Compassionate use of remdesir and convalescent plasma therapy for the treatment of COVID-19 infection in Nepal: a prospective observational study

Abstract

Executive Summary: Background As of December 2020, the COVID-19 pandemic has infected over 80 million people and caused over 1.7 million deaths worldwide. Over 250 thousand cases of infection and over 1800 deaths have occurred in Nepal. An approved antiviral therapy for the treatment of COVID-19 in Nepal is not available. International infectious diseases authorities, such as IDSA (Infectious Diseases Society of America) and US NIH (United States National Institute of Health) panel, recommend Remdesivir for hospitalized patients with severe COVID-19 patients. Similarly, as an investigational treatment of COVID-19, the European Commission Directorate-General for Health and Food Safety and the United States Food and Drug Administration (US FDA) recommended convalescent plasma therapy with antibodies against SARS CoV-2. Per the Government of Nepal’s Ministry of Health and Population (GoN MoHP) directives, guidelines and a study protocol for the treatment of COVID-19 with convalescent plasma was developed in May-June 2020. Subsequently, the GoN MoHP asked the Nepal Health Research Council (NHRC) to oversee the use of Remdesivir for the treatment of COVID-19. In August 2020, the protocol was amended. The amendment included Remdesivir in the study to provide a coordinated approach for the safe and effective administration of convalescent plasma and Remdesivir for COVID-19 treatment.

Methods This was a prospective, observational study to evaluate the safety and outcomes of convalescent plasma and Remdesivir treatment of hospitalized COVID-19 patients. Patients received convalescent plasma, Remdesivir, or both treatments. Other antiviral drugs were not allowed while the patient was in the study. Other drugs necessary for patient management (such as steroids) were allowed. Patients 18 years and older with laboratory-confirmed COVID-19 infection with positive PCR tests were enrolled from twelve NHRC approved study site hospitals. The study sites were later expanded to include over 50 hospitals. Clinical severity of COVID-19 patients was determined by the local site investigators based on the Nepal Medical Council’s COVID-19 Guidelines. Intravenous Remdesivir was administered to patients with moderate to severe COVID-19 infection based on predefined eligibility criteria. Based on severity, patients received a five-to-ten-day course of Remdesivir, with 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining therapy. Convalescent plasma therapy (CPT) was administered to patients with severe or life-threatening COVID-19 infection, or as judged by the treating provider to be at high risk of progression to severe or life-threatening disease, or to patients who progressed to severe or life-threatening infection despite being on Remdesivir for 48 hours or longer. This study was approved by the NHRC Ethics Review Board (ERB) and registered with ClinicalTrials.gov (NCT04570982).

Results Between July 30, 2020 and October 31, 2020, total 1315 patients were enrolled in the study. Complete data were available for 1083 patients who had reached the study endpoint, and whose outcome was recorded. Of the 1315 patients, most were from Bagmati Province (71.1%), Lumbini Province (12.8%), and Province 2 (7.1%). Their mean age was 55.8 years (SD 15.7, range 18-99 years), 73.7% were male, 92.5% were married, and 25.6% were health care workers (HCWs). The most common comorbidities were heart disease (33%), diabetes (29.1%), hypertension (19.1%), smoking (12.7%), and chronic lung disease (11%). Fever (81.5%), cough (72.3%), and shortness of breath (80.3%) were the most common symptoms. At baseline, the mean O2 saturation was 89.6%. Baseline exam measures and labs were as expected for COVID-19 patients. Most patients were classified as having a severe infection (64%). Moderate infections were reported in 24.2% and life-threatening infections in 11.7% of patients. More than three-quarters of the patients (1099; 83.6%) received Remdesivir alone, 76 (5.8%) patients received CPT alone, and 140 (10.6%) received both Remdesivir and CPT. The observational study ended abruptly on October 31, 2020 and was changed to a registry-only study. Thus, 209 patient outcomes were not recorded either because they were still in the hospital at the end of the study, or the site investigators had not reported their outcome. Similarly, outcomes were not available for 23 (2.1%) patients who were transferred to another facility. Of the 1083 patients for whom outcome data were available, 801 (74%) patients were discharged in good condition, 48 (4.4%) discharged with a disability, and 234 (21.6%) patients died. Among the 910 patients who received Remdesivir alone and whose outcome was recorded, 764 (84%) patients recovered and were discharged, and 146 (16%) died. The raw survival rates, i.e., recovery and discharge from hospital, were 98.4%, 85.2%, and 29.5% for moderate, severe, and life-threatening groups, respectively. The mean length of stay for the Remdesivir alone recipients was 10.7 days (SD 5.3 days) in the hospital, 7.9 (SD 4.8) days in ICU, and 4.3 (SD 4.4) days on a ventilator. Of the 910 Remdesivir recipients, 57.5% were admitted to the ICU, and 26.6% were on a ventilator. Seventy-six patients were treated with CPT alone, and 140 patients received both CPT and Remdesivir. Of the 59 patients who received CPT alone and had outcome data, 23 (39%) patients were discharged, and 36 (61%) patients died. Among the patients who died, 22 had life-threatening infections and 13 had severe COVID-19. Recovery and discharge rates (i.e., raw survival rates) among patients treated with CPT alone with severe and life-threatening infections were 59.4% and 15.4%, respectively. The average length of stay for the CPT recipients was 12.4 (SD 6) days in the hospital, 10.2 (SD 5.8) days in ICU, and 6.8 (SD 5.3) days on a ventilator. Among the 59 CPT recipients, 91.8% were on ICU, and 45.9% were on a ventilator. Similarly, of the 114 patients treated with both Remdesivir and CPT, 62 (54.4%) were discharged, and 52 (45.6%) died. Among the 52 patients who died, 22 had life-threatening, 28 had severe, and 2 had moderate COVID-19 infections. Combined recovery and discharge rates among these patients were 61.1% and 33.3% for severe and life-threatening infections, respectively. The average hospital stay for these patients was 14 (SD 6.7) days in the hospital, 10.8 (SD 6.3) days in ICU, and 8.2 (SD 7.4) days on a ventilator. Among the 114 CPT and Remdesivir recipients, 94.6% were admitted to the ICU, and 59.8% were on a ventilator. In an unadjusted model, the predicted margins for the discharge of a patient in good condition or with a disability were higher among patients who received Remdesivir (0.79; 95% CI 0.76-0.82) compared to those who received CPT alone (0.39; 95% CI 0.27-0.51) or CPT plus Remdesivir (0.51; 95% CI 0.42-0.60). Margins were not substantially altered after controlling for age, gender, severity, and steroid use. Remdesivir was found to be safe in this population: An adverse event was reported in 34 (4.5%) patients and was recorded as “none” for 730 (95.5%). No reactions were reported to be fatal. The most common events included elevated liver enzymes (2.7%) and a rise in creatinine (1%). Of the 216 patients who received CPT, ten (4.6%) were reported to have had adverse reactions. Reactions included fever (3) and rash (1). All patients completely recovered after stopping treatment.

Conclusions This report is based on a three-month observational study conducted in Nepal. Data on 1315 COVID-19 patients treated with Remdesivir and/or convalescent plasma therapy were reported by 30 hospitals until October 31, 2020. The observations, correlations, and associations from this study are summarized below. It is important to note that this is strictly a descriptive summary of an observational study. Any hypothesized results suggested by these data need to be verified in clinical trials. 1. Most of the hospitalized patients who received Remdesivir and/or CPT were older (mean age 55.8 years), male, married, and from Bagmati Province. 2. Most patients had pre-existing comorbidities, including heart disease, diabetes, hypertension, smoking, and chronic lung disease. 3. Most patients presented with fever, cough, and shortness of breath. Their mean O2 saturation was below 90%. 4. At baseline examination, the majority of the patients were classified as having severe COVID-19. 5. Most of the patients who had moderate infection received Remdesivir and had a good survival rate (98.4%). 6. Compared to those who received CPT alone or CPT plus Remdesivir, the majority of the patients who had severe COVID-19 and received Remdesivir alone had a better outcome. However, this difference cannot be attributed to the treatment alone because of other potential confounders. For example, as noted below (see no. 8), patients who received both CPT and remdesivir had more severe infections requiring ICU admission and/or a ventilator at baseline. As per the treatment protocol, CPT was added after many patients failed to improve with Remdesivir alone. 7. Patients classified with life-threatening infections had a high mortality rate (72.3%). In this group, patients who received CPT plus Remdesivir had the highest recovery rate followed by those who received Remdesivir alone. Patients who received CPT alone had the lowest survival rates. 8. Larger proportions of patients who received CPT alone (91.8%) or CPT plus Remdesivir (94.6%) were in the ICU compared to those who received Remdesivir alone (57.5%). Similarly, higher proportions of patients who received CPT with or without Remdesivir were on a ventilator compared to those who received Remdesivir alone. Higher severity of illness requiring ICU admission and a ventilator seem to have attributed to the higher mortality and longer duration of stay for patients who were treated with CPT with or without Remdesivir. 9. Both Remdesivir and CPT were well tolerated by the patients in this study, with adverse events reported in only 4.5% and 4.6%, respectively.

Recommendations The study team recommends the followings: 1. Since this is an observational study, results of this study alone should not be used as conclusive. The results of this study are useful to learn and share the local experience and to compare with similar studies done elsewhere. 2. As a standard practice, a new drug approval for clinical use requires controlled clinical trials. Approval of remdesivir and convalescent plasma should be based on the results of controlled clinical trials which are now available. We recommend continuing to collect Remdesivir data as a Registry Study until the Remdesivir is approved for COVID-19 treatment in Nepal. 3. Continue to collect data on the use of convalescent plasma therapy for COVID-19 until conclusive clinical trial results are published. 4. Correlate COVID-19 treatment outcome with antibody titer against COVID-19 for patients treated with convalescent plasma.