Anakinra for the Treatment of Chronically Inflamed White Matter Lesions in Multiple Sclerosis

Background:

Multiple sclerosis (MS) is a disease of the central nervous system (CNS). People who have MS may have lesions that form on parts of the CNS, such as the brain. Some of these lesions may be inflamed for a long time. This causes MS to progress. There is no treatment for these lesions. Researchers believe that a drug that decreases inflammation can help.

Objective:

To see if a drug called anakinra can help clear inflammation in MS brain lesions.

Eligibility:

People 18 and older with MS and at least one white matter lesion.

Design:

Participants will be screened with one or more Neuroimmunology Clinic protocols.

Participants will have a medical history and physical exam. They will have blood and urine tests. They will have a lumbar puncture. For this, a needle is inserted between the bones in the back, and cerebrospinal fluid is removed. They will also have an MRI of the brain. The MRI scanner is a cylinder surrounded by a strong magnetic field. Participants will lie on a table that slides in and out of the scanner.

Participants will repeat the above procedures throughout the study.

Participants will get their first dose of anakinra at the clinic. They will administer the rest of the doses themselves, by injection under the skin.

Participants will track their daily dosage electronically or in a written drug diary.

Participants will have 4 visits while taking the drug. At each visit, sharps boxes and empty vials will be collected.

Participants will have 2 follow-up visits after completing treatment.

The study will last 28 weeks.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: Anakinra

Detailed Description

Objective:

The overall goal of this study is to determine the safety, tolerability, and radiological efficacy of up to 12 weeks of subcutaneous injection of anakinra in people with multiple sclerosis and evidence, by magnetic resonance imaging (MRI), of chronic active (also known as smoldering ) lesions in the white matter.

Study population:

5 people with progressive or stable MS, at least one paramagnetic rim lesion on 7-tesla MRI, and no new white matter lesion formation for at least 3 months or clinical relapse for at least 12 months, will complete the study.

Design:

In this open label, dose escalation study, participants will receive up to 12 weeks of

subcutaneous anakinra with initial dose of 100 mg daily up to a target dose of 300 mg daily. Study visits will occur every 4 weeks while on treatment, with 2 follow-up visits at 4 and 12 weeks after treatment discontinuation.

Outcome measures:

The primary outcome measure is disappearance of one or more paramagnetic rims from white matter lesions identified at baseline. Secondary outcomes include safety and tolerability, clinical and radiological outcomes. Exploratory serological and CSF measures will also be obtained to investigate mechanism of action of anakinra and for biomarker development.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:
• Age greater than or equal to 18
• Ability to give informed consent
• If fertile, agreement to use an effective method of birth control during the study and for up to 3 months after the last dose of the study drug
• Agreement not to participate in any other interventional study while participating in this protocol
• Diagnosis of MS, either stable or clinically progressive
• Prior 7-tesla MRI scan, with high image quality in the judgment of the study neuroradiologist, demonstrating at least one white matter lesion with a paramagnetic rim (41)

EXCLUSION CRITERIA:

• Pregnancy or current breastfeeding
• Use of another investigational agent within 1 month of screening
• Active infection and or neutropenia (ANC < 1000 cells/microliter)
• History of lymphoma
• Known hypersensitivity to administration of anakinra
• Previous treatment with anakinra and/or TNF-receptor inhibitor
• History of asthma
• QuantiFERON-TB gold positive
• Prior treatment with anti-CD20 agent (ocrelizumab, rituximab)
• Prior treatment with anti-CD52 agent (alemtuzumab)
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial or interfere with participation for the full duration of the trial; or not in the best interest of the subject to participate, in the opinion of the treating investigator
• Renal dysfunction, as defined by Clinical Center guidelines for administration of gadolinium
• Liver dysfunction, as indicated by baseline aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 1.5 times the upper limit of normal
• Clinical relapse in the 12 months prior to dosing
• New lesion formation (by comparison of screening MRI to a previous MRI of sufficient quality) in the 3 months prior to dosing
• One or more gadolinium-enhancing lesions on the screening scan
• Change in disease-modifying therapy in the 6 months prior to dosing
• Medical contraindication for 7-tesla MRI (including, but not limited to, 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 MRI-compatible or cannot be removed)
• Psychological contraindication for 7-tesla MRI (e.g., claustrophobia)
• Contraindication to gadolinium administration.
• Active neoplastic disease or any medical condition, other than MS, that requires concurrent immunosuppression or immunomodulation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1/Active treatment; Patients with MS will be assigned to the same intervention	Drug: Anakinra; 100 mg daily weeks 1-4, 200 mg daily weeks 5-8, 300 mg daily weeks 9-12.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modulation of One or All Paramagnetic Rim Lesions	Proportion of lesions in which the paramagnetic rim has been modulated at the end of the dosing period.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the 9-hole Peg Test (9HPT)	The Nine-Hole Peg Test (9-HPT) is a standardized, quantitative assessment used to measure finger dexterity. The test is administered by asking the participant to take pegs from a container, one by one, and place them into holes on a board as quickly as possible. Participants must then remove the pegs from the holes, one by one, and replace them back into the container. The test is timed with a lower number suggesting faster finger dexterity and a higher number suggesting slower finger dexterity. The results represent the mean change from baseline to end of dosing.	24 weeks
Change in the Symbol Digit Modalities Test (SDMT)	The Symbol Digit Modalities Test (SDMT) is a neuropsychological test that assesses cognitive status, including processing speed, visual scanning, tracking, and motor speed. Participants are given a set of nine symbol-digit pairs and a sequence of symbols. They then have 90 seconds to match as many symbols in the sequence to their corresponding numbers as possible. The score is the number of correct substitutions within the 90 second interval, with a maximum of 110. The results represent a change from baseline to the end of dosing.	24 weeks
Change in the Expanded Disability Status Scale (EDSS)	The EDSS is a tool used to measure the severity of multiple sclerosis (MS). The EDSS is based on a combination of scores from eight functional systems (FS), i.e., Muscle weakness, Balance, Coordination and Tremor, Eye Movements, Speech/Swallowing, Unusual Sensations or Numbness, Bowel and Bladder, Eyesight, and Thinking and Memory, and the Disability Status Scale (DSS). The EDSS is a scale that ranges from 0 to 10, with higher scores indicating greater disability. Scores of 1.0 to 4.5 indicate a high degree of ambulatory ability, while scores of 5.0 to 9.5 indicate a loss of ambulatory ability. The results represent a change from baseline to the end of dosing.	24 weeks
Change in Paramagnetic Rim Lesion at Any Time Point	Participants underwent 7T MRI during the dosing period and the post-dosing period. The results presented describe the proportion of paramagnetic rim lesions in which the rim was diminished or disappeared during the dosing period (weeks 0-12), during the post-dosing period (weeks 12-24) and during the entire study (weeks 0-24).	Up to 24 weeks
Change in Size of Paramagnetic Rim Lesions at All Time Points, Relative to Non-rim Lesions	Paramagnetic rim lesions are multiple sclerosis plaques showing signs of low-grade, ongoing inflammation on MRI. Participants underwent MRI every 4 weeks and we compared the change in size between the participant's paramagnetic rim lesions (PRL+) and non-paramagnetic rim lesions (PRL-). At each time point, the mean group volume of each PRL+ and PRL- was calculated. The results provided include the group means and confidence limits at each time point for PRL+ and PRL- lesion type.	Every 4 weeks for the duration of the study
Changes in T1 Relaxation Time Within Paramagnetic Rim Lesions at All Time Points, Relative to Non-rim Lesions	Paramagnetic rim lesions are multiple sclerosis plaques showing signs of low-grade, ongoing inflammation on MRI. T1 relaxation time is a measure of brain damage on MRI. Participants underwent MRI every 4 weeks and we compared the change in T1 relaxation time between the participant's paramagnetic rim lesions (PRL+) and non-paramagnetic rim lesions (PRL-) at each time point. The results provided include the group means and confidence limits at each time point for PRL+ and PRL- lesion type.	Every 4 weeks for the duration of the study

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 25, 2019
• Primary Completion (Actual): October 24, 2023
• Study Completion (Actual): October 24, 2023

Study Registration Dates

• First Submitted: July 18, 2019
• First Submitted That Met QC Criteria: July 18, 2019
• First Posted (Actual): July 19, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 9, 2024
• Last Verified: October 25, 2023

More Information

Terms related to this study

• Keywords: White Matter; Chronic Active Lesions; Ultra-high-field (7T) MRI; Interleukin-1 (IL-1); Paramagnetic Rim
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis; Sclerosis; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: 190124; 19-N-0124

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No