-
1.
A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects.
Yang, XM, Yang, Y, Yao, BF, Ye, PP, Xu, Y, Peng, SP, Yang, YM, Shu, P, Li, PJ, Li, S, et al
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2023;:106598
-
-
Free full text
-
Abstract
Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.
-
2.
Additive benefit of rehabilitation on physical status, symptoms and mental health after hospitalisation for severe COVID-19 pneumonia.
Asimakos, A, Spetsioti, S, Mavronasou, A, Gounopoulos, P, Siousioura, D, Dima, E, Gianniou, N, Sigala, I, Zakynthinos, G, Kotanidou, A, et al
BMJ open respiratory research. 2023;(1)
Abstract
INTRODUCTION The potential additive benefits of rehabilitation beyond spontaneous recovery post-COVID-19 currently remain unknown. METHODS In this prospective, interventional, non-randomised parallel assignment two-arm study, we investigated the effects of an 8-week rehabilitation programme (Rehab, n=25) added to usual care (UC) versus UC (n=27) on respiratory symptoms, fatigue, functional capacity, mental health and health-related quality of life in patients with COVID-19 pneumonia, 6-8 weeks post-hospital discharge. The rehabilitation programme included exercise, education, dietary and psychological support. Patients with chronic obstructive pulmonary disease, respiratory and heart failure were excluded from the study. RESULTS At baseline, groups were not different in mean age (56 years), gender (53% female), intensive care unit admission (61%), intubation (39%), days of hospitalisation (25), number of symptoms (9) and number of comorbidities (1.4). Baseline evaluation was conducted at median (IQR) 76 (27) days after symptoms onset. Groups were not different regarding baseline evaluation outcomes. At 8 weeks, Rehab showed significantly greater improvement in COPD Assessment Test by a mean±SEM (95% CI) 7.07±1.36 (4.29-9.84), p <0.001 and all three fatigue questionnaires: Chalder-Likert: 5.65±1.27 (3.04-8.25), p <0.001; bimodal: 3.04±0.86 (1.28-4.79), p=0.001; Functional Assessment of Chronic Illness Therapy: 6.37±2.09 (2.08-10.65), p=0.005 and Fatigue Severity Scale: 1.36±0.433 (0.47-2.25), p=0.004. At 8 weeks rehab also showed significantly greater improvment in Short Physical Performance Battery: 1.13±0.33 (0.46-1.79), p=0.002; Hospital Anxiety and Depression Scale (HADS) Anxiety: 2.93±1.01 (0.67-5.18), p=0.013; Beck Depression Inventory: 7.81±3.07 (1.52-14.09), p=0.017; Montreal Cognitive Assessment: 2.83±0.63 (1.5-4.14), p <0.001; EuroQol (EQ-5D-5L) Utility Index: 0.21±0.05 (0.1-0.32), p=0.001 and Visual Analogue Scale: 6.57±3.21 (0.2-13.16), p=0.043. Both groups significantly improved 6-min walking distance by approximately 60 m and pulmonary function measures, whereas post-traumatic stress disorder measurement IES-R (Impact of Event Scale, Revised) and HADS-Depression score were not different between groups at 8 weeks. A 16% attrition rate was observed in the rehabilitation group exhibiting a threefold increase in training workload. There were no adverse effects reported during exercise training. DISCUSSION These findings highlight the added value of rehabilitation post-COVID-19 to amplify the natural course of physical and mental recovery that otherwise would remain incomplete with UC.
-
3.
Favipiravir in patients hospitalised with COVID-19 (PIONEER trial): a multicentre, open-label, phase 3, randomised controlled trial of early intervention versus standard care.
Shah, PL, Orton, CM, Grinsztejn, B, Donaldson, GC, Crabtree Ramírez, B, Tonkin, J, Santos, BR, Cardoso, SW, Ritchie, AI, Conway, F, et al
The Lancet. Respiratory medicine. 2023;(5):415-424
Abstract
BACKGROUND COVID-19 has overwhelmed health services globally. Oral antiviral therapies are licensed worldwide, but indications and efficacy rates vary. We aimed to evaluate the safety and efficacy of oral favipiravir in patients hospitalised with COVID-19. METHODS We conducted a multicentre, open-label, randomised controlled trial of oral favipiravir in adult patients who were newly admitted to hospital with proven or suspected COVID-19 across five sites in the UK (n=2), Brazil (n=2) and Mexico (n=1). Using a permuted block design, eligible and consenting participants were randomly assigned (1:1) to receive oral favipiravir (1800 mg twice daily for 1 day; 800 mg twice daily for 9 days) plus standard care, or standard care alone. All caregivers and patients were aware of allocation and those analysing data were aware of the treatment groups. The prespecified primary outcome was the time from randomisation to recovery, censored at 28 days, which was assessed using an intention-to-treat approach. Post-hoc analyses were used to assess the efficacy of favipiravir in patients aged younger than 60 years, and in patients aged 60 years and older. The trial was registered with clinicaltrials.gov, NCT04373733. FINDINGS Between May 5, 2020 and May 26, 2021, we assessed 503 patients for eligibility, of whom 499 were randomly assigned to favipiravir and standard care (n=251) or standard care alone (n=248). There was no significant difference between those who received favipiravir and standard care, relative to those who received standard care alone in time to recovery in the overall study population (hazard ratio [HR] 1·06 [95% CI 0·89-1·27]; n=499; p=0·52). Post-hoc analyses showed a faster rate of recovery in patients younger than 60 years who received favipiravir and standard care versus those who had standard care alone (HR 1·35 [1·06-1·72]; n=247; p=0·01). 36 serious adverse events were observed in 27 (11%) of 251 patients administered favipiravir and standard care, and 33 events were observed in 27 (11%) of 248 patients receiving standard care alone, with infectious, respiratory, and cardiovascular events being the most numerous. There was no significant between-group difference in serious adverse events per patient (p=0·87). INTERPRETATION Favipiravir does not improve clinical outcomes in all patients admitted to hospital with COVID-19, however, patients younger than 60 years might have a beneficial clinical response. The indiscriminate use of favipiravir globally should be cautioned, and further high-quality studies of antiviral agents, and their potential treatment combinations, are warranted in COVID-19. FUNDING LifeArc and CW+.
-
4.
GRAd-COV2 vaccine provides potent and durable humoral and cellular immunity to SARS-CoV-2 in randomized placebo-controlled phase 2 trial.
Capone, S, Fusco, FM, Milleri, S, Borrè, S, Carbonara, S, Lo Caputo, S, Leone, S, Gori, G, Maggi, P, Cascio, A, et al
Cell reports. Medicine. 2023;(6):101084
Abstract
The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccine portfolios. GRAd-COV2 is a gorilla adenovirus-based COVID-19 vaccine candidate encoding prefusion-stabilized spike. The safety and immunogenicity of GRAd-COV2 is evaluated in a dose- and regimen-finding phase 2 trial (COVITAR study, ClinicalTrials.gov: NCT04791423) whereby 917 eligible participants are randomized to receive a single intramuscular GRAd-COV2 administration followed by placebo, or two vaccine injections, or two doses of placebo, spaced over 3 weeks. Here, we report that GRAd-COV2 is well tolerated and induces robust immune responses after a single immunization; a second administration increases binding and neutralizing antibody titers. Potent, variant of concern (VOC) cross-reactive spike-specific T cell response peaks after the first dose and is characterized by high frequencies of CD8s. T cells maintain immediate effector functions and high proliferative potential over time. Thus, GRAd vector is a valuable platform for genetic vaccine development, especially when robust CD8 response is needed.
-
5.
Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2).
Kwon, O, Senna, MM, Sinclair, R, Ito, T, Dutronc, Y, Lin, CY, Yu, G, Chiasserini, C, McCollam, J, Wu, WS, et al
American journal of clinical dermatology. 2023;(3):443-451
-
-
Free full text
-
Abstract
BACKGROUND The oral Janus kinase (JAK) inhibitor baricitinib has demonstrated efficacy for severe alopecia areata (AA) over 36 weeks. There are limited data on the longer-term treatment of AA. OBJECTIVE The aim of this study was to evaluate the efficacy and safety of baricitinib for AA in adults with ≥50% scalp hair loss through 52 weeks of continuous therapy in two phase III trials (BRAVE-AA1 and BRAVE-AA2). METHODS Patients randomized to baricitinib at baseline in BRAVE-AA1 (N = 465) and BRAVE-AA2 (N = 390) retained their treatment allocation through Week 52. Efficacy outcomes included the proportion of patients achieving a Severity of Alopecia Tool (SALT) score ≤ 20 (≤ 20% scalp hair loss). Data were censored after permanent treatment discontinuation or if collected remotely due to the coronavirus disease 2019 (COVID-19) pandemic. RESULTS Response rates for hair regrowth increased over the 52-week period. Of patients treated with baricitinib 4 mg and 2 mg, respectively, 40.9% and 21.2% in BRAVE-AA1 and 36.8% and 24.4% in BRAVE-AA2 achieved a SALT score ≤ 20 at Week 52. The most frequent treatment-emergent adverse events included upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection, creatine phosphokinase elevation, and COVID-19 infection. LIMITATION There were no comparisons with placebo. CONCLUSION Efficacy of baricitinib for adults with severe AA continuously improved over 52 weeks, indicating that long-term treatment may be necessary to observe maximum clinical benefit. There were no new safety signals. CLINICALTRIALS REGISTRATION ClinicalTrials.gov NCT03570749 and NCT03899259. Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: Week-52 Results from BRAVE-AA1 and BRAVE-AA2.
-
6.
Adjunctive use of oral MAF is associated with no disease progression or mortality in hospitalized patients with COVID-19 pneumonia: The single-arm COral-MAF1 prospective trial.
Spadera, L, Lugarà, M, Spadera, M, Conticelli, M, Oliva, G, Bassi, V, Apuzzi, V, Calderaro, F, Fattoruso, O, Guzzi, P, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2023;:115894
Abstract
Based on a growing body of evidence that a dysregulated innate immune response mediated by monocytes/macrophages plays a key role in the pathogenesis of COVID-19, a clinical trial was conducted to investigate the therapeutic potential and safety of oral macrophage activating factor (MAF) plus standard of care (SoC) in the treatment of hospitalized patients with COVID-19 pneumonia. Ninety-seven hospitalized patients with confirmed COVID-19 pneumonia were treated with oral MAF and a vitamin D3 supplement, in combination with SoC, in a single-arm, open label, multicentre, phase II clinical trial. The primary outcome measure was a reduction in an intensive care unit transfer rate below 13% after MAF administration. At the end of the study, an additional propensity score matching (PSM) analysis was performed to compare the MAF group with a control group treated with SoC alone. Out of 97 patients treated with MAF, none needed care in the ICU and/or intubation with mechanical ventilation or died during hospitalization. Oxygen therapy was discontinued after a median of nine days of MAF treatment. The median length of viral shedding and hospital stay was 14 days and 18 days, respectively. After PSM, statistically significant differences were found in all of the in-hospital outcomes between the two groups. No mild to serious adverse events were recorded during the study. Notwithstanding the limitations of a single-arm study, which prevented definitive conclusions, a 21-day course of MAF treatment plus SoC was found to be safe and promising in the treatment of hospitalized adult patients with COVID-19 pneumonia. Further research will be needed to confirm these preliminary findings.
-
7.
Combination of aspirin and rosuvastatin for reduction of venous thromboembolism in severely injured patients: a double-blind, placebo-controlled, pragmatic randomized phase II clinical trial (The STAT Trial).
