Body Fat Reduction Effect of Bifidobacterium breve B-3: A Randomized, Double-Blind, Placebo Comparative Clinical Trial.

This double-blind, randomized clinical trial aimed to evaluate the efficacy and safety of Bifidobacterium breve B-3 (BB-3) for reducing body fat. Healthy individuals were randomized into the BB-3 or placebo group (1:1). Dual-energy X-ray absorptiometry was used to evaluate body fat reduction objectively. In the BB-3 group, body weight was lower than before BB-3 ingestion. Regarding waist circumference, hip circumference, and waist/hip circumference ratio, waist circumference and hip circumference were lower in the BB-3 group than in the placebo group at 12 weeks; the waist/hip circumference ratio was found to decrease at each visit in the BB-3 group, although there was no significant difference in the amount of change after 12 weeks. BB-3 did not cause any severe adverse reactions. Body fat was significantly lower in the BB-3 group than in the placebo group. In conclusion, ingesting BB-3 significantly reduces body weight, waist circumference, and hip circumference. Thus, BB-3 is safe and effective for reducing body fat.

A phase 3, randomised, double-blind, placebo-controlled clinical trial evaluation of the efficacy and safety of a SARS-CoV-2 recombinant spike RBD protein vaccine in adults (ABDALA-3 study).

Background: The pandemic of COVID-19 raised the urgent need for safe and efficacious vaccines against SARS-CoV-2. We evaluated the efficacy and safety of a new SARS-CoV-2 virus receptor-binding domain (RBD) vaccine. Methods: A phase 3, multicentre, randomised, double-blind, placebo-controlled trial was carried out at 18 clinical sites in three provinces of the south-eastern region of Cuba. Subjects (healthy or those with controlled chronic diseases) aged between 19 and 80 years, who gave written informed consent were eligible. Subjects were randomly assigned (1:1, in blocks) to two groups: placebo, and 50 µg RBD vaccine (Abdala). The product was administered intramuscularly, 0.5 mL in the deltoid region, in a three-dose immunization schedule at 0-14-28 days. The organoleptic characteristics and presentations of the vaccine and placebo were identical. All participants (subjects, clinical researchers, statisticians, laboratory technicians, and monitors) remained blinded during the study period. The main endpoint was to evaluate the efficacy of the Abdala vaccine in the prevention of symptomatic COVID-19. The trial is registered with the Cuban Public Registry of Clinical Trials, RPCEC00000359. Findings: Between March 22 to April 03, 2021, 48,290 subjects were included (24,144 and 24,146 in the placebo and Abdala groups, respectively) in the context of predominant D614G variant circulation. The evaluation of the main efficacy outcomes occurred during May-June 2021, starting at May 3rd, in the context of high circulation of mutant viruses, predominantly VOC Beta. The incidence of adverse reactions for individuals in the placebo and Abdala vaccine groups were 1227/24,144 (5.1%) and 1621/24,146 (6.7%), respectively. Adverse reactions were mostly mild, and from the injection site, which resolved in the first 24-48 h. No severe adverse events with demonstrated cause-effect relationship attributable to the vaccine were reported. Symptomatic COVID-19 disease was confirmed in 142 participants in the placebo group (78.44 incidence per 1000 person-years, 95% confidence interval [CI], 66.07-92.46) and in 11 participants in Abdala vaccine group (6.05 incidence per 1000 person years; 95% CI 3.02-10.82). The Abdala vaccine efficacy against symptomatic COVID-19 was 92.28% (95% CI 85.74-95.82). Moderate/serious forms of COVID-19 occurred in 30 participants (28 in the placebo group and only 2 in the Abdala vaccine group) for a vaccine efficacy of 92.88% (95% CI 70.12-98.31). There were five critical patients (of which four died), all in the placebo group. Interpretation: The Abdala vaccine was safe, well tolerated, and highly effective, fulfilling the WHO target product profile for COVID-19 vaccines. Those results, along with its immunization schedule and the advantage of easy storage and handling conditions at 2-8 °C, make this vaccine an option for the use in immunization strategies as a key tool for the control of the pandemic. Funding: Centre for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba.

Effectiveness and safety of Qingfei Dayuan granules for treating influenza and upper respiratory tract infections manifested by the pulmonary heat-toxin syndrome: A multicenter, randomized, double-blind, placebo-controlled trial.

