Efficacy and safety of a new ranibizumab biosimilar CKD-701 using a pro re nata treatment regimen in neovascular age-related macular degeneration: A phase 3 randomized clinical trial
NCT04857177 | Not reported | Yoon CK et al. (2022)
Yoon, C. K., Oh, J., Bae, K., Park, U. C., Yu, K-S., Yu, H. G. Efficacy and safety of a new ranibizumab biosimilar CKD-701 using a pro re nata treatment regimen in neovascular age-related macular degeneration: A phase 3 randomized clinical trial. PLoS ONE, 2022; 17(11): e0275611.
Locations
25 centers in South Korea
Study Period
September 2019 – March 2021
Study Design
Phase 3, multicenter, randomized, double-blind, parallel-group trial
Study Population
Experimental Group
Control Group
Follow-up Time: 12 months
Outcomes
Durability
Number of injections
The average number of administrations of the investigational drug during the entire clinical trial period:
• 8.36 (±3.13) in the CKD-701 group and 8.26 (±2.92) in the reference group.
• No statistically significant difference was observed between the groups (P = 0.619).
The mean number of administrations during the PRN phase:
• 5.76 (±2.76) in the CKD-701 group and 5.43 (±2.75) in the reference group.
• There was no statistically significant difference between groups (P = 0.298).
Vision
Vision Maintaining
(Cochran–Mantel–Haenszel Test (Covariate: PCV presence)
The proportion of Patients Losing <15 Letters at 3 months (Primary Outcome):
• CKD-701 = 143/146, 97.95%
• Ranibizumab = 143/145, 98.62%
• Difference = -0.66% (95% CI: -3.63 to 2.32, p = 0.67)
The proportion of Patients Losing <15 Letters at 6 months:
• CKD-701 = 141/144, 97.92%
• Ranibizumab = 140/143, 97.90%
• Difference = 0.02% (95% CI: -3.29 to 3.33, p = 0.97)
The proportion of Patients Losing <15 Letters at 12 months:
• CKD-701 = 128/134, 95.52%
• Ranibizumab = 132/138, 95.65%
• Difference = -0.07% (95% CI: -4.93 to 4.79, p = 0.98)
The proportion of patients gaining ≥15 Letters at 3 months (Primary Outcome):
• CKD-701 = 24/146, 16.44%
• Ranibizumab = 25/145, 17.24%
• Difference = -0.89% (95% CI: -9.44 to 7.67, p = 0.84)
The proportion of patients gaining ≥15 Letters at 6 months:
• CKD-701 = 31/144, 21.53%
• Ranibizumab = 28/143, 97.90%
• Difference = 1.92% (95% CI: -7.43 to 11.26, p = 0.69)
The proportion of patients gaining ≥15 Letters at 12 months:
• CKD-701 = 33/134, 24.63%
• Ranibizumab = 29/138,21.01%
• Difference = -3.53% (95% CI: -6.43 to 13.48, p = 0.49)
The proportion of Patients Losing ≥15 Letters at 3 months (Primary Outcome):
• CKD-701 = 3/146, 2.05%
• Ranibizumab = 2/145, 1.38%
• Difference = 0.66% (95% CI: -2.32 to3.63, p = 0.67)
The proportion of Patients Losing ≥15 Letters at 6 months:
• CKD-701 = 3/144, 2.08%
• Ranibizumab = 3/143, 2.10%
• Difference = -0.02% (95% CI: -3.23 to 3.29, p = 0.99).
The proportion of Patients Losing ≥15 Letters at 12 months:
• CKD-701 = 6/134, 4.48%
• Ranibizumab = 6/138, 4.35%
• Difference = 0.07% (95% CI: -4.79 to 4.93, p = 0.98)
Best-corrected visual acuity (BCVA)
( Paired t-test or Wilcoxon signed rank test result for change from baseline)
Mean Change in BCVA (ETDRS Letters) in the least squares mean (SE) from baseline to 3 months:
• CKD-701 = 7.14 (0.84)
• Ranibizumab = 6.28 (0.83)
• Difference = 0.87 (95% CI: -1.29 to 3.02, p = 0.43).
Mean Change in BCVA (ETDRS Letters)from baseline to 6 months:
• CKD-701 = 6.93 (0.99)
• Ranibizumab = 7.36 (0.99)
• Difference = -0.38 (95% CI: -3.31 to 2.54, p = 0.80).
Mean Change in BCVA (ETDRS Letters)from baseline to 12 months:
• CKD-701 = 6.84 (1.14)
• Ranibizumab = 7.22 (1.11)
• Difference = -0.38 (95% CI: -3.31 to 2.54, p = 0.80).
Other
N/A
Immunognicity
Cumulative incidence of antidrug antibodies up to 12 months:
• CKD-701 =0/156, 0%
• Ranibizumab = 2/156, 1.3%
• No statistically significant difference was observed between the administration groups at all time points (all P>0.05)
Pharmokinetics
A total of 22 patients were analyzed for PK. Based on comparable Cmax and AUClast values, the PK profiles of the CKD-701 and reference drugs were similar.
Anatomic
Central Retinal Thickness (CRT)
(Covariance analysis)
Mean change (±SD) from baseline to 1 months:
• CKD-701 =-97.36 (±10.07) µm
• Ranibizumab = -98.87(±10.07) µm
• Difference: p >0.05
Mean change (±SD) from baseline to 3 months:
• CKD-701 = -119.3 (±11.96) µm
• Ranibizumab = -124.5 (±11.94) µm
• Difference: p>0.05
Mean change (±SD) from baseline to 6 months:
• CKD-701 =-118.16 (±12.39) µm
• Ranibizumab = -128.81 (±12.36) µm
• Difference: p >0.05
Mean change (±SD) from baseline to 12 months:
• CKD-701 = -123.5 (±13.35) µm
• Ranibizumab = -130.8 (±13.08) µm
• Difference: p >0.05
Fluid status
The proportion of patients without intraretinal or subretinal fluid (IRF or SRF) at 3, 6, and 12 months was not different (all P>0.05):
• The CKD701 arm (54.11%, 48.61%, and 50.00%, respectively)
• The reference arm (64.14%, 48.25%, and 52.17%, respectively)
Safety
Participants with at least one treatment-emergent AEs (TEAEs)
(Chi-square test or Fisher’s exact test)
• AE: CKD-701: 80/156, 51.28% vs. Ranibizumab: 77/154, 50.0% (p = 0.82)
• Adverse drug reaction (ADR): 28/156, 17.95% vs. Ranibizumab: 20/154, 12.99% (p = 0.23)
• Serious AEs (SAEs): 16/156, 10.26% vs. Ranibizumab: 15/154, 9.74% (p = 0.88)
• Serious adverse drug reaction: 2/156, 1.28% vs. Ranibizumab: 3/154, 1.95% (p = 0.68)
• Adverse event of special interest: 6/156, 3.85% vs. Ranibizumab: 8/154, 5.19% (p = 0.57)
• Ocular AE at test eye: 30/156, 19.23% vs. Ranibizumab: 27/154, 17.53% (p = 0.70)
• Ocular AE at fellow eye: 14/156, 8.97% vs. Ranibizumab: 10/154, 6.49% (p = 0.41)
• Non-Ocular AE: 52/156, 33.33% vs. Ranibizumab: 54/154, 35.06% (p = 0.75)
Patients with ocular AE in > 1.5%
(Chi-square test or Fisher’s exact test)
• Dry eye: CKD-701: 10/156, 6.41% vs. Ranibizumab:5/154, 3.25% (p = 0.19)
• Neovascular AMD: 8/156, 5.13% vs. Ranibizumab: 4/154, 2.60% (p = 0.25)
• Vitreous floaters: 5/156, 3.21% vs. Ranibizumab: 1/154,0.65% (p = 0.21)
• Conjunctival hemorrhage: 1/156, 0.64% vs. Ranibizumab: 4/154, 2.60% (p = 0.21)
• Retinal hemorrhage: 3/156, 1.92% vs. Ranibizumab: 2/154, 1.30% (p = 1.00)
• Cataract: 3/156, 1.92% vs. Ranibizumab: 1/154, 0.65% (p = 0.62)
• Eye pruritus: 3/156, 1.92% vs. Ranibizumab: not reported (p = 0.25)
Patients with non-ocular AE in >1.5%
(Chi-square test or Fisher’s exact test)
• Nasopharyngitis: CKD-701: 5/156, 3.21% vs. Ranibizumab: 3/154, 1.95% (p = 0.72)
• Pneumonia: 1/156, 0.64% vs. Ranibizumab: 3/154, 1.95% (p = 0.379)
• Back pain: 3/156, 1.92% vs. Ranibizumab: 1/154,0.65% (p = 0.62)
• Gastritis: 1/156, 0.64% vs. Ranibizumab: 4/154, 2.60% (p = 0.21)
• Urticaria: 3/156, 1.92% vs. Ranibizumab: 2/154, 1.30% (p = 1.00)
• Hypertension: 2/156, 1.28% vs. Ranibizumab: 3/154, 1.95% (p = 0.68)
Conclusion
CKD-701 demonstrated equivalent efficacy, safety, and immunogenicity to reference ranibizumab under a PRN treatment regimen, supporting its use as a biosimilar for nAMD treatment.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “Stratified randomization is performed…through the Interactive Web Response System. Participants, investigators, and site personnel remained blinded throughout the study.” “The demographic characteristics of the patients enrolled in both arms were comparable in terms of age, height, and weight.”
Missing Outcome Data
High risk
Note: The missingness likely depended on true value: The missingness was unbalanced between the two groups both in reasons and the rate (10/146=6.4 % > 5% vs. 8/156=5.1%>5%).
Selection of the Reported Results
Low risk Note: Registration with the protocol.
Deviations from Intended Observations
High risk Note: This is a double-blinded study. However, inappropriate analysis was applied for the primary outcome using a per-protocol (PP) set. In addition, the missingness was unbalanced between the two groups in reasons and the rates (10/146 = 6.4 % > 5% vs. 8/156=5.1%>5%). There was potential for a substantial impact (on the result) of the failure to analyze participants in the group to which they were randomized.
Measurement of the Outcome
Low risk Note: This is a double-blinded study. In addition, the primary outcome was measured using “…a centralized and independent image reading center (Seoul Reading Center).”
Overall
High risk
Categories: Wet AMD