Open-label, Observational, Prospective, 9-month Study to Assess the Efficacy of Ofatumumab on Microglia in Patients With Relapsing Forms of Multiple Sclerosis

Official Summary

We aim to assess the effect of Ofatumumab on microglial activation using \[F-18\]PBR06 PET in MS patients in relation to changes in serum markers, MRI abnormalities and clinical impairment longitudinally over 9 months. Specific Aims: Specific Aim 1: To determine the effect of Ofatumumab on microglial activation in MS over 9 months. Specific Aim 2: To determine the time course of effect of Ofatumumab on microglial activation and its relationship with peripheral B-cell depletion, serum neurofilament light (sNfL) chain and glial-fibrillary acid protein (GFAP) levels and other serum biomarkers Specific Aim 3: To determine the relationship of PET changes following Ofatumumab initiation with 3T MRI changes and clinical parameters.

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 60 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 10 participants

Study Arms

• Subjects diagnosed with relapsing forms of multiple sclerosis (EXPERIMENTAL)
  We plan to enroll 10 subjects with relapsing MS. All enrolled subjects will receive Ofatumumab 20 mg every 4 weeks, subcutaneously for 9 months during the study. Loading doses will be administered initially at 1, 7 and 14 days. During the study period, all enrolled subjects will undergo five PET scans using \[F-18\] PBR06 at day 0, 5, 28, 90 (3 Months) and 273 (9 Months) after starting treatment with Ofatumumab.

Interventions

• DRUG: Ofatumumab — Ofatumumab (OMB157) is a fully human anti-CD20 monoclonal antibody (mAb) self-administered by a once-monthly subcutaneous injection that is in development for MS. Ofatumumab drug product (also referred as OMB157) is formulated as 20 mg/0.4 mL (50 mg/mL) solution for injection, provided in autoinjectors, for subcutaneous administration. The autoinjectors contain a small overfill to allow for a complete withdrawal of the labeled amount (20 mg) of ofatumumab.
• DRUG: [F-18]PBR06 — PET radiopharmaceutical. Subjects will undergo \[F-18\]PBR06-PET (microglial activation).

Primary Outcomes

• Glial Activity Load on PET (Baseline, 3 Months, and 9 Months)

Secondary Outcomes

• % CD19 Counts (Baseline, 5 Days, and 9 Months)

Eligibility Criteria

Inclusion Criteria:

* Patients diagnosed with active, relapsing MS course (defined by Lublin 2014 criteria). Active disease is defined by at least 1 relapse during the previous 1 year or 2 relapses during the previous 2 years or a positive gadolinium-enhancing MRI scan or MRI scan with new or unequivocally enlarging T2 lesions in previous year.
* Age 18 to 60 years
* EDSS 0 to 5.5
* Subjects either untreated or treated with disease modifying therapies other than those listed in exclusion criteria
* Agree to start treatment with ofatumumab and comply with study procedures for the duration of the study
* No other systemic disease or neurological disorders requiring chronic or acute steroid or other immunosuppressive treatment
* No known hypersensitivity reactions to contrast agents
* None of the exclusion criteria

Exclusion Criteria:

* Subjects suspected of not being able or willing to cooperate or comply with study protocol requirements in the opinion of the investigator.
* Subjects with primary progressive MS or SPMS without disease activity.
* Disease duration of more than 10 years in patients with an EDSS score of 2 or less
* Subjects meeting criteria for neuromyelitis optica.
* Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 6 months after stopping study medication. Highly effective contraception methods include:
* Total abstinence (when this is in line with the preferred and usual lifestyle of the subject, if accepted by the local regulation). NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal ARE NOT acceptable methods of contraception
* Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
* For female subjects on the study, the vasectomized male partner should be the sole partner
* Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking investigational drug.
* In case local regulations deviate from the contraception methods listed above, local regulations apply and will be described in the ICF.
* Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential.
* Subjects with active chronic disease (or stable but treated with immune therapy) of the immune system other than MS (e.g. rheumatoid arthritis, scleroderma, Sjögren's syndrome, Crohn's disease, ulcerative colitis, etc.) or with an immunodeficiency syndrome.
* Subjects with a history of the following:

  1. History of any malignancy
  2. History of alcohol or drug abuse
  3. Primary or secondary immunodeficiency
  4. Prior hematopoietic stem cell transplantation
  5. History of transplantation or anti-rejection therapy
* Subjects with the following laboratory abnormalities:

  1. Abnormal CD19+ B-cell levels at screening (defined as CD19 count \<110 cells per microliter)
  2. Leukopenia (defined as white blood cell (WBC) count \<4000 WBCs per microliter)
  3. Lymphopenia (defined as lymphocyte count \<1000 lymphocytes per microliter)
  4. Hypogammaglobulinemia defined as a level of \<500mg/dL will be excluded. All subjects with low serum immunoglobulins should be evaluated by a hematologic expert prior to exclusion in the study.
  5. Any abnormality of liver function tests, including ALT/SGPT, AST/SGOT, Alkaline phosphatase, total or direct bilirubin or GGT
* Subjects with active systemic bacterial, viral or fungal infections, or known to have acquired immunodeficiency syndrome (AIDS).
* Subjects with neurological symptoms consistent with PML or confirmed PML.
* Subjects at risk of developing or having reactivation o

Trial Locations

• Brigham MS Center, 60 Fenwood Road, Boston, Massachusetts, United States

Study Officials

• Tarun Singhal, MD — PRINCIPAL_INVESTIGATOR
  Brigham and Women's Hospital

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