Supplementary material 7 to:
Fluvoxamine for the treatment of COVID-19

Nyirenda JLZ, Sofroniou M, Toews I, Mikolajewska A, Lehane C, Monsef I, Abu-taha A, Maun A, Stegemann M, Schmucker C
https://doi.org/10.1002/14651858.CD015391

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Analyses

Analysis group 1 — Fluvoxamine plus standard care compared to placebo plus standard care for outpatients with mild COVID-19

Analysis or subgroup title No. of studies No. of participants Statistical method Effect size
1.1 All-cause mortality (at day 28) 2 1649 Risk Ratio (M-H, Random, 95% CI) 0.69 [0.38, 1.27]
1.2 All-cause hospital admission or death (before hospital admission) 2 1649 Risk Ratio (M-H, Random, 95% CI) 0.55 [0.16, 1.89]
1.3 Serious adverse events 2 1649 Risk Ratio (M-H, Random, 95% CI) 0.56 [0.15, 2.03]
1.4 Adverse events (any grade) 2 1649 Risk Ratio (M-H, Random, 95% CI) 1.06 [0.82, 1.37]

Figures and tables

Analysis 1.1: All-cause mortality (at day 28)

Study or Subgroup Lenze 2020 (1) TOGETHER 2021 (2) Total (95% CI) Total events: Heterogeneity: Not applicable Test for overall effect: Z = 1.18 (P = 0.24) Test for subgroup differences: Not applicable Fluvoxamine Events 0 17 17 Total 80 741 821 Placebo Events 0 25 25 Total 72 756 828 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI Not estimable 0.69 [0.38 , 1.27] 0.69 [0.38 , 1.27] Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favours fluvoxamine Favours placebo Risk of Bias A + + B + + C - + D + + E + + F - + Footnotes (1) Patient recruitment between 04/2020 and 08/2020. No vaccination was available at this time. (2) Participant recruitment between January 2021 and August 2021. Vaccination was introduced during this time (6% of entire study population received at least 1 vaccine). Risk of bias legend (A) Bias arising from the randomization process (B) Bias due to deviations from intended interventions (C) Bias due to missing outcome data (D) Bias in measurement of the outcome (E) Bias in selection of the reported result (F) Overall bias

Analysis 1.2: All-cause hospital admission or death (before hospital admission)

Study or Subgroup Lenze 2020 (1) TOGETHER 2021 (2) Total (95% CI) Total events: Heterogeneity: Tau² = 0.49; Chi² = 1.82, df = 1 (P = 0.18); I² = 45% Test for overall effect: Z = 0.94 (P = 0.35) Test for subgroup differences: Not applicable Fluvoxamine Events 1 76 77 Total 80 741 821 Placebo Events 5 99 104 Total 72 756 828 Weight 23.5% 76.5% 100.0% Risk Ratio M-H, Random, 95% CI 0.18 [0.02 , 1.50] 0.78 [0.59 , 1.04] 0.55 [0.16 , 1.89] Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favours fluvoxamine Favours placebo Risk of Bias A + + B + + C + + D + + E + + F + + Footnotes (1) Participant recruitment between April 2020 and August 2020. No vaccination was available at this time. (2) Participant recruitment between January 2021 and August 2021. Vaccination was introduced during this time (6% of entire study population received at least 1 vaccine). Risk of bias legend (A) Bias arising from the randomization process (B) Bias due to deviations from intended interventions (C) Bias due to missing outcome data (D) Bias in measurement of the outcome (E) Bias in selection of the reported result (F) Overall bias

Analysis 1.3: Serious adverse events

Study or Subgroup Lenze 2020 (1) TOGETHER 2021 (2) Total (95% CI) Total events: Heterogeneity: Tau² = 0.56; Chi² = 1.93, df = 1 (P = 0.16); I² = 48% Test for overall effect: Z = 0.88 (P = 0.38) Test for subgroup differences: Not applicable Fluvoxamine Events 1 77 78 Total 80 741 821 Standard care/placebo Events 5 96 101 Total 72 756 828 Weight 25.0% 75.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.18 [0.02 , 1.50] 0.82 [0.62 , 1.09] 0.56 [0.15 , 2.03] Risk Ratio M-H, Random, 95% CI 0.02 0.1 1 10 50 Favours fluvoxamine Favours placebo Risk of Bias A + + B + + C - + D - - E + + F - - Footnotes (1) Patient recruitment between 04/2020 and 08/2020. No vaccination was available at this time. (2) Participant recruitment between January 2021 and August 2021. Vaccination was introduced during this time (6% of entire study population received at least 1 vaccine). Risk of bias legend (A) Bias arising from the randomization process (B) Bias due to deviations from intended interventions (C) Bias due to missing outcome data (D) Bias in measurement of the outcome (E) Bias in selection of the reported result (F) Overall bias

Analysis 1.4: Adverse events (any grade)

Study or Subgroup Lenze 2020 (1) TOGETHER 2021 (2) Total (95% CI) Total events: Heterogeneity: Tau² = 0.00; Chi² = 0.92, df = 1 (P = 0.34); I² = 0% Test for overall effect: Z = 0.43 (P = 0.67) Test for subgroup differences: Not applicable Fluvoxamine Events 11 92 103 Total 80 741 821 Standard care/placebo Events 6 92 98 Total 72 756 828 Weight 7.6% 92.4% 100.0% Risk Ratio M-H, Random, 95% CI 1.65 [0.64 , 4.23] 1.02 [0.78 , 1.34] 1.06 [0.82 , 1.37] Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favours fluvoxamine Favours placebo Risk of Bias A + + B + + C - + D - - E + + F - - Footnotes (1) Participant recruitment between April 2020 and August 2020. No vaccination was available at this time. (2) Participant recruitment between January 2021 and August 2021. Vaccination was introduced during this time (6% of entire study population received at least 1 vaccine). Risk of bias legend (A) Bias arising from the randomization process (B) Bias due to deviations from intended interventions (C) Bias due to missing outcome data (D) Bias in measurement of the outcome (E) Bias in selection of the reported result (F) Overall bias