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Protective Role of Oxcarbazepine in Multiple Sclerosis (PROXIMUS)

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ClinicalTrials.gov Identifier: NCT02104661
Recruitment Status : Completed
First Posted : April 4, 2014
Last Update Posted : April 18, 2018
Sponsor:
Collaborators:
National Multiple Sclerosis Society
Novartis Pharmaceuticals
Barts & The London NHS Trust
University College, London
Royal Free Hospital NHS Foundation Trust
Southend University Hospital
Basildon and Thurrock University Hospitals NHS Foundation Trust
St George's Healthcare NHS Trust
Barnet and Chase Farm Hospitals NHS Trust
Information provided by (Responsible Party):
Queen Mary University of London

April 1, 2014
April 4, 2014
April 18, 2018
October 2014
January 31, 2018   (Final data collection date for primary outcome measure)
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.
Same as current
Complete list of historical versions of study NCT02104661 on ClinicalTrials.gov Archive Site
  • 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
  • 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.
  • 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.
  • 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).
  • 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
Same as current
  • 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.
  • 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.
  • 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
Same as current
 
Protective Role of Oxcarbazepine in Multiple Sclerosis
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.

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.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Multiple Sclerosis
  • Drug: Oxcarbazepine
    Oxcarbazepine 150mg tablet, over encapsulated and back-filled with Microcrystalline Cellulose/Magnesium Stearate 1%.
    Other Name: Trileptal
  • Drug: Placebo
    Placebo in a matched capsule containing Microcrystalline Cellulose/Magnesium Stearate 1%.
  • Experimental: OxCarbazepine Treatment
    Treated for 48 weeks with OxCarbazepine 150mg twice a day alongside current DMDs.
    Intervention: Drug: Oxcarbazepine
  • Placebo Comparator: OxCarbazepine Placebo
    Treated for 48 weeks with matched placebo 1 tablet twice a day alongside current DMDs
    Intervention: Drug: Placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
30
60
January 31, 2018
January 31, 2018   (Final data collection date for primary outcome measure)

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.]
Sexes Eligible for Study: All
18 Years to 60 Years   (Adult)
No
Contact information is only displayed when the study is recruiting subjects
United Kingdom
 
 
NCT02104661
8722
2013-002419-87 ( EudraCT Number )
14-LO-0185 ( Other Identifier: NRES Committee London - Harrow )
Yes
Not Provided
Plan to Share IPD: No
Queen Mary University of London
Queen Mary University of London
  • National Multiple Sclerosis Society
  • Novartis Pharmaceuticals
  • Barts & The London NHS Trust
  • University College, London
  • Royal Free Hospital NHS Foundation Trust
  • Southend University Hospital
  • Basildon and Thurrock University Hospitals NHS Foundation Trust
  • St George's Healthcare NHS Trust
  • Barnet and Chase Farm Hospitals NHS Trust
Principal Investigator: Gavin Givannoni Queen Mary University of London
Principal Investigator: Monica Calado Marta Barts & The London NHS Trust
Queen Mary University of London
April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP