A Systems Approach to Understanding Disease Processes in Multiple Sclerosis

Completed

• Conditions: Multiple Sclerosis
• Interventions: Drug: All patients in the study will be treated with ocrelizumab

• Registration Number: NCT05081700
• Lead Sponsor: Providence Health & Services

Brief Summary

This pilot study will establish a proof of concept for using a systems biology approach to characterize the dynamics of MS disease processes. The primary objective of the study is to identify multi-omic (genetic, proteomic, biochemical and/or microbial) factors that correlate with clinical and subclinical MS disease activity. Identification of such biomarkers could have an immediate clinical utility in identification of MS patients prone to more aggressive disease earlier in their disease course, thus affording the opportunity to better individualize therapy.

In addition, insights from better understanding of the complex interplay of various systems biology factors should improve our understanding of MS in general. The study will recruit 14 patients with relapsing MS who are initiating treatment with ocrelizumab, and follow them for 30 months.

Detailed Description

The main purpose of the study is to improve the understanding of MS and to look at the genetic factors that may influence how MS progresses. This will involve collecting blood and stool samples, patient questionnaires, and MS-related assessments.

About 67 mL (13 tsp) of blood will be collected at the first visit, and again at 6 months, 12 months, and 30 months after first visit.

Participants will receive standard treatment (ocrelizumab) and have standard exams, MRIs, and tests while on the study.

Study participation is about 30 months, which includes about 9 study visits. Some study visits may be up to 5 hours long. 14 people will take part in this study.

Study Timeline

• Study Start: 2020-05-11
• Study First Submitted: 2020-11-13
• Study First Submitted QC: 2021-10-13
• Study First Posted: 2021-10-18
• Primary Completion: 2023-06-27
• Study Completion: 2023-11-03
• Status Verified: 2024-09
• Last Update Submitted: 2024-09-30
• Last Update Posted: 2024-10-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 14

Inclusion Criteria

1. Able to understand the purpose and risk of the study and provide written informed consent.
2. Male or female patients aged 18 to 60, inclusive at time of consent, who meet FDA approved indications to receive ocrelizumab treatment.
3. Have a definite diagnosis of relapsing MS (RMS) (Lublin et al. 2014).
4. Screening EDSS ≤ 5.0.
5. Have a length of disease duration since disease symptom onset ≤ 15 years.
6. Documentation of 1 or more on-DMT relapses, or 1 brain MRI revealing new or enlarged T2 lesion(s) over the 2 years prior to the screening visit (this could include DMT naïve patients).
7. Patient does not have any clinically significant medical conditions based on medical history, physical examination, and laboratory screening, as defined by the investigator, which would interfere with the conduct of the study.
8. Patient is willing and able to comply with the protocol assessments and visits, in the opinion of the investigator.
9. For women of childbearing potential: agreement to use an effective birth control method and avoid breastfeeding during the study period, and for those patients who have received ocrelizumab, for at least 6 months after the last dose.

Inclusion criteria for those patients who have completed the core study and are re-consenting and re-enrolling to complete the month 30 visit. Patients must fulfill all of the following criteria to participate in the study:

1. Able to understand the purpose and risk of the study and provide written informed consent.
2. Have participated in the core study and continue to receive ocrelizumab.
3. Have not passed week 120±14 days post initial ocrelizumab dose in the core study.
4. Diagnosis of relapsing MS at time of consent.
5. Patient is willing and able to comply with the protocol assessments and visits, in the opinion of the investigator.
6. For women of childbearing potential: agreement to use an effective birth control method and avoid breastfeeding during the study period and for at least 6 months after the last dose of ocrelizumab.

Exclusion Criteria

1. Diagnosis of progressive MS at screening.

2. Patient is unable to undergo MRI with gadolinium contrast imaging for any reason.

3. Known presence of other neurological disorders, including but not limited to, the following:

   1. History of cerebrovascular disorders.
   2. History or known presence of CNS tumor.
   3. History or known presence of potential metabolic causes of myelopathy.
   4. History of peripheral neuropathy.
   5. History or known presence of infectious disease of the CNS.
   6. History of genetically inherited CNS degenerative disorder.
   7. Neuromyelitis optica spectrum disorder, anti-Aquaporin 4 IgG, or Anti-MOG IgG .
   8. History of progressive multifocal leukoencephalopathy (PML).
   9. History or known presence of any other concurrent systemic or nervous system autoimmune disorders, potentially causing progressive neurologic disease.
   10. History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral contusion, spinal cord compression).

4. Exclusions related to general health:

   1. Pregnancy or lactation.
   2. Chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study.
   3. History or currently active primary or secondary immunodeficiency.
   4. Lack of peripheral venous access.
   5. Hypersensitivity to ocrelizumab or to any of its excipients.
   6. Significant or uncontrolled non-neurological systemic disease.
   7. Significant active infections must be treated and resolved before possible inclusion in the study.
   8. Patients in an immunocompromised state.
   9. Patients with history of malignancy, except for adequately treated basal cell skin cancer or in situ cervical cancer.

5. Exclusions Related to Medications:

   1. Your last COVID-19 vaccine should be given at least 2 weeks before and all vaccines should be given at least 6 weeks before the first infusion of ocrelizumab. Live/live attenuated vaccines should be avoided during treatment and safety follow-up period until B cells are peripherally repleted to at least the lower limit of normal. COVID-19 vaccines are permitted per investigator discretion during ocrelizumab treatment.
   2. Treatment with any investigational agent within 24 weeks of screening (Visit 1) or five half-lives of the investigational drug (whichever is longer) or treatment with any experimental procedures for MS (e.g., treatment for chronic cerebrospinal venous insufficiency) within 24 weeks of screening (Visit 1).
   3. Previous treatment with B-cell targeted therapies (i.e., rituximab, ocrelizumab, atacicept, tabalumab, belimumab, ofatumumab, or obinutuzumab).
   4. Any previous treatment with total body irradiation, or bone marrow transplantation.
   5. Previous treatment with natalizumab in the past 4 weeks prior to baseline (Day 0) or fingolimod in the last 2 weeks prior to screening (Visit 1).
   6. Patients previously treated with teriflunomide, unless an accelerated elimination procedure is implemented and/or teriflunomide serum level of less than 2 mcg/ml is documented prior to screening (Visit 1).
   7. Previous treatment with azathioprine, mycophenolate mofetil or methotrexate in the last 12 weeks prior to screening (Visit 1).
   8. Previous treatment with cyclosporine or cladribine at any time in the past in the last 96 weeks prior to screening (Visit 1).
   9. Previous treatment with mitoxantrone, alemtuzumab, or cyclophosphamide at any time.
   10. Treatment with dalfampridine unless on stable dose for ≥30 days prior to screening (Visit 1). Wherever possible, patients should remain on stable doses throughout the treatment period.

6. Exclusions related to laboratory findings:

   1. Positive serum β-human chorionic gonadotropin (hCG) measured at screening.
   2. Positive screening tests for hepatitis B (hepatitis B surface antigen [HbsAg] positive, or positive hepatitis B core antibody [total HbcAb], or other comparable tests confirmed by a positive viral DNA polymerase chain reaction [PCR]), within the 6 months prior to Day 0.
   3. Positive tuberculin skin test or Quantiferon Gold TB test, unless previously documented treatment for latent TB within the 12 months prior to Day 0 or a negative test within the 12 months prior to Day 0.
   4. Evidence of acute or chronic hepatitis, or evidence of clinically significantly impaired hepatic function through clinical and laboratory evaluation including alkaline phosphatase >1.5x ULN, ALT or AST >2x ULN; GGT>3x ULN or bilirubin >ULN.
   5. Any other clinically significant laboratory abnormality which may put the patient at risk.

Exclusion criteria for those patients who have completed the core study and are re-consenting and re-enrolling to complete the month 30 visit. Patients must be excluded from participating in the study if they meet any of the following criteria:

1. Exclusions related to general health:

   1. Pregnancy or lactation.
   2. Chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study.

2. Exclusions Related to Medications:

   1. Live/live attenuated vaccines should be avoided during treatment and safety follow-up period until B cells are peripherally repleted to at least the lower limit of normal. COVID-19 vaccines are permitted per investigator discretion during ocrelizumab treatment.
   2. Treatment with dalfampridine unless on stable dose. Wherever possible, patients should remain on stable doses throughout the treatment period.

3. Exclusions related to laboratory findings:

   1. Any clinically significant laboratory abnormality during the study which may put the patient at risk.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Patients with relapsing MS	All patients in the study will be treated with ocrelizumab	Patients with relapsing remitting MS who are intending to receive ocrelizumab.

Primary Outcome Measures

Name	Time	Method
Proportion of relapse free patients	6, 12, and 30 months	Number of participants free of MS relapse at 6, 12, and 30 months divided by total number of participants.

Secondary Outcome Measures

Name	Time	Method
Correlates of T2 lesions on-study MRI activity	12, 24, and 30 months	Number of new and/or unique T2 lesions for each participant compared to screening
Low Contrast Visual Acuity (LCVA)	6, 12, and 30 months	Changes in LCVA to assess MS activity levels at baseline compared to 6, 12, and 30 months. Test performed on right eye, left eye, and binocular (both eyes). Scale ranges from minimum 20/200 to maximum 20/16. Higher score indicates better result.
Expanded Disability Status Scale (EDSS)	12 and 30 months	Changes in EDSS to assess MS activity levels at baseline compared to 12 and 30 months. The EDSS provides a total score on a scale that ranges from minimum 0 to maximum 10. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability
Timed 25-Foot Walk (T25FW)	6, 12, and 30 months	Changes in T25FW to assess MS activity levels at baseline compared to 6, 12, and 30 months. Scale ranges from minimum 0 seconds to maximum 180 seconds. Lower score indicates better result.
9-Hole Peg Test (9HPT)	6, 12, and 30 months	Changes in 9HPT to assess MS activity levels at baseline compared to 6, 12, and 30 months. Scales ranges from minumum 0 seconds to maximum 300 seconds (5 minutes). Lower score indicates better result.
Annualized relapse rate (ARR)	12 and 30 months	Changes in ARR to assess MS activity levels at baseline compared to 12 and 30 months. Total number of relapses divided by total number of participants.
Correlates of gadolinium enhancing lesions on-study MRI activity	12, 24, and 30 months	Number of new and/or enlarged gadolinium enhancing lesions for each participant compared to screening
Beck Depression Inventory (BDI-2)	6, 12, and 30 months	Changes in BDI-2 to assess MS activity levels at baseline compared to 6, 12, and 30 months. Scale ranges from minimum 0 to maximum 63. Lower score indicates better result.
Modified Fatigue Impact Scale (MFIS)	6, 12, and 30 months	Changes in MFIS to assess MS activity levels at baseline compared to 6, 12, and 30 months. Scale ranges from minimum 0 to maximum 84. Lower score indicates better result.
Symbol digit modality test (SDMT)	6, 12, and 30 months	Changes in SDMT to assess MS activity levels at baseline compared to 6, 12, and 30 months. Scale ranges from minimum 0 to maximum 110. Higher score indicates better result.

Trial Locations

Locations (2)

Providence Neurological Specialties West; 🇺🇸 Portland, Oregon, United States

Swedish Medical Center Multiple Sclerosis Center; 🇺🇸 Seattle, Washington, United States