Effect of Ocrelizumab on Brain Innate Immune Microglial Cells Activation in MS Using PET-MRI With 18F-DPA714

Phase 3

Recruiting

• Conditions: Multiple Sclerosis; Relapse; Primary Progressive Multiple Sclerosis
• Interventions: Drug: Ocrelizumab

• Registration Number: NCT03691077
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Brief Summary

Ocrelizumab is a humanized anti-CD20 monoclonal antibody that showed in phase III trials a powerful effect on relapse rate and lesion load accumulation in the relapsing form of multiple sclerosis (RMS). This therapeutic agent also showed for the first time a significant reduction of disability progression in Primary Progressive Multiple Sclerosis (PPMS) patients, whereas all other anti-inflammatory drugs had failed to do so in well-conducted studies. This raises the possibility that ocrelizumab, beyond its effects on the adaptive immune system activation underlying white matter lesions and clinical relapses, could beneficially influence other mechanisms involved in the progressive phase of the disease, such as the innate immune microglial cells activation, that has been described to persist in a diffuse manner in the Central Nervous system (CNS). To date the activation of these cells is not accessible to classical Magnetic Resonance Imaging (MRI) techniques, impeding the full investigation of the therapeutic efficacy of drugs such as ocrelizumab.

Detailed Description

The first dose of ocrelizumab will be administered as two 300-mg IV infusions (600 mg total) in 250 mL 0.9% sodium chloride each separated by 14 days (i.e., Days 1 and 15), followed by one 600-mg IV infusion in 500 mL 0.9% sodium chloride every subsequent doses (i.e., every 24 weeks) for 72 weeks.

Premedication with 100 mg of methylprednisolone (or an equivalent) approximately 30 minutes prior to each ocrelizumab infusion and additional premedication with an antihistaminic drug (e.g., diphenhydramine) approximately 30 - 60 minutes before each infusion of ocrelizumab to reduce the frequency and severity of infusion-related reactions (IRRs). The addition of an antipyretic (e.g., acetaminophen/ paracetamol) may also be considered.

Patients will undergo PET scan with 18F-DPA714 and MRI exams at different time points as mentioned in the assessment table.

Disease will be clinically monitored at different time points with classical tests including EDSS, MSFC, BICAMS.

Laboratory analyses on complete blood count, lymphocytes subsets count, neurofilament will be done. Analyses will not be limited to the above mentioned list.

Pregnancy tests and genetics will be done. An optional lumbar puncture will be performed at baseline to assess cytokinic profile predictive of disease evolution and cortical pathology. Patients who refuse to have a lumbar puncture can be included in the clinical trial if they have eligibility criteria.

TSPO polymorphism will be checked at baseline with other screening lab tests.

Study Timeline

• Study First Submitted: 2018-09-28
• Study First Submitted QC: 2018-09-28
• Study First Posted: 2018-10-01
• Study Start: 2018-11-11
• Status Verified: 2023-09
• Last Update Submitted: 2023-09-04
• Last Update Posted: 2023-09-06
• Primary Completion: 2024-05
• Study Completion: 2024-09

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 51

Inclusion Criteria

Not provided

Exclusion Criteria

1. Inability to complete an MRI (contraindications for MRI include but are not restricted to weight ≥ 140 kg, pacemaker, cochlear implants, presence of foreign substances in the eye, intracranial vascular clips, surgery within 6 weeks of entry into the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI, contraindication to gadoteric acid etc.).

2. Impossibility to complete a PET scan: pregnancy, nuclear medicine irradiation in the year preceding baseline visit for clinical research and one year after the end of their participation in the study, lactation.

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

   1. History of ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack) or ischemia of the spinal cord
   2. History or known presence of CNS or spinal cord tumor (e.g., meningioma, glioma)
   3. History or known presence of potential metabolic causes of myelopathy (e.g., untreated vitamin B12 deficiency)
   4. History or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, human T-lymphotropic virus 1 (HTLV-1), herpes zoster myelopathy)
   5. History of genetically inherited progressive CNS degenerative disorder (e.g., hereditary paraparesis; MELAS [mitochondrial myopathy, encephalopathy, lactic acidosis, stroke] syndrome)
   6. Neuromyelitis optica
   7. History or known presence of systemic autoimmune disorders potentially causing progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, Sjogren's syndrome, Behçet's disease)
   8. History or known presence of sarcoidosis
   9. History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral contusion, spinal cord compression) - General Health:

