The following article focuses on randomised controlled trials involving hospitalised patients with confirmed COVID-19. It features details regarding blood oxygenation, pulmonary function, etc. The trial was designed to assign patients in a 1:1 ratio to receive either Lopinavir-Ritonavir or standard care alone.
A randomized controlled, open-label trial was performed involving hospitalized adult patients with confirmed SARS-CoV-2 infection and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or PaO2/FiO2 =< 300 mmHg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone.
The primary endpoint was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.
Patients in the lopinavir–ritonavir group had a shorter stay in the ICU than those in the standard-care group (median, 6 days vs 11 days), and the duration from randomization to hospital discharge was numerically shorter (median, 12 days vs 14 days). In addition, the percentage of patients with clinical improvement at day 14 was higher in the lopinavir–ritonavir group than in the standard-care group (45.5% vs. 30.0%). There were no significant differences for other outcomes such as duration of oxygen therapy, duration of hospitalization, and time from randomization to death.
Patients in the study were assessed for eligibility on the basis of a positive RT-PCR for SARS-CoV-2 present in the respiratory tract. (Male and Non pregnant females >= 18y/o)
Other inclusion criteria
- Pneumonia confirmed by chest imaging
- SaO2 =< 94% (While breathing ambient air)
- PaO2/FiO2 =< 300 mmHg
- A physician’s decision that involvement in the trial was not in the patient’s best interest.
- The presence of any condition that would not allow the protocol to be followed safely.
- The presence of any known allergy or hypersensitivity to lopinavir–ritonavir.
- The presence of any known severe liver disease (e.g – cirrhosis, with an alanine aminotransferase level >5× the upper limit of the normal range or an aspartate aminotransferase level >5× the upper limit of the normal range)
- The use of medications that are contraindicated with lopinavir–ritonavir and that could not be replaced or stopped during the trial period
- Pregnancy or breast-feeding, or known HIV infection, because of concerns about the development of resistance to lopinavir–ritonavir if used without combining with other antiretrovirals.
Note – Patients who were unable to swallow received lopinavir–ritonavir through a nasogastric tube.
This was an open-label, individually randomized, controlled trial conducted from January 18, 2020, through February 3, 2020 (the date of enrollment of the last patient), at Jin Yin-Tan Hospital, Wuhan, Hubei Province, China.
Due to the emergency nature of the trial, placebos of lopinavir–ritonavir were not prepared. Eligible patients were randomly assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and 100 mg, orally) twice daily, plus standard care, or standard care alone, for 14 days.
Standard care included:
- Supplemental oxygen
- Noninvasive and invasive ventilation
- Antibiotic agents
- Vasopressor support
- Renal-replacement therapy
To balance the distribution of oxygen support between the two groups as an indicator of severity of respiratory failure, randomization was stratified on the basis of respiratory support methods at the time of enrollment: no oxygen support or oxygen support with nasal duct or mask, or high-flow oxygen, noninvasive ventilation, or invasive ventilation including ECMO.
Clinical and Lab monitoring
Patients were assessed once daily by trained nurses using diary cards that captured data on a seven-category ordinal scale and on safety from day 0 to day 28, hospital discharge, or death. 16 Serial oropharyngeal swab samples were obtained on day 1 (before lopinavir–ritonavir was administered) and on days 5, 10, 14, 21, and 28 until discharge or death had occurred.
Using quantitative real-time RT-PCR, RNA was extracted from clinical samples. These samples were obtained for all 199 patients who were still alive at every time point. Sampling did not stop when a swab at a given time point was negative. Baseline throat swabs were tested for detection of E gene, RdRp gene, and N gene, and samples on the subsequent visits were quantitatively and qualitatively detected for E gene.
The primary endpoint was the time for clinical improvement. 18 Ordinal scales have been used as endpoints in clinical trials in patients hospitalized with severe influenza.16-19 The seven-category ordinal scale consisted of the following categories:
- Not hospitalized with resumption of normal activities;
- Not hospitalized, but unable to resume normal activities;
- Hospitalized, not requiring supplemental oxygen;
- Hospitalized, requiring supplemental oxygen;
- Hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both;
- Hospitalized, requiring ECMO, invasive mechanical ventilation, or both;
Safety outcomes included adverse events that occurred during treatment, serious adverse events, and premature discontinuation of treatment.
Of the 199 patients who underwent randomization, 99 patients were assigned to receive lopinavir–ritonavir and 100 patients to standard care alone. Of the 99 patients assigned to receive lopinavir–ritonavir, 94 (94.9%) received treatment as assigned.
In the lopinavir-ritonavir group, 5 patients did not receive any doses of lopinavir-ritonavir: 3 because of early death within 24 hours after randomization and 2 others because the attending physician refused to prescribe lopinavir-ritonavir after randomization.
The median age of patients was 58 years, and 60.3% of the patients were men. The median interval time between symptom onset and randomization was 13 days. During the trial, systemic glucocorticoids were administered in 33.0% of the patients in the lopinavir–ritonavir group and in 35.7% of those in the standard-care group.
Patients assigned to lopinavir–ritonavir did not have time for clinical improvement different from that of patients assigned to standard care alone in the intention-to-treat population. In the modified intention-to-treat population, the median time to clinical improvement was 15 days in the lopinavir–ritonavir group, as compared with 16 days in the standard-care group. In the intention-to-treat population, lopinavir–ritonavir treatment within 12 days after the onset of symptoms was not found to be associated with a shorter time to clinical improvement, similar results were found regarding later treatment with lopinavir–ritonavir. In addition, when the time to clinical deterioration was compared between the two groups, no difference was observed
The 28-day mortality was numerically lower in the lopinavir–ritonavir group than in the standard-care group for either the intention-to-treat population or the modified intention-to treat population. Patients in the lopinavir–ritonavir group had a shorter stay in the ICU than those in the standard-care group (median, 6 days vs 11 days), and the duration from randomization to hospital discharge was numerically shorter (median, 12 days vs 14 days). In addition, the percentage of patients with clinical improvement at day 14 was higher in the lopinavir–ritonavir group than in the standard-care group (45.5% vs. 30.0%). There were no significant differences for other outcomes such as duration of oxygen therapy, duration of hospitalization, and time from randomization to death.
Reference Link : https://www.nejm.org/doi/full/10.1056/NEJMoa2001282