Clinical trial NCT03764735
Conditions: Dry Eye Syndrome
Keywords: Dry Eye Dry Eye Syndrome SkQ1 KCS Keratoconjunctivitis
Sponsor: Mitotech, SA
Start date: 2018-12-06; Completion date: 2019-02-09
Enrollment: 452 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate whether SkQ1 ophthalmic solutions are safe and effective compared to placebo for the treatment of the signs and symptoms of dry eye syndrome.

Detailed description:
Multi-center, double-masked, randomized, placebo-controlled study comprising 5 visits over the course of approximately 9 weeks. Qualified subjects are randomized 1:1:1 to receive either High Dose SkQ1 ophthalmic solution, Low Dose SkQ1 ophthalmic solution, or Placebo (vehicle of SkQ1 ophthalmic solution).

The Primary Endpoints are:

Change from Baseline (Visit 2) to Visit 5 in Corneal Fluorescein Staining;

Change from Baseline (Visit 2) to Visit 5 in Grittiness Symptom

Arms: arm 1: SkQ1 (Vehicle) arm 2: Low-dose ophthalmic solution arm 3: High-dose ophthalmic solution
Interventions: intervention 1: Low Dose - SkQ1 intervention 2: High dose - SkQ1 intervention 3: SkQ1 (Vehicle)
Intervention descriptions: intervention 1: SkQ1 Low dose ophthalmic solution intervention 2: SkQ1 High Dose ophthalmic solution intervention 3: Vehicle for SkQ1 ophthalmic solution

Protocol documents:
Prot_SAP_000.pdf: 
SkQ1 ophthalmic solution  
Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
Confidential 
Page 1 of 76 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Protocol Title: 
A Phase 3, Multi-Center, Randomized, Double-Masked, 
Placebo-Controlled Clinical Study to Assess the Safety 
and Efficacy of SkQ1 Ophthalmic Solution in the 
Environment and During Challenge in the Controlled 
Adverse Environmental (CAE®) Model for the Treatment 
of Dry Eye Syndrome 
Protocol Number: 
VISTA-1 / 18-110-0004 
Study Phase: 
3 
Product Name: 
SkQ1 Ophthalmic Solution 
IND Number: 
113433 
Indication: 
Dry Eye Syndrome (DES) 
Investigators: 
Multi-Center 
 
Sponsor: 
Mitotech, SA 
42, rue de la Vallée 
L-2661 
Luxembourg 
 
Contract Research 
Organization: 
Ora. Inc. 
300 Brickstone Square, 3rd Floor 
Andover, MA 01810 
 
IRB: 
Alpha IRB 
1001 Avenida Pico 
Suite C, #497 
San Clemente, CA 92673 
 
 
 
Date 
Original Protocol: 
Version 1.0   13 September 2018 
Confidentiality Statement 
This protocol contains confidential, proprietary information of Ora, Inc. and/or Mitotech. 
Further dissemination, distribution or copying of this protocol or its contents is strictly 
prohibited. 
 




SkQ1 ophthalmic solution  
Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
Confidential 
Page 3 of 76 
SYNOPSIS 
Protocol Title: 
A Phase 3, Multi-Center, Randomized, Double-
Masked, Placebo-Controlled Clinical Study to 
Assess the Safety and Efficacy of SkQ1 Ophthalmic 
Solution in the Environment and During Challenge 
in the Controlled Adverse Environmental (CAE®) 
Model for the Treatment of Dry Eye Syndrome 
Protocol Number: 
VISTA-1 / 18-110-0004 
Study Drug: 
1) 0.155 µg/mL SkQ1 ophthalmic solution 
2) 1.55 µg/mL SkQ1 ophthalmic solution  
3) Placebo SkQ1 ophthalmic solution (Vehicle of 
SkQ1 ophthalmic solution) 
Study Phase: 
3 
Study Objective: 
The objective of this study is to compare the safety 
and efficacy of SkQ1 ophthalmic solution to placebo 
for the treatment of the signs and symptoms of dry 
eye syndrome. 
 
Overall Study Design 
 
Structure: 
Multi-center, double-masked, randomized, placebo-
controlled study 
Duration: 
An individual subject’s participation is estimated to 
be approximately 9 weeks (63 days) 
Controls: 
Placebo SkQ1 ophthalmic solution (Vehicle of SkQ1 
ophthalmic solution) 
Dosage/Dose Regimen: 
Subjects eligible to be randomized will receive one 
of the following treatments to be administered 
bilaterally 1-2 drops 
 for 56 days (from Visit 2 
to Visit 5). 
1) 0.155 µg/mL SkQ1 ophthalmic solution  
2) 1.55 µg/mL SkQ1 ophthalmic solution 
3) Placebo SkQ1 ophthalmic solution (Vehicle) 
During a 7-day study run-in period (beginning at the 
end of Visit 1 for the purpose of subject selection) 
prior to randomization, all subjects will receive 1-2 
drops of Placebo SkQ1 ophthalmic solution 
(Vehicle) bilaterally 
   
Summary of Visit Schedule: 
5 visits over the course of approximately 9 weeks 
• Visit 1 = Day -7 ± 1 day, Environmental 
Screening 
• Visit 2 = Day 1, Baseline, Environmental 
Screening Confirmation, Randomization and 
Initiation of Double-Masked Treatment 




















SkQ1 ophthalmic solution  
Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
Confidential 
Page 13 of 76 
TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ............................................................................................................13 
LIST OF ABBREVIATIONS .....................................................................................................17 
1 
INTRODUCTION...............................................................................................................18 
2 
STUDY OBJECTIVES .......................................................................................................20 
3 
CLINICAL HYPOTHESES ..............................................................................................20 
4 
OVERALL STUDY DESIGN ............................................................................................20 
5 
STUDY POPULATION .....................................................................................................21 
5.1 
Number of Subjects (approximate) ........................................................................ 21 
5.2 
Study Population Characteristics .......................................................................... 21 
5.3 
Inclusion Criteria .................................................................................................... 21 
5.4 
Exclusion Criteria .................................................................................................... 22 
5.5 
Withdrawal Criteria (if applicable) ....................................................................... 23 
6 
STUDY PARAMETERS ....................................................................................................24 
6.1 
Efficacy Measures .................................................................................................... 24 
6.1.1 
Primary Efficacy Variables .......................................................................... 24 
6.1.2 
Secondary Efficacy Variables ...................................................................... 24 
6.1.3 
Criteria for Effectiveness ............................................................................. 24 
6.2 
Safety Measures ....................................................................................................... 25 
7 
STUDY MATERIALS ........................................................................................................25 
7.1 
Study Drug(s) ........................................................................................................... 25 
7.1.1 
Run-In .......................................................................................................... 25 
7.1.2 
Study Drug(s)/ Formulation(s) ..................................................................... 25 
7.1.3 
Study Drug Packaging Configuration .......................................................... 25 
7.1.4 
Study Drug Storage and Accountability ...................................................... 25 
7.1.5 
Instructions for Dispensation, Use, and Administration .............................. 26 
7.2 
Other Study Supplies .............................................................................................. 26 
8 
STUDY METHODS AND PROCEDURES .....................................................................27 
8.1 
Subject Entry Procedures ....................................................................................... 27 
8.1.1 
Overview ...................................................................................................... 27 
8.1.2 
Informed Consent......................................................................................... 27 


SkQ1 ophthalmic solution  
Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
Confidential 
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8.1.3 
Washout Intervals ........................................................................................ 27 
8.1.4 
Procedures for Final Study Entry ................................................................. 27 
8.1.5 
Methods for Assignment to Treatment Groups: .......................................... 27 
8.2 
Concurrent Therapies ............................................................................................. 28 
8.2.1 
Prohibited Medications/Treatments ............................................................. 28 
8.2.2 
Escape Medications ..................................................................................... 28 
8.2.3 
Special Diet or Activities ............................................................................. 28 
8.3 
Examination Procedures ......................................................................................... 28 
8.3.1 
Procedures to be Performed at Each Study Visit with Regard to 
Study Objective(s) ..................................................................................................... 28 
8.4 
Schedule of Visits, Measurements and Dosing ..................................................... 35 
8.4.1 
Scheduled Visits........................................................................................... 35 
8.4.2 
Unscheduled Visits ...................................................................................... 35 
8.5 
Compliance with Protocol ....................................................................................... 35 
8.6 
Subject Disposition .................................................................................................. 36 
8.6.1 
Completed Subjects ..................................................................................... 36 
8.6.2 
Discontinued Subjects .................................................................................. 36 
8.7 
Study Termination .................................................................................................. 36 
8.8 
Study Duration ........................................................................................................ 36 
8.9 
Monitoring and Quality Assurance ....................................................................... 36 
9 
ADVERSE EVENTS ..........................................................................................................37 
9.1 
Adverse Event .......................................................................................................... 37 
9.1.1 
Severity ........................................................................................................ 37 
9.1.2 
Relationship to Study Drug .......................................................................... 38 
9.1.3 
Expectedness ................................................................................................ 38 
9.2 
Serious Adverse Events ........................................................................................... 39 
9.3 
Procedures for Reporting Adverse Events ............................................................ 40 
9.3.1 
Reporting a Suspected Unexpected Adverse Reaction ................................ 40 


SkQ1 ophthalmic solution  
Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
Confidential 
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9.3.2 
Reporting a Serious Adverse Event ............................................................. 40 
9.4 
Procedures for Unmasking of Study Drug ............................................................ 41 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ............. 41 
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES............................41 
10.1 Analysis Populations ............................................................................................... 41 
10.2 Statistical Hypotheses .............................................................................................. 42 
10.3 Sample Size .............................................................................................................. 43 
10.4 Statistical Analysis ................................................................................................... 44 
10.4.1 General Considerations ................................................................................ 44 
10.4.2 Unit of Analysis ........................................................................................... 44 
10.4.3 Missing Data ................................................................................................ 44 
10.4.4 Multiplicity Adjustments ............................................................................. 45 
10.4.5 Primary Efficacy Analyses .......................................................................... 45 
10.4.6 Secondary Efficacy Variables ...................................................................... 46 
10.4.7 Safety Variables ........................................................................................... 46 
10.4.8 Interim Analyses .......................................................................................... 47 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ............................................47 
11.1 Protection of Human Subjects................................................................................ 47 
11.1.1 Subject Informed Consent............................................................................ 47 
11.1.2 Institutional Review Board (IRB) Approval ................................................ 47 
11.2 Ethical Conduct of the Study ................................................................................. 47 
11.3 Subject Confidentiality ........................................................................................... 48 
11.4 Documentation ......................................................................................................... 48 
11.4.1 Retention of Documentation ........................................................................ 48 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Study Drug ............................................................................................................... 49 
11.5.1 Labeling/Packaging...................................................................................... 49 
11.5.2 Storage of Study Drug ................................................................................. 49 
11.5.3 Accountability of Study Drug ...................................................................... 49 


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Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
Confidential 
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11.5.4 Return or Disposal of Study Drug ............................................................... 49 
11.6 Recording of Data on Source Documents and electronic Case Reports 
Forms (eCRFs)......................................................................................................... 49 
11.7 Handling of Biological Specimens .......................................................................... 50 
11.1 Publications .............................................................................................................. 50 
12 
REFERENCES ....................................................................................................................51 
13 
APPENDICES .....................................................................................................................52 
Appendix 1:  Schedule of Visits and Measurements .................................................................52 
Appendix 2:  Examination Procedures, Tests, Equipment, and Techniques .........................54 
Appendix 3: Amendment Summary of Changes.......................................................................74 
Appendix 4:  Sponsor and Ora Approvals ................................................................................75 
Appendix 5:  Investigator’s Signature .......................................................................................76 
 
 


SkQ1 ophthalmic solution  
Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
Confidential 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
ANCOVA 
Analysis of covariance 
 
 
 
 
 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
DES 
Dry Eye Syndrome 
DHHS 
Department of Health and Human Services 
eCRF 
electronic case report form 
EKG 
electrocardiograph 
ERC 
ethical review committee 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IND 
investigational new drug application 
IOP 
intraocular pressure 
IRB 
institutional/independent review board 
ITT 
intent-to-treat 
IUD 
intra uterine device 
KCS 
keratoconjunctivitis sicca 
kg 
kilogram 
LASIK 
laser in situ keratomileusis 
logMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGD 
meibomian gland dysfunction 
mL 
milliliter 
mm 
millimeter 
µg  
microgram  
mmHg 
millimeters of mercury 
OD 
right eye 
OS 
left eye 
OSDI 
ocular surface disease index 
OU 
both eyes 
OTC 
over-the-counter 
 
 
 
 
 
VA 
visual acuity 










SkQ1 ophthalmic solution  
Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
Confidential 
Page 22 of 76 
5.4 Exclusion Criteria 
Subjects must not: 
a. Have participated in the previous SkQ1 ophthalmic solution Phase 2 
treatment study; 
b. Have any clinically significant slit lamp findings at Visit 1 that may 
include active blepharitis, meibomian gland dysfunction (MGD), lid 
margin inflammation or active ocular allergies that require therapeutic 
treatment, and/or in the opinion of the investigator may interfere with 
study parameters; 
c. Be diagnosed with an ongoing ocular infection (bacterial, viral, or 
fungal), or active ocular inflammation (e.g. follicular conjunctivitis) at 
Visit 1; 
d. Have worn contact lenses within 7 days of Visit 1 or anticipate using 
contact lenses during the study; 
e. Have used any eye drops within 2 hours of Visit 1; 
f. Have previously had laser-assisted in situ keratomileusis (LASIK) 
surgery within the last 12 months; 
g. Have used Restasis®,Xiidra® or CEQUATM within 60 days of Visit 1; 
h. Have had any ocular and/or lid surgeries within 6 months of Visit 1 or 
any planned over the study period; 
i. Be using or anticipate using temporary punctal plugs during the study 
that have not been stable within 30 days of Visit 1; 
j. Be currently taking any topical ophthalmic prescription (including 
medications for glaucoma) or over-the-counter (OTC) solutions, 
artificial tears, gels or scrubs, and cannot discontinue these 
medications for the duration of the trial (excluding medications 
allowed for the conduct of the study); 
k. Have corrected visual acuity greater than or equal to logMAR+0.7 as 
assessed by Early Treatment of Diabetic Retinopathy Study (ETDRS) 
scale in both eyes at Visit 1; 
l. Have an uncontrolled systemic disease; 
m. Be a woman who is pregnant, nursing or planning a pregnancy; 
n. Be unwilling to submit a urine pregnancy test at Visit 1 and Visit 5 (or 
early termination visit) if of childbearing potential. Non-childbearing 




























SkQ1 ophthalmic solution  
Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
Confidential 
Page 36 of 76 
8.6 Subject Disposition 
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
8.6.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
• adverse events; 
• protocol violations; 
• administrative reasons (e.g., inability to continue due to scheduling 
changes); 
• lost to follow up; 
• sponsor termination of study; 
• subject choice (e.g. withdrawal of consent); and 
• other 
Note: In addition, any subject may be discontinued for any sound medical 
reason at the discretion of the investigator. 
Notification of a subject discontinuation and the reason for discontinuation 
will be made to Ora and/or study sponsor and will be clearly documented 
on the eCRF. 
8.7 Study Termination 
The study may be stopped at any time by the investigator, the sponsor, and/or Ora 
with appropriate notification. 
8.8 Study Duration 
An individual subject’s participation will involve 5 visits over approximately a 9-
week period (63 days). 
8.9 Monitoring and Quality Assurance 
During the course of the study a monitor, or designee, will make routine site visits to 
review protocol compliance, assess study drug accountability and storage conditions, 
subject safety, and ensure the study is being conducted according to the pertinent 
regulatory requirements.  The review of the subjects’ medical records will be 
performed in a manner that adequately maintains subject confidentiality.  Further 
details of the study monitoring will be outlined in a monitoring plan. 
Regulatory authorities of domestic and foreign agencies, Ora, Inc. quality assurance, 
the sponsor and/or its designees may carry out on-site inspections and/or audits, 
which may include source data checks.  Therefore direct access to the original source 
data will be required for inspections and/or audits.  All inspections and audits will be 


SkQ1 ophthalmic solution  
Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
Confidential 
Page 37 of 76 
carried out giving consideration to data protection as well as subject confidentiality to 
the extent that local, state, and federal laws apply. 
9 ADVERSE EVENTS 
9.1 Adverse Event 
An adverse event is defined as any untoward medical occurrence associated with the 
use of a drug in humans, whether or not the event is considered drug-related.  An 
adverse event can therefore be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease occurring after the subject started 
dosing with the study drug, without any judgment about causality.  Any pre-existing 
medical condition that worsens after administration of the study drug will also be 
considered a new adverse event.   
If there is a worsening of a medical condition that was present prior to the 
administration of the study drug, this should also be considered a new adverse event 
and reported.  Any medical condition present prior to the administration of the study 
drug that remains unchanged or improved should not be recorded as a treatment 
emergent adverse event at subsequent visits unless it worsens during treatment. 
Study drug includes the investigational drug under evaluation and any comparator 
drug, placebo, or any other medications required by the protocol given during any 
stage of the study. 
Documentation regarding the adverse event should be made as to the nature, date of 
onset, end date, severity, relationship to study drug, action(s) taken, seriousness, and 
outcome of any sign or symptom observed by the physician or reported by the patient 
upon indirect questioning.  
9.1.1 Severity 
Severity of an adverse event is defined as a qualitative assessment of the 
degree of intensity of an adverse event as determined by the investigator 
or reported to him/her by the patient/subject.  The assessment of severity 
is made irrespective of relationship to study drug or seriousness of the 
event and should be evaluated according to the following scale: 
• Mild: Event is noticeable to the subject, but is easily tolerated and 
does not interfere with the subject’s daily activities. 
• Moderate: Event is bothersome, possibly requiring additional 
therapy, and may interfere with the subject’s daily activities. 
• Severe: Event is intolerable, necessitates additional therapy or 
alteration of therapy, and interferes with the subject’s daily 
activities. 


SkQ1 ophthalmic solution  
Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
Confidential 
Page 38 of 76 
9.1.2 Relationship to Study Drug 
The relationship of each adverse event to the study drug should be 
determined by the investigator using these explanations: 
• Definite: When there are good reason and sufficient documentation 
to demonstrate a direct causal relationship between investigational 
product and AE; 
• Probable: When there are good reasons and sufficient 
documentation to assume a causal relationship in the sense of 
plausible, conceivable, likely but not necessarily highly probable. 
• Possible: When there is sufficient information to accept the 
possibility of a causal relationship in the sense of not impossible 
and not unlikely, although the connection is uncertain or doubtful, 
for example, due to missing data or insufficient evidence. 
None: When there is sufficient information to accept a lack of a 
causal relationship, in the sense of impossible and improbable. 
• Unclassified: When the causal relationship is not assessable for 
whatever reason due to insufficient evidence, conflicting data or 
poor documentation. 
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the study drug caused the adverse event.  
“Reasonable possibility” means there is evidence to suggest a causal 
relationship between the study drug and the adverse event.  Types of 
evidence that would suggest a causal relationship between the study drug 
and the adverse event include: a single occurrence of an event that is 
uncommon and known to be strongly associated with drug exposure (e.g., 
angioedema, hepatic injury, Stevens-Johnson Syndrome); one or more 
occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the 
drug (e.g., tendon rupture); an aggregate analysis of specific events 
observed in a clinical trial (such as known consequences of the underlying 
disease or condition under investigation or other events that commonly 
occur in the study population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment group than in a 
concurrent or historical control group. 
9.1.3 Expectedness 
The expectedness of an adverse event should be determined based upon 
existing safety information about the study drug using these explanations: 
• Unexpected: An adverse event that is not listed in the 
Investigator’s brochure or is not listed at the specificity or severity 
that has been observed. 
• Expected: An adverse event that is listed in the Investigator’s 
brochure at the specificity and severity that has been observed. 


SkQ1 ophthalmic solution  
Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
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Page 39 of 76 
• Not Applicable: Any adverse event that is unrelated to the study 
drug. 
Adverse events that are mentioned in the Investigator’s brochure as 
occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with 
the particular drug under investigation are to be considered unexpected. 
The investigator should initially classify the expectedness of an adverse 
event, but the final classification is subject to the Medical Monitor’s 
determination. 
9.2 Serious Adverse Events 
An adverse event is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening adverse event; 
Note:  An adverse event is considered “life-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject 
at immediate risk of death.  It does not include an adverse event that, had it 
occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization; 
Note:  The term “inpatient hospitalization” refers to any inpatient admission 
(even if less than 24 hours).  For chronic or long-term inpatients, inpatient 
admission includes transfer within the hospital to an acute/intensive care 
inpatient unit.  Inpatient hospitalization does not include:  emergency room 
visits; outpatient/same-day/ambulatory procedures; observation/short stay 
units; rehabilitation facilities; hospice facilities; nursing homes; or clinical 
research/phase 1 units. 
Note:  The term “prolongation of existing hospitalization” refers to any 
extension of an inpatient hospitalization beyond the stay anticipated or 
required for the reason for the initial admission as determined by the 
investigator or treating physician. 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
Note:  A serious adverse event specifically related to visual threat would be 
interpreted as any potential impairment or damage to the subject’s eyes (e.g., 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic 
nerve). 


SkQ1 ophthalmic solution  
Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
Confidential 
Page 40 of 76 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, are life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
9.3 Procedures for Reporting Adverse Events 
All adverse events and their outcomes must be reported to Ora, the study sponsor, and 
the IRB as required by the IRB, federal, state, or local regulations and governing 
health authorities and recorded on the appropriate eCRF.  
9.3.1 Reporting a Suspected Unexpected Adverse Reaction 
All adverse events that are ‘suspected’ and ‘unexpected’ are to be reported 
to Ora, the study sponsor and the IRB as required by the IRB, federal, 
state, or local regulations and governing health authorities. 
9.3.2 Reporting a Serious Adverse Event 
To ensure subject safety, all serious adverse events, regardless of 
relationship to the study drug, must be immediately reported.  All 
information relevant to the serious adverse event must be recorded on the 
appropriate eCRF.  The investigator is obligated to pursue and obtain 
information requested by Ora and/or the sponsor in addition to that 
information reported on the eCRF.  All subjects experiencing a serious 
adverse event must be followed up and the outcome reported. 
In the event of a serious adverse event, the investigator must notify Ora 
and the sponsor immediately (within 24 hours); obtain and maintain in 
his/her files all pertinent medical records, information, and medical 
judgments from colleagues who assisted in the treatment and follow-up of 
the subject; provide Ora and the study sponsor with a complete case 
history, which includes a statement as to whether the event was or was not 
suspected to be related to the use of the study drug; and inform the IRB of 
the adverse event within their guidelines for reporting serious adverse 
events.  
Serious adverse events should be reported within one day to the contacts 
listed below:  
                                   
 
                                    
 
                            
 
 
 


SkQ1 ophthalmic solution  
Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
Confidential 
Page 41 of 76 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.4 Procedures for Unmasking of Study Drug 
All subjects, investigators, and study personnel involved with the conduct of the study 
will be masked with regard to treatment assignments. When medically necessary, the 
investigator may need to determine what treatment arm has been assigned to a 
subject.  When possible (i.e., in non-emergent situations), Ora and/or the study 
sponsor should be notified before unmasking study drug. 
If an investigator identifies a medical need for unmasking the treatment assignment of 
a subject, he/she should contact Ora and/or the medical monitor prior to unmasking 
the identity of the IP, if possible. Ora will ask the site to complete and send them the 
Unmasking Request Form. Ora will notify Mitotech and jointly will determine if the 
unmasking request should be granted. They may consult the medical monitor as 
needed. The result of the request will be documented on the Unmasking Request 
Form. If approval is granted to unmask a subject, written permission via the 
Unmasking Request Form will be provided to the investigator. The investigator will 
unmask the subject 
. The investigator will complete the Unmasking 
Memo form and include it in the subject’s study file and provide a copy for the Trial 
Master File (TMF). For each unmasked request, the reason, date, signature, and name 
of the person who unmasked the subject, must be noted in the subject’s study file. 
9.5 Type and Duration of the Follow-up of Subjects after Adverse 
Events 
Adverse events that are ongoing at the end of the study visit will be followed.  Phone 
calls will be placed with any subject who experiences an adverse event until the issue 
is resolved or the condition is considered ongoing and stable. 
10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
10.1 Analysis Populations 
Intent-to-Treat Population – The intent-to-treat (ITT) population includes all 
randomized subjects. The primary and secondary efficacy analyses will be performed 












SkQ1 ophthalmic solution  
Sponsor: Mitotech, SA 
Clinical Trial Protocol: VISTA-1 / 18-110-0004 
Final V 1.0 13Sep2018 
Confidential 
Page 47 of 76 
10.4.8 Interim Analyses 
There will be no interim analyses. 
11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE 
ISSUES 
This study will be conducted in compliance with the protocol, Good Clinical Practices 
(GCPs), including the International Conference on Harmonization (ICH) Guidelines, and 
in general, consistent with the Declaration of Helsinki.  In addition, all applicable local, 
state, and federal requirements relevant to the use of study drugs in the countries involved 
will be adhered to. 
11.1 Protection of Human Subjects 
11.1.1 Subject Informed Consent 
Informed consent/assent must take place before any study specific 
procedures are initiated.  Signed and dated written informed consent must 
be obtained from each subject prior to enrollment into the study.   
All informed consent forms must be approved for use by the sponsor and 
receive approval/favorable opinion from an IRB prior to their use.  If the 
consent form requires revision (e.g., due to a protocol amendment or 
significant new safety information), it is the investigator’s responsibility to 
ensure that the amended informed consent is reviewed and approved by 
Ora prior to submission to the governing IRB and that it is read, signed 
and dated by all subjects subsequently enrolled in the study as well as 
those currently enrolled in the study. 
11.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with Institutional Review 
Board regulations (U.S. 21 CFR Part 56.103).  The investigator must 
obtain appropriate IRB approval before initiating the study and re-
approval at least annually. 
Only an IRB approved version of the informed consent form will be used. 
11.2 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 


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11.3 Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the investigator and his/her staff with adequate precautions 
as to ensure that the confidentiality of the data in accordance with local, state, and 
federal laws and regulations. 
Monitors, auditors and other authorized representatives of Ora, the sponsor, the IRB 
approving this study, the FDA, the DHHS, other domestic government agencies, and 
other foreign regulatory agencies will be granted direct access to the study subject’s 
original medical and study records for verification of the data and/or clinical trial 
procedures. Access to this information will be permitted to the aforementioned 
individuals to the extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but 
the subject’s identity will not be disclosed in these documents. 
11.4 Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic 
charts, the investigator’s study subject files, as well as the results of diagnostic tests 
such as X-rays, laboratory tests, and EKGs.  The investigator’s copy of the eCRF 
serves as the investigator’s record of a subject’s study-related data. 
11.4.1 Retention of Documentation 
All study-related source documents, correspondence, patient records, 
consent forms, record of the distribution and use of all study drug and 
copies of case report forms should be maintained on file for at least two 
years after the last approval of a marketing application in an ICH region 
and until there are no pending or contemplated marketing applications in 
an ICH region; or until at least two years have elapsed since the formal 
discontinuation of clinical development of the study drug. These 
documents will be retained for a longer period if required by the 
applicable regulatory requirements or by an agreement with the sponsor.  
It is the responsibility of the sponsor to inform the investigator/institution 
as to when these documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons 
withdraws from the responsibility of keeping study records, custody must 
be transferred to a person who will accept the responsibility.  The sponsor 
must be notified in writing of the name and address of the new custodian. 




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through the incorrect entry and writing the revision next to the corrected data).  An 
individual who has corrected a data entry should make clear who made the correction 
and when, by adding to the correction his/her initials as well as the date of the 
correction 
11.7 Handling of Biological Specimens 
Tear samples will be submitted to one or more central laboratories and/or analytical 
laboratories for processing, storage and analysis. All laboratories meet Good 
Laboratory Practice requirements. 
11.1 Publications 
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study.  Authorship will be established before writing the manuscript.  
Ora and the study sponsor will have the final decision regarding the manuscript and 
publication. 
 
 


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Markovets AM, Fursova AZ, Kolosova NG. Therapeutic action of the 
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Neroev VV, Archipova MM, Bakeeva LE, et al. Mitochondria-targeted 
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