Clinical trial NCT05081700: A Systems Approach to Understanding Disease Processes in Multiple Sclerosis
Official title: A Systems Approach to Understanding Disease Processes in Multiple Sclerosis
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Multiple Sclerosis
Keywords: multi-omic factors
Lead sponsor: Providence Health & Services
Sponsor class: OTHER
Collaborators: name: Institute for Systems Biology
name: Genentech, Inc.
First posted: 2021-10-18
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: PROBABILITY_SAMPLE
Study population: Study patients will be recruited from the population of relapsing MS patients initiating treatment with ocrelizumab, who are being followed at the Swedish MS Center in Seattle, Washington and the Providence MS Center in Portland, Oregon.

MS population and a reference non-MS population

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of relapse free patients
timeFrame: 6, 12, and 30 months
Secondary outcomes:
measure: Annualized relapse rate (ARR)
timeFrame: 12 and 30 months
measure: Correlates of T2 lesions on-study MRI activity
timeFrame: 12, 24, and 30 months
measure: Correlates of gadolinium enhancing lesions on-study MRI activity
timeFrame: 12, 24, and 30 months
measure: Expanded Disability Status Scale (EDSS)
timeFrame: 12 and 30 months
measure: Timed 25-Foot Walk (T25FW)
timeFrame: 6, 12, and 30 months
measure: 9-Hole Peg Test (9HPT)
timeFrame: 6, 12, and 30 months
measure: Low Contrast Visual Acuity (LCVA)
timeFrame: 6, 12, and 30 months
measure: Symbol digit modality test (SDMT)
timeFrame: 6, 12, and 30 months
measure: Modified Fatigue Impact Scale (MFIS)
timeFrame: 6, 12, and 30 months
measure: Beck Depression Inventory (BDI-2)
timeFrame: 6, 12, and 30 months
Other outcomes:
measure: Whole genome sequencing
timeFrame: 6, 12, and 30 months
measure: Blood analysis plasma
timeFrame: 6, 12, and 30 months
measure: Blood analysis serum
timeFrame: 6, 12, and 30 months
measure: Extracellular vesicle analysis plasma
timeFrame: 6, 12, and 30 months
measure: Stool analysis gut microbiome
timeFrame: 12 and 30 months
Locations:
city: Portland
country: United States
facility: Providence Neurological Specialties West
state: Oregon
city: Seattle
country: United States
facility: Swedish Medical Center Multiple Sclerosis Center
state: Washington
Study officials:
affiliation: Providence Health & Services
name: Stanley Cohan, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ontaneda D, Thompson AJ, Fox RJ, Cohen JA. Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function. Lancet. 2017 Apr 1;389(10076):1357-1366. doi: 10.1016/S0140-6736(16)31320-4. Epub 2016 Nov 24.
citation: Steinman L, Zamvil SS. Beginning of the end of two-stage theory purporting that inflammation then degeneration explains pathogenesis of progressive multiple sclerosis. Curr Opin Neurol. 2016 Jun;29(3):340-4. doi: 10.1097/WCO.0000000000000317.
citation: Fraussen J, de Bock L, Somers V. B cells and antibodies in progressive multiple sclerosis: Contribution to neurodegeneration and progression. Autoimmun Rev. 2016 Sep;15(9):896-9. doi: 10.1016/j.autrev.2016.07.008. Epub 2016 Jul 7.
citation: Price ND, Magis AT, Earls JC, Glusman G, Levy R, Lausted C, McDonald DT, Kusebauch U, Moss CL, Zhou Y, Qin S, Moritz RL, Brogaard K, Omenn GS, Lovejoy JC, Hood L. A wellness study of 108 individuals using personal, dense, dynamic data clouds. Nat Biotechnol. 2017 Aug;35(8):747-756. doi: 10.1038/nbt.3870. Epub 2017 Jul 17.
citation: Hellberg S, Eklund D, Gawel DR, Kopsen M, Zhang H, Nestor CE, Kockum I, Olsson T, Skogh T, Kastbom A, Sjowall C, Vrethem M, Hakansson I, Benson M, Jenmalm MC, Gustafsson M, Ernerudh J. Dynamic Response Genes in CD4+ T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis. Cell Rep. 2016 Sep 13;16(11):2928-2939. doi: 10.1016/j.celrep.2016.08.036.
citation: Hakansson I, Tisell A, Cassel P, Blennow K, Zetterberg H, Lundberg P, Dahle C, Vrethem M, Ernerudh J. Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosis. Eur J Neurol. 2017 May;24(5):703-712. doi: 10.1111/ene.13274. Epub 2017 Mar 6.
citation: Cekanaviciute E, Yoo BB, Runia TF, Debelius JW, Singh S, Nelson CA, Kanner R, Bencosme Y, Lee YK, Hauser SL, Crabtree-Hartman E, Sand IK, Gacias M, Zhu Y, Casaccia P, Cree BAC, Knight R, Mazmanian SK, Baranzini SE. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10713-10718. doi: 10.1073/pnas.1711235114. Epub 2017 Sep 11.