Effect of Cyproheptadine on Ventilatory Support-free Days in Critically Ill Patients with COVID-19: An Open-label, Randomized Clinical Trial

HIGHLIGHTS

The number of ventilatory support-free days during the first 28 days was not different between the two groups.

Cyproheptadine does not appear to be a therapeutic option for patients with coronavirus disease 2019 (COVID-19).

INTRODUCTION

Since the discovery of the first cases of COVID-19 in December 2019 in Wuhan, China, more than 6 million people have died from the disease worldwide.¹ The pathophysiological features of the severe form of COVID-19 include a pneumonic process with diffuse alveolar damage, inflammatory infiltrate, and microvascular thrombosis.² According to certain research, COVID-19 patients had higher levels of platelet activation and reactivity, with an increase in platelet activation markers such as thromboxane B2, platelet factor 4, and plasma serotonin in relation to patients with acute respiratory distress syndrome (ARDS) of other etiologies.^3–6

Serotonin is a mediator of pulmonary vascular tone and pulmonary hypoxic vasoconstriction. Experimental studies have shown that serotonin-mediated pulmonary vasoconstriction can be inhibited by cyproheptadine, a 5HT-2 receptor antagonist.^7,8 Serotonin release has also been shown to be associated with pulmonary fibrosis, with cyproheptadine attenuating this evolution by reducing transforming growth factor-β (TGF- β) release.⁹

Fluvoxamine, a selective serotonin reuptake inhibitor, has shown benefits in outpatients with COVID-19.^10,11 One potential mechanism is that fluvoxamine may reduce the storage of serotonin in platelets, thereby reducing the hyper serotoninergic state that occurs after platelet activation. The use of serotonin receptor antagonists, such as cyproheptadine, may be beneficial in the period in which serotonin release has already occurred.^12,13

Considering this evidence and biological plausibility, the purpose of this study is to determine whether treatment with cyproheptadine, a serotonin receptor antagonist, in comparison to standard care, increases ventilatory support-free days during the first 28 days in patients with hypoxemic respiratory failure admitted to the intensive care unit (ICU) and needing ventilatory support (invasive or non-invasive).

MATERIALS AND METHODS

This is a randomized, single-center, open-label clinical trial performed in the ICUs of Hospital de Clínicas de Porto Alegre (HCPA), Brazil. The study was approved by the Research Ethics Committee of Hospital de Clínicas de Porto Alegre (CAAE 46381721.8.1001.5327; approval date: 07/12/2021). This study was conducted by the Helsinki declaration of 1975. Before randomization, each patient’s or their legal representative’s informed consent was obtained verbally or in writing. An impartial, external data and safety monitoring committee (DSMC) oversaw the study. The study protocol was recorded in the ClinicalTrials.gov database (NCT04979221) before initiation.

Patients at least 18 years of age who were admitted to the ICU requiring invasive or non-invasive ventilatory support due to COVID-19, confirmed by Real-time Reverse Transcription – Polymerase Chain (RT-PCR) or antigen testing, were evaluated for eligibility. Exclusion criteria were ventilatory support for more than 48 hours, tracheostomy, pregnancy or breastfeeding, refusal to consent, expected death within 24 hours of randomization, previous use of serotonin reuptake inhibitors, use of monoamine oxidase inhibitors, glaucoma, inability to use the enteral route, history of seizure, readmission to the ICU, allocation to another study, or treatment limitation.

Randomization was done through an online web-based system using computer-generated random numbers. Eligible patients were randomized in a 1:1 ratio to receive usual care plus cyproheptadine or usual care alone.

Cyproheptadine was administered to patients assigned to the intervention group at a dose of 8 mg every 8 hours for 10 days. According to the institution’s clinical practice, standard care (diagnostic testing, antibiotic administration, fluid resuscitation, hemodynamic management, and ventilatory support) was used in both arms.

Demographic characteristics, SAPS 3, time of symptom onset, comorbidities, and other clinical and laboratory variables were collected. Ventilatory support [non-invasive ventilation, high-flow nasal catheter, and invasive mechanical ventilation (MV)], intravenous sedation, neuromuscular block, prone position, vasopressor, renal replacement therapy, and thromboembolic phenomena were collected daily until day 28. Patients were followed up until hospital discharge.

OUTCOMES

The number of days that a patient remained alive and not receiving ventilator support for at least 48 consecutive hours over the first 28 days was the primary outcome. Patients who were discharged from the hospital before 28 days were considered alive and free of ventilatory support at 28 days. Nonsurvivors on day 28 were regarded as not having any days without ventilator support. Secondary outcomes were the length of invasive MV, length of ICU and hospital stay, and ICU and hospital mortality.

RESULTS

Between July 2021 and December 2021, 179 patients with confirmed COVID-19 infection were admitted to the ICU. Of these, 139 patients were excluded. Of the 40 patients included in the final analysis, 19 were randomized to receive cyproheptadine and 21 to the control group (Fig. 1).

The characteristics of patients at inclusion are described in Table 1. Disease severity, assessed by SAPS 3, PaO₂/FiO₂ ratio at admission, and need for MV before randomization, as well as vaccination status, were similar between the two groups. All patients received dexamethasone. No patient used remdesivir, tocilizumab, baricitinib or convalescent plasma.

The mean time to start cyproheptadine after ICU admission was 13.5 ± 9.0 hours. Only two patients discontinued the use of cyproheptadine before completing 10 days of treatment. One patient had an episode of generalized tonic-clonic seizure and discontinued use on the second day. The other patient had episodes of vomiting after ingesting cyproheptadine and discontinued the intervention on the 6th day.

The number of ventilatory support-free days during the first 28 days was not different between the two groups (15.0; 95% CI, 0.0–24.0 days in the control group vs 7.0; 95% CI, 0.0–19.0 days in the intervention group; p = 0.284) (Table 2). There was no significant difference in the length of stay in the ICU (14.5 ± 11.7 in the control group vs 22.5 ± 17.1 in the intervention group; p = 0.121) and in the hospital (19.6 ± 11.9 in the control group vs 26.9 ± 17.7 in the intervention group; p = 0.165), and in ICU and hospital mortality (Table 2).

In a post hoc multivariate analysis with adjustment for age, immunosuppression, C-reactive protein at admission, SAPS 3, obesity, vaccination status, PaO₂/FiO₂ ratio at admission and MV before randomization, the number of ventilatory support-free days remained without significant difference between groups (unstandardized ß-coefficient –4.32, 95% CI, 11.13–2.49).

Adverse events are described in Table 3. There was no difference in the incidence of adverse events between patients in the control group and patients who received cyproheptadine.

DISCUSSION

In this randomized clinical trial of patients with COVID-19 in need of ventilatory support, cyproheptadine plus usual care compared to usual care alone did not increase the number of ventilatory support-free days during the first 28 days. To the best of our knowledge, this is the first clinical trial that has evaluated the use of cyproheptadine in critically ill patients with COVID-19.

According to certain research, COVID-19 patients had higher levels of platelet activation and reactivity compared to healthy controls.^3–5,15 In addition, platelet activation was shown to be associated with disease severity.⁴ Zaid et al. found that platelet hyperreactivity is increased in patients with COVID-19 even in comparison with patients with ARDS of other etiologies.⁶ Platelet hyperreactivity may be implicated in the high incidence of systemic and pulmonary vascular thrombosis seen in patients with COVID-19.^16,17 Platelet activation releases a series of bioactive molecules, such as serotonin. Patients with COVID-19, with or without ARDS, have significantly higher levels of serotonin than patients with ARDS of other etiologies or healthy controls.⁶ Whether the elevation of serum serotonin in these patients is just a marker of platelet hyperreactivity or whether it represents a mechanism in the pathophysiology of COVID-19 remains to be explored.

Two clinical trials showed benefits in the use of fluvoxamine, a selective serotonin reuptake inhibitor, in outpatients with COVID-19.^10,11 Although one of the suggested mechanisms is the anti-inflammatory action through the activation of the sigma-1 receptor (S1R), a potential mechanism is that fluvoxamine may reduce the storage of serotonin in platelets, consequently reducing the hyper serotoninergic state that occurs after platelet activation.^13,18 This second mechanism would enhance the therapeutic potential of cyproheptadine. At an earlier stage, fluvoxamine would reduce the serotonin load on platelets, before serotonin is released by platelet activation. In a more advanced phase, such as in critically ill patients requiring ventilatory support, in which the release of serotonin has already occurred from platelet activation, it makes sense to administer a serotonin receptor antagonist, such as cyproheptadine. Unfortunately, in our study, the use of cyproheptadine at this stage of the disease showed no benefit. We even found a tendency in patients who used cyproheptadine to have longer ventilatory support, in addition to a greater need for invasive MV, with a consequent longer length of stay in the ICU and hospital. As with the other medications tested for this viral infection, the timing of cyproheptadine administration may be a determining factor for the results. An intermediate phase, neither so early as to not have a hyper serotoninergic state, nor so late as to have multiorgan dysfunction, seems to be the ideal period. The patients in our study were in an early stage of critical illness. The median time to symptom onset was less than 10 days and less than a third of patients were on MV at the time of randomization. In addition, ventilatory support for more than 48 hours was an exclusion criterion.

This study has several limitations. First, one of the key limitations of our study is the notable concern that we did not reach the anticipated number of patients as calculated by the sample size estimation. This shortfall raises concerns about the statistical power of our findings and the ability to detect potentially meaningful effects, especially considering the nature of negative studies where smaller sample sizes can impact the ability to detect statistically significant differences or associations. Second, the study was open-label due to the costs of producing the placebo. Although this is a limitation, we believe that its impact is mitigated due to the nature of the primary outcome. Finally, the study was developed in only one center, which limits the generalizability of the results.

CONCLUSION

In patients with COVID-19 and need of ventilatory support, our study found that the addition of cyproheptadine to usual care did not increase the number of ventilatory support-free days in 28 days. However, it is crucial to acknowledge the limitations of our study, such as the lower-than-anticipated sample size, which may have affected the statistical power to detect potential effects.

AUTHORS’ CONTRIBUTIONS

Márcio MB, Wagner LN, Marcos FR, Patricia S, Edino P, Miriane MSM and Thiago CL have made substantial contributions to the conception and design of the study and to acquisition of data; Márcio MB and Thiago CL performed the analysis and the interpretation of data; all authors read and approved the final manuscript.

ORCID

Márcio Manozzo Boniattihttps://orcid.org/0000-0001-9921-0785

Wagner Luis Nedelhttps://orcid.org/0000-0003-2539-4256

Marcos Frata Rihlhttps://orcid.org/0000-0003-4019-4949

Patricia Schwarzhttps://orcid.org/0000-0003-0370-7602

Edino Parolohttps://orcid.org/0000-0003-0963-4491

Miriane Melo Silveira Morettihttps://orcid.org/0000-0002-5365-5997

Thiago Costa Lisboa https://orcid.org/0000-0003-4306-2212

REFERENCES

1. WHO Coronavirus (COVID-19) dashboard. Available from: www.covid19.who.int.

2. Carsana L, Sonzogni A, Nasr A, Rossi RS, Pellegrinelli A, Zerbi P, et al. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: A two-centre descriptive study. Lancet Infect Dis 2020;20(10):1135–1140. DOI: 10.1016/S1473-3099(20)30434-5.

3. Manne BK, Denorme F, Middleton EA, Portier I, Rowley JW, Stubben C, et al. Platelet gene expression and function in patients with COVID-19. Blood 2020;136(11):1317–1329. DOI: 10.1182/blood.2020007214.

4. Hottz ED, Azevedo-Quintanilha IG, Palhinha L, Teixeira L, Barreto EA, Pão CRR, et al. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood 2020;136(11):1330–1341. DOI: 10.1182/blood.2020007252.

