To the Editor,
We published in the December 2021 issue of Clinical Microbiology and Infection the preliminary results of the DisCoVeRy trial regarding the efficacy of lopinavir/ritonavir, lopinavir/ritonavir plus interferon (IFN)-β-1a, and hydroxychloroquine in hospitalized patients with COVID-19 [1]. These three experimental repurposed treatments did not show clinical or virological benefit in the studied population. Of note, the number of patients included was low as inclusion in those arms of the trial was prematurely stopped by the data safety monitoring board (DSMB). Here, after completion of data monitoring, we report the final analysis, including two secondary endpoints which were not previously reported.
Briefly, the DisCoVeRy trial is a phase 3 open-label randomized, controlled trial evaluating the efficacy and safety of repurposed drugs in adults hospitalized for COVID-19, sponsored by Inserm (NCT04315948). The trial was approved by the Ethics Committee (CPP Ile-de-France-III, approval #20.03.06.51,744). Eligible participants were adults (aged ≥18 years) hospitalized with a PCR-positive (<72 hours) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pulmonary rales or crackles with a peripheral oxygen saturation ≤94% or requiring supplemental oxygen. The primary endpoint was the clinical status at day 15 as measured on the following 7-point ordinal scale of the WHO Master Protocol (version 3.0, March 3, 2020), analyzed using a proportional odds model: (1) not hospitalized, no limitation on activities; (2) not hospitalized, limitation on activities; (3) hospitalized, not requiring supplemental oxygen; (4) hospitalized, requiring supplemental oxygen; (5) hospitalized, on non-invasive ventilation or high flow oxygen devices; (6) hospitalized, on invasive mechanical ventilation or Extracorporeal membrane oxygenation (ECMO); and (7) death. Full details on the trial design are available in [1].
In the final dataset, 603 participants were randomized and 593 were evaluable for analysis—control arm (n = 149), lopinavir and ritonavir arm (n = 147), lopinavir and ritonavir plus IFN-ß-1a arm (n = 147), and hydroxychloroquine arm (n = 150). Regarding the primary endpoint, the final adjusted OR (aOR) for clinical improvement using the 7-point ordinal scale at day 15 were not in favour of experimental treatments—lopinavir and ritonavir vs. control, aOR 0.82 (95% CI, 0.54–1.25); lopinavir and ritonavir plus IFN-ß-1a vs. control, aOR 0.69 (95% CI, 0.45–1.05); hydroxychloroquine vs. control, aOR 0.94 (95% CI, 0.62–1.41) (Table 1 ). Some modifications were observed regarding the secondary outcomes; full results are available elsewhere [2]. In-hospital mortality was not affected by any treatment arm (Table 1). Three-month mortality was significantly higher for participants assigned to the lopinavir/ritonavir plus IFN-ß-1a arm than participants assigned to the control arm, while no difference was observed for the lopinavir/ritonavir and the hydroxychloroquine arms (Table 1). In addition, participants assigned to the lopinavir/ritonavir plus IFN-ß-1a had a significantly longer time to hospital discharge, either when considered as a single endpoint or as composite endpoints (Table 1).
Table 1.
Primary and secondary outcomes for patients included in the DisCoVeRy trial for L/r, L/r plus IFN-β-1a, and HCQ, according to disease severity at baseline
| Overall (N = 593) |
Control (n = 149) |
L/r (n = 147) |
L/r + IFN-ß-1a (n = 147) |
HCQ (n = 150) |
L/r vs. control effect measure (95% CI) |
L/r + IFN-ß-1a vs. control effect measure (95% CI) |
HCQ vs. control effect measure (95% CI) |
||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Moderate (n = 379) | Severe (n = 214) | Moderate (n = 95) | Severe (n = 54) | Moderate (n = 95) | Severe (n = 52) | Moderate (n = 93) | Severe (n = 54) | Moderate (n = 96) | Severe (n = 54) | ||||
| 7-point ordinal scale at day 15, n (%) | |||||||||||||
| 1. Not hospitalized, no limitations on activities | 83 (21.9) | 3 (1.4) | 22 (23.2) | 1 (1.9) | 21 (22.1) | 1 (1.9) | 20 (21.5) | 0 (0.0) | 20 (20.8) | 1 (1.9) | OR = 0.82 (0.54 to 1.25) [P = 0.36] | OR = 0.69 (0.45 to 1.05) [P = 0.08] | OR = 0.94 (0.62 to 1.41) [P = 0.76] |
| 2. Not hospitalized, limitation on activities | 155 (40.9) | 16 (7.5) | 44 (46.3) | 6 (11.1) | 37 (38.9) | 2 (3.8) | 37 (39.8) | 1 (1.9) | 37 (38.5) | 7 (13.0) | |||
| 3. Hospitalized, not requiring supplemental oxygen | 53 (14.0%) | 25 (11.7%) | 8 (8.4%) | 5 (9.3%) | 14 (14.7%) | 6 (11.5%) | 13 (14.0%) | 6 (11.1%) | 18 (18.8%) | 8 (14.8%) | |||
| 4. Hospitalized, requiring supplemental oxygen | 40 (10.6) | 32 (15.0) | 10 (10.5) | 10 (18.5) | 10 (10.5) | 9 (17.3) | 9 (9.7) | 6 (11.1) | 11 (11.5) | 7 (13.0) | |||
| 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices | 6 (1.6%) | 8 (3.7%) | 1 (1.1%) | 2 (3.7%) | 2 (2.1%) | 1 (1.9%) | 2 (2.2%) | 3 (5.6%) | 1 (1.0%) | 2 (3.7%) | |||
| 6. Hospitalized, on invasive mechanical ventilation or ECMO | 27 (7.1) | 107 (50.0) | 6 (6.3) | 24 (44.4) | 8 (8.4) | 29 (55.8) | 8 (8.6) | 28 (51.9) | 5 (5.2) | 26 (48.1) | |||
| 7. Death | 15 (4.0) | 23 (10.7) | 4 (4.2) | 6 (11.1) | 3 (3.2) | 4 (7.7) | 4 (4.3) | 10 (18.5) | 4 (4.2) | 3 (5.6) | |||
| 7-point ordinal scale at day 29, n (%) | |||||||||||||
| 1. Not hospitalized, no limitations on activities | 150 (39.6) | 20 (9.3) | 36 (37.9) | 7 (13.0) | 35 (36.8) | 6 (11.5) | 36 (38.7) | 1 (1.9) | 43 (44.8) | 6 (11.1) | OR 0.95 (0.63 to 1.43) (p = 0.80 | OR 0.80 (0.53 to 1.21) (p = 0.29) | OR 1.26 (0.84 to 1.90) (p = 0.27) |
| 2. Not hospitalized, limitation on activities | 135 (35.6) | 34 (15.9) | 35 (36.8) | 5 (9.3) | 39 (41.1) | 8 (15.4) | 31 (33.3) | 9 (16.7) | 30 (31.3) | 12 (22.2) | |||
| 3. Hospitalized, not requiring supplemental oxygen | 40 (10.6) | 47 (22.0) | 11 (11.6) | 15 (27.8) | 9 (9.5) | 8 (15.4) | 10 (10.8) | 11 (20.4) | 10 (10.4) | 13 (24.1) | |||
| 4. Hospitalized, requiring supplemental oxygen | 14 (3.7) | 20 (9.3) | 5 (5.3) | 6 (11.1) | 3 (3.2) | 4 (7.7) | 4 (4.3) | 6 (11.1) | 2 (2.1) | 4 (7.4) | |||
| 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices | 5 (1.3) | 7 (3.3) | 1 (1.1) | 1 (1.9) | 2 (2.1) | 2 (3.8) | 1 (1.1) | 1 (1.9) | 1 (1.0) | 3 (5.6) | |||
| 6. Hospitalized, on invasive mechanical ventilation or ECMO | 14 (3.7) | 50 (23.4) | 2 (2.1) | 12 (22.2) | 3 (3.2) | 14 (26.9) | 5 (5.4) | 13 (24.1) | 4 (4.2) | 11 (20.4) | |||
| 7. Death | 21 (5.5) | 36 (16.8) | 5 (5.3) | 8 (14.8) | 4 (4.2) | 10 (19.2) | 6 (6.5) | 13 (24.1) | 6 (6.3) | 5 (9.3) | |||
| Time to improvement of 2 categories of the 7-point ordinal scale or hospital discharge within day 29, d, median (IQR) | 10 (7–17) | 21 (13–29) | 9 (6–14) | 18 (10–29) | 12 (8–17) | 28 (14–29) | 11 (8–19) | 29 (1629) | 10 (7–19) | 18 (12–29) | HR 0.70 (0.54 to 0.92) (p = 0.01) | HR 0.68 (0.52 to 0.89) (p = 0.008) | HR 0.79 (0.61 to 1.03) (p = 0.09) |
| Time to National Early Warning Score ≤2 or hospital discharge within 29 days, d, median (IQR) | 9 (5–16) | 29 (19–29) | 8 (5–14) | 29 (19–29) | 10 (6–16) | 29 (21–29) | 10 (6–18) | 29 (29–29) | 9 (5–15) | 29 (16–29) | HR 0.84 (0.64 to 1.10) (p = 0.21) |
HR 0.72 (0.54 to 0.96) (p = 0.02) | HR 0.93 (0.71 to 1.23) (p = 0.63) |
| Time to hospital discharge within 29 days, d, median (IQR) | 11 (7–21) | 29 (22–29) | 9 (6–16) | 29 (19–29) | 12 (8–21) | 29 (23–29) | 11 (8–26) | 29 (29–29) | 11 (8–21) | 29 (17–29) | HR 0.81 (0.61 to 1.08) (p = 0.15) |
HR 0.72 (0.54 to 0.97) (p = 0.03) | HR 0.84 (0.63 to 1.12) (p = 0.24) |
| Oxygenation-free days until day 29, d, median (IQR) | 22 (15–25) | 0 (0–13) | 22 (15–25) | 4 (0–14) | 22 (15–25) | 0 (0–13) | 22 (15–25) | 0 (0–7) | 22 (17–25) | 5 (0–15) | LSMD = -0.99 (-2.92 to 0.95) (p = 0.32) |
LSMD = -1.70 (-3.63 to 0.24) (p = 0.09) | LSMD = 0.06 (-1.89 to 2.01) (p = 0.95) |
| Ventilator-free days until day 29, d, median (IQR) | 29 (29–29) | 11 (0–20) | 29 (29–29) | 13 (0–22) | 29 (29–29) | 5 (0–20) | 29 (29–29) | 4 (0–16) | 29 (29–29) | 14 (1–22) | LSMD = -0.75 (-2.72 to 1.22) (p = 0.46) | LSMD = -2.07 (-4.08 to -0.05) (p = 0.05) | LSM D = 0.35 (-1.64 to 2.34) (p = 0.73) |
| In-hospital mortality,n (%) | 20 (5.3) | 36 (16.8) | 5 (5.3) | 8 (14.8) | 4 (4.2) | 10 (19.2) | 5 (5.4) | 13 (24.1) | 6 (6.3) | 5 (9.3) | OR 1.12 (0.50 to 2.51) (p = 0.70) |
OR 1.47 (0.68 to 3.18) (p = 0.32) | OR 0.89 (0.36 to 1.92) (p = 0.66) |
| Death within 28 days,n (%) | 20 (5.3) | 36 (16.8) | 5 (5.3) | 8 (14.8) | 4 (4.2) | 10 (19.2) | 5 (5.4) | 13 (24.1) | 6 (6.3) | 5 (9.3) | OR 1.12 (0.50 to 2.51) (p = 0.70) |
OR 1.47 (0.68 to 3.18) (p = 0.32) | OR 0.89 (0.36 to 1.92) (p = 0.66) |
| Death within 90 days,n (%) | 23 (6.1) | 46 (21.5) | 5 (5.3) | 8 (14.8) | 5 (5.3) | 12 (23.1) | 7 (7.5) | 17 (31.5) | 6 (6.3) | 9 (16.7) | OR 1.41 (0.65 to 3.06) (p = 0.39) |
OR 2.11 (1.01 to 4.39) (p = 0.04) | OR 1.17 (0.53 to 2.58) (p = 0.70) |
Analyses were stratified on the disease severity at baseline (moderate: 7-point ordinal scale 3 or 4; severe: 7-point ordinal scale 5 or 6), and adjusted effect measures are reported in the table. Abbreviations: ECMO, Extracorporeal membrane oxygenation; HCQ, hydroxychloroquine; HR, hazard ratio; IFN, interferon; IQR, interquartile range; LRT, L/r, Lopinavir/ritonavir; lower respiratory tract; LSMD, least-square mean difference; NP, nasopharyngeal.
The previously reported higher rate of participants experiencing any adverse event in the lopinavir/ritonavir plus IFN-ß-1a arm was no longer significant in the final dataset—control arm (n = 113/149, 75.8%), lopinavir/ritonavir plus IFN-ß-1a arm (n = 122/145, 84.1%; p = 0.08 vs. control); it remained significantly higher in the lopinavir and ritonavir arm (n = 125/147, 85.0%; p = 0.05 vs. control). Regarding the reporting of any serious adverse event, the proportion remained significantly higher in both lopinavir and ritonavir-containing arms than in the control arm—control arm (n = 58/149, 38.9%), lopinavir and ritonavir arm (n = 76/147, 51.7%; p = 0.02 vs. control), lopinavir/ritonavir plus IFN-ß-1a arm (n = 80/145, 55.2%; p = 0.01 vs. control). No significant difference was observed regarding safety data in the hydroxychloroquine arm.
Overall, the final results of the DisCoVeRy trial for the efficacy and safety of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a, and hydroxychloroquine confirm what was observed in the preliminary report. They support recommendations against the use of hydroxychloroquine and lopinavir and ritonavir in hospitalized patients with COVID-19. The results of the lopinavir and ritonavir plus IFN-ß-1a arm raise interesting questions. Indeed, because defects in IFN signaling pathways have been shown to be associated with severe COVID-19 [3], one could assume that IFN treatment might improve COVID-19 clinical outcome. Here, results suggest a detrimental effect of IFN-ß-1a treatment—participants assigned to the lopinavir and ritonavir plus IFN-β-1a arm had significantly longer time to hospital discharge (alone or combined in composite endpoints) and higher 90-day mortality than untreated controls, whereas these outcomes were not significantly different between participants assigned to lopinavir/ritonavir alone or to the control arm. Overall, this suggests that IFN-ß-1a administration is not always appropriate, and that screening of IFN signalling pathways may be required to identify patients who would most benefit from IFN treatment [4].
Transparency declaration
F.R. reports personal fees from Gilead Sciences, personal fees from M.S.D., personal fees from Pfizer, personal fees from TheraTechnologies, personal fees from ViiV Healthcare, outside the submitted work. F.G. reports grants from BioMerieux, personal fees and non-financial support from Gilead, non-financial support from Corevio, outside the submitted work. G.P. reports grants and personal fees from Gilead Sciences, grants and personal fees from Merck, grants and personal fees from ViiV Healthcare, grants and personal fees from TheraTechnologies, outside the submitted work. K.L. reports personal fees and non-financial support from Gilead, personal fees and non-financial support from Janssen, personal fees and non-financial support from MSD, personal fees and non-financial support from ViiV Healthcare, personal fees and non-financial support from Abbvie, during the conduct of the study. Y.Y. has nothing to disclose. He has been a board member receiving consultancy fees from ABBVIE, BMS, Gilead, MSD, J&J, Pfizer, and ViiV Healthcare, however all these activities have been stopped in the 03 past years. F.L. reports personal fees from Gilead, personal fees and non-financial support from MSD, non-financial support from Astellas, non-financial support from Eulmedica, outside the submitted work. A.K. reports personal fees from Baxter, personal fees from Aspen, personal fees from Aguettant, outside the submitted work. S.N. reports personal fees from MSD, personal fees from Pfizer, personal fees from Gilead, personal fees from Biomérieux, personal fees from BioRad, outside the submitted work. FD reports personal fees from Gilead, outside the submitted work. J.N. reports non-financial support from MSD France, non-financial support from GILEAD Sciences, personal fees from PASCALEO, outside the submitted work. JM reports non-financial support from GILEAD, outside the submitted work. A.M. reports personal fees from MSD, personal fees from GILEAD, personal fees from JANSSEN, personal fees from Viiv Healthcare, outside the submitted work. M.H. reports grants from Fonds Erasme-COVID-Université Libre de Bruxelles, grants from Belgian health Care Knowledge Center, during the conduct of the study; personal fees from Gilead advisory board on education on invasive fungal infections, personal fees from Pfizer: moderator for session on Isavuconazole, outside the submitted work. D.C. reports personal fees from Gilead, grants and personal fees from Janssen, outside the submitted work. C.B. reports personal fees from Da Volterra, personal fees from Mylan Pharmaceuticals, outside the submitted work. F.M. reports grants from Sanofi, grants and personal fees from Da Volterra, outside the submitted work. All other authors have nothing to disclose.
The study was founded by Programme Hospitalier de Recherche Clinique (PHRC-20-0351) (Ministry of Health), from the DIM One Health Île-de-France (R20117HD), and from REACTing, a French multi-disciplinary collaborative network working on emerging infectious diseases. Sanofi provided hydroxychloroquine, AbbVie provided lopinavir/ritonavir and Merck provided IFN-β-1a, all free of charge. The funding sources had no role in the analysis of the data nor in the decision of publication.
Editor: L. Scudeller
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.cmi.2022.04.016.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
References
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