Clinical trial NCT02192970
Conditions: Retinal Detachment Proliferative Vitreoretinopathy
Keywords: Retinal detachment Proliferative vitreoretinopathy
Sponsor: University of Wisconsin, Madison
Start date: 2015-01-21; Completion date: 2019-11-11
Enrollment: 101 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The investigators hypothesize that bevacizumab instilled into the vitreous after primary retinal detachment surgery will reduce the formation of proliferative vitreoretinopathy and subsequent retinal re-detachment.

Detailed description:

Arms: arm 1: Pars plana vitrectomy will be performed in the typical manner. After laser retinopexy and prior to air-gas exchange, intravitreal bevacizumab will be administered through the trocar. Either perfluoropropane (C3F8) or sulfur hexafluoride (SF6) gas will then be administered for long-term retinal tamponade and the vitrectomy ports closed in the usual manner. arm 2: Review records over the past 5 years of patients who underwent vitrectomy for retinal detachment repair to found out the percentage of those who had re-detachment of the retina within 6 months after surgery.
Interventions: intervention 1: Bevacizumab
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 10 
Title  
 
Bevacizumab against recurrent retinal detachment (BEARRD) 
 
PI Name and Institutional Affiliation 
 
Michael M. Altaweel, MD, Professor, Department of Ophthalmology and Visual Sciences, 
University of Wisconsin School of Medicine and Public Health 
 
Protocol Version date 
 
July 18, 2017 
 
Current Co-Investigators 
Barbara A. Blodi, MD 
Jonathan S. Chang, MD 
Ronald P. Danis, MD 
Justin L. Gottlieb, MD 
Mihai Mititelu, MD, MPH 
T. Michael Nork, MD, MS 
Kimberly Stepien, MD 
Michael Possin, MD 
Zackery Oakey, MD 
 
Previous Co-Investigators 
Michael Ip, MD (left UW position) 
Eric P. Brinton, MD (completed retina fellowship) 
Patrick P. Sassani, MD (completed retina fellowship) 
Jeremy A. Lavine, MD, PhD (completed residency program) 
Krishna Surapaneni, MD (completed residency program) 
Paul Boeke, MD (completed retina fellowship) 
Alex Ringeisen, MD (completed residency program) 
Angeline Wang, MD (completed residency program) 
 
Study Coordinator  
Angie Adler, CCRC 
 
Funding Sponsor 
 
Clinical Research FA Davis Funds, Department of Ophthalmology and Visual Sciences, 
University of Wisconsin, Madison 
 
Project Summary 
 
Rhegmatogenous retinal detachment (RD) is a serious vision threatening condition. Pars plana 
vitrectomy (PPV) is the most common and successful surgical procedure to repair 


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rhegmatogenous RD. With the introduction of small-gauge (23 and 25 gauge) PPV, the success 
of PPV for rhegmatogenous RD has improved to nearly 87% with only one surgical procedure1,2.  
In the remaining 13%, however, PPV failure causes poor visual outcomes, averaging 20/100 
visual acuity1. The primary reason for primary PPV failure is proliferative vitreoretinopathy 
(PVR)3. PVR develops when retinal and subretinal cells are released into the vitreous after a 
retinal break3. The vitreous, which is rich in growth factors, promotes proliferation and fibrosis 
of these retinal cells, leading to tractional and/or recurrent rhegmatogenous RD3. Unfortunately, 
recent pharmacologic attempts to prevent PVR development in clinical trials have failed1,4,5. 
Interestingly, inhibition of vascular endothelial growth factor (VEGF) signaling prevents PVR 
progression and recurrent RD in experimental animal models6. This finding led us to hypothesize 
that bevacizumab, a ubiquitously used and safe anti-VEGF medication used intraocularly, could 
be a potential therapeutic prophylaxis against PVR and recurrent RD. 
 
The primary goal of this study will be to determine if intra-operatively administered 
bevacizumab can reduce the incidence of recurrent RD and PVR. During routine PPV repair of 
rhegmatogenous RD, a single dose of bevacizumab will be administered through the trocar at the 
end of surgery. This method of administration has the advantage of eliminating any risk of 
intraocular injection, including the risks of RD, infection, and lens damage. The only risk of this 
study is that of the medication itself, which has been shown to be safe in a large prospective 
randomized clinical trial7 and is now widely used as first line treatment for exudative macular 
degeneration, diabetic macular edema, and retinal vein occlusions. Our study will begin with a 
retrospective review of our current surgical practice to determine our institution’s success rate 
for primary PPV to repair retinal detachment. Success will be defined as one PPV to repair RD 
after 6 months follow up, and failure will be stratified by cause with specific attention directed 
toward PVR. We intend to query the most recent 4-6 years to identify a control group of 
approximately 400 patients, all receiving PPV. We then intend to enroll patients into the study 
over a one-year period, estimating enrollment of approximately 100 patients in this prospective 
cohort study. We will follow patients for 6 months post-operatively, primarily including visual 
acuity and ophthalmoscopy to determine incidence of recurrent RD and PVR.  
 
This proof-of-concept study will address whether anti-VEGF therapy can reduce the incidence of 
recurrent RD and PVR. Should this study be positive, a larger prospective randomized clinical 
trial can be explored to confirm our findings and possibly establish anti-VEGF therapy in the 
peri-operative period as the gold standard prophylaxis against PVR. Future considerations will 
address whether additional anti-VEGF injections in the post-operative period can further reduce 
the incidence of PVR.  
 
Background and Significance 
 
Rhegmatogenous RD is an important cause of severe vision loss, occurring in approximately 
10.5 per 100,000 patients annually8. A rhegmatogenous RD develops after a break in the retina 
allows liquefied vitreous to enter the sub-retinal space and dissect the retina from the retinal 
pigment epithelium (RPE) and choroid. Recent advances in small-gauge vitrectomy technology 
have greatly improved anatomical success rates and visual outcomes. Briefly, the vitreous gel is 
removed from the vitreous cavity, the subretinal fluid is drained thereby flattening the retina, 
adhesions are created between the retina and RPE with laser, and the vitreous cavity is filled with 


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long acting gas to tamponade the retina against the RPE. In two independent studies of primary 
PPV for rhegmatogenous RD, 87% of patients have complete success and require no additional 
retinal operations1,2. In those patients requiring no further surgery, final median visual acuity is 
approximately 20/401. However, in the group of patients who require further retinal surgeries, 
final median visual acuity significantly decreases to worse than 20/1001. The primary cause for 
surgical failure and worsened visual acuity is PVR. 
 
PVR develops in 5–10% of patients after rhegmatogenous RD1,3. PVR begins when retinal and 
sub-retinal cells are liberated into the vitreous gel after a retinal break. The most common cells 
found in PVR membranes are retinal glial cells, RPE cells, fibroblasts, and inflammatory cell 
types3. The vitreous gel contains a multitude of growth factors and it is hypothesized that 
exposure of these cell types to vitreous causes proliferation of glial and RPE cells, and 
differentiation of RPE cells to fibroblasts and myofibroblasts3. These cell types adhere to the 
retina and form contractile epi-retinal membranes that open old retinal breaks or create new 
retinal breaks, causing tractional and recurrent rhegmatogenous RD. PVR-associated recurrent 
RDs are then treated surgically with a combination of secondary and thorough PPV, scleral 
buckling, membrane peeling of PVR membranes, and/or long-term tamponade with silicone oil. 
Although anatomic success rates are high, with up to 90% success with one additional surgery 
and 99% success after multiple surgeries, visual acuity outcomes are poor with median final 
visual acuity of less than 20/1001,3. These results demonstrate the need for effective prophylaxis 
against PVR. 
 
Despite our knowledge of the pathophysiology of PVR, no clinical trials have identified any 
useful prophylactic pharmaceutical agents against PVR. Based upon the model of RPE and 
retinal glial cell proliferation in the pathogenesis of PVR, agents such as 5-fluorouracil1,9 (5-FU) 
and daunorubicin5 have been studied as prophylactic agents to prevent PVR and recurrent RD. In 
patients with known PVR, daunorubicin did not improve surgical outcomes or final visual 
acuity5. In patients at high risk for PVR development, 5-FU in combination with low molecular 
weight heparin (LMWH) did reduce PVR and decrease the number of retinal operations9. 
However, 5-FU and LMWH as an adjunctive therapy in primary PPV for all comers had no 
effect upon PVR, retinal surgeries, or final visual acuity1. Finally, triamcinolone was investigated 
to reduce PVR via its anti-inflammatory properties, but in conjunction with PPV, membrane 
peeling, and silicone oil tamponade for PVR-associated RD, triamcinolone had no effect upon 
retinal re-attachment, PVR, or visual acuity4. Thus, there is no effective prophylaxis against PVR 
and further investigation is warranted. 
 
As discussed earlier, the current pathophysiologic model is that the vitreous gel is rich in 
cytokines and growth factors that drive PVR. It is hypothesized that molecules like platelet-
derived growth factor (PDGF) stimulate proliferation of RPE and glial cells, while transforming 
growth factor β (TGF-β) and connective tissue growth factor (CTGF) promote fibrosis3. Many 
studies have focused on PDGF and its receptors as key early steps in the pathogenesis of PVR. 
Activation of the PDGF receptor α (PDGFRα) increases PVR, and inhibition of PDGFRα 
reduces PVR in a rabbit model10-12. This pro-PVR effect, however, is not driven by PDGF but 
instead stimulated by non-PDGF growth factors that indirectly activate PDGFRα13,14. 
Interestingly, VEGF inhibits PDGF-driven direct PDGFRα activation and increases non-PDGF 
indirect PDGFRα stimulation15. This finding led to the hypothesis that VEGF functions as a key 


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switch that determines if PDGFRα is stimulated by PDGF or non-PDGF ligands, which activate 
PVR. Thus, VEGF promotes PVR by inhibiting its inhibitor. Confirming this hypothesis, 
ranibizumab, a VEGF antagonist, reduces non-PDGF-stimulated PDGFRα activation and 
decreases experimental PVR in a rabbit model6. Therefore, ranibizumab is a potential therapeutic 
to prevent PVR by modulating PDGFRα signaling. 
 
Ranibizumab is a safe and effective therapeutic for the treatment of exudative age-related 
macular degeneration (AMD), diabetic macular edema, and central retinal vein occlusion. 
Ranibizumab was first approved for the treatment of classic and occult choroidal 
neovascularization in exudative AMD16,17. The safety profile of ranibizumab is excellent with no 
increased systemic adverse events and a very low risk (0.05%) of local infection. Bevacizumab is 
a second anti-VEGF agent that costs up to 40-fold less than ranibizumab. Off label usage of 
bevacizumab led to the Comparison of AMD Treatments Trial (CATT), which investigated the 
efficacy and safety of intra-vitreal bevacizumab injection. The CATT trial found that 
ranibizumab and bevacizumab were equally efficacious with equally few systemic and local 
adverse events7. Based upon this trial, bevacizumab is now first line standard of care treatment 
for exudative AMD and additionally for diabetic macular edema and retinal vein occlusions. 
 
Risks associated with intravitreal administration of bevacizumab as seen in the CATT trial are 
endophthalmitis, retinal detachment, and cataract. The risk of retinal detachment and cataract 
occur because a needle is used to penetrate the pars plana to administer the drug. In this study, 
bevacizumab will be delivered via the previously placed surgical cannula, thereby eliminating 
the risk of retinal detachment and cataract from the drug administration. Endophthalmitis is a 
risk factor for any eye surgery. 
 
Since bevacizumab is a safe and useful anti-VEGF agent, we hypothesize that bevacizumab 
could reduce PVR. We plan to investigate if bevacizumab can be used as a prophylactic agent 
against PVR by providing a one-time dose of bevacizumab intra-operatively. Bevacizumab (1.25 
mg/0.05 mL) will be administered at the end of primary vitrectomy surgery for rhegmatogenous 
RD. This potential prophylactic is known to be incredibly safe with very low patient risk and 
could potentially be the first biologic prophylaxis against PVR. 
 
Specific Aims/Study Objectives 
 
Purpose 
 
To investigate if intravitreal bevacizumab injection during primary vitrectomy surgery can 
reduce recurrent RD and PVR. 
 
Duration 
 
The study will last 6 months for each subject. In prior studies of recurrent RD after primary RD 
repair1, 6 months is the typical end point used and most recurrent RD occurs between 6 weeks 
and 3 months. We plan to enroll every patient with rhegmatogenous RD that qualifies for a 
primary vitrectomy RD repair surgery. We plan to enroll patients over 1 year, estimating 
approximately 100 enrolled patients. These 100 patients will be compared to retrospective 


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historical data from 400 patients who underwent retinal detachment surgery at UW Hospital over 
the last 4-6 years. The data analysis will be performed at the end of the study. It is expected that 
the study will be completed and the results will be available within 18 months from time of 
commencement. 
 
Outcome measures 
 
Primary: Complete success of primary vitrectomy surgery, defined as retinal re-attachment 
without the need for any additional surgical procedures. 
Secondary: Visual acuity and presence of PVR. 
 
Research Design and Methods 
 
Recruitment and Location 
Subjects are patients with a rhegmatogenous RD who are under the care of one of the 
ophthalmologists at University of Wisconsin Hospital and Clinics (UWHC). Ophthalmologists 
involved in the patients’ clinical care will be the first to approach patients about the study. For 
patients who are interested and meet the criteria, the treating ophthalmologist will explain the 
study, guide the patient through the study specific consent form, and answer subject questions. 
 
Subjects 
 
Subject population 
 
The study population will consist of approximately 100 eyes of patients recruited by 
ophthalmologists at UWHC. 
• Inclusion criteria 
o Age ≥ 18 years 
o Eyes with rhegmatogenous retinal detachment 
• Exclusion criteria 
o Presence of PVR 
o Need for a procedure other than primary PPV such as a scleral buckle with or 
without PPV, laser retinopexy, or pneumatic retinopexy.  
o Recent intravitreal injection of an anti-VEGF agent less than 3 months prior 
o Secondary retinal detachment repair 
o Use of silicone oil as tamponade agent 
o Patients less than 18 years of age 
o Pregnancy 
o Known previous adverse response or contraindication to intravitreal bevacizumab 
o History of stroke or malignant hypertension in the previous 6 months 
 
Consent procedures 
 
The patients will be assessed by the treating physician for eligibility for the study. The results of 
a standard care dilated funduscopic exam, done for clinical purposes, will be used to determine 
research eligibility. For the patients who qualify for the study, the treating physician will explain 


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the study to them, including the risks. The subjects will have the opportunity to ask questions. 
They will receive a copy of the consent form. Patients who agree will then be asked to sign the 
consent form. Patients may be able to take the consent form home prior to signing for further 
consultation if desired. Women of childbearing age who are unsure of their pregnancy status will 
be excluded from the study unless they first undergo a pregnancy test.  
 
Research Design 
 
1. This is a prospective case series of approximately 100 eyes with rhegmatogenous RD over a 
one-year duration. These patients will be compared to a historical population of 400 patients who 
underwent retinal detachment surgery at UW Hospital over the last 4-6 years. Previous studies 
estimate an approximately 86.7% complete success rate for primary vitrectomy. Because each 
surgeon has different rates, we will compare our prospective 100 cases to our own internal 
controls. We will begin the study with a retrospective review of our own success rates. In order 
to determine the primary success rate, we will query Healthlink for 400 records from between 
September 2, 2009 and September 2, 2014 of patients receiving PPV surgery. We will define this 
as retinal re-attachment without the need for subsequent retinal surgical procedures during a 6-
month follow up duration. We will also stratify our failures into categories, including PVR, new 
primary retinal break, and other. We will identify a stable rate of primary PPV success in our 
control group to ensure that no trend toward improvement over time exists.  
 
2. Patients identified as candidates who express interest in participating will sign a consent form 
and will clinically undergo standard care primary PPV surgery for retinal re-attachment. 
 
3. PPV will be performed in the typical manner with initial core vitrectomy, followed by 
peripheral vitrectomy. Air fluid exchange will be performed and the sub-retinal fluid drained. 
Once the retina is flat, endolaser will be applied as appropriate for closure of retinal breaks. After 
laser retinopexy and prior to air-gas exchange, intravitreal bevacizumab will be administered 
through a cannula. Either perfluoropropane (C3F8) or sulfur hexafluoride (SF6) gas will then be 
administered for long-term retinal tamponade and the vitrectomy ports closed in the usual 
manner. Studies have shown no adverse effects from bevacizumab when used in a gas-filled 
eye.19, 20 The administration of bevacizumab is the only part of the surgery that will differ from 
the standard of care. 
 
4. All patients will be subsequently examined at 1 day, 1 week, and 1 month post-operatively in 
the usual manner. Patient’s intraocular pressure and visual acuity will be measured at these visits. 
Study activities will take place at the standard care visits that happen 3 months and 6 months 
postoperatively, within a one-month window. The following clinical data will be collected from 
these visits for the study: visual acuity, intraocular pressure, presence and grade of PVR, and 
attachment of the retina. Grading of PVR will be based on the updated Retina Society 
classification18, but modified for simplicity. Grade A is defined as pigment clumps, Grade B is 
defined as wrinkling on the retinal surface, and Grade C is defined as full-thickness rigid retinal 
folds (e.g. star fold).  
 
Data and Safety Monitoring Plan 
 


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The only risk of this study involves the intraocular drug bevacizumab. Bevacizumab will be 
delivered via the previously placed cannula so there will no be no risk associated with the 
method of intraocular injection. Patients who have a known previous adverse response to 
bevacizumab will be excluded from the study. 
 
The CATT trial demonstrated the safety of intra-ocular bevacizumab in 1200 patients7. The 
CATT trial found a 2-3% risk of arterial thromboembolic events, <1% risk of worsening 
hypertension, 1% risk of venous thromboembolic events, and 20% risk of hospitalization of any 
cause7. All of these events were equal to the control group and general population, after being 
adjusted for age and overall risk factors7. Nevertheless, we will use a questionnaire, similar to the 
CATT trial, which monitors for the above events at the 3-month and 6-month visit. The 
questionnaire will ask: 
1. Since your surgery or most recent BEARRD visit, have you had any hospitalizations? 
2. Since your surgery or most recent BEARRD visit, have you any heart attacks or strokes? 
3. Since your surgery or most recent BEARRD visit, have you had any blood clots? 
4. Since your surgery or most recent BEARRD visit, have you had any episodes of 
uncontrolled blood pressure requiring hospitalization or emergency room care? 
Since we are mostly investigating rare events in a small study population, the results of this 
questionnaire will be analyzed after 50 patients to determine if bevacizumab caused any 
increased risk to the study population. For such a small study, the principal investigator will be 
responsible for monitoring the safety data. Since there is no control study population, the event 
rates in the CATT trial will be used as the control group. For hypertension, arterial 
thromboembolic events, and venous thromboembolic events, the expected rate is a low 1-2 
events among 50 people, requiring 9 events for any group to reach statistically significance that 
would warrant stopping the study using Fisher’s exact test. For hospitalizations, 20 events would 
be needed to meet statistical significance to stop the study using the same methodology. The data 
will be analyzed after 50 patients complete their 3-month visit, again after 50 patients complete 
their 6-month visit, and at study conclusion. The study will be stopped if the above criteria are 
met. After 50 patients complete their 6-month visit and at study conclusion, the safety data will 
be reviewed, and the results will be communicated to the IRB. Patients who withdraw 
prematurely will be included for analysis of treatment effect if there are adequate data points for 
analysis. 
 
It is unknown whether bevacizumab poses a risk to pregnant females or fetuses. Therefore, any 
woman of childbearing age who is unsure of her pregnancy status will be excluded from the 
study unless she first undergoes a pregnancy test. A urine pregnancy test will be provided at no 
charge to the patient. Women who are of childbearing age and are sexually active will need to be 
on birth control for three months after receiving the study medication. Abstinence is an 
acceptable form of birth control. 
 
Potential risks 
 
The potential risks related to study participation include: 
1. Increased inflammation and endophthalmitis. Although extremely rare, it is possible to have 
an increase in inflammation and even endophthalmitis from bevacizumab.  


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2. Large, controlled trials and meta-analyses have been done looking at adverse events from 
bevacizumab. These have shown that “anti-VEGF monoclonal antibodies did not 
significantly increase overall mortality, cardiovascular mortality, stroke, myocardial 
infarction, VTEs, or hypertension. While the informational drug brochure for bevacizuamb 
states arterial thromboembolic events, hypertension, gastrointestinal perforation, and 
hemorrhage have have been reported from unapproved intravitreal use, these events are 
“reported voluntarily from a population of uncertain size, it is not always possible to reliably 
estimate their frequency or establish a causal relationship to drug exposure.”  
3. Confidentiality breach 
Protection of subjects 
Patients will be examined at study enrollment and at post-operative visits including 1 day, 1 
week, 1 month, 3 months, and 6 months as would be done regardless of the study. The visits will 
include a standard ophthalmologic examination including visual acuity, intraocular pressures, 
and slit lamp biomicroscopy. All complications will be recorded. Patients will be instructed to 
call immediately for an appointment if they notice any standard care surgery risks such as a 
change in the vision, appearance of the eye, or development of pain in the eye. Data collection 
forms will include the study identification number; no names will be used in the forms. 
Presentations and publications will not identify individual patients.  
Statistical Considerations 
A Chi-square test will be used to compare percentage success of primary vitrectomy for retinal 
detachment with bevacizumab to our internal control standard over the last 4-6 years. Based 
upon power calculations, we estimate a roughly 15% percent failure rate in our current practice. 
With a goal of a 60% reduction in failure rate, 100 prospective subjects versus about 400 control 
subjects will provide a power of 80% at the standard α error of 5%. A Chi-square test will also 
be used to compare the percentage of patients with PVR in our prospective case series versus our 
control population. Unpaired t tests will be performed to compare visual acuity (VA) and 
intraocular pressure. 
Data and Record Keeping 
Research intervention will be conducted in a private room; collection of sensitive information 
about subjects will be limited to the amount necessary to achieve the aims of the research. Data 
collection forms will include the name code and study identification number; no names will be 
used in the forms. Presentations and publications will not identify individual patients.  
All paper data will be stored in locked cabinets. All the electronic data will be stored in 
password-protected computers. This will be kept at UWHC sites in a room with number lock 
available only to individuals listed in study protocol. The confidentiality of records will be 
maintained in accordance with applicable state and federal laws. All the identifiers and 
information in paper format will be shredded. The electronic data will be deleted at the 
conclusion of study.


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