Retinopathy of Prematurity
Conditions
Keywords
Vascular Endothelial Growth Factor, Angiogenesis Inhibitor, Premature infants, Bevacizumab, Zone I or Posterior Zone II ROP, Aggressive Posterior ROP, Stage 3 ROP, Neonatal Intensive Care Unit
Brief summary
The purpose of this study was to determine the efficacy and additional advantages of intravitreal bevacizumab in the treatment of ROP for both Zone I and Zone II Posterior.
Detailed description
This phase 2 study assessed the anti-neovascularization activity of intravitreal bevacizumab, as determined by regression of neovascular vessels of retinopathy of prematurity (ROP), in neonates with acute stage 3 ROP in zone I or posterior zone II with plus disease. This study enrolled 150 confirmed cases of vision threatening ROP which have definite plus disease \[ranging from Early Treatment for Retinopathy of Prematurity, to Cryotherapy for Retinopathy of Prematurity . This was done because of the controversy regarding determining plus disease and the increasing concern that many infants are being treated whose ROP would spontaneously regress. Bevacizumab will be administered intravitreally using 0.625 mg (0.025 ml) injections into each eye. There was no intent to give additional doses unless there was a recurrence of vision threatening stage 3 ROP with plus disease since the disease is self limited by completion of vascularization. Clinical response and any evidence of ocular toxicities were documented by retinal imaging system (manufactured by Clarity Medical Systems, Inc.) taken pre-injection, one week and one month post injection, and at 6 months of age (54 weeks postmenstrual age)(window of 50 to 70 weeks PMA)(primary outcome) and at 12 months of age (80 weeks postmenstrual age)(window of 75 to 100 weeks PMA)(structural documentation). Using the same retinal imaging system, fluorescein angiograms have been taken when possible to document structural outcomes in greater detail. No evidence of systemic toxicities were documented by appropriate clinical and laboratory tests.
Interventions
DRUGBevacizumab
Anti-angiogenic drug: intravitreal injection of 0.625 mg (0.025 ml) once into each eye.
PROCEDUREConventional Laser for ROP
Conventional Laser is applied to the Avascular Peripheral Retina (Anterior to the Vascularized Posterior Retina)
Sponsors
The University of Texas Health Science Center, Houston
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Weeks to 22 Weeks
Healthy volunteers
No
Inclusion criteria
1. Infants who have been screened by the American Academy of Ophthalmology, the American Academy of Pediatrics, and the American Association for Pediatric Ophthalmology and Strabismus guidelines (≤1500 grams at birth and ≤30 weeks gestation) who develop Stage 3 ROP in zone I or posterior zone II. 2. Informed Consent from a parent or guardian.
Exclusion criteria
1. Infants who have a congenital systemic anomaly or have a congenital ocular abnormality. 2. Infants who cannot be treated by conventional laser therapy because of problems with media clarity. Generally, blind external cryotherapy would be utilized as an initial therapy and the infant would be excluded from the study even if the media clear subsequently. 3. Informed Consent from a parent or guardian refused. This will mean that an infant automatically will receive laser therapy. Bevacizumab (Avastin®) treatment cannot be given outside of the Protocol. No data will be used from an infant without Informed Consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Eyes Showing Recurrence of Neovascularization Arising From the Retinal Vessels and Requiring Re-treatment | 54 weeks postmenstrual age (window of 50 to 70 weeks) | For Bevacizumab: Regrowth of new vessels at the site of the original extraretinal fibrovascular proliferation and/or at the site of the anterior edge of inner retinal vascularization. For Laser: Regrowth of new vessels from the vessels at the anterior edge of inner retinal vascularization (remaining after retinal ablation). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Myopia in Zone I and Posterior Zone II of Infant Eyes | 2.5 years of age | Myopia was determined via refraction using a retinoscope and lenses. Myopia is defined as a refractive error reported in Diopters. |
| Visual Acuity | Age 7 years. | The visual acuity will be measured at 20 feet with figures or letters from all infants able to cooperate. |
Countries
United States
Participant flow
Recruitment details
Dates of recruitment: March 13, 2008 to August 4, 2010. Patients recruited were all in neonatal intensive care units.
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab for ROP-Experimental Arm Intravitreal Bevacizumab Therapy is the Experimental Arm of this Study. 31 patients had zone I ROP; 39 patients had zone II posterior ROP. | 75 |
| Conventional Laser for ROP-Control Arm Conventional Laser to the Peripheral Retina is the Control Arm of this Study. 33 patients had zone I ROP; 40 patients had posterior zone II ROP. | 75 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| August, 2010 to April, 2013 | Death | 1 | 5 |
| March, 2008 to August, 2010 | Death | 5 | 2 |
Baseline characteristics
| Characteristic | Conventional Laser for ROP-Control Arm | Bevacizumab for ROP-Experimental Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 75 Participants | 75 Participants | 150 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 0.2 years STANDARD_DEVIATION 0.1 | 0.2 years STANDARD_DEVIATION 0.1 | 0.2 years STANDARD_DEVIATION 0.1 |
| Region of Enrollment United States | 75 participants | 75 participants | 150 participants |
| Sex: Female, Male Female | 23 Participants | 26 Participants | 49 Participants |
| Sex: Female, Male Male | 52 Participants | 49 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 69 | 0 / 68 |
| serious Total, serious adverse events | 0 / 69 | 0 / 68 |
Outcome results
Primary
Number of Eyes Showing Recurrence of Neovascularization Arising From the Retinal Vessels and Requiring Re-treatment
For Bevacizumab: Regrowth of new vessels at the site of the original extraretinal fibrovascular proliferation and/or at the site of the anterior edge of inner retinal vascularization. For Laser: Regrowth of new vessels from the vessels at the anterior edge of inner retinal vascularization (remaining after retinal ablation).
Time frame: 54 weeks postmenstrual age (window of 50 to 70 weeks)
Population: Both eyes of all surviving infants were analyzed for recurrence: thus, 143 surviving infants and 286 eyes were analyzed. Reporting the number of eyes that developed recurrences
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab for ROP-Experimental Arm | Number of Eyes Showing Recurrence of Neovascularization Arising From the Retinal Vessels and Requiring Re-treatment | 6 eyes with recurrences |
| Conventional Laser for ROP-Control Arm | Number of Eyes Showing Recurrence of Neovascularization Arising From the Retinal Vessels and Requiring Re-treatment | 32 eyes with recurrences |
Secondary
Myopia in Zone I and Posterior Zone II of Infant Eyes
Myopia was determined via refraction using a retinoscope and lenses. Myopia is defined as a refractive error reported in Diopters.
Time frame: 2.5 years of age
Population: As of 6/2013, there were 13 deaths/ 26 eyes. Exclusions from surviving 137 infants/ 274 eyes: 6 infants/19 eyes with intraocular surgery--leaving: 131 infants/ 255 eyes; 14 infants/ 21 eyes had recurrence and 22 infants/ 44 eyes were lost to follow-up--leaving: 95 infants/ 190 eyes. Thus, only the refractions on these infants/ eyes are given.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bevacizumab for ROP-Experimental Arm | Myopia in Zone I and Posterior Zone II of Infant Eyes | -1.36 Diopters | Standard Deviation 3.34 |
| Conventional Laser for ROP-Control Arm | Myopia in Zone I and Posterior Zone II of Infant Eyes | -7.34 Diopters | Standard Deviation 7.44 |
| Bevacizumab Experimental Group: Posterior Zone II | Myopia in Zone I and Posterior Zone II of Infant Eyes | -0.63 Diopters | Standard Deviation 2.56 |
| Conventional Laser-Control Group: Posterior Zone II | Myopia in Zone I and Posterior Zone II of Infant Eyes | -5.20 Diopters | Standard Deviation 5.77 |
Secondary
Visual Acuity
The visual acuity will be measured at 20 feet with figures or letters from all infants able to cooperate.
Time frame: Age 7 years.