Background: Patients diagnosed with influenza and upper respiratory tract infections (URTIs) have similar clinical manifestations and biochemical indices and a low detection rate of viral pathogens, mixed infection with diverse respiratory viruses, and targeted antiviral treatment difficulty in the early stage. According to the treatment strategy of "homotherapy for heteropathy" in traditional Chinese medicine (TCM), different diseases with the same clinical symptoms can be treated with the same medicines. Qingfei Dayuan granules (QFDY), a type of Chinese herbal preparation included in the TCM Diagnosis and Treatment Protocol for COVID-19 of Hubei Province issued by the Health Commission of Hubei Province in 2021, are recommended for patients suffering from COVID-19 with symptoms of fever, cough, and fatigue, among others. Additionally, recent studies have shown that QFDY effectively alleviates fever, cough, and other clinical symptoms in patients with influenza and URTIs. Materials and methods: The study was designed as a multicenter, randomized, double-blind, placebo-controlled clinical trial for treatment for influenza and URTIs manifested by pulmonary heat-toxin syndrome (PHTS) with QFDY. A total of 220 eligible patients were enrolled from eight first-class hospitals in five cities of Hubei Province in China and randomly assigned to receive either 15 g of QFDY or a placebo three times a day for 5 days. The primary outcome was the complete fever relief time. Secondary outcomes included efficacy evaluation of TCM syndromes, scores of TCM syndromes, cure rate of each single symptom, incidence of comorbidities and progression to severe conditions, combined medications, and laboratory tests. Safety evaluations mainly involved adverse events (AEs) and changes in vital signs during the study. Results: Compared with the placebo group, the complete fever relief time was shorter in the QFDY group, 24 h (12.0, 48.0) in the full analysis set (FAS) and 24 h (12.0, 49.5) in the per-protocol set (PPS) (p ≤ 0.001). After a 3-day treatment, the clinical recovery rate (22.3% in the FAS and 21.6% in the PPS) and cure rate of cough (38.6% in the FAS and 37.9% in the PPS), a stuffy and running nose, and sneezing (60.0% in the FAS and 59.5% in the PPS) in the QFDY group were higher than those in the placebo group (p < 0.05). The number of patients taking antibiotics for more than 24 h in the placebo group (nine cases) was significantly higher than that in the QFDY group (one case) (p < 0.05). There were no significant differences between the two groups in terms of scores of TCM syndromes, incidence of comorbidities or progression to severe conditions, combined use of acetaminophen tablets or phlegm-resolving medicines, and laboratory tests (p > 0.05). Meanwhile, no significant difference was found in the incidence of AEs and vital signs between the two groups (p > 0.05). Conclusion: The trial showed that QFDY was an effective and safe treatment modality for influenza and URTIs manifested by PHTS because it shortened the complete fever relief time, accelerated clinical recovery, and alleviated symptoms such as cough, a stuffy and running nose, and sneezing during the course of treatment. Clinical trial registration: https://www.chictr.org.cn/showproj.aspx?proj=131702, identifier ChiCTR2100049695.

BCG Vaccination of Health Care Workers Does Not Reduce SARS-CoV-2 Infections nor Infection Severity or Duration: a Randomized Placebo-Controlled Trial.

Bacillus Calmette-Guerin (BCG) vaccination has been hypothesized to reduce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, severity, and/or duration via trained immunity induction. Health care workers (HCWs) in nine Dutch hospitals were randomized to BCG or placebo vaccination (1:1) in March and April 2020 and followed for 1 year. They reported daily symptoms, SARS-CoV-2 test results, and health care-seeking behavior via a smartphone application, and they donated blood for SARS-CoV-2 serology at two time points. A total of 1,511 HCWs were randomized and 1,309 analyzed (665 BCG and 644 placebo). Of the 298 infections detected during the trial, 74 were detected by serology only. The SARS-CoV-2 incidence rates were 0.25 and 0.26 per person-year in the BCG and placebo groups, respectively (incidence rate ratio, 0.95; 95% confidence interval, 0.76 to 1.21; P = 0.732). Only three participants required hospitalization for SARS-CoV-2. The proportions of participants with asymptomatic, mild, or moderate infections and the mean infection durations did not differ between randomization groups. In addition, unadjusted and adjusted logistic regression and Cox proportional hazards models showed no differences between BCG and placebo vaccination for any of these outcomes. The percentage of participants with seroconversion (7.8% versus 2.8%; P = 0.006) and mean SARS-CoV-2 anti-S1 antibody concentration (13.1 versus 4.3 IU/mL; P = 0.023) were higher in the BCG than placebo group at 3 months but not at 6 or 12 months postvaccination. BCG vaccination of HCWs did not reduce SARS-CoV-2 infections nor infection duration or severity (ranging from asymptomatic to moderate). In the first 3 months after vaccination, BCG vaccination may enhance SARS-CoV-2 antibody production during SARS-CoV-2 infection. IMPORTANCE While several BCG trials in adults were conducted during the 2019 coronavirus disease epidemic, our data set is the most comprehensive to date, because we included serologically confirmed infections in addition to self-reported positive SARS-CoV-2 test results. We also collected data on symptoms for every day during the 1-year follow-up period, which enabled us to characterize infections in detail. We found that BCG vaccination did not reduce SARS-CoV-2 infections nor infection duration or severity but may have enhanced SARS-CoV-2 antibody production during SARS-CoV-2 infection in the first 3 months after vaccination. These results are in agreement with other BCG trials that reported negative results (but did not use serological endpoints), except for two trials in Greece and India that reported positive results but had few endpoints and included endpoints that were not laboratory confirmed. The enhanced antibody production is in agreement with prior mechanistic studies but did not translate into protection from SARS-CoV-2 infection.