4. Pregnancy or lactation 2. Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressant drugs during the course of the study 3. History or currently active primary or secondary immunodeficiency 4. Lack of peripheral venous access 5. Significant, uncontrolled disease, such as cardiovascular (including cardiac arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine or gastrointestinal or any other significant disease that may preclude patient from participating in the study 6. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies 7. Congestive heart failure (New York Heart Association [NYHA] III or IV functional severity) 8. Known active bacterial, viral, fungal, mycobacterial infection or other infection [including tuberculosis [TB] or atypical mycobacterial disease (but excluding fungal infection of nail beds)] or any major episode of infection requiring hospitalization or treatment with i.v. antibiotics within 4 weeks prior to baseline visit or oral antibiotics within 2 weeks prior to baseline visit; Note: Active infections should be treated and effectively controlled before possible inclusion in the study 9. History or known presence of recurrent or chronic infection 10. History of malignancy, including solid tumors and hematological malignancies, except basal cell carcinoma, in situ squamous cell carcinoma of the skin, and in situ carcinoma of the cervix of the uterus that have been previously completely excised with documented, clear margins 11. History of alcohol or drug abuse within 24 weeks prior to baseline 12. History or laboratory evidence of coagulation disorders 13. History of major opportunistic infections (i.e. cryptococcosis, Pneumocystis pneumonia, progressive multifocal leukoencephalopathy [PML]) 14. History of recurrent aspiration pneumonia requiring antibiotic therapy 15. Hypersensitivity to the active substance or to any of the excipients (Sodium Acetate Trihydrate, Glacial Acetic Acid, Trehalose Dihydrate, Polysorbate 20, Water for Injection)

• Laboratory Findings:

  1. TSPO polymorphism indicating a low affinity profile.
  2. Positive serum β human chorionic gonadotropin (hCG) measured at screening and before each PET-Scan procedure
  3. Positive screening tests for hepatitis B (hepatitis B surface antigen [HBsAg] positive, or positive hepatitis B core antibody [total HBcAb] confirmed by a positive viral DNA polymerase chain reaction [PCR]) or hepatitis C (HepCAb)
  4. Lymphocyte count below lower limit of normal (LLN)
  5. CD4 count <300/μL.
  6. Absolute neutrophil count <1.0 × 103/µL

• Medications:

  1. Receipt of a live vaccine or attenuated live vaccine within 6 weeks prior to the baseline visit. In rare cases when patient requires vaccination with a live vaccine, the screening period may be extended but cannot exceed 8 weeks
  2. Treatment with any investigational agent within 24 weeks of screening 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)
  3. Treatment with Flumitrazepam, triazolam, diazepam

• Treatment of Multiple Sclerosis:

  1. Previous treatment with B-cell targeted therapies (i.e., rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab)

  2. Systemic corticosteroid therapy within 4 weeks prior to screeningii

  3. Treatment with IV immunoglobulin (Ig) within 12 weeks prior to baseline

  4. Any previous treatment with alemtuzumab, daclizumab, anti-CD4, total body irradiation or bone marrow transplantation

  5. Any previous treatment with biotin in the last month prior to screening

  6. Previous treatment with mitoxantrone, cyclosporine or cladribine in the last 96 weeks

  7. Previous treatment with azathioprine, cyclophosphamide, mycophenolate mofetil,methotrexate, or laquinimod in the last 24 weeks

  8. Previous treatment with teriflunomide, unless an accelerated elimination procedure is implemented before screening visit. Accelerated elimination procedure after stopping treatment with teriflunomide:

     1. cholestyramine 8g is administered 3 times daily for a period of 11 days, or cholestyramine 4g three times a day can be used, if cholestyramine 8g three times a day is not well tolerated,
     2. alternatively, 50g of activated powdered charcoal is administered every 12 hours for a period of 11 days

  9. Previous treatment with natalizumab in the last 12 weeks

  10. Previous treatment with fingolimod or dimethyl fumarate if at baseline the lymphocyte count is below lower limit of normality (LLN). Apart from the lymphocytes count within normal ranges, 12 weeks of a washout period of fingolimod or dimethylfumarate would be required before the start of ocrelizumab administration

  11. History of recurrent aspiration pneumonia requiring antibiotic therapy

  12. Treatment with fampridine/dalfamipridine (Fampyra®)/Ampyra®) unless on stable dose for ≥ 30 days prior to screening. Wherever possible, patients should remain on stable doses throughout the 96-week treatment period

  13. Treatment with β interferons, glatiramer acetate, plasmapheresis, or other immunomodulatory therapies within 4 weeks prior to baselinei

Healthy volunteers:

