A Pilot Study to Treat Adults With Non-Alcoholic Steatohepatitis With Oral Idebenone
Phase: PHASE1
Conditions: Non Alcoholic Steatohepatitis, Fibrosis
Sponsor: Stanford University

A Pilot Study to Treat Adults with Non-Alcoholic 
Steatohepatitis with Oral Idebenone 
Study Protocol and Statistical Analysis Plan 
NCT04669158 
September 15, 2021 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
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6. PROTOCOL 
 
Title: A Pilot Study to treat adults with Non-Alcoholic Steatohepatitis with oral 
Idebenone 
 
 
Primary Investigator: 
Natalie J. Torok, MD, MSc 
Stanford School of Medicine, GI/ Hepatology 
Address: 300 Pasteur Drive 
 
Phone: 
 
 
 
 
 
 
 
Funding Sponsor: 
NIDDK  
Address; 21, Center Drive, Bethesda, MD 20892 
Phone; 
 
 
 
 
Study Product: 
 
Idebenone  (2-(10-hydroxydecyl)-5,6-dimethoxy-3-
methylcyclohexa-2,5-diene-1,4-dione) 
 
 
 
 
Protocol Date:  
January 7, 2021 
Amendment 1 Date: 
September 15, 2021 
 
 
 
 
IND Number: 
 
 
 
 
 
 
 
 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
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Protocol Synopsis 
Protocol Title 
A Pilot Study to treat adults with Non-Alcoholic Steatohepatitis with oral 
Idebenone 
Product 
Idebenone  (2-(10-hydroxydecyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-
diene-1,4-dione) 
Objective 
To evaluate the safety and tolerability of oral idebenone in adults with non-
alcoholic steatohepatitis (NASH) 
Secondary 
Objective(s) 
To explore the efficacy of oral idebenone in NASH patients, a) by 
assessing serum liver chemistries, and b) improvement in liver stiffness as 
assessed by MRE.  
Study Design 
Randomized, Double-blinded, prospective pilot study 
Study 
Population 
Adults of 18 years of age or older diagnosed with NASH Clinical Research 
Network NAFLD activity score (NAS) (NAS score >4, and/or fibrosis stage 
1-3) 
Number of 
Participants 
45, 1:2 randomization 
Duration of 
Participation 
~18 months 
Screening period: 1-4 weeks; Treatment period: 48 weeks; Post treatment 
monitoring period; 12 weeks (to monitor for adverse events and liver tests) 
Study Center 
Stanford Medical Center, and affiliated hepatology clinics.  
Dose Schedule 
Idebenone, initially 200mg by mouth (P.O.) once a day for 2 weeks, then 
200 mg twice a day for 2 weeks, then 3 times per day for the remainder of 
the study. If we observe no toxicity, we will continue with these doses for 
the treatment period.  
Reference 
Therapy 
The drug will be tested against placebo, that follows the same 
dosing/schedule, as above.  
Biomarkers 
Schedule 
Hepatic enzymes, CBC, serum metabolic panel: at 0, 2, 4, 6, 12, 24, 36, 
and 48 weeks during treatment period and at 4, and 12 weeks after the last 
dose Serum idebenone metabolite studies at 4, 24 and 48 weeks. 
Magnetic resonance elastography (MRE): at the time of enrollment, and at 
the time of completion at 48 weeks. 
FIB4 to assess fibrosis at 24w. (serum test) 
Serum peripheral mononuclear blood cells (PMBCs) at the 24 and 48 week 
blood draw will be collected to study target engagement. 
 
 
Statistical 
Methodology 
The study has sufficient sample size to provide preliminary safety profile 
and secondary outcome measures. This is based on the two group t-test 
for fold change assuming log-normal distribution (unequal n's) to detect 1.5 
kPa decrease in stiffness in the treatment group at the 0.05 level (2-sided) 
with 83% power. 
Estimated start: April 2021 
Estimated finish: December 2022 (includes 6 months observation period post study). 
 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
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6.1. 
Study Protocol 
BACKGROUND 
Nonalcoholic Steatohepatitis (NASH): NAFLD is characterized by the accumulation of 
fat droplets (steatosis) in the liver and is highly prevalent in the USA (24%) (1). 
Steatosis when accompanied by inflammation and fibrosis can lead to NASH, the more 
progressive form of the disease, that eventually culminates in cirrhosis and/or 
hepatocellular carcinoma (2). The rate of NASH doubled between 2005 and 2010, and 
soon NASH will be the most common cause of liver transplantation in the USA and 
worldwide (3). Currently, there is no FDA-approved medical therapy for NASH.  Obesity 
and type 2 diabetes mellitus (T2DM) are associated with more advanced stages of the 
disease and faster progression (4). Increased production of reactive oxidant species 
(ROS) is an early feature of NASH and is directly linked to fibrogenesis (5).  Of the 
ROS-generating enzymes in the liver, nicotinamide adenine dinucleotide phosphate 
(NADPH) oxidases (NOXs) emerged as major sources, and are implicated in the 
production of high levels of ROS during fibrogenesis (6-8).  
 
NADPH oxidase (NOX) and Src homology 2 domain containing collagen-related 
proteins (Shc): NOX family proteins transfer electrons donated by NADPH across 
biological membranes to form superoxide (O−2) (9). Our group has previously shown 
that NADPH oxidases (NOXs) are central sources of ROS in the liver (4). Hepatocytes, 
hepatic stellate cells (HSC) and macrophages express the phagocytic NOX2 (gp91phox) 
(22). During activation of NOX2, the regulatory subunit p47phox coordinates membrane 
translocation of the other subunits, assembling the active oxidase, and catalyzing the 
formation of superoxide (10).  Our group has identified for the first time that Src 
homology 2 domain containing collagen-related proteins (Shc) are able to bind to and 
activate NOX2, resulting in an oxidative burst (11).  Shc is encoded by SHC1 gene and 
has three isoforms, p46Shc, p52Shc and p66Shc (12).  The association between p52 
Shc and NOX2 provides a strong rationale for targeted treatment with idebenone that 
inhibits Shc and its association with NOX2, therefore preventing oxidative bursts.  (The 
results have been discussed in detail in this IND, section. 3.4).  
 
Idebenone: Idebenone was originally developed in 1985 Takeda Company Ltd. as a 
potent antioxidant for the treatment of Alzheimer's disease (13). Idebenone has been 
approved in Europe for the treatment of Leber’s hereditary optic neuropathy (LHON), an 
inherited disease characterized by progressive loss of sight in children and adolescence 
of 12 years and older (EMA/452944/2015, EMEA/H/C/003834).  
Idebenone’s anti-oxidant activity is linked to regulating NAD(P)H:quinone 
oxidoreductase-1 (NQO1). Additionally, it can induce generation of adenosine 
triphosphate (ATP) in the mitochondria by cytoplasmic-mitochondrial electron transfer to 
complex III, and reduce liver free fatty acids (FFAs) by acting as peroxisome 
proliferator-activated receptor alpha (PPAR-α) agonist, which in turn induces free fatty 
acid (FFA) β-oxidation.  Our group has proven its ability to inhibit p52Shc, and this 
mechanism is the target of this application. Through inhibition of p52Shc, as described 
above, idebenone inhibits the activation of NOX2, and therefore reduces oxidative 
stress in the liver. This in turn reduces inflammation and fibrosis in patients with NASH. 
Idebenone also improves insulin signaling and lipid peroxidation in mouse livers 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
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(Pharmacology is discussed in detail in the PD/PK section of this IND application) (11, 
14). 
 
