Clinical Trial of Idebenone in Primary Progressive Multiple Sclerosis (IPPoMS)

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.

- INCLUSION CRITERIA:

1. PP-MS as determined by the 2005 modification of McDonald s diagnostic criteria

2. Age from 18-65 years (inclusive)

3. Expanded Disability Status Scale (EDSS) measure of neurological disability from 1
(no disability, clinical signs only) to 7 (ambulatory with bilateral support)

4. Able to provide informed consent

5. Willing to participate in all aspects of trial design and follow-up

6. If able to become pregnant or to father a child, agreeing to commit to the use of
a reliable/accepted method of birth control (i.e. hormonal contraception (birth
control pills, injected hormones, vaginal ring), intrauterine device, barrier
methods with spermicide (diaphragm with spermicide, condom with spermicide) or
surgical sterilization (hysterectomy, tubal ligation, or vasectomy in a partner))
for the duration of treatment arm of the study

7. Not receiving any immunomodulatory/immunosuppressive therapies for a period of at
least 3 months before enrollment in the study

8. No exposure to idebenone, coenzyme-Q(10) or other dietary supplements (such as
antioxidants, mitochondrial-function promoting supplements or vitamins in excess
of 3 times recommended daily doses) for a period of at least 1 month before
enrollment in the study

EXCLUSION CRITERIA:

1. Alternative diagnoses that can explain neurological disability and MRI findings

2. Clinically significant medical disorders that, in the judgment of the investigators,
could cause CNS tissue damage or limit its repair, or might expose the patient to
undue risk of harm or prevent the patient from completing the study

3. History of hypersensitivity reaction to idebenone or coenzyme-Q (10)

4. Pregnant or lactating women. All women of child-bearing potential must have a negative
pregnancy test prior to the medication phase of the study.

5. Abnormal screening/baseline blood tests exceeding any of the limits defined below:

i. Serum alanine transaminase or aspartate transaminase levels greater than 3 times
the upper limit of normal values

ii. Total white blood cell count < 3,000/mm(3)

iii. Platelet count < 85,000/mm(3)

iv. Serum creatinine level > 2.0 mg/dl or eGFR (estimated glomerular filtration rate)
<30

v. Positive pregnancy test

6. Patients who are receiving any immunosuppressive therapies (including cytostatic
agents) due to the concern that these drugs may contribute to neurodegeneration or
limit CNS repair