Frank G Holz1, Pravin U Dugel2, Georges Weissgerber3, Robin Hamilton4, Rufino Silva5, Francesco Bandello6, Michael Larsen7, Andreas Weichselberger3, Andreas Wenzel3, Anne Schmidt8, Dominik Escher8, Laura Sararols9, Eric Souied10. 1. Department of Ophthalmology, University of Bonn, Bonn, Germany. 2. Retinal Consultants of Arizona, Phoenix, Arizona; USC Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California. Electronic address: pdugel@gmail.com. 3. Alcon, a Novartis company, Fort Worth, Texas. 4. NIHR BRC at Moorfields Eye Hospital and Moorfields Eye Hospital, NHS Foundation Trust, Ophthalmology, London, United Kingdom. 5. Centro Hospitalar e Universitário de Coimbra, Faculty of Medicine, University of Coimbra, and Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal. 6. Università Vita-Salute, Istituto Scientifico San Raffaele, Milan, Italy. 7. Department of Ophthalmology, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark. 8. ESBATech, A Novartis company, Zurich, Switzerland. 9. Hospital General de Catalunya, Barcelona, Spain. 10. Service Universitaire d'Ophtalmologie, Hôpital Intercommunal, Université Paris Est, Créteil, France.
Abstract
PURPOSE: To assess the safety and efficacy of different doses of RTH258 applied as single intravitreal administration compared with ranibizumab 0.5 mg in patients with neovascular age-related macular degeneration (AMD). DESIGN: Six-month, phase 1/2, prospective, multicenter, double-masked, randomized, ascending single-dose, active-controlled, parallel-group study. PARTICIPANTS: A total of 194 treatment-naive patients, aged ≥50 years, with primary subfoveal choroidal neovascularization secondary to AMD. METHODS: Patients received a single intravitreal injection of RTH258 0.5 mg (n = 11), 3.0 mg (n = 31), 4.5 mg (n = 47), or 6.0 mg (n = 44), or ranibizumab 0.5 mg (n = 61). MAIN OUTCOME MEASURES: The primary efficacy end point was the change from baseline to month 1 in central subfield thickness (CSFT) measured by spectral-domain optical coherence tomography. The secondary efficacy end point was the duration of treatment effect measured as time from the initial injection to receipt of post-baseline therapy (PBT) guided by protocol-defined criteria. Adverse events (AEs) were recorded throughout the study. RESULTS:RTH258 demonstrated noninferiority compared with ranibizumab in mean change in CSFT from baseline to month 1 for the 4.5- and 6.0-mg dose groups (margin: 40 μm, 1-sided alpha 0.05). The difference in CSFT change at month 1 comparison with ranibizumab was 22.86 μm (90% confidence interval [CI], -9.28 to 54.99) and 19.40 μm (95% CI, -9.00 to 47.80) for RTH258 4.5 and 6 mg, respectively. The median time to PBT after baseline therapy was 60 and 75 days for patients in the RTH258 4.5- and 6.0-mg groups, respectively, compared with 45 days for ranibizumab. Changes in best-corrected visual acuity with RTH258 were comparable to those observed with ranibizumab. The most frequent AEs reported for the RTH258 groups were conjunctival hemorrhage, eye pain, and conjunctival hyperemia; the majority of these events were mild in intensity. CONCLUSIONS: This first-in-human study of RTH258 demonstrated noninferiority in the change in CSFT at 1 month for the 4.5- and 6.0-mg doses compared with ranibizumab and an increase of 30 days in the median time to PBT for the 6.0-mg dose. There were no unexpected safety concerns, and the results support the continued development of RTH258 for the treatment of neovascular AMD.
RCT Entities:
PURPOSE: To assess the safety and efficacy of different doses of RTH258 applied as single intravitreal administration compared with ranibizumab 0.5 mg in patients with neovascular age-related macular degeneration (AMD). DESIGN: Six-month, phase 1/2, prospective, multicenter, double-masked, randomized, ascending single-dose, active-controlled, parallel-group study. PARTICIPANTS: A total of 194 treatment-naive patients, aged ≥50 years, with primary subfoveal choroidal neovascularization secondary to AMD. METHODS:Patients received a single intravitreal injection of RTH258 0.5 mg (n = 11), 3.0 mg (n = 31), 4.5 mg (n = 47), or 6.0 mg (n = 44), or ranibizumab 0.5 mg (n = 61). MAIN OUTCOME MEASURES: The primary efficacy end point was the change from baseline to month 1 in central subfield thickness (CSFT) measured by spectral-domain optical coherence tomography. The secondary efficacy end point was the duration of treatment effect measured as time from the initial injection to receipt of post-baseline therapy (PBT) guided by protocol-defined criteria. Adverse events (AEs) were recorded throughout the study. RESULTS:RTH258 demonstrated noninferiority compared with ranibizumab in mean change in CSFT from baseline to month 1 for the 4.5- and 6.0-mg dose groups (margin: 40 μm, 1-sided alpha 0.05). The difference in CSFT change at month 1 comparison with ranibizumab was 22.86 μm (90% confidence interval [CI], -9.28 to 54.99) and 19.40 μm (95% CI, -9.00 to 47.80) for RTH258 4.5 and 6 mg, respectively. The median time to PBT after baseline therapy was 60 and 75 days for patients in the RTH258 4.5- and 6.0-mg groups, respectively, compared with 45 days for ranibizumab. Changes in best-corrected visual acuity with RTH258 were comparable to those observed with ranibizumab. The most frequent AEs reported for the RTH258 groups were conjunctival hemorrhage, eye pain, and conjunctival hyperemia; the majority of these events were mild in intensity. CONCLUSIONS: This first-in-human study of RTH258 demonstrated noninferiority in the change in CSFT at 1 month for the 4.5- and 6.0-mg doses compared with ranibizumab and an increase of 30 days in the median time to PBT for the 6.0-mg dose. There were no unexpected safety concerns, and the results support the continued development of RTH258 for the treatment of neovascular AMD.
Authors: Hong Xin; Nilima Biswas; Pin Li; Cuiling Zhong; Tamara C Chan; Eric Nudleman; Napoleone Ferrara Journal: Proc Natl Acad Sci U S A Date: 2021-05-25 Impact factor: 11.205
Authors: Sharon D Solomon; Kristina Lindsley; Satyanarayana S Vedula; Magdalena G Krzystolik; Barbara S Hawkins Journal: Cochrane Database Syst Rev Date: 2019-03-04