Healthy Volunteers
Conditions
Keywords
gadobutrol, Intrathecal, lymphatics clearance
Brief summary
Background: Cerebrospinal fluid (CSF) is the liquid that fills the space around the brain and spinal cord. Researchers do not fully understand how CSF flows and drains around the brain. They want to test a tracer (gadobutrol)-a special dye injected into the CSF-to find out if it is safe to use and can help them get clearer pictures of the CSF during magnetic resonance imaging (MRI) scans of the brain. Objective: To test gadobutrol in the CSF during MRI scans of healthy people. Eligibility: Healthy volunteers aged 18 years and older. They must be screened under NIH protocol 89N0045. Design: Participants will check into the clinic for a 3-day stay. They will have a lumbar puncture: An area on their lower back will be numbed. A thin needle will be inserted into the space around the spinal cord. A sample of CSF will be taken for research. Then a low dose of gadobutrol will be injected into the CSF. Participants will have 4 or 5 MRI scans of the brain-30 minutes, 4 hours, 8 hours (this one is optional), 24 hours, and 48 hours after receiving the gadobutrol. For the scan, they will lie on a table that slides into a cylinder. Special padding will be used to hold their head still. The MRI uses magnetic fields to create images of the inside of the body. Blood and urine samples will also be collected at each scan. Participants will return for an additional MRI 1 week after they leave the clinic. They will have 2 follow-up phone calls 4 and 12 weeks after the start of the study.
Detailed description
Study Description: In this study, we will gather safety data on and establish the technical feasibility of bypassing the blood-brain-barrier (BBB) with intrathecal (IT) gadolinium-based contrast agent (GBCA) tracer injection (0.25 ml gadobutrol at a concentration of 1.0 mmol/ml) to dynamically image the subarachnoid space (SAS) in human healthy volunteers. We will also obtain preliminary data on whether this approach will enable us to reliably visualize physiological meningeal lymphatic drainage pathways within the parasagittal dura (PSD) and connections to cerebrospinal fluid (CSF) compartments using serial contrast-enhanced magnetic resonance imaging (CE-MRI) with minimal confounding signal from tracer blood egress. In exploratory analysis, we will quantify temporal clearance kinetics and investigate distribution patterns of GBCA enhancement in the PSD, CSF spaces, and brain parenchyma in up to 12 healthy volunteers using repeated in vivo CE-MRI over 10 days. Safety/tolerability of the IT GBCA administration will be assessed descriptively over the entire 12-week study period. Objectives: Primary objective: To track safety/tolerability of IT GBCA administration in healthy human volunteers. Secondary objective: To establish technical feasibility of dynamic subarachnoid-space imaging using IT GBCA administration in healthy human volunteers. Exploratory objectives: To explore patterns of dynamic meningeal lymphatic clearance pathway interconnections in vivo under physiological conditions in human healthy volunteers, and to obtain preliminary data regarding the effect of aging on CSF dynamics and CSF-to-blood tracer clearance. Endpoints: Primary endpoint: Occurrence of intervention-emergent adverse events at the participant level assessed descriptively over the 12-week study period. Secondary outcome measure: MRI detection status (yes/no) of contrast in the cerebral SAS at 24 hours. Exploratory outcome measures: Changes in contrast-to-noise ratio (CNR) and clearance kinetics of SAS to brain parenchyma over 48h.
Interventions
DRUGGadobutrol
contrast agent
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: To be eligible to participate in this study, an individual must meet all the following criteria: * Healthy volunteer. * Age \>= 18 years. To explore age-related effects on tracer dynamics and clearance, 3 cohorts of participants will be recruited: 1) 18-30 years, 2) 30-55 years, and 3) \>55 years; with 2 males and 2 females in each age group. * Able to give written and oral informed consent. * Prior evaluation under NIH protocol 89N0045.
Exclusion criteria
An individual who meets any of the following criteria will be excluded from participation in this study: * History of chronic neurological illness, or significant concurrent medical illness. * Contraindication to 3- or 7-tesla MRI * Hypersensitivity reactions to contrast agents. * History of severe allergic reactions. * Pregnancy or breastfeeding. * Renal dysfunction or other serious comorbidities. * Platelet count \<100,000/microliter, INR \> 1.5 or prolonged PT or aPTT at baseline. * Any of the following imaging findings: Mass effect, midline shift, herniation (tonsillar, uncal, subfalcine), or Chiari malformation. * History of seizures or seizure disorder. * Anti-coagulation therapy. * Unwilling to allow coded samples to be processed offsite. * Unwilling to have coded samples and/or data saved or used in other studies.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of intervention-emergent adverse events at the participant level assessed descriptively | 12-week study period. | Systematic recording of adverse events is essential to determine the safety of IT gadobutrol, especially given its off-label use in healthy volunteers. With the limited sample size of this Phase 1 study, safety assessment is appropriately based on a descriptive evaluation rather than formal hypothesis testing. Monitoring known procedure- and contrast-related risks (e.g., post-lumbar puncture headache, nausea, dizziness) as well as any unexpected adverse events over the study and follow-up period provides the critical foundation for ethical justification and regulatory decision-making and is a prerequisite for future feasibility and efficacy-driven studies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participant-level MRI detection status (yes/no) of contrast in the cerebral SAS | 24 hours | Technical feasibility is assessed by determining whether IT administered GBCA can be visually detected in the cerebral SAS at 24 hours under exploratory Phase 1 conditions. As this is a pilot safety study with limited prior human data, feasibility is not used as a stopping criterion. Instead, MRI visibility of contrast will inform adaptive dose escalation. If no or insufficient contrast enhancement is observed in 3 to 5 participants at the initial dose level (0.25 ml), the dose may be escalated to 0.5 ml to improve detectability. This predefined adaptation is intended to support appropriate dose selection for subsequent studies while maintaining the focus on safety. |
Countries
United States
Contacts
CONTACTMaria I Gaitan, M.D.
CONTACTDaniel S Reich, M.D.
PRINCIPAL_INVESTIGATORDaniel S Reich, M.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Outcome results
None listed