Effect of Corticosteroids on Inflammation at the Edge of Acute Multiple Sclerosis Plaques

The Effect of Corticosteroids on Inflammation at the Edge of Acute Multiple Sclerosis Plaques: An Investigator-Blinded Study

Background:

Multiple sclerosis (MS) affects the brain, spinal cord, and optic nerves. MS lesions can appear on the MRI (magnetic resonance imaging) scans in many ways. Sometimes they light up from the outer edge and fill inward. This is called ring enhancement. Researchers think this type of lesion may not heal as well as others. Corticosteroids are the standard treatment to reduce symptoms of MS relapse. But there is no standard treatment for people with enhancing MS lesions without signs of MS relapse. Researchers want to see if a short-term high-dose course of corticosteroids helps heal those lesions.

Objective:

To study the effects of short-term high-dose corticosteroids on ring-enhancing MS.

Eligibility:

Adults ages 25 and older who:

• Have MS and a rim-enhancing lesion on a prior brain MRI
• Are enrolled in another NINDS protocol

Design:

Participants will be screened under another protocol

Participants will be randomly assigned to get either no treatment or 3 days of treatment with a corticosteroid.

Participants will have:

• 1 baseline visit
• 3 days of high-dose steroids, intravenous or oral. If IV, participants will receive methylprednisolone by IV each day. Participants will also be prescribed medicine to protect their stomach.
• Follow-up visits will be at week 13 and week 25 after randomization to treatment or no treatment.

Visits include medical history and physical exam. Participants will have blood and urine tests. Participants will also have neurological exams and MRIs. Participants lie on a table that slides into a cylinder. They are in the scanner 1.5-2 hours. They get a dye through a catheter: A needle guides a thin plastic tube into an arm vein.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: Methylprednisolone; Drug: Prednisone

Detailed Description

Objectives. The primary aim of this pilot study is to assess the effects of short-term, high-dose corticosteroid administration on the 12-week evolution of multiple sclerosis lesions with centripetal enhancement pattern on magnetic resonance imaging (MRI), in particular with respect to the development of a hypointense rim on 7-tesla phase images. In our prior work, the phase rim has been associated with persistent deleterious inflammation with poor repair and ongoing neurodegeneration within lesions.

Study population. Up to 30 multiple sclerosis patients with asymptomatic contrast-enhancing lesions will be enrolled. Patients are randomly assigned to either 3 days of corticosteroids (intravenous methylprednisolone a 1000 mg/day or oral prednisone at 1250mg/day) or to no treatment.

Design. This is a multi-site study with Johns Hopkins University. Some analysis of identifiable data will be conducted at Johns Hopkins University JHU under a reliance agreement. Patients will not be consented to the study or participate in study interventions/procedures at JHU. Patients undergo serial brain MRIs with gadolinium-based contrast agent on both 3- and 7-tesla scanners over an approximate 25-week period. 3-tesla scans are obtained at baseline and week 25. 7-tesla scans are obtained at baseline and at weeks 13 and 25. Participants with one or more centripetal/rim-enhancing lesions at the baseline scan are randomized and followed. Clinical evaluation and blood testing are performed at baseline and weeks 13 and 25.

Outcome measures. The primary outcome measure is the presence or absence, on the week-13 7-tesla scan, of a hypointense phase rim in each of the lesions followed over time. Secondary outcome measures include the presence or absence of a hypointense phase rim at week 25, as well as the lesion volume and intralesional median R1 relaxation rate at weeks 13 and 25. From 3-tesla scans, we will measure the change in normalized intralesional proton density-weighted and T1-weighted signal, as well as the R1 relaxation rate, between baseline and week 25. We will also assess for the presence or absence of a hypointense phase at 3T. Additional exploratory outcome measures, including clinical and immunological assessments, will also be collected.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Daniel S Reich, M.D.; Phone Number: (301) 496-1801; Email: reichds@ninds.nih.gov
• Study Contact Backup: Name: Shari L Sawney; Phone Number: (301) 496-3825; Email: shari.sawney@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR); Phone Number: TTY8664111010 800-411-1222; Email: prpl@cc.nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:
• Multiple sclerosis, as defined by the 2017 Revised McDonald Criteria;
• Age 25 or older;
• Ability to provide informed consent;
• Able to participate in study procedures and provide high-quality clinical research and imaging data, based on limited artifacts on prior MRI scans and, when possible to determine;
• Presence of a gadolinium enhancing lesion on the screening (3T or 7T) brain MRI that demonstrates either centripetal/rim enhancement or a phase rim, or both;
• Simultaneously participates in another screening or natural history protocol within the NINDS Neuroimmunology Clinic at the time of study entry.
• Willing to use birth control if able to conceive a child

EXCLUSION CRITERIA:

• Medical contraindications for MRI (e.g., any non-organic implant or other device such as a cardiac pacemaker or infusion pump or other metallic implants, objects, or body piercings that are not MRIcompatible or cannot be removed);
• Psychological contraindications for MRI (e.g., claustrophobia), to be assessed at the time the medical history is collected;
• Treatment with systemic steroids in previous 30 days (non-systemic administration of steroids, such as topical or local injection, is acceptable);
• Experiencing new neurological symptoms, with onset in previous 2 weeks, attributable to MS relapse;
• Pregnancy or current breastfeeding;
• Screening labs, only if required per current NIH Clinical Center guidelines for kidney-function screening before gadolinium-based MRI contrast, demonstrating estimated glomerular filtration rate <60 mL/min;
• Known hypersensitivity to gadolinium-based contrast agents;
• Medical contraindications to corticosteroid administration (e.g., diabetes, gastric ulcer)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methylprednisolone; 3 day course of intravenous methylprednisolone 1000 mg/day	Drug: Methylprednisolone; 3 days of corticosteroids (intravenous methylprednisolone at 1000 mg/day
Experimental: prednisone; 3-day course of oral prednisone 1250 mg/day	Drug: Prednisone; 3 days of corticosteroids (oral prednisone at 1250 mg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the presence or absence of a hypointense phase rim around each lesion followed over time	At week 13, the presence or absence of a hypointense phase rim around each lesion followed over time.	at 13 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lesion volume and intralesional median R1 relaxation rate as determined from the 7T MP2RAGE scan,	Lesion volume and intralesional median R1 relaxation rate at weeks 13 and 25, as determined from the 7T MP2RAGE scan, comparing corticosteroid and no-treatment groups.	at week 13 and 25
The presence or absence of a hypointense phase rim around each lesion followed over time.	At week 25, the presence or absence of a hypointense phase rim around each lesion followed over time.	at week 25
The presence or absence of a 3T hypointense phase rim around each lesion	The presence or absence of a 3T hypointense phase rim around each lesion at week and 25	at week 25
The change in normalized intralesional proton density-weighted and T1-weighted signal, as well as the R1 relaxation rate, from 3T scan.	From 3-tesla scans, we willmeasure the change in normalized intralesional proton density-weighted and T1-weighted signal, as wellas the R1 relaxation rate, between baseline and week 25.	week 25

Collaborators and Investigators

• Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Daniel S Reich, M.D., National Institute of Neurological Disorders and Stroke (NINDS)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): October 5, 2016
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: May 26, 2016
• First Submitted That Met QC Criteria: May 26, 2016
• First Posted (Estimated): May 27, 2016

Study Record Updates

• Last Update Posted (Actual): April 5, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: October 25, 2023

More Information

Terms related to this study

• Keywords: MRI; MS; Gadolinium; Centripetal Enhancement; 7 Tesla
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Inflammation; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Prednisone
• Other Study ID Numbers: 160114; 16-N-0114

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .All IPD that results in publication
• IPD Sharing Time Frame: 6 months after publication
• IPD Sharing Access Criteria: Will be shared under tech transfer agreements
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

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