Single-Arm Study Assessing the Effects of Pneumatic Vitreolysis on Macular Hole
Phase: NA
Conditions: Vitreomacular Traction (VMT), Full-thickness Macular Holes (MH)
Sponsor: Jaeb Center for Health Research

 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
 
DRCR Retina Network 
 
 
 
 
Single-Arm Study Assessing the Effects of 
Pneumatic Vitreolysis on Macular Hole 
(Protocol AH) 
 
 
IDE Sponsor: Jaeb Center for Health Research (JCHR) 
 
Version 3.0 
 
12 August 2019 
 
NCT03677869 
 

 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
Signature Page 
Single-Arm Study Assessing the Effects of Pneumatic 
Vitreolysis on Macular Hole 
Protocol Identifying Number: DRCR Retina Network AH 
IDE Sponsor: Jaeb Center for Health Research 
Version Number: 3.0 
12 August 2019 
 
 
 
JCHR Principal Investigator 
 
Name, degree 
Adam Glassman, MS  
 
Signature / Date 
 
 
 
 
 
 
 
 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
KEY ROLES 
 
Protocol Chair 
 
Name, degree 
Calvin E. Mein, MD 
Title 
Ophthalmologist 
Institution Name 
Retinal Consultants of San Antonio, San Antonio, TX 
 
JCHR Coordinating Center Director 
 
Name, degree 
Adam Glassman, MS 
Title 
Director of DRCR Retina Network Coordinating Center 
Institution Name 
Jaeb Center for Health Research, Tampa, FL 
 
Network Chair 
 
Name, degree 
Daniel F. Martin, MD 
Title 
Chairman, Cole Eye Institute 
Institution Name 
Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 
 
Medical Monitor 
 
Name, Title 
Robert Lindblad, Senior Medical Officer 
Ashraf El Fiky, Medical Officer 
Institution Name 
The EMMES Corporation 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
TABLE OF CONTENTS 
Chapter 1: Background Information and Study Synopsis .......................................................... 1-1 
1.1. 
Introduction ................................................................................................................... 1-1 
1.1.1 Vitreoretinal Interface Abnormalities ......................................................................... 1-1 
1.1.2 Treatments for VMT with Macular Hole .................................................................... 1-1 
1.1.3 Pneumatic Vitreolysis (PVL) ...................................................................................... 1-1 
1.2. 
Rationale ........................................................................................................................ 1-2 
1.3 
Study Objectives ........................................................................................................... 1-2 
1.4 
Potential Risks and Benefits of C3F8 Gas Injection ....................................................... 1-2 
1.4.1 
Known Potential Risks .............................................................................................. 1-2 
1.5 
General Considerations ................................................................................................. 1-4 
Chapter 2: Study Participant Eligibility and Enrollment ........................................................... 2-1 
2.1 Participant Recruitment and Enrollment ............................................................................ 2-1 
2.2 Participant Eligibility Criteria ............................................................................................ 2-1 
2.2.1 Participant-Level Criteria............................................................................................ 2-1 
2.2.2 Study Eye Criteria ....................................................................................................... 2-2 
2.3 Screening Evaluation and Baseline Testing ....................................................................... 2-3 
2.3.1 Baseline Testing Procedures ....................................................................................... 2-3 
Chapter 3: Baseline Treatment ................................................................................................... 3-1 
3.1 Treatment ........................................................................................................................... 3-1 
3.2 Injection Procedure ............................................................................................................ 3-1 
3.2.1 Intravitreous Injection Technique ............................................................................... 3-1 
3.2.2 Aqueous Sample Collection ........................................................................................ 3-1 
3.3 Participant Instructions Post-Injection ............................................................................... 3-1 
Chapter 4: Follow-Up Visits and Testing .................................................................................. 4-1 
4.1 Study Visits ........................................................................................................................ 4-1 
4.1.1 Procedures at Study Visits .......................................................................................... 4-1 
4.1.2 Unscheduled Visits ..................................................................................................... 4-1 
4.2 Treatment During Follow Up............................................................................................. 4-1 
4.2.1 Criteria for Vitrectomy ............................................................................................... 4-1 
4.2.2 Treatment for Other Conditions in the Study Eye ...................................................... 4-2 
4.2.3 Treatment in the Non-Study Eye ................................................................................ 4-2 
Chapter 5: Study Device ............................................................................................................ 5-1 
5.2 Study Device Accountability Procedures .......................................................................... 5-1 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
5.3 Safety Measures ................................................................................................................. 5-1 
Chapter 6: Adverse Events, Device Issues, and Stopping Rules ............................................... 6-1 
6.1 Adverse Events .................................................................................................................. 6-1 
6.1.1 Definitions................................................................................................................... 6-1 
6.1.2 Reportable Adverse Events ......................................................................................... 6-2 
6.1.3 Relationship of Adverse Event to Study Device......................................................... 6-2 
6.1.4 Intensity of Adverse Event.......................................................................................... 6-2 
6.1.5 Coding of Adverse Events .......................................................................................... 6-3 
6.1.6 Outcome of Adverse Event ......................................................................................... 6-3 
6.2 Reportable Device Issues ................................................................................................... 6-4 
6.3 Pregnancy Reporting .......................................................................................................... 6-4 
6.4 Timing of Event Reporting ................................................................................................ 6-4 
6.5 Stopping Criteria ................................................................................................................ 6-4 
6.5.1 Criteria for Suspending or Stopping Overall Study .................................................... 6-4 
6.6 Independent Safety Oversight ............................................................................................ 6-4 
6.7 Risks ................................................................................................................................... 6-5 
Chapter 7: Miscellaneous Considerations .................................................................................. 7-1 
7.1 Prohibited Medications, Treatments, and Procedures ........................................................ 7-1 
7.2 Participant Withdrawal ...................................................................................................... 7-1 
7.3 Discontinuation of Study ................................................................................................... 7-1 
7.4 Confidentiality ................................................................................................................... 7-1 
7.5 Participant Compensation .................................................................................................. 7-1 
Chapter 8: Statistical Considerations ......................................................................................... 8-1 
8.4 Outcome Measures............................................................................................................. 8-1 
8.5 Analysis Cohorts ................................................................................................................ 8-2 
8.6 Analysis of the Primary Outcome ...................................................................................... 8-3 
8.7 Analysis of the Secondary and Exploratory Outcomes ..................................................... 8-3 
8.8 Safety Analyses .................................................................................................................. 8-4 
8.9 Intervention Adherence ...................................................................................................... 8-5 
8.10 Protocol Adherence and Retention .................................................................................. 8-5 
8.11 Baseline Descriptive Statistics ......................................................................................... 8-5 
8.12 Planned Interim Analyses ................................................................................................ 8-5 
8.13 Subgroup Analyses .......................................................................................................... 8-5 
8.14 Multiple Testing ............................................................................................................... 8-6 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
Chapter 9: Data Collection and Monitoring ............................................................................... 9-1 
9.1 Case Report Forms and Device Data ................................................................................. 9-1 
9.2 Study Records Retention.................................................................................................... 9-1 
9.3 Quality Assurance and Monitoring .................................................................................... 9-1 
9.4 Protocol Deviations ............................................................................................................ 9-2 
Chapter 10: Ethics/Protection of Human Participants ............................................................. 10-1 
10.1 Ethics/Protection of Human Participants Ethical Standard ........................................... 10-1 
10.2 Institutional Review Boards ........................................................................................... 10-1 
10.3 Informed Consent Process ............................................................................................. 10-1 
10.3.1 Consent Procedures and Documentation ................................................................ 10-1 
10.3.2 Participant and Data Confidentiality ....................................................................... 10-1 
10.3.3 Future Use of Stored Specimens ............................................................................. 10-2 
Chapter 11: References ............................................................................................................ 11-1 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AUC 
Area Under the Curve 
CI 
Confidence Interval 
CRF 
Case Report Form 
DSMC 
Data and Safety Monitoring Committee 
E-ETDRS 
Electronic-Early Treatment Diabetic Retinopathy Study 
ERM 
Epiretinal Membrane  
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization  
ID 
Identification 
IDE 
Investigational Device Exemption 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board  
ITT 
Intention-To-Treat  
JCHR 
Jaeb Center for Health Research 
MH 
Macular Hole 
OCT 
Optical Coherence Tomography 
PVD 
Posterior Vitreous Detachment 
PVL 
Pneumatic Vitreolysis 
SADE 
Serious Adverse Device Event 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
UADE 
Unanticipated Adverse Device Effect 
VMT 
Vitreomacular Traction 
VMA 
Vitreomacular Adhesion 
 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
PROTOCOL SUMMARY 
PARTICIPANT AREA 
DESCRIPTION 
Title 
Single-Arm Study Assessing the Effects of Pneumatic Vitreolysis on 
Macular Hole 
Précis 
Eyes with vitreomacular traction (VMT) and full-thickness macular 
hole (MH) will be enrolled into a non-randomized cohort treated 
with PVL to determine the proportion with VMT release and MH 
closure and to assess factors associated with success.  
Investigational Device 
Intraocular gas (C3F8) injection  
Objectives 
To obtain estimates of the proportion of eyes with MH closure of the 
inner retinal layers for eyes with VMT and full-thickness MHs 
treated with PVL. 
Rationale 
Understanding the rates of VMT release and MH closures in eyes 
with full-thickness MH treated with PVL is of interest. Surgery 
would result in nearly 100% hole closure and VMT release, making 
vitrectomy a poor control group choice. Spontaneous resolution of 
MH is highly unlikely, making an observation arm unnecessary. 
Therefore, these eyes will be enrolled into a non-randomized cohort 
treated with PVL to assess the outcomes of treatment.  
Study Design 
Single-arm study  
Number of Sites 
Approximately 50 sites  
Endpoint 
Primary Outcome: Proportion of eyes with MH closure of the inner 
retinal layers without rescue treatment at 8 weeks. 
 
Key Secondary Outcomes: proportion of eyes with central VMT 
release without rescue treatment, proportion of eyes with rescue 
treatment, mean change in visual acuity 
 
Key Safety Outcomes: retinal tear, retinal detachment, traumatic 
cataract, cataract extraction, vitreous hemorrhage, intraocular 
pressure (IOP) increase, and endophthalmitis. 
Population 
Key Inclusion Criteria 
• Age ≥ 18 years. 
• Able and willing to avoid high altitude until gas resolution 
(approximately 6 to 8 weeks)  
• For phakic patients, able and willing to avoid supine 
positioning until gas resolution (approximately 6 to 8 weeks)  
• Able and willing to position face down for at least 50% of the 
time for at least 4 days post-injection  
• At least 1 eye with: 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
PARTICIPANT AREA 
DESCRIPTION 
o Central vitreomacular adhesion on OCT that is no larger 
than 3000 microns, confirmed by a central reading center 
o Full-thickness MH that is ≤ 250 microns at the narrowest 
point as measured on OCT, confirmed by a central 
Reading Center 
o Best corrected E-ETDRS visual acuity equivalent of 
20/25 to 20/400 
 
Key Exclusion Criteria 
 
• Other condition that might affect visual acuity during the 
course of the study (e.g., retinal vein occlusion, advanced 
age-related macular degeneration, or macular edema induced 
by a condition other than VMT) 
• High level myopia (-8.00 diopters or more myopic if phakic 
or retinal abnormalities consistent with pathologic myopia if 
phakic or pseudophakic) 
• Prior gas injection, ocriplasmin injection, or intraocular 
injection for any reason 
• Prior vitrectomy 
• History of advanced glaucoma that contraindicates intraocular 
gas injection 
Sample Size 
50 eyes 
Treatment Groups 
C3F8 injection only 
Participant Duration 
24 weeks 
Protocol 
Overview/Synopsis 
1. Informed consent will be obtained.  
2. Eligibility will be assessed, including reading center 
confirmation of VMT and MH on OCT.  
3. Eligible eyes with VMT and MH will be treated with C3F8 
injection. 
4. Follow-up visits will occur at 1, 4, 8, and 24 weeks and 
consist of visual acuity testing, ocular exam, and OCT. 
5. The primary outcome assessment will be the proportion of 
eyes at 8 weeks with full-thickness MH closure of inner 
retinal layers without rescue treatment.  
 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
SCHEMATIC OF STUDY DESIGN 
 
Dropped Ineligible
Informed Consent Obtained
Baseline Testing
Reading Center 
Review
Injection of C3F8
Gas (0.3 mL)
1 Week
4 Weeks
8 Weeks
(Primary 
Outcome)
24 Weeks
Dropped 
Ineligible

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
SCHEDULE OF STUDY VISITS AND PROCEDURES 
 
Enrollment 
Visit*  
1, 4, 8, and 24 
weeks 
E-ETDRS best corrected visual acuity a 
X 
X 
OCT b 
X 
X 
Eye exam c 
X 
X 
Reading center eligibility confirmation d  
X 
 
Gas injection 
X 
 
* All baseline testing must occur within 8 days prior to enrollment.  
a, Both eyes at all visits; includes protocol refraction in study eye only at each visit and in both eyes at 
enrollment and 8 weeks. Electronic ETDRS (E-ETDRS) testing using the Electronic Visual Acuity Tester 
that has been validated against 4-meter chart ETDRS testing. 
b, Both eyes at baseline; study eye only at follow up visits. 
c, Both eyes at baseline; study eye only at each follow-up visit. Includes slit lamp exam (including 
assessment of lens), measurement of intraocular pressure, and dilated ophthalmoscopy. Scleral depression 
is required at baseline to confirm eligibility. During follow up, the eye exam should be extensive enough 
to identify adverse events of interest. An extended ophthalmoscopy including a scleral depression is 
required at 1, 4, and 8 weeks. 
d, Reading center review of the OCT for eligibility must occur prior to enrollment. 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
 
 
 
 
 
 
1-1 
CHAPTER 1: BACKGROUND INFORMATION AND STUDY SYNOPSIS 
1 
1.1. Introduction 
2 
1.1.1 Vitreoretinal Interface Abnormalities  
3 
Disorders of the vitreoretinal interface represent a spectrum of abnormalities that develop as the 
4 
posterior hyaloid separates from the internal limiting membrane. Vitreomacular adhesion (VMA) 
5 
occurs when the posterior hyaloid remains attached to the internal limiting membrane centrally. 
6 
Overall, about 1.5% of the population is estimated to have eye diseases caused by or associated 
7 
with VMA.1 The incidence of VMA diagnoses is expected to increase with widespread use of 
8 
spectral-domain optical coherence tomography (SD-OCT). Vitreomacular traction (VMT) is 
9 
diagnosed when VMA results in traction, distortion of retinal architecture, and patient 
10 
symptomatology.2  
11 
Advanced VMT can lead to macular holes (MH), in which tractional forces create small full-
12 
thickness defects on the posterior fundus, often requiring surgical intervention.2 Regarding the 
13 
incidence of idiopathic full-thickness macular holes, a population-based study showed idiopathic 
14 
macular holes occur at an age and sex-adjusted incidence in 8.69 eyes per 100,000 population 
15 
per year.3 The female to male ratio was determined to be 3.3 to 1, and bilateral idiopathic MHs 
16 
occurred in 11.7% of patients and accounted for 20.9% of the affected eyes.3 In another study of 
17 
a large population of patients with age-related macular degeneration (15,196 with non 
18 
neovascular age-related macular degeneration (AMD) and 12,716 with neovascular AMD), 0.7% 
19 
were found to have MHs (1.1% with non-neovascular AMD and 0.3% with neovascular AMD).4 
20 
Regarding MH prevalence globally, the Baltimore Eye Study reported a prevalence of 3.3 per 
21 
1,000 persons in Maryland,5 the Beaver Dam Eye Study showed a prevalence of 2.9 per 1,000 
22 
persons in Wisconsin, the Blue Mountains Eye Study showed a prevalence of 0.2 per 1,000 
23 
persons in Australia,6 the Beijing Eye Study showed a prevalence of 0.9 per 1,000 persons in 
24 
China,7 and Sen et al. reported a prevalence of 1.7 per 1,000 persons in Southern India.8  
25 
1.1.2 Treatments for VMT with Macular Hole 
26 
For eyes with VMT with MH, prompt treatment is indicated to restore central vision and prevent 
27 
retinal detachment. In the MIVI-TRUST trial, ocriplasmin was successful in 60% in eyes with an 
28 
MH of < 250 microns.9 However, there have been multiple anecdotal reports of substantial 
29 
ocular complications associated with intraocular administration of ocriplasmin,10-14 including 
30 
transient vision loss, persistent dyschromatopsia, electroretinographic abnormalities, subluxation 
31 
of the crystalline lens likely related to zonulolysis, and disturbance or dehiscence of the ellipsoid 
32 
layer documented by OCT. These adverse events have created major concerns among many 
33 
retinal surgeons in the clinical use of this drug.10-14 Therefore, vitrectomy is currently the first 
34 
line therapy for VMT with MH. Although MH closure is usually successful after vitrectomy 
35 
(approaching 100% success rate in several series), there are associated downsides including cost, 
36 
patient discomfort, length of time a large bubble resides in the eye, and possible adverse events 
37 
such as endopthalmitis, retinal detachment, and cataract progression.15 
38 
1.1.3 Pneumatic Vitreolysis (PVL) 
39 
Pneumatic vitreolysis (intraocular injection of expansile gas to induce a posterior vitreous 
40 
detachment [PVD]) has been suggested as a potential treatment alternative to vitrectomy or 
41 
ocriplasmin for VMT with MH. In 1995, Chan et al. first demonstrated and reported the utility of 
42 
intraocular gas (C3F8) injection where 13 of 17 (76%) stage 1 or stage 2 macular holes closed 
43 
after injection.16 Subsequently, Jorge et al. showed success in the induction of PVD (6 of 6 eyes) 
44 
and macular hole closure (5 of 6 eyes) with C3F8 in small case series.17, 18 Mori et al.19 reported 5 
45 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
 
 
 
 
 
 
1-2 
of 10 eyes had hole closure after gas.19 Steinle et al. reported a success rate of 83% (25 of 30 
46 
eyes) with C3F8 gas in a retrospective case series for treatment of VMT syndrome.20 In a 2016 
47 
retrospective review of 15 consecutive eyes receiving C3F8 gas for pneumatic vitreolysis 
48 
performed in 2 centers, Chan and Mein reported a success rate of 100% for VMT release and 
49 
67% for hole closure in eyes with small stage 2 MH ≤ 250 microns.21 In 2019, Chan and Mein 
50 
provided an update on this study and reported a success rate of 95.7% for VMT release and 
51 
65.2% for hole closure among 23 eyes with small stage 2 MH ≤ 250 microns.22 
52 
1.2. Rationale 
53 
Understanding the rates of MH closure and VMT release in eyes with full-thickness macular 
54 
holes treated with PVL is of interest given the low cost and convenience of gas injection in the 
55 
office setting as well as a low rate of adverse events reported in prior retrospective studies. 
56 
Although spontaneous macular hole closure is possible, this occurs infrequently.23 It is likely that 
57 
eyes with these characteristics would need prompt treatment, making randomization to a sham 
58 
arm inappropriate. Prior studies have established the benefit of vitrectomy for treatment of 
59 
macular holes, reporting 80 to 90% success rates in MH closure with associated visual benefit, 
60 
making vitrectomy an unnecessary (and expensive) control group choice.23-27 Therefore, these 
61 
eyes will be enrolled into a non-randomized cohort treated with PVL to assess the outcomes of 
62 
treatment.  
63 
 
64 
If a large percentage of eyes can achieve MH closure with a simple in-office, low-cost 
65 
procedure, while averting the invasiveness and expense of a vitrectomy for this condition, this 
66 
would provide a viable first-line treatment option. Even if this proposed study finds that PVL is 
67 
only moderately successful, physicians and patients may decide to attempt PVL in the office 
68 
first, before proceeding with more costly, invasive surgery. Thus, even without a control group, 
69 
the results from this study will provide data of value for physicians and patients to make 
70 
informed decisions about treatment course.  
71 
1.3 Study Objectives 
72 
Primary 
73 
1. To obtain estimates for the proportion of eyes with MH closure of the inner retinal layers 
74 
for eyes with VMT and full-thickness macular holes treated with PVL  
75 
1.4 Potential Risks and Benefits of C3F8 Gas Injection 
76 
1.4.1 Known Potential Risks 
77 
Potential risks of C3F8 gas injection include the following: 
78 
• Pain, discomfort, redness, or itching lasting for a few days is likely. 
79 
• Subconjunctival hemorrhage or floaters will commonly occur as a result of the injection. The 
80 
floaters are typically reduced after 6 to 8 weeks, but some floaters may persist. 
81 
• Immediately following the injection, there may be elevation of IOP. Pressure usually returns 
82 
to normal spontaneously, but may need to be treated with topical drugs or a paracentesis to 
83 
lower the pressure. The likelihood of permanent loss of vision from elevated IOP is less than 
84 
1%. 
85 
• Although it has not been reported in prior case series, endophthalmitis could theoretically 
86 
develop. The risk of endophthalmitis from other intraocular injections is less than 1%. 
87 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
 
 
 
 
 
 
1-3 
• A retinal tear or detachment could occur. The risk of retinal breaks or detachment after gas 
88 
injection is approximately 5-13%. The risk of retinal detachment is increased if there are pre-
89 
existing peripheral retinal abnormalities such as lattice degeneration or cystic tufts. 
90 
• There is a possibility of traumatic cataract from the injection. The risk of developing a 
91 
cataract from the injection is <1%  
92 
• If paracentesis is performed, there is a similar risk of traumatic cataract from paracentesis. 
93 
• If vitrectomy is required while gas is in the eye, there is high likelihood of cataract formation 
94 
during surgery that may require cataract removal at the time of vitrectomy.  
95 
• Limited and transient uveitis may develop after gas injection. Persistent uveitis is uncommon. 
96 
• Limited transient conjunctival or episcleral hemorrhage is common shortly after gas 
97 
injection. It is usually inconsequential and clears spontaneously from a few days to a week or 
98 
two.  
99 
• Limited vitreous hemorrhage or opacities after gas injection is uncommon but may occur 
100 
occasionally after gas injection, particularly given a history of active anticoagulation therapy 
101 
or predisposing risk for hemorrhage. If present, it usually resolves from a few days to a few 
102 
months. Marked intraocular hemorrhage requiring a surgical intervention after gas injection 
103 
is exceedingly rare (< 1%). 
104 
• Pre-existing epiretinal fibrosis may sometimes progress or new epiretinal fibrosis may 
105 
develop after gas injection.  
106 
• The development of excessive scarring on top of or under the retina after gas injection is 
107 
exceedingly rare. When this occurs, it is usually associated with advanced retinal 
108 
detachment, which is also uncommon after gas injection. 
109 
Additional risks if the participant does not follow post-injection instructions: 
110 
• Intraocular pressure may increase if the patient experiences changes in elevation (i.e. travel 
111 
by air or over mountain ranges) while the gas bubble is still present in the eye. 
112 
• Loss of vision or blindness is possible if nitrous oxide anesthesia is administered with the gas 
113 
bubble still present in the eye. 
114 
• Incorrect head positioning following the gas injection may lead to glaucoma or cataracts. 
115 
 
116 
1.4.2 Known Potential Benefits 
117 
Potential benefits from participation in the study for eyes treated with PVL include, improved 
118 
visual acuity, improved quality of vision, closure of MH, and avoidance of more invasive and 
119 
expensive procedures, i.e., vitrectomy, ocriplasmin. 
120 
1.4.3 Risk Assessment 
121 
The risk level is considered to be research involving greater than minimal risk. 
122 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
 
 
 
 
 
 
1-4 
1.5 General Considerations 
123 
The study is being conducted in compliance with the policies described in the study policies 
124 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
125 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
126 
The DRCR Retina Network procedures manuals provide details of the procedures.  
127 
Data will be directly collected in electronic case report forms, which will be considered the 
128 
source data. 
129 
There is no restriction on the number of subjects to be enrolled by each site towards the overall 
130 
recruitment goal. However, recruitment will be monitored on an ongoing basis and the sponsor 
131 
can decide to place recruitment at a particular site on hold as needed. 
132 
All consented participants will be logged. The protocol is considered a significant risk device 
133 
study because intraocular injection of C3F8 is experimental for this indication. Therefore, an 
134 
investigational device exemption (IDE) from the U.S. Food and Drug Administration (FDA) is 
135 
required to conduct the study. 
 
136 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
 
 
 
 
 
 
2-1 
CHAPTER 2: STUDY PARTICIPANT ELIGIBILITY AND ENROLLMENT 
137 
2.1 Participant Recruitment and Enrollment 
138 
Enrollment will proceed with the goal of at least 50 participants deemed eligible by Reading 
139 
Center and treated with C3F8. Participants who have signed consent may be permitted to continue 
140 
into the study, if eligible, even if the enrollment goal has been reached. 
141 
Study participants will be recruited from approximately 50 clinical centers in the United States. 
142 
Approximately 5 participants are expected to be enrolled each month, resulting in 10 months of 
143 
recruitment, for a total study duration of 16 months. 
144 
All eligible participants will be included without regard to gender, race, or ethnicity. There is no 
145 
restriction on the number of participants to be enrolled by each site toward the overall 
146 
recruitment goal. 
147 
Potential eligibility may be assessed as part of a routine-care examination. Before completing 
148 
any procedures or collecting any data that are not part of usual care, written informed consent 
149 
will be obtained. 
150 
The study protocol will be discussed with the potential study participant by study staff. The 
151 
potential study participant will be given the Informed Consent Form to read. Potential study 
152 
participants will be encouraged to discuss the study with family members and their personal 
153 
physicians(s) before deciding whether to participate in the study. 
154 
As part of the informed consent process, each participant will be asked to sign an authorization 
155 
for release of personal information. The investigator, or his or her designee, will review the 
156 
study-specific information that will be collected and to whom that information will be disclosed. 
157 
After speaking with the participant, questions will be answered about the details regarding 
158 
authorization. 
159 
2.2 Participant Eligibility Criteria 
160 
2.2.1 Participant-Level Criteria 
161 
Inclusion 
162 
To be eligible, the following inclusion criteria must be met: 
163 
1. Age ≥ 18 years  
164 
• Participants < 18 years old are not being included because the condition is so rare in 
165 
this age group that the diagnosis may be questionable.  
166 
2. At least one eye meets the study eye criteria listed in section 2.2.2 
167 
3. Able and willing to provide informed consent 
168 
4. Able and willing to avoid high altitude travel, including airline travel, until gas resolution 
169 
(approximately 6 to 8 weeks) 
170 
5. For phakic patients, able and willing to avoid supine position until gas resolution 
171 
(approximately 6 to 8 weeks) 
172 
6. Able and willing to position face down for at least 50% of the time for at least 4 days post-
173 
injection (to facilitate macular hole closure) 
174 
7. Able and willing to wear wristband that informs any medical personnel that the patient has a 
175 
gas bubble in the eye  
176 

Jaeb Center for Health Research 
 
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2-2 
Exclusion 
177 
A potential participant is not eligible if any of the following exclusion criteria are present:  
178 
8. A condition that, in the opinion of the investigator, would preclude participation in the study 
179 
(e.g., unstable medical status that might preclude completion of follow up) 
180 
9. Participation in an investigational trial within 30 days of enrollment that involves treatment 
181 
with any drug or device that has not received regulatory approval for the indication being 
182 
studied at the time of study entry 
183 
• Note: study participants should not receive another investigational drug or device while 
184 
participating in the study 
185 
10. Known contraindication to any component of the treatment 
186 
11. Known allergy to any drug used in the procedure prep (including povidone iodine) 
187 
12. Potential participant is expecting to move out of the area of the clinical center to an area not 
188 
covered by another clinical center during the 6 months following enrollment 
189 
13. Anticipated surgery requiring anesthesia within the 6 months following enrollment 
190 
• Participants cannot receive nitrous oxide until gas resolution  
191 
14. For women of child-bearing potential: pregnant at the time of enrollment 
192 
• Women who are potential study participants should be questioned about the potential for 
193 
pregnancy. Investigator judgement may be used to determine when a pregnancy test is 
194 
needed 
195 
2.2.2 Study Eye Criteria 
196 
The participant must have at least one eye meeting all of the inclusion criteria and none of the 
197 
exclusion criteria listed below. 
198 
A participant can have only one study eye. If both eyes are eligible at the time of enrollment, the 
199 
study eye will be selected by the investigator and participant before injection.  
200 
The eligibility criteria for a study eye are as follows: 
201 
Inclusion 
202 
a. Full-thickness macular hole that is ≤ 250 microns at the narrowest point, confirmed by 
203 
central reading center 
204 
b. Central vitreomacular adhesion on OCT that is no larger than 3000 microns with visible 
205 
separation of the vitreous on either side as seen on horizontal and vertical scans, confirmed 
206 
by central reading center  
207 
• Presence of epiretinal membrane is neither a requirement nor exclusion 
208 
c. Visual acuity letter score of at least 19 (approximate Snellen equivalent 20/400 or better) and 
209 
at most 83 (20/25 or worse) 
210 
Exclusion 
211 
d. Other ocular condition that might affect visual acuity during the course of the study or 
212 
require intraocular treatment (e.g., retinal vein occlusion, substantial age-related macular 
213 
degeneration, or macular edema induced by a condition other than VMT) 
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• If diabetic retinopathy is present, severity level must be microaneurysms only or better (≤ 
215 
diabetic retinopathy severity level 20). 
216 
• Presence of drusen is acceptable; however, eyes with geographic atrophy or neovascular 
217 
age-related macular degeneration involving the macula are excluded.  
218 
e. High level of myopia (spherical equivalent of -8.00 diopters or more myopic if phakic, or 
219 
retinal abnormalities consistent with pathologic myopia if phakic or pseudophakic) 
220 
f. History of prior gas injection, ocriplasmin injection, or intraocular injection for any reason 
221 
g. History of prior vitrectomy 
222 
h. History of uncontrolled glaucoma 
223 
• Intraocular pressure must be < 30 mmHg, with no more than one topical glaucoma 
224 
medication, and no documented glaucomatous field loss for the eye to be eligible 
225 
i. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular 
226 
surgery, etc.) within prior 4 months or major ocular surgery anticipated within the next 6 
227 
months following enrollment 
228 
j. History of YAG capsulotomy performed within 4 months prior to enrollment 
229 
k. Aphakia or anterior chamber intraocular lens  
230 
l. Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or 
231 
substantial blepharitis 
232 
m. Uveitis  
233 
n. Retinal history or pathology that might predispose an eye to an increased risk of retinal 
234 
detachment from the procedure 
235 
• Untreated retinal tears, not retinal holes, are an exclusion. It is up to the investigator to 
236 
determine whether extent of lattice degeneration or other pathology might increase the 
237 
risk of retinal detachment 
238 
o. Any contraindication to paracentesis (e.g., history of narrow angle glaucoma) 
239 
p. Lenticular or zonular instability 
240 
2.3 Screening Evaluation and Baseline Testing 
241 
After informed consent has been signed, the potential participant will be evaluated for study 
242 
eligibility through the elicitation of a medical history and performance of an ocular examination 
243 
by study personnel to screen for exclusionary conditions. 
244 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
245 
date per investigator discretion. 
246 
All testing does not need to be completed on the same day provided it is within the windows 
247 
specified below. Reading Center confirmation of VMT with full-thickness macular hole on OCT 
248 
must be completed prior to enrollment.  
249 
2.3.1 Baseline Testing Procedures 
250 
The following procedures are needed to confirm eligibility and/or to serve as baseline measures 
251 
for the study:  
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• If a procedure has been performed using the study technique and by study certified 
253 
personnel as part of usual care, then it does not need to be repeated specifically for the 
254 
study if it was performed within the defined time windows specified below.  
255 
• The testing procedures are detailed in the DRCR Retina Network Procedures Manuals. 
256 
Visual acuity testing, ocular exam, and OCT will be performed by DRCR Retina 
257 
Network certified personnel.  
258 
1. Self-reported demographics (date of birth, sex, race, and ethnicity) 
259 
2. Medical history (pre-existing medical conditions, concomitant medications, as well as ocular 
260 
diseases, surgeries, and treatments) 
261 
• Medical history will be obtained by medical charts if available at the enrolling site; 
262 
otherwise, it will be self-reported 
263 
3. Electronic-ETDRS visual acuity testing at 3 meters using the Electronic Visual Acuity Tester 
264 
(including protocol refraction) in each eye (within prior 8 days) 
265 
4. Spectral-Domain OCT using Zeiss Cirrus or Heidelberg Spectralis on each eye (within prior 
266 
8 days) 
267 
• OCT scans of the study eye will be promptly sent to the central reading center for 
268 
grading and a participant cannot be enrolled until reading center confirmation of 
269 
eligibility has been received.  
270 
5. Ocular examination on each eye including slit lamp, measurement of IOP, lens assessment, 
271 
and dilated ophthalmoscopy (within prior 8 days)  
272 
• Scleral depression to rule out any retinal tears pre-operatively will be required for the 
273 
baseline eye exam to confirm eligibility. 
 
274 

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3-1 
CHAPTER 3: BASELINE TREATMENT 
275 
3.1 Treatment 
276 
The C3F8 gas injection must be given on the day of enrollment.  
277 
3.2 Injection Procedure 
278 
3.2.1 Intravitreous Injection Technique 
279 
The injection is preceded by a povidone iodine prep of the conjunctiva. A subconjunctival 
280 
injection of lidocaine may be administered at the discretion of the investigator. The injection will 
281 
be performed using sterile technique. Pre-injection paracentesis should be considered due to the 
282 
4x expansion of C3F8 gas and the associated risk of shallowing of the anterior chamber. 
283 
However, the choice of when or whether or not to do a paracentesis is ultimately at the 
284 
investigator’s discretion. The full injection procedure is described in the protocol-specific study 
285 
procedures manual. Topical antibiotics in the pre-, peri-, or post-injection period should not be 
286 
used without prior approval from the Protocol Chair or Coordinating Center designee.  
287 
3.2.2 Aqueous Sample Collection 
288 
Participation in the ancillary sample collection component is not a requirement for participation 
289 
in this study. It is expected that sites with the capability to ship intraocular fluids will participate. 
290 
At the time of consent into the main study, participants will have the option of signing the 
291 
ancillary sample collection portion of the informed consent form to indicate their willingness to 
292 
provide the sample for future use. If paracentesis is performed and participant consent is 
293 
obtained, aqueous fluid already being drawn as part of paracentesis may be collected and shipped 
294 
on dry ice to a central laboratory for storage for future analyses. Sites will be encouraged to 
295 
collect samples when performing paracentesis, though sample collection will not be required. 
296 
Details regarding collection, sample labeling, storage, and shipment can be found in the 
297 
procedures manual. 
298 
3.3 Participant Instructions Post-Injection 
299 
Participants will be given a post-injection instruction sheet informing them of all post-injection 
300 
requirements and risks if they do not follow these requirements. Participants will be instructed to 
301 
position face down for at least 50% of the time for at least 4 days post-injection. Participants will 
302 
be instructed to avoid high altitude travel until the surgeon confirms the gas bubble has cleared. 
303 
Phakic participants will be asked to avoid the supine position and lie on one side or the stomach 
304 
during sleeping hours until the surgeon confirms that the gas bubble has cleared. All participants 
305 
will be instructed to wear a wristband to notify healthcare providers that they should not receive 
306 
nitrous oxide anesthesia until the gas bubble has cleared.
307 

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CHAPTER 4: FOLLOW-UP VISITS AND TESTING 
308 
4.1 Study Visits 
309 
The schedule of protocol-specified follow-up visits is as follows: 
310 
• 1 week (- 4 days to + 3 days) 
311 
• 4 (±1) weeks 
312 
• 8 (±2) weeks 
313 
• 24 (±4) weeks 
314 
4.1.1 Procedures at Study Visits 
315 
The following procedures will be performed at each visit, unless otherwise specified: 
316 
1. E-ETDRS visual acuity testing (best corrected) in each eye 
317 
• A protocol refraction in the study eye is required at each visit. Refraction in the non-study 
318 
eye is only required at the 8 week visit. When a refraction is not performed, the most 
319 
recently performed refraction is used for the testing. 
320 
2. Spectral-Domain OCT using Zeiss Cirrus or Heidelberg Spectralis on the study eye  
321 
• The same machine type (Cirrus or Spectralis) used at baseline must be used during follow 
322 
up. 
323 
3. Ocular exam in the study eye only, including slit lamp examination with lens assessment, 
324 
measurement of IOP, and dilated ophthalmoscopy 
325 
• The eye exam should be extensive enough to identify adverse events of interest 
326 
• An extended ophthalmoscopy including a scleral depression is required at 1, 4, and 8 
327 
weeks to identify any retinal tears or detachments 
328 
All of the testing procedures do not need to be performed on the same day, provided that they are 
329 
completed within the time window of a visit. If data from a testing procedure is unusable (e.g., if 
330 
OCT is ungradable), the participant may be asked to repeat the procedure during an additional 
331 
visit, whether part of usual care or solely to repeat the procedure. 
332 
4.1.2 Unscheduled Visits 
333 
Additional visits may occur as required for usual care of the study participant. 
334 
Testing procedures at unscheduled visits are at investigator discretion. However, it is 
335 
recommended that procedures performed should follow the standard DRCR Retina Network 
336 
protocol. 
337 
4.2 Treatment During Follow Up 
338 
4.2.1 Criteria for Vitrectomy 
339 
Vitrectomy should not be performed due to failure of macular hole closure prior to 4 weeks 
340 
without chair approval. Between 4 and 8 weeks, vitrectomy may only be performed (but is not 
341 
required) if the macular hole size is not improving from baseline. After 8 weeks, vitrectomy can 
342 
be performed at investigator discretion.  
343 

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4.2.2 Treatment for Other Conditions in the Study Eye 
344 
An eye should not be enrolled that is anticipated to require intraocular treatment for another 
345 
condition during the study. If a condition requiring prompt treatment develops during follow up, 
346 
the treatment is at investigator discretion.  
347 
4.2.3 Treatment in the Non-Study Eye 
348 
Treatment in the non-study eye is at investigator discretion, except that gas injection for VMT is 
349 
not permitted in the non-study eye during the study.  
350 

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5-1 
CHAPTER 5: STUDY DEVICE 
351 
5.1 Description of the Investigational Device 
352 
Perfluoropropane C3F8 is an inert gas under pressure and is administered by injection into the 
353 
vitreous cavity. It was approved by the FDA in February 1993 (P900066) for the use of placing 
354 
pressure on detached retina. 
355 
 
356 
5.2 Study Device Accountability Procedures 
357 
Each participating site will use their own commercially available perfluoropropane C3F8. It must 
358 
be stored at room temperature. Prior to each injection, the investigator must confirm that the 
359 
cylinder pressure is at least 50 psi and that the cylinder is not expired.  
360 
5.3 Safety Measures 
361 
Preparation of the perfluoropropane C3F8 injection will be performed in accordance with 
362 
manufacturer labelling. The full injection procedure is described in the protocol-specific study 
363 
procedures manual. 
364 

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6-1 
CHAPTER 6: ADVERSE EVENTS, DEVICE ISSUES, AND STOPPING RULES  
365 
6.1 Adverse Events 
366 
6.1.1 Definitions 
367 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
368 
relationship between the adverse event and the device(s) under investigation (see section 6. 2 for 
369 
reportable adverse events for this protocol). 
370 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
371 
• Results in death. 
372 
• Is life-threatening (a non-life-threatening event which, had it been more severe, might 
373 
have become life-threatening, is not necessarily considered a serious adverse event). 
374 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
375 
• Results in persistent or significant disability, incapacity, or substantial disruption of the 
376 
ability to conduct normal life functions (e.g, sight threatening). 
377 
• Is a congenital anomaly or birth defect. 
378 
• Is considered a significant medical event by the investigator based on medical judgment 
379 
(e.g., may jeopardize the participant or may require medical or surgical intervention to 
380 
prevent one of the outcomes listed above). 
381 
In general, an ocular adverse event should be reported as serious (considered sight threatening) if 
382 
it meets one of the following criteria: 
383 
1. It causes a decrease of ≥ 30 letters in visual acuity compared with the last visual 
384 
acuity measurement prior to onset (e.g. central retinal artery occlusion). 
385 
2. In the opinion of the investigator, it requires prompt surgical intervention (e.g. 
386 
vitrectomy, vitreous tap, intravitreous antibiotics, laser or cryosurgical retinopexy) to 
387 
prevent permanent loss of sight. Examples include endophthalmitis, retinal tear, or 
388 
rhegmatogenous retinal detachment. 
389 
Ocular adverse events that do not have the potential to result in permanent loss of sight would 
390 
not be considered serious. 
391 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
392 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 
393 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
394 
investigational plan or application (including a supplementary plan or application), or any other 
395 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
396 
welfare of participants (21 CFR 812.3(s)). 
397 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which 
398 
the device may have caused or to which the device may have contributed (Note that an Adverse 
399 
Event Form is to be completed in addition to being reported on a Gas Injection Form). 
400 
Device Complaints: A device complication or complaint is something that happens to a device or 
401 
related to device performance, whereas an adverse event happens to a participant. A device 
402 
complaint may occur independently from an AE, or along with an AE. An AE may occur without 
403 
a device complaint or there may be an AE related to a device complaint. 
404 

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6-2 
Device Malfunction: Any failure of a device to meet its performance specifications or otherwise 
405 
perform as intended. Performance specifications include all claims made in the labeling for the 
406 
device. The intended performance of a device refers to the intended use for which the device is 
407 
labeled or marketed. (21 CFR 803.3) 
408 
6.1.2 Reportable Adverse Events 
409 
For this protocol, a reportable adverse event includes any untoward medical occurrence that 
410 
meets one of the following criteria: 
411 
1) an ocular AE (study eye), 
412 
2) a serious AE, 
413 
3) an Adverse Device Effect (ADE) as defined in section 6.1.1, or 
414 
4) An AE occurring in association with a study procedure.  
415 
All reportable Adverse Events whether they are volunteered by the participant, discovered by 
416 
study personnel during questioning, or detected through physical examination, testing procedure, 
417 
or other means, will be reported on an Adverse Event Form online. Each Adverse Event Form is 
418 
reviewed by the Medical Monitor to verify the coding and the reporting that is required. 
419 
6.1.3 Relationship of Adverse Event to Study Device 
420 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
421 
by determining if there is a reasonable possibility that the adverse event may have been caused 
422 
by the study device. 
423 
To ensure consistency of adverse event causality assessments, investigators should apply the 
424 
following general guideline when determining whether an adverse event is related: 
425 
Yes 
426 
There is a plausible temporal relationship between the onset of the adverse event and the study 
427 
intervention, and the adverse event cannot be readily explained by the participant’s clinical state, 
428 
intercurrent illness, or concomitant therapies; or the adverse event follows a known pattern of 
429 
response to the study intervention. 
430 
No 
431 
Evidence exists that the adverse event has an etiology other than the study intervention (e.g., 
432 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
433 
medication); or the adverse event has no plausible temporal relationship to study intervention. 
434 
6.1.4 Intensity of Adverse Event 
435 
The intensity of an adverse event will be rated on a 3 point scale: (1) mild, (2) moderate, or (3) 
436 
severe. It is emphasized that the term severe is a measure of intensity: thus a severe adverse 
437 
event is not necessarily serious. For example, itching for several days may be rated as severe, but 
438 
may not be clinically serious. 
439 
MILD: Usually transient, requires no special treatment, and does not interfere with the 
440 
participant’s daily activities. 
441 
MODERATE: Usually causes a low level of inconvenience or concern to the participant and may 
442 
interfere with daily activities, but is usually ameliorated by simple therapeutic measures. 
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6-3 
SEVERE: Interrupts a participant’s usual daily activities and generally requires systemic drug 
444 
therapy or other treatment. 
445 
6.1.5 Coding of Adverse Events 
446 
Adverse events will be coded using the MedDRA dictionary. The Medical Monitor will review 
447 
the investigator’s assessment of causality and may agree or disagree. Both the investigator’s and 
448 
Medical Monitor’s assessments will be recorded. The Medical Monitor will have the final say in 
449 
determining the causality. 
450 
Adverse events that continue after the participant’s discontinuation or completion of the study 
451 
will be followed until their medical outcome is determined or until no further change in the 
452 
condition is expected. 
453 
6.1.6 Outcome of Adverse Event 
454 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
455 
COMPLETE RECOVERY/RESOLVED – The participant recovered from the AE/SAE without 
456 
sequelae. Record the AE/SAE stop date. 
457 
RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had stabilized 
458 
without change in the event anticipated. Record the AE/SAE stop date. 
459 
FATAL – A fatal outcome is defined as the SAE that resulted in death. Only the event that was 
460 
the cause of death should be reported as fatal. Adverse events and serious adverse events that 
461 
were ongoing at the time of death; however, were not the cause of death, will be recorded as 
462 
resolved at the time of death. 
463 
ONGOING – An ongoing AE/SAE is defined as the event was ongoing with an undetermined 
464 
outcome. 
465 
 
An ongoing outcome for which further improvement or worsening is possible will 
466 
require follow up by the site in order to determine the final outcome of the AE/SAE. 
467 
 
An ongoing outcome that is medically stable (further change not expected) will be 
468 
documented as such and will not require additional follow up.  
469 
 
The outcome of an ongoing event at the time of death that was not the cause of death, 
470 
will be updated and recorded as resolved with the date of death recorded as the stop 
471 
date. 
472 
All adverse events occurring during the study and continuing at study termination should be 
473 
followed by the participant’s physician and evaluated with additional tests (if necessary) until 
474 
diagnosis of the underlying cause, or resolution. Follow-up information should be recorded on 
475 
source documents.  
476 
If any reported serious, related, or unexpected adverse events or UADEs are present when a 
477 
participant completes the study, or if a participant is withdrawn from the study due to a serious, 
478 
related, or unexpected adverse event of UADE, the participant will be contacted for re-evaluation 
479 
within 2 weeks. If the adverse event has not resolved, additional follow up will be performed as 
480 
appropriate. Every effort should be made by the Investigator or delegate to contact the 
481 
participant until the adverse event has resolved or stabilized. 
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6-4 
6.2 Reportable Device Issues 
483 
All UADEs, ADEs, device complaints, and device malfunctions will be reported the Gas 
484 
Injection Form irrespective of whether an adverse event occurred. 
485 
6.3 Pregnancy Reporting 
486 
If pregnancy occurs, the participant will remain in follow up for the duration of the study. The 
487 
occurrence of pregnancy will be reported on an AE Form. 
488 
6.4 Timing of Event Reporting 
489 
Serious adverse events and unexpected device-related adverse events must be reported to the 
490 
Coordinating Center within 24 hours via completion of the online case report form. 
491 
The Coordinating Center will notify all participating investigators of any adverse event that is 
492 
serious, related, and unexpected. Notification will be made within 10 days after the Coordinating 
493 
Center becomes aware of the event. 
494 
Each principal investigator is responsible for reporting serious study-related adverse events and 
495 
abiding by any other reporting requirements specific to his or her Institutional Review Board or 
496 
Ethics Committee. 
497 
Upon receipt of a UADE report, the JCHR will investigate the UADE and if indicated, report the 
498 
results of the investigation to the sites’ IRBs, and the FDA within 10 working days of the JCHR 
499 
becoming aware of the UADE per 21CFR 812.46(b) (2). The Medical Monitor must determine if 
500 
the UADE presents an unreasonable risk to participants. If so, the Medical Monitor must ensure 
501 
that all investigations, or parts of investigations presenting that risk, are terminated as soon as 
502 
possible but no later than 5 working days after the Medical Monitor makes this determination 
503 
and no later than 15 working days after first receipt notice of the UADE. 
504 
Device malfunctions will be handled by the site and manufacturer.  
505 
6.5 Stopping Criteria 
506 
6.5.1 Criteria for Suspending or Stopping Overall Study 
507 
The Data and Safety Monitoring Committee (DSMC) will be informed of all unanticipated 
508 
adverse device events that occur during the study and will review compiled safety data at 
509 
periodic intervals. The DSMC may request suspension of study activities or stoppage of the 
510 
study if deemed necessary based on the totality of safety data available. 
511 
The study may be discontinued by the Executive Committee (with approval of the DSMC) prior 
512 
to the preplanned completion of follow up for all study participants. 
513 
6.6 Independent Safety Oversight 
514 
A Data and Safety Monitoring Committee will approve the protocol, template Informed Consent 
515 
Form, and substantive amendments and provide independent monitoring of adverse events. 
516 
Cumulative adverse event data are tabulated semi-annually for review by the DSMC. Following 
517 
each DSMC data review, a summary will be provided to IRBs. A list of specific adverse events 
518 
to be reported expeditiously to the DSMC will be compiled and included as part of the DSMC 
519 
Monitoring Plan document.  
520 

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6-5 
6.7 Risks 
521 
The potential risks associated with use of the study device are described in section 1.4.1. 
522 
Additional risks are minor or infrequent and include the following:  
523 
Risks Related to Testing Procedures 
524 
Many of the testing procedures in this study are part of daily ophthalmologic practice in the 
525 
United States and pose few if any known risks.  
526 
• Dilating eye drops will be used as part of the exam. There is a small risk of inducing a 
527 
narrow-angle glaucoma attack from the pupil dilation. However, all participants will have 
528 
had prior pupil dilation usually on multiple occasions and therefore the risk is extremely 
529 
small.  
530 
Risks Related Specifically to the Pre-Injection Preparation  
531 
• There are potential side effects to subconjunctival anesthetic, which are rare. They include, 
532 
but are not limited to, the following: damage to the eyeball by the needle, damage to the optic 
533 
nerve, double vision lasting 24 hours or more. 
534 
• Complications associated with paracentesis are uncommon, but may include uveitis, flat 
535 
anterior chamber, corneal wound leak, hyphema, anterior vitreous prolapse, or pupillary 
536 
block glaucoma and cataract. Under certain circumstances, such complications may lead to 
537 
vision loss.  
538 
Risks if Pregnant 
539 
According to the C3F8 package insert, there are no known teratogenic effects when injected into 
540 
the eye; however, caution should be used in pregnant women. Therefore, patients will not be 
541 
allowed to participate in this study if pregnant. Women who become pregnant during the study 
542 
will be asked to stay in the study since there is no follow-up treatment with the investigational 
543 
product. 
 
544 

Jaeb Center for Health Research 
 
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7-1 
CHAPTER 7: MISCELLANEOUS CONSIDERATIONS 
545 
7.1 Prohibited Medications, Treatments, and Procedures 
546 
The participant will be instructed that nitrous oxide anesthesia must not be administered unless 
547 
the investigator has confirmed that the gas bubble is no longer present. Wristbands notifying 
548 
healthcare providers of this will be given to participants following the intravitreous injection, and 
549 
must be worn until the investigator confirms that the gas bubble has cleared. 
550 
7.2 Participant Withdrawal 
551 
Participation in the study is voluntary and a participant may withdraw at any time. If a study 
552 
participant is considering withdrawal from the study, the principal investigator should personally 
553 
speak to the individual about the reasons and every effort should be made to accommodate him 
554 
or her.  
555 
The goal for the study is to have as few losses to follow up as possible. The Coordinating Center 
556 
will assist in the tracking of study participants who cannot be contacted by the site. The 
557 
Coordinating Center will be responsible for classifying a study participant as lost to follow up. 
558 
For participants who withdraw, their data will be used up until the time of withdrawal. 
559 
7.3 Discontinuation of Study 
560 
The study may be discontinued by the Executive Committee (with approval of the DSMC) prior 
561 
to the preplanned completion of follow up for all study participants. 
562 
7.4 Confidentiality 
563 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
564 
used instead of their name. Protected health information gathered for this study will be shared 
565 
with the coordinating center, the Jaeb Center for Health Research in Tampa, FL. The 
566 
Coordinating Center will be provided with contact information for each study participant. 
567 
Permission to obtain such information will be included in the Informed Consent Form. The 
568 
contact information may be maintained in a secure database and will be maintained separately 
569 
from the study data. Phone contact from the Coordinating Center will be made with each study 
570 
participant in the first month after enrollment. Additional phone contacts from the Coordinating 
571 
Center will be made if necessary to facilitate the scheduling of the study participant for follow-
572 
up visits. A participant-oriented newsletter and a study logo item may be sent once. Study 
573 
participants will be provided with a summary of the study results in a newsletter format after 
574 
completion of the study by all participants.  
575 
7.5 Participant Compensation  
576 
Participant compensation will be specified in the informed consent form.
577 

Jaeb Center for Health Research 
 
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8-1 
CHAPTER 8: STATISTICAL CONSIDERATIONS 
578 
8.1 Statistical and Analytical Plans 
579 
The approach to sample size and statistical analyses are summarized below. A detailed statistical 
580 
analysis plan will be written and finalized prior to first review of data. The analysis plan synopsis 
581 
in this chapter contains the framework of the anticipated final analysis plan. 
582 
8.2 Statistical Hypotheses 
583 
As this is a single-arm study, there are no formal statistical hypotheses that will be evaluated. 
584 
8.3 Sample Size 
585 
8.3.1 Outcome Projections 
586 
Several case series provide estimates of stage 2 MH closure with PVL using C3F8 gas. Chan et 
587 
al. (1995) reported MH closure in 3 of 6 eyes (50%) within 9 weeks of injection.16 Jorge et al. 
588 
(2006) reported MH closure in 5 of 6 eyes (83%) one month after injection.17, 18 Finally, Chan et 
589 
al. (2017) reported MH closure in 8 of 15 eyes (53%) within 9 weeks of injection.21 
590 
8.3.2 Sample Size Estimates 
591 
Table 1 shows anticipated confidence interval half widths for various sample sizes and true 
592 
proportions of MH closure. These calculations assume a Type I error rate of 5%. 
593 
Table 1: Anticipated Confidence Interval Half Widths 
594 
MH Closure  
Sample Size 
25 
50 
75 
85% 
13.8% 
9.9% 
8.1% 
70% 
16.9% 
12.3% 
10.2% 
50% 
18.2% 
13.4% 
11.0% 
The sample size for this study was chosen for convenience and set at 50 eyes. 
595 
8.4 Outcome Measures 
596 
For the outcomes below, rescue treatment includes vitrectomy, ocriplasmin, or additional 
597 
pneumatic vitreolysis during the course of the study.  
598 
Primary Outcome:  
599 
• Proportion of eyes with MH closure of the inner retinal layers* without rescue treatment 
600 
at 8 weeks.  
601 
o For purposes of description only, the distribution of eyes by the following 
602 
categories at 8 weeks will be tabulated without statistical comparison: 
603 
▪ MH closure without rescue treatment 
604 
▪ MH closure with rescue treatment 
605 
▪ No MH closure and no rescue treatment 
606 
▪ No MH closure despite rescue treatment 
607 
Secondary Outcomes: 
608 
• Proportion of eyes with MH closure of the inner retinal layers* without rescue treatment 
609 
through 24 weeks (time-to-event analysis). 
610 

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• Proportion of eyes with central VMT release* without rescue treatment through 24 weeks 
611 
(time-to-event analysis). 
612 
o For purposes of description only, the following will be tabulated without 
613 
statistical comparison at 8 weeks and 24 weeks: 
614 
▪ MH closure with central VMT release without rescue treatment 
615 
▪ MH closure without central VMT release without rescue treatment 
616 
▪ MH closure with central VMT release with rescue treatment 
617 
▪ MH closure without central VMT release with rescue treatment 
618 
• Proportion of eyes with central VMT release and vitreopapillary traction release* without 
619 
rescue treatment through 24 weeks (time-to-event analysis). 
620 
• Mean change in visual acuity letter score from baseline at 8 and 24 weeks. 
621 
• Proportion of eyes with at least 10-letter gain (increase) in visual acuity from baseline at 
622 
8 and 24 weeks. 
623 
• Proportion of eyes with at least 10-letter loss (decrease) in visual acuity from baseline at 
624 
8 and 24 weeks. 
625 
• Proportion of eyes receiving rescue treatment before the 8-week visit. 
626 
• Proportion of eyes receiving rescue treatment before the 24-week visit. 
627 
o For purposes of description only, the following will be tabulated without 
628 
statistical comparison: 
629 
▪ Proportion of eyes receiving rescue treatment before the 24-week visit or 
630 
for which rescue treatment is planned at the 24-week visit and medical 
631 
records confirm rescue treatment occurred within the subsequent 12 
632 
weeks. 
633 
▪ Type of rescue treatment. 
634 
Exploratory Outcomes: 
635 
• Proportion of eyes with MH closure of the inner retinal layers with outer retinal lucency* 
636 
without rescue treatment at 8 and 24 weeks.28 
637 
• Proportion of eyes with ellipsoid zone* integrity at 8 and 24 weeks. 
638 
*Determined by masked grader at the central reading center. 
639 
To ensure that statistical outliers do not have undue impact on analyses of continuous outcomes, 
640 
change in continuous outcomes from baseline will be truncated to ± 3 standard deviations based 
641 
on the overall mean and standard deviation at 8 weeks. 
642 
8.5 Analysis Cohorts  
643 
• Intention-To-Treat (ITT) Analysis Cohort: all enrolled participants irrespective of 
644 
treatment received. 
645 
• Safety Analysis Cohort: all enrolled participants irrespective of treatment received.  
646 
• Per Protocol Analysis Cohort: only participants that complete the initial treatment (PVL) 
647 
and do not receive any non-protocol treatments during follow up. Vitrectomy performed 
648 
according to the criteria in section 4.2.1 is considered per-protocol and will be included in 
649 
this analysis. 
650 

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8-3 
The primary analysis will follow the ITT principle and include all enrolled participants. 
651 
A per-protocol analysis will be performed to provide additional information regarding the 
652 
magnitude of the treatment effect. The per-protocol analysis will only be performed if at least 
653 
10% of enrolled participants would be excluded by these criteria (e.g., 5 or more participants if 
654 
exactly 50 are enrolled). 
655 
The ITT analysis is considered the primary analysis. If the results of the per-protocol and ITT 
656 
analyses give inconsistent results, the per-protocol analysis will be interpreted with caution. In 
657 
this scenario, exploratory analyses will be performed to evaluate possible factors contributing to 
658 
the difference. 
659 
8.6 Analysis of the Primary Outcome 
660 
The primary outcome of MH closure of the inner retinal layers without rescue treatment through 
661 
8 weeks is a binary variable that is graded by the central reading center. The proportion of eyes 
662 
meeting the primary outcome will be determined and the 95% Wilson (Score) confidence 
663 
interval will be calculated.  
664 
Since the chance of re-opening after closure before 8 or 24 weeks is highly unlikely, an eye with 
665 
MH closure of the inner retinal layers without rescue treatment at any time prior to 24 weeks will 
666 
be considered to have met the outcome through 24 weeks if the patient is lost to follow-up. 
667 
Similarly, any eye receiving rescue treatment prior to 24 weeks will be considered not to have 
668 
met the outcome through 24 weeks because rescue treatment has been given.  
669 
Multiple imputation will be used to impute missing data for eyes lost to follow-up that did not 
670 
have prior MH closure or rescue treatment documented. The imputation model will include 
671 
presence of ERM within 1 mm of the center of the macula at baseline and MH status at 1, 4, 8, 
672 
and 24 weeks. 
673 
A sensitivity analysis will be conducted using the same approach as above but without multiple 
674 
imputation (i.e., complete-case analysis). 
675 
8.7 Analysis of the Secondary and Exploratory Outcomes 
676 
The ITT analysis cohort will be used for all secondary and exploratory outcomes. 
677 
8.7.1 Secondary Efficacy Outcomes 
678 
Macular hole closure of the inner retinal layers without rescue treatment through 24 weeks is a 
679 
time-to-event outcome. A Kaplan-Meier curve will be constructed and the cumulative probability 
680 
with 95% confidence interval will be estimated for the final time point. Data from eyes not 
681 
observed to have closure or that receive rescue treatment will be censored on the date of their 
682 
final visit. 
683 
Central VMT release without rescue treatment and central VMT release with vitreopapillary 
684 
traction release without rescue treatment through 24 weeks are time-to-event outcomes graded by 
685 
the central reading center and will be analyzed as above. The latter analysis will be adjusted for 
686 
vitreopapillary traction status at baseline. 
687 
Change in visual acuity letter score from baseline at 8 and 24 weeks is a continuous outcome. 
688 
The mean and 95% confidence interval will be calculated for each time point. Missing data will 
689 
be imputed with multiple imputation. The imputation model will include presence of ERM 
690 
within 1 mm of the center of the macula at baseline, baseline visual acuity, change in visual 
691 
acuity from baseline at 1, 4, 8 and 24 weeks, and MH status at 1, 4, 8, and 24 weeks. 
692 

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8-4 
The proportion of eyes with at least 10-letter gain (increase) or loss (decrease) in visual acuity 
693 
from baseline at 8 and 24 weeks are binary variables. Wilson (Score) 95% confidence intervals 
694 
will be calculated for each time point. The imputed data sets described above for the mean 
695 
change in visual acuity from baseline will be utilized. 
696 
The proportion of eyes receiving rescue treatment before 8 and 24 weeks is a binary variable. 
697 
Wilson (Score) 95% confidence intervals will be calculated for each time point. Complete-case 
698 
analysis (no imputation of missing data) will be used for this outcome. 
699 
8.7.2 Exploratory Efficacy Outcomes 
700 
The proportion of eyes with MH closure of the inner retinal layers with outer retinal lucency at 8 
701 
and 24 weeks is a binary variable graded by the central reading center. Wilson (Score) 95% 
702 
confidence intervals will be calculated for each time point. Complete-case analysis (no 
703 
imputation of missing data) will be used for this outcome. 
704 
The proportion of eyes with ellipsoid zone integrity at 8 and 24 weeks is a binary variable graded 
705 
by the central reading center (loss of integrity and no loss of integrity). Wilson (Score) 95% 
706 
confidence intervals will be calculated for each time point. Complete-case analysis (no 
707 
imputation of missing data) will be used for this outcome. 
708 
8.8 Safety Analyses 
709 
All reportable adverse events will be categorized as study eye or systemic. All events will be 
710 
tabulated in a listing of each reported Medical Dictionary for Regulatory Activities (MedDRA) 
711 
term and summarized over each MedDRA System Organ Class. All enrolled participants will be 
712 
included in safety analyses. 
713 
The frequency of each ocular adverse event occurring at least once per eye will be calculated. 
714 
The proportion of eyes experiencing each outcome will be calculated along with 95% Wilson 
715 
(Score) confidence intervals. The following ocular adverse events are of primary interest:  
716 
o Endophthalmitis 
717 
o Retinal detachment 
718 
o Retinal tear 
719 
o Traumatic cataract 
720 
o Cataract extraction in eyes phakic at baseline 
721 
o Vitreous hemorrhage  
722 
o Adverse IOP events (composite outcome) 
723 
▪ Increase in IOP ≥ 10 mmHg from baseline (at a follow-up visit) 
724 
▪ IOP ≥ 30 mmHg (at a follow-up visit) 
725 
▪ Initiation of medication to lower IOP that was not in use at baseline 
726 
▪ Glaucoma procedure 
727 
The frequency of each systemic adverse event occurring at least once per participant will be 
728 
calculated. The following systemic adverse events are of primary interest: 
729 
o Death 
730 
o Serious adverse event (at least one) 
731 

Jaeb Center for Health Research 
 
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8-5 
The following systemic adverse events are of secondary interest: 
732 
o For each MedDRA System Organ Class, proportion of participants with at least one 
733 
serious adverse event 
734 
In addition, the following will be tabulated: 
735 
o Number of adverse events thought by investigator to be related to treatment 
736 
8.9 Intervention Adherence 
737 
Adherence will be defined as completion of PVL. 
738 
8.10 Protocol Adherence and Retention 
739 
Protocol deviations and visit completion rates (excluding deaths) will be tabulated. 
740 
8.11 Baseline Descriptive Statistics 
741 
Baseline characteristics will be tabulated and summary statistics appropriate to the distribution 
742 
will be reported. 
743 
8.12 Planned Interim Analyses 
744 
There is no formal interim analysis planned for this study. The Data and Safety Monitory 
745 
Committee (DSMC) will review safety and outcome data approximately every 6 months while 
746 
the study is ongoing. 
747 
8.13 Subgroup Analyses 
748 
Subgroup analyses, i.e., assessments of effect modification, will be conducted to detect factors 
749 
associated with the primary outcome. These analyses will be considered exploratory.  
750 
Subgroup analyses will be conducted using logistic regression. The relative risk for the subgroup 
751 
factor (estimated using the method of Localio et al. 200729), 95% confidence interval, and P 
752 
value will be presented. To aid in interpretation of the relative risk, observed outcome 
753 
proportions will be reported for each subgroup. Subgroup analyses will use data from eyes that 
754 
complete the 8-week visit or have MH closure or rescue treatment prior to 8 weeks (i.e., 
755 
complete case analysis as described in section 8.6).  
756 
The primary subgroup analysis will evaluate the effect of ERM presence within 1 mm of the 
757 
center of the macula at baseline. Previous reports have suggested rates of VMT release and MH 
758 
closure differ depending on the presence of ERM.  
759 
Secondary subgroup analyses will include ERM presence at the site of vitreous adhesion, lens 
760 
status (phakic or pseudophakic), components of VMT severity grade,30 length of adhesion on 
761 
OCT (less than or equal to 1500 microns or greater than 1500 microns), and diabetes status (has 
762 
diabetes or does not have diabetes).  
763 
There are no data to suggest that the treatment effect will vary by sex or race/ethnicity. However, 
764 
both of these factors will be evaluated in exploratory subgroup analyses as mandated by National 
765 
Institutes of Health (NIH) guidelines. 
766 
Subgroup factors will be analyzed as categorical and continuous or ordinal variables where 
767 
possible. Secondary and exploratory subgroup analyses will only be conducted if there are at 
768 
least 10 eyes in each subgroup. 
769 

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8.14 Multiple Testing 
770 
Because this is a single-arm study without treatment group comparisons, there will be no 
771 
adjustments made for multiple testing. 
772 

Jaeb Center for Health Research 
 
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9-1 
CHAPTER 9: DATA COLLECTION AND MONITORING 
773 
9.1 Case Report Forms and Device Data 
774 
The main study data are collected through electronic case report forms (CRFs). These electronic 
775 
CRFs from the study website are considered the primary source documentation. 
776 
Each participating site will maintain appropriate medical and research records for this trial in 
777 
compliance with ICH E6 and regulatory and institutional requirements for the protection of the 
778 
confidentiality of participants. 
779 
9.2 Study Records Retention 
780 
Study documents should be retained for a minimum of 3 years following the NIH grant cycle for 
781 
which the last visit was completed (expected to be December 31, 2026). These documents should 
782 
be retained for a longer period, however, if required by local regulations. No records will be 
783 
destroyed without the written consent of JCHR.  
784 
9.3 Quality Assurance and Monitoring 
785 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
786 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
787 
conducted and data are generated, documented, and reported in compliance with the protocol, 
788 
Good Clinical Practice (GCP), and the applicable regulatory requirements. Adverse events will 
789 
be prioritized for monitoring. 
790 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
791 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical 
792 
Investigations — A Risk-Based Approach to Monitoring” (August 2013). Study conduct and 
793 
monitoring will conform with 21 Code of Federal Regulations (CFR) 812. 
794 
The most important data for monitoring at the site are participant eligibility and adverse events. 
795 
Therefore, the RBM plan will focus on these areas. As much as possible, remote monitoring will 
796 
be performed in real time with on-site monitoring performed to evaluate the verity and 
797 
completeness of the key site data. Elements of the RBM may include the following: 
798 
• Qualification assessment, training, and certification for sites and site personnel 
799 
• Oversight of Institutional Review Board (IRB) coverage and informed consent 
800 
procedures 
801 
• Central (remote) data monitoring: validation of data entry, data edits, audit trail, protocol 
802 
review of entered data and edits, statistical monitoring, study closeout 
803 
• On-site monitoring (site visits): source data verification, site visit report 
804 
• Communications with site staff 
805 
• Patient retention and visit completion 
806 
• Quality control reports 
807 
• Management of noncompliance 
808 
• Documenting monitoring activities 
809 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
 
 
 
 
 
 
9-2 
• Adverse event reporting and monitoring 
810 
Coordinating Center representatives or their designees may visit the study facilities at any time in 
811 
order to maintain current and personal knowledge of the study through review of the records, 
812 
comparison with source documents, or observation and discussion of the conduct and progress of 
813 
the study. 
814 
9.4 Protocol Deviations 
815 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
816 
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
817 
the study site staff. As a result of deviations, corrective actions are to be developed by the site 
818 
and implemented promptly. 
819 
The site primary investigator and study staff are responsible for knowing and adhering to their 
820 
IRB requirements. Further details about the handling of protocol deviations will be included in 
821 
the monitoring plan.
822 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
 
 
 
 
 
 
10-1 
CHAPTER 10: ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
823 
10.1 Ethics/Protection of Human Participants Ethical Standard 
824 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
825 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
826 
21 CFR Part 56, and the ICH E6. 
827 
10.2 Institutional Review Boards 
828 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
829 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
830 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
831 
require review and approval by the IRB before the changes are implemented to the study. All 
832 
changes to the consent form will be IRB approved. In the event of an amendment, a 
833 
determination will be made regarding whether previously consented participants need to be re-
834 
consented. 
835 
10.3 Informed Consent Process 
836 
10.3.1 Consent Procedures and Documentation 
837 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
838 
the study and continues throughout the individual’s study participation. Extensive discussion of 
839 
risks and possible benefits of participation will be provided to the participants and their families. 
840 
Consent forms will be IRB-approved and the participant will be asked to read and review the 
841 
document. The investigator will explain the research study to the participant and answer any 
842 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 
843 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
844 
research participants. Participants will have the opportunity to carefully review the written 
845 
consent form and ask questions prior to signing. 
846 
The participants should have the opportunity to discuss the study with their surrogates or think 
847 
about it prior to agreeing to participate. The participant will sign the informed consent document 
848 
prior to any procedures being done specifically for the study. The participants may withdraw 
849 
consent at any time throughout the course of the trial. A copy of the informed consent document 
850 
will be given to the participants for their records. The rights and welfare of the participants will 
851 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
852 
affected if they decline to participate in this study. 
853 
10.3.2 Participant and Data Confidentiality 
854 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
855 
and the JCHR and their agents. This confidentiality is extended to cover biological samples in 
856 
addition to the clinical information relating to participants. Therefore, the study protocol, 
857 
documentation, data, and all other information generated will be held in strict confidence. No 
858 
information concerning the study or the data will be released to any unauthorized third party 
859 
without prior written approval of the JCHR. 
860 
The study monitor, other authorized representatives of the JCHR, or representatives of the IRB 
861 
may inspect all documents and records required to be maintained by the investigator, including 
862 
but not limited to medical records (office, clinic, or hospital) and pharmacy records for the 
863 
participants in this study. The clinical study site will permit access to such records. 
864 

Jaeb Center for Health Research 
 
Gas for Macular Hole Protocol V3.0 8-12-19 
 
 
 
 
 
 
10-2 
The study participant’s contact information will be securely stored at each clinical site for 
865 
internal use during the study. At the end of the study, all records will continue to be kept in a 
866 
secure location for as long a period as dictated by local IRB and institutional regulations. 
867 
Study participant research data that is for the purposes of statistical analysis and scientific 
868 
reporting will be transmitted to and stored at the coordinating center, the Jaeb Center for Health 
869 
Research (JCHR) in Tampa, FL. This will not include the participant’s contact or identifying 
870 
information. Rather, individual participants and their research data will be identified by a unique 
871 
study identification number. The study data entry and study management systems used by 
872 
clinical sites and by JCHR research staff will be secured and password protected. At the end of 
873 
the study, all study databases will be de-identified and archived at JCHR. 
874 
10.3.3 Future Use of Stored Specimens 
875 
With the participant’s approval, de-identified biological samples will be stored at a central 
876 
repository for future research into the causes, complications, and treatments of retinal diseases. 
877 
The repository will also be provided with a code-link that will allow linking the biological 
878 
specimens with the phenotypic data from each participant, maintaining the masking of the 
879 
identity of the participant. 
880 
During the conduct of the study, an individual participant can choose to withdraw consent to 
881 
have biological specimens stored for future research. However, withdrawal of consent with 
882 
regard to biosample storage will not be possible after the study is completed. 
 
883 

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11-1 
CHAPTER 11: REFERENCES 
884 
1. 
Jackson TL, Nicod E, Simpson A, Angelis A, Grimaccia F, Kanavos P. Symptomatic 
885 
vitreomacular adhesion. Retina. 2013;33(8):1503-11. 
886 
2. 
Duker JS, Kaiser PK, Binder S, et al. The International Vitreomacular Traction Study 
887 
Group classification of vitreomacular adhesion, traction, and macular hole. 
888 
Ophthalmology. 2013;120(12):2611-9. 
889 
3. 
McCannel CA, Ensminger JL, Diehl NN, Hodge DN. Population-based incidence of 
890 
macular holes. Ophthalmology. 2009;116(7):1366-9. 
891 
4. 
Rao P, Yonekawa Y, Abbey A, al. e. Prevalence and surgical outcomes of macular hole 
892 
in eyes with age-related macular degeneration. Retina 2017;1(2):158-64. 
893 
5. 
Rahmani B, Tielsch JM, Katz J, et al. The cause-specific prevalence of visual impairment 
894 
in an urban population. The Baltimore Eye Survey. Ophthalmology. 1996;103(11):1721-
895 
6. 
896 
6. 
Mitchell P, Smith W, Chey T, Wang JJ, Chang A. Prevalence and associations of 
897 
epiretinal membranes. The Blue Mountains Eye Study, Australia. Ophthalmology. 
898 
1997;104(6):1033-40. 
899 
7. 
Wang S, Xu L, Jonas JB. Prevalence of full-thickness macular holes in urban and rural 
900 
adult Chinese: the Beijing Eye Study. Am J Ophthalmol. 2006;141(3):589-91. 
901 
8. 
Sen P, Bhargava A, Vijaya L, George R. Prevalence of idiopathic macular hole in adult 
902 
rural and urban south Indian population. Clin Exp Ophthalmol. 2008;36(3):257-60. 
903 
9. 
Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for 
904 
vitreomacular traction and macular holes. N Engl J Med. 2012;367(7):606-15. 
905 
10. 
Fahim AT, Khan NW, Johnson MW. Acute panretinal structural and functional 
906 
abnormalities after intravitreous ocriplasmin injection. JAMA Ophthalmol. 
907 
2014;132(4):484-6. 
908 
11. 
Freund KB, Shah SA, Shah VP. Correlation of transient vision loss with outer retinal 
909 
disruption following intravitreal ocriplasmin. Eye (Lond). 2013;27(6):773-4. 
910 
12. 
Hager A, Seibel I, Riechardt A, Rehak M, Joussen AM. Does ocriplasmin affect the RPE-
911 
photoreceptor adhesion in macular holes? Br J Ophthalmol. 2015;99(5):635-8. 
912 
13. 
Kim JE. Safety and complications of ocriplasmin: ocriplasmin, ocriplasmin; oh, how safe 
913 
art thou? JAMA Ophthalmol. 2014;132(4):379-80. 
914 
14. 
Tibbetts MD, Reichel E, Witkin AJ. Vision loss after intravitreal ocriplasmin: correlation 
915 
of spectral-domain optical coherence tomography and electroretinography. JAMA 
916 
Ophthalmol. 2014;132(4):487-90. 
917 
15. 
Steel DH, Lotery AJ. Idiopathic vitreomacular traction and macular hole: a 
918 
comprehensive review of pathophysiology, diagnosis, and treatment. Eye (Lond). 
919 
2013;27 Suppl 1:S1-21. 
920 
16. 
Chan CK, Wessels IF, Friedrichsen EJ. Treatment of idiopathic macular holes by induced 
921 
posterior vitreous detachment. Ophthalmology. 1995;102(5):757-67. 
922 
17. 
Costa RA, Cardillo JA, Morales PH, Jorge R, Uno F, Farah ME. Optical coherence 
923 
tomography evaluation of idiopathic macular hole treatment by gas-assisted posterior 
924 
vitreous detachment. Am J Ophthalmol. 2001;132(2):264-6. 
925 
18. 
Jorge R, Costa RA, Cardillo JA, Uno F, Bonomo PP, Farah ME. Optical coherence 
926 
tomography evaluation of idiopathic macular hole treatment by gas-assisted posterior 
927 
vitreous detachment. Am J Ophthalmol. 2006;142(5):869-71. 
928 

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Gas for Macular Hole Protocol V3.0 8-12-19 
 
 
 
 
 
 
11-2 
19. 
Mori K, Saito S, Gehlbach PL, Yoneya S. Treatment of stage 2 macular hole by 
929 
intravitreous injection of expansile gas and induction of posterior vitreous detachment. 
930 
Ophthalmology. 2007;114(1):127-33. 
931 
20. 
Steinle NC, Dhoot DS, Quezada Ruiz C, et al. Treatment of Vitreomacular Traction with 
932 
Intravitreal Perfluoropropane (C3f8) Injection. Retina. 2017;37(4):643-50. 
933 
21. 
Chan CK, Crosson JN, Mein CE, Daher N. Pneumatic Vitreolysis for Relief of 
934 
Vitreomacular Traction. Retina. 2017. 
935 
22. 
Chan C. Pneumatic Vitreolysis for Resolving Focal Vitreomacular Traction: An Update 
936 
on Clinical Outcome . 2019 Retina Society, 52nd Scientific Program, Landmark Hotel, 
937 
London, UK, Sept 11 to 15, 2019. 
938 
23. 
Parravano M, Giansanti F, Eandi CM, Yap YC, Rizzo S, Virgili G. Vitrectomy for 
939 
idiopathic macular hole. Cochrane Database Syst Rev. 2015(5):CD009080. 
940 
24. 
Rao P, Yonekawa Y, Abbey A, Shah A, Wolfe J, Faia L. Prevalence and surgical 
941 
outcomes of macular hole in eyes with age-related macular degeneration. 
942 
Ophthalmololgy Retina. 2017;1(2):158-64. 
943 
25. 
Kumagai K, Furukawa M, Ogino N, Uemura A, Demizu S, Larson E. Vitreous surgery 
944 
with and without internal limiting membrane peeling for macular hole repair. Retina. 
945 
2004;24(5):721-7. 
946 
26. 
Spiteri Cornish K, Lois N, Scott NW, et al. Vitrectomy with internal limiting membrane 
947 
peeling versus no peeling for idiopathic full-thickness macular hole. Ophthalmology. 
948 
2014;121(3):649-55. 
949 
27. 
Tadayoni R, Gaudric A, Haouchine B, Massin P. Relationship between macular hole size 
950 
and the potential benefit of internal limiting membrane peeling. Br J Ophthalmol. 
951 
2006;90(10):1239-41. 
952 
28. 
Grewal DS, Reddy V, Mahmoud TH. Assessment of Foveal Microstructure and Foveal 
953 
Lucencies Using Optical Coherence Tomography Radial Scans Following Macular Hole 
954 
Surgery. Am J Ophthalmol. 2015;160(5):990-9 e1. 
955 
29. 
Localio AR, Margolis DJ, Berlin JA. Relative risks and confidence intervals were easily 
956 
computed indirectly from multivariable logistic regression. J Clin Epidemiol. 
957 
2007;60(9):874-82. 
958 
30. 
John VJ, Flynn HW, Jr., Smiddy WE, et al. Clinical course of vitreomacular adhesion 
959 
managed by initial observation. Retina. 2014;34(3):442-6. 
960 
 
961