Effect of Lactoferrin on Clinical Outcomes of Hospitalized Patients with COVID-19: The LAC Randomized Clinical Trial.

As lactoferrin is a nutritional supplement with proven antiviral and immunomodulatory abilities, it may be used to improve the clinical course of COVID-19. The clinical efficacy and safety of bovine lactoferrin were evaluated in the LAC randomized double-blind placebo-controlled trial. A total of 218 hospitalized adult patients with moderate-to-severe COVID-19 were randomized to receive 800 mg/die oral bovine lactoferrin (n = 113) or placebo (n = 105), both given in combination with standard COVID-19 therapy. No differences in lactoferrin vs. placebo were observed in the primary outcomes: the proportion of death or intensive care unit admission (risk ratio of 1.06 (95% CI 0.63-1.79)) or proportion of discharge or National Early Warning Score 2 (NEWS2) ≤ 2 within 14 days from enrollment (RR of 0.85 (95% CI 0.70-1.04)). Lactoferrin showed an excellent safety and tolerability profile. Even though bovine lactoferrin is safe and tolerable, our results do not support its use in hospitalized patients with moderate-to-severe COVID-19.

Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial.

Background: An in silico screen was performed to identify FDA approved drugs that inhibit SARS-CoV-2 main protease (Mpro), followed by in vitro viral replication assays, and in vivo pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral replication. Methods: A 2-center, randomized, double-blind, placebo-controlled trial was performed among patients hospitalized with COVID-19 infection. Enrolled patients were randomized 2:1 to atovaquone 1500 mg BID versus matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Saliva was collected at baseline and twice per day for up to 10 days for RNA extraction for SARS-CoV-2 viral load measurement by quantitative reverse-transcriptase PCR. The primary outcome was the between group difference in log-transformed viral load (copies/mL) using a generalized linear mixed-effect models of repeated measures from all samples. Results: Of the 61 patients enrolled; 41 received atovaquone and 19 received placebo. Overall, the population was predominately male (63%) and Hispanic (70%), with a mean age of 51 years, enrolled a mean of 5 days from symptom onset. The log10 viral load was 5.25 copies/mL vs. 4.79 copies/mL at baseline in the atovaquone vs. placebo group. Change in viral load did not differ over time between the atovaquone plus standard of care arm versus the placebo plus standard of care arm. Pharmacokinetic (PK) studies of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, with an inverse correlation between BMI and atovaquone levels, (Rho -0.45, p = 0.02). In post hoc analysis, an inverse correlation was observed between atovaquone levels and viral load (Rho -0.54, p = 0.005). Conclusion: In this prospective, randomized, placebo-controlled trial, atovaquone did not demonstrate evidence of enhanced SARS-CoV-2 viral clearance compared with placebo. However, based on the observed inverse correlation between atovaquone levels and viral load, additional PK-guided studies may be warranted to examine the antiviral effect of atovaquone in COVID-19 patients.

Pyridostigmine reduces mortality of patients with severe SARS-CoV-2 infection: A phase 2/3 randomized controlled trial.

