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Protective Role of Oxcarbazepine in Multiple Sclerosis (PROXIMUS)

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ClinicalTrials.gov Identifier: NCT02104661
Recruitment Status : Recruiting
First Posted : April 4, 2014
Last Update Posted : January 10, 2017
Sponsor:
Collaborators:
Information provided by (Responsible Party):

Study Description
Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Multiple Sclerosis Drug: Oxcarbazepine Drug: Placebo Phase 2

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 Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: OxCarbazepine as a Neuroprotective Agent in MS: A Phase 2a Trial
Study Start Date : October 2014
Estimated Primary Completion Date : December 2017
Estimated Study Completion Date : March 2018

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

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 Name: 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%.


Outcome Measures

Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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.

  4. 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).

  5. 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


Other Outcome Measures:
  1. 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.

  2. 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.

  3. 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


Eligibility Criteria

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.]
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02104661


Contacts
Contact: Monica Calado Marta m.calado-marta@qmul.ac.uk

Locations
United Kingdom
Barts Health NHS Trust Recruiting
London, United Kingdom, E1 1BB
Contact: Monica Calado Marta       m.calado-marta@qmul.ac.uk   
Contact: Omeada Adams    0207 882 7150    omeada.adams@bartshealth.nhs.uk   
Principal Investigator: Gavin Giovannoni         
Principal Investigator: Monica Calado Marta         
Sub-Investigator: Olga Ciccarelli         
Sub-Investigator: Jeremy Chataway         
Sub-Investigator: Klaus Schmierer         
Sub-Investigator: Raj Kapoor         
Sponsors and Collaborators
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
Investigators
Principal Investigator: Gavin Givannoni Queen Mary University of London
Principal Investigator: Monica Calado Marta Barts & The London NHS Trust
More Information

Publications:
Al-Izki S et al. Selective targeting of neuroprotection to MS lesions: sodium channel blockers in experimental autoimmune encephalomyelitis. In: Multiple Sclerosis Journal.; 2011:S53-S276
Lidster K et al. Neuroprotection in a novel optic neuritis model. In: Multiple Sclerosis Journal.; 2011:S227-S505 17
Hobart J. The Multiple Sclerosis Impact Scale (MSIS-29). In: Quality of Life Measurement in Neurodegenerative and Related Conditions. Cambridge University Press; 2011:pp. 24-40
Paling D et al. Total sodium concentration is increased in lesions and normal appearing white matter in Multiple Sclerosis. In: ISMRM.; 2012
Schneider T. Mapping the axon diameter index in the corpus callosum is clinically feasible. In: ISMRM.; 2012
Petzold A, Altintas A, Andreoni L, Bartos A, Berthele A, Blankenstein MA, Buee L, Castellazzi M, Cepok S, Comabella M, Constantinescu CS, Deisenhammer F, Deniz G, Erten G, Espiño M, Fainardi E, Franciotta D, Freedman MS, Giedraitis V, Gilhus NE, Giovannoni G, Glabinski A, Grieb P, Hartung HP, Hemmer B, Herukka SK, Hintzen R, Ingelsson M, Jackson S, Jacobsen S, Jafari N, Jalosinski M, Jarius S, Kapaki E, Kieseier BC, Koel-Simmelink MJ, Kornhuber J, Kuhle J, Kurzepa J, Lalive PH, Lannfelt L, Lehmensiek V, Lewczuk P, Livrea P, Marnetto F, Martino D, Menge T, Norgren N, Papuć E, Paraskevas GP, Pirttilä T, Rajda C, Rejdak K, Ricny J, Ripova D, Rosengren L, Ruggieri M, Schraen S, Shaw G, Sindic C, Siva A, Stigbrand T, Stonebridge I, Topcular B, Trojano M, Tumani H, Twaalfhoven HA, Vécsei L, Van Pesch V, Vanderstichele H, Vedeler C, Verbeek MM, Villar LM, Weissert R, Wildemann B, Yang C, Yao K, Teunissen CE. Neurofilament ELISA validation. J Immunol Methods. 2010 Jan 31;352(1-2):23-31. doi: 10.1016/j.jim.2009.09.014. Epub 2009 Oct 24.

Responsible Party: Queen Mary University of London
ClinicalTrials.gov Identifier: NCT02104661     History of Changes
Other Study ID Numbers: 8722
2013-002419-87 ( EudraCT Number )
14-LO-0185 ( Other Identifier: NRES Committee London - Harrow )
First Posted: April 4, 2014    Key Record Dates
Last Update Posted: January 10, 2017
Last Verified: January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Sclerosis
Multiple Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Oxcarbazepine
Carbamazepine
Neuroprotective Agents
Anticonvulsants
Voltage-Gated Sodium Channel Blockers
Sodium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP3A Inducers
Cytochrome P-450 Enzyme Inducers
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Psychotropic Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Protective Agents