Idebenone has been extensively studied as a potential therapeutic agent for 
neurological diseases, including Alzheimer’s disease, Huntington’s disease, Friedrich’s 
ataxia (FRDA) and multi-infarct dementia. In these clinical trials, different doses and 
regimens were employed, and in all of them idebenone was found to be safe and well 
tolerated. In phase I trials and dose escalation trials, no dose-limiting toxicity was 
observed up to the maximum dose tested (75 mg/kg) (18). In a double-blinded, placebo-
controlled trial in patients with Huntington’s disease, 100 patients were randomized to 
receive 90mg idebenone or placebo three times every day for 12 months. Ninety-one 
patients completed the study, and none of the patients left the trial due to adverse 
events attributed to idebenone (19). Data from the phase 2 and 3 clinical trials for 
Alzheimer’s disease, in which patients received 120mg, 240mg, or 360mg idebenone 
three times per day for up to 2 years, suggest a benign toxicity profile (20).  The most 
frequently cited adverse effects that occurred in the idebenone group were 
gastrointestinal symptoms such as anorexia, nausea and diarrhea. 
Idebenone demonstrated rapid absorption in the species tested (rat, mouse and dog). 
After a single dose, 91% was found to be absorbed in rats and 62% in dogs, with t-max 
occurring within 1 hour. However, due to a high first pass metabolism, less than 1% of 
parent idebenone reaches the systemic circulation. The terminal half-lives of total 
radioactivity in the plasma of rats and dogs after oral administration of [14C] idebenone 
were 4.5 and 15.4 hrs, respectively.  As idebenone has high first pass metabolism rate 
we opted for lower doses that are likely to have local hepatic effects.  Also, this will 
further diminish the possibility of systemic affects.   
 
HYPOTHESIS   
The overarching hypothesis is that idebenone is a well-tolerated and safe treatment in 
patients with NASH.  This Phase 1/2a study will provide the safety and tolerability data 
necessary to further advance the development of this therapeutic strategy.  We will 
collect serum biomarker and liver stiffness data that will help in gauging its efficacy. 
 
STUDY OBJECTIVES 
Primary objective: To assess the safety and efficacy of idebenone in adults with 
NASH.  
Secondary objectives: To evaluate changes in biomarkers of disease progression and 
liver stiffness in adults treated with Idebenone for 48 weeks compared to placebo: 
• Serum aminotransferases, and GGT levels  
• Fasting markers of insulin resistance (HOMA)  
• Lipid profile (triglycerides, HDL, LDL)  
• Liver stiffness, using MRE.  Will include MR-PDFF as well, to evaluate steatosis.   
• Idebenone Metabolites in NASH patients 
 
 
 
Protocol Design Schema 
Prior to Enrollment 
Total number of participants-45:  Obtain informed consent. Screen potential 
participants by inclusion and exclusion criteria; obtain full history, document. 
Obtain laboratory tests, and MRE as outlined in detail in Section 6.1.1.  

Pilot Study of Idebenone for NASH; PI: Torok, Natalie
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Visit 1.
Start
Visit 2
2 weeks
Visit 3
4 weeks
Visit 4
12 weeks
Visit 5
24 weeks
Visit 6
36 weeks
Visit 7
48 weeks
Visit 8
52 weeks
Visit 9
60 weeks
If it has been> 8 weeks since the "Screen/Baseline Assessment ": laboratory 
evaluation repeated, as outlined in 6.1.1.Study medications are distributed at 1 
capsule a day. 
Follow-up assessments of study endpoints and safety. Physical examination, 
serum and urine specimens will be collected as per 6.1.1 and AUDIT 
questionnaire done. 
Follow-up assessments of study endpoints and safety. Physical examination, 
serum and urine specimens will be collected as per 6.1.1 and AUDIT 
questionnaire done. If safe, medication dose will be increased to 3 capsules/day.
End of treatment assessment: 
safety, physical exam, serum, urine 
tests as per 6.1.1, AUDIT, MRE
Placebo Arm:
15 participants
Idebenone treatment arm: 
30 participants 
Follow-up assessments of study endpoints and safety. Physical examination, 
serum and urine specimens will be collected as per 6.1.1 and AUDIT 
questionnaire done. If safe, medication dose will be increased to 2 capsules/day. 
Randomize
Follow-up assessments of study endpoints and safety. Physical examination, 
serum and urine specimens will be collected as per 6.1.1 and FIB4 done.  We will 
collect PMBCs from the same blood draw. AUDIT questionnaire will be done. 
Follow-up assessments of study endpoints and safety.  Physical examination, 
serum and urine specimens will be collected as per 6.1.1 and AUDIT 
Follow-up assessments of study endpoints and safety. Physical examination, 
serum and urine specimens will be collected as per 6.1.1 and AUDIT 
questionnaire done. 
Follow-up assessments of study endpoints and safety. Physical examination, 
serum and urine specimens will be collected as per 6.1.1 and AUDIT 
questionnaire done. 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
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Study Design:   
This is a prospective phase 1/2a, randomized, double-blinded, placebo-controlled, 
single center study of safety and efficacy of oral idebenone in adults 18 years of age or 
older with non-alcoholic steatohepatitis (NASH). Following IRB approval and written 
informed consent, 45 participants will be enrolled in the study and randomized at a 1:2 
ratio on REDCap data capturing software. Participants will be randomized to two groups 
and receive the following capsules: placebo, idebenone at escalating doses of 200mg 
by mouth (P.O.) once a day for 2 weeks, then 200 mg twice a day for 2 weeks, then 3 
times per day for the remainder of the study (up to 48 weeks). Monitoring and safety 
evaluation will continue for 12 weeks after the final dose. 
 
Study Population, Subject Selection, and Withdrawal    
Male or non-pregnant female patients ≥ 18 years of age with non-alcoholic 
steatohepatitis and who meet all the eligibility criteria will be enrolled and 
randomized to 2 arms (placebo, and idebenone).  There will be a total of 45 
patients enrolled in the study, with 1:2 randomization (15 placebo, 30 patients on 
idebenone). Inclusion and exclusion will be evaluated and confirmed with the PI, 
or other clinicians on the delegation (DOA) log. 
 
Inclusion Criteria: 
1) Male or non-pregnant/ non-lactating women ≥ 18 years of age  
2) Diagnosis of NASH: NASH Clinical Research Network (CRN) NAFLD activity 
score (NAS) of 4 or greater with a score of 1 for each of the following (steatosis 
scored 0-3, lobular inflammation scored 0-3, ballooning scored 0-2) on biopsies: 
• Steatosis 
• Lobular inflammation 
• Hepatocyte ballooning 
3) Fibrosis F1-3, on liver biopsy or MRE or Fibroscan; within 6 months of 
enrollment, with MELD<10 
4) Women of childbearing potential must agree to at least two methods of 
contraception, and males must agree to practice birth control during the study 
and up to 30 days after the last dose of idebenone.  
5) Will not participate in any other clinical trial for the duration of the study 
6) Will not consume alcohol for the duration of the study  
7) If on vitamin E or pioglitazone prior to the study, will have been on stable 
therapies for 6-12 months prior to enrolment 
 
Exclusion Criteria: 
1) Presence of any other form of liver disease, including viral hepatitis, autoimmune 
hepatitis, alcoholic liver disease, genetic causes of chronic liver disease) 
2) ALT>300 U/l 
3) Total serum bilirubin ≥ to 1.3 mg/dL (Gilbert’s Syndrome patients excepted) 
4) International Normalized Ratio (INR) ≥ 1.3 
5) MELD>10 
6) Serum creatinine >2.0mg/dl and/or GFR < 50 ml/min/1.73m2  
7) Known alcohol abuse or alcohol use disorder (AUDIT profile and/or pos. urine 
ethylglucuronide): 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
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• >20 g/day for women 
• >30 g/day for men 
8)  Active substance abuse 
9)  Any medical condition that prevents MRE, MR-PDFF 
10) Platelet count ≤150,000//mm3 
11) Cirrhosis  
12) Hemoglobin <11 g/dl in females or <12 g/dl in males 
13) Presence/history of HCC  
14) History of liver transplantation 
15) History of bariatric surgery 
16) History of inflammatory bowel disease 
17) History of cardiovascular disease, long QT syndrome. 
18) Subjects who have participated in investigational drug trials and took any 
investigational drugs within 60 days prior to the first dose of idebenone. 
19) Any concerns regarding being able to consent or compliance by enrolling 
physician 
 
Recruitment and Screening: 
Potential subjects will be identified by the investigators at hepatology clinics at Stanford 
University. A member of the research team (clinical research coordinator) will initiate the 
consenting process for those who meet eligibility criteria. Consenting will be done by the 
investigator or sub-investigator medical licensed doctors.  
 
Early Withdrawal and Replacement: 
Participants who do not adhere to protocol requirements (early drop-out, non-adherence 
or other non-safety related issue) will be removed from the study and replaced. 
Participants who are removed for drug-related severe adverse events or meet exclusion 
criteria during the study will not be replaced.  Patients who progress to cirrhosis during 
the 48 weeks of the study will be taken off of the treatment protocol (Idebenone or 
placebo) and replaced. However, we will continue to follow outcomes for these patients 
throughout the course of the study.  During consenting process, participants will be 
informed about their right to withdraw from the study at any time. The investigators will 
schedule an Early Termination and Follow-up Visits.  
 
Data Collection and Early Withdrawal Visits: 
Even though subjects may be withdrawn prematurely from the study, follow-up safety 
data will be collected during the follow-up period.  
• Physical exam: Vital signs (blood pressure, pulse, O2 saturation on RA),  
• Laboratory Tests: CBC with differential, INR, ALT, AST, Alkaline phosphatase, 
Total bilirubin, Glucose, BUN, Creatinine, Sodium, Potassium, Chloride, Albumin, 
Total cholesterol. 
 
Other Permitted Treatments 
Participants may continue standard therapy including other treatment for other co-
morbidities e.g. T2DM. All participants will receive the study drug in addition to the other 
drugs for standard of care, and will be asked to maintain the same doses of medications 
if clinically stable and warranted.  

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
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STUDY DRUG 
Treatment Regimen 
Idebenone capsules will be given at 200 mg by mouth (P.O.) once a day for 2 weeks, 
then 200 mg twice a day for 2 weeks, then 3 times per day for the remainder of the 
study. If we observe no toxicity, we will continue with these doses for the treatment 
period. The dosing of the placebo will follow the same time course.  Capsules will be 
taken preferably with food for 48 weeks, as absorption and bioavailability are improved 
with food intake.  Clinical visits have been added 2 weeks after each dose increase to 
assess for adverse reactions and clinical assessment (at 2weeks, 4weeks, and 6 weeks 
post-initial dose). Dose de-escalation e.g. from the 200 mg three times a day to 200 mg 
two times a day dosing will be permitted if side effects e.g. gastrointestinal symptoms 
are noted.  Once de-escalated subjects will continue on that dose for the remainder of 
time.  
  
Adherence to the Study Protocol and Medication 
Participant’s compliance will be monitored by follow-up phone calls performed by 
qualified research personnel. These follow-ups will be done every 2 weeks for the first 
24 weeks and every 4 weeks for the rest of the study (except when the times and 
follow-up phone calls fall on the same day as follow-up visits).  
 
Rationale for Dose Selection 
The currently approved dose for idebenone in Europe is 300 mg three times a day.  
Since idebenone is extensively metabolized in the liver, local therapeutic levels could be 
reached at a lower dosing.  Therefore, we will study idebenone at a maximum dose of 
200 mg three times a day.  Idebenone has an excellent safety profile that has been 
studied in multiple trials at dosages up to 2250 mg a day.  
 
Rationale for study length: 
Our rationale is treating patients for 48 weeks is that we are looking at fibrosis as an 
outcome, and shorter time frames, e.g. 24 weeks are insufficient to address this.  Most 
clinical trials addressing NASH fibrosis are at least of 48 weeks duration.  While other 
outcomes, e.g. necroinflammation is possible to assess after shorter duration of 
treatment (e.g. 24 weeks), fibrosis has not showed a significant signal only after 24 
weeks of treatment.  Nevertheless, we will assess fibrosis by FIB4 at 24 weeks. 
 
Receiving, Storage, Dispensing and Returning of Study Drug 
The study drug will be provided by HBC Health Solutions in ready-to-use form, and will 
be stored at Stanford’s investigational clinical pharmacy.  The placebo was 
manufactured and provided by Bravado Pharmaceuticals.  Upon receipt of the of the 
study drug, an inventory will be performed, and a receipt log will be filled out and signed 
by the person accepting the shipment. Designated study staff will count and verify all 
the items noted in the shipment inventory.  Any damaged or unusable study drug in a 
given shipment (active drug or placebo) will be documented in the study files. Labeling 
and dispensing will be performed at Stanford’s investigational clinical pharmacy. 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
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Idebenone (and placebo) capsules will be stored at controlled room temperature (15C-
30oC) protected from light and humidity, and will be continuously recorded in the 
temperature log.  
 
6.1.1. STUDY PROCEDURE 
Participants will be recruited from Stanford Hospital Liver Clinics. Research coordinators 
will primarily evaluate patients with NASH for eligibility. Patients who received a liver 
biopsy as per standard of care in the previous 6 months, will be informed and those who 
are willing to participate in the study will be consented by the investigators. After 
consenting, participants will be randomized.  
 
Screen/Baseline assessment (t= -1 to -6 weeks) 
Prior to enrollment each participant will undergo medical screen and be introduced 
to study procedures.  This will be performed concurrently with the patient’s clinic 
visit.  If the patient qualifies, the following assessment will be done:  
• Prior to any study-related protocols, informed consent is obtained 
• Procedures as per standard medical care: 
o Full medical history  
o Complete physical examination including height/weight, waist and 
hip circumference, blood pressure, heart rate, O2 saturation  
o Baseline laboratory tests: CBC with differential, Liver tests: ALT, 
AST, Total bilirubin, Alkaline phosphatase, GGT; Comprehensive 
metabolic panel (fasting): Sodium, Potassium, Bicarbonate, 
Creatinine, BUN, Ca++, Phosphate, Albumin Glucose, Insulin, 
Glycosylated hemoglobin, HOMA-IR, ANA, anti-smooth muscle 
antibody, AMA, ceruloplasmin, α1-antitrypsin, ferritin; Lipid panel 
(fasting): Total cholesterol, LDL, HDL, Triglyceride; Coagulation 
studies: PT, INR 
o Calculation of MELD score 
• Additional studies as part of the protocol: 
 serum pregnancy test 
 AUDIT screen and urinary ethylglucuronide  
 MRE imaging will be obtained and will be used to analyze shear 
stiffness at different areas. Cross-sectional images will represent 
the stiffness generated from wave propagation data and analysis.  
Co-localized regions of interests will be established to allow 
detection of longitudinal changes. We will also include PDFF mode 
to assess steatosis.  
 
