Clinical trial NCT04239820: Effect of Cladribine Treatment on Microglial Activation in the CNS
Official title: Effect of Cladribine Treatment on Microglial Activation in the CNS
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Multiple Sclerosis
Lead sponsor: Turku University Hospital
Sponsor class: OTHER_GOV
First posted: 2020-01-27
Enrollment: 15
Sex: ALL
Minimum age (years): 45
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The research will recruit MS patients who are initiating cladribine treatment and are followed-up at the Neurology Outpatient Clinic at the areas of the Hospital District of Southwest Finland, Helsinki and Uusimaa Hospital District, Pirkanmaa Hospital District and Satakunta Hospital District. The study will not interfere with the initiation or dosage of the medication in any manner. The patient's treating neurologist will select the most suitable medication on the basis of the patient's clinical status, and patients initiating cladribine medication will be offered the option to participate in this imaging study.

Brief summary: To evaluate the effect of cladribine treatment on microglial activation with conventional MRI, QSM-post processing and TSPO-PET imaging in late stage relapsing remitting multiple sclerosis patients.

Detailed description: Objective: To evaluate with multimodal magnetic resonance (MR) imaging and TSPO-PET imaging whether cladribine treatment has an effect on disease progression-related pathology in late stage relapsing remitting multiple sclerosis (RRMS) patients.

Background: In Multiple Sclerosis (MS), plaques in the white and grey matter of the brain represent the best known pathological changes of the disease, but a significant inflammation process has also been detected outside these plaques in connection with the disease. This extensive, diffuse inflammatory process correlates with the progression of the disease. According to neuropathological research, the diffuse inflammatory process outside the plaques is connected with powerful activation of microglia, oxidative stress, and deficiencies in mitochondrial activity. The activation of microglial cells can be measured in vivo in patients using positron-emission tomography (PET) scanning and so-called 18 kilodalton translocator protein (TSPO) -radioligands. TSPO-radioligands, such as the 11C-PK11195 radioligand, bind to TSPO molecules, which manifest in activated, but not un-activated, microglia.

Cladribine is an immune cell depleting treatment for RRMS. Our hypothesis is that monitoring the treatment of MS could be carried out using TSPO-PET and Quantitative susceptibility mapping (QSM)-MRI scanning, and these multimodal imaging methods could be used to assess the impact of the cladribine medication on the disease process leading to progression and disability by measuring the activation status of microglial cells.

An age-matched historical control group of 10 untreated RRMS patients that have been previously imaged at a 12-18 months interval will be used for comparison.

Study population: 15 late stage RRMS-patients Methods: Clinical evaluation, brain QSM-MRI and PET imaging with 11C-PK11195 radiotracer will be performed at baseline and 18 months.

Eligibility criteria: Inclusion Criteria:

* Signing the informed consent form
* Cladribine treatment is planned and indicated and is according to label
* 45-55 years of age at the time of signing the research informed consent form
* RRMS diagnosis in accordance with McDonald 2017 criteria

Exclusion Criteria:

* Patients with other neurodegenerative disease than MS
* Abnormal lymphocyte counts
* Patients with human immunodeficiency virus (HIV).
* Patients with active chronic infection (tuberculosis or hepatitis).
* Patients with active malignancy.
* Patients with moderate or severe renal impairment (creatinine clearance \<60 mL/min)
* Patients that are pregnant or breast-feeding
* Corticosteroid treatment within 4 weeks of imaging
* Patients with significant abnormal findings other than MS in the screening MRI.
* Patients with claustrophobia, or a history of moderate to severe anxiety disorder or panic attacks (which could potentially lead to preterm termination of the imaging)
* Contraindication to PET scan investigations
* Exposure to experimental radiation in the past 12 months such that radiodosimetry limits would be exceeded by participating in this study.
* Intolerance to previous PET scans; i.e. previous hypersensitivity reactions to any PET ligand or imaging agent or failure to participate in and comply with previous PET scans.
* Patients with previous alemtuzumab administration
* Patients with less than 6 months since previous administration of ocrelizumab or rituximab (or with abnormal B-cell counts)
* Patients with less than 1 month since previous administration of other disease modifying therapy

Primary outcomes:
measure: 11C-PK11195 binding in MS patient brain
timeFrame: baseline, 18 months
Secondary outcomes:
measure: MRI metrics
timeFrame: Baseline, 18 months
measure: Expanded Disability Status Scale
timeFrame: Baseline, 18 months
measure: Multiple Sclerosis Composite Score
timeFrame: Baseline, 18 months
measure: Blood biomarkers
timeFrame: Baseline, 18 months
measure: 11C-PK11195 difference in RRMS and historical healthy controls
timeFrame: Baseline, 18 months
measure: QSM-signal in MS patient brain
timeFrame: baseline, 18 months
Other outcomes:
Locations:
city: Turku
country: Finland
facility: Turku PET Centre
state: Finland Proper
Study officials:
affiliation: Turku University Hospital, division of clinical neurosciences
name: Laura Airas, Professor
role: PRINCIPAL_INVESTIGATOR
References: