Randomized Clinical Trial Assessing the Effects of Pneumatic Vitreolysis on Vitreomacular Traction
Phase: PHASE3
Conditions: Vitreomacular Traction
Sponsor: Jaeb Center for Health Research

 
Gas for VMT v3.0 7-24-19  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DRCR Retina Network 
 
 
 
 
Randomized Clinical Trial Assessing the 
Effects of Pneumatic Vitreolysis on 
Vitreomacular Traction  
(Protocol AG) 
 
 
IDE Sponsor: Jaeb Center for Health Research (JCHR) 
 
Version 3.0 
 
24 July 2019 
 
NCT03647267 
 

 
Gas for VMT v3.0 7-24-19  
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature Page 
Randomized Clinical Trial Assessing the Effects of 
Pneumatic Vitreolysis on Vitreomacular Traction  
Protocol Identifying Number: DRCR Retina Network AG 
IDE Sponsor: Jaeb Center for Health Research 
Version Number: 3.0 
24 July 2019 
 
 
 
JCHR Principal Investigator 
 
Name, degree 
Adam Glassman, MS 
 
Signature / Date 
 
 
 
 
 
 
 
 

Jaeb Center for Health Research 
Gas for VMT v3.0 7-24-19  
 
 
 
 
 
 
 
 
 
 
 
 
 
KEY ROLES 
 
Protocol Chair 
 
Name, degree 
Clement K. Chan, MD, FACS 
Title 
Medical Director 
Institution Name 
Southern California Desert Retina Consultants, Palm Desert, CA 
 
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 VMT v3.0 7-24-19  
 
 
 
 
 
 
 
 
 
 
 
 
 
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 ................................................................................................... 1-1 
1.1.3 Pneumatic Vitreolysis (PVL) ...................................................................................... 1-2 
1.2. 
Rationale ........................................................................................................................ 1-2 
1.3 
Study Objectives ........................................................................................................... 1-2 
1.4 
Potential Risks and Benefits of C3F8 Gas Injection ....................................................... 1-3 
1.4.1 Known Potential Risks ................................................................................................ 1-3 
1.4.2 Known Potential Benefits ........................................................................................... 1-4 
1.4.3 Risk Assessment ......................................................................................................... 1-4 
1.5 
General Considerations ................................................................................................. 1-4 
Chapter 2: Study Participant Eligibility and Enrollment ........................................................... 2-1 
2.1 Randomized Trial 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 ....................................................................... 2-4 
2.3.1 Baseline Testing Procedures ....................................................................................... 2-4 
2.4 Randomization of Eligible Participants ............................................................................. 2-5 
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 
3.2.3 Sham Injection Technique .......................................................................................... 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 ............................................................................................ 4-2 
4.2.1 Criteria for Vitrectomy ............................................................................................... 4-2 

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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 
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 ............................................................................................ 6-5 
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 
8.1 Statistical and Analytical Plans .......................................................................................... 8-1 
8.2 Statistical Hypotheses ........................................................................................................ 8-1 
8.3 Sample Size ........................................................................................................................ 8-1 
8.3.1 Outcome Projections: .................................................................................................. 8-1 
8.3.2 Sample Size Estimates ................................................................................................ 8-1 
8.4 Outcome Measures............................................................................................................. 8-2 
8.5 Analysis Cohorts ................................................................................................................ 8-3 

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8.6 Analysis of the Primary Efficacy Outcome ....................................................................... 8-3 
8.7 Analysis of the Secondary and Exploratory Efficacy Outcomes ....................................... 8-4 
8.8 Safety Analyses .................................................................................................................. 8-5 
8.8.1 Ocular Adverse Events ............................................................................................... 8-5 
8.8.2 Systemic Adverse Events ............................................................................................ 8-6 
8.9 Intervention Adherence ...................................................................................................... 8-6 
8.10 Protocol Adherence and Retention .................................................................................. 8-6 
8.11 Baseline Descriptive Statistics ......................................................................................... 8-6 
8.12 Planned Interim Analyses ................................................................................................ 8-6 
8.13 Subgroup Analyses .......................................................................................................... 8-6 
8.14 Multiple Testing ............................................................................................................... 8-7 
8.15 Assessment of Confounding ............................................................................................ 8-7 
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 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 VMT v3.0 7-24-19  
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
SDH 
Shape Discrimination Hyperacuity 
SD 
Standard Deviation 
UADE 
Unanticipated Adverse Device Effect 
VMT 
Vitreomacular Traction 
VMA 
Vitreomacular Adhesion 
 

JAEB CENTER FOR HEALTH RESEARCH 
Gas for VMT v3.0 7-24-19  
 
 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL SUMMARY 
PARTICIPANT AREA 
DESCRIPTION 
Title 
Randomized Clinical Trial Assessing the Effects of 
Pneumatic Vitreolysis on Vitreomacular Traction 
Précis 
Eyes with idiopathic symptomatic vitreomacular traction 
(VMT) without a macular hole will be randomly assigned to 
0.3-mL intraocular gas (C3F8) injection or sham injection to 
determine if pneumatic vitreolysis (PVL) is effective in 
releasing VMT. 
Investigational Device 
0.3-mL intraocular gas (C3F8) injection  
Objectives 
Primary 
1. To compare the proportion of eyes with central 
VMT release on OCT after pneumatic vitreolysis 
with gas injection versus observation (sham 
injection) in eyes with VMT without an associated 
macular hole.  
Secondary 
2. To evaluate visual function outcomes at 24 weeks 
after gas injection is performed compared with sham 
injection.  
Study Design 
Multi-center, randomized clinical trial 
Number of Sites 
Approximately 50 sites 
Endpoint 
Primary Outcome: Proportion of eyes with central VMT 
release on optical coherence tomography (OCT) without 
rescue treatment at 24 weeks. 
 
Key Secondary Outcomes: Proportion of eyes with rescue 
treatment, mean change in visual acuity 
 
Key Safety Outcomes: Retinal tear, retinal detachment, 
macular hole development, 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 travel 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). 
• 
At least one eye with each of the following: 

JAEB CENTER FOR HEALTH RESEARCH 
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PARTICIPANT AREA 
DESCRIPTION 
o central vitreomacular adhesion on OCT that is 
no larger than 3000 microns, confirmed by 
central reading center, 
o decreased visual function (e.g. metamorphopsia 
or other visual symptom) that is attributed to 
VMT,  
o best corrected Early Treatment Diabetic 
Retinopathy Study (ETDRS) visual acuity 
equivalent of 20/32 to 20/400, and 
o prompt vitrectomy not required 
Key Exclusion Criteria 
• 
Macular or lamellar hole. 
• 
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). 
o Note: Epiretinal membrane is not an 
exclusion nor a requirement.  
• 
High level myopia (-8.00 diopters or more negative 
if phakic; retinal abnormalities consistent with 
pathologic myopia if phakic or pseudophakic). 
• 
Prior gas injection, ocriplasmin injection, or 
intraocular injection for any reason. 
• 
Prior vitrectomy. 
Sample Size 
Minimum of 124 eyes 
Treatment Groups 
Random assignment (1:1) to one of the following: 
Group A: PVL (0.3-mL C3F8 injection) 
Group B: Observation (Sham injection) 
Participant Duration 
24 weeks 
Protocol 
Overview/Synopsis 
1. Informed consent will be obtained for screening.  
2. Eligibility will be assessed, including reading center 
confirmation of VMT on OCT.  
3. Eligible eyes will be randomly assigned to C3F8 
injection (0.3 mL) or sham injection, which will be 
performed on the day of randomization.  
4. Follow-up will occur at 1, 4, 12 and 24 weeks and 
consist of vision testing (including visual acuity and 
visual function (myVisionTrack), ocular exam, and 
OCT.  
5. Rescue vitrectomy may be performed if there is a 10 
or more letter decrease at one visit or 5 or more 
letter decrease at two consecutive visits compared 

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PARTICIPANT AREA 
DESCRIPTION 
with baseline that is thought to be associated with 
VMT, or a complication that requires prompt 
surgical intervention (e.g. macular hole, retinal 
detachment, non-clearing vitreous hemorrhage). 
Otherwise, alternative treatment may not be 
performed without discussion with and approval 
from the protocol chair or designee.  
6. The primary outcome assessment will be the 
proportion of eyes with central VMT release on 
OCT at 24 weeks without rescue treatment. 

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SCHEMATIC OF STUDY DESIGN 
 
Dropped Ineligible
Informed Consent Obtained
Baseline Testing
Randomization
Injection of C3F8
Gas (0.3 mL)
1 week
4 week
12 week
24 week
Primary Outcome
Observation 
(Sham injection)
1 week
4 week
12 week
24 week
Primary Outcome
Reading Center Review
Dropped 
Ineligible
Follow-Up Treatment 
Vitrectomy permitted in both arms if 
one of the following: 
1) Visual acuity decreases ≥10 
letters at one visit or ≥5 
letters at two consecutive 
visits 
2) Complication requires 
prompt surgical 
intervention (e.g., macular 
hole) 
Follow-Up Treatment 
Vitrectomy permitted in both arms if 
one of the following: 
1) Visual acuity decreases ≥10 
letters at one visit or ≥5 
letters at 2 consecutive 
visits (not including the 1-
week visit) compared with 
baseline that is thought to 
be related to VMT. 
2) Complication requires 
prompt surgical 
intervention (e.g., macular 
hole, retinal detachment, 
non-clearing vitreous 
hemorrhage). 

JAEB CENTER FOR HEALTH RESEARCH 
Gas for VMT v3.0 7-24-19  
 
 
 
 
 
 
 
 
 
 
 
 
 
SCHEDULE OF STUDY VISITS AND PROCEDURES 
 
 
Baseline Testing 
and 
Randomization*  
1 and 4 weeks 
 
12 and 24 
weeks 
E-ETDRS best corrected visual acuity a 
X 
X 
X 
Visual function testing  
(myVisionTrack) b 
X 
 
X 
OCT c 
X 
X 
X 
Eye exam d 
X 
X 
X 
Reading center eligibility confirmation e 
X 
 
 
Randomized treatment (gas or sham 
injection) 
X 
 
 
* All baseline testing must occur within 8 days prior to randomization. Baseline testing and randomization can occur 
on the same day if eligibility is confirmed by reading center on day of screening.  
 
a, Both eyes at all visits; includes protocol refraction in study eye only at 1, 4, and 12 weeks and in both eyes at baseline and 24 
weeks; E-ETDRS refers to electronic ETDRS testing using the Electronic Visual Acuity Tester that has been validated against 4-
meter chart ETDRS testing. 
b, At baseline, 12, and 24 weeks. 
c, Both eyes at baseline; study eye only at follow up visits.  
d, Both eyes at baseline; study eye only at each follow-up visit. Includes slit lamp exam (including assessment of lens), 
measurement of IOP, 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 12 weeks. 
e, Reading center review of the OCT for eligibility must occur prior to randomization.

Jaeb Center for Health Research 
 
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1-1 
 
 
 
 
CHAPTER 1: BACKGROUND INFORMATION AND STUDY SYNOPSIS 
1 
 
2 
1.1. Introduction 
3 
1.1.1 Vitreoretinal Interface Abnormalities  
4 
Disorders of the vitreoretinal interface represent a spectrum of abnormalities that develop as the 
5 
posterior hyaloid separates from the internal limiting membrane. Vitreomacular adhesion (VMA) 
6 
occurs when the posterior hyaloid remains attached to the internal limiting membrane centrally. 
7 
Overall, about 1.5% of the population is estimated to have eye diseases caused by or associated 
8 
with VMA.1 The incidence of VMA diagnoses is expected to increase with widespread use of 
9 
spectral-domain optical coherence tomography (OCT). Vitreomacular traction (VMT) is 
10 
diagnosed when VMA results in traction, distortion of retinal architecture, and patient 
11 
symptomatology.2 The prevalence of VMT has been reported to be 22.5 per 100,000 of the 
12 
population, with an annual incidence of 0.6 per 100,0002. However, these rates, determined 
13 
before widespread use of spectral-domain OCT, are likely an underestimation. Advanced VMT 
14 
can lead to macular holes (MH), in which tractional forces create small, full-thickness defects on 
15 
the posterior fundus, often requiring surgical intervention.2  
16 
1.1.2 Treatments for VMT 
17 
Treatment options for VMT include observation, vitrectomy, and intraocular injection of 
18 
ocriplasmin. Observation may not be an optimal choice in symptomatic patients. There have 
19 
been multiple reports in the literature of spontaneous resolution of VMT. 3-8 Based on a 
20 
Cochrane Eyes and Vision systematic review of 4 trials with 932 eyes, the 28-day VMA release 
21 
rate among eyes in the control groups (sham or saline injection) is estimated to be 97 of 1000 
22 
eyes.9 In the Intravitreal Injection-Traction Release Without Surgical Treatment (MIVI-TRUST) 
23 
trials,10 10% of the placebo-vehicle injected eyes developed a spontaneous posterior vitreous 
24 
detachment (PVD) by 28 days, increasing to about 13% through 180 days. The Ocriplasmin for 
25 
Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) Trial 
26 
reported success of VMT release of 6% in the sham group at 28 days, increasing to 14% over 2 
27 
years.11 In a 2014 retrospective case series, John et al6 reported spontaneous PVD in 32% of eyes 
28 
with focal VMA (documented by spectral-domain OCT) and good vision (mean visual acuity: 
29 
20/37) with a median follow-up time of 18 months. Thus, observation alone may yield a 
30 
spontaneous resolution of visual impairment after a waiting period of sufficient time, although 
31 
the precise timing of the spontaneous resolution is unpredictable and can be prolonged.  
32 
Vitrectomy is a viable alternative to observation. However, vitrectomy is costly and carries a risk 
33 
of complications such as endophthalmitis, retinal detachment and cataract progression, even 
34 
when performed by experienced surgeons. Therefore, vitrectomy is generally reserved for eyes 
35 
with more advanced VMT associated with relatively poor visual acuity level.  
36 
In 2012, the MIVI-TRUST trial showed that ocriplasmin (Jetrea®), a proteolytic enzyme for 
37 
treatment of symptomatic VMA, induced a PVD in 26.5% of eyes versus 10.1% of placebo-
38 
vehicle injected eyes.10, 12 The success was shown to increase to 40% in eyes without epiretinal 
39 
membrane.10 In 2016, Lim et al reported in the Macula Society Collaborative Retrospective 
40 
Study a rate of 45% in release of VMT after ocriplasmin.13 Based on the Cochrane Eyes and 
41 
Vision systematic review, the 28-day release rate among eyes treated with ocriplasmin is 
42 
estimated to be 237 of 1000 eyes.9 However, there have been multiple anecdotal reports of 
43 

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substantial ocular complications associated with intraocular administration of ocriplasmin,14-18 
44 
including transient visual loss, persistent dyschromatopsia, electroretinographic abnormalities, 
45 
subluxation of the crystalline lens likely related to zonulolysis, and disturbance or dehiscence of 
46 
the ellipsoid layer documented by OCT. These adverse events have created major concerns 
47 
among many retinal surgeons in the clinical use of this drug.14-18 In a recent American Society of 
48 
Retina Specialists Preferences and Trends Survey, only 7% of retina specialists recommended 
49 
ocriplasmin as first line therapy for VMT and visual acuity of 20/60 or worse.19 
50 
1.1.3 Pneumatic Vitreolysis (PVL) 
51 
Pneumatic vitreolysis (intraocular injection of expansile gas to induce a PVD) has been 
52 
suggested as a potential treatment alternative to ocriplasmin for resolving VMT without surgery. 
53 
Chan et al first demonstrated and reported the utility of intraocular gas (C3F8) injection in 
54 
eliciting a PVD (95%) in 1995.20 Subsequently, Costa et al, and Jorge et al showed a high rate of 
55 
success in the induction of PVD (100%) with C3F8 in small case series.21, 22 Recently, Rodrigues 
56 
et al, in a series of fifteen eyes, showed resolution of VMT in 40% at one month and 60% by 6 
57 
months after injection of C3F8 gas.23 Steinle et al reported a success rate of 83% with C3F8 gas in 
58 
a retrospective case series for treatment of VMT syndrome.24 In a 2016 retrospective review of 
59 
50 consecutive eyes receiving C3F8 gas for PVL performed in 2 centers, Chan and Mein reported 
60 
a success rate of 86% in VMT release (80% success for VMT-only eyes and 100% for small 
61 
stage 2 MH [≤ 250 microns]).25 In 2019, Chan and Mein provided an update on this study and 
62 
reported a success rate of 85% among 80 eyes (80.7% in eyes with VMT-only, 95.7% in eyes 
63 
with macular hole).26 However, all of these cited case series involving PVL involved relatively 
64 
small numbers of cases and did not incorporate control arms for comparison.  
65 
1.2. Rationale 
66 
Given the low cost and convenience of gas injection in the office setting as well as a low rate of 
67 
adverse events reported in prior retrospective studies, PVL may serve as an alternative to either 
68 
potentially less effective observation or much more costly treatments with well-established 
69 
associated adverse events such as ocriplasmin or vitrectomy for managing VMT. Although many 
70 
eyes with VMT have good vision and are not symptomatic, there are also many patients who 
71 
experience central visual loss or symptoms such as metamorphopsia due to persistent VMT. 
72 
Therefore, a randomized clinical trial is indicated to evaluate the safety and efficacy of 
73 
intraocular gas injection for treatment of VMT without a MH in patients who are symptomatic 
74 
and desire intervention.  
75 
The purpose of this study is not to compare release rates directly with vitrectomy. Instead, the 
76 
goal is to evaluate PVL compared with observation to determine if it is a viable first-line 
77 
treatment option to consider before resorting to vitrectomy. If PVL is successful for managing 
78 
VMT, its use may reduce the need for current therapies by both resolving VMT and preventing 
79 
MH formation in early cases and by closing small stage-2 MH in the advanced cases.  
80 
1.3 Study Objectives 
81 
Primary 
82 
1. To compare the proportion of eyes with central VMT release on OCT from PVL with gas 
83 
injection versus observation (sham injection) in eyes with VMT without an associated 
84 
MH.  
85 

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Secondary 
86 
2. To evaluate visual function outcomes at 24 weeks after gas injection is performed 
87 
compared with observation. 
88 
1.4 Potential Risks and Benefits of C3F8 Gas Injection 
89 
1.4.1 Known Potential Risks 
90 
• Pain, discomfort, redness, or itching lasting for a few days is likely. 
91 
• Subconjunctival hemorrhage or floaters will commonly occur as a result of the injection. The 
92 
floaters are typically reduced after 6 to 8 weeks, but some floaters may persist. 
93 
• Immediately following the injection, there may be elevation of IOP. It usually returns to 
94 
normal spontaneously, but may need to be treated with topical drugs or a paracentesis to 
95 
lower the pressure. The likelihood of permanent loss of vision from elevated IOP is less than 
96 
1%. 
97 
• Although it has not been reported in prior case series, endophthalmitis could theoretically 
98 
develop. The risk of endophthalmitis from other intraocular injections is less than 1%. 
99 
• A retinal tear or detachment could occur. The risk of retinal breaks and/or detachment after 
100 
gas injection is approximately 5-13%. The risk of retinal detachment is increased if there are 
101 
pre-existing peripheral retinal abnormalities such as lattice degeneration or cystic tufts. 
102 
• There is a possibility of traumatic cataract from the injection. The risk of developing a 
103 
cataract from the injection is <1%.  
104 
• If paracentesis is performed, there is a similar risk of traumatic cataract from the 
105 
paracentesis. 
106 
• If vitrectomy is required while gas is in the eye, there is high likelihood of cataract formation 
107 
during surgery that may require cataract removal at the time of vitrectomy.  
108 
• Progression to MH after gas injection is a potential complication. Previous retrospective 
109 
studies have shown this complication to be <5% 
110 
• Limited and transient uveitis may develop after gas injection. Persistent uveitis is uncommon. 
111 
• Limited transient conjunctival or episcleral hemorrhage is common shortly after gas 
112 
injection. It is usually inconsequential and clears spontaneously from a few days to a week or 
113 
two.  
114 
• Limited vitreous hemorrhage after gas injection is uncommon but may occur occasionally 
115 
after gas injection, particularly given a history of active anticoagulation therapy or 
116 
predisposing risk for hemorrhage. If present, it usually resolves from a few days to a few 
117 
months. Marked hemorrhage requiring a surgical intervention after gas injection is 
118 
exceedingly rare (<1%). 
119 
• Pre-existing epiretinal fibrosis may sometimes progress or new epiretinal fibrosis may 
120 
develop after gas injection.  
121 