BACKGROUND: Respiratory failure in severe coronavirus disease 2019 (COVID-19) is associated with a severe inflammatory response. Acetylcholine (ACh) reduces systemic inflammation in experimental bacterial and viral infections. Pyridostigmine increases the half-life of endogenous ACh, potentially reducing systemic inflammation. We aimed to determine if pyridostigmine decreases a composite outcome of invasive mechanical ventilation (IMV) and death in adult patients with severe COVID-19. METHODS: We performed a double-blinded, placebo-controlled, phase 2/3 randomized controlled trial of oral pyridostigmine (60 mg/day) or placebo as add-on therapy in adult patients admitted due to confirmed severe COVID-19 not requiring IMV at enrollment. The primary outcome was a composite of IMV or death by day 28. Secondary outcomes included reduction of inflammatory markers and circulating cytokines, and 90-day mortality. Adverse events (AEs) related to study treatment were documented and described. RESULTS: We recruited 188 participants (94 per group); 112 (59.6%) were men; the median (IQR) age was 52 (44-64) years. The study was terminated early due to a significant reduction in the primary outcome in the treatment arm and increased difficulty with recruitment. The primary outcome occurred in 22 (23.4%) participants in the placebo group vs. 11 (11.7%) in the pyridostigmine group (hazard ratio, 0.47, 95% confidence interval 0.24-0.9; P = 0.03). This effect was driven by a reduction in mortality (19 vs. 8 deaths, respectively). CONCLUSION: Our data indicate that adding pyridostigmine to standard care reduces mortality among patients hospitalized for severe COVID-19.

Favipiravir and/or nitazoxanide: a randomized, double-blind, 2×2 design, placebo-controlled trial of early therapy in COVID-19 in health workers, their household members, and patients treated at IMSS (FANTAZE).

BACKGROUND: The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with the first presentation of symptoms, followed by a later 'inflammatory' phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with a better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease. METHODS: Trial design: Phase IIA randomised, double-blind, 2 × 2 design, placebo-controlled, interventional trial. RANDOMISATION: Participants will be randomised 1:1 by stratification, with the following factors: gender, obesity, symptomatic or asymptomatic, current smoking status presence or absence of comorbidity, and if the participant has or has not been vaccinated. BLINDING: Participants and investigators will both be blinded to treatment allocation (double-blind). DISCUSSION: We propose to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and patients treated at the Mexican Social Security Institute (IMSS) facilities. Participants with or without symptomatic COVID-19 or who tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus ('viral load') in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04918927 . Registered on June 9, 2021.

A platform trial design for preventive vaccines against Marburg virus and other emerging infectious disease threats.

BACKGROUND: The threat of a possible Marburg virus disease outbreak in Central and Western Africa is growing. While no Marburg virus vaccines are currently available for use, several candidates are in the pipeline. Building on knowledge and experiences in the designs of vaccine efficacy trials against other pathogens, including SARS-CoV-2, we develop designs of randomized Phase 3 vaccine efficacy trials for Marburg virus vaccines. METHODS: A core protocol approach will be used, allowing multiple vaccine candidates to be tested against controls. The primary objective of the trial will be to evaluate the effect of each vaccine on the rate of virologically confirmed Marburg virus disease, although Marburg infection assessed via seroconversion could be the primary objective in some cases. The overall trial design will be a mixture of individually and cluster-randomized designs, with individual randomization done whenever possible. Clusters will consist of either contacts and contacts of contacts of index cases, that is, ring vaccination, or other transmission units. RESULTS: The primary efficacy endpoint will be analysed as a time-to-event outcome. A vaccine will be considered successful if its estimated efficacy is greater than 50% and has sufficient precision to rule out that true efficacy is less than 30%. This will require approximately 150 total endpoints, that is, cases of confirmed Marburg virus disease, per vaccine/comparator combination. Interim analyses will be conducted after 50 and after 100 events. Statistical analysis of the trial will be blended across the different types of designs. Under the assumption of a 6-month attack rate of 1% of the participants in the placebo arm for both the individually and cluster-randomized populations, the most likely sample size is about 20,000 participants per arm. CONCLUSION: This event-driven design takes into the account the potentially sporadic spread of Marburg virus. The proposed trial design may be applicable for other pathogens against which effective vaccines are not yet available.

Double-Blind, Randomized, Placebo-Controlled Study on hzVSF-v13, a Novel Anti-Vimentin Monoclonal Antibody Drug as Add-on Standard of Care in the Management of Patients with Moderate to Severe COVID-19.

Humanized Virus Suppressing Factor-variant 13 (hzVSF-v13), a monoclonal IgG4 antibody against vimentin, was investigated in moderate to severe COVID-19 pneumonia through a Phase II study. Patients were randomized to two different IV doses of the test drug or saline with standard of care. Overall, 64 patients were recruited, and 62 entered the efficacy assessment in the full analysis set. Primary endpoint: The clinical failure rate at day 28 was 15.8% for placebo, 9.1% for low-dose hzVSF-v13 and 9.5% for high-dose hzVSF-v13 (not significant). A trend toward better efficacy was shown in several secondary endpoints, with statistical significance between low-dose hzVSF-v13 and placebo in terms of the rate of improved patients on the ordinal scale for clinical improvement (OSCI): 90.0% vs. 52.63% (p = 0.0116). In the severe stratum, the results of low-dose hzVSF-v13 vs. placebo were 90.0% and 22.2% for OSCI (p = 0.0092), 9 days and 14 days for time to discontinuation of oxygen therapy (p = 0.0308), 10 days and 15 days for both time to clinical improvement (TTCI) and time to recovery (TTR) and p = 0.0446 for both TTCI and TTR. Change from baseline of NEWS2 score at day 28 was -3.4 vs. + 0.4 (p = 0.0441). The results propose hzVSF-v13 as a candidate in the treatment of severe COVID-19.

Aspirin as a Treatment for ARDS: A Randomized, Placebo-Controlled Clinical Trial.

BACKGROUND: There is no pharmacologic treatment for ARDS. Platelets play an important role in the pathophysiology of ARDS. Preclinical, observational, and clinically relevant models of ARDS indicate aspirin as a potential therapeutic option. RESEARCH QUESTION: Is enteral aspirin (75 mg, once daily) safe and effective in improving surrogate outcomes in adult patients with ARDS? STUDY DESIGN AND METHODS: This randomized, double-blind (patient and investigator), allocation-concealed, placebo-controlled phase 2 trial was conducted in five UK ICUs. Patients fulfilling the Berlin definition of ARDS were randomly assigned at a 1:1 ratio to receive enteral aspirin (75 mg) or placebo, for a maximum of 14 days, using a computer-generated randomization schedule, with variable block size, stratified by vasopressor requirement. The primary end point was oxygenation index (OI) on day 7. Secondary outcomes included safety parameters and other respiratory physiological markers. Analyses were by intention to treat. RESULTS: The trial was stopped early, due to slow recruitment, after 49 of a planned 60 patients were recruited. Twenty-four patients were allocated to aspirin and 25 to placebo. There was no significant difference in day 7 OI [aspirin group: unadjusted mean, 54.4 (SD 26.8); placebo group: 42.4 (SD 25); mean difference, 12.0; 95% CI, -6.1 to 30.1; P = .19]. Aspirin did not significantly impact the secondary outcomes. There was no difference in the number of adverse events between the groups (13 in each; OR, 1.04; 95% CI, 0.56-1.94; P = .56). INTERPRETATION: Aspirin was well tolerated but did not improve OI or other physiological outcomes; a larger trial is not feasible in its current design. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02326350; URL: www. CLINICALTRIALS: gov.

Pleiotropic effects of vitamin D including aspects of COVID-19

Vitamin D is provided by nutritional sources or by skin synthesis under the influence of UV light. In the liver, vitamin D is converted to 25(OH)-vitamin D and finally in the kidney to 1,25(OH)2-vitamin D, which is a hormone regulating bone andmineralmetabolism. Besides the kidneys, other organs are also capable of making 1,25(OH)2-vitamin D, which exerts autocrine and paracrine effects. For these pleiotropic effects, a continuous vitamin D supply (daily supplements) with moderate doses is more effective than high-dose bolus applications. Beside the classical effects of 1,25(OH)2-vitamin D on the musculoskeletal system, there is good evidence for extraskeletal effects on the immune system. A good vitamin D supply can reduce the risk of respiratory infections. At the present time, the preventive and therapeutic use of vitamin D regarding COVID-19 (coronavirus disease 19) is of great interest.

WHO guidance on COVID-19 vaccine trial designs in the context of authorized COVID-19 vaccines and expanding global access: Ethical considerations.

While the degree of COVID-19 vaccine accessibility and uptake varies at both national and global levels, increasing vaccination coverage raises questions regarding the standard of prevention that ought to apply to different settings where COVID-19 vaccine trials are hosted. A WHO Expert Group has developed guidance on the ethical implications of conducting placebo-controlled trials in the context of expanding global COVID-19 vaccine coverage. The guidance also considers alternative trial designs to placebo controlled trials in the context of prototype vaccines, modified vaccines, and next generation vaccines.

Efficacy and safety of current medications for treating severe and non-severe COVID-19 patients: an updated network meta-analysis of randomized placebo-controlled trials.

BACKGROUND: Many recent studies have investigated the role of drug interventions for coronavirus disease 2019 (COVID-19) infection. However, an important question has been raised about how to select the effective and secure medications for COVID-19 patients. The aim of this analysis was to assess the efficacy and safety of the various medications available for severe and non-severe COVID-19 patients based on randomized placebo-controlled trials (RPCTs). METHODS: We did an updated network meta-analysis. We searched the databases from inception until July 31, 2021, with no language restrictions. We included RPCTs comparing 49 medications and placebo in the treatment of severe and non-severe patients (aged 18 years or older) with COVID-19 infection. We extracted data on the trial and patient characteristics, and the following primary outcomes: all-cause mortality, the ratios of virological cure, and treatment-emergent adverse events. Odds ratio (OR) and their 95% confidence interval (CI) were used as effect estimates. RESULTS: From 3,869 publications, we included 61 articles related to 73 RPCTs (57 in non-severe COVID-19 patients and 16 in severe COVID-19 patients), comprising 20,680 patients. The mean sample size was 160 (interquartile range 96-393) in this study. The median duration of follow-up drugs intervention was 28 days (interquartile range 21-30). For increase in virological cure, we only found that proxalutamide (OR 9.16, 95% CI 3.15-18.30), ivermectin (OR 6.33, 95% CI 1.22-32.86), and low dosage bamlanivimab (OR 5.29, 95% CI 1.12-24.99) seemed to be associated with non-severe COVID-19 patients when compared with placebo, in which proxalutamide seemed to be better than low dosage bamlanivimab (OR 5.69, 95% CI 2.43-17.65). For decrease in all-cause mortality, we found that proxalutamide (OR 0.13, 95% CI 0.09-0.19), imatinib (OR 0.49, 95% CI 0.25-0.96), and baricitinib (OR 0.58, 95% CI 0.42-0.82) seemed to be associated with non-severe COVID-19 patients; however, we only found that immunoglobulin gamma (OR 0.27, 95% CI 0.08-0.89) was related to severe COVID-19 patients when compared with placebo. For change in treatment-emergent adverse events, we only found that sotrovimab (OR 0.21, 95% CI 0.13-0.34) was associated with non-severe COVID-19 patients; however, we did not find any medications that presented a statistical difference when compared with placebo among severe COVID-19 patients. CONCLUSION: We conclude that marked variations exist in the efficacy and safety of medications between severe and non-severe patients with COVID-19. It seems that monoclonal antibodies (e.g., low dosage bamlanivimab, baricitinib, imatinib, and sotrovimab) are a better choice for treating severe or non-severe COVID-19 patients. Clinical decisions to use preferentially medications should carefully consider the risk-benefit profile based on efficacy and safety of all active interventions in patients with COVID-19 at different levels of infection.

Repeated Transcranial Magnetic Stimulation for Improving Cognition in Alzheimer Disease: Protocol for an Interim Analysis of a Randomized Controlled Trial.

BACKGROUND: Many clinical trials investigating treatment efficacy require an interim analysis. Recently we have been running a large, multisite, randomized, placebo-controlled, double-blind clinical trial investigating the effect of repetitive transcranial magnetic stimulation (rTMS) treatment for improving or stabilizing the cognition of patients diagnosed with Alzheimer disease. OBJECTIVE: The objectives of this paper are to report on recruitment, adherence, and adverse events (AEs) to date, and to describe in detail the protocol for interim analysis of the clinical trial data. The protocol will investigate whether the trial is likely to reach its objectives if continued to the planned maximum sample size. METHODS: The specific requirements of the analytic protocol are to (1) ensure the double-blind nature of the data while doing the analysis, (2) estimate the predictive probabilities of success (PPoSs), (3) estimate the numbers needed to treat, (4) re-estimate the initial required sample size. The initial estimate of sample size was 208. The interim analysis will be based on 150 patients who will be enrolled in the study and finish at least 8 weeks of the study. Our protocol for interim analysis, at the very first stage, is to determine the response rate for each participant to the treatment (either sham or active), while ensuring the double-blind nature of the data. The blinded data will be analyzed by a statistician to investigate the treatment efficacy. We will use Bayesian PPoS to predict the success rate and determine whether the study should continue. RESULTS: The enrollment has been slowed significantly due to the COVID-19 pandemic and lockdown. Nevertheless, so far 133 participants have been enrolled, while 22 of these have been withdrawn or dropped out for various reasons. In general, rTMS has been found tolerable with no serious AE. Only 2 patients dropped out of the study due to their intolerability to rTMS pulses. CONCLUSIONS: Overall, the study with the same protocol is going as expected with no serious AE or any major protocol deviation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02908815; https://clinicaltrials.gov/ct2/show/NCT02908815. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31183.

