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Efficacy and Safety of Ofatumumab in Treatment of Pemphigus Vulgaris

This study has been terminated.
(Novartis has acquired the rights to ofatumumab and terminated the OPV116910 and OPV117059 studies. This decision is not linked to any safety consideration.)
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline ( Stiefel, a GSK Company )
ClinicalTrials.gov Identifier:
NCT01920477
First received: July 3, 2013
Last updated: May 12, 2016
Last verified: May 2016
  Purpose

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 is 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 is 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 will result.


Condition Intervention Phase
Pemphigus
Biological: Ofatumumab
Biological: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Time to sustained remission on minimal steroid therapy [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: No ]
    Time from randomization to the time of the subject's initial reduction of prednisone/prednisolone dose to <=10 mg/day and maintained a dose <=10 mg/day with no new or nonhealing (established) lesions for >=8 weeks and maintained the status until Week 60 will be assessed

  • Duration of remission on minimal steroid therapy [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: No ]
    Sum of all periods of absence of new or nonhealing (established) lesions while on an oral prednisone/prednisolone dose of <=10 mg/day up to Week 60 will be assessed.


Secondary Outcome Measures:
  • Proportion of subjects achieving remission on minimal steroid therapy at Week 60 [ Time Frame: Week 60 ] [ Designated as safety issue: No ]
    Proportion of subjects achieving absence of new or nonhealing (established) lesions while on an oral prednisone/prednisolone dose of <=10 mg/day at Week 60 will be assessed.

  • Time to remission while on minimal steroid therapy by Week 60. [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: No ]
    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 (established) lesions for >=8 weeks by Week 60 will be assessed

  • Time to remission off steroid therapy by Week 60 [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: No ]
    Time from randomization to the time of the subjects initial reduction of all steroids for >=8 weeks with an absence of new or nonhealing (established) lesions by Week 60 will be assessed

  • Proportion of subjects achieving remission while off steroid therapy by Week 60 [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: No ]
    Proportion of subjects with initial reduction of all steroids for >=8 weeks with an absence of new or nonhealing (established) lesions by Week 60 will be assessed

  • Number of days a subject maintained minimal steroid therapy by Week 60. [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: No ]
    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.

  • Time to initial flare/relapse by Week 60 [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: No ]
    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 will be assessed

  • Proportion of subjects with no flare/relapse by Week 60 [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: No ]
    Proportion of subjects achieving absence of new or nonhealing (established) 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 will be assessed

  • Cumulative dose of corticosteroids [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: Yes ]
    Exposure to corticosteroids over a period of 60 weeks will be assessed

  • Change from Baseline in B-lymphocyte counts in peripheral blood [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: No ]
    Change from Baseline in B-lymphocyte counts in peripheral blood at prespecified time points (Day 0 and every four weeks till Week 60) and at the time of any opportunistic infection will be assessed

  • Time to repletion of CD19+ B-cells to either >=Baseline level or >=Lower Limit of Normal (LLN) , whichever [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Time to repletion of CD19+ B-cells to either >=Baseline level (observation at Week 0) or >=LLN (110 cell/mcgL), whichever is lower will be assessed

  • Composite of population pharmacokinetics (PK) of ofatumumab [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: No ]
    Plasma (trough) concentrations of ofatumumab, Exposure-response relationship, PK parameters include: Maximum concentration (Cmax); time to maximum concentration (tmax); and area under the time-concentration curve (AUC).

  • Immunogenicity of ofatumumab [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: Yes ]
    Immunogenicity will be assessed by the incidence, titer, and type of human anti-human antibody (HAHA) immune response

  • Safety and tolerability of ofatumumab assessed by Adverse events (AEs). [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: Yes ]
    AEs assessment include: Frequency and severity of AE, AE relationship to IP, frequency and severity of SAE, AE of special interest, Frequency and severity of infections, Percentage of subject withdrawals due to treatment-related AEs, AEs leading to permanent discontinuation of study drug, Postinjection systemic reactions, Injection site reactions

  • Change from Baseline in Vital signs [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: Yes ]
    Vital signs include: pulse rate, temperature, systolic and diastolic blood pressure.

  • Change from Baseline in laboratory parameters [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: Yes ]
    Laboratory parameters include: hematology, clinical chemistry, and urinalysis

  • Effect of demographic factors, including Baseline covariates on PK parameters of ofatumumab as data permits. [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: No ]
    Demographic factors such as age, race, and sex.

  • Frequency of Vital signs of Clinical Concern [ Time Frame: Up to 60 weeks ] [ Designated as safety issue: Yes ]
    Vital signs of Clinical Concern are a subset based on pre-defined levels.


Enrollment: 35
Study Start Date: August 2013
Estimated Study Completion Date: May 2021
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ofatumumab
Subject will receive 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) will be provided in prefilled glass syringes containing 0.4 milliliters (mL) (20 mg) of concentration 50 mg/mL drug product
Placebo Comparator: Placebo
Subject will receive 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 containing 0.4 mL of normal saline.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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; Is of childbearing potential, defined as a woman who has functional ovaries, ducts, and a uterus with no documented impairment that would cause sterility. This includes women with oligomenorrhea (even severe), women who are perimenopausal, and women who have just begun to menstruate. Subject must have a negative serum pregnancy test at screening and must agree to the consistent and correct use of acceptable methods of contraception during heterosexual intercourse, beginning when the subject provides informed consent and lasting until 12 months after last dose of investigational product.

Acceptable methods of contraception are limited to the oral contraceptives (either combined or progesterone only), injectable progesterone, levonorgestrel implants, estrogenic vaginal ring, percutaneous contraceptive patches, intrauterine device or intrauterine system with a documented failure rate of <1% per year, male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study; this male must be the subject's sole partner, double barrier method (condom and an occlusive cap [diaphragm or cervical/vault caps] with a vaginal spermicidal agent [foam/gel/film/cream/suppository]) and complete abstinence from heterosexual intercourse, For Japan subjects, in the list of acceptable methods of contraception, the following methods are not applicable in Japan: oral contraceptives with progestogen alone, injectable progesterone, levonorgestrel implants, estrogenic vaginal ring, percutaneous contraceptive patches, vaginal spermicidal foam, gel, film, and cream French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

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 with any of the following within the specified periods: any time: ofatumumab, total body irradiation, bone marrow transplantation, anti-CD4 ; within 2 weeks: systemic steroids (except for prednisone/prednisolone) ; within 6 weeks: live vaccine ; within 8 weeks: azathioprine, cyclosporine, dapsone, mycophenolate, methotrexate and tacrolimus; within 6 months:cladribine, cyclophosphamide, plasmapheresis, immunoabsorption or immunoglobulin therapy, alemtuzumab, mitoxantrone; and within 18 months: Rituximab or other drugs affecting the number and function of B-cells- Confirmed progressive multifocal leukoencephalopathy (PML), or neurological findings potentially consistent with PML
  • Evidence or history of clinically significant infection including: Chronic or ongoing active infectious disease requiring long term systemic treatment, including, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, or active hepatitis C; Positive test for hepatitis B surface antigen (HBsAg). For HBsAg negative, but hepatitis B core antibody (anti-HBc/HBcAb positive (regardless of hepatitis B surface antibody [HbsAb] status), an HBV deoxyribonucleic acid (DNA) test will be performed and the subject will be excluded if results are positive; Consult with a physician experienced in the care and management of subjects with hepatitis B to manage/treat subjects who are anti-HBc positive; History of positive serology for human immunodeficiency virus; Previous serious opportunistic or atypical infections; Prior history, or suspicion, of tuberculosis (TB);

For Japan: Evidence or history of clinically significant infection or medical condition including: Pneumocystis pneumonia or interstitial pneumonia (based on results of screening posterior-anterior chest X-ray, KL-6, and beta-D glucan). Order these tests from a local laboratory during screening and as part of a work-up for a subject with signs or symptoms of potential concern during the study; Based on the Japanese Guideline for Hepatitis B, for subjects who are HBsAg negative, anti-HBc (HBcAb) negative, but HBsAb positive, an HBV DNA test will be performed and the subject will be excluded from the study if results are positive; If any of the following criteria for TB screening are met:Past medical history for latent or active TB before screening; Sign(s) or symptom(s) suggestive of active TB in medical history on examination; Recent close contact with a patient with active TB; Positive interferon-gamma release assay or tuberculin skin test within 1 month before the first dose of study treatment; Chest x-ray, taken within 3 months before first dose of study treatment, shows evidence indicating currently active or previous TB.

For South Korea: Evidence or history of clinically significant infection including: For subjects who are HBsAg negative, anti-HBc (HBcAb) negative, but HBsAb positive, an HBV DNA test will be performed and the subject will be excluded from the study if results are positive; If any of the following criteria for TB screening are met: Past medical history for latent or active TB before screening, Sign(s) or symptom(s) suggestive of active TB in medical history on examination; Recent close contact with a patient with active TB; Positive interferon-gamma release assay or tuberculin skin test within 1 month before the first dose of study treatment; Chest x-ray, taken within 3 months before first dose of study treatment, shows evidence indicating currently active or previous TB.

  • 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).
  • White blood cells (WBC) <3.8 GI/L (<3800/mm^3), neutrophils <2 GI/L (<2000/mm^3), platelets <130 GI/L (130,000/mm^3), circulating IgG, IgA, or IgM levels <10% of the LLN and requiring treatment in the opinion of the investigator, alanine aminotransferase (ALT) >2.0 times the upper limit of normal (ULN), aspartate aminotransferase (AST) >2.0 X ULN, alkaline phosphatase (ALP) >1.5 X ULN, bilirubin >1.5 X ULN (except in cases of isolated predominantly indirect hyperbilirubinemia due to Gilbert's syndrome).
  • 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) (ECG to be obtained during Screening/prior to receiving the first dose of study drug).
  • Woman who is breastfeeding.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01920477

  Show 39 Study Locations
Sponsors and Collaborators
Stiefel, a GSK Company
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Responsible Party: Stiefel, a GSK Company
ClinicalTrials.gov Identifier: NCT01920477     History of Changes
Other Study ID Numbers: 116910 
Study First Received: July 3, 2013
Last Updated: May 12, 2016
Health Authority: United States: Food and Drug Administration
Japan: PMDA (Pharmaceuticals and Medical Devices Agency)
Europe: European Medicines Agency

Keywords provided by GlaxoSmithKline:
Pemphigus
(MAB)
autoimmune disorder
human CD20 antigen
subcutaneous
Pemphigus vulgaris
Phase 3
monoclonal antibody
ofatumumab
PV
rare disease

Additional relevant MeSH terms:
Pemphigus
Skin Diseases, Vesiculobullous
Skin Diseases
Autoimmune Diseases
Immune System Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 28, 2016