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The effectiveness of inhaled glucocorticoids in shortening the time to symptom resolution or preventing hospitalization or death among outpatients with mild-to-moderate coronavirus disease 2019 (Covid-19) is unclear. We conducted a decentralized, double-blind, randomized, placebo-controlled platform trial in the United States to assess the use of repurposed medications in outpatients with confirmed coronavirus disease 2019 (Covid-19). Nonhospitalized adults 30 years of age or older who had at least two symptoms of acute infection that had been present for no more than 7 days before enrollment were randomly assigned to receive inhaled fluticasone furoate at a dose of 200 μg once daily for 14 days or placebo. The primary outcome was the time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Key secondary outcomes included hospitalization or death by day 28 and a composite outcome of the need for an urgent-care or emergency department visit or hospitalization or death through day 28. Of the 1407 enrolled participants who underwent randomization, 715 were assigned to receive inhaled fluticasone furoate and 692 to receive placebo, and 656 and 621, respectively, were included in the analysis. There was no evidence that the use of fluticasone furoate resulted in a shorter time to recovery than placebo (hazard ratio, 1.01; 95% credible interval, 0.91 to 1.12; posterior probability of benefit [defined as a hazard ratio >1], 0.56). A total of 24 participants (3.7%) in the fluticasone furoate group had urgent-care or emergency department visits or were hospitalized, as compared with 13 participants (2.1%) in the placebo group (hazard ratio, 1.9; 95% credible interval, 0.8 to 3.5). Three participants in each group were hospitalized, and no deaths occurred. Adverse events were uncommon in both groups. Treatment with inhaled fluticasone furoate for 14 days did not result in a shorter time to recovery than placebo among outpatients with Covid-19 in the United States. (Funded by the National Center for Advancing Translational Sciences and others; ACTIV-6 ClinicalTrials.gov number, NCT04885530.).

In a trial in China involving participants with symptomatic mild-to-moderate Covid-19, VV116 (an oral analogue of remdesivir) was noninferior to nirmatrelvir–ritonavir with respect to the time to sustained clinical recovery.

Simnotrelvir has in vitro activity against SARS-CoV-2. In this phase 2–3 trial in China, simnotrelvir given within 72 hours after symptom onset led to symptom resolution approximately 36 hours faster than placebo.

Patients undergoing kidney transplant are at risk of severe COVID-19. Our single-center retrospective analysis evaluated the outcomes of kidney transplant outpatients with COVID-19 who were managed with reduced immunosuppression and treatment with molnupiravir. Between January 2022 and May 2023, we included 93 patients (62 men, average age 56 years), serum creatinine 127 (101–153) µmol/L. Molnupiravir was administered, and immunosuppressive therapy was reduced immediately following the confirmation of SARS-CoV-2 infection by PCR, which was 2 (1–3) days after the onset of symptoms. Only three (3.2%) patients required hospitalization, and one patient died. Acute kidney injury was observed in two patients. During the follow-up period of 19 (15–22) months, there was no significant increase in proteinuria, no acute or new chronic graft rejection, and kidney graft function remained stable; serum creatinine was 124 (106–159) µmol/L post-COVID-19 infection and 128 (101–161) µmol/L at the end of the follow-up period. Our results demonstrate that early initiation of molnupiravir treatment combined with a temporary reduction in immunosuppressive therapy results in favorable clinical outcomes in patients with COVID-19, with preservation of good graft function and no episodes of graft rejection.

Evaluate the efficacy of AYUSH 64, a standard polyherbal Ayurvedic drug in COVID-19. During the first pandemic wave, 140 consenting and eligible hospitalized adult participants with mild-moderate symptomatic disease (specific standard RT-PCR assay positive) were selected as per a convenience sample, and randomized (1:1 ratio) to an open-label (assessor blind) two-arm multicentric drug trial; standard of care (SOC as per Indian guidelines) versus AYUSH 64 combined with SOC (AYUSH plus). Participants were assessed daily and discharged once clinical recovery (CR, primary efficacy) was achieved which was based on a predetermined set of criteria (resolution of symptoms, normal peripheral oximetry, and negative specific RT-PCR assay). Each participant was followed using an indigenous software program(mobile phone) and completed a 12-week study period. The dose of AYUSH 64 was 2 tablets oral, 500 mg each, bid for 12 weeks (AYUSH plus only). Significant P was <0.05 (two-sided). On randomization, the groups were found well matched. The mean interval time from randomization to CR was significantly superior in the AYUSH plus group [mean 6.45 days versus 8.26 days, 95% Confidence Interval of the difference -3.02 to -0.59 (P = 0.003, Student's 't test] as per-protocol analysis (134 participants); significant (P = 0.002) on an intention to treat analysis. 70% of the participants in AYUSH plus recovered during the first week (P = 0.046, Chi-square) and showed a significantly better change in physical health, fatigue, and quality of life measures. 48 adverse events, mostly mild and gut related, were reported by each group. There were 20 patient withdrawals (8 in AYUSH plus) but none due to an AE. There were no deaths. Daily assessment (hospitalization) and supervised drug intake ensured robust efficacy data. The open-label design was a concern (study outcome). AYUSH 64 in combination with SOC hastened recovery, reduced hospitalization, and improved health in COVID-19. It was considered safe and well-tolerated. Further clinical validation (Phase III) is required. CTRI/2020/06/025557.

Objectives To investigate the potential efficacy of Nigella sativa (NS) oil supplementation on the outcomes of patients with mild Coronavirus Disease 2019 (COVID-19). Trial design Prospective, two-arm, parallel-group, randomised (1:1 allocation ratio), open-label, controlled, exploratory phase II clinical trial of oral NS oil in patients with mild COVID-19. Participants Inclusion Criteria: - Patients with mild COVID19 (defined as upper respiratory tract infection symptoms in the absence of clinical or radiological signs of pneumonia). - Adult (18 - 65 years old). - Written informed consent by the patient (or legally authorized representative) prior to initiation of any study procedures. - All patients should understand and agree to comply with planned study procedures. - Polymerase chain reaction (PCR)-confirmed infection with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) from throat swab. Exclusion Criteria: - Patients with pneumonia or severe illness requiring admission to intensive care unit. - Severe chronic kidney disease (i.e. estimated glomerular filtration rate [eGFR] < 30 mL / min ) or end stage renal disease requiring dialysis - Severe chronic liver disease (Alanine transaminase [AlT] or Aspartate transaminase [AST] > 5 times the upper limit of normal). - Pregnancy or breast feeding. - Anticipated transfer within 72 hours to another hospital that is not a study site. - Allergy to the study medication The trial is currently conducted on patients recruited from King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Intervention and comparator Intervention group: Nigella sativa oil (MARNYS® Cuminmar) 500 mg softgel capsules, one capsule orally twice daily for 10 days plus standard of care treatment (antipyretic, antitussive). Comparator group: standard of care treatment. Main outcomes Proportion of patients who clinically recovered (defined as 3 days of no symptoms) within 14 days after randomisation. Randomisation Patients will be randomly assigned to treatment or control groups in a 1:1 ratio using a computer-generated randomization scheme (Random permuted blocks of 10) developed using the web-based program: http://www.randomization.com . Blinding (masking) No blinding. Numbers to be randomised (sample size) Up to 200 eligible patients will be randomly assigned to either treatment or control groups. Trial Status Protocol version 1, as of July 14, 2020. Recruitment was started on May 21, 2020. The intended completion date is December 31, 2020. Trial registration ClinicalTrials.gov Identifier: NCT04401202 . Date of trial registration: May 26, 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Objectives • Primary objective: to evaluate the effect of intravenous melatonin (IVM) on mortality in adult patients admitted to the intensive care unit (ICU) with COVID-19. • Secondary objectives: ◦ To evaluate the effect of IVM on ICU length of stay. ◦ To evaluate the effect of IVM on the length of mechanical ventilation (MV). ◦ To evaluate if the use of IVM is associated with an increase in the number of ventilator-free days. ◦ To evaluate if the use of IVM is associated with a reduced number of failing organs as determined by the sequential organ failure assessment (SOFA) scale. ◦ To evaluate if the use of IVM is associated with a reduction of the frequency and severity of COVID-19-associated thromboembolic phenomena. ◦ To evaluate if the use of IVM is associated with a decreased systemic inflammatory response assessed by plasma levels of ferritin, D-dimer, C-reactive protein, procalcitonin and interleukin-6. ◦ To evaluate if the use of IVM is associated with an improvement in hematologic parameters. ◦ To evaluate if the use of IVM is associated with an improvement in biochemical parameters. ◦ To evaluate if the use of IVM is associated with an improvement in blood gas analysis parameters. ◦ To evaluate adverse events during the 28 day study period. Trial design Phase II, single center, double-blind, placebo-controlled randomized trial with a two-arm parallel group design and 2:1 allocation ratio. Participants Only critically ill adult patients that fulfill all of the inclusion criteria and none of the exclusion criteria will be included. The study will be conducted in a mixed ICU of a publicly funded tertiary referral center in Madrid, Spain with a 30-bed capacity and 1100 admissions per year. • Inclusion criteria: ◦ Patient, family member or legal guardian has provided written Informed Consent. ◦ Age ε 18 years. ◦ Confirmed SARS-CoV-2 infection with compatible symptoms AND a positive RT-PCR. ◦ Admission to the ICU with acute hypoxemic respiratory failure attributed to SARS-CoV-2 infection. ◦ ICU length of stay of less than 7 days prior to randomization with or without MV and without signs of improvement in respiratory failure (MURRAY score at randomization greater or equal to the MURRAY score at ICU admission). • Exclusion criteria: ◦ Participant in a different COVID-19 study in which the study drug is under clinical development and hasn’t been previously authorized for commercialization. ◦ Liver enzymes > 5 times the upper normal range. ◦ Chronic kidney disease with GFR < 30 mL/min/1.73 m 2 (stage 4 or greater) or need for hemodialysis. ◦ Pregnancy. A pregnancy test will be performed on every woman younger than 55 years of age prior to inclusion. ◦ Terminal surgical or medical illness. ◦ Autoimmune disease. ◦ Any patient condition that can prevent the study procedures to be carried out at the treating physician’s judgement. Intervention and comparator All patients will receive standard-of-care treatment according to the current institutional protocols. In addition, patients will be randomized in a 2:1 ratio to receive: • Experimental group (12 patients): 7 days of 5 mg per Kg of actual body weight per day of intravenous melatonin every 6 hours. Maximum daily dose 500 mg per day. • Control group (6 patients): 7 days of 5 mg per Kg of actual body weight per day of intravenous identically-looking placebo every 6 hours. After 3 days of treatment, 3 intensive care physicians will evaluate the participant and decide whether or not to complete the treatment based on their clinical assessment: • If objective or subjective signs of improvement or no worsening of the general clinical condition, respiratory failure, inflammatory state or multi-organ failure are observed, the participant will continue the treatment until completion. • If an adverse effect or clinical impairment is observed that is objectively or subjectively attributable to the study drug the treatment will be stopped. Main outcome Mortality in each study group represented in frequency and time-to-event at day 28 after randomization Randomization The randomization sequence was created using SAS version 9.4 statistical software (programmed and validated macros) with a 2:1 allocation. No randomization seed was pre-specified. The randomization seed was generated using the time on the computer where the program was executed. Blinding (masking) Participants, caregivers and study groups will be blinded to arm allocation. Numbers to be randomized (sample size) A total of 18 patients will be randomized in this trial: 12 to the experimental arm and 6 to the control arm. Trial Status Protocol version 2.0, June 5 th 2020. Trial status: recruitment not started. The first patient is expected to be recruited in October 2020. The last patient is anticipated to be recruited in August 2021. Trial registration EU Clinical Trials Register. Date of trial registration: 10 July 2020. URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001808-42/ES Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Objectives This study aims to determine the protection provided by Shenfu injection (a traditional Chinese medicine) against development of organ dysfunction in critically ill patients with coronavirus disease 2019 (COVID-19). Trial design This study is a multicenter, randomized, controlled, open-label, two-arm ratio 1:1, parallel group clinical trial. Participants The patients, who are aged from 18 to 75 years old, with a confirmed or suspected diagnosis of severe or critical COVID-19, will be consecutively recruited in the study, according to the guideline on diagnosis and treatment of COVID-19 (the 7 th version) issued by National Health Commission of the People’s Republic of China. Exclusion criteria include pregnant and breastfeeding women, atopy or allergies to Shenfu Injection (SFI), severe underlying disease (malignant tumor with multiple metastases, uncontrolled hemopathy, cachexia, severe malnutrition, HIV), active bleeding, obstructive pneumonia caused by lung tumor, severe pulmonary interstitial fibrosis, alveolar proteinosis and allergic alveolitis, continuous use of immunosuppressive drugs in last 6 months, organ transplantation, expected death within 48 hours, the patients considered unsuitable for this study by researchers. The study is conducted in 11 ICUs of designated hospitals for COVID-19, located in 5 cities of China. Intervention and comparator The enrolled patients will randomly receive 100 ml SFI (study group) or identical volume of saline (control group) twice a day for seven consecutive days. Patients in the both groups will be given usual care and the necessary supportive therapies as recommended by the latest edition of the management guidelines for COVID-19 (the 7 th version so far). Main outcomes The primary endpoint is a composite of newly developed or exacerbated organ dysfunction. This is defined as an increase in the sequential organ failure assessment (SOFA) score of two or more, indicating sepsis and involvement of at least one organ. The SOFA score will be measured for the 14 days after enrolment from the baseline (the score at randomization). The secondary endpoints are shown below: • SOFA score in total • Pneumonia severity index score • Dosage of vasoactive drugs • Ventilation free days within 28 days • Length of stay in intensive care unit • Total hospital costs to treat the patient • 28-day mortality • The incidence of adverse drug events related to SFI Randomisation The block randomization codes were generated by SAS V.9.1 for allocation of participants in this study. The ratio of random distribution is 1:1. The sealed envelope method is used for allocation concealment. Blinding (masking) The patients and statistical personnel analyzing study data are both blinded. The blinding of group assignment is not adopted for the medical staff. Numbers to be randomised (sample size) This study is expected to recruit 300 patients with COVID-19, (150 in each group). Trial Status Protocol version 2.0, February 15, 2020. Patient recruitment started on February 25, and will end on August 31, 2020. Trial registration Chinese Clinical Trial Registry: ChiCTR2000030043. Registered February 21, 2020, http://www.chictr.org.cn/showprojen.aspx?proj=49866 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Introduction: Paxlovid (nirmatrelvir/ritonavir) is a new oral antiviral drug that is used for coronavirus disease 2019 (COVID-19) and is administered to patients with mild to moderate disease for five consecutive days. This meta-analysis aimed to evaluate the efficacy of Paxlovid in COVID-19 patients. Methodology: PubMed, Embase, Cochrane Library, and Web of Science databases were searched to identify relevant publications up to 9 March 2023. Three randomized controlled trial (RCT) studies, one prospective cohort study, and 25 retrospective cohort studies were identified for the meta-analysis. Results: There was a significant difference between the Paxlovid and control groups in terms of hospitalization (RR = 0.53; 95% CI: 0.24–0.69, p < 0.001), all-cause mortality (RR = 0.36; 95% CI: 0.27–0.50, p < 0.001), hospitalization or death (RR = 0.50; 95% CI: 0.37–0.67, p < 0.001), intensive care unit admission (RR = 0.45; 95% CI: 0.27–0.73, p = 0.001), and emergency department visits (RR = 0.67; 95% CI: 0.54–0.83, p < 0.001). However, no significant difference was found between the two groups in terms of COVID‐19 rebound (OR = 1.18; 95% CI: 0.82–1.68, p = 0.37). In addition, the Paxlovid group had a significantly shorter hospital length of stay (weighted mean difference WMD = -1.11; 95% CI, -1.81, -0.41; I2 > 50%, p < 0.05), and polymerase chain reaction negative conversion time (WMD = -2.75; 95% CI, -3.60, -1.89, I2 > 50%, p < 0.05) than that of the control group. Conclusions: Paxlovid can be considered an effective therapeutic agent for treating patients with COVID-19.

Insufficient investment and fears about rebound and side effects are driving down use of a lifesaving antiviral. Insufficient investment and fears about rebound and side effects are driving down use of a lifesaving antiviral. Credit: Thomas Hansmann/AP/Shutterstock A lab technician visually inspects COVID-19 Paxlovid tablet samples in Freiburg, Germany.