Clinical trial NCT00950248
Conditions: Primary Progressive Multiple Sclerosis
Keywords: Idebenone Magnetic Resonance Imaging (MRI) Magnetic Resonance Spectroscopy Mitochondrial Enhancer Multiple Sclerosis MS Primary Progressive Multiple Sclerosis
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2009-11-01; Completion date: 2018-08-06
Enrollment: 85 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

* Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system that progressively weakens and destroys the pathways of the nervous system. About 10 percent to 15 percent of patients develop primary-progressive MS (PP-MS), characterized by progressive accumulation of disability from the disease onset, without any marked improvements or relapses. There are currently no effective treatments for PP-MS.
* Idebenone is a manmade drug that is similar to a naturally occurring compound known as coenzyme Q10, a common dietary supplement. Research data suggest that idebenone may be able to limit demyelination and death of brain cells and thereby slow or halt the progression of neurological dysfunction such as that occurring in MS.

Objectives:

\- To evaluate the safety and effectiveness of using idebenone to treat primary progressive MS.

Eligibility:

\- Individuals between 18 and 65 years of age who have been diagnosed with primary progressive multiple sclerosis.

Design:

* The study will last 3 years and will be divided into two parts: a 1-year pretreatment baseline and 2 years of treatment with either idebenone or a placebo.
* Pre-treatment study: approximately 5 clinic visits over 1 year.
* Visit 1: Comprehensive medical history and neurological examination, with brain scans and neurological tests.
* Visit 2: Magnetic resonance imaging (MRI) scan of the spine and lymphocytapheresis (withdrawal of white blood cells for testing).
* Visit 3: Lumbar puncture.
* Visit 4: Skin biopsy.
* Visit 5: Repeat MRI of the brain and spinal cord, as well as neurological tests; these tests will be scheduled over 2 days.
* After the five pretreatment visits, patients will receive a 6-month supply of study medication (either idebenone or a placebo) to take three times a day with food
* Patients will continue to have regular followup clinic visits with brain MRI scans, blood tests, and other evaluations of brain and nervous system function. Randomly selected participants will have additional MRI scans for further safety precautions.

Detailed description:
Objective: The goal of this study is to assess the safety, therapeutic efficacy and mechanism of action of idebenone in primary-progressive multiple sclerosis (PP-MS) patients.

Study Population: Adult, untreated patients with PP-MS with disability ranging from none to moderately severe will be included in the trial. The upper age limit in this study has been set at 65; setting an age limit should permit us to focus on the potential neuroprotective effect of idebenone in PP-MS and limit the confounding factor of the natural aging process and its known negative influence on neuro-regeneration. Published data indicate that higher doses (10-50 mg/kg) of idebenone per day are required for beneficial effects on neurological disability in comparison to the lower doses (5-10mg/kg) that are sufficient for beneficial effects on cardiac/systemic functions in Friedreich s ataxia (FRDA) patients. Therefore, in order to target the CNS compartment, we will use a daily dose of 2250mg (750mg 3 times per day), which will provide target values of 10-50mg/kg for virtually all adult patients.

Design: This is a Phase I/II safety/efficacy trial with an adaptive trial design: one year of pretreatment baseline period serves the dual purpose of collecting patient-specific biomarkers of disease progression and collecting longitudinal neuroimaging and clinical data for selection of primary outcome measures. This baseline period is then followed by a double-blind, idebenone versus placebo treatment phase for a total of 2 years. Based on preliminary sample size estimates, current enrollment calls for a total of 66 patients (33 per arm).

Outcome Measures: Quantitative neuroimaging measures of central nervous system (CNS: i.e. brain and spinal cord) tissue destruction and clinical and functional (i.e. electrophysiological) measures of neurological disability will be collected every 6-12 months. Additionally, biomarkers focusing on analysis of reactive oxygen species (ROS) and oxidative stress will be collected every 12 months. The trial is currently powered using progression of brain atrophy as detected by SIENA methodology as the primary outcome measure. However, this may not be the most sensitive outcome available. In recognition of this, the trial has an adaptive design: i.e. it incorporates analysis of progression of CNS tissue destruction as measured by quantitative MRI markers and clinical/paraclinical markers defined as secondary outcome measures in the first 30 enrolled patients during the one year pre-treatment baseline, before randomization. All defined outcome measures collected in the first 30 enrolled patients will be transformed into z-scores and compared for the robustness of longitudinal change over the coefficient of variation. This will permit to select the most sensitive and most accurate outcome measure for detecting progression of CNS tissue damage. As a result, the primary outcome measure of this trial will be the comparison of individualized rates of brain atrophy progression between the idebenone and placebo groups after 2 years of treatment, unless the predetermined analysis of the pre-treatment baseline period in the first 30 enrolled subjects determines that one of the predefined secondary outcome measures has a higher z-score than brain atrophy measurement. In this case, the primary outcome would be the efficacy of idebenone versus placebo in inhibiting patient-specific slopes of functional or structural deterioration as measured by this more sensitive biomarker of CNS tissue destruction, yet to be defined by the analysis of the 1-year longitudinal data from pre-treatment baseline.

Arms: arm 1: Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. arm 2: Placebo tablets administered orally as five tablets, three times per day with food.
Interventions: intervention 1: Idebenone intervention 2: placebo
Intervention descriptions: intervention 1: idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD\&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) intervention 2: lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD\&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc)

Protocol documents:
Prot_000.pdf: 
Neuroimmunology Branch/NINDS/NIH 
IPPoMS Clinical Trial Protocol 
1 
April 13, 2017 
 
 
 
1. Title Page 
 
Protocol Title: 
Double Blind Placebo-Controlled Phase I/II Clinical Trial of Idebenone in Patients 
with Primary Progressive Multiple Sclerosis (IPPoMS) 
Protocol Number: 09-N-0197 
Date of This Submission/Version: 06-14-2018 V28 
Principal Investigator 
 
 
 
Lead Associate Investigator 
Name, Degree 
Branch/Institute Bldg/Rm 
Phone 
E-mail 
Alison 
Wichman, MD 
NDU/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 
Tanya Lehky, MD NINDS 
10-CRC/7-5680 301-496-7428 
lehkyt@mail.nih.gov 
Govind 
Bhagavatheeshwa 
ran, PhD 
NIB/NINDS 
10/5C103 
301-496-1801 
bhagavatheeshg@ninds.ni 
h.gov 
Rosalind Hayden, 
RN 
OCD/NINDS 10/5C101 
301-827-9002 
haydenre@ninds.nih.gov 
Elena Romm, MS 
NDU/NIND 
S 
10/5C103 
301-594-2697 
RommE@ninds.nih.gov 
Jenifer Dwyer, 
RN 
NDU/NIND 
S 
10/5C101 
301-496-0064 
JDwyer@cc.nih.gov 
Laura Kannaian, 
RN 
NDU/NIND 
S 
10/5C103 
301-496-0586 
kannaianl@cc.nih.gov 
Alison Wichman, 
MD 
NDU/NIND 
S 
10/5C101 
301-496-0064 
wichmana@ninds.nih.gov 
Carlo Pierpaoli, 
MD, PhD 
DIR/NICHD 
13/3W16 
301-402-2289 
pierpaoc@mail.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 
NDU/NINDS 
10/5C103 
301-402-4488 
bielekovab@ninds.nih.gov 


Neuroimmunology Branch/NINDS/NIH 
IPPoMS Clinical Trial Protocol 
2 
April 13, 2017 
 
 
 
Name, Degree 
Branch/Institute Bldg/Rm 
Phone 
E-mail 
Bibiana 
Bielekova, MD 
NIB/NINDS 
10/5C103 
301-402-4488 
bielekovab@ninds.nih.gov 
 
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 
 
Date of IRB approval: n/a 
FWA #  
 
 
Data and Safety Monitoring Board 
No 
 Yes 
 
Technology Transfer Agreement 
 No 
 Yes 
Agreement type and number: Clinical trial agreement CTA#2009-0004 
Expiration Date: 6/1/2019 
 
Confidential Disclosure Agreement 
 No 
 Yes 
Samples are being stored 
 No 
 Yes 


Neuroimmunology Branch/NINDS/NIH 
IPPoMS Clinical Trial Protocol 
3 
April 13, 2017 
 
 
 
2. Contents 
1. 
Title Page ..................................................................................................................................... 1 
2. 
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 .................................................................................. 10 
4.5 Idebenone pharmacokinetic, pharmacodynamic and toxicity data .......................................... 11 
4.5.1 
Preclinical studies ........................................................................................................ 11 
4.5.2 
Clinical studies ............................................................................................................. 12 
4.5.3 
Pharmacokinetics and product metabolism in humans ................................................ 13 
4.5.4 
Product information ..................................................................................................... 16 
4.5.5 
Storage and handling .................................................................................................... 16 
4.6 Rationale for the use of Idebenone in PP-MS .......................................................................... 16 
4.7 Rationale for current study design ........................................................................................... 18 
4.7.1 
Figure 1 ........................................................................................................................ 18 
5. 
STUDY OBJECTIVES OR HYPOTHESES ............................................................................. 22 
5.1 
Hypothesis ........................................................................................................................... 22 
5.2 
Goals of the study ................................................................................................................ 22 
6. 
SUBJECTS ................................................................................................................................ 23 
6.1 
Study population .................................................................................................................. 23 
6.2 
Inclusion criteria .................................................................................................................. 24 
6.3 
Exclusion criteria ................................................................................................................. 24 
7. 
STUDY DESIGN AND METHODS ......................................................................................... 25 
7.1 
Study overview .................................................................................................................... 25 
7.2 
Recruitment ......................................................................................................................... 25 
7.3 
Screening methods .............................................................................................................. 26 
7.4 
Study design ........................................................................................................................ 26 
7.5 
Study procedures ................................................................................................................. 27 
7.5.1 
Study visits ................................................................................................................... 27 
7.5.2 
Clinical and functional evaluations .............................................................................. 27 
7.5.3 
Neuroimaging evaluation ............................................................................................. 27 
7.5.4 
Optical coherence tomography (OCT) ......................................................................... 28 
7.5.5 
Transcranial magnetic stimulation (TMS) and Central motor conduction time 
(CMCT) calculation ................................................................................................................... 28 
7.5.6 
Immunological and laboratory evaluation ................................................................... 29 
7.5.7 
Drug administration ..................................................................................................... 30 
7.5.8 
Records ........................................................................................................................ 31 
7.5.9 
Storage of data and samples ......................................................................................... 31 
7.6 
Follow-up/termination procedures ...................................................................................... 31 
7.6.1 
Trial termination procedures ........................................................................................ 31 


Neuroimmunology Branch/NINDS/NIH 
IPPoMS Clinical Trial Protocol 
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April 13, 2017 
 
 
7.6.2 
Assessment of the efficacy of blinding ........................................................................ 32 
7.6.3 
Release of allocation code............................................................................................ 32 
8. 
RISKS/DISCOMFORTS ........................................................................................................... 32 
8.1 
Risks associated with Idebenone therapy ............................................................................ 32 
8.2 
Risks of lymphocytapheresis ............................................................................................... 33 
8.3 
Risks of MRI ....................................................................................................................... 34 
8.4 
Risks of lumbar puncture .................................................................................................... 34 
8.5 
Risk of OCT ........................................................................................................................ 35 
8.6 
Risk of electrophysiological studies .................................................................................... 35 
8.6.1 
Risk of TMS ................................................................................................................. 35 
8.6.2 
Risk of nerve conduction studies ................................................................................. 35 
8.7 
Risk of skin biopsy .............................................................................................................. 35 
8.8 
Risk Rehab Evaluation ........................................................................................................ 35 
9. 
SUBJECT MONITORING ........................................................................................................ 35 
9.1 
Parameters to be monitored ................................................................................................. 35 
9.1.1 
Expected Adverse Events............................................................................................. 35 
9.1.2 
Monitoring of adverse events ....................................................................................... 36 
9.2 
Toxicity tables/criteria to be used ....................................................................................... 37 
9.2.1 
Definition of Adverse Event (AE) ............................................................................... 37 
9.2.2 
Severity of Adverse events .......................................................................................... 37 
9.2.3 
Definition of Serious Adverse Event (SAE) ................................................................ 38 
9.2.4 
Assessment of causality ............................................................................................... 38 
9.2.5 
Treatment of adverse events ........................................................................................ 39 
9.3 
Criteria for individual subject withdrawal........................................................................... 39 
10. 
OUTCOME MEASURES ...................................................................................................... 39 
10.1 
Primary outcome measure ............................................................................................... 40 
10.2 
Secondary outcome measures .......................................................................................... 40 
10.2.1 Neuroimaging outcomes .............................................................................................. 40 
10.2.2 Clinical/functional outcomes ....................................................................................... 40 
10.3 
Exploratory outcome measures ........................................................................................ 40 
10.3.1 Neuroimaging .............................................................................................................. 40 
10.3.2 Clinical ......................................................................................................................... 41 
10.3.3 Biological/immunological ............................................................................................ 41 
11. 
STATISTICAL ANALYSIS .................................................................................................. 41 
11.1 
Data acquisition and processing ...................................................................................... 41 
11.2 
Statistical analyses of outcome measures ........................................................................ 41 
11.3 
Handling of missing/unobtainable data ........................................................................... 45 
11.4 
Power analysis and sample size calculation .................................................................... 46 
11.5 
Selection of primary outcome measure ........................................................................... 47 
11.6 
Accrual number request ................................................................................................... 50 
11.7 
New power analysis ......................................................................................................... 50 
12. 
HUMAN SUBJECT PROTECTION ...................................................................................... 51 
12.1 
Subject selection .............................................................................................................. 51 
12.2 
Justification for exclusion of children ............................................................................. 51 
12.3 
Study safeguards .............................................................................................................. 51 
12.4 
Qualifications of investigators ......................................................................................... 52 
13. 
BENEFITS .............................................................................................................................. 53 
13.1 
Direct Benefit .................................................................................................................. 53 


Neuroimmunology Branch/NINDS/NIH 
IPPoMS Clinical Trial Protocol 
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April 13, 2017 
 
 
13.2 
Indirect Benefit ................................................................................................................ 53 
14. 
SUMMARY/CLASSIFICATION OF RISK: ......................................................................... 53 
15. 
CONSENT DOCUMENTS AND PROCESS ........................................................................ 53 
16. 
DATA AND SAFETY MONITORING ................................................................................. 54 
16.1 
Monitoring plan for the study as a whole ........................................................................ 54 
16.2 
DSMB plans .................................................................................................................... 54 
16.2.1 The proposed members of the DSMB are as follows .................................................. 54 
16.2.2 Role of DSMB ............................................................................................................. 54 
16.2.3 Proposed meeting frequency/ schedule ........................................................................ 54 
16.3 
Criteria for stopping the study ......................................................................................... 54 
17. 
Quality Assurance (QA) .......................................................................................................... 55 
17.1 
Quality assurance monitor ............................................................................................... 55 
17.2 
Quality assurance plan ..................................................................................................... 55 
18. 
ADVERSE EVENTS REPORTING ...................................................................................... 55 
19. 
ALTERNATIVES TO PARTICIPATION OR ALTERNATIVE THERAPIES ................... 56 
20. 
PRIVACY ............................................................................................................................... 56 
21. 
CONFIDENTIALITY ............................................................................................................. 56 
21.1 
For medical records ......................................................................................................... 56 
21.2 
For research data .............................................................................................................. 56 
21.3 
For stored samples ........................................................................................................... 56 
22. 
CONFLICT OF INTEREST/TECHNOLOGY TRANSFER ................................................. 56 
23. 
RESEARCH AND TRAVEL COMPENSATION ................................................................. 57 
24. 
REFERENCES ....................................................................................................................... 58 
25. 
23. ATTCHAMENTS/APPENDICES ................................................................................... 66 
25.1 
Flow chart ........................................................................................................................ 66 
25.2 
Eligibility checklist .......................................................................................................... 67 
23.3 Case Report Forms (CRFs) .................................................................................................... 68 
23.4 Rating scales .......................................................................................................................... 69 
23.4.1 Expanded Disability Status Scale (EDSS) ...................................................................... 69 
23.4.2 Scripps NRS .................................................................................................................... 70 
Scripps NRS ............................................................................................................................... 70 
23.5 Modified McDonald’s Diagnostic Criteria for PP-MS .......................................................... 71 
23.6 Recruiting advertisements ...................................................................................................... 72 
23.7 MS Patient Questionnaire ...................................................................................................... 78 
23.8 Investigator’s Brochure .......................................................................................................... 78 
23.9 Clinical trial agreement (CTA) .............................................................................................. 78 


Neuroimmunology Branch/NINDS/NIH 
IPPoMS Clinical Trial Protocol 
6 
April 13, 2017 
 
 
 
3. PRECIS 
 
3.1 Objective 
The goal of this study is to assess the safety, therapeutic efficacy and mechanism of action of 
idebenone in primary-progressive multiple sclerosis (PP-MS) patients. 
 
3.2 Study Population 
Adult, untreated patients with PP-MS with disability ranging from none to moderately severe will 
be included in the trial. The upper age limit in this study has been set at 65; setting an age limit 
should permit us to focus on the potential neuroprotective effect of idebenone in PP-MS and limit 
the confounding factor of the natural aging process and its known negative influence on neuro- 
regeneration. Published data indicate that higher doses (10-50 mg/kg) of idebenone per day are 
required for beneficial effects on neurological disability in comparison to the lower doses (5- 
10mg/kg) that are sufficient for beneficial effects on cardiac/systemic functions in Friedreich’s 
ataxia (FRDA) patients. Therefore, in order to target the CNS compartment, we will use a daily 
dose of 2250mg (750mg 3 times per day), which will provide target values of 10-50mg/kg for 
virtually all adult patients. 
 
3.3 Design 
This is a Phase I/II safety/efficacy trial with an adaptive trial design: one year of pre-treatment 
baseline period serves the dual purpose of collecting patient-specific biomarkers of disease 
progression and collecting longitudinal neuroimaging and clinical data for selection of primary 
outcome measures. This baseline period is then followed by a double-blind, idebenone versus 
placebo treatment phase for a total of 2 years. Based on preliminary sample size estimates, current 
enrollment calls for a total of 66 patients (33 per arm). 
 
3.4 Outcome Measures 
Quantitative neuroimaging measures of central nervous system (CNS: i.e. brain and spinal cord) 
tissue destruction and clinical and functional (i.e. electrophysiological) measures of neurological 
disability will be collected every 6-12 months. Additionally, biomarkers focusing on analysis of 
reactive oxygen species (ROS) and oxidative stress will be collected every 12 months. The trial is 
currently powered using progression of brain atrophy as detected by SIENA methodology as the 
primary outcome measure. However, this may not be the most sensitive outcome available. In 
recognition of this, the trial has an adaptive design: i.e. it incorporates analysis of progression of 
CNS tissue destruction as measured by quantitative MRI markers and clinical/paraclinical markers 
defined as secondary outcome measures in the first 30 enrolled patients during the one year pre- 
treatment baseline, before randomization. All defined outcome measures collected in the first 30 
enrolled patients will be transformed into z-scores and compared for the robustness of longitudinal 
change over the coefficient of variation. This will permit to select the most sensitive and most 
accurate outcome measure for detecting progression of CNS tissue damage. As a result, the primary 
outcome measure of this trial will be the comparison of individualized rates of brain atrophy 
progression between the idebenone and placebo groups after 2 years of treatment, unless the 
predetermined analysis of the pre-treatment baseline period in the first 30 enrolled subjects 
determines that one of the predefined secondary outcome measures has a higher z-score than brain 
atrophy measurement. In this case, the primary outcome would be the efficacy of idebenone versus 
placebo in inhibiting patient-specific slopes of functional or structural deterioration as measured by 
this more sensitive biomarker of CNS tissue destruction, yet to be defined by the analysis of the 1- 
year longitudinal data from pre-treatment baseline. 


Neuroimmunology Branch/NINDS/NIH 
IPPoMS Clinical Trial Protocol 
7 
April 13, 2017 
 
 
 
 
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; 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-7R 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 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 


Neuroimmunology Branch/NINDS/NIH 
IPPoMS Clinical Trial Protocol 
8 
April 13, 2017 
 
 
 
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 
“oligodendrycyte 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. What is the pathophysiological substrate of this more diffuse, 
degenerative disease process? 
 
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. 
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). 


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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 recently 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. 
 
The respiratory burst system of activated microglia/macrophages represents one of the most 
abundant sources of reactive oxygen species (ROS) in the brain, in addition to the electron- 
transport chain of mitochondria. 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). 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: 
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). 


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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. 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, creating a vicious cycle 
of mitochondrial damage. 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) 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. 
Thus, resultant damage to the demyelinated axon would be a combination of 
oxidative damage with Ca2+-mediated excitotoxicity, leading to programmed 
cell death or necrosis. However, the Na+/Ca2+ exchanger was found only in 
acutely demyelinated axons and not in chronically-demyelinated axons (Black, 
Kocsis et al. 1990), suggesting that the mechanism of axonal damage might 
differ between these two conditions. 
 
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) could slow down the accumulation of 


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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 
http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=221. 
 
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), which however, did not 
reach statistical significance. 
 
Although the use of immunomodulatory agents in progressive MS is widespread, despite lack of 
demonstrated efficacy in placebo-controlled trials, the debate about such erroneous contemporary 
practices continues. Specifically, while individual providers argue that there may be patients with 
progressive MS who respond to immunomodulatory agents, the statisticians point to the fact that 
such responses have to be marginal in view of negative efficacy data and do not take into account 
side effects from these therapies and associated costs both for patients and the society (Ioannidis 
2013). Therefore, use of immunomodulatory drugs for progressive MS outside of clinical trials 
cannot be advisable and recommendation against such use was recently endorsed by AAN among 
its “Top five choosing wisely” recommendations (Langer-Gould, Anderson et al. 2013). 
 
 
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 
parent molecule is converted to metabolites by first pass metabolism. In the initial steps of 
metabolism, the side chain of parent idebenone undergoes a process of oxidative shortening leading 
to the metabolites QS-10, QS-8, QS-6 and QS-4 (the number refers to the number of carbon atoms 
in the side-chain). Parent idebenone and all of the short-chain metabolites are modified further by 
conjugation (glucuronidation or sulfatation) resulting in conjugated forms of idebenone (Idebenone- 
C) as well as QS-10-C, QS-8-C, QS-6-C and QS-4-C. 
The bioanalytical methods allow measurement of either 
• parent idebenone and unconjugated metabolites (idebenone, QS-10, QS-6, QS-4) 
• or the combined measurement of conjugated molecules plus unconjugated forms of the 
same molecules, referred to as 'total idebenone', 'total QS-10', 'total QS-6' and 'total QS-4', 
respectively. 
 
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: 


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In rats and dogs oral idebenone is rapidly absorbed and extensively metabolized in the intestinal 
mucosa and liver. The primary route of metabolism is -oxidative shortening of the side chain. 
The major metabolites are QS-10, QS-8, QS-6, and QS-4 (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 parent 
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, dose-dependency for plasma levels was found between 10 and 
100 mg/kg/day, but there were no differences between 100 and 500 mg/kg/day. 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). Exposure in rats an dogs at this dose level exceeds by >3-fold the exposure in human 
subjects receiving a dose of 750mg idebenone tid and thus an adequate safety margin should exist 
at human doses up to 2250mg/day. Results from bridging toxicity studies conducted by Santhera 
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. 
 
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 
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. 
 
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. 


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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. 
Overall, more than 8 million patients have received idebenone treatment. This represents more than 
59,900 patient-years experience. 
 
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 


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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 free 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 (non-metabolized and non- 
conjugated) idebenone in plasma amounts to between 0.1% and 1% of total (free plus 
conjugated) idebenone1, indicating a very high first-pass effect. Therefore the plasma 
concentrations of parent idebenone are very low even after relatively high doses. e.g. Cmax 
and AUC of free idebenone after dosing of 2250 mg/day for two weeks are 22.4 ng/ml and 
32.2 mg/L x hr respectively. For the conjugated metabolites in the same study (SNT-I-003), 
Cmax and AUC are 5229 ng/ml and 32221 mg/L x hr respectively. The amount of the total 
metabolites QS10, QS6 and QS4 is in the same order of magnitude as that of total 
idebenone. The pharmacokinetics of idebenone is linear as assessed by the amounts of total 
idebenone. Increasing the oral dose of idebenone five or seven fold results in corresponding 
increases in the AUC of total idebenone. 
 
There is a food effect, as assessed in study SNT-I-001, which is slight and more pronounced 
at the higher dose. Repeated daily dosing does not lead to relevant accumulation of the 
metabolites indicating no enzyme auto-inhibition. In addition, there is no indication that 
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 total idebenone between the age 
groups were detected, as shown in the table below: 
 
 
 
 
 
 
 
 


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Group/Dose 
tmax 
(h) 
Cmax 
(ng/ml) 
AUC(0-8) 
(h*ng/ml) 
t1/2 
(h) 
CHILDREN 
Mean 
1.5 
10927.0 
57341.8 
9.2 
SD 
0.6 
1843.8 
5719.0 
1.0 
Median 
1.5 
10711.0 
56366.3 
9.0 
ADOLESCENTS 
Mean 
2.8 
11462.4 
64717.0 
10.4 
SD 
1.1 
5045.0 
20811.6 
2.2 
Median 
2.0 
9849.0 
61428.9 
10.2 
ADULTS 
Mean 
3.2 
11205.6 
64083.9 
12.7 
SD 
2.7 
3665.3 
15306.1 
4.4 
Median 
2.0 
10225.0 
60176.6 
11.6 
1 Total idebenone and metabolites were analyzed after deconjugation of analytes in plasma. “Total” values therefore 
reflect total conjugated plus free non-conjugated analytes. 
 
 
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 total 
idebenone and total QS-10 than subjects with normal renal function, but patients with 
impaired renal function and undergoing hemodialysis have similar exposure values of total 
idebenone and only slightly higher values of total QS-10 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 total idebenone, 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 total idebenone and total QS-10 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 


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data and post-marketing experience available for the Takeda formulation can be considered to be 
relevant also to the Santhera formulation. 
 
 
Product information 
The study medication is manufactured by Santhera Pharmaceuticals and will be provided as 150 mg 
tablets with matching placebo 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 and placebo 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: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, 
titanium dioxide, talc). 
 
Placebo film-coated tablets SNT-MC17/F03 
Ingredients: lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: 
Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 
3550, polyvinylalcohol, titanium dioxide, talc). 
 
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 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) 
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). 


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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 Coenzyme Q10 
content (Geromel, Darin et al. 2002), making it superior to natural Coenzyme Q10 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 Coenzyme Q10 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), although the desired prospective, double blind clinical trials 
in these patients have not been performed. 
 
Perhaps the best documented and clinically meaningful example of sustained therapeutic benefit of 
idebenone in neurodegenerative disease is represented by Friedreich’s ataxia (FRDA). 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 have reduced ATP biosynthesis, down to 30% of normal. 
(Lodi 1999). 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 
very 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 


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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. 
 
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). 
 
Based on this background information, we propose to use idebenone in a proof-of-principle 
placebo-controlled cross-over Phase I/II clinical trial for PP-MS (Figure 1). Because there are no 
other therapeutic options for PP-MS, a placebo arm is both ethically justifiable and important to 
ensure an unbiased evaluation of MRI, clinical and immunological outcome measures. 1:1 
randomization between active treatment and placebo will optimize statistical power for detecting 
differences in the outcome measures. 
 
4.7.1 
Figure 1 
Idebenone in PP-MS clinical trial design 
 
 
 
 
Figure 1: At least one year of pre-treatment baseline will be followed by 1:1 randomization to placebo and 
idebenone 


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There has not been a single successful therapeutic trial in PP-MS thus far and it has become 
obvious that outcome measures widely used in RR-MS trials are not suitable for PP-MS cohorts. 
Specifically, reliance on CEL as an outcome measure that allowed rapid screening of promising 
therapeutic agents in phase II trials of RR-MS patients is not possible in PP-MS, because these 
patients have a paucity of CEL and the frequency of CEL does not correlate with the development 
of clinical disability. However, current measurements of clinical disability are too insensitive to 
detect disease progression in individual PP-MS patients within 2-3 year time frame. As a 
consequence, promising agents for PP-MS have been tested so far in large, multi-center phase II/III 
trials, which are prohibitively expensive. Therefore, there is a great need to develop more sensitive 
measures of CNS tissue destruction that could be utilized as outcomes for smaller phase II trials in 
PP-MS. Currently the only measure that may theoretically fulfill this need is the individualized rate 
of development of brain atrophy as measured by SIENA methodology. However, it is highly 
probable that several newer measures of CNS tissue destruction, such as a decrease in the NAA/Cr 
ratio measured by MRS or quantitative T1 relaxation time, may be more sensitive than brain 
atrophy. The reason for this is that irreversible neuronal dysfunction may occur before the 
development of brain atrophy and that reactive gliosis, which is evident in the pathology of PP-MS, 
may to a large extent compensate volumetrically for the tissue loss associated with demyelination 
and neuronal drop-out. However, there are currently no available longitudinal measurements of 
these biomarkers to allow sample size estimates. 
 
The possible solutions for this problem are twofold: We could perform a natural history study on 
PP-MS patients, collect longitudinal data and based on their analysis, design a new therapeutic trial 
of idebenone in the PP-MS population. However, this approach would pose significant delay for the 
therapeutic part of the trial and would also complicate recruitment efforts: even though none of the 
current disease modifying therapies (DMT) used in MS proved their efficacy in PP-MS, the 
relentless progression of neurological disability drives many PP-MS patients and their physicians to 
try unproved therapies. The second solution is to collect longitudinal data on PP-MS patients just 
before randomization to the treatment phase of the protocol. There are several advantages to this 
approach: 
1) 
Because the longitudinal baseline (pre-randomization) data can be analyzed while 
patients proceed to the treatment phase, the administration of treatment does not have to 
be delayed until all patients complete pre-treatment baseline. 
2) 
The NDU “natural history protocol” 09-N-0032, where patients with suspected MS 
undergo diagnostic work-up, explores the feasibility and utility of the proposed 
outcome measures. Hence, patients evaluated under this protocol with a final diagnosis 
of PP-MS can easily proceed to the therapeutic protocol, if so desired, and the data 
collected at NIB during the diagnostic work-up can be utilized as baseline (pre- 
randomization) data for the current therapeutic protocol. Historically, the baseline data 
have also been collected under NIB protocol 89-N-0045. 
3) 
Finally, evidence indicates that the rate of CNS tissue destruction differs significantly 
among individual PP-MS patients, but remains intra-individually relatively stable (i.e. 
linear) during a 3-5 year follow-up (Ingle, Stevenson et al. 2003). Therefore, collecting 
1 year of pre-treatment data on all patients in the therapeutic trial will allow us to 
calculate individualized rates of CNS tissue destruction and assess the therapeutic effect 
750mg tid for 2 years. All outcome measures will be collected every 6-12 months as indicated. 


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of idebenone in relationship to these individualized rates of CNS tissue destruction. 
This is expected to increase the power of the trial to detect therapeutic effect (see 
below) without the need to stratify randomization of patients based on the rate of CNS 
tissue destruction, which is not feasible from the practical standpoint. 
 
Based on this background, we propose to use an adaptive trial design: We will employ a pre- 
treatment baseline period of at least 12 months, where MRI, clinical and biomarker measurements 
will be collected in all patients for dual purpose: 
1) To obtain longitudinal quantitative MRI, clinical and electrophysiological data in 
untreated PP-MS patients before randomization that will be utilized for the selection of 
the most sensitive primary outcome measure. This will be done on the first 30 patients 
and subsequent analysis will be used for selection of the most sensitive primary 
outcome measure and for adjusting sample size calculation (see sample size calculation, 
Section 11) if the primary outcome measure is different than brain atrophy measured by 
SIENA methodology and 
2) To obtain patient-specific pre-randomization baseline for all collected outcome 
measures, which is expected to increase the statistical power of randomized trials with 
continuous outcome measures (Murray, Barer et al. 2005, Young, Lees et al. 2005, 
Frost, Kenward et al. 2008). This is because previous longitudinal studies in PP-MS 
demonstrated that although there is extensive inter-individual variability in the rate of 
CNS tissue destruction, intra-individually, these rates are relatively stable within 3-5 
year follow-up periods (Ingle, Stevenson et al. 2002, Ingle, Stevenson et al. 2003, 
Stevenson, Ingle et al. 2004). In other words: the longitudinal data for the exact MRI, 
clinical and electrophysiological biomarkers of CNS tissue destruction and clinical 
disability that we propose to collect in this trial are not available. However, based on 
published longitudinal studies using analogous, but presumably less sensitive 
biomarkers of CNS tissue destruction (e.g. ventricular atrophy, cross-sectional cervical 
spinal cord atrophy collected at 1.5T MRI etc (Ingle, Stevenson et al. 2003)) we make 
two assumptions (Figure 2A): 1. CNS tissue destruction develops in a linear manner 
within a 3-5 year time-frame in the majority of PP-MS patients and 2. The slopes of the 
linear development of CNS tissue destruction differ among individual patients. Based 
on these two assumptions, our trial design will allow adjustment for the individualized 
rates of development of CNS tissue destruction (Figure 2B), which is expected to 
increase our power to detect treatment relevant differences between placebo and active 
therapy groups (Murray, Barer et al. 2005, Young, Lees et al. 2005, Frost, Kenward et 
al. 2008). 
 
The details of analyses of pre-randomization data on the first 30 subjects and the methods for 
selection of the most sensitive outcome measure are described in detail in Section 11, under 
Statistical Analyses. 
 
Both active drug and placebo will be supplied by Santhera Pharmaceuticals. 
 
We will use a 2250 mg/day dose (5x150mg tablets three times per day). This dose was well 
tolerated in Phase I trials in adult patients (Bodmer, Vankan et al. 2009) and ensures that each 
treated patient will receive 10-50mg/kg of idebenone per day, which represents the estimated dose 
required for CNS efficacy (Di Prospero, Baker et al. 2007). 


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Figure 2 
Efficacy measures adjusted for individualized rates of development of CNS tissue destruction 
in PP-MS 
 
Figure 2: 
A/ Current trial is based on three 
assumptions, which are supported by the 
literature (Ingle, Stevenson et al. 2003): 
1. The slopes of CNS tissue 
destruction are linear for the 
majority of PP-MS patients. 
Therefore, the collection of 2-3 
time-points for each biomarker 
during the baseline period will 
allow estimation of the individual 
slopes of CNS tissue destruction 
2. The slopes of CNS tissue 
destruction differ among individual 
PP-MS patients 
3. The cross-sectional data (i.e. single, 
initial measurement of the 
biomarker) do not predict the 
slope/rate of CNS tissue destruction 
 
B/ Current trial and proposed analyses 
use the assumptions indicated above in 
order to increase the statistical power: 
for each patient, the area under curve 
(AUC) will be calculated for those 
biomarkers measured every 6 months 
and the AUC during the baseline period 
will be compared to the AUC during the 
second year of treatment in order to 
calculate the difference between these 
two measures. These individualized 
differences will be then compared on a 
group level between active treatment 
and placebo arms. For biomarkers 
collected every 12 months, the average 
of 2 baseline time-points (year -1 and 0) 
will be compared to the average of 2 
therapy time-points (year 1 and 2) in an 
analogous manner. 
 
 
Because this is a pilot study testing a novel mechanism of action (i.e. neuroprotection) in PP-MS 
with a very limited patient cohort, we need to optimize the trial design and select a patient 
population that is most likely to benefit from neuroprotective therapy in PP-MS. Specifically, we 
need to employ a patient population in which neuroprotection and repair are still feasible. 
Epidemiological data indicate that the major determinant of relentless progression of disability is a 
patient’s age, and not necessarily disease duration (Confavreux and Vukusic 2006). This may be 
due to the fact that natural repair mechanisms, including CNS plasticity and remyelination, 
decrease with aging (Crutcher 2002, Confavreux and Vukusic 2006). It is likely that these natural 


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repair mechanisms are necessary for achieving effective neuroprotection. Furthermore, the aging 
process is characterized by decreased ECT function and accumulation of mitochondrial DNA 
mutations (Lenaz, Bovina et al. 2002), which may complicate the differentiation between PP-MS- 
associated and aging-related mitochondrial dysfunction. The implementation of an upper age limit 
will eliminate these confounding factors. Because PP-MS is usually diagnosed in the early/late 
forties, we will limit the age of enrollment in this trial to 65. Setting an age limit will minimize the 
contribution of aging to the development of CNS atrophy and will ensure that aging will not limit 
CNS repair mechanisms. In contrast, we will not limit the disease duration. Because the most 
important outcome measures are neuro-imaging measures and those clinical/functional measures 
that are not necessarily skewed toward ambulation, we will include patients with moderate 
disability, up to EDSS 7.0 (i.e. patients who can ambulate with bilateral assistance). We will 
exclude non-ambulatory patients because of difficulties they would experience with prolonged 
MRIs, which are necessary for this protocol. 
 
As such, the trial design is Phase I/II, double-blind, placebo controlled, baseline versus treatment 
with 2 parallel study groups of idebenone versus placebo (Figure 1). 
 
Because of the paucity of suitable outcome measures for Phase II neuroprotective trials in MS, we 
will use/develop and validate several novel outcome measures in clinical, neuroimaging and 
immunological categories. 
 
 
5. STUDY OBJECTIVES OR HYPOTHESES 
 
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 determine the safety of long-term (24 months) idebenone therapy at 2250 mg/day in 
patients with PP-MS. 
2. To determine the efficacy of idebenone versus placebo in inhibiting individualized rates of 
CNS tissue destruction as measured by clinical biomarkers and quantitative imaging 
biomarker of brain atrophy (i.e. ventricular volume) 
 
The secondary goals are: 
1. To investigate the mechanism of action of idebenone in PP-MS. 
2. To determine/define biomarkers of mitochondrial dysfunction and oxidative damage in PP- 
MS patients. 
3. To define biomarkers indicative of therapeutic effect of idebenone on mitochondrial 
dysfunction and on limiting oxidative damage in PP-MS patients. 
4. To collect longitudinal data in the placebo arm that will allow us to evaluate whether the 
assumptions on which we based our primary analysis (i.e. that the CNS tissue destruction is 
intra-individually linear, but inter-individually different within 3 year time period) are 


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correct or not. This will allow us to calculate more precise sample size/power calculations 
for future neuroprotective trials in PP-MS. 
 
 
6. SUBJECTS 
 
6.1 Study population 
 
The study population will consist of 66 patients (33 per arm) with clinically definite PP-MS; age 
18-65 (inclusive) with disability ranging from none to moderately severe (EDSS 1-7, inclusive). 
We will exclude children, because a diagnosis of PP-MS is virtually nonexistent in children, and we 
will limit the age of the participants up to 65, because of evidence that remyelination and repair 
strategies may be ineffective in older patients (Crutcher 2002, Confavreux and Vukusic 2006). 
 
Interested patients (i.e. those who respond to the advertisement or are referred by an outside 
physician) will be interviewed over the phone by one of the investigators and will be asked to fill 
out the standard NIB questionnaire (Appendix G, page 71) utilized also by the NIB natural history 
protocols 09-N-0032, and 89-N-0045. Patients will be informed that the information collected in 
the questionnaire is necessary for us to determine their eligibility to enter the protocol and that 
collection and review of these personal data will be performed under NIH/NINDS principles for 
patient confidentiality. Verbal consent for collection and review of the personal data will be 
obtained from interested patients by study investigators. The following standard language for 
obtaining verbal phone consent will be used: 
 
“Thank you for calling the Neuroimmunology Branch. I am 
(name). The Neuroimmunology Branch studies multiple sclerosis, 
along with other diseases of the central nervous system. If you are 
interested in participating in one of our studies, I will send you our 
screening questionnaire. This questionnaire will expedite the 
screening process to see if you qualify for any of our current or 
future studies. The questionnaire takes about 10 minutes to 
complete. If you appear to be eligible for a study, you will be 
invited to come to the NIH for a clinical visit and possible 
enrollment in one of our studies. 
The questionnaire asks you to provide confidential information 
related to your health. You must understand the risks and possible 
benefits of completing this questionnaire and then you can decide 
whether to continue. 
First, the benefits. There is no direct medical benefit to you from 
completing this questionnaire, but we should be able to determine 
whether it is worth your time to come in for a clinical visit and 
possible enrollment in a study. 
Now the risks. Some of the information requested in the 
questionnaire is very personal. We will keep it as confidential as 
possible, using secure computers and locked files. 
Your participation in this screening questionnaire is completely 
voluntary. You do not have to answer every question, but if you 
skip too many questions, we may not be able to determine if you 


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are eligible for any NIB studies. There is no payment for 
completing this questionnaire. If you have questions or concerns 
about this process, you may contact our clinical staff at 301-496- 
0064. Do you agree to participate?” 
 
The date and time the consent is obtained will be documented and witnessed, and this will be 
included in the research record. 
 
6.2 Inclusion criteria 
 
1. PP-MS as determined by the 2005 modification of McDonald’s diagnostic criteria (see 
appendix E, page 64) (Polman, Reingold et al. 2005) 
2. Age from 18-65 years (inclusive) 
3. EDSS measure of neurological disability from 1 (no disability, clinical signs only) to 7 
(ambulatory with bilateral support) (Kurtzke 1983) at the time of first screening visit to 
NIH. 
4. Able to provide informed consent 
5. Willing to participate in all aspects of trial design and follow-up 
6. If able to become pregnant or to father a child, agreeing to commit to the use of a 
reliable/accepted method of birth control (i.e. hormonal contraception (birth control 
pills, injected hormones, vaginal ring), intrauterine device, barrier methods with 
spermicide (diaphragm with spermicide, condom with spermicide) or surgical 
sterilization (hysterectomy, tubal ligation, or vasectomy) for the duration of treatment 
arm of the study 
7. Not receiving any immunomodulatory/immunosuppressive therapies for a period of at 
least 3 months before enrollment in the study 
8. No exposure to idebenone, coenzyme-Q10 or other dietary supplements (such as 
antioxidants, mitochondrial-function promoting supplements or vitamins in excess of 3 
times recommended daily doses) for a period of at least 1 month before enrollment in 
the study 
 
A single patient (NIB 334) has been granted an amendment to inclusion criteria #2. NIB 334 meets 
all remaining inclusion and none of the exclusion criteria for the study. This patient has no 
comorbidities. If this patient is completes the baseline and is dosed with idebenone/placebo, he will 
be analyzed the same as other patients.  The FDA was consulted, and expressed no objections to 
this plan. 
 
 
6.3 Exclusion criteria 
 
1. Alternative diagnoses that can explain neurological disability and MRI findings 
2. Clinically significant medical disorders that, in the judgment of the investigators could 
cause CNS tissue damage or limit its repair, or might expose the patient to undue risk of 
harm or prevent the patient from completing the study 
3. History of hypersensitivity reaction to idebenone or coenzyme-Q10 
4. Pregnant or lactating women. All women of child-bearing potential must have a 
negative pregnancy test prior to the medication phase of the study. 
5. Abnormal screening/baseline blood tests exceeding any of the limits defined below: 


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i. Serum alanine transaminase or aspartate transaminase levels greater than 3 
times the upper limit of normal values 
ii. Total white blood cell count < 3,000/mm3 
iii. Platelet count < 85,000/mm3 
iv. Serum creatinine level > 2.0 mg/dl or eGFR (glomerular filtration rate) <30 
v. Positive pregnancy test 
6. Patients who are receiving any immunosuppressive therapies (including cytostatic 
agents) due to the concern that these drugs may contribute to neurodegeneration or limit 
CNS repair 
 
 
7. STUDY DESIGN AND METHODS 
 
7.1 Study overview 
 
This is a Phase I/II, double-blind, placebo controlled, baseline versus treatment with 2 parallel 
study groups (Figure 1) and an adaptive trial design. 
 
Based on current sample size estimates we expect to screen up to 85 PP-MS to yield at least 66 
patients that will finish the treatment phase of the study. These patients will be randomized 1:1 to 
receive either active therapy (idebenone 750mg po tid) or matched placebo. The treatment phase of 
the trial will be preceded by a 1 year pre-treatment baseline period, which will serve a dual purpose: 
1. To collect individualized data on biomarkers of CNS tissue damage and 2. To use these 
longitudinal data for the selection of the primary outcome measure and for more precise sample 
size estimates. 
 
 
7.2 Recruitment 
 
This protocol will be advertised on the NIH website and through patient support groups such as the 
National MS Society (NMSS). Active recruitment will include a letter to neurologists in the greater 
Washington DC area and to MS specialists in the states of Virginia, West Virginia, Maryland, 
Delaware, New Jersey and Pennsylvania. We have contracted the recruitment services of the North 
American Research Committee on Multiple Sclerosis (NARCOMS). The NARCOMS registry is a 
database of MS patient volunteers who are interested in participating in research. NARCOMS 
collects volunteer data, and then will match the volunteers to applicable studies. Volunteers are 
then mailed information about the studies they match, and the participant is able to contact the 
studies they are interested in. Finally, eligible patients will also be recruited from NIB natural 
history protocols (09-N-0032 and 89-N-0045). Because this natural history protocol collects 
identical clinical, MRI and paraclinical data as the present protocol, we will use data already 
collected under the natural history protocol in order to fulfill the requirements of the pre-treatment 
baseline. This will allow eligible PP-MS patients to proceed to the randomization and treatment 
phase of the current protocol without unnecessary delay. 
 
Patient advertisement (for NIH website and for NMSS bulletin) and the letter to the neurologists are 
provided in Appendix F. 


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7.3 Screening methods 
 
Patients who contact the study either through physician or self referral will be screened initially by 
phone. Interested patients may be requested to complete the NIB MS questionnaire (Appendix G) 
and to provide pertinent medical records (including MRI of the brain/spinal cord). The blank 
questionnaire may be sent to the potential patient by mail, fax, or email. The completed 
questionnaire and medical records are then mailed or faxed to the protocol research contact. Upon 
receipt of the records and imaging studies, the patient will be contacted to confirm the receipt of the 
requested information and, provided that review of the documentation does not identify any 
exclusion criteria, the patient will be invited to participate in the study. Interested patients will be 
scheduled for outpatient admission to the Clinical Center. 
 
Subjects who sign the informed consent but are excluded later based on abnormal laboratory 
findings will be defined as screen failures and counted toward patient accrual. When 30 subjects 
complete the pre-treatment baseline, we will perform an interim analysis for more precise sample 
size calculations (See Sample size calculation, section 11) and for selection of the most sensitive 
primary outcome measure. This analysis will not require unblinding, and will not affect final 
statistical analysis. Instead, it will help us to perform more precise power calculations based on 
longitudinal data collected utilizing neuroimaging biomarkers specific for this trial. We expect that 
this interim analysis will allow us to increase the power and/or decrease the sample size, based on 
assumptions specified under Section 11 and outlined in Figure 2. 
 
To allow for approximately 20% screening failures, the accrual ceiling (based on current estimates 
of sample size) will be set at 80 patients. 
 
 
7.4 Study design 
 
All eligible patients will undergo combined neurological, neuroimaging and research 
biomarker/immunological evaluations as outlined in Fig. 1 for the baseline period. The complete 
baseline evaluation will require approximately 4 outpatient visits in approximately 1 year. Each 
outpatient visit will last 3-5 hours. 
 
Patients who complete the baseline period will be randomized to active treatment or placebo by 
block stratification (by block size of 2) using a single condition: 1. Age (age <50 and age ≥50). 
Because epidemiological data indicate that age is a major determinant of the efficiency of CNS 
repair (Crutcher 2002, Confavreux and Vukusic 2006), this randomization strategy will ensure that 
both placebo and active treatment groups are comparable in this respect. The majority of patients 
are diagnosed with PP-MS around age 40. Furthermore, using block size of 2 will assure balanced 
distribution of the first 30 patients into placebo and active treatment groups (i.e. 15 patients per 
group). Randomization will be performed by the NIH pharmacy. The NIH pharmacy will maintain 
the study code key and release it to the investigators only after completion of the trial and 
finalization of the database. The NIH pharmacy may release the study code to the DSMB, if 
requested. 
 
After randomization, patients will be followed by combined neurological, neuroimaging and 
research biomarker/immunological evaluations as outlined in Fig. 1 for an additional 24 months. 


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The time commitment will include at least 6 outpatient visits in the 2 year period. Each outpatient 
visit will last 2-5 hours. 
 
According to the negotiated CTA, Santhera Inc. will supply a sufficient amount of idebenone for 
completion of the proposed trial (i.e. 2 year dosing for 40 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 
 
Each study visit (Figure 1) and MRIs 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 timepoints noted. Biological samples (CSF, whole 
blood, apheresis sample) should be collected within 4 weeks of the MRI examination as indicated 
in Figure 1. Blood samples at baseline and 1 year of treatment will be collected concomitantly with 
CSF samples. 
 
7.5.2 
Clinical and functional evaluations: 
to be performed every 6 months 
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 may 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 
c. Balance assessment 
The assessment of strength and spasticity may require the use of surface EMG. 
 
 
7.5.3 
Neuroimaging evaluation: 
MRI imaging will consist of combined MRI of the brain and upper cervical spinal cord, 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- 


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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). This is confirmed 
in our experience in this trial thus far, where true CEL are extremely rare at baseline and their 
incidence is not increased during the treatment phase. Therefore, we will administer contrast only at 
the first NIH MRI to identify those patients who may have very rare form of inflammatory PP-MS. 
Clinical judgment will determine if Gd is administered during the remaining 3T brain MRI scans. 
The total scan time without Gd administration is approximately 60 minutes. With Gd, the scan time 
increases to 90 minutes. Because more disabled patients have difficulties with long scans and it is 
paramount for the integrity of quantitative MRI data to avoid patient movement, the elimination of 
contrast administration from subsequent scans will improve tolerability of MRI procedure and 
improve MRI data quality without compromising the safety of patients. 
 
7.5.4 
Optical coherence tomography (OCT) 
To be performed every 12 months 
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 
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 
neurons and recorded at the target muscle, and is used to calculate the central motor conduction 
time (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). 


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7.5.6 
Immunological and laboratory evaluation 
The immunological and laboratory evaluation will include: 
1. Diagnostic/clinical blood-work (clinical care/safety): Baseline labs on untreated patients may be 
collected under this protocol, or our natural history protocols (09-N-0032 or 89-N-0045). CBC, 
Chemistry panel including liver function tests will be performed every 3 months for the first 
year of treatment and every 6 months for the second year of treatment as part of the safety 
measures. Laboratory evaluations that are performed at times when no NIH MRI/clinical visit is 
scheduled can be performed outside of NIH with results (including normal values) 
communicated to NIH investigators. 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 1. 
2. Research Blood (up to 60 cc total):Research blood will be obtained approximately every 12 
months (2 baseline and 2 treatment samples); this will be aliquoted and stored or used at the 
time of collection to meet the Biological/Immunological outcomes stated in section 10. 
3. CBC: Additional CBC may be performed in coordination with the research blood if a CBC is 
not already indicated at these timepoints. This information will be collected solely for research 
purposes. 
4. Lumbar puncture (research): Every patient will undergo a lumbar puncture twice during 
protocol duration: once at baseline (can be diagnostic LP from which 15-20cc of CSF has been 
obtained for research for total of 25cc of CSF collected in total) and once after 1 year of therapy 
(month 12). If the participant has undergone lumbar puncture at any time during their 
participation in the screening protocol and an adequate sample is already available, this may 
replace the baseline LP at the discretion of the Principle Investigator. From 15-20cc of research 
specimen, immune cells will be isolated and expanded and the CSF supernatant will be 
aliquoted and stored. Lumbar puncture procedure last from 30 minutes to 2 hours. The lumbar 
puncture will usually be done on an inpatient or day hospital floor of the Clinical Center. The 
procedure may be performed under fluoroscopic guidance by a credentialed neuroradiologist in 
Diagnostic Radiology, if there is a patient medical or scheduling need to do so. This involves a 
small amount of ionizing radiation (0.023 rem per LP). This is substantially less than the limits 
imposed by the guidelines of the NIH Radiation Safety Committee (5.0 rem per year for adults). 
 
5. Pharmacokinetic (PK) studies (research): Random sampling PK studies may be performed from 
the CSF twice during the duration of the protocol; at the time of LP. The first sample may be 
collected at baseline, prior to administration of study medication. The second sample may be 
collected at month 12 (+/- 2 weeks) of therapy, between 1 and 4 hours after idebenone intake 
(time selected randomly and documented in the research database). For the analysis of free and 
total idebenone and its metabolites free and total QS-10, total QS-6 and total QS-4, 8 ml CSF 
will be taken into two different tubes: 1. For the measurement of total idebenone and its 
metabolites total QS-10, total QS-6 and total QS-4: 0.5ml of CSF will be collected. For the 
measurement of free idebenone and its metabolite free QS-10 (i.e. active substances): 0.5ml of 
CSF will be collected. 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 


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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) 
6. Lymphocytapheresis (research): collecting between 2-4x109 peripheral blood mononuclear cells 
PBMC, will be performed 3 times during trial: once during pre-treatment baseline and after 1 
(month 12) and 2 (month 24) years of treatment. This procedure is performed solely for 
research purposes. If the participant has undergone lymphocytapheresis at any time during their 
participation in the screening protocol and an adequate sample is already available, this may 
replace the baseline lymphocytapheresis at the discretion of the Principle Investigator. This 
procedure may last up to 2.5 hours. If the 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 (up to 4x109) will be used for immunological studies. 
7. Skin biopsy (research): the punch skin biopsy will be collected once during baseline period. 
Skin biopsy will be used for isolation, expansion and cryopreservation of fibroblasts for future 
studies. Specifically, the fibroblast will be transformed to induced pluripotent stem cells (iPS), 
which can then be differentiated into neurons and glial cells. The purpose of these future studies 
is to evaluate if neurons from PP-MS patients are more susceptible to oxidative damage than 
neurons from other forms of MS (RR-MS and SP-MS) and neurons derived from patients with 
other disorders (i.e. controls). These future studies will be performed only after sufficient 
number of control samples of fibroblasts are collected/banked under alternative NIB protocols. 
 
 
7.5.7 
Drug administration 
 
We requested a new investigational new drug (IND) number from Food and Drug Administration 
(FDA) on 3/9/09. A copy of this protocol has been submitted to the FDA for review. 
 
Idebenone (150mg tablets) or placebo 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 to monitor compliance. 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 
(Appendix H). 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 and matching placebo are supplied in high density polyethylene (HDPE) bottles, 
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. 


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7.5.8 
Records 
 
The NINDS/Clinical center record will be used for trial-related documentation. Specific trial- 
related pages will include: 
 
1. Inclusion and exclusion criteria checklist 
2. Documentation of the history and physical examination (using structured NIB progress note). 
3. A copy of the written informed consent. 
4. A record of all research tests, scores, and results. 
5. Documentation of all clinical laboratory results. 
6. Documentation of any concomitant medications taken by the patient. 
7. 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, blood, CSF, expanded fibroblasts and peripheral blood 
mononuclear cells (PBMC) derived from aphereses, will be coded and stored in secured freezers on 
the NIH campus. All patients enrolled in this protocol will be assigned a 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 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 
 
7.6.10 
Trial termination procedures 
The individual participation in the trial will end with the last trial visit at month 24. 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 24) 
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 last scheduled visit (month 24) 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. Because no interim analysis requiring unblinding of patient allocation is planned, there 
will be no termination of the trial based on therapeutic futility. 


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As of this protocol amendment, data analysis has been completed 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. Data and samples from this study will be transferred 
into protocol 09-N-0032 for continued analysis. Participants will be formally informed of the study 
results by a written letter (uploaded to PTMS). 
 
 
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 assessed 
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. 
 
7.6.11 
Assessment of the efficacy of blinding 
Efficacy of blinding will be assessed two times during the trial duration for research subjects and 
clinical evaluators: At month 6 and after completion of the trial. These evaluations will be 
administered in person. Similarly, efficacy of blinding for those investigators/data assessors who 
perform analysis of neuroimaging and immunological data will be assessed twice: at the beginning 
of their analysis and at the end. Because some of the data acquired during therapy time-points 
(especially biological/immunological markers) are likely to be influenced by treatment allocation, 
investigators performing immunological assays will have no access to clinical/MRI data and vice 
versa. The only person who will have access to all data simultaneously and who will monitor 
integrity and technical quality of performed analyses will be the PI. However, the PI will not serve 
as a clinical evaluator. 
 
7.6.12 
Release of allocation code 
The allocation code will be provided to the investigators by the NIH pharmacy only after all the 
required analyses (i.e. all primary and secondary outcome measures) have been collected, research 
databases have been locked and assessment of blinding has been performed. 
 
 
 
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. The most relevant adverse reaction data is provided by a 
recent placebo-controlled study with 48 Friedreich’s Ataxia patients below the age of 18 years. Due 
to the limited sample, frequencies can not be reliably calculated. 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, 


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disturbance in attention, angina pectoris, vomiting, reflux oesophagitis, musculoskeletal chest pain, 
myalgia, chromaturia, upper abdominal pain. 
 
Clinical trials with idebenone have previously been performed in indications other than FRDA, 
predominantly in older patient populations (mainly in Alzheimer’s dementia) not readily comparable 
with FRDA. 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. 
 
Idebenone has not been administered (to our knowledge) to patients with presumed immune- 
mediated disorders and therefore the effect of idebenone on dysregulated immune responses in 
humans is currently unknown and difficult to predict. Because several functions of the immune 
system are dependent of the formation of ROS, a potent antioxidant may theoretically inhibit these 
functions. Among these are oxidative burst used by granulocytes and monocytes/macrophages to 
kill intracellular pathogens and granzyme A-, B- and K-mediated killing utilized by natural killer 
(NK) cells and some T cells. Granzyme-B mediated killing is only partially dependent on the 
formation of ROS, as it predominantly relies on activation of caspases. Because some of these 
immune functions (oxidative burst of monocytes/macrophages, including microglia and granzyme- 
B-mediated killing by cytotoxic T cells) are thought to contribute to CNS tissue damage in MS, 
theoretical inhibition of these functions by idebenone may have an overall beneficial effect in PP- 
MS patients. 
 
Inhibition of oxidative burst utilized by granulocytes and monocytes/macrophages can theoretically 
lead to increased rates of infections; however, this was not observed in double-blinded placebo 
controlled randomized trials, including those that targeted elderly and disabled patients (e.g. AD), 
which are known to be more susceptible to infectious complications. Therefore, idebenone is 
considered to be a safe and well tolerated agent. 
 
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 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. 


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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 
monthly 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 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. 


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Lumbar puncture may be done in the radiology department under fluoroscopic guidance for patient 
medical or scheduling needs. The total radiation exposure during the 2 procedures is 0.046 rem, 
which is well below the guideline of 5 rem per year allowed for 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 
 
8.6.13 
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. 
 
8.6.14 
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 of skin biopsy 
 
Pain at the biopsy site is usually minimal; bleeding and infection are rare. The biopsy site usually 
heals with a very small, nearly unnoticeable scar, but may leave a raised scar or visible lump. 
 
8.8 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 
 
9.1.15 
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, Friedreich’s Ataxia, cerebrovascular accident (stroke), multi-infarct 
dementia, and other neurodegenerative diseases (e.g. Huntington’s disease). The most frequently 
and consistently experienced adverse reactions reported across these trials have been headache, 
diarrhea, nausea and dyspepsia. Events (reported by  3% of patients) across double-blinded 


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placebo controlled randomized trials included abdominal pain (8.9%), diarrhea (6.6%), flu-like 
syndrome (5.5%), accidental injury (4.6%), depression (4.6%), upper respiratory tract infection 
(4.5%), headache (3.9%), back pain (3.7%), agitation (3.5%), urinary tract infection (3.2%), and 
dizziness (3.0%). The events occurred with similar frequency in patients receiving placebo and 
thus were not felt to be drug related. These events are typically mild to moderate in severity and 
reversible. 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. 
 
9.1.16 
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 25). 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 and his/her treatment assignment would be revealed to 
the investigators and the DSMB. 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. Extensive laboratory monitoring of the following will occur every 6 months for the 
study duration: CBC with differential, Chemistry panel 20, and urinalysis and pregnancy test (for 
females with childbearing potential). Additionally, laboratory monitoring (CBC, chemistry panel 
with liver function tests) will be performed every 3 months after initiation of dosing of idebenone 
for the first year of treatment and every 6 months thereafter. 
 
 
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 25, must be 
recorded and reported to the FDA in accordance with federal regulations and NIH procedures. Any 
SAE reported by the patient after month 24, 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 


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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 same timelines mandatory for initial reports. An SAE that is considered completely 
unrelated to one previously reported, will be reported separately as a new event. 
 
NINDS will provide Santhera Pharmaceuticals (Switzerland) Ltd. with 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 CTA. 
 
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. 
 
9.2.17 
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. 
 
9.2.18 
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) 
 
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. 


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9.2.19 
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.) 
 
9.2.20 
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: 
 
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 


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9.2.21 
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. 
 
1.2 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 study visits as indicated in section 7.5.6). 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 or for patients with no CEL observed on MRIs collected during baseline period 
(expected to be majority of PP-MS patients), the number of CEL recorded on a 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 


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10.1 
Primary outcome measure 
 
The primary outcome measure of the IPPOMS is the rate of disability progression, assessed with 
the Area Under the Curve (AUC) of the CombiWISE scores during the 2-year treatment period. 
The CombiWISE data collected during the 1-year pre-treatment period will be utilized by including 
both the pre-treatment disability progression (AUC of CombiWISE scores during the pre-treatment 
period) and severity of the disability (CombiWISE score at pre-randomization baseline) as 
covariates in the statistical analysis. 
CombiWISE was developed based on the pre-determined analysis of 58 candidate outcomes 
collected in 1 year pre-treatment phase in 1 training (IPPOMS1) and 2 validation (IPPOMS2 and 
RIVITALISE) cohorts, as described in detail in recent publication (Kosa, Ghazali et al. 
2016).CombiWISE is a continuous scale ranging from 0 to 100, has strong correlation with EDSS 
(i.e., scale used for regulatory approval of MS drugs; rho = 0.9805, p<0.0001, n=303) and has the 
strongest power among all 58 tested outcomes (Kosa, Ghazali et al. 2016). 
 
 
10.2 
Secondary outcome measures 
 
10.2.1 
Neuroimaging outcomes 
 
1. Inhibition of individualized rates of enlargement of ventricular volume: effect of 
idebenone versus placebo on individualized rates of enlargement of segmented volume 
of lateral and 3rd ventricles 
 
10.2.2 
Clinical/functional outcomes 
 
1. Progression in EDSS-plus, as defined in (Cadavid, Cohen et al. 2017). EDSS-plus 
response will be analyzed using a cox proportional hazards model. 
2. Progression of lower extremity disability as assessed by 25 foot walk component of 
MSFC 
3. Progression of upper extremity/fine motor movements disability as assessed by non- 
dominant hand 9 hole peg test component of MSFC 
4. Progression of neurological disability as assessed by Scripps NRS 
5. Progression of neurological disability as assessed by EDSS 
 
 
10.3 
Exploratory outcome measures 
 
10.3.1. Neuroimaging 
 
1. Progression of retinal nerve fiber thinning as detected by OCT (comparing idebenone to 
placebo) 


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10.3.2. Clinical 
 
1. Progression in cognitive dysfunction as assessed by Symbol Digit Modality Test 
(comparing Idebenone to placebo) 
2. Progression of neurological disability as assessed by MSFC 
 
 
 
10.3.3. Biological/immunological 
 
1. Analysis of changes in CSF albumin quotient between idebenone and placebo (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 activated/pro-inflammatory 
microglia/monocytes (sCD14) 
3. Analysis of changes in CSF lactate/pyruvate ratio, as a biomarker of extra-mitochondrial 
glucose metabolism 
4. Analysis of changes in CSF growth differentiation factor 15 (GDF15), as a putative 
biomarker of mitochondrial dysfunction 
5. Analysis of changes in CSF neurofilament light chain (NF-L), a biomarker of axonal 
damage 
 
 
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 imaging biomarker of ventricular volume 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. Codes will be broken only after all pre-specified quantifiable data constituting 
primary and secondary outcomes are collected and recorded in the database. 
 
 
11.2 
Statistical analyses of outcome measures 
 
 
Further details of the statistical analysis (e.g. definition of analysis populations) will be defined in a 
Statistical Analysis Plan which will be finalized before the database lock and opening of the 
treatment code. 
 
Introduction 


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a) For data collected only at 2 time-points (i.e. single collection during pre-treatment 
baseline and single collection at 1 year of therapy), such as CSF data, we will calculate 
for each individual %-change between baseline and therapy time-points 
b) For data collected every 6 months (i.e. clinical data and quantitative brain MRI data) 
we will calculate area under curve (AUC) for 3 data points obtained during pre- 
treatment baseline period and compare it to AUC for 5 data points obtained during the 
treatment period. 
 
The rational for using AUC (as opposed to linear regressions) is explained in detail in 
Figure 3: 
 
 
 
Figure 3: There are two possible ways how changes in outcomes collected every 6 months (e.g., primary outcome: 
CombiWISE) can be analyzed: 1. As a change in regression slopes (left panel) or 2. As a change in AUC (right panel). 
There are two major problems with regression slopes: First, the baseline pre-treatment period slope is derived only 
from 3 measurements. Because these measurements are spread equally apart, the least squares linear regression slopes 
are calculated only from 1st and 3rd measurement, whereas the middle (2nd) measurement affects only the intercept. 
Consequently, even though we have three baseline measurements, only two of them would be de-facto utilized for 
final outcome comparison. Furthermore, as depicted in the left panel, if the drug has both neuroprotective effect 
(which decreases slope) and promotes structural or functional repair (which decreases intercept), comparing slopes 
would de-facto ignore the latter potentially important mechanism of action (MOA). In contrast, measuring changes in 
disability progression between untreated and treated period using AUC (right panel) eliminates both stated 
disadvantages of progression slopes. This method uses all measured data and correctly deals with the improvements in 
disability by subtracting parts of the curve that are below the baseline (i.e. CombiWISE measure at the initiation of 
therapy) from the AUC part that is above the baseline. 
The only problem with AUC is unequal length of the compared periods: while pre-treatment baseline period has 1-year 
length, the treatment period for IPPOMS trial has length of 2 years. It may be intuitive to divide 2-year AUC period by 
2 to obtain equivalent yearly measurements, but that is incorrect. As depicted in the left panel, if the progression slopes 
were linear, the AUC derived from 2-year period needs to be divided by 4 to get equivalent yearly AUC progression. 
We have validated correctness of this adjustment by analyzing blinded 2 year CombiWISE data from 50 patients who 
finished 2 years of study and by comparing average AUC derived from splitting Year 1 and Year 2 of this longitudinal 
cohort, versus calculating AUC from the entire 2-year period. We observed that these two measurements strongly 
correlate with each other (r2=0.905) with following linear regression formula: 
Y = -0.77 + 3.96*X, where X is average yearly AUC and Y is 2-year AUC measured in the same patient. 
Consequently, this mathematical analysis confirmed that 2-year AUC must be divided by 4 to obtain equivalent yearly 
change. The intercept (-0.77) represents improvement in disability, which is incorrectly ignored when the treatment 
period is split into two yearly AUCs. 


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Statistical Hypothesis 
 
The hypothesis to be tested for the primary efficacy endpoint CombiWISE is: 
 
H0: 
There is no difference between idebenone and placebo in the disability progression 
during the 2-year treatment period. 
 
The alternative superiority hypothesis is 
 
HA: 
The disability progression in idebenone-treated patients is slower than in the 
placebo-treated patients during the 2-year treatment period. 
 
In addition to the difference between the treatment groups, the within-group changes in each 
treatment group will be evaluated by comparing the disability progression during the pre-treatment 
period to the progression during the treatment period. 
 
The analysis for the primary outcome measure CombiWISE will be performed in all randomized 
patients using a two-sided type I error rate of α = 0.05. 
 
 
 Primary Analysis of the Primary Outcome Measure 
 
The AUCs of the CombiWISE scores during the 2-year treatment period will be analyzed using an 
Analysis of Covariance (ANCOVA) model with the AUC of the pre-treatment CombiWISE scores, 
Baseline (Month 0) CombiWISE score and Baseline age as covariates. 
 
The incomplete data in the CombiWISE scores during the 2-year treatment period will be managed 
with the single imputation algorithm defined in Section 5.3. 
 
The within group changes will be tested using paired t-test within each treatment group. For this 
analysis, to compare the 1-year pre-treatment period changes to 2-year treatment period changes, the 
treatment period AUC values will be divided by 4. 
 
Sensitivity Analyses of the Primary Outcome Measure 
 
1. Random coefficient regression model with random intercept and slope will be fitted to the 
response data. All CombiWISE scores will be included as response variables in the model. 
In order to model random intercept and slope for pre-and post-treatment separately, factor 
period (pre vs. post) will be created: pre -treatment (Month -12 to 0) vs. post-treatment 
(Month 0 (+1 day) to 24). Exact days from the first visit, instead of month will be used as 
Time in the model. In addition to the random slopes and intercepts, the model will include 
the fixed effect for treatment group (idebenone or placebo), period (nested within 
treatment), interaction between Time and period (nested in treatment) and covariates: 
Baseline (Month 0) CombiWISE score and Baseline age. The interaction between Time and 
period (nested within treatment) will be used to examine the hypothesis of four slopes are 
same (slopes for placebo group at pre- and post-treatment, slopes for idebenone group at 
period pre-and post-treatment). The pairwise comparisons of the four slopes or intercepts, 


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such as slope (or intercept) at post-treatment for idebenone group vs. that for placebo group, 
and slope (or intercept) for idebenone group at post-treatment vs. that at pre-treatment 
period can be constructed and performed using the statement “estimate”. This analysis 
includes only the observed CombiWISE scores as response variables and as the model can 
manage incomplete data, no imputation will be done. 
 
2. Mixed Model for Repeated Measures (MMRM) will be fitted to the response data. The 
observed CombiWISE scores from all scheduled post-baseline visits (Month 6, 12, 18 and 
24) will be used as response variables in the model. The model will include visit, treatment 
group (idebenone or placebo) and the interaction between visit and treatment group as fixed 
factors. The Baseline (Month 0) CombiWISE score, baseline age and the rate of decline in 
the CombiWISE scores during the pre-treatment period will be used as covariates in the 
model. Both the overall treatment difference at all visits (Months 6, 12, 18 and 24 post- 
randomization) and the treatment difference separately at each visit will be estimated from 
the model. The overall treatment difference will be tested based on the fixed factor for the 
treatment group and the visit-specific treatment differences will be tested with contrasts 
derived from the fixed factor for treatment group and the interaction term between visit and 
treatment group. The focus of this analysis will be on the early treatment difference 
observed at Month 6 post-randomization and the treatment difference at the last study visit 
(Month 24 post-randomization). An unstructured covariance structure will be applied for the 
MMRM. The denominator degrees of freedom will be computed using the Kenward-Roger 
method. The covariate for the rate of decline will be calculated separately for each subject 
from the CombiWISE scores observed during the pre-treatment period using a random 
coefficient regression model with random intercept, random slope and time (exact number 
of days since the first assessment) as an explanatory factor. 
 
3. Multiple Imputation (MI) assuming data missing at random (MAR) will be done to compare 
idebenone to placebo. MI techniques based on Pattern Mixture Models (PMM) will be 
applied in this sensitivity analysis. This methodology will structure data based on the 
missing data patterns. The method will be based on a missingness pattern having a 
monotone structure, i.e. if among the observations during the 2-year treatment period one 
CombiWISE score is missing, all subsequent scores after this missing value will also be 
treated as missing. For patients with intermittent missing values, before performing MI 
based on the PMM, it will be necessary to create a monotone missingness pattern. 
Intermittent missing values will be imputed using the Markov Chain Monte Carlo (MCMC) 
methodology which assumes a multivariate normal distribution over all variables included 
in the imputation model. This first MI step is planned to be repeated 1000 times, creating 
1000 different datasets with a monotone missing data structure. Seed value of 1995 will be 
used in the MI procedure. The imputation is based on the missing at random (MAR) 
assumption, i.e. the missing data are assumed to follow the same model as the other patients 
in their respective treatment arm. 
 
After this, the remaining missing data will be imputed using a method for monotone 
missingness, also based on the MAR assumption. Thus, for each of the 1000 created dataset 
with a monotone missing data pattern, missing values will be imputed based on a sequential 
procedure reflecting the monotone missing data pattern. Patients with the first missing value 
occurring at Month 3 will have their missing Month 3 value replaced by an imputed value 
from a regression model with treatment group, Month 0 CombiWISE score, the pre- 


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treatment slope and baseline age as explanatory variables. In the next step, patients with 
their Month 6 value missing will have their missing Month 6 value replaced by an imputed 
value from a regression model with all factors defined above and Month 3 value as 
explanatory variables. Similar procedure will be used to replace the missing values at all 
subsequent visits. 
 
The imputed datasets generated with the approach described above do contain only non- 
missing values and are used as input in the model for the sensitivity analysis of the primary 
outcome variable. MMRM similar as described in Sensitivity Analysis 2 will thus be run on 
each of the 1000 generated imputed datasets and the difference between the treatment 
groups will be estimated. Finally, the results from these analyses will be combined to derive 
an overall estimate of the treatment difference. In addition to the estimates, corresponding 
95% confidence intervals and p-values will be calculated. 
 
4. Multiple Imputation assuming data missing not at random (MNAR) will be done to compare 
idebenone to placebo. Control group based assumption (Copy Reference imputation) will be 
used, i.e. the trajectories of the patients are assumed to follow the placebo group trajectories 
after the discontinuation. Methods similar to the procedure described above will be used to 
generate monotone missing data. After this, the missing data will be imputed sequentially 
for each visit (first Month 3, followed by all subsequent visits). Only the data from the 
control group (placebo group) will be used as input for each imputation of both treatment 
groups. 
 
 
Secondary Endpoints 
 
Continuous variables will be analyzed using random coefficient regression models and/or MMRMs 
similar to the one defined above for the primary outcome variable 
 
Categorical Endpoints will be analyzed using cox proportional hazards models, with treatment 
group, baseline values (if applicable) and baseline age as covariates. 
 
 
11.3 
Handling of missing/unobtainable data 
 
All efforts will be made to collect a complete set of data by employing 1-2 week flexibility in 
scheduling and repeating inadequate quality MRI scans. 
 
With the exception of the primary endpoint (AUCs) and the sensitivity analyses, for continuous and 
categorical endpoints, no data imputation will be made and missing data will be handled by the 
models itself. 
 
The following single imputation method is applicable for handling of missing data to calculate 
AUCs of CombiWISE scores and MRI data. 
 
If 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: 


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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 24), we will substitute the data for this time-point by the average of 2 preceding 
time-points. 
b. For data obtained once at baseline and once at treatment phase (i.e. CSF), 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 
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. 
For missing data for CombiWISE calculation, the CombiWISE formula (Kosa, Ghazali et al. 2016) 
specifies handling of the inability to perform either 25FW or non-dominant hand 9HPT as a 
separate variable. 
 
 
11.4 
Original Power analysis and sample size calculation 
 
Assumptions for the initial sample size calculation were: 
 
1) Rate of development of CNS atrophy in early PP-MS patients is equivalent, or greater than the 
rate of development of brain atrophy in RR-MS patients and similar to rate of development of 
brain atrophy in SP-MS patients (Fox, Jenkins et al. 2000) 
2) Rate of development of brain atrophy in PP-MS patients varies considerably between 
individuals, ranging from +1.8%/year to -3.6%/year (Mean -1.03%, SD 1.3%) for BPF and 
from +1.7%/year to -4.2%/year (Mean -1.50%, SD 1.6%) for grey matter fraction (Sastre- 
Garriga, Ingle et al. 2005) 
3) Within 5 years of follow-up, the rate of development of brain atrophy, ventricular atrophy, 
cervical cord atrophy and the rate of accumulation of T2LV and T1LV seem to be significantly 
more stable intra-individually than inter-individually (Ingle, Stevenson et al. 2003), although 
the intra-individual coefficient of variation values are not provided in this publication 
4) Due to these inter-individual differences in the rate of accumulation of brain atrophy, the 
reported sample size estimates in SP-MS patients utilizing changes in brain atrophy detected by 
SIENA methodology applied to 1.5T MRI scans, indicates that to detect 50% therapeutic effect 
in a therapeutic trial of 2 year duration with 80% power and 5% significance, the minimum 
number of subjects is 33 per arm (Altmann, Jasperse et al. 2008). The relevant data from this 
recent publication using SIENA methodology for calculation of whole brain atrophy in SP-MS 


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patients by Altmann, Jasperse et al. are summarized in the table below (selected conditions for 
current trial are highlighted): 
 
Duration 
of 
Therapy 
Expected 
therapeutic 
effect: 
90% power 
80% power 
30% 
Th effect 
40% 
Th effect 
50% 
Th effect 
30% 
Th 
effect 
40% 
Th 
effect 
50% 
Th 
effect 
1 year 
Min# subj/arm 
212 
120 
77 
158 
89 
57 
2 years 
Min# subj/arm 
123 
69 
45 
92 
52 
33 
3 years 
Min# subj/arm 
107 
60 
39 
80 
45 
29 
 
Collecting at least 12 months of pre-treatment baseline volumetric MRI data (i.e. rate of 
development of brain atrophy, gray matter atrophy, ventricular enlargement and spinal cord 
atrophy) and clinical data will allow us to calculate individualized rates of CNS tissue destruction 
and disability progression. Based on the data described under 1)-3), employing such individualized 
rates of development of CNS tissue destruction for the determination of therapeutic effect between 
active drug and placebo is expected to significantly increase the power for detection of group 
differences, effectively decreasing the number of subjects necessary for demonstrating therapeutic 
efficacy of an experimental neuroprotective therapy (Figure 2). Additionally, employing more 
sensitive methodology (3T magnet strength) and novel analyses (e.g. volumetric analysis of entire 
cervical spinal cord) may further increase power for detection of group differences. 
 
However, NDU did not have any longitudinal data on a PP-MS cohort that could be utilized for 
exact sample size analysis and the only longitudinal data that were published at the inception of this 
trial and could be utilized for sample size calculation were those based on whole brain atrophy as 
detected by SIENA methodology. Therefore, we used published sample size estimates for the SP- 
MS patients (Altmann, Jasperse et al. 2008) and targeted patient accrual to reach 66 treated patients 
(33 per arm). 
 
In 2016 we performed and published pre-determined analysis of the 58 outcome measures (see 
section 11.5) collected in 1 year pre-treatment baseline period on first ≥30 IPPOMS patients and 
validated our findings in the 2 validation cohorts consisting of 34 remaining IPPOMS patients and 
29 SP-MS patients from RIVITALISE trial (Kosa, Ghazali et al. 2016). This analysis demonstrated 
that above-stated assumptions were incorrect, that brain atrophy measured by SIENA technology 
was no more sensitive than clinical outcomes. Instead, based on this pre-defined analysis we 
selected CombiWISE as primary outcome and brain ventricular atrophy measured by 
LesionTOADS methodology as secondary outcome. 
 
 
 
11.5 
Selection of primary outcome measure 
Based on the analysis of data from pre-randomization baseline period for the first 30 patients 
 
Based on higher resolution of 3T versus 1.5T MRI scans and some indication from studies, either 
published or reported at conferences, that show that alternative measures, such as e.g. gray matter 
atrophy or MRS may be more sensitive than whole brain atrophy in detecting CNS tissue damage 
longitudinally (Fisher, Lee et al. 2008), we will employ an adaptive trial design that will allow us to 


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select most robust (i.e. most sensitive and most accurate) primary outcome measure for the final 
analysis. 
 
Specifically, we will analyze MRI and clinical/paraclinical quantitative data when 30 patients reach 
month 0 (i.e. will complete pre-randomization baseline period)(Kosa, Ghazali et al. 2016). From 
this analysis we will calculate the rate of progression of CNS tissue destruction as assessed by MRI 
and clinical biomarkers defined in Section 10.2, for individual patients and for the entire cohort. 
Because SIENA methodology for detection of progression of brain atrophy, which is currently 
utilized as the default primary outcome measure, calculates progression of brain atrophy as a %-age 
of baseline brain tissue, we will perform the same type of analysis for every other defined outcome; 
i.e. we will quantify the biomarker at month -12 (baseline) and months -6 and 0 and will express the 
values measured at months -6 and 0 as a %-age of the baseline value (i.e. assigning 100% to the 
value measured at month -12). For the 1st level of analysis, we will compare all outcome measures 
based on the measurements collected at month 0 (see Figure 4A for explanation). For each 
biomarker (i.e. outcome measure) we will calculate the z-score as the average change from baseline 
divided by the standard deviation (SD). Biomarkers with the most robust change from baseline and 
lowest spread of values will have the highest z-score. Figure 4A shows 3 hypothetical biomarkers: 
Biomarker 1 has on average the lowest magnitude of change from baseline (i.e. low sensitivity) and 
relatively high spread (i.e. low accuracy), leading to the lowest z-score. Biomarker 2 has the most 
robust change from baseline (i.e. high sensitivity), but also the widest spread of values (i.e. lowest 
accuracy), resulting in low z-score. Biomarker 3 has an intermediate change from baseline (i.e. 
intermediate sensitivity) but very low spread of values (i.e. high accuracy), resulting in the highest 
z-score. Biomarker 3 would be selected as the primary outcome measure. 
 
 
 
 
If we encounter a situation in which two or several biomarkers have identical or very similar z- 
scores in the first level of analysis, we will then evaluate these biomarkers based on data collected 
at month -6 (i.e. at Mo -6; Figure 4B). 
Figure 4: 
A/ First level of comparative analysis: all outcome measures will be expressed as %-age of baseline values for all 30 
patients. We will calculate z-scores for all outcome measures as Average (30 changes from baseline)/SD and select 
the biomarker with largest z-score as primary outcome measure. 
B/ Second level of comparative analysis: if two biomarkers had identical or very similar z-scores in the first level of 
analysis, we would evaluate z-scores based on data collected at -6 months using identical methodology. 


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The logic of choosing to compare z-scores rather than the simpler selection of the biomarker giving 
the most robust difference from baseline is as follows: the absolute difference of the longitudinal 
measurements of a biomarker from its baseline value is the combination of biological progression 
of the disease and of any technical inaccuracy of measurement. From the biological standpoint, PP- 
MS is a progressive disease – patients may have periods of stabilization, but in contrast to RR-MS, 
there are no periods of improvement. Therefore, if in some patients we measure improvement from 
baseline, we can assume this is most likely due to technical inaccuracy of measurement, than due to 
the biology of this disease. Because technical errors should be random (i.e. may result in apparent 
improvements as much as in exaggerated progression) a greater spread of biomarker values 
between patients would likely reflect greater technical measurement errors. Therefore, using 
standard deviation as a denominator will ensure selection of an outcome measure that combines the 
greatest sensitivity for detecting CNS tissue destruction and the greatest accuracy of measurement. 
 
If, based on this analysis, we identify an outcome measure that is more sensitive and more precise 
than whole brain atrophy measured by SIENA methodology, we will select this new measure as the 
primary outcome measure. 
 
This analysis was performed and published, including measurements of z-scores (Kosa, Ghazali et 
al. 2016). We have compared total of 58 clinical, imaging, electrophysiological and optical 
coherence tomography outcomes. In the first IPPOMS cohort (which ended up being 35 patients 
because we lost some MRI outcomes due to technical issues such as poor quality of scans and the 
protocol stipulated minimum of 30 patients per outcome) we observed that total of 15 outcomes 
reached statistical significance based on un-adjusted p-values (See Table 2 in the (Kosa, Ghazali et 
al. 2016)). We then validated these 15 outcomes for their ability to reliably detect yearly MS 
disease progression in 2 independent validation cohorts: IPPOMS2 cohort (n=34) and RIVITALISE 
cohort (n=29). Seven out of 15 outcomes validated statistically-significant change in both 
independent validation cohorts, when properly adjusting for multiple comparisons. Surprisingly, the 
default primary outcome for IPPOMS protocol, brain atrophy measured by SIENA methodology 
was not validated. While six MRI biomarkers (ventricular volume and 5 diffusion-tensor imaging 
[DTI] markers) validated statistically-significant change in both validation cohorts, our enthusiasm 
for these outcomes was lowered by observation that only one of them, ventricular atrophy, showed 
any correlation with clinical outcomes. This measure had mild correlation with 2 cognitive scales 
(PASAT and SDMT) and with a MS functional composite (MSFC) scale. However, this correlation 
was observed only in the cross-sectional paradigm, which benefited from a broad range of 
disabilities present in merged untreated progressive MS cohort (n=98). In contrast, we observed 
absolutely no correlation between any MRI outcome and any clinical measure in 1-year 
longitudinal paradigm – in other words, change on MRI biomarkers did not correlate with change in 
any clinical outcome. The article explains in length why this is so, documenting poor signal-to- 
noise ratio (SNR) of even best performing MRI biomarkers for the level of change observed in the 
1-year longitudinal MS data in comparison to scan-re-scan variability observed in MRI technical 
controls (i.e. healthy donors scanned twice at each scanner). 
 
Because of this we concluded that MRI outcomes utilized in small Phase II trial will be unlikely to 
predict change on clinical outcome (used for Phase III trial), which is a definition of a “surrogacy”. 
Therefore, we sought alternative outcome. We noticed that clinical scales were much better 
correlated, even though they too had relatively low SNR. One way to decrease the noise of the 
measurement is to use repeated measure analysis. Therefore, we hypothesized that to the degree to 


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which clinical scales reflect overlapping biology (i.e. measure overlapping neurological disability) 
to that degree they represent repeated measure analysis. Thus, rationally combining clinical scales 
would allow us to differentiate between disability caused by a structural lesion (which would affect 
multiple clinical scales congruently) from the performance noise, which would have random 
distribution among clinical scales. We have tested this hypothesis by designing Combinatorial 
Weight-Adjusted Neurological Clinical Scale (CombiWISE version 1), where we selected 
contributing clinical scales and adjusted their “weights” in final formula proportionally to z-scores 
(defined in the IPPOMS protocol and measured in the first [IPPOMS1] cohort). After we validated 
that CombiWISE v1 outperforms all other clinical and MRI biomarkers, we used statistical learning 
based on random permutations of the modeling cohort, to mathematically optimize CombiWISE 
outcome (Kosa, Ghazali et al. 2016). 
 
Not only mathematically-optimized CombiWISE outperformed all remaining 57 studied outcomes, 
but it also retained highly statistically significant correlations with majority of clinical outcomes, 
including EDSS that is currently used for regulatory approval of MS drugs. However, in 
comparison to EDSS, which is ordinal scale from 0-10, CombiWISE is a continuous scale from 0- 
100. One point change in EDSS corresponds on average to 7.50 point change in CombiWISE with a 
standard error of 0.10, making CombiWISE significantly more sensitive (and specific) measure of 
neurological disability (Kosa, Ghazali et al. 2016). 
 
 
11.6 
Accrual number request 
 
Up to 85 subjects are planned to be recruited based on current sample size calculation, to account 
for 20% drop-out and final number of treated subjects 33 per arm (66 total). These recruitment 
numbers were already achieved and interim analysis of the outcomes showed enhanced, rather than 
diminished power of new primary outcome (CombiWISE) in comparison to original default 
primary outcome (Brain atrophy measured by SIENA). 
 
11.7 
New power analysis 
 
If the above-described analysis of secondary outcome measures identifies a new primary outcome, 
we will conduct a new power analysis for the selected new primary outcome, using two-sample t- 
test with estimates of mean and standard deviation of changes from baseline collected on the first 
30 enrolled patients. Based on this new power analysis, we will amend the protocol to indicate the 
final accrual number request. 
 
The new power analysis for CombiWISE, EDSS and ventricular volume change has been published 
for both within-group and between-group designs (Kosa, Ghazali et al. 2016). Using absolute 
change in the CombiWISE AUC outcome determined from the pre-treatment baseline data in 
IPPOMS cohort, following power calculation for AUC was derived: 
 
Drug 
effect 
untreated 
treated 
difference 
Actual 
Power 
N Pairs 
Distribution 
Normal 
50% 
51.24 
25.62 
25.62 
0.807 
28 
Method 
Exact 
45% 
51.24 
28.18 
23.06 
0.806 
34 
Number of Sides 
2 
40% 
51.24 
30.75 
20.50 
0.802 
42 
Standard Deviation 
46.2 
35% 
51.24 
33.31 
17.94 
0.807 
55 
Correlation 
0.5 


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30% 
51.24 
35.87 
15.37 
0.801 
73 
Nominal Power 
0.8 
25% 
51.24 
38.43 
12.81 
0.804 
105 
Null Difference 
0 
20% 
51.24 
40.99 
10.25 
0.802 
162 
Alpha 
0.05 
 
 
This demonstrates that substituting default primary outcome (Brain atrophy measured by SIENA 
(Altmann, Jasperse et al. 2008)) with CombiWISE primary outcome will significantly enhance 
power of the IPPOMS trial from estimated 80% of power to detect at least 50% drug effect to more 
than 80% power to detect at least 40% drug effect. Additionally, while brain atrophy measured by 
SIENA does not correlate with clinical outcomes, CombiWISE has strong, highly significant 
correlations with EDSS, which is used for regulatory approval of MS treatments, both in cross- 
sectional and longitudinal paradigms (i.e. yearly change in CombiWISE correlated with yearly 
change in EDSS). Therefore, CombiWISE can predict efficacy on EDSS outcome, but does so in 
considerably smaller cohorts and/or trials of shorter duration (Kosa, Ghazali et al. 2016). 
 
 
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 trial. The age limits are 18-65 
years, inclusive. The rational for this age limit is explained in detail under Section 4.7. The upper 
age limitation is scientifically justified in this very early stage of clinical trial; if idebenone proves 
its therapeutic efficacy in this optimally selected patient population, further studies will be required 
to determine the exact age limit of its efficacy in this disorder. This will permit to use more 
equitable populations in later phases of clinical development of idebenone for PP-MS. 
 
12.2 
Justification for exclusion of children 
 
Patients under the age of 18 are excluded 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. 
 
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. 


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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 and 
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. Dr. 
Bielekova will be responsible for all aspects of the research. All pre-planned immunological, 
cellular and molecular biomarker studies will be performed in her laboratory and under her 
direction. Dr. Bielekova will not obtain informed consent or serve as a treating or evaluating 
physician due to a conflict of interest, and because thanks to her supervision of biomarker studies, 
she may become inadvertently unblinded to treatment allocation. 
 
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 board-certified neurologist with full 
clinical privileges. All above-mentioned investigators will have direct clinical contact with patients 
and all can obtain informed consent. 
 
Jenifer Dwyer is 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. Lehky, Wichman, 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. Carlo Pierpaoli, MD, PhD is an internationally recognized expert 
in diffusion tensor imaging (DTI) analysis and tool development. He has developed TORTOISE, 
which is a state of the art DTI processing software. He will participate in the analysis of DTI 
images by testing clinical utility of the new DTI tools developed in his laboratory. Elena Romm is 
biologist with long-term experience in sample collection and processing. She will supervise 
collection, processing and storage of all biological samples: CSF, serum, apheresis/whole blood 
samples for PBMC collection and skin biopsy. She will serve as the primary laboratory contact and 
will keep updated database of biological sample collection and storage. Dr. Bhagavatheeshwaran, 
Dr. Pierpaoli, and Ms. Romm will not obtain informed consent. 


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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: 
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 will obtain informed consent, as noted in the Qualifications of 
Investigators section. 
 
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. 
 
On occasion, it may be necessary to obtain informed written consent by a phone discussion process. 
It may be necessary, for example if a participant has completed screening under protocol 09-N- 
0032, and has met all inclusion criteria except the washout period from a previous treatment. In 
some cases, waiting for completion of the washout phase may result in their being too old to enroll 
in this study. As most of our participants are traveled from other states, it is impractical to fly 
participants back to NIH solely for the consent process. For telephone/written consent, the 
following process will be followed. 
This study and its consent form will be reviewed with the participant in person at their 09-N-0032 
screening visits. Their questions will be answered. If they are interested in participating, they will 
be provided with an unsigned copy of the consent form to take home with them, or a copy will be 
mailed to them with a postage paid addressed return envelope. Once they meet all eligibility criteria 
(including completion of a washout period if needed), they will be contacted by telephone by 
someone authorized to obtain consent for the study. They will be asked to have a witness with them 
at the time of the telephone call. The consent form information will be reviewed again over the 


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phone and any further questions answered. If they agree to participate, the patient will sign and date 
the consent form, and have a witness sign and date the consent form. They will return the signed 
consent form to NIH. After the investigator who obtained consent signs the consent form, a 
complete signed copy will be sent to the participant. The original, signed consent form will be sent 
to medical records and an additional copy maintained in research records. The consent process will 
be documented in the medical and research records. 
 
Information that is gained through this study will be available to the participating patients. 
Consent forms are attached. 
 
16. DATA AND SAFETY MONITORING 
 
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 
 
16.2.3 
The proposed members of the DSMB are as follows 
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 
 
16.2.4 
Role of DSMB 
a. Monitor/review AE on yearly basis and SAE within 15 days of receiving the 
SAE report. 
 
16.2.5 
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. 
 
1.3 Criteria for stopping the study 
All SAEs will be communicated to the DSMB. Depending on the nature of the SAE and its 
potential relationship to the study medication, the DSMB may request unblinding of the 
treatment allocation for any patient that suffers SAE(s) and will decide on further action. 


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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 to ensure adequate protection of the rights, welfare, and safety of human subjects and 
the quality and integrity of the resulting data. 
 
18. ADVERSE EVENTS REPORTING 
 
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 on the Problem Report Form 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 on the Problem Report Form not more than 14 days after 
the PI first learns of the event. 
 
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. The NINDS is also responsible for providing Santhera Pharmaceuticals (Switzerland) 
Ltd. with 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 CTA. 


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Santhera Pharmaceuticals (Switzerland) Ltd. is responsible, in collaboration with United BioSource 
Corporation (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 studies 
with the same active moiety, 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 studies and associated with the same active moiety, 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. 
 
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 anonymized 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. Anonymized 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. 
 
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. 


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• 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 clinical trial agreement (CTA#2009-0004) has been established with Santhera Pharmaceuticals 
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. 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 stock exchange 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). 


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25. ATTCHAMENTS/APPENDICES 
 
25.1 
Flow chart 
 
Pre-treatment Baseline 
Period 
(Month -12 - 0) 
Idebenone Treatment Period 
(Month 0-24) 
Month -12 
Month -11 
Month -10 
Month -6 
Month 0 
(2 days) 
Month 6 
Month 12 
(2 days) 
Month 18 
Month 24 
(2 days) 
Clinical 
Clinical evaluation 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Inclusion/Exclusion 
criteria 
√ 
√ 
Urinalysis/pregnancy 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Clinical Lab work 
√ 
√ 
√ 
√ 
√ 
√ 
Safety Lab work 
Every 3 months for the first year and 
Every 6 months for the second year 
Imaging 
MRI brain 3T (Q 6mo) 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
OCT (Q 12 mo) 
√ 
√ 
√ 
√ 
Immunology 
Research Blood 
(< 60ml) 
√ 
√ 
√ 
√ 
Lymphocytapheresis * 
√ 
√ 
√ 
Lumbar puncture 
√ 
√ 
Lithium Heparin (5mL) 
optional 
√ 
√ 
Skin biopsy 
√ 
 
NB: all studies to be completed within 4 weeks +/- date indicated with exception of baseline 
lymphocytapheresis, lumbar puncture and skin biopsy, which can be performed anytime during pre- 
treatment baseline period. 
*120 cc of whole blood may be collected in the place of Lymphocytapheresis if there is a 
contraindication. 


 
25.2 
Eligibility checklist 
 
Inclusion criteria 
 
 PP-MS as determined by the 2005 modification of McDonald’s diagnostic criteria 
(Polman, Reingold et al. 2005) 
 Age between 18-65 years (inclusive) 
 EDSS measure of neurological disability from 1 (no disability, clinical signs only) to 7 
(ambulatory with bilateral support) (Kurtzke 1983) 
 Able to provide informed consent 
 Willing to participate in all aspects of trial design and follow-up 
 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 
 Not receiving any immunomodulatory/immunosuppressive therapies for a period of at 
least 3 months before enrollment in the study 
 No exposure to idebenone, coenzyme-Q10 or other dietary supplements (such as 
antioxidants, mitochondrial-function promoting supplements or vitamins in excess of 3 
times recommended daily doses) for a period of at least 1 month before enrollment in the 
study 
 
Exclusion criteria 
 
 Alternative diagnoses that can explain neurological disability and MRI findings 
 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 
 History of hypersensitivity reaction to idebenone or coenzyme Q10 
 Pregnant or lactating women. All women of child-bearing potential must have negative 
pregnancy test prior to the treatment phase of the study. 
 Abnormal screening/baseline blood tests exceeding any of the limits defined below: 
o Serum alanine transaminase or aspartate transaminase levels greater than 3 times 
the upper limit of normal values 
o Total white blood cell count < 3,000/mm3 
o Platelet count < 85,000/mm3 
o Serum creatinine level > 2.0 mg/dl or eGFR (glomerular filtration rate) <30 
o Positive pregnancy test 
 Patients who are receiving any immunosuppressive therapies (including cytostatic agents) 
due to the concern that these drugs may contribute to neurodegeneration or limit CNS 
repair 


CNS IRB Protocol Template (rev.1-17-08) 
page 68 of 78 
 
 
23.3 Case Report Forms (CRFs) 
 
Trial data will be captured using the NIH Clinical Research Information System (CRIS) in the 
structured Neuroimmunology note. Additional data are captured in CRIS that may be useful in 
verifying the compliance to the study protocol, such as appointment dates, orders, adverse event 
documentation, etc. 


CNS IRB Protocol Template (rev.1-17-08) 
page 69 of 78 
 
 
APPENDIX D: 
 
 
23.4 Rating scales 
 
23.4.1 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 


CNS IRB Protocol Template (rev.1-17-08) 
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23.4.2 Scripps NRS 
 
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: 


CNS IRB Protocol Template (rev.1-17-08) 
page 71 of 78 
 
 
23.5 Modified McDonald’s Diagnostic Criteria for PP-MS 
(Polman, Reingold et al. 2005) 
 
1) One year of disease progression (retrospectively or prospectively determined) 
2) Plus two of the following: 
a. Positive brain MRI (≥9 T2 lesions or ≥4 T2 lesions with positive VEP) 
b. Positive spinal cord MRI (≥2 focal T2 lesions) 
c. Positive CSF (isoelectric focusing evidence of oligoclonal IgG bands or increased IgG index, 
or both) 
 
As with RR-MS, the alternative diagnoses that could explain insidious progression of neurological 
disability or MRI/CSF findings need to be searched for and ruled out before the diagnosis of MS can 
be concluded. 


CNS IRB Protocol Template (rev.1-17-08) 
page 72 of 78 
 
 
23.6 Recruiting advertisements 
 
 
 
If so, you may qualify for an NIH research study. 
The Neuroimmunology Branch (NIB) of the National Institutes of Health is conducting a 
study to investigate the efficacy of an oral experimental drug in primary progressive multiple 
sclerosis. The study will be conducted at the NIH Clinical Center in Bethesda, Maryland, on 
an outpatient basis. 
The study involves a one year baseline after which participants will receive the medication  
or placebo for 2 years. Medical evaluations, MRIs, and blood work will be performed at 
scheduled intervals during the 3-year study. The visits will last 2-5 hours each and will be 
every month the first 3 months and then every 6 months for the remainder of the study. 
There is no cost for participation. 
Travel reimbursement will be provided. 
 
Please call 301-496-0064 for more information about 
participating in this study. Please refer to study 
number 09-N-0197. www. ClinicalTrials.gov 
Do you have 
Primary Progressive Multiple Sclerosis? 
We are seeking participants: 
• ages between 18-65 
• diagnosis of Primary Progressive Multiple Sclerosis 
• not taking any immunomodulatory drugs 


CNS IRB Protocol Template (rev.1-17-08) 
page 73 of 78 
 
 
 
 
 
Researchers at the NIB are seeking adults ages 18-65 with a diagnosis of Primary 
Progressive Multiple Sclerosis to participate in a randomized, placebo  
controlled, double blind study investigating the efficacy of Idebenone in this 
disease. Participation will include medical evaluations, MRI, bloodwork, and 
lumbar puncture performed at the NIH Clinical Center on an outpatient basis. 
 
Q. What’s involved in the study? 
A. This study is a randomized, placebo  controlled,  double  blind  study. 
Individuals who qualify and decide to participate will be randomly assigned to 
receive the study drug or a placebo. Neither the individual nor the  
investigators will know which patients are taking the study drug, until the 
conclusion of the trial. All individuals participating  in the trial will be monitored 
at scheduled intervals, and at the conclusion of the trial, based on clinical and 
MRI assessments, it will be determined if the study drug is effective in this 
disease. 
 
Q. How may I benefit? 
A. If this drug proves to be effective, the progression of your disease may slow 
down or even improve. 
Do you have Primary Progressive Multiple Sclerosis? 


CNS IRB Protocol Template (rev.1-17-08) 
page 74 of 78 
 
 
 
Q. Are there risks involved? 
A. Over 8 million individuals have been treated with Idebenone for other neurological 
conditions, including Alzheimer’s disease. Idebenone has been found to be well 
tolerated and safe. The most common side effects reported have been 
gastrointestinal symptoms, including nausea, diarrhea and loss of appetite. 
 
Q. Will this cost me any money? 
A. No, you will not be charged for any part of the study. 
 
Q. How much time does the study take? 
A. The study will last 3 years. During the initial screening period, you will need to be 
seen several times over approximately a 3 month period. After that, you will need 
to return approximately every 6 months. Over the 3 years, you will have a total of 
approximately 15 visits. Visits may vary in length, but are usually from two to five 
hours long. We will try to schedule visits at times that are most convenient for you. 
 
Q. How will my primary neurologist be involved? 
A. You will remain in the care of a non-NIH neurologist who will manage any 
symptoms and guide treatment decisions that are unrelated to the clinical trial. 
NIH may make recommendations for your care, but will not act as your primary 
neurologists. All management related to the clinical trial, such as MRIs and 
bloodwork, will be performed at the NIH. 


CNS IRB Protocol Template (rev.1-17-08) 
page 75 of 78 
Dear ……………., 
 
 
 
Thank you for your interest in our research. We are beginning a new research study to explore the 
efficacy of an experimental drug, idebenone, in primary progressive multiple sclerosis. This study 
will take place at the National Institutes of Health, within the National Institute of Neurological 
Disorders and Stroke (NINDS). The study will be a randomized, blinded, placebo-controlled trial. 
 
We are seeking patients age 18-65 who have a diagnosis of primary progressive multiple sclerosis 
and who are not on immunomodulatory treatment. The study will last three years. Upon entering the 
study, patients will undergo serial MRI studies and clinical examinations which will be performed 
monthly for 3 months. Following this, patients will enter a pre-treatment phase of 12 months 
duration, during which clinical visits, MRI imaging and blood work will be performed every 6 
months.  Patients will then be randomized to receive treatment or placebo, with continued 
monitoring by clinical exam, MRI and bloodwork at scheduled intervals. In addition to the MRI 
imaging and clinical exams, participating patients will undergo a spinal tap at the time of enrollment 
and again after one year of treatment. 
 
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 and also cell membrane antioxidant. Idebenone has been extensively studied as a potential 
therapeutic agent for neurological diseases, including Alzheimer’s disease, Huntington’s disease, 
Friedrich’s ataxia 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 these 
studies, the most frequently cited adverse effects that occurred more often in the idebenone group 
were gastrointestinal symptoms such as anorexia, nausea, and diarrhea. 
 
If you know of any patients who might qualify for this study, we would greatly appreciate if you 
could provide the patient and their family member/caregiver with a copy of the enclosed 
advertisement so that they can contact us. We also plan to meet with as many professionals as 
possible to describe this study in further detail. Please contact us at 301-496-0064 if you would like 
further information regarding this study. 
 
Sincerely, 


CNS IRB Protocol Template (rev.1-17-08) 
page 76 of 78 
Dear ……………., 
 
 
 
Thank you for your interest in our research. We are beginning a new study to explore the efficacy of 
an experimental drug, idebenone, in primary progressive multiple sclerosis. This study will take 
place at the National Institutes of Health, within the National Institute of Neurological Disorders and 
Stroke (NINDS). The study will be a randomized, blinded, placebo-controlled trial; this means that 
patients who qualify and decide to participate will either receive the study drug or a placebo, and 
neither the patient nor the investigators will know who is on the drug and who is not until the end of 
the study. Assignment to receive drug or placebo will be random. 
 
A key feature of MS is demyelination, which is the loss of the insulating myelin sheath which 
usually protects brain and spinal cord cells and allows them to communicate effectively with other 
brain and spinal cord cells. One of the hypotheses explaining the continuous worsening of 
symptoms in progressive forms of MS is that when demyelination occurs, brain cells require much 
more energy to maintain their function. Eventually, the cells are unable to maintain these high 
energy demands and die. 
 
The drug we will be investigating in this clinical trial, idebenone, can improve the function of 
mitochondria – which are the power houses of cells, responsible for generating energy. As such, 
idebenone can improve energy production and use in cells, and may be able to prevent the loss of 
nerve cells in MS. In addition, idebenone is a potent antioxidant, which may also help in reducing 
the loss of nerve cells. 
 
Idebenone is an oral medication and has been extensively studied in several neurological diseases. 
In these clinical trials, idebenone was found to be safe and well tolerated. In these studies, the most 
frequent side effects were gastrointestinal symptoms such as loss of appetite, nausea, and diarrhea. 
 
If you have a diagnosis of primary progressive multiple sclerosis, are between18-65 years of age, 
and are not on any immunomodulatory treatment, you may be eligible. The study will last three 
years. Upon entering the study, you would undergo a series of MRIs and clinical examinations 
which will be performed monthly for 3 months. This is part of a pre-treatment phase of 12 months, 
during which clinical visits, MRI imaging and blood work will then be performed at 6 months and 
one year. This baseline period is critical in order to be able to interpret the final results of trial. After 
this one year baseline, you would be randomized to receive treatment or placebo, and would have 
continued monitoring by clinical exam, MRI and bloodwork at scheduled intervals. In addition to the 
MRI imaging and clinical exams, all participating patients will undergo a lumbar puncture at the 
time of enrollment and again after one year of treatment. 
 
If you would like further information regarding this study, please call us at 301- 496-0064. Travel or 
transportation assistance may be discussed with a member of our research team. 
 
Sincerely, 


CNS IRB Protocol Template (rev.1-17-08) 
page 77 of 78 
 
 
09-N-0197 Multiple Sclerosis 
Social Media 
Facebook and Twitter Draft 
Date: 01/24/2012 
 
NIH researchers are studying primary-progressive multiple sclerosis to see if they can stop or slow 
symptoms with certain medications. Learn more: clinicaltrials.gov, study #09-N-0197 or call the 
NIH Clinical Center Patient Recruitment office Toll-Free: 1-800-411-1222 or TTY: 1-866-411- 
1222. 


CNS IRB Protocol Template (rev.1-17-08) 
page 78 of 78 
 
 
23.7 MS Patient Questionnaire 
 
Attached in PTMS. 
 
23.8 Investigator’s Brochure 
 
Attached as pdf file or hard copy 
 
 
23.9 Clinical trial agreement (CTA) 
Attached as pdf file or hard copy 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
Double Blind Placebo-Controlled Phase I/II Clinical Trial of Idebenone in Patients with 
Primary Progressive Multiple Sclerosis (IPPoMS) 
 
 
 
Study code: 09-N-0197 
 
Study Acronym: IPPoMS 
 
 
 
 
 
 
FINAL VERSION 1.0 
14 February 2018 
 
 
 
STATISTICAL ANALYSIS PLAN 




 
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14 Feb 2018 
Study: IPPoMS 
 
Table of Contents 
 
1 
Abbreviations................................................................................................................................. 4 
2 
Introduction ................................................................................................................................... 5 
3 
Study objectives and hypotheses ................................................................................................... 5 
3.1 
Original goals of the study ...................................................................................................... 5 
3.2 
Adaption of objectives and endpoints ..................................................................................... 6 
3.3 
Statistical hypothesis ............................................................................................................... 6 
4 
Endpoints ....................................................................................................................................... 7 
4.1 
Primary safety endpoints ......................................................................................................... 7 
4.2 
Primary efficacy endpoint ....................................................................................................... 7 
4.3 
Secondary efficacy endpoints .................................................................................................. 8 
4.4 
Exploratory efficacy endpoints ............................................................................................... 9 
5 
Design and type of the study ........................................................................................................ 10 
6 
Sample size considerations .......................................................................................................... 10 
6.1 
Original sample size calculation ........................................................................................... 10 
6.2 
New sample size calculation ................................................................................................. 11 
7 
Statistical hypotheses ................................................................................................................... 12 
8 
Analysis sets ................................................................................................................................ 12 
9 
General statistical considerations ................................................................................................ 13 
10 
Demographic and other Baseline characteristics ...................................................................... 13 
11 
Concomitant medication/treatment .......................................................................................... 14 
12 
Extent of exposure to study medication ................................................................................... 14 
13 
Analysis of efficacy .................................................................................................................. 14 
13.1 
Primary endpoint: AUCs of CombiWISE scores ........................................................... 14 
13.1.1 
Primary analysis ............................................................................................................. 14 
13.1.2 
Sensitivity analyses ........................................................................................................ 15 
13.2 
Secondary Endpoints ...................................................................................................... 16 
14 
Analysis of safety ..................................................................................................................... 17 
14.1 
Disposition ..................................................................................................................... 17 
14.2 
Adverse events ............................................................................................................... 17 
15 
Execution of statistical analyses ............................................................................................... 17 
16 
Changes in the planned analyses .............................................................................................. 17 
17 
Hardware and software ............................................................................................................. 18 
18 
References ................................................................................................................................ 18 
 


 
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1 
Abbreviations 
25FW 
25 Foot Walk 
9HPT 
9 Hole Peg Test 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AUC 
Area Under the Curve 
BPF 
Brain Parenchymal Fraction 
CNS 
Central Nervous System 
CSF 
Cerebrospinal Fluid 
EDSS 
Expanded Disability Status Scale 
ITT 
Intent-To-Treat 
MAR 
Missing At Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Mission Not At Random 
MRI 
Magnetic Resonance Imaging 
MSFC 
MS functional composite 
NIH 
National Institutes of Health 
NINDS 
National Institute of Neurological Diseases and Stroke 
OCT 
Optical Coherence Tomography 
PP-MS 
Primary Progressive Multiple Sclerosis 
RR-MS 
Relapsing Remitting MS Multiple Sclerosis 
SAP 
Statistical Analysis Plan 
SNRS 
Scripps Neurological Rating Scale 
SP-MS 
Secondary Progressive Multiple Sclerosis 
SDMT 
Symbol Digit Modality Test 
 


 
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2 
Introduction 
This Statistical Analysis Plan (SAP) describes the statistical analysis as it is foreseen prior to 
breaking the blind of this study. The SAP will serve as a compliment to the study protocol and 
supersedes it in case of differences. Any deviations from the statistical analyses planned in the most 
recent version of the study protocol (version 27, 13 April 2017) are documented in this SAP and any 
major deviations from the statistical analyses planned in the SAP will be documented in the final 
clinical study report.  
3 
Study objectives and hypotheses 
The goal of this study is to assess the safety, therapeutic efficacy, and mechanism of action of 
idebenone in primary-progressive multiple sclerosis (PP-MS) patients. We hypothesize that 
idebenone, through its combined effect on facilitation of mitochondrial metabolism and limitation 
of oxygen radical-induced central nervous system (CNS) damage, will inhibit CNS tissue 
destruction in PP-MS patients. 
3.1 
Original goals of the study 
The following goals were defined in the original study protocol. 
The primary goals of the study were defined as: 
1. To determine the safety of long-term (24 months) idebenone therapy at 2250 mg/day in patients 
with PP-MS. 
2. To determine the efficacy of idebenone versus placebo in inhibiting individualized rates of CNS 
tissue destruction as measured by clinical biomarkers and quantitative imaging biomarker of 
brain atrophy (i.e. ventricular volume). 
The secondary goals of the study were defined as:  
1. To investigate the mechanism of action of idebenone in PP-MS. 
2. To determine/define biomarkers of mitochondrial dysfunction and oxidative damage in PP-MS 
patients. 
3. To define biomarkers indicative of therapeutic effect of idebenone on mitochondrial dysfunction 
and on limiting oxidative damage in PP-MS patients. 
4. To collect longitudinal data in the placebo arm that will allow us to evaluate whether the 
assumptions on which we based our primary analysis (i.e. that the CNS tissue destruction is 
intra-individually linear, but inter-individually different within 3 year time period) are correct or 
not. This will allow us to calculate more precise sample size/power calculations for future 
neuroprotective trials in PP-MS. 


 
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3.2 
Adaption of objectives and endpoints 
The study was planned to use an adaptive trial design. The trial started with a pre-treatment baseline 
period of at least 12 months, where magnetic resonance imaging (MRI), clinical and biomarker 
measurements were collected in all patients for two purposes: 
 To obtain longitudinal quantitative MRI, clinical and electrophysiological data in untreated PP-
MS patients before randomization. These data will be utilized for the selection of the most 
sensitive primary outcome measure. This will be done on the first 30 patients and subsequent 
analysis will be used for selection of the most sensitive primary outcome measure and for 
adjusting sample size calculation if the primary outcome measure is different than brain atrophy 
measured by SIENA methodology. 
 To obtain patient-specific pre-randomization baseline for all collected outcome measures. This 
is expected to increase the statistical power of the study ((Murray et al. 2005, Young et al. 2005, 
Frost et al. 2008). In the study protocol, the following two assumptions were made: 1) CNS 
tissue destruction develops in a linear manner within a 3-5 year time-frame in the majority of 
PP-MS patients and 2) the slopes of the linear development of CNS tissue destruction differ 
among individual patients. Based on these two assumptions, the trial design will allow 
adjustment for the individualized rates of development of CNS tissue destruction. 
The aim of the adaptive trial design was to allow the selection of the most robust (i.e. most sensitive 
and most accurate) primary outcome measure for the final analysis. Based on the analysis of the pre-
treatment phase, the focus of the study shifted from the analysis based on MRI to analysis of clinical 
endpoints and composite scores. For more details, see section 6 of this SAP. 
3.3 
Statistical hypothesis 
The primary goal of this study is to determine the safety of long-term (24 months) idebenone 
therapy at 2250 mg/day in patients with PP-MS. 
The primary efficacy objective of this final analysis of the IPPoMS study is to investigate the effect 
of idebenone compared with placebo on the disability progression using the CombiWISE score with 
the following statistical hypotheses: 
H0: 
There is no difference between idebenone and placebo in the disability progression during 
the 2-year treatment period. 
HA:  
The disability progression in idebenone-treated patients is slower than in the placebo-treated 
patients during the 2-year treatment period. 
In addition to the difference between the treatment groups, the within-group changes in each 
treatment group will be evaluated by comparing the disability progression during the pre-treatment 
period to the progression during the treatment period. 


 
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4 
Endpoints 
4.1 
Primary safety endpoints 
The primary safety endpoints include premature discontinuations of study treatment, serious adverse 
events and all adverse events. For more details on the analysis of the safety data, see Section 12 of 
this SAP. 
4.2 
Primary efficacy endpoint 
The primary endpoint of this study is the rate of disability progression, assessed with Area Under 
the Curve (AUC) of the CombiWISE scores during the 2-year treatment period. The CombiWISE 
data collected during the 1-year pre-treatment period will be utilized by including both the pre-
treatment disability progression (AUC of CombiWISE scores during the pre-treatment period) and 
severity of the disability (CombiWISE score at pre-randomization baseline) as covariates in the 
statistical analysis. 
Derivation of CombiWISE scores 
CombiWISE is a combinatorial weight-adjusted disability score ranging from 0 to 100, where 0 
represents no disability and 100 maximum disability. It was developed based on the pre-determined 
analysis of 58 candidate outcomes collected in 1 year pre-treatment phase in training (IPPOMS1) 
and validation (IPPOMS2 and RIVITALISE) cohorts, as described in detail in a recent publication 
(Kosa, Ghazali et al. 2016). The CombiWISE score is a composite of four scales: expanded 
disability status scale (EDSS), Scripps neurological rating scale (SNRS), 25 foot walk (25FW) and 9 
hole peg test (9HPT) performed on non-dominant hand (NDH- 9HPT). The score is calculated with 
the following formula: 
CombiWISE     =  
33.166 + 3.803 x EDSS – 0.407 x SNRS + 
2.409 x log(25FW) + 18.056 x 25FWfail +  
1.305 x log(NDH-9HPT) + 10.751 x NDHfail. 
The components of the CombiWISE are derived as follows: 
 EDSS: the EDSS score (scored as 1.0, 1.5, …, 10.0) is recorded as such and requires no 
derivation.  
 SNRS: the SNRS score, which can range between 100 (normal status) and 0 (worst possible 
score) is recorded as calculated by the investigator. 
 log(25FW) is log2 of the average of two attempts on 25FW, or 0 if at least one attempt is 
unsuccessful. 
 25FWfail is1 if patient failed either of the two attempts on 25FW; otherwise 0. 
 log(NDH-9HPT) is log2 of average of two attempts on 9HPT with non-dominant hand, or 0 if at 
least one attempt is unsuccessful. 


 
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 NDHfail is 1 if patient failed either of the two attempts on 9HPT with non-dominant hand; 
otherwise 0. 
Calculation of AUC values 
The CombiWISE is assessed at the following time points: 
 Pre-treatment baseline phase: Months -12, -6 and 0 
 Double-blind phase: Months 6, 12, 18 and 24. 
The AUC values will be calculated for both the pre-treatment baseline phase (from Months -12, -6 
and 0) and for the double-blind phase (from Months 0, 6, 12, 18 and 24). For each of the AUC 
values, at least two valid CombiWISE scores during the phase in question are required. If less than 
two values AUC values are available for any of the two phases, the AUC score will be set as 
missing. In addition, if the first value of the phase in question is missing, the CombiWISE score will 
be set as missing. 
Linear trapezoidal method will be used to calculate the AUC values. For each time interval (time 
between two visits), the AUC is calculated as 0.5 x (Y1+Y2) x (t2-t1), where Y1 and Y2 are the 
CombiWISE scores (as changes from baseline) at the beginning and end of the interval and t1 and t2 
are the start and stop dates of the interval. The time will be converted to years (number of days 
divided by 365.25) for the AUC calculation. The baseline for the pre-treatment period is the visit 
scheduled at the beginning of the pre-treatment period (Month -12) and the baseline for the double-
blind period is the visit at Month 0. 
In case of intermittent missing data between two non-missing visits, the formula for linear 
trapezoidal method will be used as such. In case of premature discontinuations, the AUC values 
after the time of discontinuation will be set as missing. 
After these calculations, the AUC values calculated for the different periods will be summed over 
the pre-treatment baseline phase (Month -12 to Month 0) and over the double-blind phase (Month 0 
to Month 24). Because the follow-up times can vary from patient to patient, the AUC values will be 
made comparable by scaling them using the follow-up time. The scaling will be done by dividing 
the AUC value by the square of the actual duration of each of the phases. For the pre-treatment 
baseline phase, the AUC will be scaled as AUC/[t0-t-12)2], where t0 and t-12 are the dates of visits at 
Month 0 and Month -12, respectively. For the double-blind phase, the AUC will be scaled as 
AUC/[tlast-t0)2], where tlast and t0 are the dates of the last visit and the visit at Month 0, respectively. 
Similarly as above, the time will be converted to years. The scaled AUCs will be used in all 
statistical analyses.  
4.3 
Secondary efficacy endpoints 
All components of the primary endpoint will be analyzed as secondary endpoints: 
 EDSS: the EDSS score (scored as 1.0, 1.5, …, 10.0) is recorded as such and requires no 
derivation.  


 
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 SNRS: the SNRS score, which can range between 100 (normal status) and 0 (worst possible 
score) is recorded as calculated by the investigator. 
 25 foot walk (25FW): 25FW is the average of two attempts of walk test. In case any of the two 
attempts is unsuccessful, 25FW will be set as missing. This endpoint will be primarily analyzed 
without any transformation to facilitate the interpretation, but in case the data are skewed, 
additional analyses may be conducted by log2 transformation of the average. 
 9 hole peg test (9HPT) performed on non-dominant hand (NDH-9HPT): NDH-9HPT is the 
average of the two attempts on 9 hole peg test. In case any of the two attempts is unsuccessful, 
NDH-9HPT will be set as missing. This endpoint will be primarily analyzed without any 
transformation to facilitate the interpretation, but in case the data are skewed, additional 
analyses may be conducted by log2 transformation of the average. Furthermore, similar analyses 
will be conducted for data based on the dominant hand and the average of the non-dominant and 
dominant hands. 
In addition, the following variables will be analyzed as secondary endpoints: 
 Neuroimaging outcomes: Inhibition of individualized rates of enlargement of ventricular 
volume: enlargement of segmented volume of lateral and 3rd ventricles. This was the primary 
endpoint of the initial protocol version. 
 EDSS-plus, as defined in (Cadavid, Cohen et al. 2017): EDSS-plus is defined as progression on 
at least 1 of 3 components (EDSS, 25FW, and/or NDH-9HPT) confirmed ≥24 weeks apart and 
with a ≥20% minimum threshold change for 25FW and NDH-9HPT. As the visits in this study 
are scheduled to be conducted with 6 month intervals, a confirmation at the next scheduled visit 
is considered sufficient, even if the time between the visits would be less than 24 weeks due to 
visit scheduling. 
4.4 
Exploratory efficacy endpoints 
 Neuroimaging: Progression of retinal nerve fiber thinning as detected by optical coherence 
tomography (OCT). 
 Cognitive dysfunction as assessed by Symbol Digit Modality Test (SDMT). 
 Neurological disability as assessed by MS functional composite (MSFC) scale. 
 Biological/immunological endpoints: 
o Changes in cerebrospinal fluid (CSF) albumin quotient (ROS are known to disrupt 
endothelial tight junctions; which may be measured as increase in CSF albumin quotient) 
o Changes in CSF biomarkers of activated/pro-inflammatory microglia/monocytes 
(sCD14) 
o Changes in CSF lactate/pyruvate ratio, as a biomarker of extra-mitochondrial glucose 
metabolism  


 
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o Changes in CSF growth differentiation factor 15 (GDF15), as a putative biomarker of 
mitochondrial dysfunction 
o Changes in CSF neurofilament light chain (NF-L), a biomarker of axonal damage. 
5 
Design and type of the study 
This is a Phase I/II safety and efficacy trial with an adaptive trial design: one year of pre-treatment 
baseline period serves the dual purpose of collecting patient-specific biomarkers of disease 
progression and collecting longitudinal neuroimaging and clinical data for selection of primary 
outcome measures. This baseline period is then followed by a double-blind, idebenone versus 
placebo treatment phase for a total of 2 years. 
6 
Sample size considerations 
6.1 
Original sample size calculation 
Assumptions for the initial sample size calculation were: 
1. Rate of development of CNS atrophy in early PP-MS patients is equivalent, or greater than the 
rate of development of brain atrophy in relapsing remitting MS (RR-MS) patients and similar to 
rate of development of brain atrophy in secondary progressive MS (SP-MS) patients (Fox, 
Jenkins et al. 2000). 
2. Rate of development of brain atrophy in PP-MS patients varies considerably between 
individuals, ranging from +1.8%/year to -3.6%/year (Mean -1.03%, SD 1.3%) for brain 
parenchymal fraction (BPF) and from +1.7%/year to -4.2%/year (Mean -1.50%, SD 1.6%) for 
grey matter fraction (Sastre-Garriga, Ingle et al. 2005). 
3. Within 5 years of follow-up, the rate of development of brain atrophy, ventricular atrophy, 
cervical cord atrophy and the rate of accumulation of T2LV and T1LV seem to be significantly 
more stable intra-individually than inter-individually (Ingle, Stevenson et al. 2003), although the 
intra-individual coefficient of variation values are not provided in this publication. 
4. Due to these inter-individual differences in the rate of accumulation of brain atrophy, the 
reported sample size estimates in SP-MS patients utilizing changes in brain atrophy detected by 
SIENA methodology applied to 1.5T MRI scans, indicates that to detect 50% therapeutic effect 
in a therapeutic trial of 2 year duration with 80% power and 5% significance, the minimum 
number of subjects is 33 per arm (Altmann, Jasperse et al. 2008). The relevant data from this 
recent publication using SIENA methodology for calculation of whole brain atrophy in SP-MS 
patients by Altmann, Jasperse et al. are summarized in the table below (selected conditions for 
current trial are highlighted) 
 
Duration 
of therapy  
Expected 
therapeutic 
effect: 
90% power 
80% power 
30% 
40% 
50% 
30% 
40% 
50% 


 
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effect 
effect 
effect 
effect 
effect 
Effect 
1 year 
Min# subj/arm 
212 
120 
77 
158 
89 
57 
2 years 
Min# subj/arm 
123 
69 
45 
92 
52 
33 
3 years 
Min# subj/arm 
107 
60 
39 
80 
45 
29 
Collecting at least 12 months of pre-treatment baseline volumetric MRI data (i.e. rate of 
development of brain atrophy, gray matter atrophy, ventricular enlargement and spinal cord atrophy) 
and clinical data will allow us to calculate individualized rates of CNS tissue destruction and 
disability progression. Based on the data described under 1-3, employing such individualized rates 
of development of CNS tissue destruction for the determination of therapeutic effect between active 
drug and placebo is expected to significantly increase the power for detection of group differences, 
effectively decreasing the number of subjects necessary for demonstrating therapeutic efficacy of an 
experimental neuroprotective therapy. Additionally, employing more sensitive methodology (3T 
magnet strength) and novel analyses (e.g. volumetric analysis of entire cervical spinal cord) may 
further increase power for detection of group differences. 
However, longitudinal data on a PP-MS cohort that could be utilized for exact sample size analysis 
was not available and the only longitudinal data that were published at the inception of this trial and 
could be utilized for sample size calculation were those based on whole brain atrophy as detected by 
SIENA methodology. Therefore, we used published sample size estimates for the SP-MS patients 
(Altmann, Jasperse et al. 2008) and targeted patient accrual to reach 66 treated patients (33 per arm). 
6.2 
New sample size calculation 
In 2016, a pre-determined analysis of the 58 outcome measures collected in 1 year pre-treatment 
baseline period on first ≥30 IPPOMS patients was performed and published and validated these 
findings with the 2 validation cohorts consisting of 34 remaining IPPOMS patients and 29 SP-MS 
patients from RIVITALISE trial (Kosa, Ghazali et al. 2016). This analysis demonstrated that above-
stated assumptions or the original sample size calculation were incorrect, that brain atrophy 
measured by SIENA technology was not more sensitive than clinical outcomes. Instead, based on 
this pre-defined analysis we selected CombiWISE as primary outcome and brain ventricular atrophy 
measured by LesionTOADS methodology as secondary outcome. 
Up to 85 subjects are planned to be recruited based on current sample size calculation, to account 
for 20% drop-out and final number of treated subjects 33 per arm (66 total). These recruitment 
numbers were already achieved and interim analysis of the blinded data of the outcomes showed 
enhanced, rather than diminished power of new primary outcome (CombiWISE) in comparison to 
original default primary outcome (Brain atrophy measured by SIENA). 
The new power analysis for CombiWISE, EDSS and ventricular volume change has been published 
for both within-group and between-group designs (Kosa, Ghazali et al. 2016). Using absolute 
change in the CombiWISE AUC outcome determined from the pre-treatment baseline data in 
IPPOMS cohort, following power calculation for AUC was derived: 
 


 
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Drug 
effeect 
CombiWISE 
AUC 
(untreated) 
CombiWISE 
AUC 
(treated) 
CombiWISE 
AUC 
(difference) 
Actual 
Power 
N Pairs 
Distribution 
Normal 
50% 
51.24 
25.62 
25.62 
80.7 
28 
Method 
Exact 
45% 
51.24 
28.18 
23.06 
80.6 
34 
Number of Sides 
2 
40% 
51.24 
30.75 
20.50 
80.2 
42 
Standard Deviation 
46.2 
35% 
51.24 
33.31 
17.94 
80.7 
55 
Correlation 
0.5 
30% 
51.24 
35.87 
15.37 
80.1 
73 
Nominal Power 
0.8 
25% 
51.24 
38.43 
12.81 
80.4 
105 
Null Difference 
0 
20% 
51.24 
40.99 
10.25 
80.2 
162 
Alpha 
0.05 
This demonstrates that substituting default primary outcome (Brain atrophy measured by SIENA 
(Altmann, Jasperse et al. 2008)) with CombiWISE primary outcome will significantly enhance 
power of the IPPOMS trial from estimated 80% of power to detect at least 50% drug effect to more 
than 80% power to detect at least 40% drug effect. Additionally, while brain atrophy measured by 
SIENA does not correlate with clinical outcomes, CombiWISE has strong, highly significant 
correlations with EDSS, which is used for regulatory approval of MS treatments, both in cross-
sectional and longitudinal paradigms (i.e. yearly change in CombiWISE correlated with yearly 
change in EDSS). Therefore, CombiWISE can predict efficacy on EDSS outcome, but does so in 
considerably smaller cohorts and/or trials of shorter duration (Kosa, Ghazali et al. 2016). 
7 
Statistical hypotheses 
The primary goal of this study is to determine the safety of long-term (24 months) idebenone 
therapy at 2250 mg/day in patients with PP-MS. 
The primary efficacy objective of this final analysis of the IPPoMS study is to investigate the effect 
of idebenone compared with placebo on the disability progression using the CombiWISE score with 
the following statistical hypotheses: 
H0: 
There is no difference between idebenone and placebo in the disability progression during 
the 2-year treatment period. 
HA:  
The disability progression in idebenone-treated patients is slower than in the placebo-treated 
patients during the 2-year treatment period. 
In addition to the difference between the treatment groups, the within-group changes in each 
treatment group will be evaluated by comparing the disability progression during the pre-treatment 
period to the progression during the treatment period. 
8 
Analysis sets 
The data will be analyzed using at least the following datasets: 


 
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 
Intention-To-Treat (ITT) Population 
The Intent-To-Treat (ITT) population includes all randomized patients who have at least one post-
baseline (post Month 0) efficacy assessment. The patients will be grouped by the randomized 
treatment group. The ITT population will be used for the analysis of the efficacy endpoints. 
 
Completer Population 
The Completer population includes all randomized patients who completed the study and have valid 
efficacy assessments up to Month 24. The patients will be grouped by the randomized treatment 
group. The Completer population will be used for the secondary analysis of the efficacy endpoints. 
 
Pre-Treatment Phase Safety Population 
The Pre-Treatment Phase Safety population includes all patients who were enrolled to the study. 
The patients will be grouped by the treatment actually received in the Double-Blind Phase. The Pre-
Treatment Safety population will be used for the safety analysis of the pre-treatment baseline phase. 
 
Safety Population 
The Safety population includes all patients who got at least one dose of idebenone or placebo during 
the double-blind phase. The patients will be grouped by the treatment actually received. The Safety 
population will be used for the analysis of the safety data from the double-blind phase. 
9 
General statistical considerations 
In general, all data collected in the study database will be summarized by descriptive statistics. 
Continuous data will be summarized using the mean, standard deviation, standard error of the mean, 
median, minimum and maximum. Categorical data will be presented in contingency tables with 
frequencies and percentages. 
All hypotheses tests and confidence intervals in this report are two-sided and statistical significance 
will be declared for p-values below 5%, unless specified otherwise. This study has one pre-defined 
endpoint. Due to the exploratory nature of the study, no adjustment of the statistical significance 
level due to multiple secondary endpoints will be done. 
10 Demographic and other Baseline characteristics 
Demographic and Baseline characteristics will be presented with descriptive statistics for the ITT 
and Safety populations. These characteristics will be based on the assessment at the study entry 
(Month -12).  
The following endpoints will be summarized: 
 Baseline age 
 Age at disease onset 


 
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 Time since disease onset at baseline 
 Body Mass Index 
 History of mononucleosis 
 European ancestry 
 Family history of MS 
 Smoking history 
11 Concomitant medication/treatment 
All concomitant medications will be listed. 
12 Extent of exposure to study medication 
The extent of exposure to the study medication will be summarized by tabulating the following: 
 The number of patients exposed to study treatment (idebenone or placebo) during the double-
blind phase. 
 Duration of exposure (days): exposure to study treatment (idebenone or placebo), where the 
duration is calculated as date of last dose minus date of first dose during the double-blind phase. 
In addition, the duration of follow-up during the pre-treatment baseline phase will be calculated 
as date of first dose during the double-blind phase minus date of first visit (Month -12). The 
durations will be summarized with descriptive statistics separately for pre-treatment baseline 
phase and for the double-blind phase. 
 Total exposure to study treatment, expressed as person years (sum of duration of exposure to 
study treatment over all patients in days divided by 365.25, classified by treatment group). The 
total exposure will be calculated for the double-blind phase and summarized by treatment group. 
For the pre-treatment baseline phase, the total follow-up time will be calculated similarly, and 
summarized by treatment group and overall. 
13 Analysis of efficacy 
13.1 
Primary endpoint: AUCs of CombiWISE scores 
13.1.1 Primary analysis 
The AUCs of the CombiWISE scores will be analyzed using an Analysis of Covariance (ANCOVA) 
model with the AUC of the pre-treatment CombiWISE scores, Baseline (Month 0) CombiWISE 
score and Baseline (Month 0) age as covariates.  


 
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The incomplete data in the CombiWISE scores during the 2-year treatment period will be managed 
with the single imputation algorithm defined in Section 4.2. 
In addition to the primary analysis comparing the between-group difference, the within group 
changes will be tested using paired t-test within each treatment group. The t-tests will be based on 
Satterthwaite's approximation. 
The analyses will be conducted both using the ITT population (primary) and Completer population 
(secondary).  
13.1.2 Sensitivity analyses 
The following sensitivity analyses will be conducted using the ITT population. 
 Random coefficient regression model: random coefficient regression model with random 
intercept and slope will be fitted to the response data. All CombiWISE scores will be included 
as response variables in the model. In order to model random intercept and slope for pre-and 
post-treatment separately, factor period (pre vs. post) will be created: pre-treatment (Month -12 
to 0) vs. post-treatment (Month 0 (+1 day) to 24). Exact clinic dates for each patient will be used 
as Time in the model. In addition to the random slopes and intercepts, the model will include the 
fixed effect for treatment group (idebenone or placebo), period (nested within treatment), 
interaction between Month and period (nested in treatment) and covariates: Baseline (Month 0) 
CombiWISE score and Baseline age. The effect of treatment and period (nested within 
treatment) factors will be used to examine the hypothesis of four intercepts are same (intercepts 
for placebo group at pre- and post-treatment, intercepts for idebenone group at period pre- and 
post-treatment). The interaction between Time and period (nested within treatment) will be used 
to examine the hypothesis of four slopes are same (slopes for placebo group at pre- and post-
treatment, slopes for idebenone group at period pre-and post-treatment). This analysis includes 
only the observed CombiWISE scores as response variables and as the model can manage 
incomplete data, no imputation will be done. 
 Mixed Model for Repeated Measures (MMRM): The change from Baseline to Month 24 in the 
CombiWISE scores will be compared between the idebenone and placebo groups using 
MMRM. The observed CombiWISE scores at Months 6, 12, 18 and 24 will be used as response 
variables in the MMRM. The treatment group, visit and interaction between treatment group and 
visit will be included as fixed factors. The pre-treatment slope (calculated with linear regression 
for each patient) and the baseline CombiWISE score will be included as covariates. An 
unstructured covariance structure will be applied for MMRM. The denominator degrees of 
freedom will be computed using the Kenward-Roger method. The difference between the groups 
at Month 24 (and at the other post-baseline visits) and within-group changes within each group 
will be estimated from the MMRM. 
 Multiple Imputation (MI) assuming data missing at random (MAR) will be done to compare 
idebenone to placebo. MI techniques based on Pattern Mixture Models (PMM) will be applied 
in this sensitivity analysis. This methodology will structure data based on the missing data 
patterns. The method will be based on a missingness pattern having a monotone structure, i.e. if 
among the observations during the 2-year treatment period one CombiWISE score is missing, all 
subsequent scores after this missing value will also be treated as missing. For patients with 
intermittent missing values, before performing MI based on the PMM, it will be necessary to 


 
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create a monotone missingness pattern. Intermittent missing values will be imputed using the 
Markov Chain Monte Carlo (MCMC) methodology which assumes a multivariate normal 
distribution over all variables included in the imputation model. This first MI step is planned to 
be repeated 1000 times, creating 1000 different datasets with a monotone missing data structure. 
Seed value of 1995 will be used in the MI procedure. The imputation is based on the missing at 
random (MAR) assumption, i.e. the missing data are assumed to follow the same model as the 
other patients in their respective treatment arm. 
After this, the remaining missing data will be imputed using a method for monotone 
missingness, also based on the MAR assumption. Thus, for each of the 1000 created dataset 
with a monotone missing data pattern, missing values will be imputed based on a sequential 
procedure reflecting the monotone missing data pattern. Patients with the first missing value 
occurring at Month 3 will have their missing Month 3 value replaced by an imputed value from 
a regression model with treatment group, Month 0 CombiWISE score, the pre-treatment slope 
and baseline age as explanatory variables. In the next step, patients with their Month 6 value 
missing will have their missing Month 6 value replaced by an imputed value from a regression 
model with all factors defined above and Month 3 value as explanatory variables.  Similar 
procedure will be used to replace the missing values at all subsequent visits. 
The imputed datasets generated with the approach described above do contain only non-missing 
values and are used as input in the model for the sensitivity analysis of the primary outcome 
variable. Random coefficient regression models similar as described in Sensitivity Analysis 1 
will thus be run on each of the 1000 generated imputed datasets and the difference between the 
treatment groups will be estimated. Finally, the results from these analyses will be combined to 
derive an overall estimate of the treatment difference. In addition to the estimates, corresponding 
95% confidence intervals and p-values will be calculated. 
 Multiple Imputation assuming data missing not at random (MNAR) will be done to compare 
idebenone to placebo. Control group based assumption (Copy Reference imputation) will be 
used, i.e. the trajectories of the patients are assumed to follow the placebo group trajectories 
after the discontinuation. Methods similar to the procedure described above will be used to 
generate monotone missing data. After this, the missing data will be imputed sequentially for 
each visit (first Month 3, followed by all subsequent visits). Only the data from the control 
group (placebo group) will be used as input for each imputation of both treatment groups. 
13.2 
Secondary Endpoints 
Continuous secondary endpoints (other than the neuroimaging outcomes) will be analyzed using 
random coefficient regression models similar to the one defined above for the primary outcome 
variable. In addition, analyses using MMRM will be conducted as well, in order to estimate the 
treatment differences separately at each visit. The neuroimaging outcomes will be analyzed by 
calculating AUC values and using ANCOVA models, similar to the primary analysis. 
Categorical time-to-event endpoints (EDSS-plus) will be analyzed using Cox Proportional hazards 
models, with treatment group as a covariate. The patients who do not have an event during the study 
will be censored at the time of the last assessment of EDSS-plus. The exact number of days from the 
date of first dose to date of event or censoring will be used as endpoint.  
The ITT population will be used for the analysis of the secondary endpoints. 


 
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14 Analysis of safety 
The safety analyses will be conducted for the following study periods and treatment groups: 
 Pre-treatment baseline phase: untreated patients, classified by the treatment group in the double-
blind phase and overall 
 Double-blind phase: Idebenone treated patients versus placebo treated patients 
14.1 
Disposition 
Number of enrolled, randomized, completed and discontinued patients will be summarized. In 
addition, the reasons for discontinuations will be tabulated. The time to premature discontinuation 
will be illustrated with Kaplan-Maier plots. 
14.2 
Adverse events 
All Adverse Events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The treatment-emergent AEs (i.e., events which start or worsen during the study 
treatment) will be tabulated by treatment group (when applicable), system organ class and preferred 
term. Both subject counts (number of patients reporting the event at least once) and event counts 
(total number of reported events) will be calculated. The percentages out of all patients will be 
calculated for the subject counts. In addition, incidence rates will be calculated by dividing the event 
count by patient years of exposure to the study treatment (double-blind phase) or by duration of 
follow-up (pre-treatment baseline phase).  
In addition, the treatment-emergent AEs will be evaluated by severity grade and by relationship to 
the study treatment. The serious AEs will also be summarized. 
15 Execution of statistical analyses 
NINDS will be responsible for the final statistical analyses. Santhera Pharmaceuticals may support 
in conduction of the analyses, but in this case analyses have to be approved by the NINDS. 
16 Changes in the planned analyses 
This SAP defines the analyses planned in the protocol in more detail and introduces additional 
sensitivity analyses of the primary endpoint. In addition, the analyses of the secondary efficacy 
endpoints and safety data have been defined in more detail. 
The following minor change was done for the analysis of the primary endpoint. The AUC values 
will be scaled to the duration of the assessment period, instead of using the calculated AUC values 
as such (and by dividing the double-blind period AUC values by 4). This change was done prior to 
unblinding of the study and was deemed as minor and not requiring a protocol amendment.  


 
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17 Hardware and software 
Statistical analysis, tables and patient data listings will be performed with SAS® version 9.4 for 
Windows (SAS Institute Inc., Cary, NC, USA). 
18 
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