Ofatumumab Subcutaneous Administration in Subjects With Relapsing-Remitting Multiple Sclerosis (MIRROR)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01457924
First received: October 20, 2011
Last updated: September 11, 2014
Last verified: August 2014
  Purpose

Ofatumumab is a novel Immunoglobulin 1ĸ ( IgG1ĸ) lytic monoclonal antibody (mAb) that specifically binds to the human Cluster of Differentiation 20 (CD20) antigen of which expression is restricted to B lymphocytes from the pre-B cell stage to the plasmacytoid immunoblast stage only. A recent trial with an anti-CD20 mAb (rituximab) demonstrated that targeting B-cells reduces the number of gadolinium-enhancing (GdE) T1 lesions and the relapse rate in relapsing-remitting multiple sclerosis (RRMS). Ofatumumab has been shown to be both well tolerated and efficacious in several indications, including a small, placebo-controlled trial in RRMS using an intravenous (IV) formulation.

This double-blind, placebo-controlled, parallel-group study will investigate the safety and efficacy of a subcutaneous formulation of ofatumumab in the treatment of subjects with RRMS. The primary objective of the study is to investigate the efficacy as assessed by magnetic resonance imaging. Other objectives will include evaluation of tolerability/safety, dose-response relationship, pharmacokinetics, pharmacodynamics, exposure-response, as well as other clinical endpoints.


Condition Intervention Phase
Multiple Sclerosis
Drug: Ofatumumab 3mg
Drug: Ofatumumab 30mg
Drug: Ofatumumab 60mg
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel-Group, Dose-Ranging Study to Investigate the MRI Efficacy and Safety of Six Months' Administration of Ofatumumab in Subjects With Relapsing-Remitting Multiple Sclerosis (RRMS)

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Cumulative number of new T1 Gadolinium Enhancing (GdE) brain lesions [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Cumulative number of new T1 GdE brain lesions at Week 12 from Screen based on MRI scans at Weeks 4, 8, and 12


Secondary Outcome Measures:
  • Cumulative number of new T1 GdE brain lesions [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    Cumulative number of new T1 GdE brain lesions at Week 24 from Screen based on MRI scans at Weeks 4, 8, 12, 16, 20, and 24

  • Change from Screen in brain volume [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    Change from Screen in brain volume at Week 24 and Week 48

  • Cumulative number of persistent Gd-enhancing brain lesions on T1-weighted MRI [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Gd-enhancing brain lesions on T1-weighted MRI based on MRI scans at Weeks 4, 8, and 12: Cumulative number of persistent lesions at Week 12 from Screen

  • Cumulative number of all Gd-enhancing brain lesions on T1-weighted MRI [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Gd-enhancing brain lesions on T1-weighted MRI based on MRI scans at Weeks 4, 8, and 12: Cumulative number of all lesions at Week 12 (new plus persistent) from Screen

  • Total volume of new Gd-enhancing brain lesions on T1-weighted MRI [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Gd-enhancing brain lesions on T1-weighted MRI based on MRI scans at Weeks 4, 8, and 12: Total volume of new lesions at Week 12 (relative to Screen)

  • Total volume of all Gd-enhancing brain lesionos on T1-weighted MRI [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Gd-enhancing brain lesions on T1-weighted MRI based on MRI scans at Weeks 4, 8, and 12: Total volume of all lesions (new plus persistent)

  • Cumulative number of new and/or newly enlarging T2 lesions [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    T2 lesions based on MRI scans from Screen to Weeks 4, 8, and 12: Cumulative number of new and/or newly enlarging lesions at Week 12

  • Volume of new and/or newly enlarging T2 lesions [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    T2 lesions based on MRI scans from Screen to Weeks 4, 8, and 12: Volume of new and/or newly enlarging T2 lesions at Week 12

  • Cumulative number of new T1 hypointense lesions [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    Cumulative number of new T1 hypointense lesions at Week 24 and Week 48 from Screen

  • Change in volume of T1 hypointense lesions [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    Change from Screen in volume of T1 hypointense lesions at Week 24 and Week 48


Enrollment: 232
Study Start Date: November 2011
Estimated Study Completion Date: May 2016
Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
Placebo and one dose of Ofatumumab 3mg over 24 weeks
Drug: Ofatumumab 3mg
3mg of investigational product
Drug: Placebo
Placebo
Experimental: Cohort 2
Two doses of Ofatumumab 3mg over 24 weeks
Drug: Ofatumumab 3mg
3mg of investigational product
Drug: Placebo
Placebo
Experimental: Cohort 3.1
Two doses of Ofatumumab 30mg over 24 weeks
Drug: Ofatumumab 30mg
30mg of investigational product
Drug: Placebo
Placebo
Experimental: Cohort 3.2
Conditioning dose of Ofatumumab 3mg at randomization, two doses of Ofatumumab 30mg over 24 weeks
Drug: Ofatumumab 3mg
3mg of investigational product
Drug: Ofatumumab 30mg
30mg of investigational product
Drug: Placebo
Placebo
Experimental: Cohort 4.1
Two doses of Ofatumumab 60mg over 24 weeks
Drug: Ofatumumab 60mg
60mg of investigational product
Drug: Placebo
Placebo
Experimental: Cohort 4.2
Conditioning dose of Ofatumumab 3mg at randomization, two doses of Ofatumumab 60mg over 24 weeks
Drug: Ofatumumab 3mg
3mg of investigational product
Drug: Ofatumumab 60mg
60mg of investigational product
Drug: Placebo
Placebo
Experimental: Cohort 5.1
Six doses of Ofatumumab 60mg over 24 weeks
Drug: Ofatumumab 60mg
60mg of investigational product
Drug: Placebo
Placebo
Experimental: Cohort 5.2
Conditioning dose of Ofatumumab 3mg at randomization, six doses of Ofatumumab 60mg over 24 weeks
Drug: Ofatumumab 3mg
3mg of investigational product
Drug: Ofatumumab 60mg
60mg of investigational product

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Able to provide signed, written informed consent to participate in the study
  • 18-55 years of age.
  • Definite diagnosis of MS according to the 2010 revisions of the McDonald diagnostic criteria for MS [Polman, 2011].
  • Subjects do not have any manifestation of another type of MS other than RRMS.
  • Subjects must have a relapsing-remitting course of disease with at least one of the following prior to screening:
  • At least one confirmed relapse within the previous year or
  • At least two confirmed relapses within the previous 2 years or
  • At least one relapse in the previous 2 years, with a GdE brain lesion on an MRI scan in the past year.
  • Expanded Disability Status Scale (EDSS) score of 0-5.5 (inclusive) at screening.
  • Neurologically stable with no evidence of relapse for at least 30 days prior to start of Screening and during the Screening Phase (subjects who relapse during the screening Phase can be re-screened, once the relapse has resolved).
  • A female subject is eligible to enter the study if she is:
  • Of non-childbearing potential
  • Of childbearing potential and NOT pregnant or nursing, has a negative serum pregnancy test at screening, and agrees to one of the following:
  • Complete abstinence from intercourse for the period from consent into the study until 6 months after the last dose of investigational product; or,
  • Consistent and correct use of one of the following acceptable methods of birth control for the period from consent into the study until 6 months after the last dose of investigational product:

Oral contraceptives (either combined or progesterone only) Injectable progesterone Levonorgestrel implants Estrogenic vaginal ring Percutaneous contraceptive patches Intrauterine device (IUD) or intrauterine system (IUS) 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 sole partner for the subject Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository).

A female is considered "Non-childbearing potential" if she is status-post hysterectomy, status-post surgical removal of both ovaries, has current, documented tubal ligation, or is postmenopausal and >2 years without menses. Female subjects who are post-menopausal <2 years must be confirmed menopausal by Follicle Stimulating Hormone (FSH) and estradiol levels.

A female is considered "childbearing potential" if she has functional ovaries, ducts, and uterus with no impairment that would cause sterility. This includes women with oligomenorrhea (even severe), and women who are perimenopausal or who have just begun to menstruate.

  • 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:

  • Unable to undergo MRI scans (e.g. due to pacemaker, severe claustrophobia, hypersensitivity to contrast media, or who lack adequate peripheral venous access).
  • Any clinically significant brain abnormality other than MS found on MRI.
  • Neurological findings consistent with Progressive Multifocal Leukoencephalopathy (PML) or confirmed PML (see Appendix 4, Section 11.4, for PML monitoring algorithm).
  • Subjects whom experience a relapse during the Screening Phase. These subjects may be eligible for re-screening after consultation with GlaxoSmithKline (GSK).
  • History of clinically significant Central Nervous System (CNS) trauma (e.g. traumatic brain injury, cerebral contusion, spinal cord compression) or a history or presence of myelopathy due to spinal cord compression by disk or vertebral disease.
  • Prior treatment with any of the following:
  • Systemic glucocorticoids or Adrenocorticotrophic hormone (ACTH) within one month prior to screening
  • Receipt of a live vaccine within 6 weeks prior to screening
  • Glatiramer acetate (Copaxone) or Interferon (IFN)-β (Betaferon, Betaseron, Avonex, or Rebif) within 3 months prior to screening
  • Any immunomodulatory therapies, excluding glatiramer acetate or IFN-β, within 6 months prior to screening including natalizumab and fingolimod (Gilenya), immunoglobulin, or plasma exchange/plasmapheresis
  • Any monoclonal antibodies at any time, other than natalizumab (Tysabri)
  • Any lymphocyte-depleting therapies, including, but not limited to: cladribine, anti-Cluster of Differentiation 4 (CD4), total body irradiation, or bone marrow transplantation
  • Any immunosuppressive agents, including, but not limited to: mitoxantrone, azathioprine, cyclosporine, cyclophosphamide, or tacrolimus
  • Past or current history of medically significant adverse effects (including allergic reactions) from:
  • Cetirizine (or equivalent)
  • Paracetamol/acetaminophen
  • Corticosteroids
  • Known hypersensitivity to components of the investigational product.
  • Past or current malignancy, except for
  • Cervical carcinoma Stage 1B (cancer is present but has not spread) or less
  • Non-invasive basal cell and squamous cell skin carcinoma
  • Cancer diagnoses with a duration of complete response (remission) >5 years
  • A history of hematologic malignancy excludes a subject from participation, regardless of response.
  • Electrocardiogram (ECG) showing a clinically significant abnormality at Screening or showing an average QT interval for heart rate corrected using Bazett's Formula (QTcB) or QT interval for heart rate corrected using Fridericia's Formula (QTcF) interval >/=450 msec (>/=480 msec for subjects with a Bundle Branch Block) over 3 consecutive ECGs.
  • Significant concurrent, uncontrolled medical condition including, but not limited to, cardiac, renal, hepatic, hematological, gastrointestinal, endocrine, immunodeficiency syndrome, pulmonary, cerebral, psychiatric, or neurological disease which in the opinion of the investigator could affect the subject's safety, impair the subject's reliable participation in the trial, impair the evaluation of endpoints, or necessitate the use of medication not allowed by this protocol.
  • History of severe, clinically significant CNS trauma (e.g. cerebral contusion, spinal cord compression) or a history or presence of myelopathy due to spinal cord compression by disk or vertebral disease.
  • Chronic or ongoing active infectious disease requiring long term systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis, or active hepatitis C.
  • Previous serious opportunistic or atypical infections.
  • Positive polymerase chain reaction (PCR) screening for John Cunningham (JC) Virus as measured by plasma John Cunningham Virus (JCV) DNA.
  • Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded.
  • Prior history, or suspicion, of tuberculosis (TB)
  • Known history of positive serology for HIV.
  • Any of the following screening laboratory values:
  • White blood cells (WBC) <3.8 GI/L.
  • Neutrophils <2 x 109/L.
  • Platelets <1.3 x 105 GI/L.
  • Circulating IgG, Immunoglobulin M (IgM), or Immunoglobulin A (IgA) levels < lower limit of normal (according to central laboratory range)
  • Alanine aminotransferase (ALT) >2.0 times the upper limit of normal
  • Aspartate aminotransferase (AST) >2.0 times the upper limit of normal
  • Alkaline phosphatase (ALP) >1.5 times the upper limit of normal
  • Bilirubin >1.5 times the upper limit of normal
  • CD4 count <500 cells/mm3.
  • CD19+ B-lymphocyte counts < lower limit of normal (according to central laboratory range)
  • Creatinine clearance <60 mL/minute (by Cockcroft and Gault).
  • Subjects known or suspected of not being able to comply with a trial protocol (e.g. due to alcoholism, drug dependency or psychological disorder).
  • A documented history of attempted suicide over the 6 months prior to the screening visit, presents with suicidal ideation of type 4 or 5 on the C-Suicide Severity Rating Scale (SSRS) at the Screening visit, OR if in the investigator's judgment, the subject is at risk for a suicide attempt.
  • Use of an investigational drug or other experimental therapy for a condition other than MS within 4 weeks, 5 pharmacokinetic half lives or duration of biological effect (whichever is longer) prior to screening. Any prior use of an investigational drug or other experimental therapy for MS at any time should be discussed with the GSK Medical Monitor.
  • Current participation in any other interventional clinical trial. Participation in a non-interventional trial requires approval of the protocol by the GSK Medical Monitor
  • French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days
  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: NCT01457924

  Show 61 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01457924     History of Changes
Other Study ID Numbers: 112831
Study First Received: October 20, 2011
Last Updated: September 11, 2014
Health Authority: United States: Food and Drug Administration
Europe: European Medicines Agency

Keywords provided by GlaxoSmithKline:
Relapsing Remitting Multiple Sclerosis
Ofatumumab

Additional relevant MeSH terms:
Sclerosis
Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 30, 2014