1. Inability to complete an MRI (contraindications for MRI include but are not restricted to weight ≥ 140 kg, pacemaker, cochlear implants, presence of foreign substances in the eye, intracranial vascular clips, surgery within 6 weeks of entry into the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI, contraindication to acid gadoteric etc.)
2. Impossibility to complete a PET scan: pregnancy, nuclear medicine irradiation in the year preceding baseline visit for clinical research
3. Known presence of any neurological disorders
4. Pregnancy or lactation
5. Lack of peripheral venous access
6. Significant, uncontrolled disease, such as cardiovascular (including cardiac arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine or gastrointestinal infectious, neoplasic or any other significant disease that may preclude patient from participating in the study
7. History of alcohol or drug abuse within 24 weeks prior to baseline
8. TSPO polymorphism indicating a low affinity profile.
9. Treatment with Flumitrazepam, triazolam, diazepam

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Ocrelizumab	Ocrelizumab	The first dose of ocrelizumab will be administered as two 300-mg IV infusions (600 mg total) in 250 mL 0.9% sodium chloride each separated by 14 days (i.e., Days 1 and 15), followed by one 600-mg IV infusion in 500 mL 0.9% sodium chloride every subsequent doses (i.e., every 24 weeks) for 72 weeks.

Primary Outcome Measures

Name	Time	Method
Determine if ocrelizumab treatment is associated with a decrease in the extent of brain white matter microglial activation.	from baseline to month 24	Percent change in the extent of 18FDPA714 positive voxels in the total white matter from baseline to month 24 in the whole cohort of MS patients.

Secondary Outcome Measures

Name	Time	Method
decrease of microglial activation as measured by [18F]DPA-714 PET in white matter lesions	between baseline and months 6 and 24	Percent change in extent of 18FDPA714 positive voxels in white matter lesions between baseline to months 6 and 24, in the whole cohort, in RMS cohort (global and splitted in RRMS and RMS having reached the SPMS phase) and in PPMS cohort.
decrease of microglial activation as measured by [18F]DPA-714 PET in in number of plaques classified as chronic active	from baseline to month 6 and month 24	Percent change in number of plaques classified as chronic active from baseline to month 6 and month 24 in the whole cohort, in RMS cohort (global and splitted in RRMS and RMS having reached the SPMS phase) and in PPMS cohort.
decrease of microglial activation as measured by [18F]DPA-714 PET in number of plaques classified as smoldering plaques	from baseline to month 6 and month 24	Percent change in number of plaques classified as smoldering plaques from baseline to month 6 and month 24 in the whole cohort, in RMS cohort (global and splitted in RRMS and RMS having reached the SPMS phase) and in PPMS cohort.
decrease of microglial activation as measured by [18F]DPA-714 PET in deep grey matter	between baseline to months 6 and 24	Percent change in extent of 18FDPA714 positive voxels in deep grey matter between baseline to months 6 and 24 in the whole cohort, in RMS cohort (global and splitted in RRMS and RMS having reached the SPMS phase) and in PPMS cohort.
decrease of microglial activation as measured by [18F]DPA-714 PET in cortical grey matter	between baseline to months 6 and 24	Percent change in extent of 18FDPA714 positive voxels in cortical grey matter between baseline to months 6 and 24 in the whole cohort, in RMS cohort (global and splitted in RRMS and RMS having reached the SPMS phase) and in PPMS cohort.
Decrease of microglial activation as measured by [18F]DPA-714 PET in normal appearing white matter	between baseline and months 6 and 24	Percent change in extent of 18FDPA714 positive voxels in normal appearing white matter between baseline and months 6 (short-term) and 24 (long-term) in the whole cohort, in RMS cohort (global and splitted in RRMS and RMS having reached the SPMS phase) and in PPMS cohort
decrease of microglial activation as measured by [18F]DPA-714 PET in the total white matter	from baseline to months 24	Percent change in extent of \[18F\]-DPA-714 positive voxels in the total white matter from baseline to month 24, in PPMS cohort and in RMS cohort (whole cohort and subgroups of RRMS and SPMS patients).
decrease of microglial activation as measured by [18F]DPA-714 PET in white matter perilesional areas	between baseline to months 6 and 24	Percent change in extent of 18FDPA714 positive voxels in white matter perilesional areas between baseline to months 6 and 24 in the whole cohort, in RMS cohort (global and splitted in RRMS and RMS having reached the SPMS phase) and in PPMS cohort.

Trial Locations

Locations (1)

Hôpital Saint-Antoine - Service de Neurologie; 🇫🇷 Paris, France