Main Treatment Period (t=0)  
After it has been determined that the participant satisfies all eligibility criteria based on 
assessments at the Screen/Baseline Visit, the participant will be enrolled. The 
participant will receive study drug by one of two options: 1) The patient will return to 
Stanford Clinic to pick up study drug or 2) the study drug will be mailed to participant. 
The patient will be instructed to start the study drug or placebo, and the day that the 
study medication is started will be t = 0. 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
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Participants will be encouraged to take the medication with food, as bioavailability and 
absorption are improved with food intake. The treatment period should start within 6 
weeks from study enrollment. If it has been> 8 weeks since the "Screen/Baseline 
Assessment Visit", any changes in health should be re-assessed and laboratory 
evaluation repeated (CBC with differential, Na+, K+, Cl-, CO2, glucose, serum 
creatinine, BUN, Ca++, Phosphorus, total bilirubin, AST, ALT, GGT, Alkaline 
phosphatase, total bilirubin, albumin,).  
 
Interim Clinic Visits During Treatment Period 
At these visits the following will occur: 
Visit at 2 weeks (+/- 4 days): 
o Monitor for adverse events and assess adherence to the study 
medication. 
o Physical examination including height/weight, waist and hip 
circumference, blood pressure, heart rate, O2 saturation  
o Laboratory tests: CBC with differential, Liver tests: ALT, AST, Total 
bilirubin, Alkaline phosphatase, GGT; Comprehensive metabolic 
panel (fasting): Sodium, Potassium, Bicarbonate, Creatinine, BUN, 
Ca++, Phosphate, Albumin Glucose, Coagulation studies: PT, INR 
o Calculation of MELD score 
o AUDIT screen and urinary ethylglucuronide  
 
Visit at 4 weeks (+/- 4 days)  : 
o Monitor for adverse events and assess adherence to the study 
medication. 
o Physical examination including height/weight, waist and hip 
circumference, blood pressure, heart rate, O2 saturation  
o Laboratory tests: CBC with differential, Liver tests: ALT, AST, Total 
bilirubin, Alkaline phosphatase, GGT; Comprehensive metabolic 
panel (fasting): Sodium, Potassium, Bicarbonate, Creatinine, BUN, 
Ca++, Phosphate, Albumin Glucose, Coagulation studies: PT, INR 
o Calculation of MELD score 
o Serum Idebenone Metabolite Studies (5 cc blood per patient)AUDIT 
screen and urinary ethylglucuronide  
 
Visit at 6 weeks (+/- 4 days): 
o Monitor for adverse events and assess adherence to the study 
medication. 
o Physical examination including height/weight, waist and hip 
circumference, blood pressure, heart rate, O2 saturation  
o Laboratory tests: CBC with differential, Liver tests: ALT, AST, Total 
bilirubin, Alkaline phosphatase, GGT; Comprehensive metabolic 
panel (fasting): Sodium, Potassium, Bicarbonate, Creatinine, BUN, 
Ca++, Phosphate, Albumin Glucose, Coagulation studies: PT, INR 
o Calculation of MELD score 
o AUDIT screen and urinary ethylglucuronide 
 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
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Visit at 12 weeks(+/- 7 days): 
o Monitor for adverse events and assess adherence to the study 
medication. 
o Physical examination including height/weight, waist and hip 
circumference, blood pressure, heart rate, O2 saturation  
o Laboratory tests: CBC with differential, Liver tests: ALT, AST, Total 
bilirubin, Alkaline phosphatase, GGT; Comprehensive metabolic 
panel (fasting): Sodium, Potassium, Bicarbonate, Creatinine, BUN, 
Ca++, Phosphate, Albumin Glucose, Insulin, Glycosylated 
hemoglobin, HOMA-IR, Coagulation studies: PT, INR 
o Lipid screen 
o Calculation of MELD score 
o AUDIT screen and urinary ethylglucuronide  
 
Visit at 24 weeks(+/- 7 days): 
o Monitor for adverse events and assess adherence to the study 
medication. 
o Physical examination including height/weight, waist and hip 
circumference, blood pressure, heart rate, O2 saturation  
o Laboratory tests: CBC with differential, Liver tests: ALT, AST, Total 
bilirubin, Alkaline phosphatase, GGT; Comprehensive metabolic 
panel (fasting): Sodium, Potassium, Bicarbonate, Creatinine, BUN, 
Ca++, Phosphate, Albumin Glucose, Insulin, Glycosylated 
hemoglobin, HOMA-IR, Coagulation studies: PT, INR 
o Calculation of MELD score 
o Collect PMBCs from peripheral blood draw, as above (5 cc 
blood/patient) to assess target engagement (decrease in Shc 
phosphorylation). 
o Idebenone Metabolite Studies (serum) 
o FIB-4 measurement for Interim analysis of fibrosis 
o AUDIT screen and urinary ethylglucuronide  
Visit at 36 weeks(+/- 7 days): 
o Monitor for adverse events and assess adherence to the study 
medication. 
o Physical examination including height/weight, waist and hip 
circumference, blood pressure, heart rate, O2 saturation  
o Laboratory tests: CBC with differential, Liver tests: ALT, AST, Total 
bilirubin, Alkaline phosphatase, GGT; Comprehensive metabolic 
panel (fasting): Sodium, Potassium, Bicarbonate, Creatinine, BUN, 
Ca++, Phosphate, Albumin Glucose, Insulin, Glycosylated 
hemoglobin, HOMA-IR, Coagulation studies: PT, INR 
o Calculation of MELD score 
o AUDIT screen and urinary ethylglucuronide  
 
Visit at 48 weeks(+/- 7 days): 
o Monitor for adverse events and assess adherence to the study 
medication. 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
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o Physical examination including height/weight, waist and hip 
circumference, blood pressure, heart rate, O2 saturation  
o Laboratory tests: CBC with differential, Liver tests: ALT, AST, Total 
bilirubin, Alkaline phosphatase, GGT; Comprehensive metabolic 
panel (fasting): Sodium, Potassium, Bicarbonate, Creatinine, BUN, 
Ca++, Phosphate, Albumin Glucose, Insulin, Glycosylated 
hemoglobin, HOMA-IR, Coagulation studies: PT, INR, lipid screen 
o Calculation of MELD score 
o Collect PMBCs from peripheral blood draw, as above (5 cc 
blood/patient) to assess target engagement (decrease in Shc 
phosphorylation). 
o Idebenone Metabolite Studies (serum) 
o MRE imaging will be obtained and will be used to analyze shear 
stiffness at different areas, following treatment.  PDFF mode to 
assess steatosis.  
o AUDIT screen and urinary ethylglucuronide 
o  
Telephone Contact During Treatment Period Follow-up telephone contact is done 
every 2 weeks (+/- 7 days)  for the first 24 weeks and every 4 weeks(+/- 7 days)  for the 
rest of the study. Study personnel will document any AEs, changes in health, study drug 
adherence, protocol deviations, etc. based on the phone call. The timing of telephone 
contact can occur within ± 7 days of scheduled time period.  
 
Unscheduled Visits  
Unscheduled visits will take place for an unexpected pregnancy or any complication or 
AE/SAE that requires an extra visit. These visits will be documented in the source 
document and the unscheduled visit case report form.  
 
Dose De-escalation During Treatment Period  
For participants receiving idebenone 200 mg po three times per day, dose de-escalation 
to 200 mg po two times per day, and then 200 mg daily for gastrointestinal side effects 
(e.g. diarrhea, bloating, abdominal discomfort) will be allowed. Once de-escalated, the 
participant will continue on this dose for the remainder of the treatment period. 
 
Clinic Visits Post-Treatment (4 and 12 weeks post treatment)*  
As part of routine clinical care the patient will be seen in clinic at approximately at 4 and 
12 weeks after completing treatment.  Timing can occur ± 1 month of scheduled time 
period to accommodate participant schedule. At these visits the following will occur: 
o Monitor for adverse events and assess adherence to the study 
medication. 
o Physical examination including height/weight, waist and hip 
circumference, blood pressure, heart rate, O2 saturation  
o Laboratory tests: CBC with differential, Liver tests: ALT, AST, Total 
bilirubin, Alkaline phosphatase, GGT; Comprehensive metabolic 
panel (fasting): Sodium, Potassium, Bicarbonate, Creatinine, BUN, 
Ca++, Phosphate, Albumin Glucose, , Glycosylated hemoglobin, 
HOMA-IR, Coagulation studies: PT, INR 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
13 
 
o Calculation of MELD score 
*A clinic visit at Stanford is preferred, however, for participants who live out of the Bay 
Area, the visit may occur via telehealth/telephone contact. In this case, standard of care 
blood laboratories may be performed at a local clinical laboratory. Blood and imaging 
procedures that are only part of study protocol will not be performed. 
For the serum metabolite studies: patients will take their morning dose of study medication with 
food.  1.5 hrs. later blood draw (5cc) in a Heparin tube will be performed in conjunction with the 
SOC labs.  Un-identified (coded) serum and PMBC samples (pellets, previously processed by 
the PI’s lab) will be sent to UC Davis by the PI to our collaborator (Dr. Cortopassi) who will 
perform idebenone metabolite assessment, and Shc target engagement studies on PMBCs.  
Table of Treatment Events 
Procedures 
Screening 
weeks -6 to -1 * 
Enrollment/Base
-line* 
Study Visit 2 2w 
Study Visit 3: 4w 
Study Visit 3: 6w 
 
Study Visit 4: 
12w 
Study Visit 5: 
24w 
Study Visit 6: 36 
w 
Study Visit 7: 48 
weeks 
St
t d
Study Visit 8: 52 
weeks 
Final Study Visit 
9: 60w 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Administer study 
intervention 
 
X 
X 
X 
X 
 
 
 
X 
 
 
Concomitant 
medication review 
X 
 
Physical exam 
(including height and 
weight) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
X 
 
 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
serum chemistry a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test b 
X 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Autoimmune panel, 
ANA, ASMA, AMA 
X 
 
 
 
 
 
 
 
 
 
 
ceruloplasmin 
X 
 
 
 
 
 
 
 
 
 
 
Alpha 1 AT 
X 
 
 
 
 
 
 
 
 
 
 
Ferritin 
X 
 
 
 
 
 
 
 
 
 
 
Lipid panel 
X 
 
 
 
 
X 
 
 
X 
 
 
Coag. Studies, PT, INR 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine ethylgluc. 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
AUDIT screen 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
14 
 
Procedures 
Screening 
weeks -6 to -1 * 
Enrollment/Base
-line* 
Study Visit 2 2w 
Study Visit 3: 4w 
Study Visit 3: 6w 
 
Study Visit 4: 
12w 
Study Visit 5: 
24w 
Study Visit 6: 36 
w 
Study Visit 7: 48 
weeks 
St
t d
Study Visit 8: 52 
weeks 
Final Study Visit 
9: 60w 
Adverse event review 
and evaluation 
X 
 
 MRE 
XΩ 
 
 
 
 
 
 
 
XΩ 
 
 
Idebenone serum 
metabolites 
 
 
 
X 
 
 
X 
 
X 
 
 
FIB-4 
 
 
 
 
 
 
X 
 
X 
 
 
Periph. Blood PBMC 
 
 
 
 
 
 
X 
 
X 
 
 
Complete Case 
Report Forms (CRFs) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
*These procedures can occur on the same day of enrollment/baseline visit. Review of previous clinic labs 
as part of screening.  If labs were done >8w, repeat labs on the day of enrollment. 
 
Ω MRE can occur +/-4 weeks from scheduled visit, to allow patient flexibility 
 
ENDPOINTS  
 
Primary Endpoint  
Safety and tolerability: assess the number of adverse events and the number of 
participants with adverse events by severity, causality, and type. 
 
Secondary Endpoints 
To evaluate changes in biomarkers of disease progression and liver stiffness in adults 
treated with idebenone for 48 weeks compared to placebo: 
• Serum aminotransferases, and GGT levels  
• Fasting markers of insulin resistance (HOMA, adipo-IR index)  
• Lipid profile (triglycerides, HDL, LDL)  
• Liver stiffness, using MRE.  Will include MR-PDFF as well, to evaluate steatosis.   
• Assess target engagement (PMBC Shc phosphorylation) 
• Evaluate surrogate markers (FIB 4). 
• Idebenone metabolite studies 
 
STATISTICAL CONSIDERATIONS  
 
Sample Size  
The selection of 15 participants for the placebo group and 30 participants for the 
idebenone group was based on clinical judgment and past experience with observing 
potential treatment response.  This number takes into account potential attrition, and a 
15-20% placebo effect that has been previously observed in NASH studies.  The study 
has sufficient sample size to provide preliminary safety profile and secondary outcome 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
15 
 
measures. This is based on the two group t-test for fold change assuming log-normal 
distribution (unequal n's) to detect 1.5 kPa decrease in stiffness in the treatment group 
at the 0.05 level (2-sided) with 83% power. 
 
Statistical Methodology  
Descriptive statistics such as the number of observations, mean, median, standard 
deviation, minimum, and maximum will be presented for continuous variables. Other 
descriptive statistics such as counts, proportions, and/or percentages will be presented 
to summarize discrete variables. A 95% confidence level will be used for confidence 
intervals.  
 
Demographics and Baseline Characteristics  
The number of participants who either completed the study or were discontinued early 
from the study will be summarized. Demographic and baseline characteristics will also 
be summarized by dose group. These variables include race, age, gender, and selected 
clinical variables recorded prior to initiation of study drug. Study drug administration will 
be summarized in terms of number of days of dosing and reasons for final 
discontinuation of the study drug.  
 
Safety and Clinical Laboratory Analyses  
Adverse events will be summarized by Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term. Prior and concomitant medications 
will be summarized by World Health Organization (WHO) drug class.  
Summary statistics for changes from baseline will be presented for laboratory values, 
such as hematology and serum chemistry data, and physical examination results. 
Continuous laboratory measurements will be described at each visit using descriptive 
statistics; observed values and changes from baseline will be summarized.  
 
Analyses of Secondary Outcomes  
Summary statistics for changes from baseline will be presented for the various 
secondary endpoints. Continuous measurements will be described at each visit using 
descriptive statistics; observed values and changes from baseline will be summarized.  
 
Data Monitoring  
Data entry, database management, and data quality assurance will be led by the study 
coordinator. Interim data analysis will occur after 5 participants have completed the 
study, and then final data analysis at completion of study.  
 
