Clinical Trial of Idebenone in Primary Progressive Multiple Sclerosis (IPPoMS)
Condition: Primary Progressive Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

        -  Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system that
           progressively weakens and destroys the pathways of the nervous system. About 10 percent
           to 15 percent of patients develop primary-progressive MS (PP-MS), characterized by
           progressive accumulation of disability from the disease onset, without any marked
           improvements or relapses. There are currently no effective treatments for PP-MS.

        -  Idebenone is a manmade drug that is similar to a naturally occurring compound known as
           coenzyme Q10, a common dietary supplement. Research data suggest that idebenone may be
           able to limit demyelination and death of brain cells and thereby slow or halt the
           progression of neurological dysfunction such as that occurring in MS.

      Objectives:

      - To evaluate the safety and effectiveness of using idebenone to treat primary progressive
      MS.

      Eligibility:

      - Individuals between 18 and 65 years of age who have been diagnosed with primary progressive
      multiple sclerosis.

      Design:

        -  The study will last 3 years and will be divided into two parts: a 1-year pretreatment
           baseline and 2 years of treatment with either idebenone or a placebo.

        -  Pre-treatment study: approximately 5 clinic visits over 1 year.

        -  Visit 1: Comprehensive medical history and neurological examination, with brain scans
           and neurological tests.

        -  Visit 2: Magnetic resonance imaging (MRI) scan of the spine and lymphocytapheresis
           (withdrawal of white blood cells for testing).

        -  Visit 3: Lumbar puncture.

        -  Visit 4: Skin biopsy.

        -  Visit 5: Repeat MRI of the brain and spinal cord, as well as neurological tests; these
           tests will be scheduled over 2 days.

        -  After the five pretreatment visits, patients will receive a 6-month supply of study
           medication (either idebenone or a placebo) to take three times a day with food

        -  Patients will continue to have regular followup clinic visits with brain MRI scans,
           blood tests, and other evaluations of brain and nervous system function. Randomly
           selected participants will have additional MRI scans for further safety precautions.
    

Detailed description: 
      Objective: The goal of this study is to assess the safety, therapeutic efficacy and mechanism
      of action of idebenone in primary-progressive multiple sclerosis (PP-MS) patients.

      Study Population: Adult, untreated patients with PP-MS with disability ranging from none to
      moderately severe will be included in the trial. The upper age limit in this study has been
      set at 65; setting an age limit should permit us to focus on the potential neuroprotective
      effect of idebenone in PP-MS and limit the confounding factor of the natural aging process
      and its known negative influence on neuro-regeneration. Published data indicate that higher
      doses (10-50 mg/kg) of idebenone per day are required for beneficial effects on neurological
      disability in comparison to the lower doses (5-10mg/kg) that are sufficient for beneficial
      effects on cardiac/systemic functions in Friedreich s ataxia (FRDA) patients. Therefore, in
      order to target the CNS compartment, we will use a daily dose of 2250mg (750mg 3 times per
      day), which will provide target values of 10-50mg/kg for virtually all adult patients.

      Design: This is a Phase I/II safety/efficacy trial with an adaptive trial design: one year of
      pretreatment baseline period serves the dual purpose of collecting patient-specific
      biomarkers of disease progression and collecting longitudinal neuroimaging and clinical data
      for selection of primary outcome measures. This baseline period is then followed by a
      double-blind, idebenone versus placebo treatment phase for a total of 2 years. Based on
      preliminary sample size estimates, current enrollment calls for a total of 66 patients (33
      per arm).

      Outcome Measures: Quantitative neuroimaging measures of central nervous system (CNS: i.e.
      brain and spinal cord) tissue destruction and clinical and functional (i.e.
      electrophysiological) measures of neurological disability will be collected every 6-12
      months. Additionally, biomarkers focusing on analysis of reactive oxygen species (ROS) and
      oxidative stress will be collected every 12 months. The trial is currently powered using
      progression of brain atrophy as detected by SIENA methodology as the primary outcome measure.
      However, this may not be the most sensitive outcome available. In recognition of this, the
      trial has an adaptive design: i.e. it incorporates analysis of progression of CNS tissue
      destruction as measured by quantitative MRI markers and clinical/paraclinical markers defined
      as secondary outcome measures in the first 30 enrolled patients during the one year
      pre-treatment baseline, before randomization. All defined outcome measures collected in the
      first 30 enrolled patients will be transformed into z-scores and compared for the robustness
      of longitudinal change over the coefficient of variation. This will permit to select the most
      sensitive and most accurate outcome measure for detecting progression of CNS tissue damage.
      As a result, the primary outcome measure of this trial will be the comparison of
      individualized rates of brain atrophy progression between the idebenone and placebo groups
      after 2 years of treatment, unless the predetermined analysis of the pre-treatment baseline
      period in the first 30 enrolled subjects determines that one of the predefined secondary
      outcome measures has a higher z-score than brain atrophy measurement. In this case, the
      primary outcome would be the efficacy of idebenone versus placebo in inhibiting
      patient-specific slopes of functional or structural deterioration as measured by this more
      sensitive biomarker of CNS tissue destruction, yet to be defined by the analysis of the
      1-year longitudinal data from pre-treatment baseline.
    

Intervention name(s): Idebenone; placebo
Intervention type(s): Drug; Other
Intervention description(s): idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc); lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc)
Other intervention name(s): SNT-MC17/F02; SNT-MC17/F03
Intervention MeSH terms: Idebenone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Idebenone; Magnetic Resonance Imaging (MRI); Magnetic Resonance Spectroscopy; Mitochondrial Enhancer; Multiple Sclerosis; MS; Primary Progressive Multiple Sclerosis