5. Zaid Y, Puhm F, Allaeys I, Naya A, Oudghiri M, Khalki L, et al. Platelets Can Associate with SARS-Cov-2 RNA and Are Hyperactivated in COVID-19. Circ Res 2020;127(11):1404–1418. DOI: 10.1161/CIRCRESAHA.120.317703.

6. Zaid Y, Guessous F, Puhm F, Elhamdani W, Chentoufi L, Morris AC, et al. Platelet reactivity to thrombin differs between patients with COVID-19 and those with ARDS unrelated to COVID-19. Blood Adv 2021;5(3):635–639. DOI: 10.1182/bloodadvances.2020003513.

7. Daicoff GR, Chavez FR, Anton AH, Swenson EW. Serotonin-induced pulmonary venous hypertension in pulmonary embolism. J Thorac Cardiovasc Surg 1968;56(6):810–816. PMID: 5722112.

8. McGoon MD, Vanhoutte PM. Aggregating platelets contract isolated canine pulmonary arteries by releasing 5-hydroxytryptamine. J Clin Invest 1984;74(3):828–833. DOI: 10.1172/JCI111499.

9. Skurikhin EG, Andreeva TV, Khmelevskaya ES, Ermolaeva LA, Pershina OV, Krupin VA, et al. Effect of antiserotonin drug on the development of lung fibrosis and blood system reactions after intratracheal administration of bleomycin. Bull Exp Biol Med 2012;152(4):519–523. DOI: 10.1007/s10517-012-1567-1.

10. Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: A randomized clinical trial. JAMA 2020;324(22):2292–2300. DOI: 10.1001/jama.2020.22760.

11. Reis G, Dos Santos Moreira-Silva EA, Silva DCM, Thabane L, Milagres AC, Ferreira TS, et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: The TOGETHER randomised, platform clinical trial. Lancet Glob Health 2022;10(1):e42–e51. DOI: 10.1016/S2214-109X(21)00448-4.

12. Facente SN, Reiersen AM, Lenze EJ, Boulware DR, Klausner JD. Fluvoxamine for the early treatment of sars-cov-2 infection: A review of current evidence. Drugs 2021;81(18):2081–2089. DOI: 10.1007/s40265-021-01636-5.

13. Hashimoto Y, Suzuki T, Hashimoto K. Old drug fluvoxamine, new hope for COVID-19. Eur Arch Psychiatry Clin Neurosci 2022;272(1):161–163. DOI: 10.1007/s00406-021-01326-z.

14. Menga LS, Cese LD, Bongiovanni F, Lombardi G, Michi T, Luciani F, et al. High failure rate of noninvasive oxygenation strategies in critically ill subjects with acute hypoxemic respiratory failure due to COVID-19. Respir Care 2021;66(5):705–714. DOI: 10.4187/respcare.08622.

15. Comer SP, Cullivan S, Szklanna PB, Weiss L, Cullen S, Kelliher S, et al. COVID-19 induces a hyperactive phenotype in circulating platelets. bioRxiv medRxiv 2020. DOI: https://doi.org/10.1101/2020.07.24.20156240.

16. Moll M, Zon RL, Sylvester KW, Chen EC, Cheng V, Connell NT, et al. VTE in ICU Patients With COVID-19. Chest 2020;158(5):2130–2135. DOI: 10.1016/j.chest.2020.07.031.

17. Maatman TK, Jalali F, Feizpour C, Douglas A 2nd, McGuire SP, Kinnaman G, et al. Routine venous thromboembolism prophylaxis may be inadequate in the hypercoagulable state of severe Coronavirus disease 2019. Crit Care Med 2020;48(9):e783–e790. DOI: 10.1097/CCM.0000000000004466.

18. Ishima T, Fujita Y, Hashimoto K. Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells. Eur J Pharmacol 2014;727:167–173. DOI: 10.1016/j.ejphar.2014.01.064.