RISK and DISCOMFORTS 
1. 
Idebenone:  Idebenone is currently not FDA approved for use in the United 
States. However, clinical experience suggests that idebenone is safe and well-tolerated 
oral medication. The safety of oral idebenone as high as 360 mg three times a day for 
up to 2 years has been demonstrated in humans.  On the ClinicalTrials.gov site there 
have been 31 trials with idebenone, mostly for neurodegenerative disorders. Of these, 
there are ongoing trials for Phase 3 studies in Duchenne’s muscular dystrophy 
(SIDEROS, NCT03603288) at sites within the US, as well as a single study for early 
Parkinson’s (NCT04152655). In Europe, Idebenone has been authorized in the EU 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
16 
 
since 8 September 2015 (EMEA/H/C/003834) for the treatment of visual impairment in 
adolescent and adult patients with Leber's Hereditary Optic Neuropathy (LHON). 
According to the summary of risk assessment 
(https://www.ema.europa.eu/en/documents/rmp-summary/raxone-epar-risk-
management-plan-summary_en.pdf), there were no reports on SAEs with idebenone. 
The most common reported side effects with Idebenone are nasopharyngitis, cough and 
mild to moderate diarrhea (affecting up to 1 in 10 people). Changes in blood test results, 
e.g. low level of white blood cells, or low level of red blood cells, or low level of platelets 
may occur however these are very rare and are classified as “unknown frequency” 
based on prior studies. 
Chromaturia: The metabolites of idebenone are colored and may cause chromaturia, 
i.e. a reddish-brown discoloration of the urine. This effect is harmless, not associated 
with hematuria, and does not require any change in dose or discontinuation of 
treatment. Caution should be exercised to ensure that the chromaturia does not mask 
changes of urine color due to other reasons (e.g. renal or blood disorders).  
 
2. 
Venipuncture: The risks of venipuncture include temporary discomfort, pain, and 
anxiety from the needle stick, bruising, and, rarely, infection. To minimize risk, all blood 
draws will follow hospital/clinical procedures and be drawn by experienced 
phlebotomists will be used for blood. 
 
3. 
MR elastogram: MRE is an FDA approved noninvasive test used to assess liver 
stiffness (measured in kPa) as a measure of liver fibrosis.  During the exam a special 
pad is placed on the abdomen, over the gown. It applies low-frequency vibrations that 
pass through the liver. The MRI system generates images of the waves passing through 
the liver and processes the information to create cross-sectional images that show the 
stiffness of tissue. During measurement, participants may feel a slight vibration on the 
skin.  All precautions will be followed as per standard of care in terms of MRI use. 
 
4. 
Privacy:  Participation in research may involve a loss of privacy, but information 
about participants will be handled as confidentially as possible and in compliance with 
HIPPA regulations. Patient names and medical record numbers will be recorded for 
study management purposes. This information will not be included in the hard copy data 
case report forms or the electronic database used for data analysis, and will be 
maintained in a locked file in a lockable office. It will not be disclosed to others. 
Study data will be identified by a unique study code for each patient. Hard copy study 
data will be maintained in a separate locked research file in a lockable office. The 
electronic data set, which will be identified by the unique study codes, will be keyed into 
a computer that is password protected and encrypted. Access to study data will be 
limited to research personnel who have completed protocol specific training. 
 
SAFETY MONITORING AND ADVERSE EVENTS  
 
Adverse Events Definition  
An adverse event (AE) is any untoward or unfavorable medical occurrence in humans 
which occurs during the participant's participation of a clinical study, whether or not it is 
considered drug-related. Any changes in clinical status, routine labs, physical 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
17 
 
examinations, etc. that is considered clinically significant by the study investigator are 
considered AEs. We are using National Cancer Institute’s Common Terminology 
Criteria for Adverse Events version 5 (CTCAE v.5) grading system.  The following 
grades, which refer the severity of the AE, are described here: 
 
The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for 
each AE based on this general guideline:  
 
Grade 1  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.  
Grade 2  
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL).  
Grade 3  
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL.  
Grade 4  
Life-threatening consequences; urgent intervention indicated.  
Grade 5  
Death related to AE.  
 
An extensive description of the type of AE’s described by this system can be found 
online 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_5x7.pdf). 
 
The most common side effects of idebenone have been reported to be diarrhea, 
nausea, and mild gastrointestinal symptoms. The CTCAE grading system will be used 
to grade these symptoms, as well as any others that arise during and shortly after the 
trial ( < 30 days). The grade of these symptoms, rather than the presence of the 
symptoms themselves, will be used to determine if study drug administration should be 
stopped in individual patients or all patients within the study.  
 
Monitoring and handling AEs: 
The main symptoms described in previous trials are diarrhea, nausea and malaise.  
These were usually self-limited and observed at the beginning of the study. 
1. Mild symptoms:  diarrhea e.g. 2-3 loose stools a day, non-watery, may 
recommend supportive treatment e.g. fiber supplementation.  For nausea taking 
the medication with meals is helpful. Nausea that interferes with daily activities or 
food intake will be addressed, as below. 
2. Moderate to severe symptoms: diarrhea with stools >5 a day, watery stools, or 
nausea interfering with daily activities will mandate dose reduction, as described 
earlier. 
 
Suspected Adverse Reaction (SAR)  
A Suspected Adverse Reaction (SAR) is any adverse event for which there is a 
reasonable possibility that the investigational drug caused the adverse event. For the 
purposes of safety reporting, 'reasonable possibility' means there is evidence to suggest 
a causal relationship between the drug and the adverse event. A suspected adverse 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
18 
 
reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug.  
 
Monitoring for Drug-Induced Liver Injury (DILI) 
This study follows the FDA’s Guidance for Industry, Drug-Induced Liver Injury, 
Premarketing Clinical Evaluation guidelines 
(https://www.fda.gov/regulatoryinformation/search-fda-guidance-documents/drug-
induced-liver-injurypremarketing-clinical-evaluation).  Of note, the patients recruited to 
this study will have other liver diseases excluded.  Most of them will have mild increase 
in serum aminotransferases at baseline as they have NASH diagnosis. In prior trials 
severe DILI with idebenone was not noted.  Preexisting liver disease has not been 
thought to make patients more susceptible to DILI but it may be that a diminished liver 
reserve or the ability to recover could make the consequences of injury worse.  
 
To monitor for cholestatic liver injury, we have outlined the biochemical triggers for close 
monitoring and potential DILI evaluation based on AT baseline, as listed below: 
 
Normal Baseline Status 
ALT≥3x ULN or AST ≥3x ULN and TB ≥2x ULN 
ALT≥5x ULN or AST ≥5x ULN 
ALT≥8x ULN or AST ≥8x ULN 
ALT≥3x ULN or AST ≥3x ULN and INR > 1.5 
ALP/GGT ≥2 ULN 
 
Elevated Baseline Status  
ALT≥3x BL or AST ≥3x BL and TB ≥2x BL  
ALT≥3x BL or AST ≥3x BL  
ALT≥5x BL or AST ≥5x BL  
ALT≥2x BL or AST ≥2x BL and INR > 1.5  
ALP/GGT ≥2x BL and > ULN  
ALP/GGT ≥2x BL and > ULN and ALP/GGT ≥2x BL and > ULN  
 
The following Standardized MedDRA Queries (SMQs) will be used as the triggers to 
identify subjects meeting the liver toxicity adverse events: 
• Trigger S1: Cholestasis and jaundice of hepatic origin (SMQ). Drug related hepatic 
disorders- severe events only (SMQ)  
• Trigger S2a: Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
conditions (SMQ) 
• Trigger S2b: Hepatitis, non-infectious (SMQ)  
• Trigger 3: Liver related investigations, signs and symptoms (SMQ)  
• Trigger 4: Liver related coagulation and bleeding disturbance (SMQ) 
 
In accordance with Hy’s law, cholestatic liver injury will be assumed if no other reason 
can be found to explain the combination of increased AT and TBL, such as viral 
hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury. In all patients, regular physical monitoring (symptoms, 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
19 
 
physical signs e.g. rash), and monitoring of ALT, AST and GGT will be done as per the 
protocol synopsis (initially every 2 weeks).   
 
