Protective Role of Oxcarbazepine in Multiple Sclerosis (PROXIMUS)

April 17, 2018 updated by: Queen Mary University of London

OxCarbazepine as a Neuroprotective Agent in MS: A Phase 2a Trial

People with multiple sclerosis (MS) have nerve loss even without acute inflammatory relapses, as obvious in the progressive phase of disease. Drugs that may prevent nerve loss work better in earlier stages when it is difficult to measure progressive disability. But it is now possible to measure the nerve loss as neurofilament light (NFL) in the cerebrospinal fluid (CSF). This is a trial of a neuroprotective drug, oxcarbazepine, which showed benefit in an animal model of multiple sclerosis. The investigators will use an innovative outcome, a reduction in the content of NFL in the CSF, as well as the usual clinical disability and imaging methods, to measure the success of the oxcarbazepine as a neuroprotective agent in MS. The use of NFL, a surrogate marker of neurodegeneration, allows a blinded and accurate outcome.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Patients who have been identified as potentially eligible for this trial and referred to us will be invited to take part in the study and provided with information given as a patient information sheet. This includes patients with clinical definite MS who are on any DMDs, have not had a MS relapses for at least 6 months and feel (subjective) or are observed (objective) to have progressing disability.

For screening patients will sign the informed consent form after discussion and make sure they fulfil inclusion and exclusion criteria, they will have a neurological and a brief suicidality assessment and will have safety blood and urine tests. Patients will have a lumbar puncture to measure NFL in CSF. If it is above the threshold, showing that there is ongoing damage to the myelin, we will invite them to continue in the trial.

Patients will have a baseline brain and spinal cord MRI and OCT, clinical/neurological examination and will have a repeat lumbar puncture and collection of blood, urine and saliva. Patients will be blindly randomised to oxcarbazepine vs placebo and given the bottles of medication with each participant's individualised label.

At two and four weeks after the baseline visit, patients will have a phone visit when investigators will collect details of new symptoms, new medication and generally advise participants. The tablets should have been increases to two tablets in the morning and two tablets in the evening.

Patients will be seen by the study team at 13 weeks after initiation of the drug and again at 25 and 37 weeks when they will have an OCT, lumbar puncture, collection of blood, urine and saliva after general, visual, neurological and cognitive assessments/questionnaires.

The final visit will be at week 48, when a final lumbar puncture, preceded by clinical measures including general, visual, neurological and cognitive assessments/questionnaires, MRI , OCT and blood, urine & saliva collection.

The measurement of NFL will be repeated from the CSF samples on the same at the end of the study to determine whether patients with MS who were on oxcarbazepine had a reduction in the levels of CSF NFL.

Study Type

Interventional

Enrollment (Actual)

30

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • London, United Kingdom, E1 1BB
        • Barts Health NHS Trust

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 58 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • A diagnosis of definite multiple sclerosis
  • Treatment with DMDs for at least 6 months prior to baseline visit*
  • CSF NFL level ≥ 0.380ng/mL
  • EDSS score between 3.5 and 6.0
  • No history of relapses in the 6 months prior to the baseline visit
  • A history of slow progression of disability, objective or subjective, over a period of at least 6 months prior to baseline

  • Age 18-60 years

    • [Temporary interruption is permitted at the discretion of the investigator for a period of up to 8 weeks to prevent inflammatory MS reactivation. The cases where this could happen include for example switching DMDs that require a washout period as per clinical practice. When there are safety concerns, as in Lymphopenia or other side effects induced by the DMD, the interruption period can exceed 8 weeks as per clinical need. If reactivation of MS occurs with a relapse the investigator will assess if this meets withdrawal criteria 6.]

Exclusion Criteria:

  • Pregnant or breastfeeding or unwilling to use adequate contraception.*
  • Participants with a diagnosis of primary progressive PP MS or primary relapsing PR MS.
  • A clinical relapse or pulsed intravenous or oral steroids in the 6 months preceding the baseline assessment.
  • Participants presenting with medical disorder deemed severe or unstable by the CI such as poorly controlled diabetes or arterial hypertension, severe cardiac insufficiency, unstable ischemic heart disease, abnormal liver function tests (>2.5 times ULN) and abnormal complete blood count (in particular leukopenia, as defined by a lymphocyte count <500, neutrophil count <1.5 or platelet count <100, or thrombocytopenia <1.5 LLN), or any medical condition which, in the opinion of the investigator, would pose additional risk to the participant.
  • Infection with hepatitis B or hepatitis C or human immunodeficiency virus.
  • Exposure to any other investigational drug within 30 days of enrolment in the study.
  • Judged clinically to have a suicidal risk in the opinion of the investigator based upon a clinical interview and the Columbia Suicide-Severity Rating Scale (CSSRS).
  • Prior history of malignancy unless an exception is granted by the Investigator.
  • History of uncontrolled drug or alcohol abuse within 6 months prior to screening.
  • Past untoward reactions to OxCbz or Cbz

  • Participants receiving OxCbz or Cbz in the previous 12 weeks from baseline

    • [Adequate methods of contraception are non hormonal methods such as barrier methods, intrauterine devices, surgical sterilisation (undergone by the participant or their partner). Female participants using hormonal only forms of contraception will be required to use an additional barrier method. True abstinence can be considered an acceptable method of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception. Non sexually active participants or those in same sex relationships will not be required to commence contraception.]

