Clinical trial NCT01854359
Conditions: Multiple Sclerosis Primary Progressive Multiple Sclerosis
Keywords: Multiple Sclerosis Extension Trial
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2013-03-12; Completion date: 2018-10-31
Enrollment: 61 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- The Idebenone in Patients With Primary Progressive Multiple Sclerosis (IPPoMS) trial tested a new drug for multiple sclerosis. In the IPPoMS trial, participants took either idebenone or placebo. Researchers want to give idebenone to all participants for 1 year. It is still not certain whether idebenone can slow the progression of multiple sclerosis, but this study may help answer that question.

Objectives:

* To provide idebenone to all participants on the IPPoMS trial.
* To collect data on the safety and effectiveness of idebenone for primary progressive multiple sclerosis.

Eligibility:

\- Individuals at least 18 years of age who have completed 3 years in the IPPoMS trial.

Design:

* The first study visit for this trial will happen on the same day as the last visit for the IPPoMS trial.
* Participants will provide a blood samples and will have a lumbar puncture. They will also receive a new supply of idebenone to take three times a day with food. They will keep a diary to report on any side effects.
* After this first treatment visit, participants will have two follow-up visits to the NIH 6 months apart. These visits may be scheduled over multiple days. Participants will provide blood and urine samples. They will also have imaging studies of the brain and spine.
* Participants will have phone calls with the study researchers to provide updates on their condition and any side effects.

Detailed description:
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 cerebrospinal fluid (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.

Arms: arm 1: Idebenone (150mg tablets) administered orally as five tablets, three times per day with food.
Interventions: intervention 1: Idebenone
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
 
CNS IRBProtocol Template (rev.1-17-08) 
 
IRB Panel: Blue     
 
1. TITLE PAGE 
 
Protocol Title:  
Idebenone in Patients with Primary Progressive Multiple Sclerosis Open-Label 
Extension (IPPoMS-E) 
Protocol Number: 13-N-0088 
Date of This Submission/Version: June 1, 2018 
 
Principal Investigator 
Name, Degree 
Branch/Institute Bldg/Rm 
Phone 
E-mail 
Bibiana 
Bielekova, MD 
NIB/NINDS 
10/5C103 
301-402-4488 
bielekovab@ninds.nih.gov 
 
Lead Associate Investigator 
Name, Degree 
Branch/Institute Bldg/Rm 
Phone 
E-mail 
Alison 
Wichman, MD 
NIB/NINDS 
10/5C101 
301-496-0064 
wichmana@ninds.nih.gov 
 
Associate Investigators 
Name, Degree 
Branch/ 
Institute 
Bldg/Rm 
Phone 
E-mail 
Mary Alice 
Sandford, RN, 
CRNP 
NDU/NIND
S 
10/5C103 
301-496-4747 
maryalice.sandford@nih.g
ov 
Jenifer Dwyer, 
RN 
Clinical 
Center 
10/5C101 
301-496-0064 
JDwyer@cc.nih.gov 
Laura Kannaian, 
RN 
NDU/NIND
S 
10/5C103 
301-496-0586 
kannaianl@cc.nih.gov 
Tanya Lehky, MD NINDS 
10-CRC/7-5680 
301-496-7428 
lehkyt@mail.nih.gov 
Govind 
Bhagavatheeshwa
ran, PhD 
NIB/NINDS 
10/5C103 
301-402-6391 
bhagavatheeshg@ninds.ni
h.gov 
Rosalind Hayden, 
RN 
OCD/NINDS 10/5C101 
301-827-9002 
haydenre@ninds.nih.gov 
Elena Romm, MS 
NIB/NINDS 
10/5C103 
301-594-2697 
RommE@ninds.nih.gov 
 
Research Contact  
Name, Degree 
Branch/Institute 
Bldg/Rm 
Phone 
E-mail 
Laura 
Kannaian, RN 
NDU/NINDS 
10/5C103 
301-496-0586 
kannaianl@cc.nih.gov 
 
Medical Advisory Investigator 
Name, Degree 
Branch/Institute Bldg/Rm 
Phone 
E-mail 
Bibiana 
Bielekova, MD 
NIB/NINDS 
10/5C103 
301-402-4488 
bielekovab@ninds.nih.gov 


 
 
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Total requested accrual 
 
 85 Patients 
  
 
 0  Volunteers   
  
 
Project Uses Ionizing Radiation:    No  
  Yes  
  
 
 Medically-indicated only 
  
 
 Research-related only 
  
 
 Both 
 
IND/IDE       No  
Yes (attach FDA documentation) 
  
Drug/Device/#__104,895 
  
Sponsor: National Institute of Neurological Disorders and Stroke (NINDS), Dr. Bielekova  
 
Durable Power of Attorney  
 
 No   
 Yes  
 
Multi-institutional Project 
 No   
 Yes  
 
 
 
 
 
Institution_________________    FWA #_________  
Date of IRB approval: n/a  
 
Data and Safety Monitoring Board  
No   
 Yes  
 
Technology Transfer Agreement  
 No   
 Yes  
Agreement type and number: MCRADA #2012-0244  
Expiration Date: 12/5/2020 
 
Confidential Disclosure Agreement     
 No  
 Yes 
 
Samples are being stored  
 
 
 No   
 Yes  
 
 


 
 
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2. TABLE OF CONTENTS 
 
1. TITLE PAGE .................................................................................................................................... 1 
2. TABLE OF CONTENTS .................................................................................................................. 3 
3. PRECIS ............................................................................................................................................. 6 
3.1 Objective: .................................................................................................................................... 6 
3.2 Study Population: ........................................................................................................................ 6 
3.3 Design:......................................................................................................................................... 6 
3.4 Outcome Measures: ..................................................................................................................... 6 
4. INTRODUCTION/SCIENTIFIC RATIONALE .............................................................................. 7 
4.1 Multiple Sclerosis (MS) .............................................................................................................. 7 
4.2 Primary progressive MS (PP-MS) ............................................................................................... 7 
4.3 Mechanisms of tissue injury in PP-MS ....................................................................................... 8 
4.4 Therapeutic options for PP-MS patients ................................................................................... 12 
4.5 Idebenone pharmacokinetic, pharmacodynamic and toxicity data ........................................... 12 
4.5.1. Preclinical studies: ............................................................................................................. 13 
4.5.2 Clinical studies ................................................................................................................... 14 
4.5.3 Pharmacokinetics and product metabolism in humans ...................................................... 15 
4.5.4 Product information ............................................................................................................ 17 
4.5.5 Storage and handling .......................................................................................................... 17 
4.6 Rationale for the use of Idebenone in PP-MS ........................................................................... 17 
4.7 Rationale for current study design............................................................................................. 20 
5. STUDY OBJECTIVES OR HYPOTHESES .................................................................................. 21 
5.1 Hypothesis ................................................................................................................................. 22 
5.2 Goals of the study ...................................................................................................................... 22 
The primary goals are: ................................................................................................................. 22 
The secondary goals are: ............................................................................................................. 22 
6. SUBJECTS ...................................................................................................................................... 22 
6.1. Study population....................................................................................................................... 22 
6.2. Inclusion criteria ....................................................................................................................... 22 
6.3. Exclusion criteria ...................................................................................................................... 23 
7. STUDY DESIGN AND METHODS .............................................................................................. 23 
7.1 Study overview .......................................................................................................................... 23 
7.2 Recruitment ............................................................................................................................... 23 
7.3 Screening methods .................................................................................................................... 23 
7.4 Study design .............................................................................................................................. 23 
7.5 Study procedures ....................................................................................................................... 24 
7.5.1 Study visits ......................................................................................................................... 24 
7.5.2 Clinical and functional evaluations: ................................................................................... 24 
7.5.3 Neuroimaging evaluation: .................................................................................................. 25 
7.5.4 Optical coherence tomography (OCT) ............................................................................... 25 
7.5.5 Transcranial magnetic stimulation (TMS) and Central motor conduction time (CMCT) 
calculation ................................................................................................................................... 25 
7.5.6 Immunological and laboratory evaluation: ......................................................................... 26 
7.5.7 Drug administration:........................................................................................................... 27 
7.5.8 Records: .............................................................................................................................. 27 


 
 
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7.5.9 Storage of data and samples: .............................................................................................. 27 
7.6 
Follow-up/termination procedures........................................................................................ 28 
        7.6.1 Trial termination followup……………………………………………………………31 
8. RISKS/DISCOMFORTS ................................................................................................................ 29 
8.1 Risks associated with Idebenone therapy .................................................................................. 29 
8.2 Risks of lymphocytapheresis ..................................................................................................... 29 
8.3 Risks of MRI ............................................................................................................................. 30 
8.4 Risks of lumbar puncture .......................................................................................................... 30 
8.5 Risk of OCT .............................................................................................................................. 31 
8.6 Risk of electrophysiological studies .......................................................................................... 31 
8.6.1 Risk of TMS ....................................................................................................................... 31 
8.6.2 Risk of nerve conduction studies........................................................................................ 31 
8.7 Risk Rehab Evaluation .............................................................................................................. 31 
9. SUBJECT MONITORING ............................................................................................................. 31 
9.1 Parameters to be monitored ....................................................................................................... 31 
9.1.1 Expected Adverse Events: .................................................................................................. 31 
9.1.2 Monitoring of adverse events: ............................................................................................ 32 
9.2 Toxicity tables/criteria to be used ............................................................................................. 33 
9.2.1 Definition of Adverse Event (AE) ...................................................................................... 33 
9.2.2 Severity of Adverse events ................................................................................................. 33 
9.2.3 Definition of Serious Adverse Event (SAE) ...................................................................... 34 
9.2.4 Assessment of causality...................................................................................................... 34 
9.2.5 Treatment of adverse events: .............................................................................................. 35 
9.3 Criteria for individual subject withdrawal................................................................................. 35 
10. OUTCOME MEASURES ............................................................................................................. 36 
10.1 Primary outcome measure: ...................................................................................................... 36 
10.2 Secondary outcome measures: ................................................................................................ 36 
10.2.1 Neuroimaging outcomes: ................................................................................................. 36 
10.2.2 Clinical/functional outcomes:........................................................................................... 37 
10.2.3 Biological/immunological outcomes:............................................................................... 37 
10.3. Tertiary/exploratory outcome measures ................................................................................. 38 
10.3.1 Neuroimaging: .................................................................................................................. 38 
10.3.2 Clinical: ............................................................................................................................ 38 
11. STATISTICAL ANALYSIS ......................................................................................................... 38 
11.1 Data acquisition and processing .............................................................................................. 38 
11.2 Statistical analyses of outcome measures ................................................................................ 38 
11.3 Handling of missing/unobtainable data ................................................................................... 40 
11.4 Power analysis and sample size calculation ............................................................................ 41 
11.5 Accrual number request........................................................................................................... 41 
12. HUMAN SUBJECT PROTECTION ............................................................................................ 41 
12.1 Subject selection ...................................................................................................................... 41 
12.2 Justification for exclusion of children ..................................................................................... 41 
12.3 Study safeguards...................................................................................................................... 42 
12.4 Qualifications of investigators................................................................................................. 42 
13. BENEFITS .................................................................................................................................... 43 
13.1 Direct Benefit: ......................................................................................................................... 43 


 
 
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13.2 Indirect Benefit: ....................................................................................................................... 43 
14. SUMMARY/CLASSIFICATION OF RISK: ............................................................................... 43 
15. CONSENT DOCUMENTS AND PROCESS ............................................................................... 43 
16. DATA AND SAFETY MONITORING ....................................................................................... 43 
16.1 Monitoring plan for the study as a whole ................................................................................ 44 
16.2 DSMB plans ............................................................................................................................ 44 
16.2.1. The proposed members of the DSMB are as follows: ..................................................... 44 
16.2.2. Role of DSMB: ................................................................................................................ 44 
16.2.3 Proposed meeting frequency/ schedule: ........................................................................... 44 
16.3 Criteria for stopping the study: ................................................................................................ 44 
17. QUALITY ASSURANCE (QA) ................................................................................................... 44 
17.1 Quality assurance monitor ....................................................................................................... 44 
17.2 Quality assurance plan ............................................................................................................. 44 
18. Reporting of Unanticipated problems, adverse events and protocol deviations ........................... 45 
19. ALTERNATIVES TO PARTICIPATION OR ALTERNATIVE THERAPIES.......................... 46 
20. PRIVACY ..................................................................................................................................... 46 
21. CONFIDENTIALITY ................................................................................................................... 46 
21.1 For medical records: ................................................................................................................ 46 
21.2 For research data: .................................................................................................................... 46 
21.3 For stored samples: .................................................................................................................. 46 
22. CONFLICT OF INTEREST/TECHNOLOGY TRANSFER........................................................ 46 
23. RESEARCH AND TRAVEL COMPENSATION ....................................................................... 47 
24. REFERENCES .............................................................................................................................. 47 
25. ATTACHMENTS/APPENDICES ................................................................................................ 55 
APPENDIX A: Flow chart .............................................................................................................. 55 
Inclusion criteria .......................................................................................................................... 56 
Exclusion criteria ......................................................................................................................... 56 
APPENDIX C: Case Report Forms (CRFs) .................................................................................... 57 
APPENDIX D: Rating scales .......................................................................................................... 58 
APPENDIX E: Investigator’s Brochure .......................................................................................... 60 
 
 
 


 
 
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3. PRECIS 
 
3.1 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. 
 
3.2 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. 
 
3.3 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.  
 
3.4 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. 
 


 
 
CNS IRB Protocol Template (rev.1-17-08) 
 
 
 
 
 
 
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4. INTRODUCTION/SCIENTIFIC RATIONALE 
 
4.1 Multiple Sclerosis (MS) 
 
Multiple sclerosis (MS) is an inflammatory and demyelinating disorder of the central nervous system 
(CNS) that destroys myelin, oligodendrocytes, axons and neurons (Noseworthy, Lucchinetti et al. 
2000). The vast majority of newly diagnosed MS patients develop the relapsing-remitting form of 
the disease (RR-MS), in which periods of neurological worsening are followed by periods of 
spontaneous remission, at least at the beginning of the disease process. About 10-15% of patients 
develop primary-progressive MS (PP-MS), characterized by progressive accumulation of 
neurological disability from the disease onset, without any superimposed worsening (i.e. relapses) or 
improvements (remissions) (Miller and Leary 2007).  
 
The etiology of MS remains unclear, but disease develops in genetically susceptible individuals 
exposed to environmental triggers.  The long favored hypothesis in MS has been formulated based 
on data obtained in the animal model Experimental Autoimmune Encephalomyelitis (EAE). This 
hypothesis implicates autoreactive, myelin-targeting CD4+ T cells generated in the periphery that 
access the CNS, where they induce an inflammatory cascade that results in the injury of previously 
normal neural tissues (Sospedra and Martin 2005).  However, in contrast to EAE, neither the 
target(s) of the immune response nor the cells of the immune system responsible for CNS damage 
have been identified in MS.  
 
 
4.2 Primary progressive MS (PP-MS) 
 
PP-MS patients differ from RR-MS patients in several important characteristics: 1. They tend to be 
older at the time of disease onset (mean 40 vs. 30 years); 2. Males and females tend to be affected 
equally; 3. Clinically there is a high prevalence of cortico-spinal dysfunction characterized by 
progressive weakness and spasticity (Laule, Vavasour et al. 2010); 4: Patients have more prominent 
involvement of the spinal cord (Bieniek, Altmann et al. 2006) and generally lower amount of distinct 
white matter lesions (i.e. plaques) in the brain and less evidence for brain inflammatory activity 
(Lucchinetti and Bruck 2004) and, most importantly: 5: PP-MS patients do not respond to 
immunomodulatory therapies with proven efficacy in RR-MS (Leary and Thompson 2005).  
 
However, there are also some key similarities between PP-MS, RR-MS and secondary-progressive 
MS (SP-MS; the disease subtype that usually evolves after several years of untreated RR-MS): 1. 
Age of onset of the progressive phase is virtually identical between PP-MS and SP-MS (~40 years) 
(Ebers 2004); 2. Genetic background (e.g. HLA and IL-7Rα association (Booth, Arthur et al. 2005)) 
seems to be common to all 3 subtypes; an observation that is further supported by the fact that 
different disease types can occur within a single family; 3. Patients with all MS subtypes (~90% of 
RR-MS and 70-80% of PP-MS patients) have evidence for humoral immune responses in the CNS 
that are increased compared to the serum, or are entirely specific for the intrathecal environment (i.e. 
increased CSF IgG index and oligoclonal bands (OCB)) (Miller and Leary 2007).  
 
These differences and similarities underlie two major hypotheses about the relationship between PP-
MS and RR/SP-MS: while some authors propose these diseases are simply phenotypical variants of 


 
 
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the identical disease process, others believe that PP-MS represents a distinct degenerative form of 
the disease, in which the immune response may not be primarily driving the disease pathogenesis. 
The latter hypothesis is indirectly supported by the “MS disease heterogeneity concept”, in turn 
backed by pathological data indicating the mechanism of active demyelination seems different 
between different patients, but identical for all MS lesions within single subjects. Four pathological 
subtypes have been identified (Lucchinetti, Bruck et al. 2000), two of which probably represent 
immune-mediated pathology, whereas in the other two pathological patterns immune cells are much 
less conspicuous and degenerative pathophysiology may predominate (Lucchinetti, Bruck et al. 
2000). Specifically, pattern IV demyelination, called “oligodendrocyte degeneration in periplaque 
white matter”, with evidence of apoptosis of oligodendrocytes and paucity of T/B lymphocytes, is 
almost exclusively observed in PP-MS patients. Nevertheless, PP-MS patients were also observed to 
have pathological patterns I and II, i.e. those where presumed mechanisms of acute demyelination 
are T cell/macrophage-mediated and Ab/complement-mediated, respectively. 
 
Part of the pathophysiological controversy may reside in our inability to correctly classify patients. 
Complete reliance on clinical characteristics makes the classification highly dependent on the 
patient’s ability to recollect transient neurological deficits that may have occurred years before the 
onset of progressive disease. Additionally, if MS lesions developed in clinically silent areas, even if 
associated with inflammation, they would not cause clinical deficit and therefore would not alert the 
patient or clinician of the occurrence of a relapse. As a result, reliance on purely clinical criteria will 
inevitably lead to inclusion of a more heterogeneous patient population in the PP-MS category. One 
of the hallmarks of inflammatory lesions in RR-MS is their association with the breakdown of the 
blood-brain barrier (BBB), which can be visualized as contrast-enhancing lesions (CELs) on MRI. 
Although PP-MS patients generally have a significantly lower number of CELs (Ingle, Stevenson et 
al. 2003), patients with CELs have been classified as PP-MS based on clinical criteria (Filippi, 
Campi et al. 1995) and have been included in clinical trials of immunomodulatory therapies 
(Wolinsky, Narayana et al. 2007). Not unexpectedly, it is precisely these PP-MS patients that were 
shown to benefit from applied immunomodulatory therapy in subgroup analysis (Wolinsky, 
Narayana et al. 2007). This is very reminiscent of our experience with effectiveness of 
immunomodulatory therapies for SP-MS (Kappos, Weinshenker et al. 2004). The results of these 
trials suggest that while currently available immunomodulatory therapies effectively target that part 
of the MS disease process characterized by formation of focal CELs, they are much less effective in 
slowing down a more diffuse, degenerative process, which underlies the development of disability in 
non-inflammatory PP- and SP-MS.  
 
 
4.3 Mechanisms of tissue injury in PP-MS 
 
Both new imaging modalities (Filippi, Rocca et al. 2002; Dehmeshki, Chard et al. 2003; Filippi 
2003; Narayana, Wolinsky et al. 2004; Sastre-Garriga, Ingle et al. 2004; Rovaris, Gallo et al. 2005; 
Sastre-Garriga, Ingle et al. 2005; Ramio-Torrenta, Sastre-Garriga et al. 2006; Khaleeli, Sastre-
Garriga et al. 2007; Manfredonia, Ciccarelli et al. 2007; Rovaris, Judica et al. 2008) and 
pathological data (Lucchinetti and Bruck 2004; Kutzelnigg, Lucchinetti et al. 2005) suggest that in 
PP-MS, CNS pathology is more diffuse (Filippi, Rocca et al. 2002; Dehmeshki, Chard et al. 2003; 
Filippi 2003; Narayana, Wolinsky et al. 2004; Ramio-Torrenta, Sastre-Garriga et al. 2006; 
Khaleeli, Sastre-Garriga et al. 2007; Manfredonia, Ciccarelli et al. 2007; Rovaris, Judica et al. 


 
 
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2008) and occurs to some extent independently of focal lesions (Sastre-Garriga, Ingle et al. 2004; 
Kutzelnigg, Lucchinetti et al. 2005; Rovaris, Gallo et al. 2005). The cervical spinal cord is the major 
target of the disease process in PP-MS, underlying most of the clinical disability (Ingle, Stevenson et 
al. 2003).  The diffuse CNS process in PP-MS is characterized by microglial activation and diffuse 
axonal injury in the white matter (Kutzelnigg, Lucchinetti et al. 2005) and by cortical demyelination 
and neuronal loss in the gray matter (Kutzelnigg, Lucchinetti et al. 2005). This is consistent with new 
observations from optical coherence tomography (OCT), which demonstrated significant reduction 
in the inner nuclear layer, consistent with the presence of primary retinal pathology only in PP-MS, 
but not RR-MS or SP-MS subtypes (Albrecht, Ringelstein et al. 2012). Additionally, low level but 
persistent endothelial abnormalities and BBB leak, both in normal appearing white and gray matter 
have been observed (Leech, Kirk et al. 2007).   
 
Accumulating data indicate that oxidative stress and mitochondrial dysfunction may play a major 
role in the pathogenesis of MS, especially in the progressive stages (Gionchetti, Campieri et al. 
1994; Greco, Minghetti et al. 1999; Bizzozero, DeJesus et al. 2005; Dhib-Jalbut, Arnold et al. 2006; 
Koch, Ramsaransing et al. 2006; Koch, Mostert et al. 2007). MS patients have increased lipid 
peroxidation products in the CSF (Hunter, Nlemadim et al. 1985; Naidoo and Knapp 1992; Keles, 
Taysi et al. 2001); presence of 3-nitrotyrosine in demyelinated lesions (Liu, Zhao et al. 2001); 
evidence of nitrosative damage in the normal-appearing white matter (Bizzozero, DeJesus et al. 
2005) and increased levels of carbonyl in both white and gray matter (Bizzozero, DeJesus et al. 
2005). These findings were confirmed on brain tissue derived from 18 MS patients with progressive 
disease (SP-MS and PP-MS), where the authors demonstrated severe oxidative damage to proteins, 
nucleic acids and lipids, predominantly in the MS lesions and to a milder degree also in normal 
appearing WM (van Horssen, Schreibelt et al. 2008). In terms of cellular localization, most of the 
oxidized lipids, proteins and nucleic acids were detected in reactive astrocytes and in myelin-laden 
macrophages. Detected oxidative stress/damage was associated with strong upregulation of 
Nrf2/ARE-regulated antioxidant enzymes, such as superoxide dismutase-1 and -2, catalase and heme 
oxygenase-1. Again, these enzymes were upregulated predominantly in reactive astrocytes and 
foamy macrophages. These data indirectly suggest that reactive astrocytes and macrophages that 
phagocytosed myelin debris are the main cell types involved in detoxification of ROS and that 
astrocytes, through expression of Nrf2-ARE enzymes play a pivotal role in the maintenance of redox 
homeostasis under inflammatory CNS conditions (van Horssen, Schreibelt et al. 2008). 
Oligodendrocytes and brain endothelial cells had remarkably low expression of antioxidant enzymes 
(van Horssen, Schreibelt et al. 2008); a finding that supports previous studies indicating that 
oligodendrocytes are extremely sensitive to oxidative stress due to their impaired antioxidant defense 
mechanism (Juurlink, Thorburne et al. 1998). Other studies suggested that MS patients may have 
diminished resistance to oxidative stress, as the levels of antioxidants were found to be diminished in 
the brain (Langemann, Kabiersch et al. 1992; Bizzozero, DeJesus et al. 2005) and blood (Zagorski, 
Dudek et al. 1991; Syburra and Passi 1999) of MS patients.  
 
There are two major sources of reactive oxygen species (ROS) in the brain: 1. the respiratory burst 
of immune cells mediated by NADPH oxidases and 2. the electron-transport chain of mitochondria. 
In the intrathecal compartment of MS patients, only cells of myeloid lineage (i.e. microglia, 
monocytes/macrophages and myeloid dendritic cells) can mediate oxidative burst, because 
granulocytes are not present in MS lesions and oxidative burst of lymphocytes is 1000 fold lower 
than oxidative burst of myeloid cells. When cells of myeloid lineage become activated, they not only 


 
 
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produce ROS, but also secrete soluble factors, such as IL-12p40 and CXCL13. These soluble factors 
can be detected in the CSF as a biomarker of activated immune cells of myeloid lineage. In order to 
assess contribution of oxidative burst versus failing mitochondria to ROS generated in the intrathecal 
compartment of subjects with different MS subtypes, we measured CSF levels of lipid peroxidation 
product, 4-hydroxy-nonenal (4-HNE), IL-12p40 and CXCL13 in a large group of untreated subjects 
who presented for the diagnostic work-up of neuroimmunological diseases (Figure 1). We observed 
elevated levels of 4-HNE in all subjects with MS, but reaching statistical significance only in the PP-
MS cohort. On the other hand, biomarkers of activation of myeloid lineage, i.e. IL-12p40 and 
CXCL13, were elevated only in RR-MS patients, and subjects with other inflammatory neurological 
diseases (OIND), but not in PP-MS patients. Therefore, we conclude that while oxidative burst 
contributes to the intrathecal oxidative stress in RR-MS patients, mitochondrial dysfunction is the 
main source of CSF ROS in PP-MS patients. 
Figure 1:  
CSF levels of lipid peroxidation product 4-hydroxy-nonenal (4-HNE) and IL-12p40 and CXCL13 measured in 
the blinded fashion in a large cohort of MS patients and controls (N=167). 
CIS = clinically isolated syndrome patients who did not progress to definite MS within 1 year of follow-up, NIND = 
non-inflammatory neurological disorders, OIND = other inflammatory neurological disorders. * p<0.05, **p<0.001 
 
Mitochondria themselves may be the target of the oxidative damage in MS lesions (Lu, Selak et al. 
2000) and profound mitochondrial dysfunction was found in the gray matter of MS patients (Dutta, 
McDonough et al. 2006). Specifically, functional activities of mitochondrial electron transport chain 
(ETC) complexes I and III were decreased in MS motor cortex and this reduced mitochondrial gene 
expression was specific for neurons (Dutta, McDonough et al. 2006). Furthermore, multiple 
investigators documented accumulating presence of mitochondrial DNA mutations and existence of 
respiratory-deficient mitochondria in neurons (Kiryu-Seo, Ohno et al. ; Lu, Selak et al. 2000; 
Andrews, Nichols et al. 2005; Kidd 2005; Dutta, McDonough et al. 2006; Campbell, Ziabreva et al. 
2011; Campbell and Mahad 2012; Campbell, Ohno et al. 2012). 
On the other hand, specifically in the acute MS lesions with characteristics of pathological subtype 
III, severe mitochondrial deficiencies have been observed both in oligodendrocytes and astrocytes 
(Mahad, Ziabreva et al. 2008; Mahad, Ziabreva et al. 2009). 
It is hypothesized that mitochondrial dysfunction, which generally increases with age, may 
contribute, if not underlie the development of progressive stage of MS (Andrews, Nichols et al. 
2005). This hypothesis is based on several published observations:   


 
 
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1) Acute demyelination leads to conduction block and resultant compensatory distribution of Na 
channels from the node of Ranvier along the entire demyelinated segment. In addition to this 
topographic redistribution of Na channels, demyelinated axons revert to a stage seen in 
immature axons, with preferential use of Nav1.2 instead of Nav1.6 channels (Black, Kocsis et al. 
1990).  
2) This switch in Na channel usage and their redistribution, while allowing conduction along the 
demyelinated axon, is energetically extremely demanding, requiring a large number of ATP 
molecules to sustain the Na+/K+-ATPase pump, which is necessary to maintain the resting 
membrane potential (Black, Kocsis et al. 1990; Black, Newcombe et al. 2007). This high energy 
demand is indirectly reflected by the observed redistribution of mitochondria along 
demyelinated axons (Mutsaers and Carroll 1998) and associated axonal swelling.  
3) Presence of inflammation further exaggerates this energy deficiency of demyelinated axons, 
because some of the inflammatory mediators (e.g. NO) are known to inhibit the mitochondrial 
respiratory chain (Bolanos, Almeida et al. 1997).  
4) However, even in the absence of inflammation, it would be predicted that mitochondria would 
not be able to sustain the non-physiologically high energy demand of chronically demyelinated 
axons long-term. It is known that even during the natural aging process, mitochondrial DNA 
accumulates mutations and energy production of aging mitochondria diminishes in time.  When 
demyelination becomes widespread and sustained, as in progressive MS, then resultant 
increased energy requirement cannot be sustained by actual ATP production. This leads to 
“virtual hypoxia” (Lassmann 2003), which initiates vicious circle of enhanced generation of 
ROS by failing mitochondria, resulting in progressive oxidative damage of mitochondrial DNA, 
proteins and lipids. Damaged mitochondria show impairment of oxidative phosphorylation, 
decreased rate of electron transfer, decreased enzymatic activities and are also thought to 
produce higher levels of ROS. This, in the absence or deficiency of an effective endogenous 
detoxification system, would lead to further oxidative damage of mitochondrial DNA and 
associated lipids and proteins. Mitochondrial DNA is especially susceptible to oxidative damage 
due to lack of protective histones and less efficient repair mechanisms (Mecocci, MacGarvey et 
al. 1993).  
5) Decline in ATP production leads to accumulation of unfolded proteins in the endoplasmic 
reticulum (ER), because proper oxidative folding of proteins requires overcoming 
thermodynamically unfavorable intermediates though ATPase activities of ER chaperones. 
Resulting ER stress activates unfolded protein response (UPR), which is part of cellular 
integrated stress response (ISR). UPR/ISR leads to cellular adaptations that may lead to 
restoration of homeostasis, but only if ATP production can be restored, at least to the levels that 
support ATPase activities of ER chaperones. Only then can misfolded proteins be degraded, 
both from ER and mitochondria (Hu and Liu 2011). While respiratory-deficient mitochondria 
are degraded by combination of mitochondrial fission/fusion and mitophagy (Twig and Shirihai 
2011), restored production of proteins and lipids by ER can then lead to assembly of fully 
functional mitochondria. 
6) The resultant lack of ATP would lead to increased intra-axonal Na+ and subsequent increase in 
intra-axonal Ca2+ via reversal of the Na+/Ca2+ exchanger and enhanced Ca2+ release from ER. 
Additionally, Ca2+ is also selectively transferred from the ER to mitochondria, in order to 
stimulate ATP production, as early adaptation mechanism of ER stress. However, with 
underlying mitochondrial dysfunction, this adaptation may not lead to enhanced ATP 
production, but rather to mitochondrial-induced apoptosis. Thus, resultant damage to the 


 
 
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demyelinated axon would be a combination of oxidative damage with Ca2+-mediated 
excitotoxicity, leading to programmed cell death.  
 
There is additional evidence that supports the hypothesis of mitochondrial dysfunction underlying 
axonal degeneration in MS:  CSF concentrations of sorbitol, fructose and lactate (all metabolites of 
extramitochondrial glucose metabolism) were found to be elevated in MS, especially in progressive 
stages and to correlate with clinical measures of disability (Regenold, Phatak et al. 2008). Because 
extra-mitochondrial glucose metabolism increases with impaired mitochondrial metabolism of 
glucose, these findings strongly implicate mitochondrial dysfunction in the pathogenesis of 
progressive stages of MS. Of interest to this study, the intraventricular lactate can be measured 
serially in-vivo by MRS (Kaufmann, Shungu et al. 2004), although this methodology has not been 
applied to MS to our knowledge.  
 
 
4.4 Therapeutic options for PP-MS patients 
 
There are currently no treatments with proven therapeutic efficacy for PP-MS (Leary and Thompson 
2005). Neither interferon-beta preparations (Leary, Miller et al. 2003; Montalban 2004) nor 
glatiramer acetate (Wolinsky, Narayana et al. 2007) has been able to slow down the accumulation of 
disability in PP-MS. Several Phase II trials of Mitoxantrone in PP-MS were initiated, but none 
reported positive effects (Leary and Thompson 2005). A recently reported large multi-center, 
placebo-controlled Phase II trial of Rituximab in PP-MS also failed to demonstrate any effect on the 
accumulation of disability in this patient population (Hawker, O'Connor et al. 2009). 
 
These data collectively indicate that therapies targeting the immune system and specifically the 
formation of Gd-enhancing MS lesions do not demonstrate beneficial effect in PP-MS. In agreement 
with the reviewed hypothesis that the pathophysiology of PP-MS may rely more on 
neurodegenerative, rather than immune-mediated mechanisms of CNS tissue destruction, a pilot trial 
of the neuroprotective agent riluzole showed a mild effect on inhibiting the development of cervical 
cord atrophy in the PP-MS cohort (Kalkers, Barkhof et al. 2002), however, it did not reach statistical 
significance. 
 
 
4.5 Idebenone pharmacokinetic, pharmacodynamic and toxicity data 
 
Idebenone (2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone) is a synthetic analogue 
of coenzyme Q10, which is an indispensable constituent of the mitochondrial electron-transport 
chain (ETC) and also cell membrane antioxidant. 
 
After oral administration, idebenone undergoes rapid and extensive metabolism, whereby >99% of 
idebenone is converted to metabolites by first pass metabolism. In the initial steps of metabolism, the 
side chain of idebenone undergoes a process of oxidative shortening leading to the metabolites 
QS10, QS8, QS6 and QS4 (the number refers to the number of carbon atoms in the side-chain). 
Idebenone and all of the short-chain metabolites are modified further by conjugation 
(glucuronidation or sulfatation) resulting in conjugated forms of idebenone (Idebenone-C (IDE-C)) 
as well as QS10-C, QS8-C, QS6-C and QS4-C. 


 
 
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Bioanalytical methods allow measurement of either 
• idebenone and unconjugated metabolites (idebenone, QS10, QS6, QS4)  
• or the combined measurement of conjugated molecules plus unconjugated forms of the same 
molecules, referred to as 'IDE+IDE-C', 'QS10+QS10-C', ' QS6+QS6-C ' and ' QS4+QS4-C ', 
respectively. 
 
 
4.5.1. Preclinical studies: 
The pharmacology and toxicology of idebenone have been studied extensively in animals and 
humans (Gillis, Benefield et al. 1994).  These studies are described fully in the Investigator’s 
Brochure (Appendix G) and are summarized below: 
 
In rats and dogs oral idebenone is rapidly absorbed and extensively metabolized in the intestinal 
mucosa and liver.  The primary route of metabolism is β-oxidative shortening of the side chain.   The 
major metabolites are QS10, QS8, QS6, and QS4 (where 10, 8, 6 and 4 denote the number of carbon 
atoms in the side chain).  Glucuronide and sulfate conjugates of these metabolites are also formed.  
In rats, idebenone is 91% absorbed and 90-94% protein bound.  The Tmax of idebenone is 0.25 hours 
and the half-life is 4.5 hours.  In dogs, idebenone is 62% absorbed and 99% protein bound.  The 
Tmax is one hour and levels show a biphasic decline with half-lives of 2.2 and 15.4 hours, 
respectively.  In dogs, plasma levels were broadly dose-dependent and variable but were consistently 
increased in fed animals.  There was no evidence of accumulation of idebenone or metabolites.  In 
both rats and dogs, oral idebenone was completely excreted within 48 hours, distributed evenly 
between urine and feces.   
 
The acute oral toxicity of idebenone was low (> 10,000mg/kg in mice and male rats; ~10,000 mg/kg 
in female rats). Chronic oral toxicity studies in rats and dogs have been published (Spicer and 
Wazeter 1985; Suhara, Chiba et al. 1985).  Treatment related adverse effects were limited to local 
irritant effects mainly in the forestomach (a rodent-specific organ) in the rat and to clinical 
gastrointestinal effects (loose feces/diarrhea and emesis), without any pathological changes, in the 
dog. It can therefore be considered that no adverse effects of clinical relevance were observed at the 
highest dose used in these studies (500mg/kg/day) (Spicer and Wazeter 1985; Suhara, Chiba et al. 
1985). Results from toxicity studies conducted by Santhera, including a 39-week toxicity study in 
fed dogs, are consistent with the findings of published Takeda studies, indicating that the drug 
substance used by Santhera has a similar safety profile as the Takeda material. In a 4 week study in 
rats and a 39-week study in fed dogs, at Cmax, concentrations of idebenone in plasma were 21 – 22 
times higher in the rat, and 25 – 28 times higher in the dog, when compared with the maximum 
mean concentration observed in humans receiving idebenone 2250 mg.  For AUC0-t safety margin 
ranges of 16 – 22 in the rat and 20 - 22 in dogs were calculated, when steady state exposure at the no 
adverse effect levels is considered for each species. Taken together, the toxicokinetic data reported 
here indicate that a sufficient safety margin exists between exposure in humans at a daily dose of 
2250 mg/day of idebenone and exposure in rats and dogs, at doses which had no toxic effects 
relevant to safe use in humans.  
 
Idebenone was not genotoxic in in-vitro bacterial reverse mutation assays and in-vivo mouse 
micronucleus studies. A positive clastogenic effect was observed in an in vitro chromosome 
aberration test at very high concentrations (7500ng/ml and above) (RCC-CCR 871902). This effect 


 
 
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is not considered to pose a risk for clinical trial subjects in view of the high concentrations at which 
effects were observed and in view of the negative in vivo response on the mouse micronucleus test. 
 
Idebenone at doses up to 500mg/kg/day had no adverse effects on fertility and reproductive 
performance in rats. Idebenone administered at doses up to 500mg/kg/day in the rat and up to 
150mg/kg/day in the rabbit during the period of organogenesis had no teratogenic or embryo-fetal 
toxic effects. Doses up to 500mg/kg/day administered during late pregnancy and lactation had no 
adverse effects on the dams or on the post partum development of the pups.  
 
4.5.2 Clinical studies 
In healthy volunteers, idebenone is well tolerated when given as single oral doses up to 1050mg 
(SNT-I-004) or as multiple oral doses of 2250mg/day (750mg TID) for 14 days (SNT-I-003).   
 
Idebenone has been extensively studied as a potential therapeutic agent for neurological diseases, 
including Alzheimer’s disease (Gutzmann and Hadler 1998; Gutzmann, Kuhl et al. 2002), 
Huntington’s disease (Ranen, Peyser et al. 1996), Friedrich’s ataxia (FRDA) (Schols, Vorgerd et al. 
2001; Artuch, Aracil et al. 2002; Rustin, Rotig et al. 2002; Buyse, Mertens et al. 2003; Mariotti, 
Solari et al. 2003; Artuch, Aracil et al. 2004; Rustin, Bonnet et al. 2004; Di Prospero, Baker et al. 
2007; Pineda, Arpa et al. 2008) and multi-infarct dementia.  In these clinical trials, in which a 
variety of doses and dosing regimens were employed, idebenone was found to be safe and well 
tolerated.  In phase I trials, idebenone was shown to be well tolerated at doses of 360 mg/day for 12 
months, and at doses of 900 mg/day for four weeks.  In a double-blind, placebo controlled trial of 
idebenone for the treatment of Huntington’s disease, 100 patients were randomized to receive 
idebenone 90 mg three times per day or placebo for a period of 12 months.  Ninety-one patients 
completed the study, and no patients left the trial for adverse events attributed to idebenone.  
Idebenone was found to be safe and well tolerated in this study, but no benefit was found (Ranen, 
Peyser et al. 1996).  Experience from the phase II and III clinical trials for Alzheimer’s disease, in 
which patients received a 120 mg, 240 mg, or 360 mg three times per day for periods of up to 2 
years, suggests a relatively benign toxicity profile for this drug.  No therapeutic benefit was found.  
The most frequently cited adverse effects that occurred more often in the idebenone group were 
gastrointestinal symptoms such as anorexia, nausea, and diarrhea.  Idebenone was marketed in Japan 
from 1986 to 1998 for the treatment of cognitive difficulties following stroke.  During this period, 
idebenone was one of the most frequently prescribed drugs following stroke, with an estimated eight 
million patients treated.  Idebenone was removed from the market in Japan after a post-marketing 
study failed to demonstrate efficacy, but remains registered for cognitive disorders in Italy, Portugal, 
Argentina and Ecuador. 
 
No new issues of safety or tolerability have emerged in the course of the current Phase II and III 
clinical studies with idebenone in Friedreich’s Ataxia (FRDA), Duchenne Muscular Dystrophy, and 
Leber’s Hereditary Optic Neuropathy.  Patients (8 years or older) received doses of idebenone 
ranging from 180 or 360 mg/day to 1350 or 2250 mg/day, depending on body weight, or placebo.  
Blood and urine laboratory analyses, vital signs and ECGs have not highlighted any safety concerns 
to date. Idebenone has been approved for the treatment of FA in Canada, is available under 
provisional approval for cardiomyopathy in FA in Switzerland, and can be obtained on a “named 
patient” basis in a number of other European countries, such as France, Italy, Belgium and Spain. 
Approximately 111.4 million tablets of idebenone were sold during the period 01 April 2004 – 31 


 
 
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March 2011. Assuming that three tablets irrespective of strength were taken daily for the whole 
period, the patient exposure to idebenone in these seven years was estimated to be 102,300 patient-
years. 
 
4.5.3 Pharmacokinetics and product metabolism in humans 
Four Phase I studies were performed by Santhera, two single-dose studies, giving 150 mg idebenone 
or 7x150 mg idebenone to healthy male subjects after a standardized continental breakfast (Study 
SNT-I-002 and Study SNT-I-004), one two-way single dose study in two groups of healthy subjects 
to assess the effect of a fat-rich meal on the pharmacokinetics of idebenone 150 mg or 5x150 mg 
(Study SNT-I-001), and a two-week repeated dose study in two groups of healthy subjects to assess 
the effect of repeated dosing with either 150 mg t.i.d. or 5x150 mg t.i.d. (with the morning dose 
being given after a standardized continental breakfast) on the pharmacokinetics of idebenone (Study 
SNT-I-003). Furthermore two Phase I studies were performed at the NIH in FRDA patients (Di 
Prospero, Baker et al. 2007; Di Prospero, Sumner et al. 2007). These studies are summarized 
below: 
 
Overall conclusion of the Santhera Phase I program 
Idebenone up to 1050 mg given as a single dose and up to 750 mg t.i.d (2250 mg) given as 
repeated doses for 14.3 days was well tolerated (Bodmer, Vankan et al. 2009). The reported 
AEs are mainly gastrointestinal system disorders. There were no clinically relevant effects 
seen on hematological parameters or on biochemical parameters, in particular no effects were 
observed on renal or liver function or on lipid metabolism, including HDL and LDL 
cholesterol. 
 
Frequent monitoring of ECG morphology and QTc duration in studies SNT-I-001 and SNT-
I-003 covering the whole time interval in which idebenone was above the limit of 
quantification gave no clinically relevant abnormal findings, and in particular no 
prolongation of the QTc interval. 
 
After administration, idebenone is immediately metabolized by side chain reduction to QS10, 
QS8, QS6, and QS4. Both idebenone and its metabolites are conjugated and then rapidly 
excreted, predominantly by the kidney. Parent compound (non-metabolized and non-
conjugated) idebenone in plasma amounts to between 0.1% and 1% of total (conjugated plus 
unconjugated – IDE+IDE-C) idebenone, indicating a very high first-pass effect. Therefore 
the plasma concentrations of idebenone are very low even after relatively high doses, e.g. 
Cmax and AUC of idebenone after dosing of 2250 mg/day for two weeks are 19.2 ng/ml and 
106.2 mg/L x hr respectively. The metabolites QS10+QS10-C, QS6+QS6-C and QS4+QS4-
C were in the same order of magnitude as that of IDE+IDE-C. The pharmacokinetics of 
idebenone are linear as assessed indirectly by the amounts of IDE+IDE-C.  Increasing the 
oral dose of idebenone five or seven fold results in corresponding increases in the AUC of 
IDE+IDE-C.  
 
There is a food effect (3-7-fold increase), as assessed in study SNT-I-001, which is more 
pronounced at higher doses.  Repeated daily dosing does not lead to relevant accumulation of 
the metabolites indicating no enzyme auto-inhibition. In addition, there is no indication that 


 
 
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idebenone metabolizing enzymes are induced. Because of the high first pass effect, the 
increase of bioavailability with food is considered to be beneficial. Therefore the dosing 
recommendation for idebenone in all studies is for the daily dose to be given in three 
administrations (t.i.d.) with a meal. 
 
Overall conclusion on the NIH Phase I program in FRDA patients 
Two studies have been performed by the NIH to establish the maximum tolerated dose of 
idebenone in children, adolescents and adults with Friedreich’s ataxia when idebenone was 
administered as a single oral dose (Phase I A study) or as repeated oral doses (Phase I B 
study).  
In both Phase I studies, PK characteristics of idebenone were assessed in children, 
adolescents and adults. In the single dose study, doses up to 75 mg/kg were administered. In 
the repeated dose study a dose of 60 mg/kg was administered for 1 month. In the repeated 
dose study no relevant differences for Cmax and AUC for IDE+IDE-C between the age 
groups were detected (Di Prospero, Baker et al. 2007; Di Prospero, Sumner et al. 2007). 
Idebenone was well tolerated. AEs reported were consistent with the known safety profile, 
with GI disturbances being the most frequent reported AEs for idebenone. 
Studies in patients with impaired organ function 
Two studies were performed in patients with impaired organ function (Reports 
CV2619/EC071 for hepatic; CV2619/EC070 for renal). As expected, patients with impaired 
renal function not undergoing hemodialysis, have higher Cmax and AUC values of IDE+IDE-
C and QS10+QS10-C than subjects with normal renal function, but patients with impaired 
renal function and undergoing hemodialysis have similar exposure values of IDE+IDE-C and 
only slightly higher values of QS10+QS10-C than subjects with normal renal function. These 
data are in agreement with the finding that the metabolites of idebenone are almost 80% 
eliminated by the kidney. The study also shows that IDE+IDE-C, and most probably also the 
other even more hydrophilic metabolites, can be eliminated by hemodialysis. 
Patients with impaired hepatic function have higher exposure and longer elimination 
half-lives of IDE+IDE-C and QS10+QS10-C than subjects with normal liver function, 
indicating that the shortening of the side chain of idebenone is impaired. 
Based on the results of the two studies, it is recommended that caution be exercised in 
patients with impaired renal function not undergoing hemodialysis. Idebenone is 
contraindicated in patients with impaired liver function. 
   
Absorption of idebenone from the Takeda formulation, used in the NIH Phase I studies, and 
absorption from the Santhera formulation are similar, indicating no important differences in 
pharmacokinetic behavior between the formulations of the trial populations.  Safety and tolerability 
were good in the published NIH studies and in the Santhera studies.  Thus clinical safety/efficacy 
data and post-marketing experience available for the Takeda formulation can be considered to be 
relevant also to the Santhera formulation. 
 


 
 
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4.5.4 Product information 
The study medication is manufactured by Santhera Pharmaceuticals and will be provided as 150 mg 
tablets. 
 
The active compound, idebenone, is a yellow-orange crystalline material that melts at 52 to 54oC. 
Idebenone is readily soluble in organic solvents but is practically insoluble in water.  It is highly 
stable at room temperature. The molecular weight is 338.46. The complete description of active 
formulation is below: 
 
Idebenone 150 mg film-coated tablets SNT-MC17/F02  
Ingredients: idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 
(consisting of: aluminum lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, 
titanium dioxide, talc). 
 
4.5.5 Storage and handling 
Idebenone tablets are supplied in high density polyethylene (HDPE) bottles, and should be stored at 
room temperature (15- 25oC) and must be protected from direct sunlight. Temperature excursions are 
permitted as follows: up to 30ºC for 12 months, up to 40ºC for 6 months.    
 
 
4.6 Rationale for the use of Idebenone in PP-MS 
 
As described above (Section 4.3: Mechanism of tissue injury in PP-MS), mitochondrial dysfunction 
together with aberrant formation of ROS are believed to underlie at least partially the development 
of progressive CNS tissue destruction in PP-MS. Idebenone has two key modes of action that make 
it an attractive therapeutic candidate for PP-MS: 
1) Idebenone enhances the electron flow in the mitochondrial ETC. Specifically, idebenone 
can substitute for Coenzyme Q10 (CoQ10) as an electron carrier and distribute the 
electrons between the various dehydrogenases and the cytochrome segments of the 
respiratory chain (Sugiyama and Fujita 1985; Sugiyama, Fujita et al. 1985; Imada, 
Fujita et al. 1989; Geromel, Darin et al. 2002). Perhaps more importantly, due to lower 
lipophylicity of idebenone in comparison to CoQ10, idebenone (but not CoQ10) can be 
reduced by cytosolic enzymes NAD(P)H:quinone oxidoreductases (NQO), which are 
significantly upregulated during oxidative stress, including in MS tissue (van Horssen, 
Schreibelt et al. 2006). Because NQO enzymes reduce idebenone in 2 electron step 
reaction, no semiquinone radical is generated. It is generation of the semiquinone 
intermediate that leads to production of ROS during mitochondrial electron transfer. 
Resultant cytosolic-mitochondrial shuttling of idebenone partially restores ATP 
production under conditions with impaired function of the ETC complex I (Haefeli, Erb 
et al. 2011). This mechanism is likely the explanation for the observed efficacy of 
idebenone in partially restoring visual function in patients with Leber’s hereditary optic 
neuropathy (LHON; MIM 535000), a genetic condition with dysfunctional ETC 
complex I (Klopstock, Yu-Wai-Man et al. 2011). Because mutations in mtDNA affecting 
ETC complex I (Kalman, Lublin et al. 1995; Kalman, Laitinen et al. 2007; Campbell, 


 
 
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Ziabreva et al. 2011), and resultant dysfunction of ETC complex I has been detected in 
MS brain tissue (Andrews, Nichols et al. 2005; Dutta, McDonough et al. 2006; 
Campbell and Mahad 2012) and in aging (Stefanatos and Sanz 2011), it is expected that 
idebenone may similarly potentiate ATP production in PP-MS subjects. 
2) Idebenone functions as an anti-oxidant against membrane damage caused by lipid 
peroxidation, including lipid peroxidation that occurs in brain mitochondria (Suno and 
Nagaoka 1984; Sugiyama, Fujita et al. 1985; Suno and Nagaoka 1989; McDaniel, 
Neudecker et al. 2005). However, it is unclear if the in-vivo achievable concentrations of 
idebenone are sufficient for this mechanism of action (MOA) to occur. 
 
In view of the hypothesized involvement of mitochondrial dysfunction, and particularly the reduced 
activity of the ETC, idebenone is a rational treatment choice in PP-MS based on its pharmacological 
properties. Furthermore, idebenone is known to cross the blood-brain barrier (Torii, Yoshida et al. 
1985) and is readily taken up by cells, even those with normal CoQ10 content (Geromel, Darin et al. 
2002), making it superior to natural CoQ10 for treatment of CNS diseases with presumed 
mitochondrial dysfunction. 
 
There are several secondary effects of idebenone described in the literature, which may be useful 
from the standpoint of the presumed pathophysiology of PP-MS:  
3) Animal studies have documented neuroprotective properties of idebenone in-vitro in 
different models of excitotoxicity (by NMDA and kainite-agonists) (Miyamoto and 
Coyle 1990; Bruno, Battaglia et al. 1994).  
4) Idebenone induces nerve growth factor expression in animals (Nitta, Murakami et al. 
1994), which represented the basis for its presumed neuroprotective effect in 
Alzheimer’s disease (AD) (Gutzmann and Hadler 1998; Gutzmann, Kuhl et al. 2002). 
However, this beneficial effect on AD is only very mild and perhaps not highly clinically 
relevant (Thal, Grundman et al. 2003).  
5) Idebenone has potential CNS anti-inflammatory activity, as it inhibits metabolism of 
arachidonic acid by cyclooxygenase and lipoxygenase (Civenni, Bezzi et al. 1999).  
6) Idebenone may substitute for CoQ10 in non-mitochondrial locations such as in 
lysosomes, peroxisomes and plasma membranes, protecting these organelles from ROS-
associated damage (Geromel, Darin et al. 2002) 
 
Due to its effect as a scavenger of oxygen radicals and facilitating effect on ETC, idebenone has 
been used extensively with reported success in patients with mitochondrial diseases (Mashima, 
Hiida et al. 1992; Ikejiri, Mori et al. 1996; Napolitano, Salvetti et al. 2000; Lerman-Sagie, Rustin et 
al. 2001; Geromel, Darin et al. 2002). As mentioned above, the first randomized trial of idebenone 
in LHON demonstrated improvements of vision in the active therapy arm in comparison to placebo, 
although statistical significance was obtained only for secondary outcomes (Klopstock, Yu-Wai-Man 
et al. 2011). LHON is the most common mitochondrial disorder, causing progressive loss of vision. 
Pathogenic mutations of mtDNA, which affect ETC complex I, lead to decreased ATP synthesis 
accompanied by increased mitochondrial production of ROS. Painless loss of vision on one eye, 
which usually occurs in early adulthood, is followed by progressive irreversible blindness of the 
second eye usually within 3 months. Idebenone not only significantly inhibited the worsening of 
eyesight in the less affected eye in patients with discordant visual acuities, but also caused general 
improvement in all visual outcomes (i.e. including in the eyes that were chronically blind), although 


 
 
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this improvement did not reach statistical significance for the primary outcome, which was best 
recovery of visual acuity considering both eyes (Klopstock, Yu-Wai-Man et al. 2011).  These 
objective improvements of visual function in the intention to treat analysis correlated with the 
patients’ global impression of change. In the group of patients who could not read any letters on the 
vision chart at baseline, 20% of the eyes of the patients receiving idebenone were able to read at 
least one full line on the chart at week 24, while none of the patients in the placebo group showed 
such improvements (p=0.008). Additionally, idebenone treatment caused significant improvements 
in color contrast sensitivity (by 13.63-14.51%, p=0.004). These functional data were supported by 
OCT data that demonstrated a trend toward maintaining retinal nerve fiber thickness in the 
idebenone group (Klopstock, Yu-Wai-Man et al. 2011).  
 
We consider the data from LHON highly relevant for MS because of the known association between 
LHON and MS, called Harding’s syndrome (Vanopdenbosch, Dubois et al. 2000). It appears that 
carrying a primary LHON mutation dramatically increases the risk for development of MS: 
Harding’s syndrome occurs 50 times more frequently than would be expected from the individual 
prevalence rates for LHON and MS (Palace 2009; Stys, Zamponi et al. 2012). As we described 
above, demyelination causes secondary mtDNA mutations and functional defects in ETC complex I 
that are pathophysiologically similar to inborn genetic errors associated with LHON. 
 
There was also a therapeutic benefit of idebenone observed in Phase II trials in the 
neurodegenerative disease Friedreich’s ataxia (FRDA), which unfortunately did not reach statistical 
significance in the confirmatory Phase III trial (Meier, Perlman et al. 2012). FRDA is the most 
common hereditary ataxia inherited as an autosomal recessive GAA expansion in the first intron of 
the frataxin gene. Frataxin is a nuclear encoded protein, which is exported to the mitochondria. 
Frataxin plays an important role in the assembly of mitochondrial FE/S clusters that are key 
components of the ETC. Its decreased expression therefore leads to reduced activity of the ETC, 
mitochondrial damage with subsequent increased formation of reactive oxygen species (ROS). It 
was demonstrated that FRDA has reduced ATP biosynthesis. The reduced activity of the ETC in 
combination with secondary oxidative damage is believed to underlie the development of 
neurological disability and hypertrophic cardiomyopathy and diabetes, which are characteristic 
clinical presentations of this disease. Idebenone has been studied extensively in FRDA (Schols, 
Vorgerd et al. 2001; Artuch, Aracil et al. 2002; Rustin, Rotig et al. 2002; Buyse, Mertens et al. 
2003; Mariotti, Solari et al. 2003; Artuch, Aracil et al. 2004; Rustin, Bonnet et al. 2004; Di 
Prospero, Baker et al. 2007; Pineda, Arpa et al. 2008), including successful studies performed at 
intramural NIH by the Neurogenetics Branch research group under the leadership of Dr. Kenneth 
Fischbeck (Di Prospero, Baker et al. 2007) in collaboration with Santhera. This study demonstrated 
that intermediate to high (10-50mg/kg) doses of idebenone were effective in slowing the progression 
of disability in FA patients as compared to low dose idebenone (4-8mg/kg) and placebo. Because 
previous trials using lower doses of idebenone in FRDA demonstrated a positive effect on cardiac 
function but not on neurological function (Mariotti, Solari et al. 2003), it is likely that higher doses 
of idebenone are necessary for penetration into the CNS. This conclusion is fully supported by 
above-mentioned Phase III trial (IONIA) that studied two weight-adjusted doses of idebenone: low 
dose (450/900mg) or high dose 1350/2250mg) and its open label extension (IONIA-E), where 
patients who received the higher dose of idebenone (1350/2250mg) for 18 months significantly 
improved in neurological function (Meier, Perlman et al. 2012). 
 


 
 
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In conclusion, the three major effects of idebenone (facilitating ETC mitochondrial function, 
antioxidant/scavenger of ROS and potentially also anti-inflammatory) make it an excellent candidate 
agent for the treatment of PP-MS based on the neurodegenerative hypothesis described above. 
Additionally, idebenone is an oral therapy with extensive safety and tolerability data. 
 
 
4.7 Rationale for current study design 
 
The clinical experience with use of antioxidants in MS is very limited: although a few trials of 
antioxidants in MS have been reported (Jensen and Clausen 1986; Spitsin, Hooper et al. 2001; 
Yadav, Marracci et al. 2005), all have been small studies of short duration and offered only very 
limited insight on clinical efficacy (Spitsin, Hooper et al. 2001).  
 
Idebenone is currently being used in a proof-of-principle placebo-controlled, Phase I/II clinical trial 
for PP-MS (IPPoMS trial; Protocol Number 09-N-0197). Patients who have completed the 2 year 
treatment period of the IPPoMS study will be given the opportunity to enter the current open-label 
extension (IPPoMS-E) study. The IPPoMS study stipulates, in accordance with FDA Good Clinical 
Practice (GCP) recommendations, that the blind will be broken only after all study subjects have 
completed all study visits and all outcomes have been logged into the database. Therefore, patients 
will have to decide whether they want to participate in the IPPoMS-E study without having 
knowledge about their assignment to idebenone versus placebo group during IPPoMS trial. This 
could cause an ethical dilemma for patients who might have been in the idebenone arm during the 
IPPoMS trial and did not experience satisfactory therapeutic response, because the option to 
participate in IPPoMS-E would theoretically prevent them from pursuing other therapeutic options. 
However, because there are currently no effective therapies for PP-MS, we deem this theoretical 
problem not applicable to IPPoMS-E trial. 
 
The IPPoMS-E population will comprise both patients randomized to idebenone or to placebo in the 
IPPoMS study. Therefore all safety and efficacy assessments conducted for the IPPoMS study will 
also be conducted for the IPPoMS-E (Figure 2). This is particularly important for patients 
randomized to placebo in IPPoMS now receiving idebenone for the first time in IPPoMS-E. 
 
The aim of the present study is extend the data on safety, efficacy and effects on CSF biomarkers of 
idebenone 2250mg/day (5x150mg tablets three times per day) in patients with PP-MS, over a period 
of 1 year. Considering the dynamics of improvements in neurological function observed in double 
blind placebo-controlled trial of idebenone in LHON (Klopstock, Yu-Wai-Man et al. 2011) and in 
FRDA (Di Prospero, Baker et al. 2007) we believe that if there was a meaningful therapeutic effect 
of idebenone in PP-MS, then one year of active therapy would provide sufficient time to observe a 
difference in the rate of accumulation of neurological disability as compared to the 3 years of natural 
history from the IPPoMS placebo arm. IPPoMS-E will also provide safety and efficacy data for an 
additional 1 year in patients randomized to idebenone in IPPoMS.  
 
Furthermore, the IPPoMS-E study will significantly expand the amount of longitudinal CSF 
biomarker data for idebenone-exposed PP-MS subjects. In patients randomized originally to active 
drug, IPPoMS-E study will effectively provide three yearly CSF samples on idebenone therapy. 
Such longitudinal CSF biomarker data on active therapy can be then compared to longitudinal CSF 


 
 
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biomarker data off therapy (i.e. 3 yearly CSF samples in the original placebo arm) for mathematical 
modeling studies that may provide support for, or contest, a potential neuroprotective effect of 
idebenone in PP-MS (see section 11: Statistical analysis).  Furthermore, the number of paired CSF 
samples before and after idebenone therapy may theoretically increase up to 100% (if all patients 
choose to continue in IPPoMS-E protocol), although we consider it likely that some patient will 
decline participation in IPPoMS-E. This expansion of paired baseline versus treatment CSF samples 
will effective provide confirmatory cohort for validation of the changes induced by idebenone 
treatment that were defined in original IPPoMS trial (see section 11: Statistical analysis).   
 
Figure 2: IPPoMS-E trial design 
 
 
 
We believe that expansion of efficacy on clinical, imaging and biomarker data may be highly 
important for supporting or refuting presumed therapeutic equipoise of idebenone and placebo in PP-
MS and for selecting the optimal patient population and optimal trial design for the confirmatory 
trial in case IPPoMS and IPPoMS-E trials indicate therapeutic efficacy. 
 
 
5. STUDY OBJECTIVES OR HYPOTHESES 
 


 
 
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5.1 Hypothesis 
 
We hypothesize that idebenone, through its combined effect on facilitation of mitochondrial 
metabolism and limitation of oxygen radical-induced CNS damage, will inhibit CNS tissue 
destruction in PP-MS patients. 
 
5.2 Goals of the study 
The primary goals are: 
1. To extend long-term (36 months) data on the safety and tolerability of idebenone at 2250 
mg/day in patients with PP-MS. 
2. To extend CSF biomarker data by significantly expanding (up to 2 fold if all eligible patients 
proceed to IPPOMS-E) the matched “baseline” vs. “idebenone treatment” CSF samples, 
which will be analyzed for biomarkers of oxidative stress, mitochondrial function and CNS 
tissue integrity. 
3. To extend efficacy data for idebenone on CNS tissue destruction as measured by quantitative 
imaging biomarkers and clinical/functional biomarkers in patients previously completing 
IPPoMS (Protocol Number 09-N-0197). For patients originally randomized to active drug, 
the idebenone longitudinal data will be extended for total of 3 years, for patients originally 
randomized to placebo, 3 year pre-treatment or placebo-treatment period will be compared to 
1 year idebenone therapy period. 
The secondary goals are:  
1. To further investigate the mechanism of action of idebenone in PP-MS. 
2. To better define biomarkers indicative of therapeutic effect of idebenone on mitochondrial 
dysfunction and on limiting oxidative damage in PP-MS patients. 
 
 
6. SUBJECTS 
 
6.1. Study population 
 
Eligible patients completing the IPPoMS trial will be offered the opportunity to enroll in this 
IPPoMS-E study. 
 
It is important that no break in study medication between the IPPoMS randomized phase and the 
present study occurs. Such a break in therapy will render interpretation of study outcomes in this 
trial more difficult.  However, if a patient does finish the IPPoMS randomization phase before this 
IPPoMS-E study is approved for use, they will be allowed to enter the IPPoMS-E trial. 
 
6.2. Inclusion criteria 
 
1. Completion of 3 years in study IPPoMS (Protocol Number 09-N-0197) 
2. Able to provide informed consent  
3. Adults, at least 18 years of age. 
4. Willing to participate in all aspects of trial design and follow-up 


 
 
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5. 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  
 
6.3. Exclusion criteria 
 
1. Pregnant or lactating women. All women of child-bearing potential must have a negative 
pregnancy test  
2. Patients dropping out of IPPoMS due to AEs considered related to study medication 
 
 
7. STUDY DESIGN AND METHODS 
 
7.1 Study overview 
 
This is a Phase II open-label trial of the safety and efficacy of idebenone at 2250 mg/day with one 
year treatment period. Patient-specific biomarkers of disease progression and longitudinal 
neuroimaging and clinical data will be collected as for the randomized study.  
 
7.2 Recruitment 
 
Eligible patients completing the IPPoMS (Protocol Number 09-N-0197) will be offered the 
opportunity to enroll in this open-label extension study IPPoMS-E.  
 
7.3 Screening methods 
 
Not applicable. 
 
7.4 Study design 
 
Patients will be given idebenone (2250 mg/day, given as five 150 mg tablets, three times a day) and 
will be followed by combined neurological, neuroimaging and research biomarker/immunological 
evaluations every 6 months for 1 year. In addition, patients will have safety labs drawn at month 25 
which can be drawn at NIH or at an outside lab with results (including normal values) communicated 
to NIH investigators.  Telephone interviews will occur 1 week, 1 month (Mo 25) and 2 months (Mo 
26) after initiation of dosing.  Patient’s safety and change in neurological function will be assessed 
during the telephone interview with an investigator (Figure 2). 
 
The IPPoMS-E Baseline information will be provided by the results of the IPPoMS Month 24 
assessments. 
 
The time commitment will include extension of the last visit on IPPoMS trial (which will serve as 
initial visit in IPPoMS-E trial) and 2 additional prolonged outpatient or inpatient visits in the 1 year 


 
 
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period. Each prolonged visit will have procedures that together last at least 8 hours spread over 1-3 
days. 
 
According to negotiated MCRADA, Santhera Inc. will supply sufficient amount of idebenone for 
completion of the proposed trial (i.e. 1 year dosing for up to 85 patients). There is no negotiated 
provision for Santhera to continue to provide drug on a compassionate basis for any of the patients 
after completion of the trial. 
 
7.5 Study procedures 
7.5.1 Study visits 
 
The last study visit in IPPoMS will serve as the baseline visit for this extension study, at which time 
informed consent will be obtained and patient will undergo the first lumbar puncture and associated 
research bloodwork under IPPoMS-E protocol.  Each subsequent IPPoMS-E study visit (Figure 2) 
and MRI should occur as indicated. These time points are approximated. To accommodate for 
patient scheduling needs or clinical necessity, study visits will be accepted within a +/- 4 week 
window of the time points noted. Biological samples (CSF, whole blood or apheresis sample) should 
be collected within 4 weeks of the MRI examination as indicated in Figure 2. Blood samples at the 
IPPoMS mo 24 visit and 36 month IPPoMS-E will be collected concomitantly with CSF samples in 
the IPPoMS-E trial.  
 
Because most patients enrolled in IPPoMS trial do not live locally, their clinical visits will be 
associated with travel to NIH for either inpatient or outpatient visits lasting 1-3 days. During these 
extended visits all study procedures pertaining to a specific study time point will be performed. We 
estimate that the total duration of all study procedures pertaining to a single study timepoint is 8-12 
hours. 
 
7.5.2 Clinical and functional evaluations:  
1. Comprehensive neurological evaluation 
2. Expanded Disability Status Scale (EDSS (Kurtzke 1983)) 
3. Scripps Neurological Rating Scale (NRS (Sharrack and Hughes 1996)) 
4. MS Functional Composite Scale (MSFC (Cutter, Baier et al. 1999), which consists of 3 
functional tests: 
a. Paced Auditory Single Digit Addition Test (PASAT) – measure of cognitive skills 
b. Timed 25 foot walk – measure of ambulation 
c. 9-hole peg test – measure of fine finger motor movements 
5. Symbol Digit Modality Test (Sepulcre, Vanotti et al. 2006) 
6. Extensive evaluation of strength, balance and gait within the context of a physical therapy 
(PT) evaluation will be performed if the subject is not too disabled to participate in these 
evaluations safely and reliably. This optional evaluation will be conducted in the 
Biomechanics Laboratory of the Rehabilitation Medicine Department, NIH, CC. It will 
include, but may not be limited to, the following: 
a. Evaluation of strength and tone 
b. Evaluation of gait  


 
 
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c. Balance assessment 
 
7.5.3 Neuroimaging evaluation: 
MRI imaging will consist of: 
1) MRI of the brain, which will be performed every 6 months. This MRI will focus on 
quantitative and volumetric analyses of brain structure and tissue integrity. Inflammatory 
activity is less prominent in PP-MS as compared to RR-MS and consequently, the vast 
majority of PP-MS patients do not have evidence of gross blood-brain barrier (BBB) 
disruption as measured by contrast-enhancing lesions (CEL). Therefore, gadolinium 
(Gd) may not be administered during every scan.  Clinical judgment will determine if Gd 
is administered during the remaining 3T brain MRI scans. The total scan time without 
Gd administration is approximately 90 minutes. With Gd, the scan time increases to 2 
hours. 
 
2) MRI of the spinal cord. This will focus on analysis of spinal cord volume and detection 
of lesions. We will investigate the feasibility and value of quantitative spinal cord 
structural integrity measures as well. This scan will be performed at Mo 30 and Gd 
administration will be based on clinical judgment. The total scan time is approximately 
75 minutes without Gd and 90 minutes with Gd. 
 
7.5.4 Optical coherence tomography (OCT)  
OCT will be performed at the conclusion of IPPoMS-E trial. OCT is a new noninvasive high-
resolution method that measures the retinal nerve fiber layer (RNFL) thickness. It works by 
measuring the echo time delay and intensity of back-reflection of light from different structures in 
the eye. Recent studies have shown that OCT can detect RNFL thinning, possibly due to axon 
degeneration, within the retinas of patients with MS, regardless of a clinical history of optic neuritis 
(Kallenbach and Frederiksen 2007).  Moreover, RNFL thickness appears associated with global 
brain atrophy, (manifested by increasing CSF volume) (Gordon-Lipkin, Chodkowski et al. 2007). As 
discussed, reliable methods of measurement of neurodegeneration in MS are lacking.  While a more 
thorough characterization is needed, evidence to date suggests that OCT may be developed as a 
novel measure of neuronal/axonal destruction reflective of neurodegeneration in MS with both 
diagnostic and prognostic potential (Gordon-Lipkin, Chodkowski et al. 2007; Kallenbach and 
Frederiksen 2007).  
 
7.5.5 Transcranial magnetic stimulation (TMS) and Central motor conduction time (CMCT) 
calculation  
TMS and CMCT may be performed for clinical care. 
Neurophysiological testing, can assess the intactness of conduction through the long tracts, such as 
the corticospinal tract (CST) (Ravnborg 1996).  Because CST is invariably affected in PP-MS, the 
use of motor evoked potentials (MEP) may be performed for clinical care. TMS is a non-invasive 
technique for evaluating the function of central motor pathways. Single pulse TMS is used to 
determine the motor evoked potential (MEP), the response generated by excitation of cortical 
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(CMCT).  In MS patients, CNS dysfunction manifests itself in the form of slowed conduction 
through demyelinated portions of the corticospinal tracts or more severe disruption of conduction as 
a result of axonal loss or severe demyelination. This results in a prolongation of CMCT or dispersion 
of the MEP response such as in a conduction block with resultant decrease in MEP amplitude (Hess, 
Mills et al. 1987; Schriefer, Hess et al. 1989).  In progressive MS patients, CMCT has been shown 
to correlate with the presence of new spinal cord lesions on MRI and changes in the leg CMCT 
(Kidd, Thompson et al. 1998).  There is other evidence that suggests that progressive MS patients 
have greater prolongation of the CMCT compared to relapsing-remitting MS, irrespective of MRI 
lesion load, suggesting that progressive MS has more perturbations of the corticospinal tracts than 
are radiologically discernible (Humm, Z'Graggen et al. 2004).  
 
7.5.6 Immunological and laboratory evaluation: 
The immunological and laboratory evaluation will include: 
 
1. Clinical blood-work (clinical care/safety): CBC, Chemistry panel including liver function tests 
will be performed one month after initiation of open label dosing (Mo 25), Mo 30, and Mo 36. 
Laboratory evaluations that are performed at times when no NIH MRI/clinical visit is scheduled 
(Mo 25) can be performed outside of NIH with results (including normal values) communicated 
to NIH investigators. PT/PTT and PFA panel may be collected as additional safety measures at 
month 30 and 36.  Urine analysis (UA) will be performed every 6 months. Pregnancy tests (for 
females of child-bearing potential) will be collected up to 24h preceding every MRI exam. All 
safety laboratory evaluations are represented in the clinical trial scheme on Figure 2.  
2. Research Blood (up to 40 cc total): Research blood will be obtained concomitantly with the LP 
Lumbar puncture (research): Every patient will undergo a lumbar puncture at the beginning of 
IPPoMS-E trial (month 24) and after 1 year of therapy (month 36).  This procedure is performed 
solely for research purposes.  From 15-20cc of research specimen, immune cells will be isolated 
and expanded and the CSF supernatant will be aliquoted and stored. In certain cases (generally 
with participants who are obese, who have limited mobility, or who have lumbar spondylosis), 
the procedure may be performed under fluoroscopic guidance by a credentialed neuroradiologist 
in Diagnostic Radiology. This involves a small amount of ionizing radiation (0.023 rem per 
year). This is substantially less than the limits imposed by the guidelines of the NIH Radiation 
Safety Committee (5.0 rem per year for adults). 
3. Lumbar puncture procedure last from 30 minutes to 2 hours. 
4. Pharmacokinetic (PK) studies (research): Random sampling PK studies may be performed from 
the CSF at the time of LP, for the analysis of IDE and IDE+IDE-C and the metabolites QS-10, 
QS-6 and QS-4, as well as QS10+QS10-C, QS6+QS6-C and QS4+QS4-C. Samples will be put 
on ice immediately and centrifuged at 4°C at 1500 g for 10 minutes within 30 minutes after 
sampling. The cell-free aliquots will be separated and stored separately in polypropylene tubes 
with a minimum of 0.5ml of CSF per tube. Samples will be stored between -70 and -80°C. The 
CSF will be collected for possible future PK studies to be performed by Santhera 
Pharmaceuticals upon completion of the collection of all trial samples, using a validated LC-
MS/MS method (Inovalab, Reinach, Switzerland) 
5. Lymphocytapheresis (research): collecting between 2-4x109 peripheral blood mononuclear cells 
PBMC, will be performed after 1 year of idebenone therapy (Mo 36).  This procedure is 
performed solely for research purposes.  This procedure may last up to 2.5 hours. If the 


 
 
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participant is unable to undergo lymphocytapheresis for any reason, 120 cc of whole blood in a 
heparinized syringe will be collected in its place.  The collected mononuclear cells will be used 
for immunological studies. 
7.5.7 Drug administration: 
 
A copy of this protocol has been submitted to the FDA under the existing IND for review. Santhera 
provided a letter of cross-reference to the IND held by them. 
 
Idebenone (150mg tablets) will be administered orally as five tablets, three times per day with food. 
Patients will receive a 6 month supply of the study medication. Patients will record drug 
administration in a drug diary. Remaining pills and bottles will be counted during clinic visits every 
6 months to assess overall drug compliance. 
 
Idebenone is a short-chain benzoquinone derivative of similar structure to ubiquinone (coenzyme 
Q10). This compound was synthesized and developed initially by Takeda Chemical Industries, Ltd. 
(Osaka, Japan) and designated as CV-2619. The chemical name for idebenone is 6-(10-
Hydroxydecyl)-2,3-dimethoxy-5-methyl-1, 4-benzoquinone. Santhera Pharmaceuticals (Switzerland) 
Ltd, will supply the drug for this study as specified by a clinical trial agreement. Idebenone is 
formulated as film-coated 150 mg tablets. For list of inactive ingredients see section 4.5.4. 
 
Idebenone with a certificate documenting analytical results, release of the product for the clinical 
study and shelf life will be provided to the NINDS by Santhera Pharmaceuticals (Switzerland) Ltd. 
Idebenone tablets are supplied in high density polyethylene (HDPE) bottles, should be stored at 
room temperature (15-25oC) and must be protected from direct sunlight. Temperature excursions are 
permitted as follows: up to 30ºC for 12 months, up to 40ºC for 6 months.    
  
7.5.8 Records: 
 
The NINDS/Clinical center record will be used for trial-related documentation. Specific trial-related 
pages will include: 
 
Inclusion and exclusion criteria checklist 
Documentation of the history and physical examination (using structured NIB progress note) 
1. A copy of the written informed consent. 
2. A record of all research tests, scores, and results. 
3. Documentation of all clinical laboratory results. 
4. Documentation of any concomitant medications taken by the patient. 
5. A record of any and all adverse events experienced during the study. 
7.5.9 Storage of data and samples: 
 
All collected samples, including serum/plasma, blood, CSF and peripheral blood mononuclear cells 
(PBMC) derived from apheresis or 120cc blood sample (see 7.5.6) will be coded and stored in 
secured freezers on the NIH campus.  All patients enrolled in this protocol will be assigned a 


 
 
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sequential code and all biological samples collected for this patient will be labeled with patient’s 
code, type of the sample, volume, number of cells (if indicated) and date of freezing. 
 
The intent is for all samples (except for those to be analyzed for idebenone and metabolite 
pharmacokinetics) to be analyzed in laboratories on the NIH campus.  As new relevant 
methodologies are developed, however, there is a conceivable future interest to process samples off-
site in a collaborating laboratory.  Patients will be made aware of this possibility at the time of 
enrollment and will be asked to consent to potential off-site processing. In this event, IRB approval 
from NIH and from the collaborating institution will be obtained, and materials will be shipped in 
accordance with NIH and federal regulations.   
 
 
7.6 Follow-up/termination procedures 
 
The individual participation in the trial will end with the last trial visit at month 36, unless the trial is 
closed prematurely. There will be a telephone interview 1 month after completion of the trial to 
verify that there has been no worsening of the clinical symptoms. In case of serious adverse events 
ongoing at the last trial visit (month 36) or of SAEs newly reported during the telephone contact, the 
patient will be invited to undergo a full examination and assessment at the study site. Additionally, 
patients will be asked to report any serious adverse event that may occur after this last interview, if 
they perceive them as possibly related to the participation in this study. The trial will be officially 
terminated after all enrolled subjects complete the telephone visit (month 37) or withdraw from the 
trial. The trial may be terminated prematurely by the DSMB if there is a concern about safety of 
idebenone in PP-MS patients.  
 
All clinical data will be prospectively acquired and entered into the NIB research database. 
Similarly, all neuroimaging volumetric data will be transcribed into the NIB research database. All 
immunological and/or biomarker data will be logged and stored in a separate research database on 
the NINDS server. In order to limit inter-assay variability, for those biomarkers that can be measured 
from cryopreserved biological samples, all time-points for individual research subjects will be run in 
parallel. All databases will be locked upon the last entry of data from the last patient who completes 
the trial. 
 
7.6.1 Premature trial termination for futility - patient follow-up 
 
As of this protocol amendment, the IPPoMS study 09-N-0197 (Blinded parent study of idebenone vs 
placebo) has completed analysis and demonstrated that idebenone, while being safe and well-
tolerated, had no significant efficacy on either primary or any secondary outcome measures, in 
comparison to placebo.  As a result, this open-label extension study will be stopped for futility.  No 
additional patients will be enrolled onto this protocol.  All participants are co-enrolled into natural 
history study 09-N-0032, and may continue follow-up under that study.  Data and samples from this 
study will be transferred into protocol 09-N-0032 for continued analysis.  Participants will be 
contacted by phone and formally informed of the study results by a written letter (uploaded to 
PTMS). Participants will return for a final study visit, and any remaining study drug will be 
collected.  The final study visit will include the following procedures: clinical evaluation, MRI and 
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8. RISKS/DISCOMFORTS 
 
8.1 Risks associated with Idebenone therapy 
 
There is considerable clinical trial and post-marketing experience indicating that idebenone is well 
tolerated and has a good safety profile. Safety data are available from 311 patients with Friedreich’s 
Ataxia (FRDA) or Leber Hereditary optic neuropathy (LHON) treated with idebenone at doses of 
between 900 and 2250 mg/day. No noteworthy imbalances in the distribution of adverse events 
(AEs) were observed for the comparison of idebenone or placebo. The most commonly observed 
adverse reactions were gastrointestinal disorders. The following reactions were observed in more 
than one patient: headache, diarrhea, nausea and dyspepsia. The following reactions were not 
observed in more than one patient at the recommended doses: white blood cell count decrease, 
disturbance in attention, angina pectoris, vomiting, reflux oesophagitis, musculoskeletal chest pain, 
myalgia, upper abdominal pain. 
 
Clinical trials with idebenone have previously been performed in indications other than FRDA and 
LHON, predominantly in older patient populations (mainly in Alzheimer’s dementia). Besides some 
of the reactions listed above, patients in these trials showed the following reactions uncommonly 
(between 1/1000 and 1/100): sleep disorders, nervousness, dizziness, changes in hepatic laboratory 
values and influenza-like symptoms. These reactions may be more likely in this elderly study 
population with CNS impairment and more concomitant medications. 
 
The IPPoMS trial will randomize up to 85 PP-MS patients either to idebenone (2250 mg/day) or to 
placebo. This study is under the supervision of a Data Safety Monitoring Board. By July 2012 
approximately 20 patients had been treated with study medication. Five Serious Adverse Events 
(SAEs) have been reported on this trial to date but all were considered unrelated to study medication 
and the DSMB had raised no safety concerns with regard to the conduct of the study. 
 
Idebenone at high doses (60-75 mg/kg/day or about 3600-4500 mg/day) may cause orange 
discoloration of urine in few patients. It is unclear if this will occur at the dose of 2250mg/day. The 
orange discoloration of urine is completely harmless and urine will be monitored every 6 months by 
urinalysis in order to ensure that hematuria or hemoglobinuria is not mistaken for the orange 
discoloration due to idebenone. 
 
8.2 Risks of lymphocytapheresis  
 
Adverse reactions associated with lymphocytapheresis include vasovagal syncope with needle 
insertion and rare hypotension secondary to volume depletion.  Because of the controlled nature of 
these procedures hypotension is unlikely.  Exclusion of patients with a history of cardiovascular 
disease further reduces the risk of this complication.  The blood thinner used to prevent blood clots 
from apheresis can cause mild muscle cramps. If these side effects occur, we can slow down blood 
flow or use a different blood thinner. If the symptoms do not go away, the apheresis can be stopped. 
There may also be bruising at the site of needle insertion.  Infection is a potential risk, but is unlikely 


 
 
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due to the closed system and the maintenance of sterile technique.  The Blood Bank has extensive 
experience with these procedures and has encountered no serious side effects. 
 
8.3 Risks of MRI 
 
People are at risk for injury from the MRI magnet if they have pacemakers or other implanted 
electrical devices, brain stimulators, dental implants, aneurysm clips (metal clips on the wall of a 
large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner or tattoos, implanted delivery pump, or shrapnel fragments. Welders 
and metal workers are also at risk for injury because of possible small metal fragments in the eye, of 
which they may be unaware. All subjects will be screened for these conditions prior to the study, and 
if they have any, they will not receive an MRI scan.   
 
Gadolinium is a contrast agent approved for use with MRI by the FDA.  No serious side effects have 
been associated with its use. The effect of gadolinium on the developing fetus remains partly 
unknown.  Animal studies have shown a delay in development but no developmental abnormalities.  
Consequently, women of childbearing potential will be entered into this study only if an effective 
means of birth control is in use.  A pregnancy test will be done prior to beginning the study and 
pregnancy tests will be done before MRIs are performed.  The risks of an IV catheter include 
bleeding, infection, or inflammation of the skin and vein with pain and swelling.  Symptoms from 
the contrast infusion are usually mild and may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number of patients, more severe 
symptoms have been reported including shortness of breath, wheezing, hives, and lowering of blood 
pressure. Subjects should not receive gadolinium-based contrast agents if they have previously had 
an allergic reaction to them.  Subjects will be asked about such allergic reactions before a contrast 
agent is administered.   People with kidney disease are at risk for a serious reaction to gadolinium 
contrast called “nephrogenic systemic fibrosis” which has resulted in a very small number of deaths.  
If patients are older than 60 or have diabetes, kidney disease or liver disease, bloodwork to assess 
kidney function will be performed within 4 weeks before any MRI scan with gadolinium contrast. 
Patients may not receive gadolinium for a research MRI scan if kidney function is not normal. The 
long term effect of noise exposure from MRI is not known. 
 
8.4 Risks of lumbar puncture 
 
Adverse effects associated with lumbar punctures include brief pain or tingling paresthesias radiating 
down the lower extremity due to the needle brushing against a nerve.  Should this occur, the needle 
can be repositioned.  Mild lower back pain at the site of needle insertion following the procedure can 
occur; this can be managed with over the counter non-steroidal anti-inflammatory agents if needed.  
In approximately one third of patients, a post-dural puncture headache may develop and persist for a 
few days; in one in 50 to 200 lumbar punctures the post-dural puncture headache can last longer than 
7 days.  Generally this headache is not severe and resolves spontaneously within days - 2 weeks.  
Should the headache persist or be severe, a blood patch can be performed.  An extremely rare 
complication of lumbar puncture includes temporary double vision related to abducens nerve palsy, 
and infection. Strict aseptic technique will be followed. Collecting additional 10-15 cc of CSF per 
procedure represents negligible risk (Evans, Armon et al. 2000). In humans the rate of CSF synthesis 
is approximately 21.5 cc/hour (Kimelberg 2004), or approximately 500cc/24hours, which represents 


 
 
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roughly 4 times the total volume of CSF in an adult patients. Therefore, the volume of 20-30cc of 
CSF that would be collected for both diagnostic and research purposes will be replenished in its 
entirety within approximately 1-1.5 hours after collection.  Lumbar puncture may be done in the 
radiology department under fluoroscopic guidance for patient medical or scheduling needs. The 
radiation exposure during this procedure is 0.023 rem, which is well below the guideline of 5 rem 
per year allowed for adult research subjects by the NIH Radiation Safety Committee. 
 
 
8.5 Risk of OCT 
 
There are no known medical risks of optical coherence tomography. 
 
8.6 Risk of electrophysiological studies 
8.6.1 Risk of TMS 
TMS is a safe procedure that has been used on thousands of people throughout the world, 
particularly the single-pulse TMS used in this study.  Most people do not find the stimulation 
painful, but sometimes strong contractions of scalp muscles can cause discomfort or headache. 
Headaches usually go away promptly with nonprescription medication. The noise of the TMS 
magnet may damage hearing; therefore the subjects will be fitted with earplugs that must be worn 
during TMS.  TMS can interfere with implanted medical devices and will not be done in people who 
have pacemakers, implanted pumps, or stimulators, such as cochlear implants or in people who have 
metal objects inside the eye or skull. 
 
8.6.2 Risk of nerve conduction studies 
The risks of the electrical stimulation using commercial isolated stimulators are low. Most subjects 
find electrical nerve shocks to be mildly uncomfortable; it is usually perceived as a brief stinging or 
tapping sensation. The intensities required for nerve conduction studies are usually well tolerated. 
 
8.7 Risk Rehab Evaluation 
The risk of physical injury in this series of noninvasive tests is minimal.  
 
 
9. SUBJECT MONITORING 
9.1 Parameters to be monitored 
9.1.1 Expected Adverse Events:  
Animal studies predict a low human toxicity profile for idebenone.  This is supported by extensive 
experience including phase I trials in normal human volunteers and phase II and III trials in patients 
with Alzheimer’s disease, FRDA, LHON, Duchene Muscular Dystrophy (DMD), cerebrovascular 
accident (stroke), multi-infarct dementia, and other neurodegenerative diseases (e.g. Huntington’s 
disease), at doses comparable to those being used in this study.  Based on the literature review of 
published data from these studies, the most frequently and consistently experienced adverse 


 
 
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reactions reported across these trials have been headache, diarrhea, nausea and dyspepsia. A 
complete list of previous adverse events, which may also be expected in this trial, may be found in 
the Investigator’s Brochure and is summarized in section 7 of that document. In addition, medical 
events typical for clinical course of PP-MS (i.e. typical neurological signs/symptoms that patient 
experienced during pre-treatment baseline and their worsening as would be expected from the 
natural history of PP-MS) can be regarded as expected events in the course of the current trial.  
9.1.2 Monitoring of adverse events: 
The patient will be instructed to contact the investigator immediately should the patient manifest any 
sign or symptom perceived as serious during the period extending from performance of the first 
study procedure (e.g. drawing of a blood sample) up to and including 1 month after the last dose 
(telephone interview at month 37). After this period of time, the patient should report to the 
investigator only adverse events that are serious and perceived as possibly related to their 
participation in this study. Additionally, the patient will be instructed to contact the investigator 
immediately if he/she believes that he/she has fathered/conceived a child.  Testing would be 
performed to verify that the subject or subject’s partner was pregnant.  If the pregnancy test were 
positive, the patient would be instructed to immediately stop taking the study drug.  The patient or 
partner would be counseled and followed closely during the pregnancy by the NIH research team 
and would implement any recommendations made by the DSMB. 
 
Patients will be physically examined by the investigator approximately every 6 months for the study 
duration. One week, one month (Mo 25) and 2 months (Mo 26) after initiation of dosing, patient’s 
safety and change in neurological function will be assessed by telephone interview with an 
investigator (Figure 2). 
 
Extensive laboratory monitoring (CBC with differential and Chemistry panel 20, which includes 
LFTs) will occur three times during the study duration: at month 25, 30, and 36 (Figure 2). 
Urinalysis and pregnancy test (for females with childbearing potential) will be performed every 6 
months (before MRI).  
 
All adverse events occurring within 1 month following the last administration of the study 
medication must be recorded on the Adverse Event Form irrespective of severity and seriousness, 
and whether or not they are considered related to the study medication. Additionally, all serious 
adverse events (SAE) brought to the attention of the investigator during the period starting from the 
day of performance of the first study procedure to the telephone interview on month 37, must be 
recorded and reported to the FDA in accordance with federal regulations and NIH procedures. Any 
SAE reported by the patient after month 37, will be subjected to expedited reporting only if judged 
to be related to the study treatment by the Investigator. 
 
The collection of complete and accurate information is of paramount importance to allow a full 
evaluation of SAEs. Each SAE will be properly documented and followed up until the event is 
resolved, subsided, stabilized, disappeared or is otherwise explained or the study patient is lost to 
follow-up. Recurrent episodes, complications, or progression of the initial SAE will be reported as 
follow-up to the original episode, regardless of when the event occurs. Follow-up of reportable SAEs 
will be submitted to the FDA, IRB and Santhera Pharmaceuticals (Switzerland) Ltd. according to the 


 
 
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same timelines mandatory for initial reports, i.e. within 7 calendar days for fatal/life-threatening and 
15 calendar days for all other SAE. An SAE that is considered completely unrelated to one 
previously reported, will be reported separately as a new event. 
When a Serious Adverse Drug Reaction occurs during the clinical trial, the NINDS will provide 
Santhera Pharmaceuticals (Switzerland) Ltd. or designee with: a) primary safety information (i.e. 
short description including at least patient’s study number, age and gender; reported SAE terms and 
causality assessment) at the time when the NINDS clinical director and the head of IRB are 
informed and no later than by Day 4; and b) copies of all Serious Adverse Drug Reaction reports 
concurrently with their submission to the FDA, including copies of any warning letters or other 
information affecting the safety and/or well-being of human subjects in research conducted under 
this MCRADA. 
9.2 Toxicity tables/criteria to be used  
Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0 (Publish date August 9, 2006).  A copy of the Common Terminology Criteria 
for Adverse Events version 3.0 can be downloaded from 
http://ctep.cancer.gov/reporting/ctc_v30.html. 
9.2.1 Definition of Adverse Event (AE) 
 
An AE is “any unfavorable and unintended diagnosis, symptom, sign (including an abnormal 
laboratory finding), syndrome or disease which either occurs during the study, having been absent 
at baseline, or, if present at baseline, appears to worsen.”  An AE is a term that is a unique 
representation of a specific event used for medical documentation and scientific analyses. 
9.2.2 Severity of Adverse events 
Grade refers to the severity of the AE. The CTCAE v3.0 displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on this general guideline: 
Grade 1 Mild AE 
Grade 2 Moderate AE 
Grade 3 Severe AE 
Grade 4 Life-threatening or disabling AE (SAE) 
Grade 5 Death related to AE (SAE) 
 


 
 
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Assessment 
Definition 
1 = Mild 
Discomfort noted, but no disruption of normal daily activities; slightly 
bothersome; relieved with or without symptomatic treatment 
2 = Moderate 
Discomfort sufficient to reduce or affect normal daily activity to some 
degree; bothersome; interferes with activities, only partially relieved 
with symptomatic treatment. 
3 = Severe 
Discomfort sufficient to reduce or affect normal daily activity 
considerably; prevents regular activities; not relieved with 
symptomatic treatment. 
 
9.2.3 Definition of Serious Adverse Event (SAE) 
 
A serious adverse event is any untoward medical occurrence or effect at any dose, that: 
• results in death,  
• is life threatening,  
• results in persistent or significant disability/incapacity,  
• requires in-patient hospitalization‡ or prolongation of existing hospitalization, 
• results in cancer, 
• is a congenital anomaly/birth defect in the offspring of a study subject, 
• is deemed, by the investigator, an important or serious medical event that may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed above should be 
considered serious (i.e., intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse.) 
9.2.4 Assessment of causality 
Every effort should be made by the investigator to explain each adverse event and assess its causal 
relationship, if any, to the study medication.  The degree of certainty with which an adverse event 
can be attributed to the study medication (or alternative causes, e.g. natural history of the underlying 
diseases, concomitant therapy, etc.) will be determined by how well the event can be understood in 
terms of one or more of the following: 
• Reaction of similar nature having previously been observed with this type of medication. 
• The event having often been reported in literature for similar types of medication. 
• Subject’s underlying clinical state or other medical conditions 
• Concomitant agents and/or therapies 
 
The causal relationship, if any, to study medication will be defined by one of the following 
terms: 
 


 
 
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Assessment 
Definition 
Definitely 
There is suspicion of a relationship between study medication and AE 
(without determining the extent of probability); there are no other more likely 
causes and study medication is suspected to have contributed to the AE 
Probable 
AE cannot be reasonably explained by other factors (i.e. clinical condition, 
environmental/toxic factors or other treatments) 
Possible 
AE can be reasonably explained by other factors (as mentioned above) 
Unlikely 
AE occurs within an unusual time frame of administration of study 
medication and can also be reasonably explained by other factors (as 
mentioned above) 
Unrelated 
There is no suspicion that there is a relationship between study medication 
and adverse event, there are other more likely causes and study medication is 
not suspected to have contributed to the AE 
 
9.2.5 Treatment of adverse events: 
Treatment of any AE is at the sole discretion of the investigator and according to current available 
best treatment. The applied measures will be recorded in the patient’s chart. 
9.3 Criteria for individual subject withdrawal   
A subject must permanently discontinue study drug treatment for any of the following reasons: 
 
1. The subject becomes pregnant (pregnancy test will be performed for female patients with 
child bearing potential during each visit). If a patient becomes pregnant, treatment must 
be immediately discontinued. The pregnancy must be reported to the NIB (treating 
physician/research nurse) and to the IRB immediately. Information about the subject, the 
subject’s pregnancy, the outcome of the pregnancy, and the status of the infant at 8 to 12 
weeks of age will also be collected. 
2. The subject desires to discontinue study drug treatment under this protocol. Patients have 
the right to withdraw from the study at any time and for any reason. The investigator also 
has the right to withdraw patients from the study in the event of an intercurrent illness, 
adverse events, treatment failure, protocol violations, administrative reasons, or other 
reasons. 
3. 1st MS safety criterion: Worsening of more than two points on the EDSS scale (Kurtzke 
1983) compared to baseline, confirmed one month later on an extra follow-up visit. The 
treatment will be discontinued, but the patient will be followed off therapy to collect all 
predetermined outcome measures as per “intention to treat” analysis.  
4. 2nd MS safety criterion: The average number of new CEL (which represents a measure of 
MS-related brain inflammatory activity) increases after initiation of idebenone therapy 3 
standard deviations above the average number of CEL during pre-treatment baseline and 
IPPoMS trial or for patients with no CEL observed on MRIs collected during baseline 
period (expected to be the majority of PP-MS patients), the number of CEL recorded on a 


 
 
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single follow-up MRI reaches 10 CEL (total). Treatment will be discontinued, but the 
patient will be followed off therapy to collect all predetermined outcome measures as per 
“intention to treat” analysis.  
5. Laboratory safety criteria: ALT (SGPT) or AST (SGOT) more than three times the upper 
limit of normal during regular laboratory monitoring and remains more than three times 
the upper limit after one week of cessation of idebenone dosing. Any other highly 
abnormal laboratory finding that is deemed critical by an investigator and that persists for 
1 week after cessation of drug dosing. 
 
The reasons for discontinuation of the study drug must be recorded in the subject’s Clinical Center 
patient file. Patients discontinuing dosing will be followed for an additional 2 months. If 
discontinuation was because of an adverse event, the patient will be followed until the event is 
resolved or stabilized. If the discontinuation was because of pregnancy, the subject will be followed 
until after the birth. 
 
 
10. OUTCOME MEASURES 
 
10.1 Primary outcome measure: 
 
The IPPoMS trial has an adaptive design that will determine the primary outcome measure for the 
IPPoMS protocol based on pre-determined analysis of the quantitative clinical and neuroimaging 
secondary outcome measures in the first 30 subjects who finish 1 year of pre-treatment baseline. 
This analysis is expected to be concluded in the spring/summer of 2013. The primary outcome 
measure that comes out of the pre-determined analysis in the IPPoMS trial will be adopted as 
primary outcome measure in the IPPoMS-E trial.  
 
10.2 Secondary outcome measures: 
10.2.1 Neuroimaging outcomes: 
 
1. Inhibition of individualized rates of development of brain atrophy: effect of idebenone on 
individualized rates of development of brain atrophy  
2. Inhibition of individualized rates of development of brain gray matter atrophy: effect of 
idebenone on individualized rates of development of segmented gray matter atrophy  
3. Inhibition of individualized rates of enlargement of ventricular volume: effect of 
idebenone on individualized rates of enlargement of segmented volume of 3rd ventricle 
4. Inhibition of individualized rates of development of cervical SC atrophy: effect of 
idebenone on individualized rates of development of SC atrophy  
5. Inhibition of individualized rates of neuroaxonal destruction as assessed by T1 relaxation 
time in the brain (ROI in normal appearing white matter and in deep gray matter): effect 
of idebenone on individualized rates of neuroaxonal destruction  


 
 
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6. Inhibition of individualized rates of neuroaxonal destruction as assessed by T1 relaxation 
time in the cervical spinal cord: effect of idebenone on individualized rates of 
neuroaxonal destruction  
7. Inhibition of individualized changes in axonal integrity as assessed by axial diffusivity 
and of changes in myelin integrity as assessed by radial diffusivity on brain DTI imaging: 
effect of idebenone on individualized rates of neuroaxonal destruction  
10.2.2 Clinical/functional outcomes: 
 
1. Progression of lower extremity disability as assessed by 25 foot walk component of 
MSFC (comparing area under curve (AUC) between 1 year of pre-treatment baseline 
collected during IPPoMS trial and one year of idebenone therapy) 
2. Progression of upper extremity/fine motor movements disability as assessed by 9 hole 
peg test component of MSFC (comparing area under curve (AUC) between 1 year of pre-
treatment baseline collected during IPPoMS trial and one year of idebenone therapy) 
3. Progression of neurological disability as assessed by MSFC (comparing area under curve 
(AUC) between 1 year of pre-treatment baseline collected during IPPoMS trial and one 
year of idebenone therapy) 
4. Progression of neurological disability as assessed by Scripps NRS (comparing area under 
curve (AUC) between 1 year of pre-treatment baseline collected during IPPoMS trial and 
one year of idebenone therapy) 
5. Progression of neurological disability as assessed by EDSS (comparing area under curve 
(AUC) between 1 year of pre-treatment baseline collected during IPPoMS trial and one 
year of idebenone therapy) 
10.2.3 Biological/immunological outcomes: 
 
1. Analysis of changes in CSF albumin quotient (ROS are known to disrupt endothelial tight 
junctions; which may be measured as increase in CSF albumin quotient) 
2. Analysis of changes in CSF biomarkers of oxidative stress and mitochondrial stress (e.g. 
4-HNE, DJ-1) 
3. Analysis of changes in CSF lactate, as a biomarker of extra-mitochondrial glucose 
metabolism  
4. Analysis of changes in CSF biomarkers of CNS tissue destruction (e.g. NCAM, OMGP 
and Contactin-2) 
5. Analysis of changes in CSF biomarkers of inflammation (e.g. CXCL13, IL-12p40, 
sCD27) 
 
 


 
 
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10.3. Tertiary/exploratory outcome measures 
10.3.1 Neuroimaging: 
 
1. Progression of Fe accumulation in deep gray matter structures of the brain as assessed by 
quantification of hypointense signal on T2* MRI imaging  
2. Progression of retinal nerve fiber thinning as detected by OCT  
10.3.2 Clinical: 
 
1. Progression in cognitive dysfunction as assessed by PASAT component of MSFC 
(comparing area under curve (AUC) between 1 year of pre-treatment baseline collected 
during IPPoMS trial and one year of idebenone therapy) 
2. Progression in cognitive dysfunction as assessed by Symbol Digit Modality Test 
(comparing area under curve (AUC) between 1 year of pre-treatment baseline collected 
during IPPoMS trial and one year of idebenone therapy) 
3. Progression of neurological dysfunction as assessed by finger and foot tapping (comparing 
area under curve (AUC) between 1 year of pre-treatment baseline collected during 
IPPoMS trial and one year of idebenone therapy) 
 
 
11. STATISTICAL ANALYSIS 
 
11.1 Data acquisition and processing 
 
All clinical, neuroimaging volumetric and biomarker data will be collected sequentially and 
analyzed in a blinded fashion from coded samples. Data will be acquired prospectively and 
transcribed to the research database. For the majority of imaging biomarkers the analysis will be 
performed only after completion of baseline or treatment periods, because the images need to be co-
registered to the first acquired image. For biomarker data that can be acquired from cryopreserved 
biological samples, baseline and treatment data points will be evaluated simultaneously, to limit 
effect of inter-assay variation. Every effort will be made to have single rater/investigator to acquire 
one type of quantifiable clinical, neuroimaging and biomarker data for the entire cohort. Statistical 
analysis will be done by NINDS statistician. 
 
11.2 Statistical analyses of outcome measures 
 
Descriptive methods will be used to analyze the safety data. Generally, for the analysis of efficacy 
data in IPPoMS-E protocol, we will utilize equivalent outcomes collected during IPPoMS trial.  
 
For primary and secondary outcome measures, we will use identical statistical approach as utilized 
in IPPoMS trial: i.e. in order to utilize all collected data, we will calculate areas under curve (AUC) 
values for each outcome, normalized per 1 year of “therapy”. Thus, we will calculate AUC for three 
different “treatments”: pre-treatment baseline (B), placebo (Pl) and for idebenone (I) treatment. We 
will compare intra-individual changes in AUC values by following linear mixed effect model: 


 
 
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AUCoutcome = treatment (B, PL, I) + group + interaction between treatment and group + covariates 
 
where “group” refers to original “placebo” versus “idebenone” groups from IPPoMS trial and the 
random part is patient. While randomization is stratified for age and therefore, we are expecting that 
the placebo and active treatment groups will be well-matched for age, we will use Age and sex as 
covariates in the model if we detect any interaction. 
 
In addition to analysis of primary and secondary outcomes, combining data collected during IPPoMS 
and IPPoMS-E studies will significantly enhance our ability to detect treatment-related changes in 
CSF biomarkers. Depending on how many subjects choose to participate in IPPoMS-E, the amount 
of paired (i.e. no treatment versus idebenone) CSF samples may theoretically increase up to 2 fold in 
comparison to IPPoMS trial. Therefore, the cohort of patients originally assigned to placebo can be 
utilized as “confirmatory” cohort for biomarker changes identified in the IPPoMS trial. This would 
effectively increase the power for detecting significant differences, as only those biomarkers found 
to be significantly changed during the IPPoMS trial would be tested in the IPPoMS-E trial, thus 
limiting the number of multiple comparisons that would need to be performed (and for which p 
values need to be properly adjusted). Again, the differences in selected CSF biomarkers between 
“no-treatment”, “placebo” and “idebenone” treatment would be analyzed using the same mixed 
effect model. 
 
Finally, combining CSF data from IPPoMS with IPPoMS-E will provide two different longitudinal 
datasets: for patients originally randomized to placebo, we will have three CSF samples off therapy 
(Mo -1: baseline, Mo 12&24: placebo) and for patients originally randomized to idebenone, we will 
have three CSF samples (Mo12, 24 and 36). These longitudinal data will allow us to calculate 
“slope” of progression and compare these slopes between two different treatments using again linear 
mixed model: 
 
Biomarker = time + treatment + interaction between time & treatment + covariate 
 
where “treatment” is either idebenone or no idebenone (i.e. pre-treatment baseline + placebo). The 
interaction between treatment and time will assess if the slopes for two treatments are parallel or not. 
It has been suggested that evaluating changes in the “slope” of progression may distinguish true 
ongoing neuroprotective effect from static “symptomatic” effect (Machado, Murray et al. 1999; 
Ginsberg 2008). In other words, under hypothetical scenario that idebenone may prove efficacious in 
PP-MS, its effect on disability may vary depending on the pathophysiology of the disease. There are 
two possible scenarios: 
1. That idebenone enhances ATP production in neurons, soon after initiation of its dosing, and 
this enhances electrical conduction in demyelinated axons. The result would be improvement 
in neurological function. However, if enhancement of ATP production does not also lead to 
neuroprotection, then the “slope” of progression after initiation of idebenone therapy would 
be parallel to the “slope” of progression off therapy. In other words, the efficacy on the 
outcome would be “static” – resetting the baseline, but not changing the “slope” (Figure 3A). 
2. That idebenone enhances ATP production in neurons, oligodendrocytes and astrocytes. This 
may, to some degree, protect all CNS cells from death. As death of neurons and 
oligodendrocytes continues on a progressive basis, a true neuroprotective drug will inhibit 


 
 
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the slope of the measured outcome (e.g. progression of disability or CNS tissue destruction) 
in comparison to no treatment. Such dynamic effect would lead to a greater absolute 
difference in the outcome with greater duration of therapy (Figure 3B). Finally, the drug may 
have both symptomatic and neuroprotective effects (Figure 3C). 
 
Figure 3:  
Possible effects on the outcome (e.g. disability) by static “symptomatic” versus true “neuroprotective” 
therapeutic  
A. Static “symptomatic” effect will “reset the baseline” but will not alter the slope of progression 
B. True neuroprotective drug will change the slope of progression, so its efficacy on the outcome (i.e. the 
absolute difference in comparison to no treatment condition) will increase with the duration of treatment 
C. Combination of static and dynamic effect on the outcome by therapeutic that has both symptomatic and 
neuroprotective effect 
 
Based on this rationale, for CSF biomarkers of CNS tissue destruction (that may be changing in 
time), we will evaluate the slopes of the change between idebenone and no idebenone treatments. 
 
11.3 Handling of missing/unobtainable data 
 
All efforts will be made to collect a complete set of data by employing 2-4 week flexibility in 
scheduling and repeating inadequate quality MRI scans. 
 
In the event that particular data points are missing for reasons other than inability to perform the test 
(i.e. because of disability) we will replace the missing data according to following algorithm: 
a. For data obtained every 6 months (i.e. clinical data and brain MRI data), the missing 
time point will be substituted by the average of 2 adjacent time-points: i.e. 6 months 
before and 6 months after the missing time-point. If the last time-point is missing (i.e. 
month 36), we will substitute the data for this time-point by the average of 2 preceding 
time-points.  
b. For data obtained once at treatment phase (i.e. CSF and apheresis data), the missing data 
cannot be replaced and the patient will be eliminated from analysis. 
 
Handling data missing because the patient was unable to perform the test due to disability: this may 
happen for clinical tests such as timed 25 foot walk (25FW), 9 hole peg test (9HPT) and PASAT. 
These data will be calculated using the following recommendations from scoring instructions for the 
MSFC: 
a. 25FW: the inability to perform 25FW will be substituted by the largest Z-score in the 
MSFC Task force database (i.e. with the slowest time of any patient in the combined 
dataset used by the Task Force in its published meta-analysis). The largest Z-score in the 


 
 
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Task Force dataset is 13.7, therefore, for a subject who could not complete the 25FW Zleg, 
average = -13.7 will be used. 
b. 9HPT: the inability to perform 9HPT will be coded as 777 and the following Z-score 
calculation formula will be applied: 
Zarm, trial# = [(1/777 – Baseline mean (1/9HPT)]/Baseline SD (1/9HPT)  
c. PASAT: In the event an individual patient cannot complete PASAT-3 due to disability, a 
score of 0 will be assigned. 
 
11.4 Power analysis and sample size calculation 
 
Sample size and power considerations are not relevant here as this is an open-label extension study 
design. 
 
11.5 Accrual number request 
 
Because up to 85 patients can be enrolled into IPPoMS study (to yield 66 subjects who complete 2 
years of dosing), theoretically up to 85 subjects can be enrolled into IPPoMS-E study. 
 
 
12. HUMAN SUBJECT PROTECTION 
 
12.1 Subject selection 
 
The investigational nature and objectives of this trial, the procedures and treatments involved, as 
well as the attendant risks, discomforts, and potential benefits will be carefully explained to the 
patient.  A signed consent form will be obtained by the principal investigator or an associate 
investigator. It will be carefully explained to patients that they may withdraw from the study at any 
time, for any reason. 
 
All adult PP-MS patients fulfilling all inclusion criteria and for whom none of the exclusion criteria 
are applicable, irrespective of gender or race are included in the IPPoMS trial. All patients who 
conclude IPPoMS trial will be eligible for IPPoMS-E study. 
 
Patients who are unable to give informed consent will be excluded, as these patients were also 
excluded in the IPPoMS Trial, and therefore will not qualify for this extension trial.  
 
12.2 Justification for exclusion of children 
 
No patients under the age of 18 are included in IPPoMS and therefore this is not relevant to this 
open-label extension study.  Patients under the age of 18 were excluded in the IPPoMS trial since the 
incidence of MS in this age group is extremely low and PP-MS is virtually non-existent. 
Consequently, insufficient numbers of patients in that age range would be available to provide 
reliable data.  
 
 


 
 
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12.3 Study safeguards 
 
Because the effects of idebenone therapy on pregnancy and breastfeeding are unknown, patients able 
to become pregnant or able to father a child will be required to use appropriate methods of 
contraception for the trial duration and all women able to become pregnant will be evaluated with a 
pregnancy test every 6 months and before any MRI. Women over age 55 who have not had a period 
for one year will be considered menopausal and will not need pregnancy testing or contraception.  
Women under the age of 55 will undergo pregnancy testing and will be required to use appropriate 
methods of contraception for the trial duration, unless there is a history of surgical menopause.   
 
12.4 Qualifications of investigators 
 
The NIB clinical team has extensive experience with Phase I/II experimental therapeutic trials in 
MS. This team has performed 7 Phase I/II clinical trials in MS in the past 10 years. The PI, Dr. 
Bibiana Bielekova is a board-certified neurologist with full clinical privileges. She underwent 
clinical research training (Core Course in Clinical Research at NIH, October 1997-June 1998, FDA’s 
Clinical Investigator Training Course, November 7-9, 2011) and served as an investigator on 5 Phase 
I/II clinical trials at NIH and 2 Phase II clinical trials at the University of Cincinnati. She will 
supervise all aspects of the clinical trial including supervision of all biological and immunological 
assays. Dr. Bielekova will not obtain informed consent or serve as a treating or evaluating physician 
due to a conflict of interest. 
 
Lead associate investigator Alison Wichman is a board certified neurologist.  She has been 
credentialed in the NIH Clinical Center continuously since 1982.  She has expertise in many aspects 
of clinical research both as a clinician, and in management roles related to research ethics, 
regulations, human subject protection, and SOP development. Mary Alice Sandford is a certified 
nurse practitioner with over 30 years of experience working with patients with neuroimmunological 
disorders, including Multiple Sclerosis. Dr. Tanya Lehky is a board-certified neurologist with full 
clinical privileges.  
 
All above-mentioned investigators will have direct clinical contact with patients and all the above 
associate investigators can obtain informed consent. The Principle Investigator will not obtain 
informed consent. 
 
Jenifer Dwyer is a registered nurse specialized in MS clinical care.  Laura Kannaian is a registered 
nurse with multiple years of experience including with MS patients.  Rosalind Hayden is a registered 
nurse with experience in research and regulatory support.  She will be involved in regulatory 
submissions, and will also supervise patient scheduling.  The above-mentioned investigators will 
have direct clinical contact with patients and they will not obtain informed consent.  
 
Drs. Wichman, Lehky, and Ms. Sandford will be responsible for patient care and assessment, 
collection of clinical and functional outcome measures and overseeing clinical safety. 
 
Dr. Bhagavatheeshwaran is a staff scientist with the NIB.  Dr. Bhagavatheeshwaran is responsible 
for MRI acquisition and analysis.  Elena Romm is biologist with long-term experience in sample 
collection and processing. She will supervise collection, processing and storage of all biological 


 
 
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samples: CSF, serum/plasma and apheresis/whole blood samples for PBMC collection. She will 
serve as the primary laboratory contact and will keep an updated database of biological sample 
collection and storage.  Dr. Bhagavatheeshwaran and Ms. Romm will not obtain informed consent. 
 
 
13. BENEFITS 
 
13.1 Direct Benefit:  
 
Participants may receive direct therapeutic benefit from participation in this study 
 
13.2 Indirect Benefit:  
 
The study will yield generalizable knowledge about the drug and disease state and will aid in 
developing future neuroprotective therapeutic trials in MS patients 
 
 
14. SUMMARY/CLASSIFICATION OF RISK:  
 
Classification of risk for the study as a whole: The risk is classified as more than minimal risk.  
 
This is a reasonable risk in relation to the anticipated potential therapeutic benefit in a patient 
population for which there are currently no therapeutic agents with proven benefit and for obtaining 
generalizable knowledge that will facilitate more rapid screening of novel neuroprotective agents in 
low-inflammatory progressive MS subtypes. 
 
 
15. CONSENT DOCUMENTS AND PROCESS 
 
Prior to any testing under this protocol, including screening or pre-treatment tests and evaluations, 
written informed consent will be obtained from the subject in accordance with local practice and 
regulations.  Study investigators (As noted in section 12.4) will obtain informed consent. 
 
The background of the proposed study and the benefits and risks of the procedures and study will be 
explained to the subject.  A copy of the informed consent document signed and dated by the subject 
will be given to the subject.  Confirmation of a subject’s informed consent will also be documented 
in the subject’s medical records prior to any testing under this protocol, including screening or pre-
treatment tests and evaluations. 
 
Information that is gained through this study will be available to the participating patients. 
 
Consent forms are attached.  
 
 
16. DATA AND SAFETY MONITORING 
 


 
 
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16.1 Monitoring plan for the study as a whole 
 
This study will be monitored by a Data and Safety Monitoring Board (DSMB). Dr. Mary Kay 
Floeter is a board-certified neurologist with full clinical privileges. She will serve as the Independent 
Medical Monitor. Dr. Floeter is independent of NIB and will be involved in crucial decision making 
regarding clinical issues that may arise during this trial. We are instituting an NIB independent 
medical monitor as a way to mitigate Dr. Bielekova’s conflict of interest (COI). Dr. Bielekova, the 
PI on the study, is co-inventor on an NIH patent related to the use of idebenone and as such will 
receive patent royalty payments.  
 
 
16.2 DSMB plans 
16.2.1. The proposed members of the DSMB are as follows:  
 
We will utilize the same DSMB that is currently monitoring IPPoMS trial: Mitchell T. Wallin, MD 
(DSMB chair) and Walter Royal, MD from MS Center of excellence, East, VA, Baltimore, MD, 
Carlos Mora, MD from Georgetown University MS center and Prof. Ludwig Kappos, MD from MS 
research group, University Hospital Basel, Switzerland  
16.2.2. Role of DSMB:  
 
Monitor/review AEs on a yearly basis and SAEs within 7 days of occurrence 
 
16.2.3 Proposed meeting frequency/ schedule:  
 
The DSMB will meet on a yearly basis via teleconference. Yearly AE data and clinical data will be 
collected and provided to the DSMB for review. Additionally, all SAEs will be communicated to the 
DSMB within 7 days of occurrence. 
 
16.3 Criteria for stopping the study:  
 
All SAEs will be communicated to the DSMB within 7 days of occurrence. The DSMB will decide 
on further action.  
 
 
17. QUALITY ASSURANCE (QA) 
17.1 Quality assurance monitor 
 
A Contract Research Organization (CRO) will monitor this protocol. 
 
17.2 Quality assurance plan 
On-site monitoring will be carried out by the CRO.  An initial visit will be conducted by the CRO, 
following final approval of the protocol by the IRB and FDA.  During the initial visit, the study team 
and the monitor determined the frequency of monitoring visits.  The frequency was set at yearly.  
The sponsor via the CRO, will be responsible for providing adequate oversight of the investigation 


 
 
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to ensure adequate protection of the rights, welfare, and safety of human subjects and the quality and 
integrity of the resulting data.   
 
 
18. REPORTING OF UNANTICIPATED PROBLEMS, ADVERSE EVENTS AND 
PROTOCOL DEVIATIONS 
  
The Principal Investigator is responsible for detecting, documenting, and reporting unanticipated 
problems, adverse events (AEs), including serious adverse events (SAEs), and deviations in 
accordance with NIH policy, IRB requirements, and federal regulations. Relatedness to the research 
of all serious adverse events will be determined by the PI in consultation with the CD. 
 
Serious unanticipated problems, serious adverse events (including deaths) that are not unanticipated 
problems, and serious protocol deviations will be reported to the IRB and CD as soon as possible 
and in writing not more than 7 days after the PI first learns of the event, unless immediate reporting 
is waived for specific serious adverse events as noted below.  Not serious unanticipated problems 
and not serious deviations will be reported to the IRB and CD as soon as possible and in writing not 
more than 14 days after the PI first learns of the event.  Written reports will be submitted in PTMS. 
 
All adverse events, deviations, and unanticipated problems will be summarized and reported at the 
time of Continuing Review. 
 
The following expected Serious Adverse Events will not be reported to the IRB immediately and 
within 7 days unless they occur at a rate or severity greater than expected:  
Hospitalization for urinary tract and kidney infections 
Hospitalization for falls resulting in injury    
 
These SAE's will be summarized at the time of continuing review.  Serious adverse events occurring 
at a greater severity or frequency than expected will be reported as Unanticipated Problems as 
delineated above.  The expected severity and frequency will be based upon each patient’s pre-
randomization history (baseline). 
 
The NINDS, holder of the investigator-IND, or her/his representative is responsible for submitting 
reportable SAEs to the FDA under its private IND application, in accordance with Federal and NIH 
requirements. When a Serious Adverse Drug Reaction occurs during the clinical trial, the NINDS is 
also responsible for providing Santhera Pharmaceuticals (Switzerland) Ltd. or designee with a) 
primary safety information (i.e. short description including at least patient’s number, age and gender; 
reported SAE terms and causality assessment) at the same time the NINDS clinical director and head 
of IRB are informed and no later than by Day 4 and b) copies of all Serious Adverse Drug Reaction 
reports concurrently with their submission to the FDA, including copies of any warning letters or other 
information affecting the safety and/or well-being of human subjects in research conducted under this 
MCRADA.   
 
Santhera Pharmaceuticals (Switzerland) Ltd. is responsible, in collaboration with UBC Geneva, for 
the processing of reportable SAEs received from the NINDS or her/his representatives. Santhera is 
also responsible for the submission of those reportable SAEs to Health Authorities (other than the 
FDA), Ethics Committees and Investigators taking part in clinical trials with the same investigational 


 
 
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medicinal product, as required by regulations. Moreover, Santhera Pharmaceuticals (Switzerland) 
Ltd. will transmit to the NINDS all reports of Serious Adverse Drug Reaction occurring in Santhera-
sponsored clinical trials and assessed as causally related to the investigational medicinal product, as 
well as any other information altering the safety profile of the study drug. 
 
 
 
 
 
19. ALTERNATIVES TO PARTICIPATION OR ALTERNATIVE THERAPIES 
 
There are currently no therapeutic alternatives with proven therapeutic benefit for PP-MS patients. 
 
Idebenone may be able to be obtained on the internet.  It is not approved by the FDA for treatment of 
MS. 
 
 
20. PRIVACY 
 
All research activities will be conducted in as private a setting as possible. 
 
 
21. CONFIDENTIALITY 
 
21.1 For medical records: 
 
Medical records will be maintained in the NIH Clinical center and released according to NIH 
regulations and Health Insurance portability and Accountability Act of 1996 (HIPAA) guidelines. 
 
21.2 For research data:  
 
Research data will be coded and locked in file cabinets if in paper form or in password protected 
electronic databases maintained on NINDS secure server or on encrypted computers at the NIH. 
Only study investigators will have access to research data. Coded data and results may be shared 
with Santhera Pharmaceuticals for research purposes and for drug filing with the FDA. 
 
21.3 For stored samples:  
 
Coded biological samples will be stored in secure freezers and liquid nitrogen tanks at the NIH. 
Anonymized samples may be made available for future testing in this or other laboratories following 
the guidelines of the Office of Human Subjects Research.  
 
 
22. CONFLICT OF INTEREST/TECHNOLOGY TRANSFER 
 
NIH guidelines on conflict of interest have been distributed to all investigators.  
 


 
 
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Dr. Bielekova has identified a conflict of interest related to this study. She is one of the co-inventors 
on an NIH patent related to the use of idebenone as therapeutic agents in humans. This conflict of 
interest is properly disclosed in the protocol and in the consent form.  
 
To resolve this conflict-of-interest, we have instituted following safeguards: 
• Dr. Bielekova will not obtain informed consent and will not serve as the treating or 
evaluating physician on this protocol. 
• Mary Kay Floeter, MD, a senior NINDS neurologist who is not part of the NIB, will serve as 
the Independent Medical Monitor under this protocol. 
• The independent DSMB will monitor the study. 
 
No other investigators identified any additional conflicts of interest. 
 
 
A Cooperative Research and Development Agreement (CRADA) with Santhera Pharmaceuticals has 
been drafted through the NIH/NINDS office of technology transfer (OTT). This agreement specifies 
that Santhera will provide idebenone without restriction for the clinical study as outlined and will 
provide $140,000 supplement for partial coverage (estimated ≥ 50%) of patient travel cost. All 
collected raw data will be the sole property of NINDS. Summary data will be made available to 
Santhera Inc. for regulatory purposes and for commercial purposes. Santhera Inc. can use these 
summary data for other purposes only after consultation with NINDS and only under confidentiality 
agreement. 
 
 
23. RESEARCH AND TRAVEL COMPENSATION  
 
Enrolled patients will not be compensated for time and research-related inconveniences.  
 
Enrolled patients will be reimbursed for travel and lodging according to NINDS guidelines (travel 
form as attachment).  
 
 
24. REFERENCES 
 
Albrecht, P., M. Ringelstein, et al. (2012). "Degeneration of retinal layers in multiple sclerosis 
subtypes quantified by optical coherence tomography." Mult Scler. 
Andrews, H. E., P. P. Nichols, et al. (2005). "Mitochondrial dysfunction plays a key role in 
progressive axonal loss in Multiple Sclerosis." Med Hypotheses 64(4): 669-677. 
Artuch, R., A. Aracil, et al. (2002). "Friedreich's ataxia: idebenone treatment in early stage patients." 
Neuropediatrics 33(4): 190-193. 
Artuch, R., A. Aracil, et al. (2004). "Cerebrospinal fluid concentrations of idebenone in Friedreich 
ataxia patients." Neuropediatrics 35(2): 95-98. 
Bieniek, M., D. R. Altmann, et al. (2006). "Cord atrophy separates early primary progressive and 
relapsing remitting multiple sclerosis." J Neurol Neurosurg Psychiatry 77(9): 1036-1039. 
Bizzozero, O. A., G. DeJesus, et al. (2005). "Evidence of nitrosative damage in the brain white 
matter of patients with multiple sclerosis." Neurochem Res 30(1): 139-149. 


 
 
CNS IRB Protocol Template (rev.1-17-08) 
 
 
 
 
 
 
page 48 of 60 
Bizzozero, O. A., G. DeJesus, et al. (2005). "Elevated protein carbonylation in the brain white matter 
and gray matter of patients with multiple sclerosis." J Neurosci Res 81(5): 687-695. 
Black, J. A., J. D. Kocsis, et al. (1990). "Ion channel organization of the myelinated fiber." Trends 
Neurosci 13(2): 48-54. 
Black, J. A., J. Newcombe, et al. (2007). "Sodium channel expression within chronic multiple 
sclerosis plaques." J Neuropathol Exp Neurol 66(9): 828-837. 
Bodmer, M., P. Vankan, et al. (2009). "Pharmacokinetics and metabolism of idebenone in healthy 
male subjects." Eur J Clin Pharmacol. 
Bolanos, J. P., A. Almeida, et al. (1997). "Nitric oxide-mediated mitochondrial damage in the brain: 
mechanisms and implications for neurodegenerative diseases." J Neurochem 68(6): 2227-
2240. 
Booth, D. R., A. T. Arthur, et al. (2005). "Gene expression and genotyping studies implicate the 
interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis." J Mol 
Med 83(10): 822-830. 
Bruno, V., G. Battaglia, et al. (1994). "Protective action of idebenone against excitotoxic 
degeneration in cultured cortical neurons." Neurosci Lett 178(2): 193-196. 
Buyse, G., L. Mertens, et al. (2003). "Idebenone treatment in Friedreich's ataxia: neurological, 
cardiac, and biochemical monitoring." Neurology 60(10): 1679-1681. 
Campbell, G. R. and D. J. Mahad (2012). "Mitochondrial changes associated with demyelination: 
consequences for axonal integrity." Mitochondrion 12(2): 173-179. 
Campbell, G. R., N. Ohno, et al. (2012). "Mitochondrial changes within axons in multiple sclerosis: 
an update." Curr Opin Neurol 25(3): 221-230. 
Campbell, G. R., I. Ziabreva, et al. (2011). "Mitochondrial DNA deletions and neurodegeneration in 
multiple sclerosis." Ann Neurol 69(3): 481-492. 
Civenni, G., P. Bezzi, et al. (1999). "Inhibitory effect of the neuroprotective agent idebenone on 
arachidonic acid metabolism in astrocytes." Eur J Pharmacol 370(2): 161-167. 
Cutter, G. R., M. L. Baier, et al. (1999). "Development of a multiple sclerosis functional composite 
as a clinical trial outcome measure." Brain 122 ( Pt 5): 871-882. 
Dehmeshki, J., D. T. Chard, et al. (2003). "The normal appearing grey matter in primary progressive 
multiple sclerosis: a magnetisation transfer imaging study." J Neurol 250(1): 67-74. 
Dhib-Jalbut, S., D. L. Arnold, et al. (2006). "Neurodegeneration and neuroprotection in multiple 
sclerosis and other neurodegenerative diseases." J Neuroimmunol 176(1-2): 198-215. 
Di Prospero, N. A., A. Baker, et al. (2007). "Neurological effects of high-dose idebenone in patients 
with Friedreich's ataxia: a randomised, placebo-controlled trial." Lancet Neurol 6(10): 878-
886. 
Di Prospero, N. A., C. J. Sumner, et al. (2007). "Safety, tolerability, and pharmacokinetics of high-
dose idebenone in patients with Friedreich ataxia." Arch Neurol 64(6): 803-808. 
Dutta, R., J. McDonough, et al. (2006). "Mitochondrial dysfunction as a cause of axonal 
degeneration in multiple sclerosis patients." Ann Neurol 59(3): 478-489. 
Ebers, G. C. (2004). "Natural history of primary progressive multiple sclerosis." Mult Scler 10 
Suppl 1: S8-13; discussion S13-15. 
Evans, R. W., C. Armon, et al. (2000). "Assessment: prevention of post-lumbar puncture headaches: 
report of the therapeutics and technology assessment subcommittee of the american academy 
of neurology." Neurology 55(7): 909-914. 
Fierro, B., G. Salemi, et al. (2002). "A transcranial magnetic stimulation study evaluating 
methylprednisolone treatment in multiple sclerosis." Acta Neurol Scand 105(3): 152-157. 


 
 
CNS IRB Protocol Template (rev.1-17-08) 
 
 
 
 
 
 
page 49 of 60 
Filippi, M. (2003). "MRI-clinical correlations in the primary progressive course of MS: new insights 
into the disease pathophysiology from the application of magnetization transfer, diffusion 
tensor, and functional MRI." J Neurol Sci 206(2): 157-164. 
Filippi, M., A. Campi, et al. (1995). "Comparison of triple dose versus standard dose gadolinium-
DTPA for detection of MRI enhancing lesions in patients with primary progressive multiple 
sclerosis." J Neurol Neurosurg Psychiatry 59(5): 540-544. 
Filippi, M., M. A. Rocca, et al. (2002). "Correlations between structural CNS damage and functional 
MRI changes in primary progressive MS." Neuroimage 15(3): 537-546. 
Geromel, V., N. Darin, et al. (2002). "Coenzyme Q(10) and idebenone in the therapy of respiratory 
chain diseases: rationale and comparative benefits." Mol Genet Metab 77(1-2): 21-30. 
Gillis, J. C., P. Benefield, et al. (1994). "Idebenone. A review of its pharmacodynamic and 
pharmacokinetic properties, and therapeutic use in age-related cognitive disorders." Drugs 
Aging 5(2): 133-152. 
Ginsberg, M. D. (2008). "Neuroprotection for ischemic stroke: past, present and future." 
Neuropharmacology 55(3): 363-389. 
Gionchetti, P., M. Campieri, et al. (1994). "Respiratory burst of circulating polymorphonuclear 
leukocytes and plasma elastase levels in patients with inflammatory bowel disease in 
remission." Dig Dis Sci 39(3): 550-554. 
Gordon-Lipkin, E., B. Chodkowski, et al. (2007). "Retinal nerve fiber layer is associated with brain 
atrophy in multiple sclerosis." Neurology 69(16): 1603-1609. 
Greco, A., L. Minghetti, et al. (1999). "Cerebrospinal fluid isoprostane shows oxidative stress in 
patients with multiple sclerosis." Neurology 53(8): 1876-1879. 
Gutzmann, H. and D. Hadler (1998). "Sustained efficacy and safety of idebenone in the treatment of 
Alzheimer's disease: update on a 2-year double-blind multicentre study." J Neural Transm 
Suppl 54: 301-310. 
Gutzmann, H., K. P. Kuhl, et al. (2002). "Safety and efficacy of idebenone versus tacrine in patients 
with Alzheimer's disease: results of a randomized, double-blind, parallel-group multicenter 
study." Pharmacopsychiatry 35(1): 12-18. 
Haefeli, R. H., M. Erb, et al. (2011). "NQO1-dependent redox cycling of idebenone: effects on 
cellular redox potential and energy levels." PLoS One 6(3): e17963. 
Hawker, K., P. O'Connor, et al. (2009). "Rituximab in patients with primary progressive multiple 
sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial." Ann 
Neurol 66(4): 460-471. 
Hess, C. W., K. R. Mills, et al. (1987). "Magnetic brain stimulation: central motor conduction 
studies in multiple sclerosis." Ann Neurol 22(6): 744-752. 
Hu, F. and F. Liu (2011). "Mitochondrial stress: a bridge between mitochondrial dysfunction and 
metabolic diseases?" Cell Signal 23(10): 1528-1533. 
Humm, A. M., W. J. Z'Graggen, et al. (2004). "Assessment of central motor conduction to intrinsic 
hand muscles using the triple stimulation technique: normal values and repeatability." Clin 
Neurophysiol 115(11): 2558-2566. 
Hunter, M. I., B. C. Nlemadim, et al. (1985). "Lipid peroxidation products and antioxidant proteins 
in plasma and cerebrospinal fluid from multiple sclerosis patients." Neurochem Res 10(12): 
1645-1652. 
Ikejiri, Y., E. Mori, et al. (1996). "Idebenone improves cerebral mitochondrial oxidative metabolism 
in a patient with MELAS." Neurology 47(2): 583-585. 


 
 
CNS IRB Protocol Template (rev.1-17-08) 
 
 
 
 
 
 
page 50 of 60 
Imada, I., T. Fujita, et al. (1989). "Effects of idebenone and related compounds on respiratory 
activities of brain mitochondria, and on lipid peroxidation of their membranes." Arch 
Gerontol Geriatr 8(3): 323-341. 
Ingle, G. T., V. L. Stevenson, et al. (2003). "Primary progressive multiple sclerosis: a 5-year clinical 
and MR study." Brain 126(Pt 11): 2528-2536. 
Jensen, G. E. and J. Clausen (1986). "Glutathione peroxidase activity, associated enzymes and 
substrates in blood cells from patients with multiple sclerosis--effects of antioxidant 
supplementation." Acta Pharmacol Toxicol (Copenh) 59 Suppl 7: 450-453. 
Juurlink, B. H., S. K. Thorburne, et al. (1998). "Peroxide-scavenging deficit underlies 
oligodendrocyte susceptibility to oxidative stress." Glia 22(4): 371-378. 
Kalkers, N. F., F. Barkhof, et al. (2002). "The effect of the neuroprotective agent riluzole on MRI 
parameters in primary progressive multiple sclerosis: a pilot study." Mult Scler 8(6): 532-
533. 
Kallenbach, K. and J. Frederiksen (2007). "Optical coherence tomography in optic neuritis and 
multiple sclerosis: a review." Eur J Neurol 14(8): 841-849. 
Kalman, B., K. Laitinen, et al. (2007). "The involvement of mitochondria in the pathogenesis of 
multiple sclerosis." J Neuroimmunol. 
Kalman, B., F. D. Lublin, et al. (1995). "Mitochondrial DNA mutations in multiple sclerosis." Mult 
Scler 1(1): 32-36. 
Kappos, L., B. Weinshenker, et al. (2004). "Interferon beta-1b in secondary progressive MS: a 
combined analysis of the two trials." Neurology 63(10): 1779-1787. 
Kaufmann, P., D. C. Shungu, et al. (2004). "Cerebral lactic acidosis correlates with neurological 
impairment in MELAS." Neurology 62(8): 1297-1302. 
Keles, M. S., S. Taysi, et al. (2001). "Effect of corticosteroid therapy on serum and CSF 
malondialdehyde and antioxidant proteins in multiple sclerosis." Can J Neurol Sci 28(2): 
141-143. 
Khaleeli, Z., J. Sastre-Garriga, et al. (2007). "Magnetisation transfer ratio in the normal appearing 
white matter predicts progression of disability over 1 year in early primary progressive 
multiple sclerosis." J Neurol Neurosurg Psychiatry 78(10): 1076-1082. 
Kidd, D., P. D. Thompson, et al. (1998). "Central motor conduction time in progressive multiple 
sclerosis. Correlations with MRI and disease activity." Brain 121 ( Pt 6): 1109-1116. 
Kidd, P. M. (2005). "Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, 
growth factors, and prospects for brain rebuilding using integrative management." Altern 
Med Rev 10(4): 268-293. 
Kimelberg, H. K. (2004). "Water homeostasis in the brain: basic concepts." Neuroscience 129(4): 
851-860. 
Kiryu-Seo, S., N. Ohno, et al. "Demyelination increases axonal stationary mitochondrial size and the 
speed of axonal mitochondrial transport." J Neurosci 30(19): 6658-6666. 
Klopstock, T., P. Yu-Wai-Man, et al. (2011). "A randomized placebo-controlled trial of idebenone in 
Leber's hereditary optic neuropathy." Brain. 
Koch, M., J. Mostert, et al. (2007). "Plasma lipid peroxidation and progression of disability in 
multiple sclerosis." Eur J Neurol 14(5): 529-533. 
Koch, M., G. S. Ramsaransing, et al. (2006). "Oxidative stress in serum and peripheral blood 
leukocytes in patients with different disease courses of multiple sclerosis." J Neurol 253(4): 
483-487. 


 
 
CNS IRB Protocol Template (rev.1-17-08) 
 
 
 
 
 
 
page 51 of 60 
Kurtzke, J. F. (1983). "Rating neurologic impairment in multiple sclerosis: an expanded disability 
status scale (EDSS)." Neurology 33(11): 1444-1452. 
Kutzelnigg, A., C. F. Lucchinetti, et al. (2005). "Cortical demyelination and diffuse white matter 
injury in multiple sclerosis." Brain 128(Pt 11): 2705-2712. 
Langemann, H., A. Kabiersch, et al. (1992). "Measurement of low-molecular-weight antioxidants, 
uric acid, tyrosine and tryptophan in plaques and white matter from patients with multiple 
sclerosis." Eur Neurol 32(5): 248-252. 
Lassmann, H. (2003). "Hypoxia-like tissue injury as a component of multiple sclerosis lesions." J 
Neurol Sci 206(2): 187-191. 
Laule, C., I. M. Vavasour, et al. (2010). "Two-year study of cervical cord volume and myelin water 
in primary progressive multiple sclerosis." Mult Scler 16(6): 670-677. 
Leary, S. M., D. H. Miller, et al. (2003). "Interferon beta-1a in primary progressive MS: an 
exploratory, randomized, controlled trial." Neurology 60(1): 44-51. 
Leary, S. M. and A. J. Thompson (2005). "Primary progressive multiple sclerosis : current and future 
treatment options." CNS Drugs 19(5): 369-376. 
Leech, S., J. Kirk, et al. (2007). "Persistent endothelial abnormalities and blood-brain barrier leak in 
primary and secondary progressive multiple sclerosis." Neuropathol Appl Neurobiol 33(1): 
86-98. 
Lerman-Sagie, T., P. Rustin, et al. (2001). "Dramatic improvement in mitochondrial cardiomyopathy 
following treatment with idebenone." J Inherit Metab Dis 24(1): 28-34. 
Liu, J. S., M. L. Zhao, et al. (2001). "Expression of inducible nitric oxide synthase and nitrotyrosine 
in multiple sclerosis lesions." Am J Pathol 158(6): 2057-2066. 
Lu, F., M. Selak, et al. (2000). "Oxidative damage to mitochondrial DNA and activity of 
mitochondrial enzymes in chronic active lesions of multiple sclerosis." J Neurol Sci 177(2): 
95-103. 
Lucchinetti, C. and W. Bruck (2004). "The pathology of primary progressive multiple sclerosis." 
Mult Scler 10 Suppl 1: S23-30. 
Lucchinetti, C., W. Bruck, et al. (2000). "Heterogeneity of multiple sclerosis lesions: implications 
for the pathogenesis of demyelination." Ann Neurol 47(6): 707-717. 
Machado, S. G., G. D. Murray, et al. (1999). "Evaluation of designs for clinical trials of 
neuroprotective agents in head injury. European Brain Injury Consortium." J Neurotrauma 
16(12): 1131-1138. 
Mahad, D., I. Ziabreva, et al. (2008). "Mitochondrial defects in acute multiple sclerosis lesions." 
Brain 131(Pt 7): 1722-1735. 
Mahad, D. J., I. Ziabreva, et al. (2009). "Mitochondrial changes within axons in multiple sclerosis." 
Brain 132(5): 1161-1174. 
Manfredonia, F., O. Ciccarelli, et al. (2007). "Normal-appearing brain t1 relaxation time predicts 
disability in early primary progressive multiple sclerosis." Arch Neurol 64(3): 411-415. 
Mariotti, C., A. Solari, et al. (2003). "Idebenone treatment in Friedreich patients: one-year-long 
randomized placebo-controlled trial." Neurology 60(10): 1676-1679. 
Mashima, Y., Y. Hiida, et al. (1992). "Remission of Leber's hereditary optic neuropathy with 
idebenone." Lancet 340(8815): 368-369. 
McDaniel, D. H., B. A. Neudecker, et al. (2005). "Idebenone: a new antioxidant - Part I. Relative 
assessment of oxidative stress protection capacity compared to commonly known 
antioxidants." J Cosmet Dermatol 4(1): 10-17. 


 
 
CNS IRB Protocol Template (rev.1-17-08) 
 
 
 
 
 
 
page 52 of 60 
Mecocci, P., U. MacGarvey, et al. (1993). "Oxidative damage to mitochondrial DNA shows marked 
age-dependent increases in human brain." Ann Neurol 34(4): 609-616. 
Meier, T., S. L. Perlman, et al. (2012). "Assessment of neurological efficacy of idebenone in 
pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by 
a 12-month open-label extension study." J Neurol 259(2): 284-291. 
Miller, D. H. and S. M. Leary (2007). "Primary-progressive multiple sclerosis." Lancet Neurol 
6(10): 903-912. 
Miyamoto, M. and J. T. Coyle (1990). "Idebenone attenuates neuronal degeneration induced by 
intrastriatal injection of excitotoxins." Exp Neurol 108(1): 38-45. 
Montalban, X. (2004). "Overview of European pilot study of interferon beta-Ib in primary 
progressive multiple sclerosis." Mult Scler 10 Suppl 1: S62; discussion 62-64. 
Mutsaers, S. E. and W. M. Carroll (1998). "Focal accumulation of intra-axonal mitochondria in 
demyelination of the cat optic nerve." Acta Neuropathol 96(2): 139-143. 
Naidoo, R. and M. L. Knapp (1992). "Studies of lipid peroxidation products in cerebrospinal fluid 
and serum in multiple sclerosis and other conditions." Clin Chem 38(12): 2449-2454. 
Napolitano, A., S. Salvetti, et al. (2000). "Long-term treatment with idebenone and riboflavin in a 
patient with MELAS." Neurol Sci 21(5 Suppl): S981-982. 
Narayana, P. A., J. S. Wolinsky, et al. (2004). "Multicentre proton magnetic resonance spectroscopy 
imaging of primary progressive multiple sclerosis." Mult Scler 10 Suppl 1: S73-78. 
Nitta, A., Y. Murakami, et al. (1994). "Oral administration of idebenone induces nerve growth factor 
in the brain and improves learning and memory in basal forebrain-lesioned rats." Naunyn 
Schmiedebergs Arch Pharmacol 349(4): 401-407. 
Noseworthy, J. H., C. Lucchinetti, et al. (2000). "Multiple sclerosis." N Engl J Med 343(13): 938-
952. 
Palace, J. (2009). "Multiple sclerosis associated with Leber's Hereditary Optic Neuropathy." J 
Neurol Sci 286(1-2): 24-27. 
Pineda, M., J. Arpa, et al. (2008). "Idebenone treatment in paediatric and adult patients with 
Friedreich ataxia: Long-term follow-up." Eur J Paediatr Neurol. 
Ramio-Torrenta, L., J. Sastre-Garriga, et al. (2006). "Abnormalities in normal appearing tissues in 
early primary progressive multiple sclerosis and their relation to disability: a tissue specific 
magnetisation transfer study." J Neurol Neurosurg Psychiatry 77(1): 40-45. 
Ranen, N. G., C. E. Peyser, et al. (1996). "A controlled trial of idebenone in Huntington's disease." 
Movement Disorders 11(5): 549-554. 
Ranen, N. G., C. E. Peyser, et al. (1996). "A controlled trial of idebenone in Huntington's disease." 
Mov Disord 11(5): 549-554. 
Ravnborg, M. (1996). "The role of transcranial magnetic stimulation and motor evoked potentials in 
the investigation of central motor pathways in multiple sclerosis." Dan Med Bull 43(5): 448-
462. 
Regenold, W. T., P. Phatak, et al. (2008). "Cerebrospinal fluid evidence of increased extra-
mitochondrial glucose metabolism implicates mitochondrial dysfunction in multiple sclerosis 
disease progression." J Neurol Sci. 
Rossini, P. M., M. D. Caramia, et al. (1987). "Mechanisms of nervous propagation along central 
motor pathways: noninvasive evaluation in healthy subjects and in patients with neurological 
disease." Neurosurgery 20(1): 183-191. 
Rovaris, M., A. Gallo, et al. (2005). "Axonal injury and overall tissue loss are not related in primary 
progressive multiple sclerosis." Arch Neurol 62(6): 898-902. 


 
 
CNS IRB Protocol Template (rev.1-17-08) 
 
 
 
 
 
 
page 53 of 60 
Rovaris, M., E. Judica, et al. (2008). "Large-scale, multicentre, quantitative MRI study of brain and 
cord damage in primary progressive multiple sclerosis." Mult Scler. 
Rustin, P., D. Bonnet, et al. (2004). "Idebenone treatment in Friedreich patients: one-year-long 
randomized placebo-controlled trial." Neurology 62(3): 524-525; author reply 525; 
discussion 525. 
Rustin, P., A. Rotig, et al. (2002). "Heart hypertrophy and function are improved by idebenone in 
Friedreich's ataxia." Free Radic Res 36(4): 467-469. 
Salle, J. Y., J. Hugon, et al. (1992). "Improvement in motor evoked potentials and clinical course 
post-steroid therapy in multiple sclerosis." J Neurol Sci 108(2): 184-188. 
Sastre-Garriga, J., G. T. Ingle, et al. (2005). "Grey and white matter volume changes in early 
primary progressive multiple sclerosis: a longitudinal study." Brain 128(Pt 6): 1454-1460. 
Sastre-Garriga, J., G. T. Ingle, et al. (2004). "Grey and white matter atrophy in early clinical stages 
of primary progressive multiple sclerosis." Neuroimage 22(1): 353-359. 
Schols, L., M. Vorgerd, et al. (2001). "Idebenone in patients with Friedreich ataxia." Neurosci Lett 
306(3): 169-172. 
Schriefer, T. N., C. W. Hess, et al. (1989). "Central motor conduction studies in motor neurone 
disease using magnetic brain stimulation." Electroencephalogr Clin Neurophysiol 74(6): 431-
437. 
Sepulcre, J., S. Vanotti, et al. (2006). "Cognitive impairment in patients with multiple sclerosis using 
the Brief Repeatable Battery-Neuropsychology test." Mult Scler 12(2): 187-195. 
Sharrack, B. and R. A. Hughes (1996). "Clinical scales for multiple sclerosis." J Neurol Sci 135(1): 
1-9. 
Sospedra, M. and R. Martin (2005). "Immunology of multiple sclerosis." Annu Rev Immunol 23: 
683-747. 
Spicer, E. J. F. and F. X. Wazeter (1985). "One Year Oral Toxicity Study with CV-2619." Japanese 
Pharmacology and Therapeutics 13(7): 379-385. 
Spitsin, S., D. C. Hooper, et al. (2001). "Inactivation of peroxynitrite in multiple sclerosis patients 
after oral administration of inosine may suggest possible approaches to therapy of the 
disease." Mult Scler 7(5): 313-319. 
Stefanatos, R. and A. Sanz (2011). "Mitochondrial complex I: a central regulator of the aging 
process." Cell Cycle 10(10): 1528-1532. 
Stys, P. K., G. W. Zamponi, et al. (2012). "Will the real multiple sclerosis please stand up?" Nat Rev 
Neurosci 13(7): 507-514. 
Sugiyama, Y. and T. Fujita (1985). "Stimulation of the respiratory and phosphorylating activities in 
rat brain mitochondria by idebenone (CV-2619), a new agent improving cerebral 
metabolism." FEBS Lett 184(1): 48-51. 
Sugiyama, Y., T. Fujita, et al. (1985). "Effects of idebenone (CV-2619) and its metabolites on 
respiratory activity and lipid peroxidation in brain mitochondria from rats and dogs." J 
Pharmacobiodyn 8(12): 1006-1017. 
Suhara, I., S. Chiba, et al. (1985). "Twenty-six-week Toxicity Study of Orally Administered 
Idebenone (CV-2619) in Rats." Japanese Pharmacology and Therapeutics 13(7): 365-379. 
Suno, M. and A. Nagaoka (1984). "Inhibition of lipid peroxidation by a novel compound, idebenone 
(CV-2619)." Jpn J Pharmacol 35(2): 196-198. 
Suno, M. and A. Nagaoka (1989). "Inhibition of brain mitochondrial swelling by idebenone." Arch 
Gerontol Geriatr 8(3): 299-305. 


 
 
CNS IRB Protocol Template (rev.1-17-08) 
 
 
 
 
 
 
page 54 of 60 
Syburra, C. and S. Passi (1999). "Oxidative stress in patients with multiple sclerosis." Ukr Biokhim 
Zh 71(3): 112-115. 
Thal, L. J., M. Grundman, et al. (2003). "Idebenone treatment fails to slow cognitive decline in 
Alzheimer's disease." Neurology 61(11): 1498-1502. 
Torii, H., K. Yoshida, et al. (1985). "Disposition of idebenone (CV-2619), a new cerebral 
metabolism improving agent, in rats and dogs." J Pharmacobiodyn 8(6): 457-467. 
Twig, G. and O. S. Shirihai (2011). "The interplay between mitochondrial dynamics and 
mitophagy." Antioxid Redox Signal 14(10): 1939-1951. 
van Horssen, J., G. Schreibelt, et al. (2006). "NAD(P)H:quinone oxidoreductase 1 expression in 
multiple sclerosis lesions." Free Radic Biol Med 41(2): 311-317. 
van Horssen, J., G. Schreibelt, et al. (2008). "Severe oxidative damage in multiple sclerosis lesions 
coincides with enhanced antioxidant enzyme expression." Free Radic Biol Med. 
Vanopdenbosch, L., B. Dubois, et al. (2000). "Mitochondrial mutations of Leber's hereditary optic 
neuropathy: a risk factor for multiple sclerosis." J Neurol 247(7): 535-543. 
White, A. T. and J. H. Petajan (2004). "Physiological measures of therapeutic response to interferon 
beta-1a treatment in remitting-relapsing MS." Clin Neurophysiol 115(10): 2364-2371. 
Wolinsky, J. S., P. A. Narayana, et al. (2007). "Glatiramer acetate in primary progressive multiple 
sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial." Ann 
Neurol 61(1): 14-24. 
Yadav, V., G. Marracci, et al. (2005). "Lipoic acid in multiple sclerosis: a pilot study." Mult Scler 
11(2): 159-165. 
Zagorski, T., I. Dudek, et al. (1991). "[Superoxide dismutase (SOD-1) activity in erythrocytes of 
patients with multiple sclerosis]." Neurol Neurochir Pol 25(6): 725-730. 
 
 
 


 
 
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25. ATTACHMENTS/APPENDICES 
 
APPENDIX A: Flow chart 
 
 
 
Month 24 
Month 24 
Week 1 
Month 25 
Month 26 
Month 30 
(Multiple days) 
 
Month 36 
(Multiple days) 
 
 
Month 37 
 
Final visit 
Informed Consent 
√ 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
√ 
 
 
 
 
 
 
 
Clinical evaluation 
 
 
 
 
√ 
√ 
 
√ 
Urinalysis/pregnancy 
 
 
 
 
√ 
√ 
 
 
Safety Lab work 
 
 
√ 
 
√ 
√ 
 
√ 
Telephone Interview 
 
√ 
√ 
√ 
 
 
√ 
 
MRI brain 3T 
 
 
 
 
 
√ 
√ 
 
      
√ 
MRI spine 3T 
 
 
 
 
 
 
√ 
 
 
OCT  
 
 
 
 
 
√ 
 
 
Research Blood 
(< 60ml) 
√ 
 
 
 
 
√ 
 
 
Apheresis* 
 
 
 
 
 
√ 
 
 
Lumbar puncture 
√ 
 
 
 
 
√ 
 
 
 
*120cc of whole blood may be collected if apheresis is unable to be performed, for any reason. 
 
These time points are approximated. To accommodate for patient scheduling needs or clinical necessity, study visits will 
be accepted within a +/- 4 week window of the time points noted. Biological samples (CSF, whole blood or apheresis 
sample) should be collected within 4 weeks of the MRI examination as indicated in Figure 2. Blood samples at 24 and 36 
months will be collected concomitantly with CSF samples.


 
 
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APPENDIX B: Eligibility checklist 
 
Inclusion criteria 
 
 Completion of 3 years in IPPoMS study (protocol 09-N-0197) 
 Able to provide informed consent  
 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 reliable 
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 
 
 Clinically significant medical disorders that, in the judgment of the investigators can 
cause CNS tissue damage or limit its repair, or that would expose the patient to undue 
risk of harm or prevent the patient from completing the study 
 Pregnant or lactating women. All women of child-bearing potential must have negative 
pregnancy test prior to the treatment phase of the study.   
 Patients who dropped out of IPPoMS due to AEs considered related to study medication 
 
 


 
 
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APPENDIX C: Case Report Forms (CRFs) 
 
In electronic format via CRIS in the structured Neuroimmunology note 
 
 


 
 
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APPENDIX D: Rating scales 
 
Expanded Disability Status Scale (EDSS): 
0.0 Normal neurological examination 
1.0 No disability, minimal signs in one FS 
1.5 No disability, minimal signs in more than one FS 
2.0 Minimal disability in one FS 
2.5 Mild disability in one FS or minimal disability in two FS 
3.0 Moderate disability in one FS, or mild disability in three or four FS. Fully ambulatory 
3.5 Fully ambulatory but with moderate disability in one FS and more than minimal disability in several others 
4.0 Fully ambulatory without aid, self-sufficient, up and about some 12 hours a day despite relatively severe disability; able to walk without aid or rest some 500 meters 
4.5 Fully ambulatory without aid, up and about much of the day, able to work a full day, may otherwise have some limitation of full activity or require minimal 
assistance; characterized by relatively severe disability; able to walk without aid or rest some 300 meters. 
5.0 Ambulatory without aid or rest for about 200 meters; disability severe enough to impair full daily activities (work a full day without special provisions) 
5.5 Ambulatory without aid or rest for about 100 meters; disability severe enough to preclude full daily activities 
6.0 Intermittent or unilateral constant assistance (cane, crutch, brace) required to walk about 100 meters with or without resting 
6.5 Constant bilateral assistance (canes, crutches, braces) required to walk about 20 meters without resting 
7.0 Unable to walk beyond approximately five meters even with aid, essentially restricted to wheelchair; wheels self in standard wheelchair and transfers alone; up and 
about in wheelchair some 12 hours a day 
7.5 Unable to take more than a few steps; restricted to wheelchair; may need aid in transfer; wheels self but cannot carry on in standard wheelchair a full day; May 
require motorized wheelchair 
8.0 Essentially restricted to bed or chair or perambulated in wheelchair, but may be out of bed itself much of the day; retains many self-care functions; generally has 
effective use of arms 
8.5 Essentially restricted to bed much of day; has some effective use of arms retains some self care functions 
9.0 Confined to bed; can still communicate and eat. 
9.5 Totally helpless bed patient; unable to communicate effectively or eat/swallow 
10.0 Death due to MS 
 
 


 
 
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Scripps NRS 
Systems Examined 
 
Maximum points 
 
Normal 
Degree of impairment 
Mild 
Mod. 
Severe 
Mentation and Mood: 
10 
10 
7 
4 
0 
Cranial nerves: 
Visual acuity 
21 
5 
3 
1 
0 
Fields, Discs, Pupils 
6 
4 
2 
0 
Eye movements 
5 
3 
1 
0 
Nystagmus 
5 
3 
1 
0 
Lower cranial nerves: 
5 
5 
3 
1 
0 
Motor: 
RU 
20 
5 
3 
1 
0 
LU 
5 
3 
1 
0 
RL 
5 
3 
1 
0 
LL 
5 
3 
1 
0 
Deep Tendon Reflexes: 
UE 
8 
4 
3 
1 
0 
LE 
4 
3 
1 
0 
Babinski: R&L (2 for each) 
4 
4 
- 
- 
0 
Sensory: 
RU 
12 
3 
2 
1 
0 
LU 
3 
2 
1 
0 
RL 
3 
2 
1 
0 
LL 
3 
2 
1 
0 
Cerebellar: 
UE 
10 
5 
3 
1 
0 
LE 
5 
3 
1 
0 
Gait: Trunk and balance: 
10 
10 
7 
4 
0 
Bladder/Bowel/Sexual dysfunction: 
0 
0 
-3 
-7 
-10 
Scripps NRS total score: 
 
 
 
 
 
 
 
 
 
 
  
 


 
 
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APPENDIX E: Investigator’s Brochure 
 
Uploaded in PTMS as pdf file