Randomized Placebo-Controlled Trial Evaluating the Ophthalmic Safety of Single-Dose Tafenoquine in Healthy Volunteers.

INTRODUCTION: Tafenoquine has been recently registered for the prevention of relapse in Plasmodium vivax malaria. OBJECTIVE: This study assessed the pharmacodynamic effects of 300-mg single-dose tafenoquine on the retina. METHODS: This phase I, prospective, multicenter, randomized, single-masked, placebo-controlled, parallel-group study was conducted between 2 February 2016 and 14 September 2017 at three US study centers. Adult healthy volunteers were randomized (2:1) to receive either a single 300-mg oral dose of tafenoquine or matched placebo on day 1. Ophthalmic assessments, including spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF), were conducted at baseline and day 90 and evaluated for pre-determined endpoints by an independent, masked reading center. RESULTS: One subject in each group met the composite primary endpoint for retinal changes identified with SD-OCT or FAF, i.e., one out of 306 (0.3%) with tafenoquine, one out of 161 (0.6%) with placebo. Both cases had unilateral focal ellipsoid zone disruption at day 90 with no effect on best-corrected visual acuity. The tafenoquine-treated subject had this abnormality at baseline, and was enrolled in error. There was no difference in ophthalmic safety between tafenoquine and placebo. CONCLUSION: There was no evidence of any pharmacodynamic effect of 300-mg single-dose tafenoquine on the retina or any short-term clinically relevant effects on ophthalmic safety. This clinical trial is registered with ClinicalTrials.gov (identifier: NCT02658435).

Clinical evaluation of pazopanib eye drops versus ranibizumab intravitreal injections in subjects with neovascular age-related macular degeneration.

PURPOSE: To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). DESIGN: Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose-ranging study of eye drops. PARTICIPANTS: A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by anti-vascular endothelial growth factor intravitreal injections. METHODS: Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n=73); pazopanib 5 mg/ml instilled 3 (n=72) or 4 times daily (n=74); pazopanib 10 mg/ml instilled 2 (n=73), 3 (n=73), or 4 times daily (n=72); or ranibizumab injection administered once every 4 weeks (n=73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed. MAIN OUTCOME MEASURES: The main outcome measures were best-corrected visual acuity (BCVA) and injection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concentrations were determined at weeks 4 and 24. RESULTS: At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3-1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by ≥50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported. CONCLUSIONS: Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone.

Clinical evaluation of pazopanib eye drops in healthy subjects and in subjects with neovascular age-related macular degeneration.

PURPOSE: To evaluate pazopanib 10 mg/mL eye drops (pazopanib) in healthy subjects and in subjects with previously untreated subfoveal choroidal neovascularization secondary to age-related macular degeneration. METHODS: Study 1 (single center, randomized, placebo-controlled, double-masked) included 3 cohorts of 12 to 13 healthy subjects each who instilled pazopanib or placebo 4 times daily for 2 weeks. Study 2 (multicenter open-label) included 19 subjects with neovascular age-related macular degeneration who instilled pazopanib 4 times daily for 12 weeks. Both studies evaluated pharmacokinetics and safety. Study 2 also evaluated efficacy. RESULTS: Steady-state concentrations of pazopanib in plasma seemed to be reached by Week 2. At Week 4 (Study 2), there were no meaningful changes from baseline in the mean central retinal thickness (37.9 µm) or best-corrected visual acuity (0.1 letters) (primary endpoint), retinal morphology, choroidal neovascularization size, or total lesion size. Complement Factor H genotype had no effect on changes from baseline in the best-corrected visual acuity or central retinal thickness. The most common pazopanib-related ocular adverse events included eye irritation (Study 1, n = 7) and instillation site pain (Study 2, n = 3). No serious adverse events were reported. CONCLUSION: Pazopanib was well tolerated. In subjects with previously untreated neovascular age-related macular degeneration, pazopanib instilled 4 times daily as monothereapy did not seem to improve the best-corrected visual acuity or decrease the central retinal thickness.