Ignite Creation Date:
2025-12-24 @ 11:30 PM
Ignite Modification Date:
2025-12-25 @ 9:18 PM
Study NCT ID:
NCT03904056
Status:
COMPLETED
Last Update Posted:
2019-04-04
First Post:
2019-02-11
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
ETDRS PRP With IVR Versus Retinal Photocoagulation Targeted to Ischemic Retina With IVR for the Treatment of PDR
Sponsor:
São Paulo State University
Organization:
Study Overview
Official Title:
ETDRS Panretinal Photocoagulation (PRP) Combined With Intravitreal Ranibizumab (IVR) Versus Retinal Photocoagulation Targeted to Ischemic Retina Combined With IVR for the Treatment of Proliferative Diabetic Retinopathy
Status:
COMPLETED
Status Verified Date:
2019-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Purpose: To compare panretinal photocoagulation (PRP) as described in ETDRS Study combined with intravitreal injection of ranibizumab (IVR) (ETDRS-PRP group) and retinal photocoagulation targeted to ischemic retina combined with IVR (ISQ-RP group) in patients with proliferative diabetic retinopathy (PDR).
Design: Randomized prospective clinical trial. Methods: Patients with PDR were assigned to receive either PRP plus IVR (20 eyes) or retinal photocoagulation targeted to ischemic areas plus IVR (20 eyes). ETDRS best-corrected visual acuity (BCVA), central subfield macular thickness (CSFT) measured by optical coherence tomography (OCT) were performed at baseline and every 4 weeks through week 48. Area of fluorescein leakage from active new vessels (FLA) was measured every 12 weeks. Full-field electroretinography (ERG) was recorded at baseline and after 3 months.
Design: Randomized prospective clinical trial. Methods: Patients with PDR were assigned to receive either PRP plus IVR (20 eyes) or retinal photocoagulation targeted to ischemic areas plus IVR (20 eyes). ETDRS best-corrected visual acuity (BCVA), central subfield macular thickness (CSFT) measured by optical coherence tomography (OCT) were performed at baseline and every 4 weeks through week 48. Area of fluorescein leakage from active new vessels (FLA) was measured every 12 weeks. Full-field electroretinography (ERG) was recorded at baseline and after 3 months.
Detailed Description:
This parallel clinical trial was approved by the local Research Ethics Committee, and all subjects gave written informed consent to participate. Between August 2014 and July 2016, all adult patients with treatment-naive PDR and a best-corrected visual acuity (BCVA) better than 20/800 evaluated at our facility were invited to participate in the study.
During the recruitment phase, twenty-three consecutive patients who met the inclusion and exclusion criteria were enrolled into the study. At baseline visit, each patient underwent detailed ophthalmologic assessment including BCVA measurement according to standardized ETDRS refraction protocols using modified ETDRS cards 1, 2 and R; applanation tonometry; slit-lamp biomicroscopy examination under mydriasis (including classification of crystalline lens opacity status using the Lens Opacities Classification System - LOCS III) (13); and indirect funduscopic examination. Digital ocular stereoscopic fundus photographs (TRC-50DX - IMAGEnet; Topcon, Tokyo, Japan), wide field fluorescein angiography and spectral domain optical coherence tomography (SD-OCT) (HRA-OCT, Heidelberg, Germany) were also performed.
Randomization and treatment groups
Patients were randomly assigned using a computer-generated sequence, to one of the following two treatment groups:
ETDRS-PRP Group: patients were treated in two sessions (week 0 and week 2) of 800-900 shots, for a total of 1600-1800 shots with a shot duration of 100 ms and power modulated in order to generate moderately white spots on the retina.
ISQ-RP Group: patients were treated with single-spot targeted retinal photocoagulation directed toward areas of retinal nonperfusion detected by fluorescein angiography. In this group, laser treatment was also performed in two sessions (week 0 and 2), with a shot duration of 100 ms, but spots were placed 1/2 burn apart and power modulated in order to generate moderately white spots on the retina.
For both groups, retinal photocoagulation was performed with single-spot full-scatter PRP using Purepoint green diode laser (Alcon, Fortworth, Texas) with an Ocular Mainster PRP 165 lens with a dynamic field of view of 180 degrees, and a 200 micron spot size (which produces a 392 micron spot size on the retina). Intravitreal injection of 0.5 mg (0.05 ml) ranibizumab (Lucentis®) (IVR) were performed 180 minutes after the first laser session (week 0) by a single retina specialist.
Intravitreal injection Intravitreal injections were performed in a clinic setting 180 minutes after retinal photocoagulation with a disposable syringe with a BD Ultra-FineTM 29G ½" needle, via the pars plana 3.5 mm posterior to the limbus, using topical anesthesia. After the procedure, optic nerve perfusion was assessed by indirect binocular ophthalmoscopy, with paracenthesis of the anterior chamber considered in cases of poor perfusion. After injection, patients were instructed to use antibiotic eyedrops (0.5% moxifloxacin), according to drug label, one drop every 4 hours for one week, in the eye which received the intravitreal injection.
Ophthalmologic evaluations Comprehensive ophthalmic evaluations, including ETDRS BCVA and central subfield macular thickness (CSFT) measured by SD-OCT as described elsewhere (15) were performed at baseline and every 4 weeks through week 48.
Area of fluorescein leakage from active new vessels (FLA) was measured by wide field fluorescein angiography at baseline and at weeks 4, 8, 12, 24, 36 and 48 using fluorescein angiography pictures taken 2.0 to 3.0 minutes after the injection of fluorescein dye. Local and systemic adverse effects, including changes in intraocular pressure and in crystalline lens status, were monitored throughout the study.
Retreatment criteria At follow-up visits from week 12 to 48, patients were treated quarterly with an IVR (0.5 mg in 0.05 ml) if FA demonstrated the presence of actively leaking retinal neovascularization. From weeks 4 to 48, patients could receive monthly IVR if SD-OCT demonstrated a CSFT of more than 300 µm.
ERG protocol Full-field ERG was performed at baseline, and 12, 24 and 48 weeks after treatment (ColorDome and Espion E2 - Diagnosys LLC, Middleton, MA, USA). ERG was executed in accordance to ISCEV standard \[20\] using DTL as positive electrodes. Skin electrodes (Red-Dot - 3M) were placed on each temporal orbital rim to serve as references, and on forehead as ground. A- and b-wave amplitude and implicit time were evaluated.
After 30 min dark adaptation, a series of flashes with increasing luminance was used as light stimuli: 0.003, 0.01 (rod ERG), 0.03, 0.1, 0.3, 1.0, 3.0 (combined rod-cone ERG) and 10 cd.s/m2. Oscillatory potentials were filtered out of combined rod-cone ERG, using an off-line fast-Fourrier algorithm set as a band-pass frequency filter (75 - 300 Hz) as previously described \[21\], and area under the curve (OP-AUC) between a- and b-wave implicit time was calculated.
Thereafter, patients were light adapted for 10 min, and photopic ERG measurements were also performed a series of increasing stimuli luminance: 0.1, 0.3, 1.0, 3.0 (cone ERG), 10.0 and 30.0 cd.s/m2, followed by the 30 Hz flicker (background during photopic stimulation = 30 cd/m2).
Sample size
The sample size estimation was based on the standard deviation of fluorescein leakage area of a previous study where PRP plus ranibizumab was used for proliferative diabetic retinopathy treatment (11). Considering this previous study, with a sample size of 15 patients per group, there is an 80% power to detect a mean difference of 2 mm2 between both groups.
Statistics Baseline data were compared using one-way analysis of variance followed by Tukey-Kramer testing for multiple mean comparisons, while group comparisons during follow-up were performed using analysis of covariance (ANCOVA) with "group", "time" and "group cross time" as effects, followed by Tukey HSD testing. Calculations were performed using JMP 10.0 (SAS). The significance level was set at p\<0.05.
During the recruitment phase, twenty-three consecutive patients who met the inclusion and exclusion criteria were enrolled into the study. At baseline visit, each patient underwent detailed ophthalmologic assessment including BCVA measurement according to standardized ETDRS refraction protocols using modified ETDRS cards 1, 2 and R; applanation tonometry; slit-lamp biomicroscopy examination under mydriasis (including classification of crystalline lens opacity status using the Lens Opacities Classification System - LOCS III) (13); and indirect funduscopic examination. Digital ocular stereoscopic fundus photographs (TRC-50DX - IMAGEnet; Topcon, Tokyo, Japan), wide field fluorescein angiography and spectral domain optical coherence tomography (SD-OCT) (HRA-OCT, Heidelberg, Germany) were also performed.
Randomization and treatment groups
Patients were randomly assigned using a computer-generated sequence, to one of the following two treatment groups:
ETDRS-PRP Group: patients were treated in two sessions (week 0 and week 2) of 800-900 shots, for a total of 1600-1800 shots with a shot duration of 100 ms and power modulated in order to generate moderately white spots on the retina.
ISQ-RP Group: patients were treated with single-spot targeted retinal photocoagulation directed toward areas of retinal nonperfusion detected by fluorescein angiography. In this group, laser treatment was also performed in two sessions (week 0 and 2), with a shot duration of 100 ms, but spots were placed 1/2 burn apart and power modulated in order to generate moderately white spots on the retina.
For both groups, retinal photocoagulation was performed with single-spot full-scatter PRP using Purepoint green diode laser (Alcon, Fortworth, Texas) with an Ocular Mainster PRP 165 lens with a dynamic field of view of 180 degrees, and a 200 micron spot size (which produces a 392 micron spot size on the retina). Intravitreal injection of 0.5 mg (0.05 ml) ranibizumab (Lucentis®) (IVR) were performed 180 minutes after the first laser session (week 0) by a single retina specialist.
Intravitreal injection Intravitreal injections were performed in a clinic setting 180 minutes after retinal photocoagulation with a disposable syringe with a BD Ultra-FineTM 29G ½" needle, via the pars plana 3.5 mm posterior to the limbus, using topical anesthesia. After the procedure, optic nerve perfusion was assessed by indirect binocular ophthalmoscopy, with paracenthesis of the anterior chamber considered in cases of poor perfusion. After injection, patients were instructed to use antibiotic eyedrops (0.5% moxifloxacin), according to drug label, one drop every 4 hours for one week, in the eye which received the intravitreal injection.
Ophthalmologic evaluations Comprehensive ophthalmic evaluations, including ETDRS BCVA and central subfield macular thickness (CSFT) measured by SD-OCT as described elsewhere (15) were performed at baseline and every 4 weeks through week 48.
Area of fluorescein leakage from active new vessels (FLA) was measured by wide field fluorescein angiography at baseline and at weeks 4, 8, 12, 24, 36 and 48 using fluorescein angiography pictures taken 2.0 to 3.0 minutes after the injection of fluorescein dye. Local and systemic adverse effects, including changes in intraocular pressure and in crystalline lens status, were monitored throughout the study.
Retreatment criteria At follow-up visits from week 12 to 48, patients were treated quarterly with an IVR (0.5 mg in 0.05 ml) if FA demonstrated the presence of actively leaking retinal neovascularization. From weeks 4 to 48, patients could receive monthly IVR if SD-OCT demonstrated a CSFT of more than 300 µm.
ERG protocol Full-field ERG was performed at baseline, and 12, 24 and 48 weeks after treatment (ColorDome and Espion E2 - Diagnosys LLC, Middleton, MA, USA). ERG was executed in accordance to ISCEV standard \[20\] using DTL as positive electrodes. Skin electrodes (Red-Dot - 3M) were placed on each temporal orbital rim to serve as references, and on forehead as ground. A- and b-wave amplitude and implicit time were evaluated.
After 30 min dark adaptation, a series of flashes with increasing luminance was used as light stimuli: 0.003, 0.01 (rod ERG), 0.03, 0.1, 0.3, 1.0, 3.0 (combined rod-cone ERG) and 10 cd.s/m2. Oscillatory potentials were filtered out of combined rod-cone ERG, using an off-line fast-Fourrier algorithm set as a band-pass frequency filter (75 - 300 Hz) as previously described \[21\], and area under the curve (OP-AUC) between a- and b-wave implicit time was calculated.
Thereafter, patients were light adapted for 10 min, and photopic ERG measurements were also performed a series of increasing stimuli luminance: 0.1, 0.3, 1.0, 3.0 (cone ERG), 10.0 and 30.0 cd.s/m2, followed by the 30 Hz flicker (background during photopic stimulation = 30 cd/m2).
Sample size
The sample size estimation was based on the standard deviation of fluorescein leakage area of a previous study where PRP plus ranibizumab was used for proliferative diabetic retinopathy treatment (11). Considering this previous study, with a sample size of 15 patients per group, there is an 80% power to detect a mean difference of 2 mm2 between both groups.
Statistics Baseline data were compared using one-way analysis of variance followed by Tukey-Kramer testing for multiple mean comparisons, while group comparisons during follow-up were performed using analysis of covariance (ANCOVA) with "group", "time" and "group cross time" as effects, followed by Tukey HSD testing. Calculations were performed using JMP 10.0 (SAS). The significance level was set at p\<0.05.
Study Oversight
Has Oversight DMC:
False
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: