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

NCT03691077 | Unknown Phase 3 DMC

• 1 other identifier: P170702J
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 1

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.

Conditions

Multiple Sclerosis; Relapse; Primary Progressive Multiple Sclerosis

Keywords

Multiple Sclerosis; Ocrelizumab; Microglial cells Activation; PET-IRM; 18F-DPA714

Outcome Measures

Primary Outcomes (1)

• Determine if ocrelizumab treatment is associated with a decrease in the extent of brain white matter microglial activation.

  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.

  from baseline to month 24

Secondary Outcomes (8)

• Decrease of microglial activation as measured by [18F]DPA-714 PET in normal appearing white matter

  between baseline and months 6 and 24

• decrease of microglial activation as measured by [18F]DPA-714 PET in the total white matter

  from baseline to months 24

• decrease of microglial activation as measured by [18F]DPA-714 PET in white matter lesions

  between baseline and months 6 and 24

• decrease of microglial activation as measured by [18F]DPA-714 PET in white matter perilesional areas

  between baseline to months 6 and 24

• 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

Study Arms (1)

Ocrelizumab

EXPERIMENTAL

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.

Drug: Ocrelizumab

Interventions

Ocrelizumab DRUG

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.

Ocrelizumab

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Signed informed consent form
• Able to comply with the study protocol, in the investigator's judgment
• Social security registration
• Age 18 - 60 years, inclusive
• For women of childbearing potential: agreement to use an acceptable birth control method during the treatment period and for at least 12 months after the last dose of study drug.
• RMS
• Have a definite diagnosis of RMS, confirmed as per the revised McDonald 2010 criteria (Polman et al. 2011);
• Absence of history of Secondary Progressive Multiple Sclerosis (SPMS) or history of Primary Progressive Multiple Sclerosis (PPMS)
• Have an active disease: Activity determined by clinical relapses and/or MRI activity (contrast-enhancing lesions; new or unequivocally enlarging T2 lesions assessed at least annually (Lublin et al. 2014))
• Neurological stability for ≥30 days prior to both screening and baseline
• EDSS of 0.0 to 5.5, inclusive, at screening
• Have a length of disease duration, from first symptom, of \< 15 years
• Have received no more than first line injectable treatments (i.e. IFNs and GA, possible switchs within this class) + 1 other treatment (e.g. teriflunomide, DMF, fingolimod, natalizumab, no switch allowed within this group). More details in section 6.1.1.2.1
• Have a suboptimal response to the last received DMT: a suboptimal response is defined by having at least one of the following events while being on a stable dose of the same DMT for at least 6 months:
• One or more clinically reported relapse(s)

You may not qualify if:

• 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.).
• 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.
• Known presence of other neurological disorders, including but not limited to, the following:
• History of ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack) or ischemia of the spinal cord
• History or known presence of CNS or spinal cord tumor (e.g., meningioma, glioma)
• History or known presence of potential metabolic causes of myelopathy (e.g., untreated vitamin B12 deficiency)
• History or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, human T-lymphotropic virus 1 (HTLV-1), herpes zoster myelopathy)
• History of genetically inherited progressive CNS degenerative disorder (e.g., hereditary paraparesis; MELAS \[mitochondrial myopathy, encephalopathy, lactic acidosis, stroke\] syndrome)
• Neuromyelitis optica
• 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)
• History or known presence of sarcoidosis
• History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral contusion, spinal cord compression) - General Health:
• Laboratory Findings:
• TSPO polymorphism indicating a low affinity profile.
• Positive serum β human chorionic gonadotropin (hCG) measured at screening and before each PET-Scan procedure

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Roche Pharma AG: collaborator
• Institut du Cerveau et de la Moelle épinière: collaborator

Study Sites (1)

Hôpital Saint-Antoine - Service de Neurologie

Paris, 75651, France

RECRUITING

MeSH Terms

Conditions

Multiple Sclerosis; Recurrence; Multiple Sclerosis, Chronic Progressive

Interventions

ocrelizumab

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Chronic Disease

Study Officials

• Bruno Stankoff, MD Ph.D

  Hôpital Saint-Antoine - Service de Neurologie

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bruno Stankoff, MD Ph.D

CONTACT

0171970651; bruno.stankoff@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: September 28, 2018
• First Posted: October 1, 2018
• Study Start: November 11, 2018
• Primary Completion: May 1, 2024
• Study Completion: September 1, 2024
• Last Updated: September 6, 2023

Record last verified: 2023-09

Locations

FR (1)