An open-label randomized clinical trial of indomethacin for mild and moderate hospitalized patients with Covid-19
The primary objective of the study was to understand the efficacy of indomethacin in preventing desaturation (SpO2 ≤ 93) and deterioration in mild and moderate covid-19 patients and compare this with a paracetamol-based arm. The secondary objective was to assess symptomatic relief in patients on indomethacin compared to patients on paracetamol. The results are striking: patients in the indomethacin arm did not develop desaturation, while 20 out of 107 patients in the paracetamol arm developed desaturation. When the SpO2 the level drops below 93, we managed the patient with low flow oxygen or placed them in a supine position to improve breathing. No patient in this study showed further deterioration. In particular, SpO2 improved after one or two doses in the indomethacin arm. Patients with marginal SpO2 level of 94 showed improvement. At the end of the seventh day, 13 patients in the paracetamol arm were at an SpO2 level of 94. In the indomethacin arm, only two patients had SpO2 levels of 94, while 97 of 103 patients had higher SpO2 greater than 97. In the paracetamol arm, only 51 patients (out of 107 patients) had SpO2level above 97.
Symptomatic relief was even more salient. The median time to become afebrile was three and seven days in the indomethacin and paracetamol arm, respectively. The median time to cough reduction was four days and seven days in the indomethacin and paracetamol arms, respectively. 59 of the 107 patients in the paracetamol arm had a fever on the seventh day, while none of the patients in the indomethacin arm had it. 49 of 75 patients taking paracetamol took seven days or more to recover from the cough; only nine of 70 patients in the indomethacin arm took seven days or more to recover. They were at level 2 on the ordinal scale. No patient in the indomethacin arm needed to continue indomethacin after the five-day regimen.
In contrast, patients who were not afebrile after the five-day treatment regimen in the paracetamol arm were continued with paracetamol at the discretion of the treating physician. One of the most critical findings came from the IQR analysis. Figures 3a,b show a thin IQR band for the reduction of fever and cough in patients on indomethacin, as well as a small error bar, compared to patients on paracetamol. A slightly wider IQR mark in myalgia may indicate the subjective nature of the relief.
The Kaplan-Meir estimator strikingly strengthens the conclusion of the benefit of indomethacin. All the figures in the supplementary appendix show a significant difference between the two treatments. The Cox regression results indicate that the relative risk with indomethacin treatment is highly significant compared to the other covariates. Indomethacin improves recovery time by 85-90% for symptomatic relief. Other covariates that affect cough recovery are admission CT score and admission cough. Fever reduction and myalgia resolution were not affected by the covariates.
The results are similar to our previous study, which used propensity score matching21. In this study, the median time to become afebrile, reduce cough, and relieve myalgia in the indomethacin arm was four, three, and four days, respectively. However, the median in the paracetamol arm was seven and eight and 6.5 days, respectively.
We monitored CRP at admission and discharge. Indomethacin effectively reduces CRP in patients with higher CRP levels on admission (>41 mg/L). In addition, the R2 value of indomethacin (0.85) was much higher than that of paracetamol (0.1). Thus, we can conclude that the consistency of indomethacin in reducing inflammation is very high.
A fourteen-day follow-up further revealed the effectiveness of the drug. In the indomethacin arm, almost 50% of patients had completely recovered compared to 28% in the paracetamol arm. The main complaint of 50% of patients who took indomethacin was fatigue. In addition, only 14% of patients had myalgia, while 10% complained of joint pain. In contrast, in the paracetamol arm, recovery was slower, with 47% complaining of myalgia, 48% fatigue, 39% joint pain and 33% complaining of other ailments.
Alkotaji et al.29 had hypothesized the importance of indomethacin in reducing cough and myalgia through its inhibitory action on bradykinin, and the mechanism and adverse effects of bradykinin are well documented. The theory proposed in this study explains the difference in symptomatic relief between the two groups.
We had hypothesized that early symptomatic relief is vital for recovery and prevents desaturation. However, 17 of the 20 patients who were desaturated in the paracetamol arm had fever beyond seven days, and eleven had cough beyond seven days. None in the indomethacin arm were desaturated. This was also reflected in the condition of the patients on the fourteenth day.
Viral load reduction was better for indomethacin. However, the difference was not significant. Therefore, seven days may be too early for an RT-PCR test.
The limitation of the study is that indomethacin was administered with standard care and not as a stand-alone treatment. With this result, indomethacin can be tried as a stand-alone treatment. Also, this is not a double-blind study. The trial only involved hospitalized patients and not in home isolation.