Clinical and Imaging Patterns of Neuroinflammation Diseases in China (CLUE)

Prospective Cohort Study of Clinical and Imaging Patterns of Neuroinflammation Diseases (CLUE)

CLUE is a prospective study to determine structural and functional changes of brain and spinal cord, as well as the inflammatory environment in patients with neuroinflammatory and demyelination disease. Subjects will receive new magnetic resonance (MR) technics including double inversion recovery (DIR) imaging diffusion kurtosis imaging (DKI), quantitative susceptibility mapping (QSM) and resting-state functional imaging and follow up for one year.

Study Overview

• Status: Recruiting
• Conditions: MRI; Multiple Sclerosis; NMO Spectrum Disorder
• Intervention / Treatment: Drug: Intravenous steroid

Detailed Description

The study is an observational study of multi model imaging to determine structural and functional changes of brain and spinal cord, as well as the inflammatory environment in patients with neuroinflammatory and demyelination disease. Brain and spinal cord involvement are common in neuroinflammatory and demyelination disease including clinical isolated syndrome (CIS), multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSDs). The pathophysiology in neuroinflammatory disease involves the intensive autoimmune inflammatory response, resulting in demyelination and neuroaxonal injury and loss. Some cerebrospinal fluid (CSF) biomarkers have been reported to indicate the pathology and reflect disease activity especially during acute stage. But they couldn't directly reflect the macroscopic and microscopic neuroaxonal change in brain and spinal cord, which seem to be important determinants of long-term severe disability in chronic neuroinflammatory disease.

Finally, new MRI techniques are the most reliable and non-invasive method to assess the structure and function of brain and spinal cord, plus to monitor disease activity in clinical practice. Double inversion recovery (DIR) imaging allows better detection of cortical and white matter lesion, which has highlighted the role in MS. Diffusion kurtosis imaging (DKI) which has been proposed to characterize the deviation of water diffusion in neural tissues from Gaussian diffusion, is promising to provide information of demyelination and subsequent inflammatory processes in brain or spinal cord. Quantitative susceptibility mapping (QSM) has enabled MRI of tissue magnetic susceptibility to advance from simple qualitative detection of hypointense blooming artifacts to precise quantitative measurement of spatial biodistributions. QSM better depicts spatial susceptibility patterns in MS lesions compared to phase-based imaging. Besides, resting-state functional imaging has the potential to map the intrinsic functional brain networks and to detect early functional brain changes in neuroinflammatory disease.

This study will be a prospective cohort study of patients with neuroinflammatory and demyelination disease. Subjects will undertake MR scans at acute stage, and required follow-up visits after 1 moth, 6 months and one year. The MR scans is necessary at each visit.

This study does not limit treatment methods. Patients commonly use high-dose intravenous steroid therapy (HD-S) during acute stage. The HD-S treatment course referred to intravenous administration of 1 g of glucocorticoid daily for 3 consecutive days and continuous dose 240 mg reduction for 60mg oral administration. Immunomodulatory therapies are necessary for the remission stage. The treatment methods include: Azathioprine (start at 50 mg per day, add 50 mg per week to 2 mg/kg*d); Mycophenolate Mofetil (The initial dose was 0.25g bid, add 0.5g per week to 0.75g bid); and Rituximab (500 mg on the 1st day, the 15th day, then 500mg per half year).

• Study Type: Observational
• Enrollment (Anticipated): 1000

Contacts and Locations

• Study Contact: Name: Yaou Liu, PhD; Phone Number: +86 1059975396; Email: yaouliu80@163.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100053
      • Recruiting
      • Beijing Tiantan Hospital
      • Contact: Yaou Liu, PhD; Phone Number: +86 1059975396; Email: yaouliu80@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

To reflect the daily practices, this study includes all patients with neuroinflammatory and demyelination disease at the beginning of the study.

Description

Inclusion Criteria:

• 18-60
• Diagnosis of neuroinflammatory and demyelination disease
• Availability of demographic and clinical data at the time disease onset
• Informed written consent obtained from the patient, and/or patient's parent(s), and/or legal representative. Assent, if old enough to grant, will be obtained from all patients under the age of 18 years.

Exclusion Criteria:

• Patients for whom MRI is contra-indicated
• Patients included in an ongoing clinical trial where the product is blinded

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
NMOSD; Patients with neuromyelitis optica spectrum disorders	Drug: Intravenous steroid; This study does not limit treatment methods.patients commonly use high-dose intravenous steroid therapy (HD-S) during acute stage. The HD-S treatment course referred to intravenous administration of 1 g of glucocorticoid daily for 3 consecutive days and continuous dose 240 mg reduction for 60mg oral administration. Immunomodulatory therapies are necessary for the remission stage. The treatment methods include: Azathioprine (start at 50 mg per day, add 50 mg per week to 2 mg/kg.d); Mycophenolate Mofetil (The initial dose was 0.25g bid, add 0.5g per week to 0.75g bid); and Rituximab (500 mg on the 1st day, the 15th day, then 500mg per half year).; Other Names: Rituximab; Mycophenolate Mofetil; Azathioprine
Multiple sclerosis(MS); Patients with multiple sclerosis	Drug: Intravenous steroid; This study does not limit treatment methods.patients commonly use high-dose intravenous steroid therapy (HD-S) during acute stage. The HD-S treatment course referred to intravenous administration of 1 g of glucocorticoid daily for 3 consecutive days and continuous dose 240 mg reduction for 60mg oral administration. Immunomodulatory therapies are necessary for the remission stage. The treatment methods include: Azathioprine (start at 50 mg per day, add 50 mg per week to 2 mg/kg.d); Mycophenolate Mofetil (The initial dose was 0.25g bid, add 0.5g per week to 0.75g bid); and Rituximab (500 mg on the 1st day, the 15th day, then 500mg per half year).; Other Names: Rituximab; Mycophenolate Mofetil; Azathioprine
Health control(HC); Healthy people without any neuroinflammation disease

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The brain structural change over time between the baseline MRI and the follow-up MRIs	To describe changes of lesions, grey matter and white matter in patients with neuroinflammatory and demyelination disease measured by DIR and QSM. The primary endpoint is the change over time between the baseline MRI and the follow-up MRIs, of the lesions and brain volumes.	On admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later
The spinal cord change over time between the baseline MRI and the follow-up MRIs.	To describe changes of lesions and integrity of fiber bundle in spinal cord in neuroinflammatory and demyelination disease patients measured by DKI. The primary endpoint is the change over time between the baseline MRI and the follow-up MRIs, of structural change in spinal cord.	On admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later
The functional change over time between the baseline MRI and the follow-up MRIs.	To describe brain functional changes in patients with neuroinflammatory and demyelination disease measured by resting-state functional imaging. The primary endpoint is the functional change over time between the baseline MRI and the follow-up MRIs	On admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline Expanded Disability Status Scale （EDSS）/ Functional Systems （FS）	admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later.] The Kurtzke Expanded Disability Status Scale (EDSS) was developed to measure the disability status of subjects with multiple sclerosis. It allows an objective quantification of the level of functioning that could be widely and reproducibly used by researchers and health care providers. The EDSS provides a total score on a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to Multiple sclerosis (MS). In addition, it also provides eight subscale measurements called Functional System (FS) scores.	On admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later
Timed 25-foot Walk	Timed 25-foot walking trials will be assessed on admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later. The Timed 25-Foot Walk test is a quantitative measure of lower extremity function. If required, the subject may use an appropriate assistive device to walk as quickly as he/she can from one end to the other end of a clearly marked, unobstructed, 25-foot course. Timing will begin when any part of the subject's foot crosses the tape. Timing will end when any part of the subject's foot crosses the finish line (identified by a taped mark on the floor). Time will be recorded in seconds. The task is immediately administered again (a maximum five-minute rest period is allowed between trials) by having the subject walk back the same distance. The average of the two values will be recorded.	On admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later
Mean change in visual acuity as assessed by Sloan 2.5% low contrast visual acuity chart.	admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later.] Low Contrast Visual Acuity: Low-contrast Sloan letter charts are readily available and provide a practical, quantitative, and standardized assessment of visual function. Each chart consists of rows of black letters (decreasing in size from top to bottom) on a white background. For this trial, 2.5% low contrast visual acuity will be measured on days 1 and 5 during the steroid phase and completion after the plasma exchange phase. Charts will be read at a 2.5-meter distance by trained examiners in the hospital room with constant lighting.	On admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later

Collaborators and Investigators

• Sponsor: Beijing Tiantan Hospital
• Investigators: Principal Investigator: Yaou Liu, PhD, Beijing Tiantan Hospital

Publications and helpful links

General Publications

• Xu Y, Ren Y, Li X, Xu W, Wang X, Duan Y, Liu Y, Zhang X, Tian DC. Persistently Gadolinium-Enhancing Lesion Is a Predictor of Poor Prognosis in NMOSD Attack: a Clinical Trial. Neurotherapeutics. 2021 Apr;18(2):868-877. doi: 10.1007/s13311-020-00973-9. Epub 2021 Jan 19.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2019
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): December 31, 2025

Study Registration Dates

• First Submitted: September 25, 2019
• First Submitted That Met QC Criteria: September 25, 2019
• First Posted (Actual): September 27, 2019

Study Record Updates

• Last Update Posted (Actual): July 20, 2022
• Last Update Submitted That Met QC Criteria: July 19, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Eye Diseases; Optic Nerve Diseases; Cranial Nerve Diseases; Myelitis, Transverse; Optic Neuritis; Multiple Sclerosis; Neuromyelitis Optica; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Azathioprine; Mycophenolic Acid
• Other Study ID Numbers: KY 2019-050-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Clinical and MR data can be shared.
• IPD Sharing Time Frame: Within 5 years after the end of the trial.
• IPD Sharing Access Criteria: Neurologist and radiologist who submitting an application to Prof. Liu.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No