Two different treatment regimens of ranibizumab 0.5 mg for neovascular age-related macular degeneration with or without polypoidal choroidal vasculopathy in Chinese patients: results from the Phase IV, randomized, DRAGON study
NCT01775124 | DRAGON | Li X et al. (2021)
Li, X., Zhu, Q., Egger, A., Chang, L., Wolf, S., Song, Y., Zhang, J., Dong, F., Xu, X., Weisberger, A. Two different treatment regimens of ranibizumab 0.5 mg for neovascular age-related macular degeneration with or without polypoidal choroidal vasculopathy in Chinese patients: results from the Phase IV, randomized, DRAGON study. Acta Ophthalmologica, 2021; 99: e336-e345.
Locations
23 centers in China
Study Period
February 2013 – November 2015
Study Design
Phase IV, randomized, double-masked, multicenter trial
Study Population
Experimental Group
Control Group
Follow-up Time: 24 months
Outcomes
Durability
The Number of Injections
The mean number of ranibizumab injections from Day 1 to Month 11:
• Monthly regimen: 11.4
• PRN regimen: 8.2
The mean number of ranibizumab injections from Month 12 to Month 23 when
both arms received PRN treatment:
• Monthly regimen: 4.8
• PRN regimen: 5.1
Duration of Ranibizumab Treatment-free Intervals
The mean duration of the first, second and
third treatment-free interval prior to
Month 12:
• Monthly regimen: not possible
• PRN regimen: 2.7, 2.0, and 1.3 months
The mean duration of the first, second and third treatment-free interval prior to Month 24 was longer in the ranibizumab PRN group than in the ranibizumab monthly group:
• For the first (3.7 months versus 2.9 months)
• For the second (3.3 months versus 2.1 months)
• For the third (3.0 months versus 1.5 months)
Vision
Best-Corrected Visual Acuity (BCVA)
Mean BCVA change from Month 3 to Month 4 through Month 12 (Primary Outcome):
• Monthly regimen=Mean 3.3 (SD 5.61)
• PRN regimen= Mean 1.7 (SD 6.87)
• The least square mean difference in this increase between both regimens was -1.6 letters (95% CI: -2.95 to -0.20)
Vision Maintaining
The number of patients who gained ≥15 letters in BCVA was slightly higher with the ranibizumab 0.5 mg monthly regimen than with the PRN regimen, while the number of patients with a loss of <15 letters or gain of ≥30 letters was comparable between both treatment regimens.
The proportion of patients who had a
BCVA score of ≥73 letters:
• Monthly regimen = 41.2% at 12 Month 12 and 38.2% at Month 24
• PRN regimen = 33.7% at 12 Month 12 and 35.5% at Month 24
The proportion of patients with BCVA ≥69 ETDRS letters were comparable between PCV and non-PCV subgroups at months 12 and 24.
Other
N/A
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Central Subfield Thickness (CFST)
Mean CSFT change at Month 12:
• Monthly regimen = -166.5 µm
• PRN regimen = -155.7
A decrease in mean CSFT was observed early (mainly during the first 2 months) with both treatment regimens and was maintained thereafter until the end of the study.
Safety
Ocular AEs
Total events:
• Monthly regimen: 54 (32.5%)
• PRN regimen: 45 (27.1%)
Conjunctival haemorrhage:
• Monthly regimen: 21 (12.7%)
• PRN regimen: 11 (6.6%)
Conjunctivitis:
• Monthly regimen: 5 (3.0%)
• PRN regimen: 2 (1.2%)
Visual acuity reduced:
• Monthly regimen: 5 (3.0%)
• PRN regimen: 1 (0.6%)
Eye pain:
• Monthly regimen: 4 (2.4%)
• PRN regimen: 1 (0.6%)
Foreign body sensation:
• Monthly regimen: 4 (2.4%)
• PRN regimen: 2 (1.2%)
Intraocular pressure increased:
• Monthly regimen: 4 (2.4%)
• PRN regimen: 12 (7.2%)
Lacrimation increased:
• Monthly regimen: 4 (2.4%)
• PRN regimen: 1 (0.6%)
Retinal haemorrhage 3 (1.8) 5 (3.0)
• Monthly regimen: 1 (1.8%)
• PRN regimen: 5 (3.0%)
Non-ocular AEs
Total events:
• Monthly regimen: 98 (59.0%)
• PRN regimen: 82 (49.4%)
Nasopharyngitis:
• Monthly regimen: 24 (14.5%)
• PRN regimen: 18 (10.8%)
Upper respiratory tract infection:
• Monthly regimen: 14 (8.4%)
• PRN regimen: 7 (4.2%)
Blood glucose increased:
• Monthly regimen: 10 (6.0%)
• PRN regimen: 5 (3.0%)
Cough:
• Monthly regimen: 8 (4.8%)
• PRN regimen: 7 (4.2%)
Hypertension:
• Monthly regimen: 8 (4.8%)
• PRN regimen: 9 (5.4%)
Dizziness:
• Monthly regimen: 5 (3.0%)
• PRN regimen: 7 (4.2%)
Blood uric acid increased 4 (2.4) 5 (3.0)
• Monthly regimen: 4 (2.4%)
• PRN regimen: 5 (3.0%)
Serious AEs (SAEs)
Total events:
• Monthly regimen: 14.5%
• PRN regimen: 14.5%
Ocular SAEs (study eye)
Total events:
• Monthly regimen: 2 (1.2%)
• PRN regimen: 2 (1.2%)
Cataract traumatic:
• Monthly regimen: 1 (0.6%)
• PRN regimen: 0
Retinal detachment:
• Monthly regimen: 1 (0.6%)
• PRN regimen: 0
Vitreous haemorrhage:
• Monthly regimen: 0
• PRN regimen: 2 (1.2%)
Non-ocular SAEs Total events:
• Monthly regimen: 21 (12.7%)
• PRN regimen: 22 (13.3%)
Cerebral infarction:
• Monthly regimen: 4 (2.4%)
• PRN regimen: 1 (0.6%)
Angina pectoris:
• Monthly regimen: 1 (1.2%)
• PRN regimen: 0
Coronary artery disease:
• Monthly regimen: 2 (1.2%)
• PRN regimen: 1 (0.6%)
Lacunar infarction 0 2 (1.2)
• Monthly regimen: 0
• PRN regimen: 2 (1.2%)
Death
One death was reported in the PRN regimen group following a myocardial infarction SAE
Conclusion
Ranibizumab 0.5 mg monthly and PRN regimens were both effective in Chinese patients with nAMD, including those with PCV. The monthly regimen led to slightly greater BCVA gains, but both regimens had similar safety profiles.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “Interactive Response Technology was used to randomize all eligible patients to one of the treatment arms.”
“Baseline demographics and ocular characteristics were similar between the monthly and PRN treatment groups.”
Missing Outcome Data
Low risk
Note: Evidence that the result was not biased by missing outcome data (sensitivity analysis): “The missing values of BCVA from months 4 to 12 were imputed using the FAS based on mean value interpolation and last observation carried forward.” “A sensitivity analysis of the primary efficacy variable was performed within the FAS in which only the observed values were used without missing data imputation.”
Selection of the Reported Results
Low risk Note: have registration with protocol.
Deviations from Intended Observations
Low risk Note: This is a double-masked study. “Efficacy analyses were performed using the full analysis set (FAS) that included all randomized patients to whom the study treatment was assigned.”
Measurement of the Outcome
Some concerns Note: This is a double-masked study. However, this is a multiple-site study, the assessment of the primary outcome may exist difference between different sites.
Overall
Some Concerns
Categories: Wet AMD