Thalidomide for the treatment of severe Covid-19: A randomized clinical trial

Background Covid-19 pneumonia is the leading cause of death in severe hospitalized patients. Thalidomide has an immunomodulatory and anti-inammatory effect and thereby decrease lung damage. Methods This study was a randomized clinical trial that was performed from April 2020 until August 2020 on 60 severe hospitalized Covid-19 pneumonia patients. All patients received the usual care for Covid-19 pneumonia based on our hospital protocols. Patients in the intervention group received thalidomide tablets 100 mg daily for 14 days added to the usual treatment. The primary outcome was the ICU admission rate. Results Thirty patients were assigned to receive thalidomide and 30 patients usual treatment. Five patients (17.9%) in the thalidomide group required ICU admission and 12 patients (52.2%) in the usual care group (P-value = 0.01). ICU admission hazard ratio was 3.3 higher in the usual care group than the thalidomide group (HR: 3.31 [95% CI: 1.16–9.45]). Hospitalization duration, intubation and mortality showed no signicant differences between the two groups (P > 0.05 for all items). No serious and major adverse effects were reported during the trial. Conclusion


Introduction
Covid-19 affected more than 117 million patients worldwide until this date and its infectivity and mortality daily increase (1). Respiratory failure, septic shock, and multiple organ dysfunction were symptoms of a critical form of Covid-19 infection (2,3). A recent study in China reported that almost 81% of Covid-19 patients had mild infection, 14% severe form, and 5% had the critical form of Covid-19 infection (3). Fatality rate of Covid-19 reported 26 % among hospitalized patients and 37 % among intubated patients in United Kingdom (4).
A signi cant decrease in the mortality rate of hospitalized Covid-19 patients who required supplementary oxygen was observed after administration of dexamethasone in RECOVERY trial (5,6). Furthermore, usage of remdesivir was associated with reduced disease progression and disease burden in hospitalized Covid-19 patients (7).
Higher levels of cytokines were detected in the severe and critical form of the disease (8,9). Thalidomide was prescribed during recent years in some groups of diseases such as Hansen disease, multiple myeloma, myelodysplastic syndrome, idiopathic pulmonary brosis (IPF), infectious and autoimmune disease (10). Reduction of TNFα, IL1β, IL6, TGFβ and augmentation of peripheral blood CD8 + T cells, plasma interleukin 12 (IL-12) levels and interferon-γ was revealed in in-vitro and in-vivo studies of thalidomide (11)(12)(13). Anti brotic effects of thalidomide in IPF were proven by preventing the proliferation of type 2 pneumocyte and increasing the type I pneumocyte in the alveolar epithelial cells (14).
Based on documents, hospitalized Covid-19 infected patients had signi cantly higher levels of IL-6 that was also accounted as one of the predictor markers of the respiratory involvement in Covid-19 patients (15). Thalidomide and low dose corticosteroid had bene cial effects in a severe Covid19 patient in some studies (16,17). They also believe that further studies are required in this regard. Due to these immunomodulatory and anti-in ammatory effects of thalidomide, we decide to evaluate its effectiveness in the treatment of severe Covid19 pneumonia patients.

Material And Methods
This study was a randomized clinical trial that was performed from April 2020 until August 2020 in Covid-19 infection and positive PCR test or lung HRCT abnormalities compatible with Covid-19 pneumonia, they were 18-75-year-old men and 50-75-year-old women admitted in hospital and had these criteria, SpO2 less than 85% at admission, no need to intubation in rst 24 hours of admission and no multiorgan failure or shock state at presentation All the patients or their legal representatives, if they were not able to provide consent, signed the informed consent.
Patients were excluded if they had hepatic failure (Child Pugh score ≥ C, AST > 5 times of the upper limit normal) or severe renal dysfunction (glomerular ltration rate (GFR) less than 30 CC per min).
Sixty patients were selected based on inclusion criteria. We collected demographic data of all patients including age, gender, the time interval between symptom onset and admission, smoking status, and comorbidities. The mean O2 saturation by the time of admission was also noted. Patients were randomly assigned in 1:1 ratio to 2 groups each containing 30 patients. Randomization was done through random sequence generation by using statistical software. The rst group received thalidomide and the other group received the usual care for Covid-19 infection.
Patients in both groups received methylprednisolone 50 mg intravenously every 12 hours for 3 days and then daily for 7 days, hydroxychloroquine 200 mg orally every 12 hours for 5 days.
For symptom control (pain, cough, nausea, and vomiting) acetaminophen codeine, diphenhydramine, dimenhydrinate, and promethazine were prescribed. Antibiotics were administered based on physician choice (Ceftriaxone, Azithromycin, and Vancomycin). All patients received enoxaparin 40 mg subcutaneously daily during hospitalization.
Patients in the intervention group received thalidomide tablets (Talidex, Alan pharmaceuticals) 100 mg daily for 14 days added to the usual treatment.
All patients were visited daily by an Internist or Pulmonologist and were followed weekly for 4 weeks using phone calls. During follow up adherence to prescribed thalidomide was monitored by a specialized nurse.
ICU admission rate of patients in both groups was assessed as the primary outcome. Rate of intubation and mortality were also evaluated and compared between two groups as the secondary outcomes.

Statistical analysis:
Data were collected and analyzed using SPSS software version 21. Continuous and categorical variables were reported as mean ± Standard deviation (SD) and frequency (percentage) and compared with independent samples t-test and Chi-squared test, respectively. Kaplan-Meir and log-rank test used for comparing the study outcomes (as the time to event data) and results were reported as hazard ratio and 95% con dence interval (95%CI). P-value < 0.05 was considered as the signi cance level.

Results
Sixty patients entered the study based on inclusion criteria and were randomized into two groups of 30 patients. Two patients in the intervention group refused to end up with treatment. Loss of follow-up in ve patients and consent withdrawal in two patients in the usual care group had occurred. Data of 51 patients were analyzed. The CONSORT ow diagram of patients is shown in Fig. 1.
Demographic characteristics of patients were analyzed and are shown in Table 1. The mean age of the patients was 61 ± 9.6 and 64.1 ± 10.7 years in the thalidomide and the usual care groups respectively. Meantime of starting symptoms until hospitalization in the thalidomide and the usual care group were 7.32 ± 3.60 and 6.78 ± 4.15 days. No signi cant differences were found between groups regarding the comorbidities and baseline characteristics (Table 1).  (Fig. 2). Six patients (26.1%) in the usual care group and 4 patients (14.3%) in the thalidomide group underwent intubation during hospitalization (P = 0.29).
The intubation hazard ratio was 1.9 higher in the usual care group than the thalidomide group but these data were not signi cant (HR: 1.95 [95% CI: 0.55-6.29]). Although the mortality rate in the thalidomide group was lower than the usual care group (four patients (14.3%) vs 6 patients (26.1%) ;), however, the difference was not statistically signi cant (HR: 1.95; 95% CI: 0.55-6.92; P = 0.291) (Fig. 3). No signi cant differences between the two groups regarding hospitalization duration was found (P > 0.05).

Discussion
Our primary results indicate that among severe hospitalized Covid-19 patients, thalidomide usage for a short duration resulted in lower ICU admission than patients who received usual care. However, there was not a signi cant difference in mortality and intubation rate among the thalidomide and the usual care groups.
RECOVERY trials show mortality reduction with dexamethasone 6 mg among hospitalized Covid-19 patients who need respiratory supports (6). UK and National Institutes of Health in the United States guidelines recommend the prescription of dexamethasone in hospitalized Covid-19 patients (19,20). Corticosteroid was used in all of our hospitalized severe Covid-19 patients.
Immune dysfunction plays an important role in Covid-19. IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ had a higher level in Covid-19 patients (21). Thalidomide is an immunomodulatory agent that had promising bene ts in pulmonary injuries induced by the H1N1 virus in mice through reduction of IL-6 and TNF-α and some other mechanisms (22,23). Inhibition of cytokine surge and regulation of immune function with thalidomide was reported in previous studies (24,25). Cytokine balance that resulted from thalidomide therapy may affect the clinical course of hospitalized patients. Based on our data, patients who received thalidomide had lower rates of ICU admission.
Thalidomide in combination with low dose corticosteroid-induced gradually reduction of in ammatory markers such as IL6, IL10, and IFN-γ, inhibition of cytokine surge, and improvement of pulmonary effusion symptoms in a patient with severe Covid-19 pneumonia (16). Li and colleagues performed another study in 2021 that evaluated the effects of thalidomide combined with short-term low-dose glucocorticoid therapy for the treatment of severe Covid-19. In this study, six patients received thalidomide along with routine care for Covid-19. In this study combination of thalidomide with a shortterm low-dose glucocorticoid was an effective and safe regimen for the treatment of severely ill Covid-19 patients (17). All of our patients in the trial received corticosteroids. Our results were in line with these ndings emphasizing the effectiveness of thalidomide therapy in combination with corticosteroids in severe Covid-19 patients.
In our study thalidomide decreased ICU admission but mortality was not signi cantly different between groups. ICU admission was our endpoint in this study. After admission to ICU, the patients were treated with other modalities such as hemoperfusion, tocilizumab, and hyper-immune plasma. Using such treatments in the ICU may explain statistically insigni cant mortality differences.
The mean time of starting symptoms until admission in our patients was about 7 days and so they were admitted in the in ammatory phase of the disease. Effectiveness of thalidomide in Covid-19 has presumably resulted from Immunomodulation so the administration of thalidomide in the in ammatory phase of the disease may be effective.
Because of uncertainty to patient's adherence for staying in quarantine after discharge, our policy in the hospital was a longer duration of hospitalization. This policy may explain the insigni cant difference regarding hospitalization duration between the thalidomide and the usual care group.
Thalidomide was prescribed for 14 days in this study and except for some minor complaints; no major adverse effects were reported.
Our small sample size is one of the limitations. We suggest trials with a larger sample size in the future.

Conclusion
The use of thalidomide in severe cases of hospitalized Covid-19 pneumonia was associated with a decreased rate of ICU admission.

Declarations
No acknowledgment  Mortality trend among patients