If we observe 3-fold or greater elevations, we will confirm results within 48 hours, 
including bilirubin levels.  We will obtain history of recent or acute illnesses, concurrent 
or new medications or exposures.  Depending on these further investigations will be 
initiated e.g. acute hepatitis panel, ethyl glucuronide, Tylenol level, cardiac workup. 
Discontinuation of treatment will be considered if:  
-ALT or AST >8xULN  
-ALT or AST >5xULN for more than 2 weeks  
-ALT or AST >3xULN and (TBL >2xULN or INR >1.5) • ALT or AST >3xULN with the 
appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, and/or eosinophilia (>5%)  
 
Serious Adverse Event Definition  
An adverse event or suspected adverse reaction or adverse reaction is considered 
serious if, in the view of either the PI or sponsor, it results in any of the following 
outcomes: 
• 
Grade 5:  -  Death  
• 
Grade 4:  
- 
Life-threatening AE: it is considered "life-threatening" if its 
occurrence, in the opinion of the investigator or sponsor, places the 
participant at immediate risk of death from the reaction as it 
occurred. It does not include an AE or SAR that, had it occurred in 
a more severe form, might have caused death. 
• 
Grade 3:  
- 
Persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions 
- 
Inpatient hospitalization or prolongation of existing hospitalization 
- 
Congenital abnormality or birth defect 
- 
Important medical event that may not result in one of the above 
outcomes, but may jeopardize the health of the study participant or 
require medical or surgical intervention to prevent one of the 
outcomes listed in the above definition of serious adverse event. 
 
Unexpected Adverse Event Definition  
An adverse event or suspected adverse reaction is considered "unexpected" if it is not 
listed in the Investigator Brochure or package insert or is not listed at the specificity, 
severity or rate of occurrence that has been observed; or, if an Investigator Brochure is 
not required or available, is not consistent with the risk information described in the 
general investigational plan or elsewhere in the IND or protocol.  
 
Identification of Adverse Events  
As all participants in this study will have pre-existing medical conditions. Those pre-
existing conditions will not be considered as adverse events. New events that occur or 
worsening through frequency or intensity of pre-existing conditions will be reported as 
adverse events.  

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
20 
 
 
Adverse events (including SAEs) may be discovered through any of these methods: 
• 
Observing or interviewing the participant. 
• 
Procedures and laboratories as performed as part of participating in the study. 
• 
Receiving an unsolicited complaint from the participant. 
 
The investigator will provide the following information about an AE: 
• 
Date of onset and resolution 
• 
Severity 
• 
Action taken with study drug product 
• 
Changes in study drug dosing 
• 
Causal relationship to study drug 
• 
Outcome 
 
All reportable drug adverse events as defined above will be recorded on the appropriate 
AE/SAE paper CRF form starting after consent has been obtained until 30 days after 
the last dose of study drug.  
 
Follow-up of Adverse Events  
All adverse events (drug related or not) must be followed until resolution, until 30 days 
after the study completion, or until 30 days after the participant prematurely withdraws 
(or is withdrawn from the study), whichever occurs first. All SAEs will be followed until 
resolution, even if not resolved by the 30 day follow-up.  
 
Guidelines for Determining Causality  
The Investigator will use the following question when assessing causality of an adverse 
event to study drug. 
-Is there a reasonable possibility that the drug caused the event? (Yes/No) 
An affirmative answer designates the event as a suspected adverse reaction. 
 
Adverse Events Reporting Procedures  
 
Serious Adverse Events  
The investigator will report to the Sponsor all serious adverse events within 24 hours of 
becoming aware of the event, regardless of relationship or expectedness. For serious 
adverse events, all requested information on the AE/SAE paper CRF will be provided. 
However, unavailable details of the event will not delay submission of the known 
information. As additional details become available, the AE/SAE paper CRF will be 
updated and submitted. Investigators or Sponsor must also submit safety reports locally 
as required by their IRB.  
 
Unexpected Non-Serious Adverse Events  
An unexpected, non-serious adverse event that is of Grade 2 severity or higher and 
study related will be recorded and reported to the Sponsor under the serious adverse 
event reporting procedure above (i.e. within 24 hours).  
 
Reporting to Health Authority  

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
21 
 
The Sponsor of the IND will report all AEs and SAEs to the FDA within the reporting 
time limits set forth by the FDA. 
 
1) 
Standard Reporting (IND Annual Report) 
This option applies if the AE is classified as one of the following: 
• 
Serious, expected, suspected adverse reactions 
• 
Serious and not a suspected adverse reaction 
• 
Pregnancies 
* Note that all adverse events (not just those requiring 24-hour reporting) will be 
reported in the Annual IND Report. 
 
2) Expedited Reporting 
 
The Sponsor must report in an IND safety report any suspected adverse reaction to 
study drug that is both serious and unexpected. The time frame for submitting an IND 
safety report to FDA and all participating investigators is no later than 15 calendar days 
after the sponsor determines that the suspected adverse reaction or other information 
qualifies for reporting. 
 
Unexpected fatal or life-threatening suspected adverse reactions represent especially 
important safety information and, therefore, must be reported more rapidly to FDA. The 
requirement for reporting any unexpected fatal or life-threatening suspected adverse 
reaction to FDA is no later than 7 calendar days after the sponsor's initial receipt of the 
information. Investigators must submit IND safety reports as required by their IRB. 
Documentation of the submission and receipt by the IRB must be retained for each IND 
safety report.  
 
Contraception and Pregnancy  
 
All men and women of child-bearing potential must agree to practice at least two 
preventive measures regarding pregnancy with the prevention measures of their 
choosing during the study and for 30 days after the last administration of idebenone. 
Acceptable birth control methods include: sexual abstinence; vasectomy and 
documentation of zero sperm count in the semen; and use of barrier contraception in 
combination with use of effective birth control by the female partner. Study participants 
will be required to disclose their method of pregnancy prevention at the initial 
screening/baseline visit.  
 
During the course of the study, any participant who becomes pregnant will be instructed 
to contact the study team immediately, and she will be required to cease dosing with her 
treatment immediately. She will be seen in an unscheduled visit during which a physical 
examination and laboratories will be performed (CBC with differential, Na+, K+, Cl-, 
CO2, glucose, serum creatinine, BUN, Ca++, Phosphorus, total bilirubin, AST, ALT, 
GGT, Alkaline phosphatase, total bilirubin, albumin, total protein). Monitoring of the 
pregnant participant shall continue until the conclusion of the pregnancy and the 
outcome must be reported. Information requested about the delivery shall include: 
Gestational age at delivery; Birth weight, length, and head circumference; Gender; 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
22 
 
Appearance, pulse, grimace, activity, and respiration (APGAR) score at 1 minute, 5 
minutes, if available; Any abnormalities. Any complication to pregnancy such as a 
congenital abnormality or birth defect shall be recorded as an SAE using the SAE 
reporting procedures described above and to the FDA.  
 
SAFETY MONITORING  
Formal Data Safety Monitoring Board (DSMB) or Data Monitoring Committee (DMC) will 
not be formed given the single-site, and small sample size. Instead, the PI, and study 
personnel will perform study safety reviews on an ongoing basis. 
 
HALTING CRITERIA  
During the course of the study, if the PI discovers conditions that indicate that the study 
should be discontinued, an appropriate procedure for terminating the study will be 
instituted, including notification of the FDA and IRB.  
 
Halting of Study Drug in Participant & Reasons for Early Termination  
Study drug administration must be halted, and the participant withdrawn from the study 
if any of the following occurs: 
 
1. 
Participant develops a serious adverse reaction (Grades 3-5). 
2. 
Participant desires to discontinue participation in the study. 
3. 
Participant is unwilling or unable to comply with the protocol. 
4. 
Participant becomes pregnant. 
5. 
The investigator feels that is in the participant's best interest to discontinue 
treatment with study drug. 
 
Halting the Study  
The study will be halted for a safety review if: 
1. 
 If 1 patient experiences a Grade 5 CTCAE, 
2.  
2 patients experience the same Grade 4 CTCAE, 
3.  
3 patients experience the same Grade 3 CTCAE, 
4.  
4 patients experience the same Grade 2 CTCAE, enrolment of new 
      
patients into the trial should be paused.  
 
5.  
If at any point in the study the Sponsor and/or Investigators feel that there 
are safety concerns in this study that put the participants at increased risk as 
compared to the original information on risk in the consenting process, the 
Investigators and/or Sponsor in discussion with the FDA can choose to stop the 
study. 
A consensus decision to halt the study will be made by the Sponsor and Investigator. 
Such a decision with its supporting documentation and possible future plans for the 
study will be submitted to, and discussed with, the FDA.  
 
RECRUITMENT and ENROLLMENT  
Potential participants will be identified by the study investigator, Dr. Natalie Torok and 
her colleagues in the Hepatology clinics, who are experts in NASH and regularly care 
for these patients. Once it has been determined that patient meets entry criteria, a 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
23 
 
knowledgeable member of the research team will be introduced to the participant and 
will initiate the informed consent process. Enrollment will be by invitation only.  
 
FACILITIES  
Study visits 
a) 
Stanford Medicine, Liver Clinic, 
 
Redwood City, CA 94063 
b) 
MRE/MR-PDFF: Stanford Hospital, Radiology, 
 Palo Alto 
CA 94304 
 
ETHICAL CONSIDERATIONS  
Prior to any study-related procedures, the investigator or designee will obtain from the 
participant a signed and dated written Informed Consent consistent with FDA/ICH 
regulations and the HIPAA Privacy Rule. A HIPAA Privacy Rule Authorization language 
will be included in the Informed Consent and must be IRB approved prior to study 
implementation. In addition, the document of Bill of Rights will be attached to the 
Informed Consent form so that the participants can read and understand the same.  
 
WITHDRAWAL FROM STUDY  
Participants may stop being in the study at any time and all study procedures 
discontinued. However, every attempt will be made to schedule an Early Termination 
Visit for any participant who is enrolled and subsequently is withdrawn, discontinues or 
drops out of the study for any reason and he/she does not complete the final 12 month 
study visit.  
 
Early Termination Visit, at these visits the following will occur: 
o 
Monitor for adverse events. 
o 
Procedures done as part of standard of care: 
 
- 
Physical exam including heart rate, blood pressure, respiratory rate, 
and weight will be performed. 
- 
Blood tests: CBC with differential, Na+, K +, Cl-, CO2, glucose, 
serum creatinine, BUN, Ca++, Phosphorus, total bilirubin, AST, 
ALT, GGT, Alkaline phosphatase, albumin, total protein. 
 
DURATION OF THE STUDY  
If enrollment proceeds as planned, the enrollment phase will take 24 months (12 
months of recruitment followed by 12 months of follow-up after last patient enrolled). An 
additional ~6 months will be needed for data analysis after the end of enrollment.  
Table 2. Timetable 
Research Activity 
-3 to 0 months 
0-24 months 
24-36 months 
Study Preparation 
(IRB Training, etc.) 
X 
 
 
Study Enrollment 
 
X 
 
Data Analysis 
 
 
X 
Manuscript 
Preparation 
 
 
X 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
24 
 
 
References: 
 
1. 
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, and Wymer M. Global 
epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of 
prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84. 
2. 
Dyson JK, Anstee QM, and McPherson S. Non-alcoholic fatty liver disease: a 
practical approach to diagnosis and staging. Frontline Gastroenterol. 
2014;5(3):211-8. 
3. 
Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global 
burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat 
Rev Gastroenterol Hepatol. 2018;15(1):11-20. 
4. 
Bettaieb A, Jiang JX, Sasaki Y, Chao TI, Kiss Z, Chen X, et al. Hepatocyte 
Nicotinamide Adenine Dinucleotide Phosphate Reduced Oxidase 4 Regulates 
Stress Signaling, Fibrosis, and Insulin Sensitivity During Development of 
Steatohepatitis in Mice. Gastroenterology. 2015;149(2):468-80 e10. 
5. 
Jiang JX, Chen X, Serizawa N, Szyndralewiez C, Page P, Schroder K, et al. Liver 
fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel 
NOX4/NOX1 inhibitor in vivo. Free Radic Biol Med. 2012;53(2):289-96. 
6. 
Crosas-Molist E, and Fabregat I. Role of NADPH oxidases in the redox biology of 
liver fibrosis. Redox Biol. 2015;6:106-11. 
7. 
Liang S, Kisseleva T, and Brenner DA. The Role of NADPH Oxidases (NOXs) in 
Liver Fibrosis and the Activation of Myofibroblasts. Front Physiol. 2016;7:17. 
8. 
Jiang JX, and Torok NJ. NADPH Oxidases in Chronic Liver Diseases. Adv 
Hepatol. 2014;2014. 
9. 
Cross AR, and Segal AW. The NADPH oxidase of professional phagocytes--
prototype of the NOX electron transport chain systems. Biochim Biophys Acta. 
2004;1657(1):1-22. 
10. 
Reinehr R, Becker S, Eberle A, Grether-Beck S, and Haussinger D. Involvement 
of NADPH oxidase isoforms and Src family kinases in CD95-dependent 
hepatocyte apoptosis. J Biol Chem. 2005;280(29):27179-94. 
11. 
Groemping Y, and Rittinger K. Activation and assembly of the NADPH oxidase: a 
structural perspective. Biochem J. 2005;386(Pt 3):401-16. 
12. 
Jiang JX, Fish SR, Tomilov A, Li Y, Fan W, Dehnad A, et al. Non-phagocytic 
Activation of NOX2 is Implicated in Progressive Non-alcoholic Steatohepatitis 
During Aging. Hepatology. 2020. 
13. 
Ahmed SBM, and Prigent SA. Insights into the Shc Family of Adaptor Proteins. J 
Mol Signal. 2017;12:2. 
14. 
Meier T, and Buyse G. Idebenone: an emerging therapy for Friedreich ataxia. J 
Neurol. 2009;256 Suppl 1:25-30. 
15. 
Tomilov A, Allen S, Hui CK, Bettaieb A, and Cortopassi G. Idebenone is a 
cytoprotective insulin sensitizer whose mechanism is Shc inhibition. Pharmacol 
Res. 2018;137:89-103. 
16. 
Schulz JB, Di Prospero NA, and Fischbeck K. Clinical experience with high-dose 
idebenone in Friedreich ataxia. J Neurol. 2009;256 Suppl 1:42-5. 

Pilot Study of Idebenone for NASH; PI: Torok, Natalie 
 
 
25 
 
17. 
Ranen NG, Peyser CE, Coyle JT, Bylsma FW, Sherr M, Day L, et al. A controlled 
trial of idebenone in Huntington's disease. Mov Disord. 1996;11(5):549-54. 
18. 
Gutzmann H, and Hadler D. Sustained efficacy and safety of idebenone in the 
treatment of Alzheimer's disease: update on a 2-year double-blind multicentre 
study. J Neural Transm Suppl. 1998;54:301-10. 
 

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