Pneumatic Vitreolysis with C₃F₈ for Vitreomacular Traction with and without Macular Hole: DRCR Retina Network Protocols AG and AH

Abstract

Objective:

To evaluate pneumatic vitreolysis (PVL) in eyes with vitreomacular traction (VMT) with and without full-thickness macular hole (FTMH).

Design:

Two multi-center (28 sites) studies: one randomized clinical trial comparing PVL with observation (sham injection) for VMT without FTMH (Protocol AG), and a single-arm study assessing PVL for closure of FTMH (Protocol AH).

Participants:

Participants were adults with central VMT in which the vitreomacular adhesion was 3000 μm or less. In AG, visual acuity (VA) was 20/32 to 20/400. In AH, eyes had FTMH (≤250 μm at the narrowest point) and VA of 20/25 to 20/400.

Intervention:

PVL using C₃F₈ gas.

Main Outcome Measures:

Central VMT release without rescue treatment at 24 weeks (AG). FTMH closure without rescue treatment at 8 weeks (AH).

Results:

From October 2018 to February 2020, 46 participants were enrolled in AG and 35 eligible participants were enrolled in AH. Higher than expected rates of retinal detachments and tears resulted in early termination of both protocols. Combining studies, 7 of 59 (12% [95% CI, 6%–23%]; 2 in AG, 5 in AH) eyes that received PVL developed rhegmatogenous retinal detachment (6) or retinal tear (1). At 24 weeks in AG, 18 of 23 eyes in the PVL group (78%) versus 2 of 22 eyes in the sham group (9%) had central VMT release without rescue vitrectomy (adjusted risk difference = 66% [95% CI, 44%–88%], P < .001). The mean change in VA letter score from baseline at 24 weeks in AG was 6.7 in the PVL group and 6.1 in the sham group (adjusted difference = −0.8 [95% CI, −6.1 to 4.5], P=.77; negative values indicate greater improvement in sham group). In AH,10 of 35 eyes (29% [95% CI, 16%–45%]) had FTMH closure without rescue vitrectomy at 8 weeks. The mean change in VA from baseline at 8 weeks in AH was −1.5 letters (95% CI, −10.3 to 7.3).

Conclusions:

In most eyes with VMT, PVL induced hyaloid release. In eyes with FTMH, PVL resulted in hole closure in approximately one third of eyes. These studies were terminated early because of safety concerns related to retinal detachments and retinal tears.

Trial Registration:

Clinical Trials.gov Identifier: NCT03677869, NCT03647267

Précis:

Pneumatic vitreolysis induced hyaloid release in most eyes with vitreomacular traction and closure of full-thickness macular hole in approximately one-third. These studies were terminated early because of safety concerns related to retinal detachments and tears.

Introduction

Disorders of the vitreoretinal interface represent a spectrum of abnormalities that develop as the posterior hyaloid separates from the internal limiting membrane. Vitreomacular adhesion occurs when the posterior hyaloid remains attached to the internal limiting membrane centrally. Vitreomacular traction (VMT) occurs when vitreomacular adhesion results in tractional distortion of macular architecture with symptomatology,¹ such as decreased central visual acuity (VA) or metamorphopsia. Progression of VMT can lead to a macular hole (MH), in which tractional forces create a full-thickness macular defect with vision loss, frequently requiring surgical intervention.¹

Treatments for VMT include observation, vitrectomy, and intraocular injection of ocriplasmin. Observation is often recommended because spontaneous resolution occurs in 10% to 30% of cases.^2–10 Vitrectomy may be recommended for severe cases but is costly and carries the risk of cataract progression, retinal detachment, and endophthalmitis. Ocriplasmin results in VMT release in 24% to 45% of cases but is rarely used due to risk of sight-threatening complications and high cost.^{4,7,8,11–19}

Vitrectomy with fluid/gas exchange is first-line treatment for most full-thickness MHs as hole closure rates approach 80% to 100%.^20–25 Disadvantages of vitrectomy include high cost, patient discomfort, the need for face-down positioning, and risk of cataract progression, retinal detachment, and endophthalmitis. Ocriplasmin results in macular hole closure in approximately 60% of cases but is infrequently used due to its cost and risk of sight-threatening complications.^13–18

Pneumatic vitreolysis is an in-office intraocular injection of an expansile gas to induce release of VMT. In 1995, Chan et al. reported VMT release after PVL using C₃F₈ gas in 95% of eyes and closure of small stage 2 macular holes by release of VMT in 50% of eyes.²⁶ Subsequent retrospective case series have reported rates of hole closure ranging from 60% to 100%.^26–30 Risks include but are not limited to retinal tear, retinal detachment, endophthalmitis, and cataract. To date, no randomized clinical trials have evaluated PVL. If safe and effective, PVL would be a less invasive, lower-cost alternative to vitrectomy.

We conducted two multi-center clinical studies to evaluate the safety and efficacy of PVL for symptomatic VMT without (Protocol AG, eFigure 1) a macular hole and with a macular hole (Protocol AH, eFigure 2).

Methods

The DRCR Retina Network conducted a randomized clinical trial (Protocol AG; ClinicalTrials.gov identifier: NCT03647267) to evaluate PVL with C₃F₈ gas injection versus sham injection for treatment of vitreomacular traction without MH and a single-arm, prospective, observational study (Protocol AH ClinicalTrials.gov identifier: NCT03677869) to estimate the rate of MH closure following PVL with C₃F₈ gas injection at 28 sites. The studies adhered to the tenets of the declaration of Helsinki and were approved by a central institutional review board. Study participants provided written informed consent. The first participants were enrolled on 16 October 2018 for AG and 14 November 2018 for AH. An independent data and safety monitoring committee (DSMC) provided oversight and recommended halting enrollment into both studies on 11 February 2020 after review of the combined data from Protocols AG and AH on the incidence of rhegmatogenous retinal detachments and retinal tears. Follow-up visits continued for enrolled participants and ended on 6 August 2020 for AG and 22 July 2020 for AH; results of both protocols are presented with combined safety data.

Protocol AG: Randomized Clinical Trial Assessing the Effects of Pneumatic Vitreolysis on Vitreomacular Traction

Methods

Participants were at least 18 years old, had central VMT in which the vitreomacular adhesion was 3000 μm or less, no macular or lamellar hole, and Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) VA score 78 to 24 letters (Snellen equivalent 20/32 to 20/400). Presence of VMT was confirmed on optical coherence tomography (OCT) by the Duke Reading Center, Durham, NC. Participants were required to avoid high altitude travel and, if phakic, avoid supine positioning until gas resolution. Prior intraocular injection and vitrectomy were exclusionary. One eye per participant was enrolled.

Randomization schedules were generated by the study statistician using computer-generated random numbers and had a permuted block design (random block sizes of 2 and 4) stratified by site and presence of epiretinal membrane in the central subfield. Study eyes were randomly assigned 1:1 to either PVL or sham injection. Treatment assignments were obtained by clinical personnel on the study website.

Treatment was given on the day of randomization. Follow-up visits occurred at 1, 4, 12, and 24 weeks. At each visit, investigators performed a dilated eye exam and certified technicians obtained spectral-domain OCT scans and E-ETDRS VA following protocol refraction. Shape discrimination hyperacuity was measured using myVisionTrack (Genentech)³¹ at randomization, 12, and 24 weeks. Participants and technicians were masked to treatment assignment, but investigators were not.

Investigators, who had experience with 10 or more intraocular gas injections, were required to use topical anesthetic, povidone iodine, and a lid speculum for PVL and sham injections. For PVL, 0.3 mL of C₃F₈ was injected into the vitreous with a 30-gauge or smaller needle. For sham injections, the hub of a needleless syringe was pressed against the conjunctival surface to simulate the pressure of an injection. Paracentesis was optional. Investigators used indirect ophthalmoscopy or a VA check to assess for complications.

Vitrectomy was permitted after 1 week if VA decreased from baseline (≥10 letters at a single visit or at least 5 letters at two consecutive visits) due to vitreomacular complications and at any time for conditions requiring prompt treatment.

Outcomes and Statistical Analysis

The primary outcome was the proportion of eyes with central VMT release on OCT at 24 weeks without rescue vitrectomy. A sample size of 124 was calculated assuming outcome rates of 30% in the sham group and 60% in the C₃F₈ group, 80% power, 5% type 1 error, and 10% loss to follow-up.

Time to central VMT release without vitrectomy, the proportion of eyes receiving vitrectomy, mean VA change from baseline, and the proportions of eyes gaining or losing 10 or more letters of VA from baseline at 24 weeks were prespecified secondary outcomes. Mean shape discrimination hyperacuity change from baseline and the proportion of eyes without ellipsoid zone integrity (i.e., sections of the ellipsoid zone are missing; graded by central reading center) at 24 weeks were prespecified exploratory outcomes. Safety outcomes included endophthalmitis, retinal tear, retinal detachment, MH development, traumatic cataract, cataract extraction, vitreous hemorrhage, and intraocular pressure (IOP) events.

In general, binary outcomes were analyzed with logistic regression, continuous outcomes with linear regression, and time-to-event outcomes with proportional hazards regression. Models for VA, hyperacuity, and ellipsoid zone integrity included the baseline value as a covariate. For time-to-event outcomes, cumulative probabilities were estimated via the Kaplan-Meier method.³² In logistic regression models, risk difference was estimated using conditional standardization and the delta method.³³ Missing VA or missing central VMT data were imputed by Markov chain Monte Carlo multiple imputation. P<.05 was considered statistically significant. Analyses were conducted with SAS version 9.4 (SAS Institute, Cary, NC).

Results

Study Participants

Forty-six participants, 37% of the recruitment goal of 124, were randomly assigned to PVL (24) or sham (22) (Figure 1A). At baseline, mean (SD) age was 72 (9) years and 31 (67%) were female (Table 1). Among study eyes, mean (SD) VA letter score was 68.5 (9.4) (Snellen equivalent 20/50), 3 (7%) had an epiretinal membrane in the central subfield, and median length of vitreomacular adhesion in the central subfield was 502 μm (interquartile range 348–682 μm). Baseline VA letter score, epiretinal membrane, and vitreomacular adhesion length were balanced between groups. Twenty-three participants (96%) in the PVL group and 22 (100%) in the sham group completed the 24-week visit.

Figure 1. Study Flow Diagram.

A. Randomization and participant flow in Protocol AG. Participants were not formally screened before obtaining informed consent. Reasons for ineligibility were not systematically collected. Visit completion at 24 weeks was prespecified as completion of any study visit from 18 to 40 weeks. B. Enrollment and participant flow in Protocol AH. Participants were not formally screened before obtaining informed consent. Reasons for ineligibility were not systematically collected. Visit completion at 24 weeks was prespecified as completion of any study visit from 18 to 40 weeks. ^a One eye that did not have full-thickness macular hole was enrolled, received PVL, and completed the 24-week visit but is not included in any analyses or subsequent levels in the flowchart PVL = pneumatic vitreolysis

Table 1.

Baseline Characteristics in Protocol AG and Protocol AH

Characteristic	Protocol AG		Protocol AH
	PVL (n=24)	Sham (n=22)	PVL (n=35)
Participant Characteristics
Age, y, mean (SD)	70 (10)	75 (8)	69 (9)
Sex, No. (%)
Female	15 (63)	16 (73)	24 (69)
Male	9 (38)	6 (27)	11 (31)
Race/Ethnicity, No. (%)
White (non-Hispanic)	16 (67)	17 (77)	27 (77)
Hispanic or Latino	4 (17)	5 (23)	5 (14)
Black/African American (non-Hispanic)	3 (13)	0	3 (9)
Unknown or not reported	1 (4)	0	0
Diabetes, No. (%)
No	16 (67)	12 (55)	27 (77)
Type 2	8 (33)	10 (45)	8 (23)
Ocular Characteristics
Visual acuity letter score
Mean (SD)	67.8 (10.3)	69.2 (8.4)	55.8 (14.0)
Mean Snellen equivalent	20/50	20/40	20/80
20/25 or better (79 letters or greater), No. (%)	0	0	2 (6)
20/32 to 20/40 (78 to 69 letters), No. (%)	15 (63)	16 (73)	2 (6)
20/50 to 20/80 (68 to 54 letters), No. (%)	6 (25)	4 (18)	20 (57)
20/100 to 20/160 (53 to 39 letters), No. (%)	3 (13)	2 (9)	6 (17)
20/200 to 20/400 (38 to 19 letters), No. (%)	0	0	5 (14)
Shape discrimination hyperacuity, logMAR
Mean (SD)	0.32 (0.27)	0.38 (0.27)	NA
Mean Snellen equivalent	20/40	20/50	NA
Intraocular pressure, mean (SD)	15 (4)	14 (3)	16 (3)
Lens status, No. (%)
Phakic	14 (58)	9 (41)	28 (80)
Posterior chamber intraocular lens	10 (42)	13 (59)	7 (20)
Lattice degeneration, No. (%)	2 (8)	0	3 (9)
Prior treatment for retinal tear, No. (%)	0	0	0
Atrophic retinal hole, No. (%)	0	0	0
Epiretinal membrane in central subfield (randomization stratification factor), No. (%)a	2 (8)	1 (5)	1 (3)
Width of vitreomacular attachment that extends within the central subfield, μm, median (IQR), No. (%)a	480 (315 to 694)	503 (427 to 646)	325 (185 to 496)b
Macular hole width at narrowest point, μm, median (IQR)a	NA	NA	79 (39 to 111)
Vitreopapillary traction at the optic nerve, No. (%)a	2 (8)	3 (14)	0
Loss of ellipsoid zone integrity in central subfield, No. (%)a	15 (63)	8 (36)	35 (100)
Loss of ellipsoid zone integrity in foveal center, No. (%)a	11 (46)	8 (36)	35 (100)

IQR = interquartile range; logMAR = logarithm of the minimum angle of resolution; NA = not applicable; PVL = pneumatic vitreolysis; SD = standard deviation.

^aGraded by central reading center.

^bUnavailable for 1 eye in which vitreomacular traction did not extend into the central subfield.

Central Vitreomacular Traction Release and Rescue Vitrectomy

At 24 weeks, the number of eyes with central VMT release without rescue vitrectomy (primary outcome) in the PVL group was 18 of 23 (78%) versus 2 of 22 (9%) in the sham group (adjusted risk difference = 66% [95% CI, 44% to 88%], P < .001) (Table 2, Figure 2). Rescue vitrectomy was performed before central VMT release in 1 of 23 eyes (4%) in the PVL group (to treat macular hole) and 0 of 22 eyes in the sham group (risk difference = 4% [95% CI, −4% to 13%], P = .31). Two eyes in the PVL group underwent vitrectomy after VMT release to treat retinal detachment. Tabulations of the primary outcome by baseline characteristics are shown in eTable 1; however, the small sample size precluded subgroup analyses.

Table 2.

Primary, Secondary, and Exploratory Efficacy Outcomes at 24 Weeks in Protocol AG

Outcome	PVL (n=23)	Sham (n=22)	Difference, % (95% CI)a	P a
Primary outcome
Proportion of eyes with central VMT release without rescue vitrectomy, No. %	18 (78)	2 (9)	66 (44 to 88)	<.001
Secondary outcomes
Rescue vitrectomy before the 24-week visit, No. (%)	1 (4)	0	4 (−4 to 13)	.31
Rescue vitrectomy before 24 weeks or planned at the 24-week visit, No. (%)	1 (4)	1 (5)	NA	NA
Central VMT status, No. %
Released without rescue vitrectomy	18 (78)	2 (9)	NA	NA
Released with rescue vitrectomy	1 (4)	0	NA	NA
Not released and no rescue vitrectomy	4 (17)	20 (91)	NA	NA
Not released despite rescue vitrectomy	0	0	NA	NA
Visual acuity letter score
Mean (SD)	73.0 (16.4)	75.3 (6.1)	NA	NA
Mean Snellen equivalent	20/40	20/32	NA	NA
Visual acuity letter score change from baselinec
Mean (SD)	6.7 (12.4)	6.1 (9.6)	−0.8 (−6.1 to 4.5)	.77
≥10-letter gain, No. (%)	8 (35)	7 (32)	−10 (−48 to 29)	.63
≥10-letter loss, No. (%)	1 (4)d	0	4 (−11 to 21)e	.53e
Exploratory outcomes
Shape discrimination hyperacuity, logMAR, mean (SD)b	0.16 (0.23) [n=19]	0.30 (0.27) [n=21]	NA	NA
Mean Snellen equivalentb	20/32 [n=19]	20/50 [n=21]	NA	NA
Change in shape discrimination hyperacuity from baseline, logMAR, mean (SD)b	−0.12 (0.22) [n=19]	−0.06 (0.20) [n=21]	−0.09 (−0.21 to 0.02)	.12
Loss of ellipsoid zone integrity in central subfield, No. (%)c	6 (27) [n=22]	11 (50)	−52 (−91 to −13)	.009
Loss of ellipsoid zone integrity in foveal center, No. (%)c	4 (18) [n=22]	8 (36)	−22 (−50 to 5)	.10

logMAR = logarithm of the minimum angle of resolution; NA = not analyzed; PVL = pneumatic vitreolysis; SD = standard deviation.

^aFor the primary outcome and secondary visual acuity outcomes, missing data were imputed by Markov chain Monte Carlo multiple imputation with 100 imputations. Outcomes related to visual acuity, shape discrimination hyperacuity, and loss of ellipsoid zone integrity were adjusted for baseline visual acuity, shape discrimination hyperacuity, and ellipsoid zone integrity, respectively. The difference column is the difference between the PVL and sham groups; positive differences indicate a larger value in the PVL group and negative values indicate a larger value in the sham group. Summary statistics and sample size are based on participants completing the 24-week visit without imputation of missing data.

^bLower values indicate better hyperacuity.

^cPer the statistical analysis plan, values lower than 3 standard deviations above or below the overall mean were truncated. This applied to one eye in the PVL group that had loss of 65 letters, which was truncated at −36.2 letters (3 standard deviations below the overall mean).

^dReason for vision loss was cataract.

^eDue to event rate of 0% in the Sham group, the risk difference was calculated using the Newcombe method^41,42 and the P value was calculated using Barnard’s exact unconditional test without imputation of missing data.

Figure 2. Time to central vitreomacular traction release without rescue vitrectomy through 24 weeks by treatment group in Protocol AG.

The cumulative probability of central vitreomacular traction release without rescue vitrectomy at 24 weeks was 76% (95% CI, 57%–90%) in the PVL group and 9% (95% CI, 2%–32%) in the sham group (hazard ratio = 19.06 [95% CI, 4.64–78.30], P<.001). PVL = pneumatic vitreolysis.

Secondary Outcomes – Visual Acuity

The mean (SD) VA letter score change from baseline at 24 weeks was 6.7 (12.4) in the PVL group (N=23) and 6.1 (9.6) in the sham group (N=22) (adjusted difference = −0.8 [95% CI, −6.1 to 4.5], P = .77; negative values indicate greater improvement in sham group after adjustment for baseline visual acuity) (Table 2, Figure 3, and eFigure 3); 8 eyes (35%) in the PVL group and 7 eyes (32%) in the sham group gained 10 or more letters (adjusted risk difference = −10% [95% CI, −48% to 29%], P = .63); 1 eye (4%) in the PVL group and zero in the sham group lost 10 or more letters (risk difference = 4% [95% CI, −11% to 21%], P = .53).

Figure 3. Visual acuity and change in visual acuity through 24 weeks by treatment group in Protocol AG.

The top panel shows visual acuity letter score and the bottom panel shows visual acuity letter score change from baseline. Orange circles and blue squares represent the mean for the PVL and sham groups, respectively, and error bars represent 95% confidence intervals. The number of eyes contributing data at each visit is given below the plot. PVL = pneumatic vitreolysis

Exploratory Outcomes

The mean (SD) shape discrimination hyperacuity change from baseline at 24 weeks was −0.12 (0.22) logMAR in the PVL group (N=19) and −0.06 (0.20) logMAR in the sham group (N=21) (adjusted mean difference = −0.09 [95% CI, −0.21 to 0.02], P = .12) (Table 2 and eFigure 4). There was loss of ellipsoid zone integrity in the central subfield at 24 weeks in 6 of 22 eyes in the PVL group (27%) and 11 of 22 eyes in the sham group (50%) (adjusted difference = −52% [95% CI, −91% to −13%], P =.009).

Protocol AH: Single-Arm Study Assessing the Effects of Pneumatic Vitreolysis on Macular Hole

Methods

Participants were at least 18 years of age, had central VMT in which the vitreomacular adhesion was 3000 μm or less, full-thickness macular hole of 250 μm or less at the narrowest point, and E-ETDRS VA score of 78 to 19 letters (Snellen equivalent 20/25 to 20/400). Presence of VMT and MH were confirmed on OCT by the reading center. Participants had to avoid high-altitude travel and, if phakic, avoid supine positioning until gas resolution. Prior intraocular injection and vitrectomy were exclusionary. One eye per participant was enrolled.

Treatment was given at enrollment. Follow-up visits occurred at 1, 4, 8, and 24 weeks. At each visit, investigators performed a dilated eye exam and certified technicians obtained OCT and E-ETDRS VA following protocol refraction.

The gas injection procedure was identical to Protocol AG. Participants were required to position face-down for 50% of the time for at least four days following the injection. Rescue vitrectomy was permitted between 4 and 8 weeks if the size of the MH did not improve following PVL; thereafter, vitrectomy could be performed at investigator discretion. Vitrectomy was permitted at any time for a condition requiring prompt intervention.

Outcomes and Statistical Analysis

The primary outcome was the proportion of eyes with MH closure of the inner retinal layers at 8 weeks without rescue vitrectomy. The sample size of 50 was chosen for convenience. Time to MH closure without vitrectomy, time to central VMT release without vitrectomy, proportion of eyes receiving vitrectomy, mean VA change from baseline, and the proportions of eyes gaining or losing 10 or more letters of VA from baseline at 8 and 24 weeks were prespecified secondary outcomes. The proportion of eyes with MH closure of the inner retinal layers with outer retinal lucency without vitrectomy and the proportion of eyes without ellipsoid zone integrity, as determined by the reading center, at 8 and 24 weeks were prespecified exploratory outcomes. Key safety outcomes were the same as Protocol AG except progression to macular hole.

Confidence intervals for proportions were estimated with the Wilson method.^34,35 Missing MH and VA data were imputed by Markov chain Monte Carlo multiple imputation.

Results

Study Participants

Thirty-five eligible participants were enrolled (Figure 1B). Mean (SD) age was 69 (9) years and 24 (69%) were female (Table 1). Among study eyes, mean (SD) VA letter score was 55.8 (14.0) (Snellen equivalent 20/80), 1 (3%) had an epiretinal membrane in the central subfield, and median MH width at the narrowest point was 79 μm (interquartile range 39–111 μm). All 35 participants (100%) completed the 8-week visit and 34 (97%) completed the 24-week visit.

Macular Hole Closure and Rescue Vitrectomy

At 8 weeks, MH closure of the inner retinal layers without rescue vitrectomy (primary outcome) occurred in 10 of 35 eyes (29%, 95% CI, 16%–45%); rescue vitrectomy was performed in 12 eyes (34%, 95% CI, 21%–51%) and was successful in 10 (Table 3). Through 24 weeks, MH closed without vitrectomy in 10 of 35 eyes (29%, 95% CI, 17%–47%) (Figure 4). Among eyes completing the 24-week visit, rescue vitrectomy was performed in 23 of 34 eyes (68%, 95% CI, 51%–81%); 1 eye that did not complete the 24-week visit had vitrectomy within 24 weeks of randomization. Primary indications for vitrectomy were MH (21 procedures in 20 eyes) and rhegmatogenous retinal detachment (5 procedures in 4 eyes). Subgroup analyses of the primary outcome are shown in eTable 2.

Table 3.

Primary, Secondary, and Exploratory Efficacy Outcomes at 8 and 24 weeks in Protocol AH

Outcome	PVLa	95% CIa
8 Weeks	n=35
Primary outcome
Proportion of eyes with macular hole closure of the inner retinal layers without rescue vitrectomy, No (%)	10 (29)	16 to 45
Secondary outcomes
Rescue vitrectomy before the 8-week visit, No (%)	12 (34)	21% to 51%
Macular hole status, No (%)
Macular hole closure without rescue vitrectomy	10 (29)	NA
Macular hole closure with rescue vitrectomy	10 (29)	NA
No macular hole closure and no rescue vitrectomy	13 (37)	NA
No macular hole closure despite rescue vitrectomy	2 (6)	NA
Visual acuity letter score		NA
Mean (SD)	54.2 (23.8)	NA
Mean Snellen equivalent	20/80	NA
Median (IQR)	61.0 (71.0 to 42.0)	NA
Median Snellen equivalent	20/63	NA
Change in visual acuity letter score from baseline
Mean (SD)	−1.5 (25.6)	−10.3 to 7.3
Median (IQR)	3.0 (−9.0 to 13.0)	NA
≥10-letter gain, No (%)	12 (34)	21% to 51%
≥10-letter loss, No (%)	8 (23)	12% to 39%
Exploratory outcomes
Macular hole closure of the inner retinal layers with outer retinal lucency without rescue vitrectomy, No (%)	4 (13) [n=31]bc	5% to 29%
Loss of ellipsoid zone integrity in central subfield, No (%)	29 (94) [n=31]bc	79% to 98%
Loss of ellipsoid zone integrity in foveal center, No (%)	28 (88) [n=32]b	72% to 95%
24 Weeks	n=34
Secondary outcomes
Rescue vitrectomy before the 24-week visit, No (%)d	23 (68)	51 to 81
Rescue vitrectomy before or planned at the 24-week visit, No (%)	24 (71)	NA
Macular hole status, No (%)
Macular hole closure without rescue vitrectomy	10 (29)	NA
Macular hole closure with rescue vitrectomy	22 (65)	NA
No macular hole closure and no rescue vitrectomy	1 (3)	NA
No macular hole closure despite rescue vitrectomy	1 (3)	NA
Visual acuity letter score
Mean (SD)	66.0 (16.5)	NA
Mean Snellen equivalent	20/50	NA
Median (IQR)	68.0 (76.0 to 56.0)	NA
Median Snellen equivalent	20/50	NA
Change in visual acuity letter score from baseline
Mean (SD)	9.2 (14.5)	4.2 to 14.3
Median (IQR)	10.0 (3.0 to 15.0)	NA
≥10-letter gain, No (%)	18 (53)	37% to 69%
≥10-letter loss, No (%)	3 (9)e	3% to 22%
Exploratory outcomes
Macular hole closure of the inner retinal layers with outer retinal lucency without rescue vitrectomy, No (%)	6 (18)	8% to 34%
Loss of ellipsoid zone integrity in central subfield, No (%)	25 (74)	57% to 85%
Loss of ellipsoid zone integrity in foveal center, No (%)	18 (53)	37% to 69%

IQR = interquartile range; NA = not analyzed; PVL = pneumatic vitreolysis; SD = standard deviation.

^aSummary statistics include participants completing the corresponding visit without imputation of missing data. For secondary visual acuity outcomes, missing data were imputed by Markov chain Monte Carlo multiple imputation (100 imputations).

^bOCT not done in 3 cases; 2 had no view due to retinal detachment, 1 had recent vitrectomy for macular hole.

^cOCT ungradable in 1 case.

^dOne eye that missed the 24-week visit underwent vitrectomy for macular hole within 24 weeks of randomization.

^eReasons for vision loss were retinal detachment, post-op after vitrectomy to repair macular hole, and unknown.

Figure 4. Time to macular hole closure without rescue vitrectomy through 24 weeks in Protocol AH.

The cumulative probability of macular hole closure without rescue vitrectomy through 24 weeks was 29% (95% CI, 17%–47%). PVL = pneumatic vitreolysis.

Secondary Outcomes

Through 24 weeks, central VMT released without vitrectomy in 33 of 35 eyes (94%, 95% CI, 83%–99%) (Figure 5). Among 35 eyes at 8 weeks, the mean VA letter score change from baseline was −1.5 (95% CI, −10.3 to 7.3), 12 eyes (34%, 95% CI, 21%–51%) gained 10 or more letters, and 8 eyes (23%, 95% CI, 12%–39%) lost 10 or more letters (Table 3 and eFigure 5). Among 34 eyes at 24 weeks, the mean VA letter score change from baseline was 9.2 (95% CI, 4.2 to 14.3), 18 eyes (53%, 95% CI, 37%–69%) gained 10 or more letters, and 3 eyes (9%, 95% CI, 3%–23%) lost 10 or more letters.

Figure 5. Time to vitreomacular traction release without rescue vitrectomy through 24 weeks in Protocol AH.

The cumulative probability of central vitreomacular traction release without rescue vitrectomy through 24 weeks was 94% (95% CI, 83%–99%). PVL = pneumatic vitreolysis.

Exploratory Outcomes

MH inner retinal layers closed with a residual outer retinal lucency without rescue vitrectomy in 4 of 31 eyes (13%, 95% CI, 5%–29%) at 8 weeks and 6 of 34 eyes (18%, 95% CI, 8%–34%) at 24 weeks (Table 3). There was loss of ellipsoid zone integrity in the central subfield in 29 of 31 eyes (94%, 95% CI, 79%–98%) at 8 weeks and 25 of 34 eyes (74%, 95% CI, 57%–85%) at 24 weeks.

Combined Safety Findings from Both Protocols:

Considering all eyes that had PVL in either Protocol AG (24) or Protocol AH (35), 7 of 59 (12%, 95% CI, 6%–23%) had a rhegmatogenous retinal detachment or retinal tear (6 detachments and 1 tear without detachment), including 2 of 24 eyes in the PVL group in AG (8%) and 5 of 35 eyes in AH (14%); all were treated with vitrectomy (Table 4 and eTable 3). Rates of retinal detachment or tear by baseline factors in the PVL groups from Protocol AG and AH are shown in eTable 4. There were no cases of retinal detachment or tear in the sham group in AG. Among phakic eyes at baseline, cataract surgery was performed in 1 of 14 (7%) in the PVL group (for traumatic cataract due to the pre-injection paracentesis) and 0 of 9 in the sham group in AG and 2 of 28 (7%) in AH. No study eyes developed endophthalmitis. There were no deaths.

Table 4.

Safety Outcomes through 24 Weeks by Group in Protocols AG and AH

	Protocol AG			Protocol AH		Combined
Event	Pneumatic Vitreolysis (n = 24)	Sham (n = 22)	P Value	Pneumatic Vitreolysis (n = 35)	95% Confidence Interval	Pneumatic Vitreolysis (n = 59)	95% Confidence Interval
Ocular safety outcomes in study eyes
Endophthalmitis	0	0	NA	0	0–10	0	0–6
Retinal detachment or retinal tear	2 (8)*	0	NA	5 (14)*	6–29	7 (12)	6–23
Rhegmatogenous retinal detachment	2 (8)	0	0.22	4 (11)	5–26	6 (10)	5–20
Retinal tear without detachment	0	0	Undefined	1 (3)	1–15	1 (2)	0–9
Vitreous hemorrhage	1 (4)	0	0.51	1 (3)	1–15	2 (3)	1–12
Macular hole†	1 (4)*	1 (5)	0.51	NA	NA	NA	NA
Adverse intraocular pressure event	2 (8)‡	2 (9)‡	1.00	7 (20)‡	10–36	9 (15)	8–27
Intraocular pressure increase ≥ 10 mmHg from baseline	1 (4)	2 (9)	NA	2 (6)	NA	3 (5)	NA
Intraocular pressure ≥30 mmHg	0	0	NA	2 (6)	NA	2 (3)	NA
Initiation of medication to lower intraocular pressure	2 (8)	0	NA	7 (20)	NA	9 (15)	NA
Glaucoma procedure	0	0	NA	0	NA	0	NA
Traumatic cataract§	1 (7) (n = 14)‖	0 (n = 9)	NA	0 (n = 28)	0–12	1 (2) (n = 42)	0–12
Cataract extraction§	1 (7) (n = 14)	0 (n = 9)	0.56	2 (7) (n = 28)	2–23	3 (7) (n = 42)	2–19
Systemic safety outcomes
Death	0	0	Undefined	0	0–10	0	0–6
Serious systemic adverse event	1 (4)	0	0.51	4 (11)	5–26	5 (8)	4–18

NA = not analyzed

^*Treated with vitrectomy.

^†Detected on clinical examination or OTC.

^‡Paracentesis was performed before injection in the pneumatic vitreolysis groups, but not the sham group.

^§Limited to eyes that were phakic at baseline.

^‖Initially diagnosed as endophthalmitis, but later determined to be traumatic cataract caused by paracentesis.

Discussion

These studies showed that PVL was effective for inducing VMT release but less effective for closing MH and had higher than expected rates of retinal detachments and tears, which led to early discontinuation of the studies. The VMT release rate in Protocol AG was consistent with previous uncontrolled studies but there was no significant difference in central VA or shape discrimination hyperacuity between the PVL and sham groups at 24 weeks. The improved VA in sham eyes without macular hole in AG highlights the favorable natural history of VMT without MH. Regression to the mean may also explain visual acuity gains observed in sham eyes. In eyes without MH in AG, PVL resulted in greater rates of intact OCT ellipsoid zone compared with sham. In almost all eyes with macular hole, PVL resulted in hyaloid release, but the macular hole closed without vitrectomy only in 29%. This rate is disappointing compared with the nearly 80% to 100% hole closure rate of vitrectomy,^20–25 especially since our cohort consisted of small macular holes that almost always close with surgery.

Pneumatic vitreolysis was associated with more complications than expected when designing the study. After 62 participants enrolled in the two studies, the DSMC noted the rate of retinal tear or detachment was above the estimate in the informed consent form (1%), an estimate derived from studies of ocriplasmin for vitreomacular traction. The DSMC recommended suspension of enrollment and for the study group to review these cases, inform investigators, and revise the informed consent form.^4,8 The informed consent form and protocol were revised to include a retinal detachment incidence range of 5 to 13% based on prior PVL and pneumatic retinopexy studies. In the largest prior study of PVL for VMT with and without a MH, 4 of 80 eyes (5%) developed a retinal tear or detachment; in studies of pneumatic retinopexy to repair retinal detachment using C₃F₈ or SF₆ gas injection, the percentage of recurrent retinal detachment or new tears ranged from 15% to 23%.^36–40 After resumption of enrollment, additional retinal tears and detachments occurred bringing the combined total from both studies to 7 of the 59 eyes that received the gas injection (12%, 95% CI, 6%–23%), and the DSMC recommended termination of recruitment. It is unclear why the combined rate of retinal detachment and tear in AG and AH was higher than in previous studies of PVL for VMT.

Most of the retinal tears and detachments in these two studies occurred in eyes with macular holes (AH). While VMT and macular hole are considered part of the same spectrum of diseases caused by vitreomacular traction, they are clinically different entities. There could be a difference in risk for retinal detachment between these conditions and difference in indication for PVL. It is unknown if modifications to the injection procedure would have resulted in a lower risk for retinal detachment and tear. Anecdotal observations suggest that gas injection at the highest point of the globe and avoidance of “fish-egg” bubbles may reduce vitreoretinal complications. Despite the higher than expected rate of retinal tears and detachment, some patients and physicians may still consider PVL for the treatment of VMT and MH. This study is too small to make definitive statements as to whether PVL should be performed.

These studies have limitations. First, the planned sample sizes were not met due to early termination, and the original sample size calculations were based on anatomic, not visual, outcomes; thus, our power to detect modest differences between treatment groups (AG) and the precision of estimated rates (AH) were relatively low. Second, follow-up ended after 24 weeks, so data on long-term outcomes are unavailable.

Conclusion

In most eyes with VMT, PVL induced hyaloid release. In eyes with macular hole, PVL resulted in hole closure in approximately one third of eyes. These studies were terminated early because of safety concerns related to retinal detachments and retinal tears.

Collaborators

Network chairs, Coordinating Center Staff, Committee Members, and the Reading Center are all compensated for their work as members of the DRCR Retina Network.

DRCR Retina Network Coordinating Center Staff: Jaeb Center for Health Research, Tampa, FL (staff as of 2/24/2021): Adam R. Glassman, MS (Jaeb Center for Health Research Interim Executive Director and DRCR Retina Network Principal Investigator), Roy W. Beck, MD, PhD (Jaeb Center for Health Research President), Alyssa Baptista, BS, Wesley T. Beaulieu, PhD, Claire T. Calhoun, MS, Sharon R. Constantine, BS, Isabella Correia, BS, Brian B. Dale, Simone S. Dupre, BS, Sandra Galusic, MSPH, Meagan Huggins, BA, Brenda L. Hunter, BS, Paula A. Johnson, MPH, Kristen Josic, PhD, Brittany Kelly, MS, Danni Liu, MSPH, , Maureen G. Maguire, PhD, Michele Melia, ScM, Carin M. Preston, MPH, Cynthia R. Stockdale, MSPH, Katie Stutz, BS, Alice Zokruah, MS

Duke Reading Center Staff: Katrina Postell Winter, BS (Lead Reader), Garrett Thompson, MD (Reader), Dee Busian, BA (Reader), Glenn J. Jaffe, MD (Director of Grading), Adiel Mora, BA (Project Manager), Lucia Foster, MA (Project Manager Assistant), John Keifer McGugan, BS (Project Manager Assistant)

DRCR Retina Network Chair: Jennifer K. Sun, MD, MPH (Joslin Diabetes Center, Beetham Eye Institute, Harvard Department of Ophthalmology) (2018-present), Daniel F. Martin, MD (Cole Eye Institute at Cleveland Clinic) (2018-Present)

DRCR Retina Network Vice Chairs: Carl W. Baker, MD (Paducah Retinal Center) (2011–2013, 2017–2019), Chirag Jhaveri, MD (Retina Consultants of Austin) (2016–2018), Mathew MacCumber, MD, PhD (Rush University Medical Center) (2018–2020), Andrew Antoszyk, MD (Charlotte Eye Ear Nose & Throat Associates, PA) (2013–2016, 2020)

National Eye Institute: Sangeeta Bhargava, PhD (2016-current) Eleanor Schron, PhD (2009–2015)

Executive Committee: Executive Committee: Andrew N. Antoszyk, MD (Charlotte Eye Ear Nose & Throat Associates, PA (2009; 2013-present), Darrell Baskin, MD (2021- Present) (San Antonio, TX Retinal Consultants of San Antonio), Roy W. Beck, MD, PhD (Jaeb Center for Health Research) (2002-present), Sangeeta Bhargava, PhD (NEI/NIH) (2016-present), Emily Chew Frederick L. Ferris III, MD (Ophthalmic Research Consultants) (2002-present), Adam R. Glassman, MS (Jaeb Center for Health Research) (2005-present), Glenn J. Jaffe, MD (Duke Reading Center) (2012-present), Lee M. Jampol, MD (Feinberg School of Medicine, Northwestern University) (2012-present), Chirag D. Jhaveri, MD (Retina Consultants of Austin) (2016-present), Mathew MacCumber, MD, PhD (Rush University Medical Center) (2018-Present), Daniel F. Martin, MD (Cole Eye Institute at Cleveland Clinic) (2017-present), Raj K. Maturi, MD (Raj K Maturi, MD, PC) (2009–2011, 2013-present), Sharon D. Solomon, MD (Baltimore, MD Wilmer Eye Institute at Johns Hopkins) (2021- present), Jennifer K. Sun, MD, MPH (Joslin Diabetes Center, Beetham Eye Institute, Harvard Department of Ophthalmology) (2009-present). Prior Members: Lloyd Paul Aiello, MD, PhD (Beetham Eye Institute, Joslin Diabetes Center, Harvard Medical School) (2002–2018; Chair 2002 – 2005), Carl W. Baker, MD (Paducah Retinal Center) (2009–2019)Barbra Blodi, MD (University of Wisconsin-Madison) (2014–2020), Neil M. Bressler, MD (Department of Ophthalmology, Johns Hopkins University School of Medicine) (2006–2019; Chair 2006–2008), Susan B. Bressler, MD (Wilmer Eye Institute) (2009–2019), Michael J. Elman, MD (Elman Retina Group, PA) (2006–2018; Chair 2009 and 2012), Judy E. Kim, MD (Medical College or Wisconsin) (2020, 2015–2017), Brandon Lujan, MD (Casey Eye Center) (2017–2020), Dennis M. Marcus, MD (Southeast Retina Center, PC) (2011–2012, 2018–2020),.

Data and Safety Monitoring Committee: Gary Abrams, MD (Kresge Eye Institute), Deborah R. Barnbaum, PhD (Kent State University), Harry Flynn, MD (Bascom Palmer Eye Institute), Kyle D. Rudser, PhD (University of Minnesota), Paul Sternberg, Jr., MD (Vanderbilt Eye Institute), Sangeeta Bhargava, PhD (NEI/NIH), Ruth S. Weinstock, MD, PhD (SUNY Upstate Medical University), Stephen Wisniewski, PhD (University of Pittsburgh), John Connett, PhD (University of Minnesota) (Chair, 2003–2015), Charles P. Wilkinson, MD (Greater Baltimore Medical Center) (2012–2018).

DRCR Retina Network clinical sites that participated on this protocol: Sites are listed in order by number of subjects enrolled into the study. The number of subjects enrolled is noted in parenthesis preceded by the site location and the site name. Personnel are listed as (I) for Study Investigator, (C) for Coordinator, (V) Visual Acuity Technician, and (P) for Photographer

DRCR Retina Network clinical sites that participated on this protocol: Sites are listed in order by number of subjects enrolled into the study. The number of subjects enrolled is noted in parenthesis preceded by the site location and the site name. Personnel are listed as (I) for Study Investigator, (C) for Coordinator, (V) Visual Acuity Technician, and (P) for Photographer

HUNTINGTON BEACH, CA Salehi Retina Institute Inc. AG (8) AH (4)

Hani Salehi-Had, MD(I); Evelyn Ceja(C); Stephanie Ramirez (C,V); Sara Ahmed, BS(C); Mailan Tran, OD(V); Scott F. Lee, OD(V); Undariya Boldbaatar(P); Janet Reyes(P)

Palm Desert, CA Southern California Desert Retina Consultants, Inc. AG (5) AH (3)

Clement K. Chan, MD, FACS(I); Steven G Lin, MD(I); Tiana Gonzales(C); Tonya M Gieser(C); Isela Aldana (C,V); Lenise E. Myers, COA(V); Kristina Pettit(P); Kenneth M. Huff, COA(P)

Indianapolis, IN Raj K. Maturi, M.D., P.C. AG (5) AH (1)

Raj K. Maturi, MD(I); Stephen J Saxe(I); Lorraine White (C,P,V); Ashley M. Harless(C); Myra K Retrum(V); Carolee K. Novak, CRC(V); Holly Fiscus(P); Yesenia Sarmiento(P)

OAKLAND, CA East Bay Retina Consultants, Inc. AG (3) AH (3)

Soraya Rofagha, MD, MPH(I); Jesse J. Jung, MD(I); Maria Zamora(C); Heidi A. Winje (C,P); Mae Kwan(V); Denise Joy Bustamante(V)

Oak Park, IL Illinois Retina Associates SC – Oak Park Site AG (1) AH (4)

Mathew W. MacCumber, MD, PhD(I); Pauline Merrill, MD(I); Ana Maria Merchan(C); Sara E. Montgomery(C); Annie Hernandez(V); Cristal Cardoza(P); Karen Parque(P)

Baltimore, MD Elman Retina Group, P.A. AG (2) AH (2)

Michael J. Elman, MD(I); Sidney A. Schechet, MD(I); JoAnn Starr(C); Kate N Kreis(C); Katherine L Wentz(V); Pamela V. Singletary, C.O.A.(V); Dallas R. Sandler(V); Christine Ringrose(V); Amy Thompson(V); Terri Cain(P); Peter Sotirakos(P); Ashley M. Metzger(P)

Overland Park, KS Mid-America Retina Consultants, P.A. AG (3) AH (1)

William N. Rosenthal, MD(I); Elizabeth N. Heim, BSN, RN(C); Sarah N. Lamaster, RN, BSN(C); Courtney J Dunn(P); Mary C Stewart, RN(P)

PADUCAH, KY The Ophthalmology Group, LLC AG (3) AH (1)

Carl W. Baker, MD(I); Jil D Baker, MT, ASCP(C); Mary J. Sharp, COA(V); Margaret J. Orr, COA(V); Kylie S. Sedberry(P); Sonya L Alcaraz(P); Alecia B. Camp(P)

San Antonio, TX Retinal Consultants of San Antonio AG (2) AH (2)

Calvin E. Mein, MD(I); Moises A. Chica, MD(I); Darrell E. Baskin, MD(I); Richard Gary Lane, MD(I); Lydia Adams(C); Vanessa D Martinez(C); Sara L Cloudt(C); Jonathan San Roman(V); Samantha Bankston(P); Brenda Nakoski(P); Jorge Castellanos(P); Christopher Sean Wienecke(P)

SANDY SPRINGS, GA Thomas Eye Group AG (4)

Paul L. Kaufman, MD(I); Kathy T. Wynne, BS, COT (C,V); Cynthia Weaver, COT(V)

BLOOMINGTON, IL Gailey Eye Clinic AH (3)

Sumit P. Bhatia, MD(I); Sara L. Ditchen, BS, CCRC(C); Andrea L Neal, COA(C)

Augusta, GA Southeast Retina Center, P.C. AG (1) AH (1)

Dennis M. Marcus, MD(I); Siobhan O. Ortiz(C); Thomas Bailey(V); Ken Ivey, COA(P)

Charlotte, NC Charlotte Eye Ear Nose and Throat Associates, PA. AG (1) AH (1)

David Browning, MD, PhD(I); Andrew N. Antoszyk, MD(I); Angela K. Price, MPH(C); Brittany A Murphy, BA, COT (C,V); Angella K. Gentile(V); Sarah A. Ennis(V); Christina Mutch(V); Loraine M. Clark, COA(P); Donna McClain, COA(P); Uma M. Balasubramaniam(P)

GRAND RAPIDS, MI Foundation for Vision Research and Retina Specialists of Michigan, P.C. AG (1) AH (1)

Scott J. Westhouse, DO(I); Thomas M. Aaberg, MD(I); Nathan F. Pezda, MD(I); Kristyn Jae Fredrick(C); Holly L. Vincent, COA(C); Shymaa Mohamed(P); Olivia P Rainey, BFA(P)

San Antonio, TX Medical Center Ophthalmology Associates AG (2)

Michael A. Singer, MD(I); Darren J. Bell, MD(I); Catherine Ellis, BS(C); Matthew R Casarez(C); Melissa Dominguez (C,P); Roxanne Gomez(V); Connie Bermea(V); Felicia Huron(P); Muayad Maallah(P); Rosa Escobar(P)

Syracuse, NY Retina-Vitreous Surgeons of Central NY, PC AH (2)

Kevin I. Rosenberg, MD(I); Laurie J. Sienkiewycz(C); Christine M. Dorr(C); Lisa Spuches(V); Lynn M. Kwasniewski(V); Abigail Miller(P); Stefanie R. DeSantis, BS(P); Jeffrey P Barker(P)

Asheville, NC Western Carolina Clinical Research, LLC AG (1)

Cameron McLure Stone, MD(I); Andrea K. Menzel, COA(C); Donna Machen(V); Lisa H. Hawkins, COA(P); Melissa Smith(P); Paula A. Price, COT(P)

Austin, TX Retina Research Center AH (1)

Chirag D. Jhaveri, MD(I); Saradha Chexal, MD(I); Daniela Mariel Wilson(C); Daniela Vega Pereira(C); Valerie Gatavaski(V); Yong Ren(P)

AYER, MA Valley Eye Physicians and Surgeons AG (1)

Gisela Velez, MD, MPH, MA(I); Oksana Mykhaylyk (C,V); Michael D. Ortega, CMA(P); Nicholas R Mastrodomenico(V); Chandapilla C. Pallipeedikayil(P); Daniel Tedstone(P)

CHATTANOOGA, TN Southeastern Retina Associates AH (1)

Richard I. Breazeale, MD(I); Francis C. DeCroos, MD(I); Steve W. McBee, Jr.(C); Courtney Duncan(V); Kate Menefee(V); David Woods, CRA, COA, CST(P)

EDMOND, OK Retina Vitreous Center AG (1)

Sandeep N. Shah, MD(I); Amy L West, BS(C); Kellie Meiwes, COA(P)

Fort Myers, FL National Ophthalmic Research Institute AG (1)

A. Thomas Ghuman, MD(I); Katrina A. Mears, MD, MSc, MRCOphth(I); Ashish G. Sharma, MD(I); Eileen Knips, RN, COA, CRA (C,P); Crystal Y. Peters, CCRC(C); Cheryl Kiesel, C.O.A., R.O.U.B. (C,P); Anita H. Leslie(V); Raymond K. Kiesel(P)

GLENDALE, CA Kent W. Small, MD, AMC AH (1)

Kent W. Small, MD(I); Fadi S. Shaya(C); Cristina Santacruz(P); Alejandra Castro(P)

Loma Linda, CA Loma Linda University AH (1)

Kakarla V. Chalam, MD(I); Samuel C. Kim, MD(I); David Isaiah Sierpina, MD(I); Michael E. Rauser, MD(I); Tina L Ramirez(C); Marcia Easterly(C); Moises Tellez(P)

PINELLAS PARK, FL Southeast Eye Institute, P.A. dba Eye Associates of Pinellas AH (1)

Jason M. Handza, DO(I); Bronson Oudshoff, CCRC(C); Christina Glover(P)

Rochester, MN Mayo Clinic AH (1)

Andrew J. Barkmeier, MD(I); Heidi Suzanne Rubin, AD(C); Joan T. Overend(V); Jean M. Burrington(V); Stephanie L. Einck(P); Shannon Goddard(P); Jaime L. Tesmer, CRA(P); Denise M. Lewison(P)

St. Louis, MO Retina Research Institute, LLC AH (1):

Kevin J. Blinder, MD(I); Rhonda F. Weeks, CCRC(C); Ginny S. Nobel, COT(C); Kara R Bockius(C); Lynda K. Boyd, C.O.T.(V); Maria A. Stuart, COA(V); Jarrod Wehmeier(P); Steve A Schremp(P)

WEST DES MOINES, IA Wolfe Clinic, P.C.- West Des Moines AG (1):

Jared S. Nielsen, MD(I); Tami Jo Woehl(C); Jamie Spillman(V); Jack Bowers(V); Paula L Bix(V); Lisa M. Boender(P); Spencer D Ridgway(P)