Data Monitoring for the Chinese Clinical Trials of Remdesivir in Treating Patients with COVID-19 During the Pandemic Crisis

Abstract

Two phase-III, double-blind, randomized clinical trials of remdesivir plus SOC (standard of care) versus placebo plus SOC have been conducted in Wuhan hospitals by Chinese investigators during the urgent COVID-19 epidemic [ClincalTrials.gov NCT04257656 and NCT04252664]. These trials have been highly anticipated worldwide. We expect investigators of the trials will soon report the clinical and laboratory findings from the medical perspective. This manuscript provides documentary style information on the process of monitoring key data and making recommendations to the sponsor and investigators based on analytical insights when dealing with the emergent situation from the statistical viewpoint. Having monitored data sequentially from 237 patients, we comment on the strength and weakness of the study design and suggest the treatment effect of remdesivir on severe COVID-19 cases. Our experience with using the Dynamic Data Monitoring (DDM) tool has demonstrated its efficiency and reliability in supporting DSMB's instantaneous review of essential data during the emergent situation. DDM, when used properly by disciplined statisticians, has shown its capability of exploring the trial data flexibly and, in the meantime, protecting the trial's scientific integrity.

Keywords: COVID-19 pandemic; DDM; DSMB; ICH; Monitoring clinical trials; Remdesivir; eDMC.

Figure 1

DSMB First Data Review: Distribution of 6-Category Scale Score by Baseline Score at Day 10. Green Color is Placebo, Red Color is Remdesivir. Number of Patients in Each Group: Placebo 51, Remdesivir 91. Median Score in Each Group: Placebo 3, Remdesivir 3.

Figure 2

DSMB First Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, on Day 3; The Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%

Figure 3

DSMB First Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, On Day 5; The Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%

Figure 4

DSMB First Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, on Day 7; The Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%

Figure 5

DSMB First Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, on Day 10; The Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash line Represented CP = 50%

Figure 6

DSMB Second Data Review: Distribution of 6-Category Scale by Baseline Score at Day 14. Green Color is Placebo, Red Color is Remdesivir. Number of Patients in Each Group: Placebo 59, Remdesivir 118. Median Score in Each Group: Placebo 3, Remdesivir 3

Figure 7

DSMB Second Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, on Day 7; the Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%

Figure 8

DSMB Second Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number Of Patients Enrolled, on Day 10; The Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%

Figure 9

DSMB Second Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, on Day 14; the Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%

Figure 10

DSMB Second Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, on Day 21; the Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%

Figure 11

DSMB Third Data Review: Distribution of 6-Category Scale by Baseline Score at Day 21. Green Color Is Placebo, Red Color Is Remdesivir. Number of Patients in Each Group: Placebo 68, Remdesivir 129. Median Score in Each Group: Placebo 3, Remdesivir 2

Figure 12

DSMB Third Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, on Day 10. The Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%

Figure 13

DSMB Third Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, on Day 14. The Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%

Figure 14

DSMB Third Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, on Day 21. The Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%

Figure 15

DSMB Third Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, on Day 28. The Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%

Figure 16

DSMB Fourth Data Review: Distribution of 6-Category Scale by Baseline Score at Day 28. Green Color Is Placebo, Red Color Is Remdesivir. Number of Patients in Each Group: Placebo 76, Remdesivir 149. Median Score in Each Group: Placebo 1, Remdesivir 1

Figure 17

DSMB Fourth Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, on Day 10. The Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%

Figure 18

DSMB Fourth Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, on Day 14. The Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%

Figure 19

DSMB Fourth Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, on Day 21. The Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%

Figure 20

DSMB Fourth Data Review: Dynamic Data Monitoring Z-Score from Stratified Wilcoxon–Mann–Whitney Rank-Sum Test Along Number of Patients Enrolled, on Day 28. The Upper Boundary of the “Promising Zone” Was Set for Conditional Probability (CP) = 90% and the Lower Boundary Was Set for CP = 5%. The Middle Dash Line Represented CP = 50%