Clinical trial NCT04025554: Anakinra for the Treatment of Chronically Inflamed White Matter Lesions in Multiple Sclerosis
Official title: Anakinra for the Treatment of Chronically Inflamed White Matter Lesions in Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Sclerosis
Keywords: Chronic Active Lesions
Ultra-high-field (7T) MRI
Interleukin-1 (IL-1)
White Matter
Paramagnetic Rim
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2019-07-19
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: * 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

Primary outcomes:
measure: Modulation of One or All Paramagnetic Rim Lesions
timeFrame: 24 weeks
Secondary outcomes:
measure: Change in the 9-hole Peg Test (9HPT)
timeFrame: 24 weeks
measure: Change in the Symbol Digit Modalities Test (SDMT)
timeFrame: 24 weeks
measure: Change in the Expanded Disability Status Scale (EDSS)
timeFrame: 24 weeks
measure: Change in Paramagnetic Rim Lesion at Any Time Point
timeFrame: Up to 24 weeks
measure: Change in Size of Paramagnetic Rim Lesions at All Time Points, Relative to Non-rim Lesions
timeFrame: Every 4 weeks for the duration of the study
measure: Changes in T1 Relaxation Time Within Paramagnetic Rim Lesions at All Time Points, Relative to Non-rim Lesions
timeFrame: Every 4 weeks for the duration of the study
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institute of Neurological Disorders and Stroke (NINDS)
name: Daniel S Reich, M.D.
role: PRINCIPAL_INVESTIGATOR
References: