Clinical trial NCT02653391
Conditions: Fuchs' Corneal Endothelial Dystrophy (FCED)
Keywords: Fuchs' Corneal Endothelial Dystrophy FCED Ocuvia™ MTP-131
Sponsor: Stealth BioTherapeutics Inc.
Start date: 2016-02-01; Completion date: 2018-12-01
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1/2 prospective, randomized, double-masked, and vehicle-controlled trial in two parts to evaluate the safety, tolerability, and efficacy of elamipretide topical ophthalmic solution in patients with Fuchs' Corneal Endothelial Dystrophy (FCED) presenting with mild to moderate corneal edema.

Detailed description:
This is a Phase 1/2 trial in two parts. Part A is a prospective, randomized, double-masked, vehicle controlled, paired-eye study in approximately 16 subjects to evaluate safety, tolerability and efficacy of elamipretide 1.0% topical ophthalmic solution in patients with Fuchs' Corneal Endothelial Dystrophy (FCED) presenting with mild to moderate corneal edema. Part B is a prospective, randomized double-masked, vehicle controlled study in approximately 11 subjects to evaluate safety, tolerability, and efficacy of elamipretide 3.0% topical ophthalmic solution in patients with FCED presenting with mild to moderate corneal edema.

Arms: arm 1: Part A Each subject will receive one drop of elamipretide 1.0% ophthalmic solution BID in the randomly selected study eye (Cohort 1). arm 2: Part B Each subject will receive one drop of elamipretide 3.0% ophthalmic solution BID in both the right and left study eyes (Cohort 2). arm 3: Part A: Each subject will receive one drop of vehicle solution BID in the paired eye of the randomly selected study eye (Cohort 1). arm 4: Part B Each subject will receive one drop of vehicle solution BID in both the right and left study eyes (Cohort 2).
Interventions: intervention 1: Part A Elamipretide 1.0% Ophthalmic Solution intervention 2: Part B Elamipretide 3.0% Ophthalmic Solution intervention 3: Part A Placebo intervention 4: Part B Placebo
Intervention descriptions: intervention 1: Part A Each subject will receive one drop of elamipretide 1.0% ophthalmic solution BID in the randomly selected study eye. intervention 2: Part B Each subject will receive one drop of elamipretide 3.0% ophthalmic solution BID in both eyes. intervention 3: Part A Each subject will receive one drop of vehicle ophthalmic solution BID in the paired eye of the randomly selected study eye. intervention 4: Part B: Each subject will receive one drop of vehicle ophthalmic solution BID in both eyes.

Protocol documents:
Prot_SAP_000.pdf: 
  
MTP-131 Ophthalmic Solution (Ocuvia™)  
  
  
Protocol SPIFD-101  
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SPIFD-101 PROTOCOL: FUCHS’ CORNEAL ENDOTHELIAL DYSTROPHY   
  
A PROSPECTIVE, RANDOMIZED, DOUBLE-MASKED, VEHICLE CONTROLLED, PAIRED-EYE  
PHASE 1/2 CLINICAL STUDY TO EVALUATE THE SAFETY, TOLERABILITY AND EFFICACY OF  
MTP-131 TOPICAL OPHTHALMIC SOLUTION (OCUVIA) IN SUBJECTS WITH FUCHS’ CORNEAL  
ENDOTHELIAL DYSTROPHY (FCED) PRESENTING WITH MILD TO MODERATE CORNEAL  
EDEMA  
 
 
 
NCT02653391 
 
 
 
18 August 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
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SPIFD-101 PROTOCOL: FUCHS’ CORNEAL ENDOTHELIAL DYSTROPHY   
  
A PROSPECTIVE, RANDOMIZED, DOUBLE-MASKED, VEHICLE CONTROLLED, PAIRED-EYE  
PHASE 1/2 CLINICAL STUDY TO EVALUATE THE SAFETY, TOLERABILITY AND EFFICACY OF  
MTP-131 TOPICAL OPHTHALMIC SOLUTION (OCUVIA) IN SUBJECTS WITH FUCHS’ CORNEAL  
ENDOTHELIAL DYSTROPHY (FCED) PRESENTING WITH MILD TO MODERATE CORNEAL  
EDEMA  
  
Study Phase:  
Phase 1/2  
  
Product Name:  
MTP-131 Ophthalmic Solution (Ocuvia™)  
  
IND Number:  
114,234  
 
  
Formulation:  
Topical Ophthalmic  
  
Study No.:  
SPIFD-101  
  
Sponsor:  
Stealth BioTherapeutics Inc.  
275 Grove Street, Suite 3-107  
Newton, MA  02466  
  
Sponsor Contact:  
Greg Gordon, MD  
  
Investigators:  
Michael B. Raizman, M.D.  
Ophthalmic Consultants of Boston – Boston, MA, USA 
  
Edward Holland, M.D.  
Cincinnati Eye Institute – Cincinnati, OH, USA  
 
  
Protocol Date/Version:  
18 August 2015 / Version 1.0  
  
Confidentiality Statement  
 
The information contained in this document is confidential and is the property of Stealth  
BioTherapeutics Inc.  No part of it may be transmitted, reproduced, published, or used by 
anyone without the written permission of Stealth BioTherapeutics Inc.   
 


  
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Table 1:  Emergency Contact Information  
Role in Study  
Name  
Address and Telephone Number  
Investigator(s)  
Michael B. Raizman, MD  
  
  
  
  
Edward Holland, M.D  
  
Ophthalmic Consultants of Boston  
50 Staniford Street, Suite 600  
Boston, MA 02114 +1 
(617) 314-2703  
  
Cincinnati Eye Institute  
580 South Loop Road, Suite 200  
Edgewood, KY 41017  
+1(859) 331-9000 ext. 4120  
Sponsor Medical Monitor  
Gregory Gordon, MD   
Stealth BioTherapeutics Inc.  
275 Grove Street, Suite 3-107  
Newton, MA 02466  
+1 (617) 936-7778  
  
  
  
  
  
  
  
  
  
  
  
  
1.  
SYNOPSIS  
Investigational Drug Product:  
MTP-131 1.0% Ophthalmic Solution  (Ocuvia™)  
Active Ingredient:  
MTP-131  


  
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Study Title:  
A Prospective, Randomized, Double-Masked, Vehicle Controlled, Paired-Eye 
Phase 1/2 Clinical Study To Evaluate the Safety, Tolerability and Efficacy of  
MTP-131 Topical Ophthalmic Solution (Ocuvia) in Subjects with Fuchs’ 
Corneal Endothelial Dystrophy (FCED) Presenting with Mild to Moderate 
Corneal Edema  
Study Number:  
SPIFD-101  
Study Phase:  
Phase 1/2  
Study Objective:  
To evaluate the safety, tolerability and efficacy of MTP-131 1.0% ophthalmic 
solution relative to vehicle administered topically two times per day (BID) for 
12 weeks in the treatment of FCED presenting with mild to moderate corneal 
edema.  
Study Design:  
This will be a prospective, randomized, double-masked, vehicle controlled, 
paired-eye, up to 2-center study in which approximately 16 FCED subjects 
presenting with mild to moderate corneal edema are planned to be treated with 
1 drop of MTP-131 1.0% ophthalmic solution in the randomly selected study 
eye BID and 1 drop of vehicle ophthalmic solution BID in the fellow control 
eye.  
  
Written informed consent will be obtained from all subjects or their legal 
guardian(s) prior to the Screening Visit. Once written consent has been 
provided, data will be collected from a complete pre-treatment examination, 
consisting of vital signs, routine blood chemistries, serum pregnancy test for 
women of child-bearing potential, measurement of best corrected visual acuity 
(BCVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) 
scale, manifest refraction, contrast sensitivity, specular microscopy, corneal 
pachymetry, Pentacam, intraocular pressure (IOP) measurement, and slit lamp 
examination.    
  
This Screening Visit examination will be performed no more than 28 days 
prior to the Baseline Visit.  If applicable, urine pregnancy testing will be 
performed prior to initiation of treatment.  
  
The study eye will be determined via randomization. Patients will be 
considered enrolled in the study upon randomization.  The day of 
randomization is defined as Study Day 1.   
  
Patients will receive one drop of MTP-131 1.0% ophthalmic solution topically 
BID to the randomly selected study eye and one drop of vehicle BID to the 
fellow control eye.  At the time of randomization, patients will be read a 
standard script explaining the importance of applying the correct drug product 
to each eye on a twice per day basis.  
Investigational Product, Dose 
and Mode of Administration:  
MTP-131 1.0% ophthalmic solution administered topically BID to the study 
eye and vehicle administered topically BID to the fellow control eye.  
Study Population:  
Approximately 16 subjects with FCED and mild to moderate corneal edema in 
both eyes (OU) documented by subject history and medical records, clinical 
examination, and ophthalmic testing procedures.  Subjects will be enrolled at 
up to 2 sites in the United States.  


  
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Inclusion Criteria:  
study:  
1.  
t must meet the following criteria to be eligible for inclusion in the  
Adults ≥18 years old at the time of Screening Visit  
2.  Diagnosis of FCED OU based on clinical and ophthalmic test 
findings  
3.  Clinical evidence of corneal edema OU diagnosed with FCED, 
including one or more of the following signs: corneal epithelial 
microcysts, corneal epithelial bullae, stromal folds, or stromal haze  
4.  Subjective complaint of progressive visual change OU or subjective 
complaint of greater visual disturbance in the morning compared to 
afternoon or evening OU  
5.  Central corneal thickness of 550 µm to 700 µm (inclusive) in both 
eyes diagnosed with FCED, as measured by ultrasonic pachymetry at 
the time of Screening Visit and Baseline Visit  
6.  Best-corrected distance visual acuity (BCVA) of 20/32 to 20/320  
(inclusive) at the time of Screening Visit and Baseline Visit OU  
7.  Media clarity sufficient for specular microscopy  
8.  Patient cooperation sufficient for adequate ophthalmic testing and 
anatomic assessment   
9. Able to self-administer eye drops as demonstrated at Screening or 
having a care provider who can do so  
10. Women of childbearing potential must agree to use one of the 
following methods of birth control from the date they sign the 
informed consent form (ICF) until after the last study visit (Followup 
Visit):  
a.) 
Abstinence, when it is in line with the preferred and 
usual lifestyle of the subject;  
b.) 
Maintenance of a monogamous relationship with a 
male partner who has been surgically sterilized by vasectomy 
(vasectomy procedure must have been conducted at least 60 
days prior to the Screening Visit or confirmed via sperm 
analysis);  
c.) 
Barrier method (e.g., condom or occlusive cap) with 
spermicidal foam/gel/film/cream AND either hormonal 
contraception (oral, implanted or injectable) or an 
intrauterine device or system.  
Note: Non-childbearing potential is defined as surgical sterilization 
(i.e., bilateral oophorectomy, hysterectomy, or tubal ligation) or 
postmenopausal (defined as not having a period for at least 12 
consecutive months prior to Screening).  
11. Able to give informed consent and willing to comply with all study 
visits and examinations  


  
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Exclusion Criteria:  
A subject who meets any of the following criteria will be excluded from the 
study:  
Ocular conditions  
1. Corneal findings of any type (including, but not limited to stromal 
haze or stromal scarring), in either eye, that, based on investigator’s 
assessment, limit the probability of visual improvement after corneal 
deturgescence  
2. Any ocular pathology requiring treatment with topical ophthalmic 
drops, with the exception of glaucoma or ocular hypertension   
3. Concurrent use of any and all topical ophthalmic medications, 
prescription and non-prescription (with the exception of study 
medication, or stable use of topical prostaglandin analogs, 
alphaadrenergic agents, and beta-blockers) 1 week prior to Screening 
Visit and throughout the duration of the study  
4. Use of topical hypertonic saline drops for 3 days prior to Screening 
and throughout the duration of the study  
5. Any active ocular or periocular infection; any history of recurrent or 
chronic infection or inflammation in either eye  
6. History of herpetic infection in either eye  
7. History of corneal disease (other than FCED) or corneal surgery in 
either eye  
8. Measurable central corneal edema based on investigator’s assessment  
9. Current use or likely need for the use of contact lens at any time 
during the study  
10. History of punctual cautery, non-dissolvable punctual plug implants 
within 1 year of the Screening Visit, or collagen punctual plugs 
within 6 weeks of the Screening Visit, or anticipated use of any of 
these treatments in either eye during the study  
11. Concurrent disease in either the study eye or fellow eye that could 
require medical or surgical intervention during the study period  
12. History of previous corneal or anterior segment surgery such as 
LASIK, photorefractive keratectomy, endothelial keratoplasty, 
penetrating keratoplasty, cataract surgery or glaucoma surgery.  
  
Systemic conditions  
13. Concurrent use of topical or systemic cyclosporine A for 3 weeks 
prior to the Screening Visit or during the study   
14. Any disease or medical condition that in the opinion of the 
investigator would prevent the subject from participating in the study 
or might confound study results  
  
General  
15. Participation in any other investigational drug or device clinical trials 
within 30 days prior to enrollment, or planning to participate in any  


  
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other investigational drug or device clinical trials within 30 days of 
study completion   
16. History of allergic reaction to the investigational drug or any of its 
components  
  
17. Current use of or likely need for any excluded medication, including 
systemic medications known to be toxic to or affect the cornea (e.g., 
carbonic anhydrase inhibitors)  
18. Women who are pregnant or lactating  
Planned Duration of 
Treatment:  
Twelve weeks, with a four week follow-up period for safety.  
Visit Schedule:  
• 
Screening (Day -28 to Day 1)  
• 
Baseline evaluation and enrollment (Day 1)  
• 
Week 1 (± 3 days)  
• 
Week 4 (± 3 days)  
• 
Week 8 (± 3 days)  
• 
Week 12 (± 3 days; End-of-Treatment Visit)  
• 
Week 16 (± 3 days; Follow-up Visit)  
Primary (Safety) Endpoints:  
• 
The incidence and severity of systemic and ocular adverse events (AEs)   
• 
Change from Baseline in slit lamp findings  
• 
Change from Baseline in intraocular pressure (IOP)  
  
Secondary (Efficacy) 
Endpoints:  
• 
Change from Baseline in central corneal thickness •  Change from 
Baseline in best corrected visual acuity (BCVA, ETDRS scale)  
• 
Change from Baseline in endothelial cell count  
• 
Change from Baseline in endothelial cell morphology including:  
o 
Hexagonality o  Cell density  
o 
Coefficient of variation  
• 
Change from Baseline in:  
o 
Corneal area affected by microcysts o 
 
Number, size, and location of corneal bullae  
o 
Severity (as determined by investigator) of 
corneal stromal folds  
• 
Change from Baseline in contrast sensitivity  
  
Sample Size:  
For this Phase 1/2 study, no formal hypothesis testing is planned.  The sample 
size of approximately 16 subjects is based on a reasonably sized study for 
demonstrating clinical safety, tolerability and initial efficacy.  


  
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Statistical Methods:  
Analysis Populations: All subjects who receive at least one dose of study drug 
will be included in the Safety Population.   
  
Safety Analyses: AEs will be summarized by system organ class (SOC) and 
preferred term (PT), presenting the number and percentage of subjects having  
 
AEs.  Severity and relationship to study drug will be listed as appropriate.  
Any formal statistical testing will be considered exploratory.   
  
Efficacy Analyses: Baseline demographic characteristics will be presented.  
Continuous variables will be summarized by descriptive statistics (sample 
size, mean, standard deviation, median, and minimum and maximum). 
Discrete variables will be summarized by frequencies and percentages.  All 
study data are to be displayed in the data listings. Statistical analysis of this 
study will be the responsibility of the sponsor or its designee. Subject 
disposition summaries will include the number of subjects treated (i.e., in the 
Safety population).  The number and percentage of subjects who complete or 
discontinue from the study will be summarized by reason.  Subject’s age, sex, 
weight, height, BMI, and other demographic characteristics will be recorded 
and summarized.  Medical history will be listed.  
 
 


  
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2.  
TABLE OF CONTENTS  
1.  SYNOPSIS .......................................................................................................................................................... 3 
2.  TABLE OF CONTENTS ........................................................................................................................................ 9 
3.  LIST OF ABBREVIATIONS AND DEFINITIONS .................................................................................................... 12 
4.  INTRODUCTION .............................................................................................................................................. 13 
4.1.  INTRODUCTION .................................................................................................................................................... 13 
5.  STUDY OBJECTIVES ......................................................................................................................................... 14 
5.1.  PRIMARY OBJECTIVES ............................................................................................................................................ 14 
6.  INVESTIGATIONAL PLAN ................................................................................................................................. 14 
6.1.  SUMMARY OF DESIGN ........................................................................................................................................... 14 
6.2.  DISCUSSION OF DESIGN AND CONTROL ..................................................................................................................... 15 
6.2.1.  Dose Justification ..................................................................................................................................... 15 
6.3.  SCHEDULE OF EVENTS ........................................................................................................................................... 15 
7.  STUDY POPULATION ....................................................................................................................................... 19 
7.1.  NUMBER OF SUBJECTS PLANNED ............................................................................................................................. 19 
7.2.  STUDY POPULATION ............................................................................................................................................. 19 
7.2.1.  Inclusion Criteria ...................................................................................................................................... 19 
7.2.2.  Exclusion Criteria ..................................................................................................................................... 20 
7.3.  DISCONTINUATION ............................................................................................................................................... 21 
7.3.1.  Discontinuation of Subjects ..................................................................................................................... 21 
8.  TREATMENTS .................................................................................................................................................. 21 
8.1.  TREATMENTS ADMINISTERED.................................................................................................................................. 21 
8.2.  DISCONTINUATION OF TREATMENT .......................................................................................................................... 22 
8.2.1.  Dose Modification .................................................................................................................................... 22 
8.2.2.  Subject Discontinuation ........................................................................................................................... 22 
8.3.  TREATMENTS ....................................................................................................................................................... 22 
8.3.1.  Study Drug Identification ......................................................................................................................... 22 
8.3.2.  Packaging, Labeling, and Storage ........................................................................................................... 22 
8.3.3.  Treatment Logistics and Accountability ................................................................................................... 22 
8.4.  MASKING ........................................................................................................................................................... 23 
8.5.  CONCOMITANT MEDICATIONS ................................................................................................................................ 23 
8.6.  STUDY VISIT DESCRIPTIONS .................................................................................................................................... 23 
8.6.1.  Screening (Day -28 to Day 1) ................................................................................................................... 23 
8.6.2.  Baseline Visit (Day 1) ............................................................................................................................... 24 
8.6.3. Week 1 (+/-3 days).................................................................................................................................... 25 
8.6.4. Week 4 (+/-3 days).................................................................................................................................... 26 
8.6.5. Week 8 (+/-3 days).................................................................................................................................... 26 
8.6.6.  End of Treatment Week 12 (+/-3 days) .................................................................................................... 27 
8.6.7.  Follow-up Week 16 (+/-3 days) ................................................................................................................ 27 
8.6.8.  Early Discontinuation Visit/Unscheduled Visits ....................................................................................... 28 


  
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9.  EFFICACY, SAFETY EVALUATIONS, SAMPLE COLLECTION AND TESTING, AND APPROPRIATENESS OF  ............. 28 
MEASURES .......................................................................................................................................................... 28 
9.1.  EFFICACY MEASURES ............................................................................................................................................ 28 
9.2.  SAFETY EVALUATIONS ........................................................................................................................................... 29 
9.2.1.  Adverse Events ......................................................................................................................................... 29 
9.3.  PRE-TREATMENT EVENTS....................................................................................................................................... 30 
9.4.  BASELINE MEDICAL CONDITIONS ............................................................................................................................. 30 
9.4.1.  Abnormal Laboratory and Other Abnormal Investigational Findings ...................................................... 30 
9.4.2.  Serious Adverse Events ............................................................................................................................ 30 
9.4.3.  Events that Do Not Meet the Definition of a Serious Adverse Event ....................................................... 31 
9.4.4.  Recording of Adverse Events .................................................................................................................... 31 
9.5.  INVESTIGATOR ASSESSMENTS ................................................................................................................................. 32 
9.5.1.  Severity/Intensity ..................................................................................................................................... 32 
9.5.2.  Relationship to the Investigational Medicinal Product ............................................................................ 32 
9.6.  ADVERSE EVENT REPORTING PERIOD ....................................................................................................................... 32 
9.7.  SERIOUS ADVERSE EVENT EXPEDITED REPORTING ....................................................................................................... 33 
9.8.  PREGNANCY AND IN UTERO DRUG EXPOSURE ............................................................................................................ 34 
9.9.  RESPONSIBILITIES TO REGULATORY AUTHORITIES, INVESTIGATORS, ETHICS COMMITTEES, AND ETHICAL/INSTITUTIONAL REVIEW 
BOARDS ..................................................................................................................................................................... 34 
9.10.  SAMPLE COLLECTION AND TESTING ........................................................................................................................ 35 
9.11.  APPROPRIATENESS OF MEASURES.......................................................................................................................... 35 
10.  SAMPLE SIZE AND STATISTICAL METHODS .................................................................................................... 36 
10.1.  DETERMINATION OF SAMPLE SIZE .......................................................................................................................... 36 
10.2.  STATISTICAL AND ANALYTICAL PLANS ..................................................................................................................... 36 
10.2.1.  General Considerations .......................................................................................................................... 36 
10.2.2.  Subject Disposition ................................................................................................................................. 36 
10.2.3.  Subject Characteristics ........................................................................................................................... 36 
10.2.4. Concomitant Therapy ............................................................................................................................. 37 
10.2.5. Treatment Compliance ........................................................................................................................... 37 
10.2.6.  Endpoints and Methodology.................................................................................................................. 37 
10.2.7.  Secondary (Efficacy) Endpoints .............................................................................................................. 37 
10.2.8.  Safety Analyses ...................................................................................................................................... 37 
11.  STUDY MONITORING .................................................................................................................................... 39 
11.1.  SOURCE DOCUMENT REQUIREMENTS ..................................................................................................................... 39 
11.2.  CASE REPORT FORM REQUIREMENTS ..................................................................................................................... 39 
11.3.  STUDY MONITORING .......................................................................................................................................... 39 
12.  DATA QUALITY ASSURANCE .......................................................................................................................... 39 
12.1.  DATA CAPTURE SYSTEM ...................................................................................................................................... 40 
13.  AUDITS AND INSPECTIONS ............................................................................................................................ 40 
14.  INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ........................................... 41 
14.1.  INFORMED CONSENT .......................................................................................................................................... 41 


  
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14.2.  SUBJECT CONFIDENTIALITY AND DATA PROTECTION .................................................................................................. 41 
14.3.  ETHICAL REVIEW ................................................................................................................................................ 41 
14.4.  REGULATORY CONSIDERATIONS ............................................................................................................................ 42 
14.4.1.  Protocol Signatures ................................................................................................................................ 42 
14.4.2.  Final Report Signature ........................................................................................................................... 42 
14.4.3.  Study Monitoring ................................................................................................................................... 42 
14.4.4.  Retention of Records .............................................................................................................................. 43 
14.4.5.  Disclosure of Information ...................................................................................................................... 43 
15. REFERENCES .................................................................................................................................................. 44 
SPONSOR’S PROTOCOL SIGNATURE PAGE ........................................................................................................... 46 
INVESTIGATOR’S PROTOCOL SIGNATURE PAGE ................................................................................................... 46 
ATTACHMENT 1.  SPIFD-101 CLINICAL LABORATORY TESTS ................................................................................. 47 
 
 
 


  
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3.  
LIST OF ABBREVIATIONS AND DEFINITIONS  
The following abbreviations and specialist terms are used in this study protocol:  
Abbreviation  
Definition or Explanation  
 
AE  
Adverse Event  
ATP  
Adenosine triphosphate  
BCVA  
Best Corrected Visual Acuity  
BID   
Twice daily   
CST  
Central Subfield Thickness  
eCRF  
Electronic Case Report Form  
EC  
Ethics committee  
ERB  
Ethical Review Board  
ETDRS  
Early Treatment Diabetic Retinopathy Study  
FCED  
Fuchs’ Corneal Endothelial Dystrophy  
GCP  
Good Clinical Practice  
ICF  
Informed Consent Form  
ICH  
International Conference on Harmonisation  
IMP  
Investigational Medicinal Product  
IOP  
Intraocular Pressure  
IRB  
Institutional Review Board  
ITT  
Intention-to-Treat  
LASIK  
Laser in-situ keratomileusis  
M1, M2  
Major metabolite of MTP-131  
MedDRA  
Medical Dictionary for Regulatory Activities  
PRDXs  
Peroxiredoxins  
PT  
Preferred term  
ROS  
Reactive Oxygen Species  
RPE  
Retinal pigmented epithelium  
SAE  
Serious Adverse Event  


  
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SLE  
Slit Lamp Examination  
SOC  
System organ class  
SUSAR  
Suspected Unexpected Serious Adverse Reaction  
 
4.  
INTRODUCTION   
 
4.1.  
Introduction  
Mitochondria normally produce a small amount of reactive oxygen species (ROS) including 
superoxide anions and hydrogen peroxide as physiological byproducts of electron transport and 
adenosine triphosphate (ATP) production.  Under conditions of metabolic or genetic stress, 
mitochondria can become a major endogenous source of ROS such as superoxide anions, 
peroxynitrite, and hydroxyl radicals.  Increased oxidative damage to the inner membrane of the 
mitochondria leads to imbalances in the electron transport chain, resulting in further increased 
superoxide and hydrogen peroxide production, which in turn can initiate a cycle of further 
damage to membrane and mitochondrial proteins and mitochondrial DNA.  Excess ROS can 
damage mitochondrial proteins and lipids to a point that triggers mitochondria to release 
cytochrome c and provoke apoptosis (Madsen-Bouterse, 2008).  Apoptotic cell death can 
manifest in the eye as visual abnormalities affecting the retina and cornea.  
Fuchs’ Corneal Endothelial Dystrophy (FCED) is a vision-threatening condition that is 
characterized by the loss of corneal endothelial cell function and quantity. FCED typically 
presents in the fourth and fifth decade of life and progresses to vision loss over another one or 
two decades (Adamis, 1993). Vision loss can result from several pathologic changes: the 
development of corneal guttae, which degrade the refractive properties of the cornea; the 
presence of stromal edema, arising from the increased permeability of Descemet’s membrane 
and endothelium along with pump dysfunction in the endothelium; and the development of 
epithelial bullae (Waring, 1982).  If untreated, the bullae may rupture, causing infection, pain, 
and eventual vascularization and opacity of the cornea (Yanoff, 1996).  FCED is thought to 
occur in about 4% of the US population over age 40 (Krachmer, 1978). At present, the only 
treatment is corneal transplantation; no non-surgical therapy is available.  
There is growing evidence that oxidative stress plays a role in the pathogenesis of FCED 
(Jurkunas, 2010). As early as 1986, decreased numbers of mitochondria and a reduced activity of 
cytochrome oxidase in mitochondria was detected in FCED corneas (Tuberville, 1986).  
Antibodies against lipid peroxidation and other ROS byproducts have shown oxidative damage 
in FCED corneas (Buddi, 2002).  A marker of oxidative damage, 8-hydroxy-2’-deoxyguanosine, 
was shown in FCED endothelial cells to co-localize to mitochondria, strongly suggesting that in 
FCED the mitochondrial genome is the target of oxidative stress (Jurkunas, 2010). In addition, 
endothelial cells and Descemet’s membrane from human corneas of patients with FCED 
demonstrate marked overexpression of clusterin, a protein that is overexpressed in many tissues 
undergoing stress (Jurkunas 2008a). Serial analysis of gene expression (SAGE) to compare the 
endothelial of normal patients and those with FCED has shown alteration in the expression of 
genes regulating cellular energy metabolism, pump functions, and apoptotic and antioxidant cell 
defense. Mitochondrial transcripts accounted for the majority of the downregulated genes 
(Elhalis, 2010). Peroxiredoxins (PRDXs) are a novel class of antioxidants that remove cellular 


  
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hydrogen peroxide and inhibit apoptosis from reactive oxygen species. PRDXs are decreased in 
FCED (Jurkunas, 2008b).    
  
MTP-131 reduces mitochondrial oxidative stress by enhancing mitochondrial function via 
selective binding and protection of cardiolipin from peroxidation (Birk, 2013).  In cell cultures, 
MTP-131 has been shown to reduce glucose- and peroxide- induced oxidative stress and 
apoptosis and to improve survival of human retinal endothelial cells (Li, 2011), human trabecular 
meshwork cells (Chen, 2011), and human retinal pigment epithelial cells (Liang, 2010).  
Intraperitoneal administration of MTP-131 in mice reduced laser-induced choroidal 
neovascularization more than 50% (Liang, 2010), and when given subcutaneously to 
streptozotocin-induced diabetic rats, reduced oxidative stress, prevented apoptosis, and reduced 
VEGF-2 receptor expression and retinal leakage of Evans Blue dye (Huang, 2013).  MTP-131 
given subcutaneously (Alam, 2012) or topically (Prusky, 2013) to high fat and/or 
streptozotocininduced diabetic mice prevented and corrected visual functional loss. As noted 
above, the pathophysiology of FCED in humans is characterized by corneal endothelial 
abnormalities that share features with the oxidative stress observed in human retinal endothelial 
cells. Thus, it is theorized that treatment with MTP-131 of subjects suffering from FCED 
associated with mitochondrial dysfunction may have an effect on mitochondrial oxidative stress 
levels and corneal disease activity.  
5.  
STUDY OBJECTIVES  
 
5.1.  
Primary Objectives  
To evaluate the safety, tolerability and efficacy of MTP-131 1.0% ophthalmic solution relative to 
vehicle administered topically two times per day (BID) for 12 weeks in the treatment of FCED 
presenting with mild to moderate corneal edema.  
6.  
INVESTIGATIONAL PLAN  
 
6.1.  
Summary of Design  
This will be a prospective, randomized, double-masked, vehicle controlled, paired-eye, up to 
2center study in which approximately 16 FCED subjects presenting with mild to moderate 
corneal edema are planned to be treated with 1 drop of MTP-131 1.0% ophthalmic solution in 
the randomly selected study eye BID and 1 drop of vehicle ophthalmic solution BID in the 
fellow control eye.  
Written informed consent will be obtained from all subjects or their legal guardian(s) prior to the 
Screening Visit. Once written consent has been provided, data will be collected from a complete 
pre-treatment examination, consisting of vital signs, routine blood chemistries, serum pregnancy 
test for women of child-bearing potential, measurement of best corrected visual acuity (BCVA) 
using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, manifest refraction, 
contrast sensitivity, specular microscopy, corneal pachymetry, Pentacam, intraocular pressure 
(IOP) measurement, and slit lamp examination.    


  
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This Screening Visit examination will be performed no more than 28 days prior to the Baseline 
Visit.  If applicable, urine pregnancy testing will be performed prior to initiation of treatment.  
The study eye will be determined via randomization. Patients will be considered enrolled in the 
study upon randomization. The day of randomization is defined as Study Day 1.   
Patients will receive one drop of MTP-131 1.0% ophthalmic solution topically BID to the 
randomly selected study eye and one drop of vehicle BID to the fellow control eye. At the time 
of randomization, patients will be read a standard script explaining the importance of applying 
the correct drug product to each eye twice a day on a daily basis.  
 
6.2.  
Discussion of Design and Control  
In this study, MTP-131 1.0% ophthalmic solution will be administered twice per day for 84 days 
to evaluate the safety, tolerability, and efficacy for the treatment of FCED.  Approximately 16 
subjects are planned to be enrolled into the study.  Randomization will be used to minimize bias 
in the assignment of subjects’ eyes to treatment or vehicle, and to increase the likelihood that 
known and unknown ocular attributes are evenly balanced across groups.  Masked treatment will 
be used to reduce potential bias during data collection and evaluation of clinical endpoints.  
  
  
6.2.1.  
Dose Justification  
The dose selected for this clinical study is based on data from nonclinical pharmacology studies 
in metabolically stressed mice, where both 1% and 3% MTP-131 applied topically once daily has 
been associated with restoration of visual function in a dose dependent manner (Prusky, 2004).  
Additionally, MTP-131 given subcutaneously to high fat and/or streptozotocin-induced diabetic 
mice prevented and corrected visual functional loss (Alam, 2012) and subcutaneously to 
streptozotocin-induced diabetic rats reduced oxidative stress, prevented apoptosis, and reduced 
VEGF-2 receptor expression and retinal leakage of Evans Blue dye (Huang, 2013).    
In the recently completed SPIOC-101 clinical trial, twice daily dosing with MTP-131 ophthalmic 
solution administered topically BID at concentrations of 0.3% and 1.0% for 28 days to subjects 
with DME and age-related macular degeneration was well tolerated at both doses and in subjects 
with both ocular conditions.  There were no significant safety or tolerability findings in that 
study.  This is consistent with the 90-day toxicology studies, completed in rabbits and dogs, in 
which no treatment-related systemic toxicity or ocular pathology affecting the major 
visioncritical structures of the eye was observed. Mononuclear cell infiltrates in the palpebral 
and bulbar conjunctivae and nictitating membranes were observed in the more sensitive species 
(dog), which regressed during a recovery phase. Although the aforementioned preclinical 
toxicological findings were reversible upon cessation of treatment, in any patient complaining of 
persistent, local ocular irritation such as stinging or burning upon instillation of drops, the 
MTP131 treatment regimen should be stopped.     
 
6.3.  
Schedule of Events   
Study assessments and procedures are presented by study visit in Table 2. 


 
 
  
  
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Table 2.  
Schedule of Events  
  
Screening 
Period  
 
 
Treatment Period  
 
Follow-up 
Period  
Early  
Discontinuation 
Visit  
Days/Weeks  
Screening  
(Day -28 to  
Day 1) a  
Day 1/ 
Baseline  
Week 1  
(± 3 days)  
Week 4  
(± 3 days)  
Week 8    
(± 3 days)  
Week 12          
(± 3 days) End-
of  
Treatment Visit  
Week 16  
(± 3 days)  
Follow-up 
Visit  
Visit  
1  
2  
3  
4  
5  
6  
7  
  
Informed consent  
X  
  
  
  
  
  
  
  
Eligibility  
X  
X  
  
  
  
  
  
  
Demographics  
X  
  
  
  
  
  
  
  
Medical/Ocular history  
X  
  
  
  
  
  
  
  
Vital signsb  
X  
X  
X  
X  
X  
X  
X  
X  
Blood and urine for 
safetyc  
X  
X  
X  
  
  
  
X  
X  
Pregnancy testd  
X  
X  
  
  
  
X  
X  
X  
ETDRS BCVA /  
manifest refractione  
X  
X  
X  
X  
X  
X  
X  
X  
Contrast sensitivity  
X  
X  
X  
X  
X  
X  
X  
X  
Specular microscopy  
  
X  
X  
X  
X  
X  
X  
X  
Corneal pachymetry  
(ultrasound)  
X  
X  
X  
X  
X  
X  
X  
X  
Pentacam  
X  
X  
X  
X  
X  
X  
X  
X  
Intraocular pressure  
X  
X  
X  
X  
X  
X  
X  
X  
Slit lamp exam  
X  
X  
X  
X  
X  
X  
X  
X  
Randomization f  
  
X  
  
  
  
  
  
  


 
 
Adverse events  
X  
X  
X  
X  
X  
X  
X  
X  
Concomitant medications 
X  
X  
X  
X  
X  
X  
X  
X  
  
Note:  All ophthalmic testing must be conducted on both eyes at each time point.   
a  Screening visit should begin at 10:00AM ± 2 hours. Screening procedures may be completed on more than one day, so long 
as all procedures are completed during the Screening Period. Screening and Baseline assessments may be combined and 
completed at a single visit. All other visits should begin at the same time of day as the Screening visit ± 1 hour, and may be  
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completed over a one or two day period at the discretion of the investigator, so long as all procedures are completed during 
the allowable window for that visit. At each visit, the measurements of corneal thickness and BCVA should occur within ± 
1.5 hour of the time in which these measurements were completed at the Baseline visit.  
 
b   
  
Vital signs include temperature, respiratory rate, sitting blood pressure and pulse. 
c 
  Blood for safety will consist of hematology panel and clinical chemistry.  Urinalysis will be performed at Baseline Visit only.  
d   
Women of childbearing potential only; serum pregnancy test to be done at screening and urine pregnancy test to be done at 
all other time points.  
e   
Manifest refraction required at Screening and Week 16 visits only.  
f    
The day of randomization is defined as Study Day 1.  
  


 
 
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7.  
STUDY POPULATION  
 
7.1.  
Number of Subjects Planned  
Approximately 16 subjects with FCED presenting with mild to moderate corneal edema are 
planned to be enrolled at up to 2 sites in the United States.  
 
7.2.  
Study Population  
Subjects who have FCED presenting with mild to moderate corneal edema.  
7.2.1.  
Inclusion Criteria  
A subject must meet the following criteria to be eligible for inclusion in the study:  
1. 
Adults ≥18 years old at the time of Screening Visit  
2. 
Diagnosis of FCED OU based on clinical and ophthalmic test findings  
3. 
Clinical evidence of corneal edema OU diagnosed with FCED, including one or more 
of the following signs: corneal epithelial microcysts, corneal epithelial bullae, stromal 
folds, or stromal haze  
4. 
Subjective complaint of progressive visual change OU or subjective complaint of 
greater visual disturbance in the morning compared to afternoon or evening OU  
5. 
Central corneal thickness of 550 µm to 700 µm (inclusive) in at least one eye 
diagnosed with FCED, as measured by ultrasonic pachymetry at the time of 
Screening Visit and Baseline Visit  
6. 
Best-corrected distance visual acuity (BCVA) of 20/32 to 20/320 (inclusive) at the 
time of Screening Visit and Baseline Visit OU  
7. 
Media clarity sufficient for specular microscopy  
8. 
Patient cooperation sufficient for adequate ophthalmic testing and anatomic 
assessment   
9. 
Able to self-administer eye drops as demonstrated at Screening or having a care 
provider who can do so  
10. 
Women of childbearing potential must agree to use one of the following methods of 
birth control from the date they sign the informed consent form (ICF) until after the 
last study visit (Follow-up Visit):  
a.) Abstinence, when it is in line with the preferred and usual lifestyle of the subject;  
b.) Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy (vasectomy procedure must have been 
conducted at least 60 days prior to the Screening Visit or confirmed via sperm 
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c.) Barrier method (e.g., condom or occlusive cap) with spermicidal 
foam/gel/film/cream AND either hormonal contraception (oral, implanted or 
injectable) or an intrauterine device or system. Note: Non-childbearing potential 
is defined as surgical sterilization (i.e., bilateral oophorectomy, hysterectomy, or 
tubal ligation) or postmenopausal (defined as not having a period for at least 12 
consecutive months prior to Screening).  
11. 
Able to give informed consent and willing to comply with all study visits and  
 
examinations  
  
7.2.2.  
Exclusion Criteria  
A subject who meets any of the following criteria will be excluded from the study: Ocular 
conditions  
1. 
Corneal findings of any type (including, but not limited to, stromal haze or stromal 
scarring), in either eye, that, based on investigator’s assessment, limit the probability 
of visual improvement after corneal deturgescence  
2. 
Any ocular pathology requiring treatment with topical ophthalmic drops, with the 
exception of glaucoma or ocular hypertension   
3. 
Concurrent use of any and all topical ophthalmic medications, prescription and 
nonprescription (with the exception of study medication, or stable use of topical 
prostaglandin analogs, alpha-adrenergic agents, and beta-blockers) 1 week (prior to 
Screening Visit and throughout the duration of the study  
4. 
Use of topical hypertonic saline drops for 3 days prior to Screening and throughout 
the duration of the study  
5. 
Any active ocular or periocular infection; any history of recurrent or chronic infection 
or inflammation in either eye  
6. 
History of herpetic infection in either eye  
7. 
History of corneal disease (other than FCED) or corneal surgery in either eye  
8. 
Central corneal edema based on investigator’s assessment  
9. 
Current use or likely need for the use of contact lens at any time during the study  
10. 
History of punctual cautery, non-dissolvable punctual plug implants within 1 year of 
the Screening Visit, or collagen punctual plugs within 6 weeks of the Screening Visit, 
or anticipated use of any of these treatments in either eye during the study  
11. 
Concurrent disease in either the study eye or fellow eye that could require medical or 
surgical intervention during the study period  
12. 
History of previous corneal or anterior segment surgery such as LASIK, 
photorefractive keratectomy, endothelial keratoplasty, penetrating keratoplasty 
cataract surgery or glaucoma surgery.  


  
  
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Systemic conditions  
13. 
Concurrent use of topical or systemic cyclosporine A for 3 weeks prior to the 
Screening Visit or during the study   
14. 
Any disease or medical condition that in the opinion of the investigator would prevent 
the subject from participating in the study or might confound study results  
General  
15. 
Participation in other investigational drug or device clinical trials within 30 days prior 
to enrollment, or planning to participate in any other investigational drug or device 
clinical trials within 30 days of study completion   
16. 
History of allergic reaction to the investigational drug or any of its components  
17. 
Current use of or likely need for any excluded medication, including systemic 
medications known to be toxic to or affect the cornea (e.g., carbonic anhydrase 
inhibitors)  
18. 
Women who are pregnant or lactating  
 
7.3.  
Discontinuation   
7.3.1.  
Discontinuation of Subjects  
A subject has the right to withdraw from the study at any time, for any reason, and without 
repercussion.  
The investigator and sponsor have the right to withdraw a subject from the study in the event of 
an intercurrent illness, AE, treatment failure, pregnancy, protocol violation, cure,  
non-compliance with study visits, and for administrative or other reasons.  An excessive rate of 
withdrawals would render the study uninterpretable; therefore, unnecessary withdrawal of 
subjects should be avoided.  
Should a subject (or a subject’s legally authorized guardian or representative) decide to 
withdraw, all efforts will be made to complete and report observations as thoroughly as possible.   
Early termination procedures should be followed.  
 
8.  
TREATMENTS  
 
8.1.  
Treatments Administered  
MTP-131 1.0% ophthalmic solution administered topically BID to the study eye and vehicle 
administered topically BID to the fellow control eye  


  
  
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8.2.  
Discontinuation of Treatment  
8.2.1.  
Dose Modification  
Dose modification for an individual subject is not allowed.  
8.2.2.  
Subject Discontinuation  
All efforts should be made to schedule an early termination visit for subjects who prematurely 
discontinue from study drug.  
Reasons for discontinuation may include, but are not limited to, the following:  
• 
Investigator determination that it is not in the best interest of the subject to continue 
participation  
• 
Investigator determination that the subject has met the rescue criteria  
• 
Pregnancy  
• 
SAE  
• 
Any other safety concerns  
 
8.3.  
Treatments  
8.3.1.  
Study Drug Identification  
All study drug is intended for ophthalmic administration.  MTP-131 ophthalmic solution or 
vehicle solution is packaged in white, 10 ml polypropylene bottles with dropper.  Each bottle 
contains nominally 3 mL of solution as either MTP-131 1.0% ophthalmic solution or vehicle.  
Each bottle also contains sodium chloride appropriate for isotonicity and acetic acid and/or 
sodium hydroxide as needed for pH adjustment.    
8.3.2.  
Packaging, Labeling, and Storage  
Study drug will be supplied as bottles containing 3 mL of MTP-131 1.0% ophthalmic solution 
paired with an equal quantity of vehicle bottles designated for use in the left or right eye.  Study 
drug bottles are to be stored in a secure area refrigerated (2-8°C) while at the investigative site, 
and are to be stored in a refrigerator by the subject.    
8.3.3.  
Treatment Logistics and Accountability  
All drug accountability records must be kept current, and the investigator must be able to account 
for all used and unused bottles of study drug.  These records should contain the dates, quantity, 
and study medication:  


  
  
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• 
Received at site   
• 
Dispensed to each subject  
• 
Returned from each subject (if applicable), and  
• 
Disposed of at the site or returned to the sponsor or designee.  
Subjects will be instructed in the proper administration of each study bottle and will be asked to 
return study medication bottles at the Week 8, Week 12, and Week 16 visits.  The clinical 
monitor responsible for the study site will provide written approval for the destruction or return 
of unused study medication bottles following reconciliation of all clinical supplies.  
 
8.4.  
Masking  
This is a double-masked, vehicle controlled, paired-eye study.   
 
8.5.  
Concomitant Medications   
Subjects may not use any medication known to be toxic to the cornea.  
Subjects may not receive any medications (approved or investigational) for any other ocular 
condition in the study eye other than the study medication from thirty days prior to Baseline until 
the End-of-Study Visit (with the exception of study medication, or stable use of topical 
prostaglandin analogs, alpha-adrenergic agents, and beta-blockers).  
All other medications must be used at a stable dose from the time of signing informed consent 
until the End-of-Study Visit.  
 
8.6.  
Study Visit Descriptions  
8.6.1.  
Screening (Day -28 to Day 1)   
Screening and Baseline assessments may be combined and completed at a single visit. All 
ophthalmic testing must be conducted on both eyes at each time point. Screening visit should 
begin at 10:00AM ± 2 hours. Screening procedures may be completed on more than one day, so 
long as all procedures are completed during the Screening Period.  All other visits should begin 
at the same time of day as the Screening visit ± 1 hour, and may be completed over a one or two 
day period, at the discretion of the investigator, so long as all procedures are completed during 
the allowable window for that visit. At each visit, the measurements of corneal thickness and 
BCVA should occur within ± 1.5 hour of the time in which these measurements were completed 
at the Baseline visit. Written ICF will be obtained from all subjects prior to conducting any 
screening procedures.  After the subject has provided the ICF, the following assessments will be 
collected:  


  
  
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• 
Inclusion/Exclusion criteria  
• 
Demographics will include ethnicity, race, eye color, history of smoking, and 
drug/alcohol abuse  
• 
Medical and ocular history and concurrent illnesses  
Concomitant medications  
• 
Record AEs: AEs that occur between the time the subject signs the ICF and the time the 
subject is dosed with study drug will be summarized in the medical history eCRF and not 
as an AE unless the event meets the definition of an SAE.  This applies to screen failures 
as well. For subjects who fail screening, AEs and updates (if applicable) must be 
recorded in the medical history eCRF until the date the subject was determined to have 
failed screening.  
• 
Vital signs will include temperature, respiratory rate, blood pressure after sitting for 15 
minutes, and pulse  
• 
BCVA (ETDRS scale) and manifest refraction  
• 
Slit lamp examination (SLE)  
• 
Intraocular pressure (Goldman applanation tonometry)  
• 
Blood draw for clinical chemistry  
• 
Blood draw for clinical hematology  
• 
Urine Pregnancy Test (UPT)   
• 
Contrast Sensitivity using VectorVision’s CSV-1000 instrument   
• 
Corneal Pachymetry by ultrasound  
• 
Pentacam  
8.6.2.  
Baseline Visit (Day 1)  
• 
Inclusion/Exclusion criteria  
• 
Vital signs will include temperature, respiratory rate, blood pressure after sitting for 15 
minutes and pulse  
• 
BCVA (ETDRS scale)   
• 
Contrast sensitivity using VectorVision’s CSV-1000 instrument  
• 
Corneal pachymetry by ultrasound  
• 
Pentacam  
• 
Slit lamp examination (SLE)   


  
  
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• 
IOP (Goldman applanation tonometry)   
• 
Specular Microscopy using Konan KSS 409SP   
• 
Blood draw for clinical chemistry and hematology  
• 
Urinalysis  
• 
Urine pregnancy test (only for women of childbearing potential)  
• 
Randomization and training on the proper administration of MTP-131  ophthalmic 
solution  
• 
Dispense study medication  
• 
Self-administration of 1 drop of MTP-131  ophthalmic solution to the study eye  
• 
Concomitant medications  
Record AEs  
8.6.3. 
Week 1 (+/-3 days)  
• 
Subjects will be examined by the investigator to determine ocular safety and tolerability.  
• 
Subjects that have no signs of ocular toxicity will continue to apply MTP-131 ophthalmic 
solution BID for the full 12 week treatment period with treatment follow-up visits at 
Weeks 4, 8, and 12.  
• 
The following assessments will be conducted:  
• 
Vital signs including temperature, respiratory rate, blood pressure after sitting for 15 
minutes and pulse  
• 
BCVA (ETDRS scale) and manifest refraction  
• 
SLE   
• 
IOP (Goldman applanation tonometry)   
• 
Specular Microscopy  
• 
Corneal pachymetry by ultrasound  
• 
Pentacam  
• 
Record AEs  
• 
Concomitant medications  
• 
Contrast sensitivity using VectorVision’s CSV-1000 instrument  
• 
Blood draw for clinical chemistry and hematology  
• 
Dispense study medication/ drug accountability  


  
  
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8.6.4.  
Week 4 (+/-3 days)  
Subjects will continue treatment as described for Day 7 and the following assessments will be 
conducted:  
• 
Vital signs including temperature, respiratory rate, blood pressure after sitting for 15 
minutes, and pulse  
• 
BCVA (ETDRS scale )  
• 
SLE   
• 
IOP (Goldman applanation tonometry)  
• 
Contrast sensitivity using VectorVision’s CSV-1000 instrument  
• 
Corneal pachymetry by ultrasound  
• 
Pentacam  
• 
Specular microscopy  
• 
Record AEs  
• 
Concomitant medications  
• 
Dispense study medication/ drug accountability  
8.6.5. 
Week 8 (+/-3 days)  
Subjects will continue treatment as described for Day 7 and the following procedures and 
assessments will be conducted:  


  
  
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• 
Vital signs including temperature, respiratory rate, blood pressure after sitting for 15 
minutes, and pulse  
• 
BCVA (ETDRS)  
• 
SLE   
• 
IOP (Goldman applanation tonometry)  
• 
Contrast sensitivity using VectorVision’s CSV-1000 instrument  
• 
Corneal pachymetry by ultrasound  
• 
Pentacam  
• 
Specular microscopy  
• 
Record AEs  
• 
Concomitant medications  
• 
Dispense study medication/ drug accountability  
8.6.6.  
End of Treatment Week 12 (+/-3 days)  
The following assessments will be conducted:  
• 
Vital signs including temperature, respiratory rate, blood pressure after sitting for 15 
minutes, and pulse  
• 
BCVA (ETDRS)  
• 
SLE   
• 
IOP (Goldman applanation tonometry)  
• 
Contrast sensitivity using VectorVision’s CSV-1000 instrument   
• 
Corneal pachymetry by ultrasound  
• 
Pentacam  
• 
Specular microscopy  
• 
Record AEs  
• 
Concomitant medications  
• 
Urine pregnancy test (only for women of childbearing potential)  
8.6.7.  
Follow-up Week 16 (+/-3 days)  
The following assessments will be conducted:  
• 
Vital signs including temperature, respiratory rate, blood pressure after sitting for 15 
minutes, and pulse  
• 
BCVA (ETDRS scale)  
• 
SLE   


  
  
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IOP (Goldman applanation tonometry)  
• 
Contrast sensitivity using VectorVision’s CSV-1000 instrument  
• 
Corneal pachymetry by ultrasound  
• 
Pentacam  
• 
Specular microscopy  
• 
Record AEs  
• 
Concomitant medications  
• 
Blood draw for clinical chemistry and hematology  
• 
Urine pregnancy test (only for women of childbearing potential)  
8.6.8.  
Early Discontinuation Visit/Unscheduled Visits  
The following assessments will be conducted:  
• 
Vital signs including temperature, respiratory rate, blood pressure after sitting for 15 
minutes, and pulse  
• 
BCVA (ETDRS scale)  
• 
SLE   
• 
IOP (Goldman applanation tonometry)  
• 
Contrast sensitivity using VectorVision’s CSV-1000 instrument  
• 
Corneal pachymetry by ultrasound  
• 
Pentacam  
• 
Specular microscopy  
• 
Record AEs  
• 
Concomitant medications  
• 
Blood draw for clinical chemistry and hematology  
• 
Urine pregnancy test (only for women of childbearing potential)    
9.  
EFFICACY, SAFETY EVALUATIONS, SAMPLE 
COLLECTION AND TESTING, AND APPROPRIATENESS  
OF MEASURES  
 
9.1.  
Efficacy Measures  
• 
Change from Baseline in central corneal thickness  
• 
Change from Baseline in best corrected visual acuity (BCVA, ETDRS scale)  


  
  
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• 
Change from Baseline in endothelial cell count  
• 
Change from Baseline in endothelial cell morphology including:  
1. Hexagonality  
2. Cell density  
3. Coefficient of variation  
• 
Change from Baseline in:  
1. Corneal area affected by microcysts  
2. Number, size, and location of corneal bullae  
3. Severity (as determined by investigator) of corneal stromal folds  
• 
Change from Baseline in contrast sensitivity  
 
9.2.  
Safety Evaluations  
The investigator is responsible for monitoring the safety of subjects who have entered this study 
and for alerting the sponsor or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the subject.  The investigator is responsible for the 
appropriate medical care of subjects during the study.  The investigator remains responsible for 
following, through an appropriate health care option, AEs that are serious, considered related to 
the study treatment or the study, or that caused the subject to discontinue before completing the 
study.    
The safety profile of MTP-131 ophthalmic solution will be assessed through the recording, 
reporting, and analyzing of adverse events, clinical evaluations, and laboratory tests.  
Comprehensive assessment of any apparent toxicity experienced by study subjects will be 
performed throughout the course of the study, from the time of the subject’s signature of 
informed consent.  Study site personnel will report any AE, whether observed by the investigator 
or reported by the subject.  The reporting period for AEs is described in Section 9.6.  
9.2.1.  
Adverse Events  
An AE is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal 
laboratory findings, or diseases that emerge or worsen relative to Baseline during administration 
of an Investigational Medicinal Product (IMP), regardless of causal relationship.  
Adverse Events may include the following:  
• 
Suspected adverse drug reactions:  side effects known, or suspected, to be caused by the 
IMP  
• 
Other medical experiences, regardless of their relationship with the IMP, such as injury, 
surgery, accidents, extensions of symptoms or apparently unrelated illnesses, and 
significant abnormalities in clinical laboratory values, psychological testing, or physical 
examination findings  
• 
Events occurring as a result of protocol interventions (pre- or post-IMP administration)  


  
  
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Reactions from IMP overdose, abuse, withdrawal, sensitivity, or toxicity.  
 
9.3.  
Pre-Treatment Events  
Untoward events and/or incidental diagnoses that occur prior to IMP administration are by 
definition, unrelated to the study drug.  Pre-treatment events or incidental diagnoses will be 
recorded on the past medical history eCRF.  However, if a pre-treatment event is assessed by the 
investigator as related to a study procedure and/or meets seriousness criteria, it will be recorded 
as an AE on the AE eCRF and processed and followed accordingly.  
 
9.4.  
Baseline Medical Conditions  
Those medical conditions related to the disease under study whose changes during the study are 
consistent with natural disease progression, or which are attributable to a lack of clinical efficacy 
of the IMP, are NOT considered as AEs and should not be recorded as such in the eCRF.  These 
are handled in the efficacy assessments and should be documented on the medical history page of 
the eCRF.   
Baseline medical conditions, not in the therapeutic area of interest/investigation, that worsen in 
severity or frequency during the study should be recorded and reported as AEs.  
9.4.1.  
Abnormal Laboratory and Other Abnormal Investigational Findings  
Abnormal laboratory findings and other objective measurements should NOT be routinely 
captured and reported as AEs.  However, abnormal laboratory findings or other objective 
measurements that   
• 
meet the criteria for a SAE,   
• 
result in discontinuation of the Investigational Medicinal Product,   
• 
require medical intervention or   
• 
are judged by the investigator to be clinically significant changes from Baseline should 
be reported on the AE pages of the eCRF.  
When reporting an abnormal laboratory finding on the AE pages of the eCRF, a clinical 
diagnosis should be recorded rather than the abnormal value itself, if this is available (for 
example, “anemia” rather than “decreased red blood cell count” or “hemoglobin = 10.5 g/dl”).  
9.4.2.  
Serious Adverse Events  
A SAE is any AE that:  
• 
Results in death.  In case of a death, the cause of death is used as the AE term, and the 
fatality is considered as the OUTCOME.  
• 
Is life-threatening.  The term “life-threatening” refers to a SAE in which the subject is at 
risk of death at the time of the event; it does not refer to an event that hypothetically 
might cause death if it were more severe.  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization.  


  
  
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• 
Results in persistent or significant disability or incapacity.  
• 
Is a congenital anomaly or birth defect.  
• 
Is otherwise medically important: Important medical events may be considered as SAEs 
when, based upon medical judgment, they may jeopardize the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
For the purposes of reporting, any suspected transmission of an infectious agent via an 
IMP is also considered an SAE and all such cases should be reported in an expedited 
manner as described in Section 9.7.  
9.4.3.  
Events that Do Not Meet the Definition of a Serious Adverse Event  
Elective hospitalizations to simplify study treatment or study procedures (e.g., an overnight stay 
to facilitate chemotherapy and related hydration therapy application) are not considered as SAEs.  
However, all events leading to unplanned hospitalizations (not documented prior to ICF signing) 
or unplanned prolongation of an elective hospitalization (e.g., undesirable effects of any 
administered treatment) must be documented and reported as SAEs.  
9.4.4.  
Recording of Adverse Events  
Complete, accurate, and consistent data on all AEs experienced for the duration of the reporting 
period will be recorded on an ongoing basis in the appropriate section of the eCRF.  Among 
these AEs, all SAEs must be additionally documented and reported using the study specific SAE 
eCRF as described in Section 9.4.2.  
It is important that each AE report include a description of the event along with the duration 
(onset and resolution dates), severity, relationship to IMP, potential causal/confounding factors, 
treatment given or other action taken (including dose modification or discontinuation of the 
IMP), and the outcome.   
As the quality and precision of acquired AE data are critical, investigators should use the AE 
definitions provided and should observe the following guidelines when completing the AE pages 
of the eCRF:  
• 
Whenever possible, recognized medical terms should be used to describe AEs rather than 
lay terms (for example, ‘influenza’ rather than ‘flu’), and abbreviations should be 
avoided.  
• 
Adverse events should be described using a specific clinical diagnosis, if available, rather 
than a list of signs or symptoms (for example, ‘congestive heart failure’ rather than 
‘dyspnea, rales, and cyanosis’).  However, signs and symptoms that are not associated 
with an identified disease or syndrome, or for which an overall diagnosis is not yet 
available, should be reported as individual AEs.   
• 
Provisional diagnoses (e.g., “suspected myocardial infarction”) are acceptable, but should 
be followed up with a definitive diagnosis if later available.  Similarly, a fatal event with 
an unknown cause should be recorded as “death of unknown cause.”  
• 
In cases of surgical or diagnostic procedures, the condition or illness leading to the 
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Adverse events occurring secondary to other events (e.g., sequelae or complications) should be 
identified by the primary cause.  A primary AE, if clearly identifiable, generally represents the 
most accurate clinical term to record in the eCRF.  
 
9.5.  
Investigator Assessments  
9.5.1.  
Severity/Intensity  
Investigators must assess the severity/intensity of AEs according to the following qualitative 
toxicity scale:  
Mild:  
The subject is aware of the event or symptom, but the event or symptom is 
easily tolerated.  
Moderate:  
The subject experiences sufficient discomfort to interfere with or reduce his 
or her usual level of activity.  
Severe:  
Significant impairment of functioning: the subject is unable to carry out usual 
activities.  
9.5.2.  
Relationship to the Investigational Medicinal Product   
Investigators must systematically assess the causal relationship of AEs to the IMP using the 
following definitions (the decisive factor being the temporal relationship between the AE and 
administration of the IMP):  
Probable:  
A causal relationship is clinically/biologically highly plausible, there is a 
plausible time sequence between onset of the AE and administration of the 
IMP, and there is a reasonable response on withdrawal.  
Possible:  
A causal relationship is clinically/biologically plausible and there is a 
plausible time sequence between onset of the AE and administration of the 
IMP.  
Unlikely:  
A causal relationship is improbable and another documented cause of the 
AE is most plausible.  
Unrelated:  
A causal relationship can be excluded and another documented cause of the 
AE is most plausible.  
 
9.6.  
Adverse Event Reporting Period  
The AE reporting period begins when the subject signs the informed consent and continues 
through the clinical study’s post-treatment follow-up period defined as 30 days after last 
administration of study drug (Day 58).  Within a study, all subjects who took at least 1 dose of 
IMP - whether they completed the treatment period or not - should enter the 30-day safety 
follow-up period as defined above.  
New protocol-related AEs (caused by any intervention required by the protocol) and updates on 
all AEs ongoing or with an unknown outcome must be recorded until the last subject visit 
required by the protocol.  A last batch of queries will be sent after the last study visit if remaining 
ongoing/unknown outcomes of reported AEs are pending.  However, SAEs and medically 


  
  
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relevant ongoing/unknown outcome AEs will be followed-up until resolution or stabilization by 
the sponsor’s Pharmacovigilance department.    
Beyond the defined reporting period, any new unsolicited SAE spontaneously reported to the 
sponsor by the investigator will be collected and processed.  This and any additional information 
on SAEs obtained after database lock will reside solely in the Pharmacovigilance study file.  
If a subject is documented as lost-to follow-up, ongoing/unknown outcome AEs will not be 
followed-up.  
For subjects who fail screening, AEs and updates must be recorded in the medical history eCRF 
until the date the subject was determined to have failed screening.  Beyond that date, only SAEs 
and medically relevant AEs will be followed-up by the sponsor’s Pharmacovigilance group and 
all data will be housed within the Pharmacovigilance study file.  
 
9.7.  
Serious Adverse Event Expedited Reporting   
In the event of an SAE occurring during the reporting period, the investigator must immediately 
(i.e., within a maximum of 24 hours after becoming aware of the event) inform the sponsor as 
detailed in the Clinical Study Pharmacovigilance Procedural Manual.  
For any SAE, the following minimum information is required as initial notification:  
• 
Investigator/Reporter with full contact information  
• 
Subject identification details (study number, site number, subject number)  
• 
Investigational medicinal product administration details (dose and dates)  
• 
Event verbatim, a brief description of signs/symptoms/or diagnosis and the date of 
onset  
• 
Seriousness criteria(ion) met  
• 
Relationship of the event to the IMP (e.g., the causality according to the 
investigator) Reporting procedures and timelines are the same for any new information 
(follow-up) on a previously reported SAE.  
All SAE reports must be completed as described in the eCRF completion guidelines and 
submitted to the Drug Safety through the Electronic Data Capture (EDC) system of the clinical 
database.  Other relevant information from the clinical database (including demographic data, 
medical history, concomitant medication, and study drug dosing information) will automatically 
be sent to the sponsor's safety department via the EDC system when the SAE form is submitted.  
For names, addresses, and telephone and fax numbers for SAE back-up reporting, refer to the 
information included in the Clinical Study Pharmacovigilance Procedural Manual.  
The investigator/reporter must respond to any request for follow-up information (e.g., additional 
information, outcome and final evaluation, specific records where needed) or to any question the 
sponsor may have on the SAE within the same timelines as described for initial reports.  This is 
necessary to permit a prompt assessment of the event by the sponsor and (as applicable) to allow 
the sponsor to meet strict regulatory timelines associated with expedited safety reporting 
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9.8.  
Pregnancy and In Utero Drug Exposure   
Only pregnancies considered by the investigator as related to study treatment (e.g., resulting from 
an interaction between study drug and a contraceptive medication) are considered adverse events 
unto themselves.  However, all pregnancies with an estimated conception date during the AE 
reporting period, as defined in Section 9.6 must be recorded in the AE section of the eCRF.  This 
applies to both pregnancies in female subjects and in female partners of male subjects.    
The investigator must notify the sponsor in an expedited manner of any pregnancy using the  
Pregnancy Form and the back-up reporting procedure as described Clinical Study  
Pharmacovigilance Procedural Manual.  Investigators must actively follow up, document, and 
report on the outcome of all pregnancies, even if subjects are withdrawn from the study.  
The investigator must notify the sponsor of these outcomes using Section II of the Pregnancy 
Form and submit the information using the back-up reporting procedure.  Any abnormal outcome 
must be reported in an expedited manner as described in Section 9.7, while normal outcomes 
must be reported within 45 days from delivery.  
In the case of an abnormal outcome, whereby the mother sustains an event, the SAE Report Form 
is required and will be submitted as described above.   
9.9.  
Responsibilities to Regulatory Authorities, Investigators, Ethics 
Committees, and Ethical/Institutional Review Boards  
The sponsor will send appropriate safety notifications to regulatory authorities in accordance 
with applicable laws and regulations.  
The investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs involving his/her subjects to the Ethics Committee and/or Ethical/Institutional 
Review Board (EC/ERB/IRB) that approved the study  
In accordance with ICH GCP guidelines, the sponsor will inform the investigator of findings that 
could adversely affect the safety of subjects, impact the conduct of the study, or alter the 
EC’s/IRB’s approval/favorable opinion to continue the study.  In particular, and in line with 
respective regulations, the sponsor will inform the investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (suspected unexpected 
serious adverse reactions or SUSARs).  The investigator should place copies of these safety 
reports in the investigator site file.  National regulations with regard to safety report notifications 
to investigators will be taken into account.  
When specifically required by regulations and guidelines, the sponsor will provide appropriate 
safety reports directly to the IRB and will maintain records of these notifications.  When direct 
reporting by the sponsor is not clearly defined by national or site-specific regulations, the 
investigator will be responsible for promptly notifying the concerned IEC/IRB of any safety 
reports provided by the sponsor and of filing copies of all related correspondence in the 
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For studies covered by the European Directive 2001/20/EC, the sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs will be carried out in accordance with that directive 
and with the related detailed guidance’s.  
 
9.10.  
Sample Collection and Testing  
Table 2 lists the schedule for sample collections in this study.  
Attachment 1 lists the laboratory tests that will be performed for this study.    
Instructions for the collection and handling of blood samples will be provided by the sponsor.   
The actual date and time (24-hour clock time) of each sampling will be recorded.  
 
9.11.  
Appropriateness of Measures  
The measures used to assess safety in this study are consistent with those widely used and 
generally recognized as reliable, accurate, and relevant.  
 


  
  
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10.  
SAMPLE SIZE AND STATISTICAL METHODS  
 
10.1.  
Determination of Sample Size  
For this Phase 1/2, a sample size of approximately 16 patients is considered sufficient.  The 
sample size of the study is based on precedent set by prior Phase 1/2 studies of similar nature and 
design.  It is considered sufficient to provide for preliminary assessment of safety and tolerability 
at each dose.  
 
10.2.  
Statistical and Analytical Plans  
10.2.1.  
General Considerations  
In general, categorical variables will be summarized by the count (N) and percentage of subjects 
(%).  Continuous variables will be summarized by the number of non-missing observations (N), 
mean, standard deviation, median, minimum, and maximum values.  
All study data are to be displayed in the data listings.  
Statistical analysis of this study will be the responsibility of the sponsor or its designee.  Subject 
disposition summaries will include the number of subjects entered and the numbers treated 
(included in the Safety population) by treatment regimen and disease group for all subjects.  The 
number and percentage of subjects who complete or discontinue from the study will be 
summarized by reason for discontinuation for each treatment regimen/disease group.  
Subject’s age, sex, weight, height, BMI, and other demographic characteristics will be recorded 
and summarized by treatment group.  Medical history will be listed.  
All study data are to be displayed in the data listings.  
Statistical analysis of this study will be the responsibility of the sponsor or its designee.  
Additional details regarding analyses will be included in separate statistical analysis plan.  
10.2.2.  
Subject Disposition  
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported.  If known, a reason for their discontinuation will be 
given.  
10.2.3.  
Subject Characteristics  
Baseline characteristics will include standard demography (e.g., ethnicity, race, eye color, history 
of smoking, and drug/alcohol abuse), disease characteristics including medical history, and 
medication history for each subject.  


  
  
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10.2.4.  
Concomitant Therapy  
Current use of or likely need for systemic medications known to be toxic to the cornea are 
prohibited from the Screening Visit until completion of the study (completion of the Follow-Up 
Visit).  
All other medications, including any over-the-counter treatments, vitamins, or supplements, must 
have been unchanged and constant for at least one month prior to the Baseline Visit and must 
remain stable through the completion of the study (completion of the Follow-up Visit).  
10.2.5.  
Treatment Compliance  
All drug compliance records must be kept current and must be made available for inspection by 
the sponsor and regulatory agency inspectors.  
10.2.6.  
Endpoints and Methodology  
10.2.6.1. Analysis Populations  
All subjects who receive at least one dose of study drug will be included in the Safety Population 
according to the treatment received.  
10.2.6.2. Primary (Safety) Endpoints The 
primary endpoints for this study include:  
• 
The incidence and severity of systemic and ocular AEs  
• 
Change from Baseline in slit lamp findings  
• 
Change from Baseline in intraocular pressure  
10.2.7.  
Secondary (Efficacy) Endpoints  
The efficacy endpoints are listed in Section 9.1.  
10.2.8.  
Safety Analyses  
AEs will be summarized by system organ class (SOC) and preferred term (PT), presenting the 
number and percentage of subjects having AEs and dose level.  Severity and relationship to study 
drug will be listed as appropriate.     
10.2.8.1. Adverse Events  
All AEs will be coded to SOC and PT using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary (version to be specified in the clinical study report).  
All reported AEs will be listed.  
In the summary tables, subjects may be counted under multiple SOCs and PTs, but for each SOC 
and PT, subjects are only counted once.  If a subject has the same AE on multiple occasions, the 
highest severity (severe > moderate > mild) or drug relationship (probable > possibly related > 
unlikely related > unrelated) recorded for the event will be presented.  If severity is missing, 
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be included in related tables (i.e., considered related).  Summary tables will be sorted by SOC, 
then PT.  
10.2.8.2. Deaths and Other Serious Adverse Events Listings 
will be provided for the following:  
• 
Deaths  
• 
SAEs  
• 
AEs leading to discontinuation of study drug  
10.2.8.3. Clinical Laboratory Evaluations  
Summary tables for laboratory parameters (including hematology, chemistry, and urinalysis) 
will include descriptive statistics by post-dosing shifts relative to Baseline where appropriate, 
and data listings of clinically significant abnormalities  
Subjects with laboratory data outside the normal range will be listed with abnormal values 
flagged.  
Shift tables (i.e., tables that show the number of subjects who are low, normal, or high at baseline 
versus each post-baseline scheduled assessment, will be produced.  
The number and percentage of subjects with urinalysis results outside the normal range will be 
presented by endpoint and visit for each treatment group.   
10.2.8.4. Vital Signs  
Vital signs will be summarized by changes from Baseline values at each dose level using 
descriptive statistics.  
10.2.8.5. Other Safety Parameters  
Any other safety data captured on the eCRF will be listed.  
10.2.8.6. Interim Analyses   
No interim analyses are planned for this study.  
 


  
  
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11. 
STUDY MONITORING  
 
11.1.  
Source Document Requirements  
The investigator will prepare and maintain adequate and accurate subject records (source 
documents).  The investigator will keep all source documents on file.  Source documents will be 
available at all times for inspection by authorized representatives of the regulatory authorities.  
 
11.2.  
Case Report Form Requirements  
Clinical data will be recorded in an electronic Case Report Form (eCRF) by the study 
investigator or authorized designee.  The investigator will ensure the accuracy, completeness, 
and timeliness of the data reported in the eCRFs.  Case report forms will be available at all times 
for inspection by authorized representatives of the regulatory authorities.  
 
11.3.  
Study Monitoring  
Site monitors contracted by the sponsor will contact and visit the investigator, and will be 
allowed to review and inspect the various records of the study on request (eCRFs and other 
pertinent data), provided that subject confidentiality is maintained, and that the inspection is 
conducted in accordance with local regulations.  
It is the site monitor’s responsibility to inspect the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol, the completeness, accuracy and consistency of the data, 
and adherence to good clinical practice (GCP) guidelines.  
The investigator agrees to cooperate with the site monitor to ensure that any problems detected 
during the course of these monitoring visits are resolved.  
 
12. 
DATA QUALITY ASSURANCE  
To ensure accurate, complete, and reliable data, the sponsor or its representatives will do the 
following:  
• 
Provide instructional material to the study sites, as appropriate  
• 
Sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the eCRFs, and study 
procedures.  
• 
Make periodic visits to the study site  
• 
Be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax  
• 
Review and evaluate eCRF data and use standard computer edits to detect errors in 
data collection  
• 
Conduct a quality review of the database  
In addition, the sponsor or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by the sponsor or 


  
  
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its representatives, and/or regulatory agencies at any time.  Investigators will be given notice 
before an audit occurs.  
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and medical records in 
the subject files as original source documents for the study.  If requested, the investigator will 
provide the sponsor, applicable regulatory agencies, and applicable IRBs with direct access to 
original source documents.  
 
12.1.  
Data Capture System  
The computerized handling of the data after receipt of the eCRFs may generate additional 
requests via electronic queries to which the investigator is obliged to respond by confirming or 
modifying the data questioned.  These requests with their responses will be appended to the 
eCRFs held by the investigator and sponsor.  
 
13. 
AUDITS AND INSPECTIONS  
This study may be subject to a quality assurance audit or inspection by the sponsor, their 
designee, and the regulatory authorities. Should this occur, the investigator will be responsible 
for:  
• 
Informing the sponsor of a planned inspection by the authorities as soon as notification is 
received  
• 
Providing access to all necessary facilities, study data, and documents for the inspection 
or audit  
• 
Communicating any information arising from inspection by the regulatory authorities to 
the sponsor immediately  
• 
Taking all appropriate measures requested by the regulatory authorities to resolve any 
problems found during the audit or inspection  
Documents subject to audit or inspection include, but are not limited to all source documents, 
eCRFs, medical records, correspondence, ICFs, IRB files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
supporting pharmacy facilities.  Conditions of study material storage are also subject to 
inspection.  In all instances, the confidentiality of the data will be respected.  
 


  
  
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14. 
INFORMED CONSENT, ETHICAL REVIEW, AND 
REGULATORY CONSIDERATIONS  
 
14.1.  
Informed Consent  
The principles of ICF are described in ICH Guidelines for GCP.  
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written ICF from each subject prior to his/her participation in the study and after the aims, 
methods, objectives, and potential hazards of the study have been explained to the subject in 
language that he/she can understand.  The ICF will be signed and dated by the subject and by the 
investigator or authorized designee who reviewed the ICF with the subject.    
Subjects who can write but cannot read will have the ICF read to them before signing and dating 
the ICF.  
Subjects who can understand but who can neither write nor read will have the ICF read to them 
in presence of an impartial witness, who will sign and date the ICF to confirm that ICF was 
given.  
The original ICF will be retained by the investigator as part of the subject's study record, and a 
copy of the signed ICF will be given to the subject.  
If new safety information results in significant changes in the risk/benefit assessment, the ICF 
will be reviewed and updated appropriately.  All study subjects will be informed of the new 
information and provide their written consent if they wish to continue in the study.    
 
14.2.  
Subject Confidentiality and Data Protection  
The investigator will take all appropriate measures to ensure that the anonymity of each study 
subject will be maintained.    
The subject's and investigators’ personal data will be treated in compliance with all applicable 
laws and regulations.    
 
14.3.  
Ethical Review  
An appropriately constituted IRB, as described in ICH Guidelines for GCP, will review and 
approve:    
• 
The protocol, ICF, and any other materials to be provided to the subjects (e.g., 
advertising) before any subject may be enrolled in the study   
• 
Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the subjects, in which 
case the IRB will be informed as soon as possible   
In addition, the IRB will be informed of any event likely to affect the safety of subjects or the 
continued conduct of the clinical study.  
Records of the IRB review and approval of all study documents (including approval of ongoing 
studies) will be kept on file by the investigator.  


  
  
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14.4.  
Regulatory Considerations  
This study will be conducted in accordance with:  
1. Consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines  
2. The ICH GCP Guideline [E6]  
3. Applicable laws and regulations  
The investigator or designee will promptly submit the protocol to applicable IRB(s). Some of the 
obligations of the sponsor may be assigned to a third party organization.  
An identification code assigned to each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other study-related data.   
14.4.1.  
Protocol Signatures  
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, the investigator will sign the protocol signature page and send a copy 
of the signed page to a sponsor representative.  
14.4.2.  
Final Report Signature  
The investigator will sign the final clinical study report for this study, indicating agreement with 
the analyses, results, and conclusions of the report.  
The sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.  
14.4.3.  
Study Monitoring  
The investigators and institution(s) will permit trial-related monitoring of the eCRF data by 
Stealth BioTherapeutics Inc., or their assignee by providing direct access to source data and/or 
documents.  The study monitor will verify the eCRFs 100 % against the source documentation.  
Deviations from the protocol with regard to subject enrollment or study conduct will also be 
noted in the source documentation, in the eCRF and a complementary database.  A sponsor 
representative will visit the site to initiate the study, prior to the first treatment of the first subject, 
and at agreed times throughout the study, including at the end of the study.  Medication 
dispensing and clinical drug supply records will be 100% verified at the study site by the study 
monitor.  It is understood that all subject specific information is confidential and no 
documentation that can link study information to the specific subject will be collected or retained 
by the sponsor.  
  


  
  
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14.4.4.  
Retention of Records  
All study related material including source documents, eCRFs and EC correspondence and 
analyses and any other documentation required by applicable laws and regulations will be 
maintained for fifteen (15) years after completion of the study or notification from the sponsor 
that the data can be destroyed, whichever comes first.  
14.4.5.  
Disclosure of Information  
Information concerning the investigational medication and patent application processes, 
scientific data or other pertinent information is confidential and remains the property of Stealth 
BioTherapeutics Inc.  The investigator may use this information for the purposes of the study 
only.  It is understood by the investigator that Stealth BioTherapeutics Inc., will use information 
developed in this clinical study in connection with the development of the investigational 
medication and, therefore, may disclose it as required to other clinical investigators and to 
regulatory agencies.  In order to allow the use of the information derived from this clinical study, 
the investigator understands that he/she has an obligation to provide complete test results and all 
data developed during this study to the sponsor.  
The investigator may not submit for publication or presentation the results of this study without 
first receiving written authorization from Stealth BioTherapeutics Inc. Stealth BioTherapeutics 
Inc., agrees that, before it publishes any results of the study, it shall provide the investigator with 
at least 30 days for review of the pre-publication manuscript prior to the submission of the 
manuscript to the publisher.  
 


  
  
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15.  
REFERENCES  
Adamis AP, Filatov V, Tripathi BJ, Tripathi RC. Fuchs’ endothelial dystrophy of the cornea. 
Surv Ophthalmol. 1993;38:149–168.  
Alam, N.M., et al., A Novel Peptide (MTP-131) that Improves Mitochondrial Function Reverses 
Visual Decline in Mouse Models of Metabolic Dysfunction Leading to Diabetes 2012: American 
Diabetes Association, 2012 Annual Meeting, Philadelphia, PA.  
Birk, A.V., et al., The Mitochondrial-Targeted Compound SS-31 Re-Energizes Ischemic 
Mitochondria by Interacting with Cardiolipin. J Am Soc Nephrol, 2013. 24(8): p. 2050-61.  
Buddi R, Lin B, Atilano SR, Zorapapel NC, Kenney MC, Brown DJ. Evidence of oxidative 
stress in human corneal diseases. J Histochem Cytochem. 2002;50:341–351.  
Chen, M., et al., Mitochondria-targeted Peptide MTP-131 alleviates mitochondrial dysfunction 
and oxidative damage in human trabecular meshwork cells. Invest Ophthalmol Vis Sci, 2011. 
52(10): p. 7027-37.  
Elhalis H, Azizi B, Jurkanis UV. Fuchs Endothelial Corneal Dystrophy. Ocul Surf. 
2010;8:173184.  
Huang, J., et al., Mitochondria-Targeted Antioxidant Peptide SS31 Protects the Retinas of 
Diabetic Rats. Curr Mol Med, 2013. 13(6): p. 935-45.  
Jurkunas UV, Bitar MS, Rawe I, Harris DL, Colby K, Joyce NC. Increased clusterin expression 
in Fuchs’ endothelial dystrophy. Invest Ophthalmol Vis Sci. 2008a; 49:2946–2955.  
Jurkunas UV, Rawe I, Bitar MS, et al. Decreased expression of peroxiredoxins in Fuchs’ 
endothelial dystrophy. Invest Ophthalmol Vis Sci. 2008b; 49:2956–2963.  
Jurkunas UV, Bitar MS, Funaki T, Azizi B.  Evidence of oxidative stress in the pathogenesis of 
Fuchs endothelial corneal dystrophy. Am J Path, 2010. 177;2278-2289.  
Krachmer JH, Purcell JJ, Jr, Young CW, Bucher KD. Corneal endothelial dystrophy. A study of 
64 families. Arch Ophthalmol. 1978;96:2036–2039.  
Li, J., et al., Mitochondria-targeted antioxidant Peptide SS31 attenuates high glucose-induced 
injury on human retinal endothelial cells. Biochem Biophys Res Commun, 2011. 404(1): p. 
34956.  
Liang, X., et al. SS31 Protects Human RPE Cells From Oxidative Damage and Reduce 
LaserInduced Choroidal Neovascularization Abstract Volume, 2010 Annual Meeting, 
Association for Vision and Ophthalmology, 2010a.  
Madsen-Bouterse, S.A. and R.A. Kowluru, Oxidative stress and diabetic retinopathy:  
pathophysiological mechanisms and treatment perspectives. Rev Endocr Metab Disord, 2008. 
9(4): p. 315-27.  
Prusky, G.T., Treating Visual Decline with MTP-131: Interim Study Report, 2013, Burke 
Medical Research Institute.  
Tuberville AW, Wood TO, McLaughlin BJ. Cytochrome oxidase activity of Fuchs’ endothelial 
dystrophy. Curr Eye Res. 1986;5:939–947.  


  
  
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Waring GO, 3rd, Bourne WM, Edelhauser HF, Kenyon KR. The corneal endothelium. Normal 
and pathologic structure and function. Ophthalmology. 1982;89:531–590.  
Yanoff M, Fine BS. Ocular Pathology. Barcelona: Mosby-Wolfe; 1996. pp. 276–278.  
   
 


  
  
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SPONSOR’S PROTOCOL SIGNATURE PAGE  
  
A PROSPECTIVE, RANDOMIZED, DOUBLE-MASKED, VEHICLE CONTROLLED,  
PAIRED-EYE PHASE 1/2 CLINICAL STUDY TO EVALUATE THE SAFETY,  
TOLERABILITY AND EFFICACY OF MTP-131 TOPICAL OPHTHALMIC SOLUTION  
(OCUVIATM) IN SUBJECTS WITH FUCHS’ CORNEAL ENDOTHELIAL DYSTROPHY  
(FCED) PRESENTING WITH MILD TO MODERATE CORNEAL EDEMA Study 
No.: SPIFD-101  
  
Sponsor:  
Stealth BioTherapeutics Inc.  
  
  
275 Grove Street, Suite 3-107  
  
  
Newton, MA 02466  
  
Protocol Date/Version: 18 August 2015 / Version 1.0   
  
Printed name:    
Gregory Gordon, MD  
Senior Director, Clinical Research  
Signature:    
 
Date:    
  
08/18/2015 
     
  
  
INVESTIGATOR’S PROTOCOL SIGNATURE PAGE  
  
A PROSPECTIVE, RANDOMIZED, DOUBLE-MASKED, VEHICLE CONTROLLED,  
PAIRED-EYE PHASE 1/2 CLINICAL STUDY TO EVALUATE THE SAFETY,  
TOLERABILITY AND EFFICACY OF MTP-131 TOPICAL OPHTHALMIC SOLUTION  
  


  
  
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(OCUVIATM) IN SUBJECTS WITH FUCHS’ CORNEAL ENDOTHELIAL DYSTROPHY 
(FCED) PRESENTING WITH MILD TO MODERATE CORNEAL EDEMA  
  
Study No.:  
SPIFD-101  
  
Sponsor:  
Stealth BioTherapeutics Inc.  
  
  
275 Grove Street, Suite 3-107  
  
  
Newton, MA  02466  
  
Protocol Date/Version: 18 August 2015 / Version 1.0   
  
I have read all pages of this clinical study protocol for which Stealth BioTherapeutics Inc. is the 
sponsor.  I agree to conduct the study as outlined in the protocol and to comply with all the terms 
and conditions set out therein.  I confirm that I will conduct the study in accordance with ICH 
GCP guidelines.  I will also ensure that sub-investigator(s) and other relevant members of my 
staff have access to copies of this protocol, and the ICH GCP guidelines to enable them to work 
in accordance with the provisions of these documents.    
  
Investigator:  
Printed name:    
  
Signature:    
  
Date:    
  
Site address:    
  
 
Attachment 1. SPIFD-101 Clinical Laboratory Tests  
 
Clinical Laboratory Tests  


  
  
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Hematology:  
Clinical Chemistry:  
Hemoglobin  
Serum Concentrations of:  
Hematocrit  
Sodium  
Erythrocyte count (RBC)  
Potassium  
Leukocytes (WBC)  
Total bilirubin  
Neutrophils, segmented  
Alkaline phosphatase  
Lymphocytes  
Alanine aminotransferase (ALT)  
Monocytes  
Aspartate aminotransferase (AST)  
Eosinophils  
Blood urea nitrogen (BUN)  
Basophils  
Creatinine  
Platelets  
Calcium  
  
Glucose (non-fasting)  
  
Albumin  
Urinalysis:  
Chloride  
Specific gravity  
Bicarbonate  
pH  
Total protein  
Protein  
  
Glucose  
Pregnancy Test   
Serum & urine  
(Women of childbearing potential only)  
Ketones  
Blood  
  


 
 
PVB57NJPAK9R2Z67ZKIH2A 
Gregory Gordon 
Party ID: 7WRGJHJ4D3HU3W8EYNK2ZU 
IP Address: 38.104.218.66 
VERIFIED EMAIL: gregory.gordon@stealthpeptides.com 
Multi-Factor 
Digital Fingerprint Checksum 
45 a0c8f9e17bfca54335d96adaefc3ac7170eb 30 
Audit 
Timestamp 
2015-08-18 12:32:37 -0700 
All parties have signed document. Signed copies sent to: Gregory Gordon and 
Kandarp Prajapati. 
2015-08-18 12:32:37 -0700 
Document signed by Gregory Gordon (gregory.gordon@stealthpeptides.com) with 
drawn signature. - 38.104.218.66 
2015-08-18 12:31:38 -0700 
Document viewed by Gregory Gordon (gregory.gordon@stealthpeptides.com). - 
38.104.218.66 
2015-08-18 11:41:47 -0700 
Document created by Kandarp Prajapati 
( kandarp.prajapati@stealthpeptides.com ). - 38.104.218.66 
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