A Randomized, Double-Masked, Multicenter Trial of Topical Acrizanib (LHA510), a Tyrosine Kinase VEGF-Receptor Inhibitor, in Treatment-Experienced Subjects With Neovascular Age-Related Macular Degeneration
NCT02355028 | Not reported | Poor SH et al. (2022)
Poor, S. H., Weissgerber, G., Adams, C. M., Bhatt, H., Browning, D. J., Chastain, J., Ciulla, T. A., Ferriere, M., Gedif, K., Glazer, L. C., Joondeph, B. C., Normand, G., Sheth, V., Watters, C., Grosskreutz, C. L. A Randomized, Double-Masked, Multicenter Trial of Topical Acrizanib (LHA510), a Tyrosine Kinase VEGF-Receptor Inhibitor, in Treatment-Experienced Subjects With Neovascular Age-Related Macular Degeneration. Am J Ophthalmol, 2022; 239:180-189.
Locations
16 clinical centers in the United States
Study Period
Not reported
Study Design
Phase 2, multicenter, randomized, double-masked, vehicle-controlled trial
Study Population
Experimental Group
Control Group
Follow-up Time: 84 days
Outcomes
Durability
Vision
Best-Corrected Visual Acuity (BCVA)
The changes in BCVA from baseline to any study visit (p>0.05).
Other
Need for Rescue Therapy
Required rescue by Day 84 (Primary Outcome):
• LHA510: 25/33 (75.8%)
• Vehicle: 25/37 (67.6%)
• Difference (Fisher’s exact test) = 8.2% (p = 0.85).
Time to First Rescue
The results did not show meaningful differences between treatment groups in the time to first ranibizumab rescue need identification up to day 84.
Immunognicity
Not reported
Pharmokinetics
Systemic exposure of LHA510 was very low. Concentrations of LHA510 ranged from below the limit of quantitation (≤0.02 ng/mL) to 0.206 ng/mL.
Anatomic
Central Subfield Thickness (CSFT)
The changes from baseline in CSFT to any study visit (p>0.05)
Safety
Patients experienced at least 1 AE
• LHA510: 34/46, 73.9%
• Vehicle: 16/45, 35.6%
Patients experienced at least 1 AE that treatment-related
• LHA510: 26/46, 56.5%
• Vehicle: 4/45, 8.9%
Ocular-related AEs (Study Eye)
Corneal opacity:
• LHA510: 19 patients, 41.3%
• Vehicle: 0
Corneal edema:
• LHA510: 8 patients, 17.5%
• Vehicle: 0
Vision blurred:
• LHA510: 6 patients, 13.0%
Eye irritation and keratopathy
• LHA510: 5 patients, 10.9% each
• Vehicle: 3 patients, 6.7%
Vital dye staining cornea present
• LHA510: 4 patients, 8.7%
Visual acuity reduced
• LHA510: 3 patients, 6.5%
Non-ocular AEs
• No deaths
• One serious AE in the LHA510 group (angina pectoris, not treatment-related).
Conclusion
Despite extensive formulation efforts, topical acrizanib (LHA510) failed to demonstrate clinical efficacy in reducing the need for rescue anti-VEGF therapy. The high incidence of corneal adverse events suggests challenges in tolerability.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “Eligible subjects were randomized in a 1:1 ratio in an unbiased masked manner by a statistical program to active drug or placebo. The identity of the individual assignments was concealed by use of investigational product (IP) with identical packaging, labeling, schedule of administration, appearance, and odor.” “No important differences were noted between treatment groups.”
Missing Outcome Data
Low risk
Note: The evidence that the result was not biased by missing outcome data is that the PPS (primary efficacy analysis set) analysis acted as the sensitivity analysis.
Selection of the Reported Results
Low risk Note: Registration with the protocol
Deviations from Intended Observations
Low risk Note: This is a double-masked study. The primary outcome analysis is based on the full analysis set (FAS), which is considered a mITT analysis.
Measurement of the Outcome
Low risk Note: This is a double-masked study. Although it is a multiple-site study, the definition for the primary outcome is consistent: “Evidence of fluid accumulation in the retina was confirmed post hoc by a reading center assessment of SD-OCT images.”
Overall
Low risk
Categories: Wet AMD