis Investigational site
• Italy
  • Lombardia
    • Milano, Lombardia, Italy, 20122
      • Novartis Investigational site
• Japan
  • Tokyo, Japan, 160-8582
    • Novartis Investigational site
• Poland
  • Warszawa, Poland, 02-008
    • Novartis Investigational site
• Romania
  • Cluj-Napoca, Romania, 400006
    • Novartis Investigational site
• United States
  • California
    • Los Angeles, California, United States, 90045
      • Novartis Investigational site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Novartis Investigational site
  • Michigan
    • Ann Arbor, Michigan, United States, 48103
      • Novartis Investigational site
  • New York
    • Buffalo, New York, United States, 14203
      • Novartis Investigational site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Novartis Investigational site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Novartis Investigational site
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Novartis Investigational site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria

• Adults (18 through 70 years of age) with clinically-documented diagnosis of PV for >2 months and <10 years.
• History of biopsy consistent with PV (Hematoxylin and Eosin staining and direct immunofluorescence). If no history, a biopsy may be performed during the Screening Period.
• At least 1 previous episode of a failed steroid taper (ie, disease flare/relapse) at a prednisone/prednisolone dose >10 mg/day. The following criteria must have been met as evidence of disease severity at the time of the failed steroid taper: a) A Pemphigus Severity of Clinical Disease score of moderate (2) or severe (3) (may be historical/retrospective assessment). b) Required a treatment change at the time of the failed steroid taper of at least one of the following: i) A steroid increase to >=20 mg/day OR ii) The addition of immunosuppressive/immunomodulatory agent/treatment OR iii) A dose increase of immunosuppressive/immunomodulatory agent/treatment
• Screening anti-Dsg antibodies consistent with a diagnosis of PV (ie, elevated antiDsg3 antibodies).
• Has initiated and received a stable dose of prednisone/prednisolone from a minimum of 20 mg/day (example: 0.25 mg/kg/day for an 80 kg person) up to a maximum of 120 mg/day or 1.5 mg/kg/day (whichever is higher) for >=2 weeks prior to randomization.
• Has exhibited PV disease control, defined as no new lesions for >=2 weeks.
• A female subject is eligible to enter the study if she: Is of non-child bearing potential, who is either surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or post-hysterectomy) or is postmenopausal without menses for >2 years. Women who are <2 years postmenopausal are required to have menopausal status confirmed by follicle-stimulating hormone (FSH) and estradiol levels at the screening evaluation. If FSH and estradiol levels do not provide confirmation of menopause, subject will be considered to be of childbearing potential.

Exclusion Criteria:

• Diagnosis of pemphigus foliaceus, paraneoplastic pemphigus, or other autoimmune blistering disease (other than pemphigus vulgaris).
• Past or current history of hypersensitivity to components of the investigational product or medically significant adverse effects (including allergic reactions) from cetirizine (or antihistamine equivalent) or paracetamol/acetaminophen.
• Prior treatment with rituximab without achieving disease control within 6 months of initiating rituximab dosing.
• Prior treatment with immunosuppressant or immunomodulation agents within the protocol specified periods
• Evidence or history of clinically significant infections

For Japan: Evidence or history of clinically significant infection or medical condition including: Pneumocystis pneumonia or interstitial pneumonia

