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. 2024 Mar 25;12(4):723.
doi: 10.3390/biomedicines12040723.

Efficacy of Alkaline Phosphatase in Critically Ill Patients with COVID-19: A Multicentre Investigator-Initiated Double-Blind Randomised Placebo-Controlled Trial

Anouk Pijpe  1   2   3   4   5 , Stephan G Papendorp  1   5 , Joost W van der Heijden  6 , Ben Vermin  7 , Iris Ertugrul  7 , Michael W J Ritt  1 , Björn Stessel  8   9 , Ina Callebaut  8   9 , Albertus Beishuizen  10 , Marcel Vlig  4 , Joost Jimmink  5 , Henk J Huijgen  11 , Paul P M van Zuijlen  2   3   5   12   13 , Esther Middelkoop  2   3   4   5 , Evelien de Jong  1   5
Affiliations

Efficacy of Alkaline Phosphatase in Critically Ill Patients with COVID-19: A Multicentre Investigator-Initiated Double-Blind Randomised Placebo-Controlled Trial

Anouk Pijpe et al. Biomedicines. .

Abstract

Background: Efforts to identify therapies to treat hospitalised patients with COVID-19 are being continued. Alkaline phosphatase (AP) dephosphorylates pro-inflammatory adenosine triphosphate (ATP) into anti-inflammatory adenosine.

Methods: In a randomised controlled trial, we investigated the safety and efficacy of AP in patients with SARS-CoV-2 infection admitted to the ICU. AP or a placebo was administered for four days following admission to the ICU. The primary outcome was the duration of mechanical ventilation. Mortality in 28 days, acute kidney injury, need for reintubation, safety, and inflammatory markers relevant to the described high cytokine release associated with SARS-CoV-2 infection were the secondary outcomes.

Results: Between December 2020 and March 2022, 97 patients (of the intended 132) were included, of which 51 were randomised to AP. The trial was terminated prematurely based on meeting the threshold for futility. Compared to the placebo, AP did not affect the duration of mechanical ventilation (9.0 days vs. 9.3 days, p = 1.0). No safety issues were observed. After 28 days, mortality was 9 (18%) in the AP group versus 6 (13%) in the placebo group (p = 0.531). Additionally, no statistically significant differences between the AP and the placebo were observed for the other secondary outcomes.

Conclusions: Alkaline phosphatase (AP) therapy in COVID-19 ICU patients showed no significant benefits in this trial.

Keywords: COVID-19; alkaline phosphatase; inflammatory response; mechanical ventilation.

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Conflict of interest statement

J.W.v.d.H. obtained a contribution for another study on alkaline phosphatase sponsored by Alloksys Lifesciences: the APhIRI-1 study (Alkaline phosphatase in renal transplantation; (ref: [21])). All other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
CONSORT flow diagram.
Figure 2
Figure 2
Kaplan–Meier survival curves by treatment group.
Figure 3
Figure 3
Levels of alkaline phosphatase over 14–day period by treatment group. Based on levels (mean ± 95% confidence intervals) of alkaline phosphatase in 45 patients from Red Cross Hospital, Beverwijk, The Netherlands.
Figure 4
Figure 4
(a) Course of values of inflammatory marker IL6 for the entire group and by tocilizumab (no/yes). (b) Course of values of inflammatory marker IL10 for the entire group and by tocilizumab (no/yes). (c) Course of values of inflammatory marker MCP–1 for the entire group and by tocilizumab (no/yes).
Figure 4
Figure 4
(a) Course of values of inflammatory marker IL6 for the entire group and by tocilizumab (no/yes). (b) Course of values of inflammatory marker IL10 for the entire group and by tocilizumab (no/yes). (c) Course of values of inflammatory marker MCP–1 for the entire group and by tocilizumab (no/yes).
Figure 4
Figure 4
(a) Course of values of inflammatory marker IL6 for the entire group and by tocilizumab (no/yes). (b) Course of values of inflammatory marker IL10 for the entire group and by tocilizumab (no/yes). (c) Course of values of inflammatory marker MCP–1 for the entire group and by tocilizumab (no/yes).
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