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial.

BACKGROUND: In the early phase of the pandemic, some guidelines recommended the use of corticosteroids for critically ill patients with COVID-19, whereas others recommended against the use despite lack of firm evidence of either benefit or harm. In the COVID STEROID trial, we aimed to assess the effects of low-dose hydrocortisone on patient-centred outcomes in adults with COVID-19 and severe hypoxia. METHODS: In this multicentre, parallel-group, placebo-controlled, blinded, centrally randomised, stratified clinical trial, we randomly assigned adults with confirmed COVID-19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) to either hydrocortisone (200 mg/d) vs a matching placebo for 7 days or until hospital discharge. The primary outcome was the number of days alive without life support at day 28 after randomisation. RESULTS: The trial was terminated early when 30 out of 1000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID-19. At day 28, the median number of days alive without life support in the hydrocortisone vs placebo group were 7 vs 10 (adjusted mean difference: -1.1 days, 95% CI -9.5 to 7.3, P = .79); mortality was 6/16 vs 2/14; and the number of serious adverse reactions 1/16 vs 0/14. CONCLUSIONS: In this trial of adults with COVID-19 and severe hypoxia, we were unable to provide precise estimates of the benefits and harms of hydrocortisone as compared with placebo as only 3% of the planned sample size were enrolled. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04348305. European Union Drug Regulation Authorities Clinical Trials (EudraCT) Database: 2020-001395-15.

COVID-19 vaccine trials: The potential for "hybrid" analyses.

BACKGROUND: Although several COVID-19 vaccines have been found to be effective in rigorous evaluation and have emerging availability in parts of the world, their supply will be inadequate to meet international needs for a considerable period of time. There also will be continued interest in vaccines that are more effective or have improved scalability to facilitate mass vaccination campaigns. Ongoing clinical testing of new vaccines also will be needed as variant strains continue to emerge that may elude some aspects of immunity induced by current vaccines. Randomized clinical trials meaningfully enhance the efficiency and reliability of such clinical testing. In clinical settings with limited or no access to known effective vaccines, placebo-controlled randomized trials of new vaccines remain a preferred approach to maximize the reliability, efficiency and interpretability of results. When emerging availability of licensed vaccines makes it no longer possible to use a placebo control, randomized active comparator non-inferiority trials may enable reliable insights. METHODS: In this article, "hybrid" methods are proposed to address settings where, during the conduct of a placebo-controlled trial, a judgment is made to replace the placebo arm by a licensed COVID-19 vaccine due to emerging availability of effective vaccines in regions participating in that trial. These hybrid methods are based on proposed statistics that aggregate evidence to formally test as well as to estimate the efficacy of the experimental vaccine, by combining placebo-controlled data during the first period of trial conduct with active-controlled data during the second period. RESULTS: Application of the proposed methods is illustrated in two important scenarios where the active control vaccine would become available in regions engaging in the experimental vaccine's placebo-controlled trial: in the first, the active comparator's vaccine efficacy would have been established to be 50%-70% for the 4- to 6-month duration of follow-up of its placebo-controlled trial; in the second, the active comparator's vaccine efficacy would have been established to be 90%-95% during that duration. These two scenarios approximate what has been seen with adenovirus vaccines or mRNA vaccines, respectively, assuming the early estimates of vaccine efficacy for those vaccines would hold over longer-term follow-up. CONCLUSION: The proposed hybrid methods could readily play an important role in the near future in the design, conduct and analysis of randomized clinical trials performed to address the need for multiple additional vaccines reliably established to be safe and have worthwhile efficacy in reducing the risk of symptomatic disease from SARS-CoV-2 infections.