• Past or current malignancy, except for cervical carcinoma Stage 1B or less, noninvasive basal cell and squamous cell skin carcinoma and cancer diagnoses with a duration of complete response (remission) >5 years
• Significant concurrent, uncontrolled medical condition that could affect the subject's safety, impair the subject's reliable participation in the study, impair the evaluation of endpoints, or necessitate the use of medication not allowed by the protocol. This includes subjects who require any systemic steroid treatment for a concurrent medical condition (other than pemphigus vulgaris).
• Use of an investigational drug or other experimental therapy within 4 weeks, 5 pharmacokinetic half-lives, or the duration of biological effect (whichever is longer) prior to Screening.
• Electrocardiogram (ECG) showing a clinically significant abnormality or showing a QTc interval ≥450 msec (≥480 msec for subjects with a bundle branch block)
• Woman who is breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ofatumumab; Subject received subcutaneous administration of ofatumumab 20 mg once every 4 weeks through Week 56, with an additional 20 mg dose (that is 40mg total) at both Week 0 and Week 4.	Biological: Ofatumumab; Ofatumumab (human monoclonal antibody) was provided in prefilled glass syringes initial syringes contained 0.6ml (60mg) of concentration 100 mg/m: drug product subsequently modified to 0.4 mL (20mg) concentration (50mg/ML) drug product
PLACEBO_COMPARATOR: Placebo; Subject received subcutaneous administration of matching placebo of ofatumumab once every 4 weeks through Week 56, with an additional dose at both Week 0 and Week 4.	Biological: Placebo; Placebo to match the active doses will consist of prefilled glass syringes filled with normal saline.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects Who Experienced Sustained Remission on Minimal Steroid Therapy	Sustained remission = time from randomization to the time of the subject's initial reduction of prednisone/prednisolone dose to <=10 mg/day and maintenance of a dose <=10 mg/day with no new or nonhealing lesions for >=8 weeks and maintenance of the status until Week 60.	Baseline up to approximately 60 weeks
Duration of Remission on Minimal Steroid Therapy	Sum of all periods of absence of new or nonhealing lesions while on an oral prednisone/prednisolone dose of <=10 mg/day up to Week 60 was assessed.	Baseline up to approximately 60 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects Achieving Remission on Minimal Steroid Therapy at Week 60	Percentage of subjects who achieved absence of new or nonhealing lesions while on an oral prednisone/prednisolone dose of <=10 mg/day for > or = 8 weeks at Week 60 was assessed. Time to remission was not estimable.	Week 60
Time to Remission While on Minimal Steroid Therapy by Week 60.	Time from randomization to the time of the subject's initial reduction of prednisone/prednisolone dose to <=10 mg/day and maintained dose at <=10 mg/day with no new or nonhealing lesions for >=8 weeks by Week 60 was assessed	Baseline up to approximately 60 weeks
Percentage of Subjects Achieving Remission While Off Steroid Therapy by Week 60	Percentage of subjects with initial reduction of all steroids for >=8 weeks with an absence of new or nonhealing (established) lesions by Week 60 were to be assessed. All subjects remained on prednisone/prednisolone so this endpoint could not be analyzed.Time to remission off steroid therapy also could not be analyzed	Baseline up to approximately 60 weeks
Number of Days a Subject Maintained Minimal Steroid Therapy by Week 60.	Number of days a subject maintained minimal steroid therapy (an oral prednisone/prednisolone dose of ≤10 mg/day in the absence of new or nonhealing lesions) by Week 60.	Baseline up to approximately 60 weeks
Time to Initial Flare/Relapse by Week 60	Time from randomization to the time of appearance of >=3 new lesions within 1 month that did not heal spontaneously within 1 week, or to the time when there was an extension of lesions that were present at the randomization by Week 60 was assessed	Baseline up to approximately 60 weeks
Percentage of Participants With no Flare/Relapse by Week 60	Percentage of participants achieving absence of new or nonhealing lesions while on an oral prednisone/prednisolone dose of <=10 mg/day and did not subsequently have a appearance of >=3 new lesions within 1 month that did not heal spontaneously within 1 week, or to the time when there was an extension of lesions that were present at the randomization by Week 60 was assessed	Baseline up to approximately 60 weeks
Plasma Trough Concentrations of Ofatumumab	Only plasma (trough) concentrations of ofatumumab were presented	4 hours post baseline, Days 1-4,7,14, Weeks 4,8,12,16,20,24,36,48,52,56, up to approximately 60 weeks
Number of Participants With Values Below Lower Limit of Normal for Immunoglobulin A	Assessed by the incidence, titer, and type of human anti-human antibody (HAHA) immune response	Baseline up to approximately 60 weeks
Number of Participants With Values Below Lower Limit of Normal for Immunoglobulin G	Assessed by the incidence, titer, and type of human anti-human antibody (HAHA) immune response	Baseline up to approximately 60 weeks
Number of Participants With Values Below Lower Limit of Normal for Immunoglobulin M	Assessed by the incidence, titer, and type of human anti-human antibody (HAHA) immune response	Baseline up to approximately 60 weeks
Largest Mean Decrease From Baseline for Immunoglobulin A, G and M	Immunoglobulins A, G and M were assessed by the incidence, titer, and type of human anti-human antibody (HAHA) immune response	Baseline up to approximately 60 weeks
Change From Baseline for CD19+ B Cell Count	CD19+ B cell count will be performed using Flow Cytometry	Baseline up to approximately 60 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 13, 2013
• Primary Completion (ACTUAL): April 13, 2016
• Study Completion (ACTUAL): January 11, 2018

Study Registration Dates

• First Submitted: July 3, 2013
• First Submitted That Met QC Criteria: August 8, 2013
• First Posted (ESTIMATE): August 12, 2013

Study Record Updates

• Last Update Posted (ACTUAL): June 6, 2019
• Last Update Submitted That Met QC Criteria: May 14, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: adult; OMB157; monoclonal antibody; ofatumumab; subcutaneous; rare disease; Phase 3; PV; vulgaris; Pemphigus; autoimmune disorder; MAB; human CD20 antigen
• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Autoimmune Diseases; Skin Diseases, Vesiculobullous; Pemphigus; Antineoplastic Agents; Ofatumumab
• Other Study ID Numbers: 116910

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No