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: OxCarbazepine Treatment
Treated for 48 weeks with OxCarbazepine 150mg twice a day alongside current DMDs.
Drug: Oxcarbazepine
Oxcarbazepine 150mg tablet, over encapsulated and back-filled with Microcrystalline Cellulose/Magnesium Stearate 1%.
Other Names:
  • Trileptal
Placebo Comparator: OxCarbazepine Placebo
Treated for 48 weeks with matched placebo 1 tablet twice a day alongside current DMDs
Drug: Placebo
Placebo in a matched capsule containing Microcrystalline Cellulose/Magnesium Stearate 1%.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Relative reduction of CSF neurofilament light chain levels
Time Frame: From baseline to week 48
CSF obtained from lumbar punctures will be used to determine neurofilament light chain levels from baseline to 48 weeks between the active and placebo treated arms.
From baseline to week 48

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety of Oxcarbazepine in multiple sclerosis patients
Time Frame: Ongoing throughout the trial
Safety of OxCbz in multiple sclerosis patients as indicated by a comparison of adverse events to expected side effects outlined in the summary of product characteristics
Ongoing throughout the trial
Relative reduction of CSF neurofilament levels
Time Frame: baseline, 24 weeks and 48 weeks
CSF obtained from lumbar punctures will be used to determine neurofilament light chain levels from baseline to 24 weeks and from 24 to 48 weeks between the active and placebo treated arms.
baseline, 24 weeks and 48 weeks
Change in clinical outcome measured by neurological examination.
Time Frame: Baseline, week 24 and week 48
A neurological examination, including EDSS and Sloan chart will be performed by a study neurologist.
Baseline, week 24 and week 48
Change in clinical outcome measured by cognitive assessment
Time Frame: Baseline, week 12, 24, 36 and 48
Cognitive assessment will consist of Symbol Digit Modalities Test (SDMT).
Baseline, week 12, 24, 36 and 48
Change in patient reported outcomes measured by questionnaires
Time Frame: Baseline, weeks 12, 24, 36 and 48
Patient questionnaires will include SF36, MSWS, MSIS-29 v2, Patient Pain Assessment and Patient Fatigue Assessment
Baseline, weeks 12, 24, 36 and 48

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
MRI scan to measure neurodegeneration
Time Frame: Baseline and week 48
MRI scan will measure brain grey matter atrophy, spinal cord atrophy and three novel measures, that have potential to detect more specific neuroaxonal abnormalities and the effect on them of a sodium blocking channel agent, such as OxCbz: (i) total sodium concentration, (ii) axonal diameter and (iii) axonal density.
Baseline and week 48
OCT to measure retinal nerve fibre layer (RNFL) for neurodegeneration
Time Frame: Baseline and weeks 24 and 48
retinal nerve fibre layer (RNFL) constitutes a good surrogate marker of neurodegeneration of the unmyelinated axons in the optic nerve after optic neuritis it has also been demonstrated that RNFL thinning occurs in SPMS not previously affected by optic neuritis.
Baseline and weeks 24 and 48
Biological samples collected to test for biomarkers of MS and correlation with response to OxCbz as a neuroprotector
Time Frame: Baseline, week 12, 24, 36 and 48
These biomarkers of MS include immunological, viral, CNS components of cellular and genetic markers in CSF/serum/urine samples. We will use these to compare between people who are treated/respond to treatment with OxCbz
Baseline, week 12, 24, 36 and 48

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Queen Mary University of London

Collaborators

Novartis Pharmaceuticals
University College, London
Barts & The London NHS Trust
Royal Free Hospital NHS Foundation Trust
Mid and South Essex NHS Foundation Trust
National Multiple Sclerosis Society
St George's Healthcare NHS Trust
Barnet and Chase Farm Hospitals NHS Trust

Investigators

  • Principal Investigator: Gavin Givannoni, Queen Mary University of London
  • Principal Investigator: Monica Calado Marta, Barts & The London NHS Trust

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2014

Primary Completion (Actual)

January 31, 2018

Study Completion (Actual)

January 31, 2018

Study Registration Dates

First Submitted

April 1, 2014

First Submitted That Met QC Criteria

April 1, 2014

First Posted (Estimate)

April 4, 2014

Study Record Updates

Last Update Posted (Actual)

April 18, 2018

Last Update Submitted That Met QC Criteria

April 17, 2018

Last Verified

April 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 8722
  • 2013-002419-87 (EudraCT Number)
  • 14-LO-0185 (Other Identifier: NRES Committee London - Harrow)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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