Ofatumumab Subcutaneous Administration in Subjects With Relapsing-Remitting Multiple Sclerosis

NCT01457924 | Completed Phase 2 Results DMC

• 1 other identifier: 112831
• Study Type: interventional
• Target: 232
• Locations: 11 countries
• Sites: 61

Brief Summary

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.

Conditions

Multiple Sclerosis

Keywords

Relapsing Remitting Multiple Sclerosis; Ofatumumab

Outcome Measures

Primary Outcomes (1)

• Cumulative Number of New Gadolinium-enhancing (GdE) T1 Lesions at Week 12

  The cumulative number of new GdE T1 lesion at Week 12 were analyzed from screening based on magnetic resonance imaging (MRI) brain scans at Weeks 4, 8, and 12. The outcome measure was analyzed using an Emax model adjusting for the presence/absence of GdE lesions on the Screening MRI and assuming the number of new lesions followed a negative binomial distribution. Dose was fitted as a continuous variable. The number of scans contributing to the cumulative number of lesions was fitted as an offset. Estimates of the rate of cumulative number of new GdE lesions per scan at Week 12 were determined from the model. The all evaluable scans (AES) dataset was used which included all evaluable on-treatment MRI scans for each participant analysed.

  Week 12

Secondary Outcomes (10)

• Cumulative Number of New GdE T1 Lesions at Week 24

  Week 24

• Change From Baseline in Brain Volume at Week 24 and Week 48

  Baseline (Week 0), Week 24 and Week 48

• Cumulative Number of Persistent GdE Brain Lesions on T1-weighted MRI at Week 12

  Week 12

• Cumulative Number of All (New Plus Persistent) GdE Brain Lesions on T1-weighted MRI at Week 12

  Week 12

• Total Volume of New GdE Brain Lesions on T1-weighted MRI at Week 12

  Week 12

Study Arms (8)

Cohort 1

EXPERIMENTAL

Placebo and one dose of Ofatumumab 3mg over 24 weeks

Drug: Ofatumumab 3mg; Drug: Placebo

Cohort 2

EXPERIMENTAL

Two doses of Ofatumumab 3mg over 24 weeks

Drug: Ofatumumab 3mg; Drug: Placebo

Cohort 3.1

EXPERIMENTAL

Two doses of Ofatumumab 30mg over 24 weeks

Drug: Ofatumumab 30mg; Drug: Placebo

Cohort 3.2

EXPERIMENTAL

Conditioning dose of Ofatumumab 3mg at randomization, two doses of Ofatumumab 30mg over 24 weeks

Drug: Ofatumumab 3mg; Drug: Ofatumumab 30mg; Drug: Placebo

Cohort 4.1

EXPERIMENTAL

Two doses of Ofatumumab 60mg over 24 weeks

Drug: Ofatumumab 60mg; Drug: Placebo

Cohort 4.2

EXPERIMENTAL

Conditioning dose of Ofatumumab 3mg at randomization, two doses of Ofatumumab 60mg over 24 weeks

Drug: Ofatumumab 3mg; Drug: Ofatumumab 60mg; Drug: Placebo

Cohort 5.1

EXPERIMENTAL

Six doses of Ofatumumab 60mg over 24 weeks

Drug: Ofatumumab 60mg; Drug: Placebo

Cohort 5.2

EXPERIMENTAL

Conditioning dose of Ofatumumab 3mg at randomization, six doses of Ofatumumab 60mg over 24 weeks

Drug: Ofatumumab 3mg; Drug: Ofatumumab 60mg

Interventions

Ofatumumab 3mg DRUG

3mg of investigational product

Cohort 1; Cohort 2; Cohort 3.2; Cohort 4.2; Cohort 5.2

Ofatumumab 30mg DRUG

30mg of investigational product

Cohort 3.1; Cohort 3.2

Ofatumumab 60mg DRUG

60mg of investigational product

Cohort 4.1; Cohort 4.2; Cohort 5.1; Cohort 5.2

Placebo DRUG

Placebo

Cohort 1; Cohort 2; Cohort 3.1; Cohort 3.2; Cohort 4.1; Cohort 4.2; Cohort 5.1

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Able to provide signed, written informed consent to participate in the study
• 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:

You may not qualify if:

• 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)

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (61)

GSK Investigational Site

Cullman, Alabama, 35058, United States

Location

GSK Investigational Site

Fullerton, California, 92835, United States

Location

GSK Investigational Site

Fairfield, Connecticut, 06824, United States

Location

GSK Investigational Site

Miami, Florida, 33136, United States

Location

GSK Investigational Site

Sunrise, Florida, 33351, United States

Location

GSK Investigational Site

Tampa, Florida, 33612, United States

Location

GSK Investigational Site

West Palm Beach, Florida, 33407, United States

Location

GSK Investigational Site

Atlanta, Georgia, 30327, United States

Location

GSK Investigational Site

Northbrook, Illinois, 60062, United States

Location

GSK Investigational Site

Fort Wayne, Indiana, 46805, United States

Location

GSK Investigational Site

Grand Rapids, Michigan, 49503, United States

Location

GSK Investigational Site

Oklahoma City, Oklahoma, 73104, United States

Location

GSK Investigational Site

Philadelphia, Pennsylvania, 19107, United States

Location

GSK Investigational Site

Nashville, Tennessee, 37204, United States

Location

GSK Investigational Site

Round Rock, Texas, 78681, United States

Location

GSK Investigational Site

Seattle, Washington, 98122, United States

Location

GSK Investigational Site

Sofia, 1000, Bulgaria

Location

GSK Investigational Site

Sofia, 1113, Bulgaria

Location

GSK Investigational Site

Sofia, 1309, Bulgaria

Location

GSK Investigational Site

Sofia, 1431, Bulgaria

Location

GSK Investigational Site

Edmonton, Alberta, T6G 1Z1, Canada

Location

GSK Investigational Site

Montreal, Quebec, H3A 2B4, Canada

Location

GSK Investigational Site

Brno, 625 00, Czechia

Location

GSK Investigational Site

Brno, 656 91, Czechia

Location

GSK Investigational Site

Jihlava, 586 33, Czechia

Location

GSK Investigational Site

Olomouc, 775 20, Czechia

Location

GSK Investigational Site

Teplice, 415 29, Czechia

Location

GSK Investigational Site

Koebenhavn Ø, 2100, Denmark

Location

GSK Investigational Site

Alzenau in Unterfranken, Bavaria, 63755, Germany

Location

GSK Investigational Site

Achim, Lower Saxony, 28832, Germany

Location

GSK Investigational Site

Hanover, Lower Saxony, 30625, Germany

Location

GSK Investigational Site

Bochum, North Rhine-Westphalia, 44791, Germany

Location

GSK Investigational Site

Cologne, North Rhine-Westphalia, 50935, Germany

Location

GSK Investigational Site

Leipzig, Saxony, 04103, Germany

Location

GSK Investigational Site

Berlin, 10961, Germany

Location

GSK Investigational Site

Berlin, 12163, Germany

Location

GSK Investigational Site

Hamburg, 22087, Germany

Location

GSK Investigational Site

Modena, Emilia-Romagna, 41126, Italy

Location

GSK Investigational Site

Verona, Veneto, 37134, Italy

Location

GSK Investigational Site

Sittard-geleen, 6162 BG, Netherlands

Location

GSK Investigational Site

Venray, 5801 CE, Netherlands

Location

GSK Investigational Site

Hamar, 2317, Norway

Location

GSK Investigational Site

Kazan', 420021, Russia

Location

GSK Investigational Site

Moscow, 107150, Russia

Location

GSK Investigational Site

Moscow, 119049, Russia

Location

GSK Investigational Site

Moscow, 127018, Russia

Location

GSK Investigational Site

Nizhny Novgorod, 603126, Russia

Location

GSK Investigational Site

Saint Petersburg, 194291, Russia

Location

GSK Investigational Site

Saint Petersburg, 197022, Russia

Location

GSK Investigational Site

Smolensk, 214018, Russia

Location

GSK Investigational Site

Baracaldo/Vizcaya, 48903, Spain

Location

GSK Investigational Site

Barcelona, 08035, Spain

Location

GSK Investigational Site

Barcelona, 08907, Spain

Location

GSK Investigational Site

Castellon, 12004, Spain

Location

GSK Investigational Site

Córdoba, 14001, Spain

Location

GSK Investigational Site

Girona, 17007, Spain

Location

GSK Investigational Site

Madrid, 28034, Spain

Location

GSK Investigational Site

Madrid, 28040, Spain

Location

GSK Investigational Site

Madrid, 28046, Spain

Location

GSK Investigational Site

Málaga, 29010, Spain

Location

GSK Investigational Site

Seville, 41071, Spain

Location

Related Publications (1)

• Bar-Or A, Grove RA, Austin DJ, Tolson JM, VanMeter SA, Lewis EW, Derosier FJ, Lopez MC, Kavanagh ST, Miller AE, Sorensen PS. Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study. Neurology. 2018 May 15;90(20):e1805-e1814. doi: 10.1212/WNL.0000000000005516. Epub 2018 Apr 25.

  PMID: 29695594 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting

Interventions

ofatumumab

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Limitations and Caveats

The incorrect exclusion of one par. from ITT pop. at Wk 24 was not considered to impact overall interpretation of data: no updates were made to source tables/analyses. This par. had withdrawn early, having never received a dose of active study drug.

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 20, 2011
• First Posted: October 24, 2011
• Study Start: November 1, 2011
• Primary Completion: August 23, 2013
• Study Completion: June 10, 2015
• Last Updated: June 6, 2018
• Results First Posted: March 1, 2018

Record last verified: 2018-05

Locations

IT (2); NO (1); RU (8); ES (11); CA (2); US (16); NL (2); DE (9); BU (4); CZ (5); DK (1)