Idebenone for Primary Progressive Multiple Sclerosis

OBJECTIVE:

A Phase I/II clinical trial is being conducted to investigate the safety, therapeutic
efficacy and mechanism of action of idebenone in primary-progressive multiple sclerosis
(PP-MS) patients (IPPoMS (Protocol Number 09-N-0197). Patients who have completed the 2-year
treatment period of IPPoMS, may enter into this open-label extension study (IPPoMS-E) if they
are found to be eligible by the Investigator and desire treatment with idebenone despite
remaining blinded as to their allocation to active treatment versus placebo during the IPPoMS
trial. The aim of this open-label extension study is gather additional data on safety,
efficacy and effects of idebenone on CSF biomarkers in these patients over a period of 1
year. This study will provide open-label idebenone for patients with PP-MS, previously
randomized to idebenone or to placebo in the blinded phase of IPPoMS.

STUDY POPULATION:

Patients who were previously enrolled in the IPPoMS (Protocol Number 09-N-0197) will be
invited to participate in the trial. The same idebenone dose used in the randomized clinical
trial (2250 mg/day) will be used in this study.

DESIGN:

This is a single group, open-label safety and efficacy extension trial with a one year
treatment period. Patient-specific biomarkers of disease progression, CSF biomarkers of
oxidative stress, longitudinal neuroimaging including quantitative measures of CNS tissue
destruction and clinical data will be collected as in the randomized study.

OUTCOME MEASURES:

The measurement and collection of data will be performed as in the randomized trial.
Quantitative neuroimaging measures of central nervous system (CNS: i.e. brain and spinal
cord) tissue destruction and clinical and functional 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 primary
outcome measure defined in the IPPoMS trial will be also utilized in IPPoMS-E. For patients
originally randomized to placebo, patient-specific slopes of disease progression during 2
years of placebo therapy (as measured by primary and secondary outcomes) will be compared to
patient-specific slopes of disease progression during 1 year of open label idebenone therapy.
Combination of IPPoMS and IPPoMS-E trials will significantly expand paired no therapy vs.
idebenone therapy CSF samples for biomarker studies. It will also provide (for the subgroup
of subjects who were originally randomized to idebenone) longitudinal CSF samples on
idebenone therapy (collected 2 years apart). This will allow calculations of intra-individual
changes in CSF biomarkers on and off idebenone therapy, which may provide important insight
into the mechanism of action of idebenone in PP-MS.

- INCLUSION CRITERIA:

- Completion of 3 years in study IPPoMS (Protocol Number 09-N-0197)

- Able to provide informed consent

- Adults, at least 18 years of age

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

- 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)) for the duration of
treatment arm of the study

EXCLUSION CRITERIA:

- Pregnant or lactating women. All women of child-bearing potential must have a negative
pregnancy test

- Patients dropping out of IPPoMS due to AEs considered related to study medication