Intravitreal bevacizumab plus propranolol for neovascular age-related macular degeneration (the BEVALOL study): a phase I clinical trial

Abstract

Background: Given the persistently large public health impact of neovascular age-related macular degeneration (nARMD) despite many years of anti-VEGF therapy as the first-line treatment and the demonstrated ability of b-blockers to reduce neovascularization, a synergistic effect between an anti-VEGF agent and an intravitreal beta-blocker is important to investigate in the quest for therapeutic alternatives that maximize efficacy and/or reduce costs. The main purpose of this study is to investigate the safety of a 0.1 ml intravitreal injection of a combination of bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) to treat nARMD.

Methods: Prospective phase I clinical trial that included patients with nARMD. Comprehensive ophthalmic evaluation was performed at baseline and included Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), biomicroscopy of the anterior and posterior segments, binocular indirect ophthalmoscopy, color fundus photography, spectral domain optical coherence tomography (OCT), OCT angiography (OCT-A), fluorescein angiography (Spectralis, Heidelberg), and full-field electroretinography (ERG). All eyes were treated with a 0.1 ml intravitreal injection of a combination of bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) within 1 week of baseline evaluation. The patients were reexamined at weeks 4, 8 and 12, and clinical evaluation and SD-OCT were performed at all follow-up visits. Additional injections of combination bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) were administered at weeks 4 and 8. At the final study evaluation (week 12), color fundus photography, OCT-A, fluorescein angiography, and full-field ERG were repeated.

Results: Eleven patients (11 eyes) completed all study visits of the 12 week study. Full field ERG b-waves did not show significant (p < 0.05) changes at week 12 compared to baseline. During the 12 week follow-up period, none of the study eyes developed intraocular inflammation, endophthalmitis or intraocular pressure elevation more than 4 mmHg over baseline. Mean ± SE BCVA (logMAR) was 0.79 ± 0.09 at baseline and was significantly (p < 0.05) improved to 0.61 ± 0.10 at week 4; 0.53 ± 0.10 at week 8; and 0.51 ± 0.09 at week 12. Mean ± SE central subfield thickness (CST) (μm) was 462 ± 45 at baseline and was significantly (p < 0.05) lower at 4, 8 and 12 weeks (385 ± 37; 356 ± 29 and 341 ± 24, respectively).

Conclusions: In this 12 week trial of a combination of intravitreal bevacizumab and propranolol for treatment of nARMD, no adverse events or signals of ocular toxicity were observed. Further studies using this combination therapy are warranted. Trial Registration Project registered in Plataforma Brasil with CAAE number 28108920.0.0000.5440 and approved in ethics committee of Clinics Hospital of Ribeirao Preto Medicine School of São Paulo University-Ribeirão Preto, São Paulo, Brazil (appreciation number 3.999.989 gave the approval).

Keywords: Age-related macular degeneration; Bevacizumab; Maculopathy; Propranolol; VEGF.

Fig. 1

ERG changes. Full-field ERG baseline and after 12 weeks of follow up showed no significant difference between before and after treatment

Fig. 2

IOP (mmHg) changes at weeks 4,8 and 12. There was no significant change in mean IOP throughout the study period

Figure. 3

LogMAR BCVA changes at weeks 4, 8 and 12. Mean (± SE) logMAR BCVA improved by 0.173 ± 0.033 (p < 0.0001), 0.254 ± 0.033 (p < 0.0001) and 0.272 ± 0.033 (p < 0.0001) compared to baseline at 4, 8, and 12 weeks, respectively

Fig. 4

CST (μm) changes at weeks 4, 8 and 12. Mean (± SE) CST decreased from baseline by 77.64 ± 20.65 (p = 0.0039), 106.54 ± 20.65 (p < 0.0001) and 121.73 ± 20.65 (p < 0.0001) at 4, 8, and 12 weeks, respectively

Fig. 5

Spectral-domain OCT B-scan and angiography c-scan pictures from patient number 1. a. B-scan OCT at baseline showing isolated and coalescent drusen, junctional subretinal hyperreflective material, and intraretinal fluid. b. OCT-A picture showing two hyperreflective spots (yellow arrows) in the avascular complex slab, suggestive of choroidal neovascularization sites or foci. c. B-scan OCT at 12 week follow-up visit showing regression of intraretinal fluid and some junctional subretinal hyperreflective material. d. OCT-A picture showing discrete reduction of hyperreflectivity in temporal inferior CNV, while there was maintenance of flow in the inferior CNV focus