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• The development of excessive scarring on top of or under the retina after gas injection is 
122 
exceedingly rare. When this occurs, it is usually associated with advanced retinal 
123 
detachment, which is also uncommon after gas injection. 
124 
Additional risks if the participant does not follow post-injection instructions: 
125 
• IOP may increase if the patient experiences changes in elevation (i.e. travel by air or over 
126 
mountain ranges) while the gas bubble is still present in the eye. 
127 
• Loss of vision or blindness is possible if nitrous oxide anesthesia is administered with the gas 
128 
bubble still present in the eye. 
129 
• Incorrect head positioning following the gas injection may lead to glaucoma or cataracts. 
130 
1.4.2 Known Potential Benefits 
131 
Potential benefits from participation in the study for eyes randomly assigned to PVL include 
132 
release of VMT, improved visual acuity, improved quality of vision, prevention of full-thickness 
133 
macular hole, and avoidance of more invasive and expensive procedures, i.e., vitrectomy, 
134 
ocriplasmin. 
135 
1.4.3 Risk Assessment 
136 
The risk level is considered to be research involving greater than minimal risk. 
137 
1.5 General Considerations 
138 
The study is being conducted in compliance with the policies described in the study policies 
139 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
140 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
141 
The DRCR Retina Network procedures manuals provide details of the procedures.  
142 
VA and OCT technicians will be masked to treatment group at all visits. The goal is for study 
143 
participants to remain masked to their treatment group assignment, although it is likely that the 
144 
gas bubble will be visible to participants in the PVL group. Investigators and study coordinators 
145 
are not masked to treatment group. 
146 
Data will be directly collected in electronic case report forms, which will be considered the 
147 
source data. 
148 
There is no restriction on the number of subjects to be enrolled by each site towards the overall 
149 
recruitment goal. However, recruitment will be monitored on an ongoing basis and the sponsor 
150 
can decide to place recruitment at a particular site on hold as needed.  
151 
All consented participants will be logged. 
152 
The protocol is considered a significant risk device study because intraocular injection of C3F8 is 
153 
experimental for this indication. Therefore, an investigational device exemption (IDE) from the 
154 
U.S. Food and Drug Administration (FDA) is required to conduct the study.
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CHAPTER 2: STUDY PARTICIPANT ELIGIBILITY AND ENROLLMENT 
156 
2.1 Randomized Trial Participant Recruitment and Enrollment 
157 
Enrollment will proceed with the goal of at least 124 participants being randomized. Participants 
158 
who have signed consent may be permitted to continue into the trial, if eligible, even if the 
159 
randomization goal has been reached. 
160 
Study participants will be recruited from approximately 50 clinical centers in the United States. 
161 
Approximately 10 participants are expected to be randomized each month, resulting in 13 
162 
months of recruitment, for a total study duration of 19 months. 
163 
All eligible participants will be included without regard to gender, race, or ethnicity. There is no 
164 
restriction on the number of participants to be enrolled by each site toward the overall 
165 
recruitment goal. 
166 
Potential eligibility may be assessed as part of a routine-care examination. Before completing 
167 
any procedures or collecting any data that are not part of usual care, written informed consent 
168 
will be obtained. 
169 
The study protocol will be discussed with the potential study participant by study staff. The 
170 
potential study participant will be given the Informed Consent Form to read. Potential study 
171 
participants will be encouraged to discuss the study with family members and their personal 
172 
physicians(s) before deciding whether to participate in the study. 
173 
As part of the informed consent process, each participant will be asked to sign an authorization 
174 
for release of personal information. The investigator, or his or her designee, will review the 
175 
study-specific information that will be collected and to whom that information will be disclosed. 
176 
After speaking with the participant, questions will be answered about the details regarding 
177 
authorization. 
178 
Once a study participant is randomized, that participant will be counted regardless of whether the 
179 
assigned treatment is received. Thus, the investigator must not proceed to randomize an 
180 
individual until he/she is convinced that the individual is eligible and will accept assignment to 
181 
either of the two treatment groups.  
182 
2.2 Participant Eligibility Criteria 
183 
2.2.1 Participant-level Criteria 
184 
Inclusion 
185 
To be eligible, the following inclusion criteria must be met: 
186 
1. Age ≥18 years.  
187 
• Participants <18 years old are not being included because the condition is so rare in this 
188 
age group that the diagnosis may be questionable.  
189 
2. At least one eye meets the study eye criteria listed in section 2.2.2. 
190 
3. Able and willing to provide informed consent. 
191 
4. Able and willing to avoid high altitude travel, including airline travel, until gas resolution 
192 
(approximately 6 to 8 weeks).  
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5. For phakic patients, able and willing to avoid supine position until gas resolution 
194 
(approximately 6 to 8 weeks). 
195 
6. Able and willing to wear wristband that informs any medical personnel that the patient has a 
196 
gas bubble in the eye  
197 
Exclusion 
198 
A potential participant is not eligible if any of the following exclusion criteria are present:  
199 
7. A condition that, in the opinion of the investigator, would preclude participation in the study 
200 
(e.g., unstable medical status that might preclude completion of follow-up) 
201 
8. Participation in an investigational trial within 30 days of randomization that involves 
202 
treatment with any drug or device that has not received regulatory approval for the indication 
203 
being studied at the time of study entry 
204 
• Note: study participants should not receive another investigational drug/device while 
205 
participating in the study 
206 
9. Known contraindication to any component of the treatment 
207 
10. Known allergy to any drug used in the procedure prep (including povidone iodine) 
208 
11. Potential participant is expecting to move out of the area of the clinical center to an area not 
209 
covered by another clinical center during the next 6 months following randomization 
210 
12. Anticipated surgery requiring anesthesia within the next 6 months following randomization 
211 
• Participants cannot receive nitrous oxide until gas resolution 
212 
13. For women of child-bearing potential, pregnant at the time of enrollment 
213 
• Women who are potential study participants should be questioned about the potential for 
214 
pregnancy. Investigator judgement may be used to determine when a pregnancy test is 
215 
needed. 
216 
2.2.2 Study Eye Criteria 
217 
The participant must have at least one eye meeting all of the inclusion criteria and none of the 
218 
exclusion criteria listed below. 
219 
A participant can have only one study eye. If both eyes are eligible at the time of randomization, 
220 
the study eye will be selected by the investigator and participant before randomization.  
221 
The eligibility criteria for a study eye are as follows: 
222 
Inclusion 
223 
a. Central vitreomacular adhesion on OCT that is no larger than 3000 microns with visible 
224 
separation of the vitreous on either side as seen on horizontal and vertical scans, confirmed 
225 
by central reading center 
226 
Note: presence of epiretinal membrane is neither a requirement nor exclusion. 
227 
b. Decreased visual function (e.g. metamorphopsia or other visual symptom) that is attributed to 
228 
VMT.  
229 
Examples of visual symptoms include: 
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a) Distortion and/or reduction in visual acuity 
231 
b) Recognized difficulty with reading, driving, or using a computer 
232 
c) Patient recognized interference with quality of life because of a and/or b.  
233 
 
234 
c. Visual acuity letter score of at least 19 (approximate Snellen equivalent 20/400 or better) and 
235 
at most 78 (20/32 or worse) 
236 
d. Investigator and participant willing to wait 6 months before surgical intervention, provided 
237 
visual acuity remains stable  
238 
• An eye that requires prompt treatment for VMT should not be enrolled 
239 
Exclusion 
240 
e. Other ocular condition that might affect visual acuity during the course of the study or 
241 
require intraocular treatment (e.g., retinal vein occlusion, substantial age-related macular 
242 
degeneration, or macular edema induced by a condition other than VMT) 
243 
• If diabetic retinopathy is present, severity level must be microaneurysms only or better (≤ 
244 
diabetic retinopathy severity level 20) 
245 
• Presence of drusen is acceptable; however, eyes with geographic atrophy or neovascular 
246 
age-related macular degeneration involving the macula are excluded  
247 
f. High level of myopia (spherical equivalent of -8.00 diopters or more myopic if phakic or 
248 
retinal abnormalities consistent with pathologic myopia if phakic or pseudophakic) 
249 
g. History of prior gas injection, ocriplasmin injection, or intraocular injection for any reason 
250 
h. History of prior vitrectomy 
251 
i. History of uncontrolled glaucoma 
252 
• IOP must be <30 mmHg, with no more than one topical glaucoma medication, and no 
253 
documented glaucomatous field loss for the eye to be eligible 
254 
j. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular 
255 
surgery, etc.) within prior 4 months or major ocular surgery anticipated within the next 6 
256 
months following randomization 
257 
k. History of YAG capsulotomy performed within 4 months prior to randomization  
258 
l. Aphakia or anterior chamber intraocular lens  
259 
m. Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or 
260 
substantial blepharitis 
261 
n. Uveitis 
262 
o. Presence of any macular hole or lamellar hole (according to reading center grading)  
263 
p. Retinal history or pathology that might predispose an eye to an increased risk of retinal 
264 
detachment from the procedure 
265 
• Untreated retinal tears, not retinal holes, are an exclusion. It is up to the investigator to 
266 
determine whether extent of lattice degeneration or other pathology might increase the 
267 
risk of retinal detachment. 
268 
q. Any contraindication to paracentesis (e.g., history of narrow angle glaucoma) 
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r. Lenticular or zonular instability 
270 
2.3 Screening Evaluation and Baseline Testing 
271 
After informed consent has been signed, a potential participant will be evaluated for study 
272 
eligibility through the elicitation of a medical history and performance of an ocular examination 
273 
by study personnel to screen for exclusionary conditions. 
274 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
275 
date per investigator discretion. 
276 
All testing does not need to be completed on the same day provided it is within the windows 
277 
specified below. Reading Center confirmation of VMT on OCT must be completed prior to 
278 
randomization.  
279 
2.3.1 Baseline Testing Procedures 
280 
The following procedures are needed to confirm eligibility and/or to serve as baseline measures 
281 
for the study:  
282 
• If a procedure has been performed using the study technique and by study certified 
283 
personnel as part of usual care, then it does not need to be repeated specifically for the 
284 
study if it was performed within the defined time windows specified below.  
285 
• The testing procedures are detailed in the DRCR Retina Network Procedures Manuals. 
286 
Visual acuity testing, ocular exam, visual function testing, and OCT will be performed by 
287 
DRCR Retina Network certified personnel.  
288 
1. Self-reported demographics (date of birth, sex, race and ethnicity) 
289 
2. Medical history (pre-existing medical conditions, concomitant medications, as well as ocular 
290 
diseases, surgeries, and treatments) 
291 
➢ Medical history will be obtained by medical charts if available at the enrolling site; 
292 
otherwise, it will be self-reported 
293 
3. Electronic-ETDRS visual acuity testing at 3 meters using the Electronic Visual Acuity Tester 
294 
(including protocol refraction) in each eye (within prior 8 days) 
295 
4. Visual function testing (myVisionTrack) (within prior 8 days) 
296 
➢ Visual function testing will be performed using the myVisionTrack application on an 
297 
iPad or tablet. myVisionTrack® is an FDA cleared application to track disease 
298 
progression in patients with certain retinal diseases. During the test, the patient will 
299 
select the circle that is shaped differently among a series of side-by-side circles on the 
300 
screen. The series continues with increasing difficulty until the patient’s visual 
301 
function is determined. Visual function is measured using the shape discrimination 
302 
hyperacuity (SDH) (logMAR) score.  
303 
5. Spectral-Domain OCT using Zeiss Cirrus or Heidelberg Spectralis on each eye (within prior 
304 
8 days) 
305 
➢ OCT scans of the study eye will be promptly sent to the central reading center for 
306 
grading and a participant cannot be randomized until reading center confirmation of 
307 
eligibility has been received 
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6. Ocular examination on each eye including slit lamp, measurement of IOP, lens assessment, 
309 
and dilated ophthalmoscopy (within prior 8 days) 
310 
➢ Scleral depression to rule out any retinal tears pre-operatively will be required for the 
311 
baseline eye exam to confirm eligibility 
312 
2.4 Randomization of Eligible Participants  
313 
Randomization may occur on the same day as baseline testing if eligibility is confirmed by the 
314 
reading center on the day of screening.  
315 
1. Prior to randomization, the participant’s understanding of the trial, willingness to accept the 
316 
assigned treatment group, and commitment to the follow-up schedule should be reconfirmed. 
317 
2. The baseline injection (or sham) must be given on the day of randomization; therefore, a 
318 
participant should not be randomized until this is possible.  
319 
3. Randomization is completed on the DRCR Retina Network website.  
320 
• Study eyes will be randomly assigned with equal probability to one of two treatment 
321 
groups:  
322 
o Group A: PVL (Intravitreous injection of 0.3 mL C3F8 gas) 
323 
o Group B: Observation (Sham injection) 
324 
Randomization will be stratified by clinical site and presence of epiretinal membrane (ERM) 
325 
within 1 mm of the center of the macula, determined by Reading Center grading. Previous 
326 
reports have suggested that the proportions of eyes with VMT release differ depending on the 
327 
presence of ERM.  
328 
Once a study participant is randomized, that participant will be counted regardless of whether the 
329 
assigned treatment is received. Thus, the investigator must not proceed to randomize an 
330 
individual until he/she is convinced that the individual is eligible and will accept whichever 
331 
treatment group is assigned through randomization. 
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CHAPTER 3: BASELINE TREATMENT 
333 
3.1 Treatment 
334 
For both groups, the baseline injection (sham or intravitreous) must be given on the day of 
335 
randomization.  
336 
3.2 Injection Procedure 
337 
3.2.1 Intravitreous Injection Technique 
338 
The injection is preceded by a povidone iodine prep of the conjunctiva. A subconjunctival 
339 
injection of lidocaine may be administered, at the discretion of the investigator. The injection 
340 
will be performed using sterile technique. Pre-injection paracentesis should be considered due to 
341 
the 4x expansion of C3F8 gas and the associated risk of shallowing of the anterior chamber. 
342 
However, the choice of when or whether or not to do a paracentesis is ultimately at the 
343 
investigator’s discretion. The full injection procedure is described in the protocol-specific study 
344 
procedures manual. Topical antibiotics in the pre-, peri-, or post-injection period should not be 
345 
used without prior approval from the Protocol Chair or Coordinating Center designee.  
346 
 
347 
3.2.2 Aqueous Sample Collection 
348 
Participation in the ancillary sample collection component is not a requirement for participation 
349 
in this study. It is expected that sites with the capability to ship intraocular fluids will participate. 
350 
At the time of consent into the main study, participants will have the option of signing the 
351 
ancillary sample collection portion of the informed consent form to indicate their willingness to 
352 
provide the sample for future use. If paracentesis is performed and participant consent is 
353 
obtained, aqueous fluid already being drawn as part of paracentesis may be collected and shipped 
354 
on dry ice to a central laboratory for storage for future analyses. Sites will be encouraged to 
355 
collect aqueous samples when performing paracentesis, though sample collection will not be 
356 
required. Details regarding collection, sample labeling, storage, and shipment can be found in the 
357 
procedures manual.  
358 
3.2.3 Sham Injection Technique 
359 
The prep will be performed as for an intravitreous injection. For the sham injection procedure, a 
360 
syringe without a needle will be used, with the hub pressed against the injection site to simulate 
361 
the force of an actual injection. 
362 
3.3 Participant Instructions Post-Injection 
363 
Participants will be given a post-injection instruction sheet informing them of all post-injection 
364 
requirements and risks if they do not follow these requirements. All participants will be 
365 
instructed to avoid high altitude travel until the surgeon confirms the gas bubble has cleared. 
366 
Phakic participants in both groups will be asked to avoid the supine position and lie on one side 
367 
or the stomach during sleeping hours until the surgeon confirms that the gas bubble has cleared. 
368 
All participants will be instructed to wear a wristband to notify healthcare providers that they 
369 
should not receive nitrous oxide anesthesia until the gas bubble has cleared. For observation 
370 
group participants, this will be the 4-week visit. 
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CHAPTER 4: FOLLOW-UP VISITS AND TESTING 
372 
4.1 Study Visits 
373 
The schedule of protocol-specified follow-up visits is as follows: 
374 
• 1 week (- 4 days to + 3 days) 
375 
• 4 (±1) weeks 
376 
• 12 (±2) weeks 
377 
• 24 (±4) weeks 
378 
4.1.1 Procedures at Study Visits 
379 
The following procedures will be performed in both groups at all visits, unless otherwise 
380 
specified: 
381 
1. E-ETDRS visual acuity testing (best corrected) in each eye. 
382 
• A protocol refraction in the study eye is required at each visit. Refraction in the non-study 
383 
eye is only required at the 24-week visit. When a refraction is not performed, the most 
384 
recently performed refraction is used for the testing. 
385 
• VA technicians will be masked to treatment group at all visits. 
386 
2. Visual function testing (myVisionTrack) at 12 and 24 weeks only  
387 
3. Spectral-Domain OCT using Zeiss Cirrus or Heidelberg Spectralis on the study eye  
388 
• The same machine type (Cirrus or Spectralis) used at baseline must be used during 
389 
follow-up 
390 
• OCT technicians will be masked to treatment group at all visits. 
391 
4. Ocular exam in the study eye only, including slit lamp examination with lens assessment, 
392 
measurement of IOP, and dilated ophthalmoscopy 
393 
• The eye exam should be extensive enough to identify adverse events of interest  
394 
• An extended ophthalmoscopy including a scleral depression is required at 1, 4, and 12 
395 
weeks to identify any retinal tears or detachments 
396 
All of the testing procedures do not need to be performed on the same day, provided that they are 
397 
completed within the time window of a visit. If data from a testing procedure is unusable (e.g., if 
398 
OCT is ungradable), the participant may be asked to repeat the procedure during an additional 
399 
visit, whether part of usual care or solely to repeat the procedure. 
400 
4.1.2 Unscheduled Visits 
401 
Additional visits may occur as required for usual care of the study participant.  
402 
Testing procedures at unscheduled visits are at investigator discretion. However, it is 
403 
recommended that procedures that are performed should follow the standard DRCR Retina 
404 
Network protocol for each procedure. 
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4.2 Treatment During Follow-Up 
406 
4.2.1 Criteria for Vitrectomy 
407 
Vitrectomy may be performed if one of the following occurs: 
408 
1. Visual acuity decreases at least 10 letters at a single visit (not including the 1-week visit) or 
409 
at least 5 letters at two consecutive visits (not including the 1-week visit) compared with 
410 
baseline that is thought to be related to VMT 
411 
2. Complication requires prompt surgical intervention (e.g., macular hole, retinal detachment, 
412 
non-clearing vitreous hemorrhage) 
413 
Otherwise, protocol chair approval must be obtained for alternative treatment. 
414 
4.2.2 Treatment for Other Conditions in the Study Eye 
415 
An eye should not be enrolled that is anticipated to require intraocular treatment for another 
416 
condition during the study. If a condition develops during follow-up requiring prompt treatment, 
417 
it is at investigator discretion.  
418 
4.2.3 Treatment in the Non-Study Eye 
419 
Treatment in the non-study eye is at investigator discretion, except that gas injection for VMT is 
420 
not permitted in the non-study eye during the study.  
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CHAPTER 5: STUDY DEVICE 
422 
5.1 Description of the Investigational Device 
423 
Perfluoropropane (C3F8) is an inert gas under pressure and is administered by injection into the 
424 
vitreous cavity. It was approved by the FDA in February 1993 (P900066) for the use of placing 
425 
pressure on detached retina. 
426 
5.2 Study Device Accountability Procedures 
427 
Each participating site will use their own commercially available perfluoropropane C3F8. It must 
428 
be stored at room temperature. Prior to each injection, the investigator must confirm that the 
429 
cylinder pressure is at least 50 psi and the cylinder is not expired.  
430 
5.3 Safety Measures 
431 
Preparation of the perfluoropropane C3F8 injection will be performed in accordance with 
432 
manufacturer labelling. The full injection procedure is described in the protocol-specific study 
433 
procedures manual.
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CHAPTER 6: ADVERSE EVENTS, DEVICE ISSUES, AND STOPPING RULES  
435 
6.1 Adverse Events 
436 
6.1.1 Definitions 
437 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
438 
relationship between the adverse event and the device(s) under investigation (see section 6. 2 for 
439 
reportable adverse events for this protocol). 
440 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
441 
• Results in death. 
442 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might 
443 
have become life-threatening, is not necessarily considered a serious adverse event). 
444 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
445 
• Results in persistent or significant disability/incapacity or substantial disruption of the 
446 
ability to conduct normal life functions (e.g. sight threatening). 
447 
• Is a congenital anomaly or birth defect. 
448 
• Is considered a significant medical event by the investigator based on medical judgment 
449 
(e.g., may jeopardize the participant or may require medical/surgical intervention to 
450 
prevent one of the outcomes listed above). 
451 
In general, an ocular adverse event should be reported as serious (considered sight threatening) if 
452 
it meets one of the following criteria: 
453 
1. It causes a decrease of ≥ 30 letters in visual acuity compared with the last visual acuity 
454 
measurement prior to onset (e.g. central retinal artery occlusion). 
455 
2. In the opinion of the investigator, it requires prompt surgical intervention (e.g. 
456 
vitrectomy, vitreous tap, intravitreous antibiotics, laser or cryosurgical retinopexy) to 
457 
prevent permanent loss of sight. Examples include endophthalmitis, retinal tear, or 
458 
rhegmatogenous retinal detachment. 
459 
Ocular adverse events that do not have the potential to result in permanent loss of sight would 
460 
not be considered serious. 
461 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
462 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 
463 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
464 
investigational plan or application (including a supplementary plan or application), or any other 
465 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
466 
welfare of participants (21 CFR 812.3(s)). 
467 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which 
468 
the device may have caused or to which the device may have contributed (Note that an Adverse 
469 
Event Form is to be completed in addition to being reported on a Gas Injection Form). 
470 
Device Complaints: A device complication or complaint is something that happens to a device or 
471 
related to device performance, whereas an adverse event happens to a participant. A device 
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complaint may occur independently from an AE, or along with an AE. An AE may occur without 
473 
a device complaint or there may be an AE related to a device complaint. 
474 
Device Malfunction: Any failure of a device to meet its performance specifications or otherwise 
475 
perform as intended. Performance specifications include all claims made in the labeling for the 
476 
device. The intended performance of a device refers to the intended use for which the device is 
477 
labeled or marketed. (21 CFR 803.3) 
478 
6.1.2 Reportable Adverse Events 
479 
For this protocol, a reportable adverse event includes any untoward medical occurrence that 
480 
meets one of the following criteria: 
481 
1) an ocular AE in the study eye, 
482 
2) a serious AE, 
483 
3) an Adverse Device Effect (ADE) as defined in section 6.1.1, or 
484 
4) an AE occurring in association with a study procedure.  
485 
All reportable adverse events whether they are volunteered by the participant, discovered by 
486 
study personnel during questioning, or detected through physical examination, testing procedure, 
487 
or other means, will be reported on an Adverse Event Form online. Each Adverse Event Form is 
488 
reviewed by the Medical Monitor to verify the coding and the reporting that is required. 
489 
6.1.3 Relationship of Adverse Event to Study Device 
490 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
491 
by determining if there is a reasonable possibility that the adverse event may have been caused 
492 
by the study device. 
493 
To ensure consistency of adverse event causality assessments, investigators should apply the 
494 
following general guideline when determining whether an adverse event is related: 
495 
Yes 
496 
There is a plausible temporal relationship between the onset of the adverse event and the study 
497 
intervention, and the adverse event cannot be readily explained by the participant’s clinical state, 
498 
intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern 
499 
of response to the study intervention. 
500 
No 
501 
Evidence exists that the adverse event has an etiology other than the study intervention (e.g., pre-
502 
existing medical condition, underlying disease, intercurrent illness, or concomitant medication), 
503 
and/or the adverse event has no plausible temporal relationship to study intervention. 
504 
6.1.4 Intensity of Adverse Event 
505 
The intensity of an adverse event will be rated on a 3 point scale: (1) mild, (2) moderate, or (3) 
506 
severe. It is emphasized that the term severe is a measure of intensity: thus a severe adverse 
507 
event is not necessarily serious. For example, itching for several days may be rated as severe, but 
508 
may not be clinically serious. 
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• MILD: Usually transient, requires no special treatment, and does not interfere with the 
510 
participant’s daily activities. 
511 
• MODERATE: Usually causes a low level of inconvenience or concern to the participant 
512 
and may interfere with daily activities, but is usually ameliorated by simple therapeutic 
513 
measures. 
514 
• SEVERE: Interrupts a participant’s usual daily activities and generally requires systemic 
515 
drug therapy or other treatment. 
516 
6.1.5 Coding of Adverse Events 
517 
Adverse events will be coded using the MedDRA dictionary. The Medical Monitor will review 
518 
the investigator’s assessment of causality and may agree or disagree. Both the investigator’s and 
519 
Medical Monitor’s assessments will be recorded. The Medical Monitor will have the final say in 
520 
determining the causality. 
521 
Adverse events that continue after the participant’s discontinuation or completion of the study 
522 
will be followed until their medical outcome is determined or until no further change in the 
523 
condition is expected. 
524 
6.1.6 Outcome of Adverse Event 
525 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
526 
• COMPLETE RECOVERY/RESOLVED: The participant recovered from the AE/SAE 
527 
without sequelae. Record the AE/SAE stop date. 
528 
• RECOVERED/RESOLVED WITH SEQUELAE: The event persisted and had stabilized 
529 
without change in the event anticipated. Record the AE/SAE stop date. 
530 
• FATAL: A fatal outcome is defined as the SAE that resulted in death. Only the event that 
531 
was the cause of death should be reported as fatal. Adverse events and serious adverse 
532 
events that were ongoing at the time of death, that were not the cause of death, will be 
533 
recorded as ‘resolved’ at the time of death. 
534 
• ONGOING: An ongoing AE/SAE is defined as the event was ongoing with an 
535 
undetermined outcome. 
536 
 
An ongoing outcome for which further improvement or worsening is possible will 
537 
require follow-up by the site in order to determine the final outcome of the AE/SAE. 
538 
 
An ongoing outcome that is medically stable (further change not expected) will be 
539 
documented as such and will not require additional follow-up.  
540 
 
The outcome of an ongoing event at the time of death that was not the cause of death, 
541 
will be updated and recorded as ‘resolved’ with the date of death recorded as the stop 
542 
date. 
543 
All adverse events occurring during the study and continuing at study termination should be 
544 
followed by the participant’s physician and evaluated with additional tests (if necessary) until 
545 
diagnosis of the underlying cause, or resolution. Follow-up information should be recorded on 
546 
source documents.  
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If any reported serious, related, or unexpected adverse events or UADEs are present when a 
548 
participant completes the study, or if a participant is withdrawn from the study due to a serious, 
549 
related, or unexpected adverse event or UADE, the participant will be contacted for re-evaluation 
550 
within 2 weeks. If the adverse event has not resolved, additional follow-up will be performed as 
551 
appropriate. Every effort should be made by the Investigator or delegate to contact the 
552 
participant until the adverse event has resolved or stabilized. 
553 
6.2 Reportable Device Issues 
554 
All UADEs, ADEs, device complaints, and device malfunctions will be reported on the Gas 
555 
Injection Form irrespective of whether an adverse event occurred. 
556 
6.3 Pregnancy Reporting 
557 
If pregnancy occurs, the participant will remain in follow-up for the duration of the study. The 
558 
occurrence of pregnancy will be reported on an Adverse Event Form. 
559 
6.4 Timing of Event Reporting 
560 
Serious adverse events and unexpected device-related adverse events must be reported to the 
561 
Coordinating Center within 24 hours via completion of the online case report form. 
562 
The Coordinating Center will notify all participating investigators of any adverse event that is 
563 
serious, related, and unexpected. Notification will be made within 10 days after the Coordinating 
564 
Center becomes aware of the event. 
565 
Each principal investigator is responsible for reporting serious study-related adverse events and 
566 
abiding by any other reporting requirements specific to his/her Institutional Review Board or 
567 
Ethics Committee. 
568 
Upon receipt of a UADE report, the JCHR will investigate the UADE and if indicated, report the 
569 
results of the investigation to the sites’ IRBs, and the FDA within 10 working days of the JCHR 
570 
becoming aware of the UADE per 21CFR 812.46(b) (2). The Medical Monitor must determine if 
571 
the UADE presents an unreasonable risk to participants. If so, the Medical Monitor must ensure 
572 
that all investigations, or parts of investigations presenting that risk, are terminated as soon as 
573 
possible but no later than 5 working days after the Medical Monitor makes this determination 
574 
and no later than 15 working days after first receipt notice of the UADE. 
575 
Device malfunctions will be handled by the site and manufacturer.  
576 
6.5 Stopping Criteria 
577 
6.5.1 Criteria for Suspending or Stopping Overall Study 
578 
The Data and Safety Monitoring Committee (DSMC) will be informed of all unanticipated 
579 
adverse device events that occur during the study and will review compiled safety data at 
580 
periodic intervals. The DSMC may request suspension of study activities or stoppage of the 
581 
study if deemed necessary based on the totality of safety data available. 
582 
The study may be discontinued by the Executive Committee (with approval of the DSMC) prior 
583 
to the preplanned completion of follow-up for all study participants. 
584 

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6.6 Independent Safety Oversight 
585 
A DSMC will approve the protocol, template informed consent form, and substantive 
586 
amendments and provide independent monitoring of adverse events. Cumulative adverse event 
587 
data are tabulated semi-annually for review by the DSMC. Following each DSMC data review, a 
588 
summary will be provided to the IRB. A list of specific adverse events to be reported 
589 
expeditiously to the DSMC will be compiled and included as part of the DSMC Monitoring Plan 
590 
document.  
591 
6.7 Risks 
592 
The potential risks associated with use of the study device are described in section 1.4.1. 
593 
Additional risks are minor and/or infrequent and include: 
 
594 
Risks Related to Testing Procedures 
595 
Many of the testing procedures in this study are part of daily ophthalmologic practice in the United 
596 
States and pose few if any known risks.  
597 
• Dilating eye drops will be used as part of the exam. There is a small risk of inducing a narrow-
598 
angle glaucoma attack from the pupil dilation. However, all participants will have had prior 
599 
pupil dilation usually on multiple occasions and therefore the risk is extremely small.  
600 
Risks Related Specifically to the Pre-Injection Preparation  
601 
• There are potential side effects to subconjunctival anesthetic, which are rare. They include, but 
602 
are not limited to, the following: damage to the eyeball by the needle, damage to the optic 
603 
nerve, double vision lasting 24 hours or more. 
604 
• Complications associated with paracentesis are uncommon, but may include uveitis, flat 
605 
anterior chamber, corneal wound leak, hyphema, anterior vitreous prolapse, and/or pupillary 
606 
block glaucoma and cataract. Under certain circumstances, such complications may lead to 
607 
vision loss.  
608 
Risks if Pregnant 
609 
According to the C3F8 package insert, there are no known teratogenic effects when injected into 
610 
the eye; however, caution should be used in pregnant women. Therefore, patients will not be 
611 
allowed to participate in this study if pregnant. Women who become pregnant during the study 
612 
will be asked to stay in the study since there is no follow-up treatment with the investigational 
613 
product. 
614 

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CHAPTER 7: MISCELLANEOUS CONSIDERATIONS 
615 
7.1 Prohibited Medications, Treatments, and Procedures 
616 
The participant will be instructed that nitrous oxide anesthesia must not be administered unless 
617 
the investigator has confirmed that the gas bubble is no longer present. Wristbands notifying 
618 
healthcare providers of this will be given to participants following the intravitreous or sham 
619 
injection, and must be worn until the investigator confirms that the gas bubble has cleared (at 4-
620 
week visit for observation group participants). 
621 
7.2 Participant Withdrawal 
622 
Participation in the study is voluntary and a participant may withdraw at any time. If a study 
623 
participant is considering withdrawal from the study, the principal investigator should personally 
624 
speak to the individual about the reasons and every effort should be made to accommodate him 
625 
or her.  
626 
The goal for the study is to have as few losses to follow-up as possible. The Coordinating Center 
627 
will assist in the tracking of study participants who cannot be contacted by the site. The 
628 
Coordinating Center will be responsible for classifying a study participant as lost to follow-up. 
629 
For participants who withdraw, their data will be used up until the time of withdrawal. 
630 
7.3 Discontinuation of Study 
631 
The study may be discontinued by the Executive Committee (with approval of the DSMC) prior 
632 
to the preplanned completion of follow-up for all study participants. 
633 
7.4 Confidentiality 
634 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
635 
used instead of their name. Protected health information gathered for this study will be shared with 
636 
the coordinating center, the Jaeb Center for Health Research in Tampa, FL.  
637 
The Coordinating Center will be provided with contact information for each study participant. 
638 
Permission to obtain such information will be included in the Informed Consent Form. The contact 
639 
information may be maintained in a secure database and will be maintained separately from the 
640 
study data. 
641 
Phone contact from the Coordinating Center will be made with each study participant in the first 
642 
month after enrollment. Additional phone contacts from the Coordinating Center will be made if 
643 
necessary to facilitate the scheduling of the study participant for follow-up visits. A participant-
644 
oriented newsletter and a study logo item may be sent once.  
645 
Study participants will be provided with a summary of the study results in a newsletter format 
646 
after completion of the study by all participants.  
647 
7.5 Participant Compensation 
648 
Participant compensation will be specified in the informed consent form.  
649 

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CHAPTER 8: STATISTICAL CONSIDERATIONS 
650 
8.1 Statistical and Analytical Plans 
651 
The approach to sample size and statistical analyses are summarized below. A detailed statistical 
652 
analysis plan will be written and finalized prior to the first review of data by treatment group. 
653 
The analysis plan synopsis in this chapter contains the framework of the anticipated final 
654 
analysis plan. 
655 
8.2 Statistical Hypotheses 
656 
A test of superiority will be used in evaluating the following hypotheses for the primary 
657 
outcome: 
658 
Null Hypothesis (H0): There is no difference in the proportion of eyes with central VMT release 
659 
without rescue treatment between the PVL and observation groups at 24 weeks. 
660 
Alternative Hypothesis (Ha): There is a difference in the proportion of eyes with central VMT 
661 
release without rescue treatment between the PVL and observation groups at 24 weeks. 
662 
Similar hypothesis tests will be conducted for all secondary, exploratory, and safety outcomes. 
663 
8.3 Sample Size 
664 
8.3.1 Outcome Projections: 
665 
Observation Group (sham injection) 
666 
In a consecutive case series of 106 eyes with a median follow-up time of 18 months,6 the 
667 
proportion of eyes with spontaneous VMT release was 32%. The proportion of eyes with VMT 
668 
release at 6 months in the Sham Groups of the randomized controlled trials MIVI-TRUST10 
669 
(N = 188) and OASIS (N = 74),11 which compared ocriplasmin versus sham for VMT, were 
670 
approximately 13% and 10%, respectively. Dugel et al.11 also found that the proportion of eyes 
671 
with VMT release was greater among eyes that had MH at baseline. Macular hole was present at 
672 
baseline in approximately 36% of the OASIS Sham Group and 25% of the MIVI-TRUST Sham 
673 
Group.  
674 
PVL group 
675 
Three case series provide estimates of VMT release with C3F8 gas. A study of 15 eyes (1 with 
676 
MH) from Rodrigues et al.23 showed release of VMT in 60% of eyes through 6 months. Steinle 
677 
et al.24 showed 83% success among 30 eyes (3 with MH) through 62 days. Finally, Chan et al.25 
678 
(2017) showed 86% success among 50 eyes (15 with MH) over 9 weeks. In addition, Chan et al. 
679 
reported higher rates of VMT release among eyes with MH. The release rate among eyes with 
680 
VMT only in Chan et al. was 80%.25 
681 
8.3.2 Sample Size Estimates 
682 
Table 1 shows sample size estimates for the primary analysis under varying assumptions for the 
683 
proportion of eyes with VMT release within the 2 groups. These calculations assume a Type I 
684 
error rate of 5%, 90% power, and a two-sided test of superiority (See Section 8.6) with a null 
685 
hypothesis of no difference between the groups (Section 8.2). 
686 

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Table 1: Comparison of Proportion with VMT Release: Total Sample Size 
687 
Release in PVL 
Group 
Release in Sham Group 
10% 
20% 
30% 
50% 
52 
104 
248 
60% 
34 
60 
112 
70% 
24 
38 
62 
For true outcome proportion of 60% (PVL) vs 30% (sham injection), a sample size of 112 (56 
688 
per group) gives 90% power to reject the null hypothesis of no difference. Adjusting for possible 
689 
loss to follow-up of 10% gives a final sample size of 124 (62 per group). 
690 
8.4 Outcome Measures 
691 
For the outcomes below, rescue treatment includes vitrectomy, ocriplasmin, or additional 
692 
pneumatic vitreolysis during the course of the study.  
693 
Primary Efficacy Outcome: 
694 
• Proportion of eyes with central VMT release* without rescue treatment at 24 weeks.  
695 
o For purposes of description only, the distribution of eyes within treatment group 
696 
by the following categories at 24 weeks will be tabulated without statistical 
697 
comparison: 
698 
▪ Central VMT release without rescue treatment 
699 
▪ Central VMT release with rescue treatment 
700 
▪ No central VMT release and no rescue treatment 
701 
▪ No central VMT release despite rescue treatment 
702 
Secondary Efficacy Outcomes: 
703 
• Proportion of eyes with central VMT release* without rescue treatment through 24 weeks 
704 
(time-to-event analysis). 
705 
• Proportion of eyes with central VMT release and vitreopapillary traction release* without 
706 
rescue treatment at 24 weeks. 
707 
• Mean change in visual acuity letter score from baseline at 24 weeks. 
708 
• Proportion of eyes with at least 10-letter gain (increase) in visual acuity from baseline at 
709 
24 weeks. 
710 
• Proportion of eyes with at least 10-letter loss (decrease) in visual acuity from baseline at 
711 
24 weeks. 
712 
• Proportion of eyes receiving rescue treatment before the 24-week visit. 
713 
o For purposes of description only, the following will be tabulated within treatment 
714 
group without statistical comparison: 
715 
▪ Proportion of eyes receiving rescue treatment before the 24-week visit or 
716 
for which rescue treatment is planned at the 24-week visit and medical 
717 
records confirm rescue treatment occurred within the subsequent 12 
718 
weeks. 
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▪ Type of rescue treatment. 
720 
Exploratory Efficacy Outcomes: 
721 
• Mean change in shape discrimination hyperacuity from baseline at 24 weeks. 
722 
• Proportion of eyes with ellipsoid zone* integrity at 24 weeks. 
723 
*Determined by masked grader at the central reading center. 
724 
To ensure that statistical outliers do not have undue impact on analyses of continuous outcomes, 
725 
change in continuous outcomes from baseline will be truncated to ± 3 standard deviations based 
726 
on the overall mean and standard deviation from both treatment groups combined at 24 weeks. 
727 
8.5 Analysis Cohorts 
728 
• Intention-To-Treat (ITT) Analysis Cohort: all randomized participants irrespective of 
729 
treatment received, and analyzed according to treatment assignment. 
730 
• Safety Analysis Cohort: all randomized participants irrespective of treatment received, 
731 
and analyzed according to treatment assignment.  
732 
• Per-Protocol Analysis Cohort: only participants that complete the initial treatment (PVL 
733 
or sham injection) and do not receive any non-protocol treatments during follow-up. 
734 
Vitrectomy performed according to the criteria in section 4.2.1 is considered per-protocol 
735 
and will be included in this analysis. 
736 
The primary analysis will follow the ITT principle. It will include all randomized participants. 
737 
The data from the ITT cohort will be analyzed according to the group to which the participants 
738 
were assigned through randomization, regardless of treatment actually received. 
739 
A per-protocol analysis will be performed to provide additional information regarding the 
740 
magnitude of the treatment effect. The per-protocol analysis will only be performed if more than 
741 
10% of randomized participants would be excluded by these criteria (e.g., 13 or more 
742 
participants if exactly 124 are enrolled). 
743 
The ITT analysis is considered the primary analysis. If the results of the per-protocol and ITT 
744 
analyses give inconsistent results, the per-protocol analysis will be interpreted with caution. In 
745 
this scenario, exploratory analyses will be performed to evaluate possible factors contributing to 
746 
the differences. 
747 
8.6 Analysis of the Primary Efficacy Outcome 
748 
The primary outcome of central VMT release without rescue treatment at 24 weeks is a binary 
749 
variable that is graded by the central reading center. Logistic regression with robust variance 
750 
estimation will be used to test the hypothesis of superiority (Section 8.2). Presence of ERM 
751 
within 1 mm of the center of the macula at baseline will be included as a covariate, as previous 
752 
reports have indicated the rate of VMT release differs by presence of ERM and the 
753 
randomization schedules were therefore stratified by presence of ERM. The relative risk 
754 
(estimated using the method of Localio et al. 200727) for the treatment group effect, 95% 
755 
confidence interval, and P value will used to compare treatment groups. To aid in interpretation 
756 
of the relative risk, observed outcome proportions will be reported for each treatment group.  
757 
Since the chance of re-attachment after release is highly unlikely before 24 weeks, an eye with 
758 
central VMT release without rescue treatment prior to 24 weeks will be considered to have met 
759 

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the outcome through 24 weeks if the patient is lost to follow-up. Similarly, any eye receiving 
760 
rescue treatment prior to 24 weeks will be considered not to have met the outcome through 24 
761 
weeks because rescue treatment will have been given.  
762 
Multiple imputation will be used to impute missing data for eyes lost to follow-up that did not 
763 
have prior release or rescue treatment documented. The imputation model will include presence 
764 
of ERM within 1 mm of the center of the macula at baseline, treatment group, and VMT status at 
765 
1, 4, 12, and 24 weeks. 
766 
A sensitivity analysis will be conducted using the same approach as above but without multiple 
767 
imputation (i.e., complete-case analysis).  
768 
8.7 Analysis of the Secondary and Exploratory Efficacy Outcomes 
769 
The ITT analysis cohort will be used for all secondary and exploratory outcomes. 
770 
8.7.1. Secondary Efficacy Outcomes 
771 
Development of central VMT release without rescue treatment through 24 weeks is a time-to-
772 
event outcome that will be modeled with Cox proportional hazards regression and robust 
773 
variance estimation. The hazard ratio along with the 95% confidence interval and P value will be 
774 
used to compare treatment groups. To aid in interpretation, a Kaplan-Meier plot will be 
775 
constructed. Data from eyes not observed to have release or that receive rescue treatment will be 
776 
censored on the date of their final visit. 
777 
The proportion of eyes with central VMT release and vitreopapillary traction release (without 
778 
rescue treatment) at 24 weeks is a binary variable graded by the central reading center that will 
779 
be analyzed with logistic regression. Analysis and imputation of missing data will be handled in 
780 
a manner similar to the primary outcome. The analysis will be adjusted for vitreopapillary 
781 
traction status at baseline. 
782 
Change in visual acuity letter score from baseline to 24 weeks is a continuous variable that will 
783 
be analyzed using a general linear model with robust variance estimation. Presence of ERM 
784 
within 1 mm of the center of the macula at baseline and baseline visual acuity will be included as 
785 
covariates. The treatment group difference, 95% confidence interval, and P value will be 
786 
presented. To aid in interpretation, least squares means and associated 95% confidence intervals 
787 
for each group will used to compare treatment groups. Serious violations of statistical 
788 
assumptions may be addressed by transformation of variables, non-parametric methods, or 
789 
categorizing continuous covariates. Missing data will be imputed with multiple imputation. The 
790 
imputation model will include presence of ERM within 1 mm of the center of the macula at 
791 
baseline, treatment group, baseline visual acuity, and change in visual acuity from baseline at 1, 
792 
4, 12, and 24 weeks, and VMT status at 1, 4, 12, and 24 weeks.  
793 
The proportion of eyes with at least 10-letter gain (increase) or loss (decrease) in visual acuity 
794 
from baseline are binary variables that will be analyzed with logistic regression and will use the 
795 
imputed data sets from the analysis of mean change in visual acuity from baseline. 
796 
The proportion of eyes receiving rescue treatment before the 24-week visit is a binary variable 
797 
that will be analyzed with logistic regression. The presence of ERM within 1 mm of the center of 
798 
the macula at baseline will be included as a covariate. Complete-case analysis (no imputation of 
799 
missing data) will be used for this outcome. 
800 

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8.7.2 Exploratory Efficacy Outcomes 
801 
Change in shape discrimination hyperacuity (measured in logMAR) is a continuous variable that 
802 
will be analyzed as above but substituting baseline and follow-up shape discrimination 
803 
hyperacuity for visual acuity. Complete-case analysis (no imputation of missing data) will be 
804 
used for this outcome. 
805 
The proportion of eyes with ellipsoid integrity at 24 weeks is a binary variable graded by the 
806 
central reading center (loss of integrity and no loss of integrity). Logistic regression adjusted for 
807 
ellipsoid zone status at baseline and the presence of ERM within 1 mm of the center of the 
808 
macula at baseline will be used to compare treatment groups. The relative risk for the treatment 
809 
group effect, 95% confidence interval, and P value will used to compare treatment groups. To 
810 
aid in interpretation of the relative risk, observed outcome proportions will be reported for each 
811 
treatment group. Complete-case analysis (no imputation of missing data) will be used for this 
812 
outcome. 
813 
8.8 Safety Analyses 
814 
All reportable adverse events will be categorized as study eye or systemic. All events will be 
815 
tabulated by treatment group in a listing of each reported Medical Dictionary for Regulatory 
816 
Activities (MedDRA) term and summarized over each MedDRA System Organ Class. All 
817 
randomized participants will be included in safety analyses. Any events occurring between 
818 
randomization and study treatment will be noted.  
819 
8.8.1 Ocular Adverse Events 
820 
The frequency of each ocular adverse event occurring at least once per eye will be calculated. 
821 
The proportion of eyes experiencing each outcome will be compared between treatment groups 
822 
with Barnard’s unconditional exact test. The following ocular adverse events are of primary 
823 
interest:  
824 
o Retinal detachment 
825 
o Retinal tear 
826 
o Macular hole development 
827 
o Cataract extraction in eyes phakic at baseline 
828 
o Vitreous hemorrhage  
829 
o Adverse IOP events (composite outcome) 
830 
▪ Increase in IOP ≥ 10 mmHg from baseline (at a follow-up visit) 
831 
▪ IOP ≥ 30 mmHg (at a follow-up visit) 
832 
▪ Initiation of medication to lower IOP that was not in use at baseline 
833 
▪ Glaucoma procedure 
834 
The number of eyes with endophthalmitis and traumatic cataract will be tabulated without 
835 
statistical comparison. 
836 

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8.8.2 Systemic Adverse Events 
837 
The frequency of each systemic adverse event occurring at least once per participant will be 
838 
calculated. The proportion of participants experiencing each outcome will be compared with 
839 
Barnard’s unconditional exact test. The following systemic adverse events are of primary 
840 
interest: 
841 
o Death 
842 
o Serious adverse event (at least one) 
843 
The following systemic adverse events are of secondary interest and will be tabulated without 
844 
statistical comparison: 
845 
o For each MedDRA System Organ Class, proportion of participants with at least one 
846 
serious event 
847 
For each treatment group, the number of adverse events (ocular or systemic) considered related 
848 
to treatment will be tabulated.  
849 
8.9 Intervention Adherence 
850 
Adherence will be defined as completion of the treatment assigned at randomization, either PVL 
851 
or sham injection. 
852 
8.10 Protocol Adherence and Retention 
853 
Protocol deviations and visit completion rates (excluding deaths) will be tabulated for each 
854 
treatment group. 
855 
8.11 Baseline Descriptive Statistics 
856 
Baseline characteristics will be tabulated by treatment group and summary statistics appropriate 
857 
to the distribution will be reported. 
858 
8.12 Planned Interim Analyses 
859 
There is no formal interim analysis planned for this study. The Data and Safety Monitory 
860 
Committee (DSMC) will review safety and outcome data approximately every 6 months while 
861 
the study is ongoing. 
862 
8.13 Subgroup Analyses 
863 
Subgroup analyses, i.e., assessments of effect modification (interaction), will be conducted for 
864 
the primary outcome. These analyses will be considered exploratory. Additionally, interpretation 
865 
of the analyses will depend on whether the primary analysis demonstrates a significant treatment 
866 
group difference; in the absence of such a difference, subgroup analyses will be interpreted with 
867 
caution.  
868 
The general approach for these exploratory analyses will be to add an interaction term for the 
869 
subgroup factor by treatment into the primary analysis model. In addition, within-subgroup 
870 
treatment effects and 95% confidence intervals will be estimated from the interaction model if 
871 
the interaction P value is less than .05. Subgroup analyses will use data from eyes that complete 
872 
the 24-week visit or have VMT release or rescue treatment prior to 24 weeks (i.e., complete case 
873 
analysis as described in section 8.6).  
874 

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The primary subgroup analysis will evaluate the effect of ERM presence within 1 mm of the 
875 
center of the macula. In previous studies, eyes with ERM treated with C3F8 for VMT had lower 
876 
release rates compared with eyes not having ERM.10, 11, 25 It is unknown what effect ERM may 
877 
have on the release rate in the observation group. 
878 
Secondary subgroup analyses will include ERM presence at the site of vitreous adhesion, lens 
879 
status (phakic or pseudophakic), components of VMT severity grade,6 length of adhesion on 
880 
OCT (less than or equal to 1500 microns or greater than 1500 microns), and diabetes status (has 
881 
diabetes or does not have diabetes).  
882 
There are no data to suggest that the treatment effect will vary by sex or race/ethnicity. However, 
883 
both of these factors will be evaluated in exploratory subgroup analyses as mandated by National 
884 
Institutes of Health (NIH) guidelines.  
885 
Subgroup factors will be analyzed as categorical and continuous or ordinal variables where 
886 
possible. Secondary and exploratory subgroup analyses will only be conducted if there are at 
887 
least 20 eyes in each subgroup for each treatment group. 
888 
8.14 Multiple Testing 
889 
There will be no formal adjustment for multiple testing. Only P ≤ .05 will be considered of 
890 
interest. 
891 
8.15 Assessment of Confounding  
892 
Imbalances between groups in important covariates are not expected to be of sufficient 
893 
magnitude to produce confounding. However, a sensitivity analysis using observed data (no 
894 
multiple imputation) will be conducted if there is an imbalance between treatment groups in any 
895 
of the following: presence of ERM, lens status, extent of VMT, diabetes status, age, or sex. 
896 
Imbalance by treatment group will not be judged using statistical testing. Instead, imbalance will 
897 
be judged by whether the imbalance is large enough to have a clinically important effect on the 
898 
primary outcome. The sensitivity analysis will mimic the primary analysis but add any 
899 
potentially imbalanced factors as covariates. 
900 

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CHAPTER 9: DATA COLLECTION AND MONITORING 
901 
9.1 Case Report Forms and Device Data 
902 
The main study data are collected through electronic case report forms (CRFs). These electronic 
903 
CRFs from the study website are considered the primary source documentation. 
904 
Each participating site will maintain appropriate medical and research records for this trial, in 
905 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
906 
confidentiality of participants. 
907 
9.2 Study Records Retention 
908 
Study documents should be retained for a minimum of 3 years following the NIH grant cycle for 
909 
which the last visit was completed (expected to be December 31, 2026). These documents should 
910 
be retained for a longer period, however, if required by local regulations. No records will be 
911 
destroyed without the written consent of JCHR.  
912 
9.3 Quality Assurance and Monitoring 
913 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
914 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
915 
conducted and data are generated, documented and reported in compliance with the protocol, 
916 
Good Clinical Practice (GCP) and the applicable regulatory requirements. Adverse events will be 
917 
prioritized for monitoring. 
918 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
919 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical 
920 
Investigations — A Risk-Based Approach to Monitoring” (August 2013). Study conduct and 
921 
monitoring will conform with 21 Code of Federal Regulations (CFR) 812. 
922 
The most important data for monitoring at the site are participant eligibility and adverse events. 
923 
Therefore, the RBM plan will focus on these areas. As much as possible, remote monitoring will 
924 
be performed in real-time with on-site monitoring performed to evaluate the verity and 
925 
completeness of the key site data. Elements of the RBM may include: 
926 
• Qualification assessment, training, and certification for sites and site personnel 
927 
• Oversight of Institutional Review Board (IRB) coverage and informed consent 
928 
procedures 
929 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
930 
review of entered data and edits, statistical monitoring, study closeout 
931 
• On-site monitoring (site visits): source data verification, site visit report 
932 
• Communications with site staff 
933 
• Patient retention and visit completion 
934 
• Quality control reports 
935 
• Management of noncompliance 
936 
• Documenting monitoring activities 
937 

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• Adverse event reporting and monitoring 
938 
Coordinating Center representatives or their designees may visit the study facilities at any time in 
939 
order to maintain current and personal knowledge of the study through review of the records, 
940 
comparison with source documents, observation and discussion of the conduct and progress of 
941 
the study. 
942 
9.4 Protocol Deviations 
943 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
944 
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
945 
the study site staff. As a result of deviations, corrective actions are to be developed by the site 
946 
and implemented promptly. 
947 
The site principal investigator and study staff are responsible for knowing and adhering to their 
948 
IRB requirements. Further details about the handling of protocol deviations will be included in 
949 
the monitoring plan. 
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CHAPTER 10: ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
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10.1 Ethical Standard 
952 
The principal investigator will ensure that this study is conducted in full conformity with 
953 
Regulations for the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 
954 
CFR Part 50, 21 CFR Part 56, and/or the ICH E6. 
955 
10.2 Institutional Review Boards 
956 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
957 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
958 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
959 
require review and approval by the IRB before the changes are implemented to the study. All 
960 
changes to the consent form will be IRB approved; a determination will be made regarding 
961 
whether previously consented participants need to be re-consented. 
962 
10.3 Informed Consent Process 
963 
10.3.1 Consent Procedures and Documentation 
964 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
965 
the study and continues throughout the individual’s study participation. Extensive discussion of 
966 
risks and possible benefits of participation will be provided to the participants and their families. 
967 
Consent forms will be IRB-approved and the participant will be asked to read and review the 
968 
document. The investigator will explain the research study to the participant and answer any 
969 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 
970 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
971 
research participants. Participants will have the opportunity to carefully review the written 
972 
consent form and ask questions prior to signing. 
973 
The participants should have the opportunity to discuss the study with their surrogates or think 
974 
about it prior to agreeing to participate. The participant will sign the informed consent document 
975 
prior to any procedures being done specifically for the study. The participants may withdraw 
976 
consent at any time throughout the course of the trial. A copy of the informed consent document 
977 
will be given to the participants for their records. The rights and welfare of the participants will 
978 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
979 
affected if they decline to participate in this study. 
980 
10.3.2 Participant and Data Confidentiality 
981 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
982 
and the JCHR and their agents. This confidentiality is extended to cover biological samples in 
983 
addition to the clinical information relating to participants. Therefore, the study protocol, 
984 
documentation, data, and all other information generated will be held in strict confidence. No 
985 
information concerning the study or the data will be released to any unauthorized third party 
986 
without prior written approval of the JCHR. 
987 
The study monitor, other authorized representatives of the JCHR, or representatives of the IRB 
988 
may inspect all documents and records required to be maintained by the investigator, including 
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but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
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participants in this study. The clinical study site will permit access to such records. 
991 
The study participant’s contact information will be securely stored at each clinical site for 
992 
internal use during the study. At the end of the study, all records will continue to be kept in a 
993 
secure location for as long a period as dictated by local IRB and institutional regulations. 
994 
Study participant research data, which is for purposes of statistical analysis and scientific 
995 
reporting, will be transmitted to and stored at the coordinating center, the Jaeb Center for Health 
996 
Research (JCHR) in Tampa, FL. This will not include the participant’s contact or identifying 
997 
information. Rather, individual participants and their research data will be identified by a unique 
998 
study identification number. The study data entry and study management systems used by 
999 
clinical sites and by JCHR research staff will be secured and password protected. At the end of 
1000 
the study, all study databases will be de-identified and archived at JCHR. 
1001 
10.3.3 Future Use of Stored Specimens 
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With the participant’s approval, de-identified biological samples will be stored at a central 
1003 
repository for future research into the causes, complications, and treatments of retinal diseases. 
1004 
The repository will also be provided with a code-link that will allow linking the biological 
1005 
specimens with the phenotypic data from each participant, maintaining the masking of the 
1006 
identity of the participant. 
1007 
During the conduct of the study, an individual participant can choose to withdraw consent to 
1008 
have biological specimens stored for future research. However, withdrawal of consent with 
1009 
regard to biosample storage will not be possible after the study is completed. 
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CHAPTER 11: REFERENCES 
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1. 
Jackson TL, Nicod E, Simpson A, Angelis A, Grimaccia F, Kanavos P. Symptomatic 
1013 
vitreomacular adhesion. Retina. 2013;33(8):1503-11. 
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2. 
Duker JS, Kaiser PK, Binder S, et al. The International Vitreomacular Traction Study 
1015 
Group classification of vitreomacular adhesion, traction, and macular hole. 
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Ophthalmology. 2013;120(12):2611-9. 
1017 
3. 
Almeida DR, Chin EK. Spontaneous resolution of vitreomacular traction in two patients 
1018 
with diabetic macular edema. Case Rep Ophthalmol. 2014;5(1):66-71. 
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4. 
Dimopoulos S, Bartz-Schmidt KU, Gelisken F, Januschowski K, Ziemssen F. Rate and 
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timing of spontaneous resolution in a vitreomacular traction group: should the role of 
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watchful waiting be re-evaluated as an alternative to ocriplasmin therapy? Br J 
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Ophthalmol. 2015;99(3):350-3. 
1023 
5. 
Hwang DJ, Park KH, Woo SJ. Spontaneous resolution of vitreomacular traction 
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syndrome with persistent vitreofoveal adhesion observed on spectral-domain optical 
1025 
coherence tomography. Can J Ophthalmol. 2012;47(5):e17-9. 
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6. 
John VJ, Flynn HW, Jr., Smiddy WE, et al. Clinical course of vitreomacular adhesion 
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managed by initial observation. Retina. 2014;34(3):442-6. 
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7. 
Theodossiadis GP, Grigoropoulos VG, Theodoropoulou S, Datseris I, Theodossiadis PG. 
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Spontaneous resolution of vitreomacular traction demonstrated by spectral-domain 
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optical coherence tomography. Am J Ophthalmol. 2014;157(4):842-51 e1. 
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8. 
Tzu JH, John VJ, Flynn HW, Jr., et al. Clinical Course of Vitreomacular Traction 
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Managed Initially by Observation. Ophthalmic Surg Lasers Imaging Retina. 
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2015;46(5):571-6. 
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Neffendorf JE, Kirthi V, Pringle E, Jackson TL. Ocriplasmin for symptomatic 
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vitreomacular adhesion. Cochrane Database Syst Rev. 2017;10:CD011874. 
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Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for 
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vitreomacular traction and macular holes. N Engl J Med. 2012;367(7):606-15. 
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11. 
Dugel PU, Tolentino M, Feiner L, Kozma P, Leroy A. Results of the 2-Year Ocriplasmin 
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for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole 
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(OASIS) Randomized Trial. Ophthalmology. 2016;123(10):2232-47. 
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12. 
Stefanini FR, Maia M, Falabella P, et al. Profile of ocriplasmin and its potential in the 
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treatment of vitreomacular adhesion. Clin Ophthalmol. 2014;8:847-56. 
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13. 
Lim J, Glassman A, Aiello L, et al. Macula Society collaborative retrospective study of 
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ocriplasmin for symptomatic vitreomacular adhesion. Ophthal Retina. 2017;1(5):413-20. 
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14. 
Fahim AT, Khan NW, Johnson MW. Acute panretinal structural and functional 
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abnormalities after intravitreous ocriplasmin injection. JAMA Ophthalmol. 
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2014;132(4):484-6. 
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15. 
Freund KB, Shah SA, Shah VP. Correlation of transient vision loss with outer retinal 
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disruption following intravitreal ocriplasmin. Eye (Lond). 2013;27(6):773-4. 
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16. 
Hager A, Seibel I, Riechardt A, Rehak M, Joussen AM. Does ocriplasmin affect the RPE-
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photoreceptor adhesion in macular holes? Br J Ophthalmol. 2015;99(5):635-8. 
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17. 
Kim JE. Safety and complications of ocriplasmin: ocriplasmin, ocriplasmin; oh, how safe 
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art thou? JAMA Ophthalmol. 2014;132(4):379-80. 
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18. 
Tibbetts MD, Reichel E, Witkin AJ. Vision loss after intravitreal ocriplasmin: correlation 
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of spectral-domain optical coherence tomography and electroretinography. JAMA 
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Ophthalmol. 2014;132(4):487-90. 
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American Society of Retina Specialists Preference and Trends (PAT) Survey 2017, 
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accessed at www.asrs.org/asrs-community/pat-survey. 
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20. 
Chan CK, Wessels IF, Friedrichsen EJ. Treatment of idiopathic macular holes by induced 
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posterior vitreous detachment. Ophthalmology. 1995;102(5):757-67. 
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21. 
Costa RA, Cardillo JA, Morales PH, Jorge R, Uno F, Farah ME. Optical coherence 
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tomography evaluation of idiopathic macular hole treatment by gas-assisted posterior 
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vitreous detachment. Am J Ophthalmol. 2001;132(2):264-6. 
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22. 
Jorge R, Costa RA, Cardillo JA, Uno F, Bonomo PP, Farah ME. Optical coherence 
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tomography evaluation of idiopathic macular hole treatment by gas-assisted posterior 
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vitreous detachment. Am J Ophthalmol. 2006;142(5):869-71. 
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Rodrigues IA, Stangos AN, McHugh DA, Jackson TL. Intravitreal injection of expansile 
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perfluoropropane (c(3)f(8)) for the treatment of vitreomacular traction. Am J Ophthalmol. 
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2013;155(2):270-6 e2. 
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Steinle NC, Dhoot DS, Quezada Ruiz C, et al. Treatment of Vitreomacular Traction with 
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Intravitreal Perfluoropropane (C3f8) Injection. Retina. 2017;37(4):643-50. 
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25. 
Chan CK, Crosson JN, Mein CE, Daher N. Pneumatic Vitreolysis for Relief of 
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Vitreomacular Traction. Retina. 2017. 
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Chan C. Pneumatic Vitreolysis for Resolving Focal Vitreomacular Traction: An Update 
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on Clinical Outcome . 2019 Retina Society, 52nd Scientific Program, Landmark Hotel, 
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London, UK, Sept 11 to 15, 2019. 
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Localio AR, Margolis DJ, Berlin JA. Relative risks and confidence intervals were easily 
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