Barrett, CD, Moore, HB, Moore, EE, Chandler, J, Sauaia, A
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis. 2023;(8):499-507
Abstract
INTRODUCTION Venous thromboembolism (VTE) remains a significant source of postinjury morbidity and mortality. Beta-hydroxy beta-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (rosuvastatin) significantly reduced pathologic clotting events in healthy populations in a prior trial. Furthermore, acetylsalicylic acid (ASA) has been shown to be noninferior to prophylactic heparinoids for VTE prevention following orthopedic surgery. We hypothesized that a combination of rosuvastatin/ASA, in addition to standard VTE chemoprophylaxis, would reduce VTE in critically ill trauma patients. METHODS This was a double-blind, placebo-controlled, randomized trial, evaluating VTE rates in two groups: ASA + statin (Experimental) and identical placebos (Control). Injured adults, 18-65 years old, admitted to the surgical intensive care unit without contraindications for VTE prophylaxis were eligible. Upon initiation of routine VTE chemoprophylaxis (i.e. heparin/heparin-derivatives), they were randomized to the Experimental or Control group. VTE was the primary outcome. RESULTS Of 112 potentially eligible patients, 33% (n = 37, median new injury severity scale = 27) were successfully randomized, of whom 11% had VTEs. The Experimental group had no VTEs, while the Control group had 6 VTEs (4 PEs and 2 DVTs) in 4 (22%) patients (P = 0.046). The Experimental treatment was not associated with any serious adverse events. Due to the COVID-19 pandemic, the study was interrupted at the second interim analysis at <10% of the planned enrollment, with significance declared at P < 0.012 at that stage. DISCUSSION The combination of ASA and rosuvastatin with standard VTE prophylaxis showed a favorable trend toward reducing VTEs with no serious adverse events. An appropriately powered phase III multicenter trial is needed to further investigate this therapeutic approach. LEVEL OF EVIDENCE Level II, Therapeutic.
-
8.
World's First Experience of the Low-Dose Radionuclide Inhalation Therapy in the Treatment of COVID-19-Associated Viral Pneumonia: Phase 1/2 Clinical Trial.
Shegay, P, Leontyev, A, Baranovskii, D, Davydov, G, Poluektova, M, Grivtsova, L, Petriev, V, Stepanenko, V, Gulidov, I, Krylov, V, et al
Current radiopharmaceuticals. 2023;(3):243-252
Abstract
OBJECTIVE Previously, low-dose radiation therapy was used for pneumonia treatment. We aimed to investigate the safety and effectiveness of carbon nanoparticles labeled with Technetium isotope (99mTc) in a form of ultradispersed aerosol in combination with standard COVID-19 therapy. The study was a randomized phase 1 and phase 2 clinical trial of low-dose radionuclide inhalation therapy for patients with COVID-19 related pneumonia. METHODS We enrolled 47 patients with confirmed COVID-19 infection and early laboratory signs of cytokine storm and randomized them into the Treatment and Control groups. We analyzed blood parameters reflecting the COVID-19 severity and inflammatory response. RESULTS Low-dose 99mTc-labeled inhalation showed a minimal accumulation of radionuclide in lungs in healthy volunteers. We observed no significant differences between the groups before treatment in WBC-count, D-dimer, CRP, Ferritin or LDH levels. We found that Ferritin and LDH levels significantly raised after the 7th day follow-up only in the Control group (p < 0.0001 and p = 0.0005, respectively), while mean values of the same indicators did not change in patients in the Treatment group after the radionuclide treatment. D-dimer values also lowered in the radionuclide treated group, however, this effect was not statistically significant. Furthermore, we observed a significant decrease in CD19+ cell counts in patients of the radionuclide-treated group. CONCLUSION Inhalation low-dose radionuclide therapy of 99mTc aerosol affects the major prognostic indicators of COVID-19- related pneumonia restraining inflammatory response. Overall, we identified no evidence of major adverse events in the group receiving radionuclide.
-
9.
Effects of a Multi-Professional Intervention on Mental Health of Middle-Aged Overweight Survivors of COVID-19: A Clinical Trial.
Ryal, JJ, Perli, VAS, Marques, DCS, Sordi, AF, Marques, MGS, Camilo, ML, Milani, RG, Mota, J, Valdés-Badilla, P, Magnani Branco, BH
International journal of environmental research and public health. 2023;(5)
Abstract
The present study aimed to investigate the effects of a multi-professional intervention model on the mental health of middle-aged, overweight survivors of COVID-19. A clinical trial study with parallel groups and repeated measures was conducted. For eight weeks, multi-professional interventions were conducted (psychoeducation, nutritional intervention, and physical exercises). One hundred and thirty-five overweight or obese patients aged 46.46 ± 12.77 years were distributed into four experimental groups: mild, moderate, severe COVID, and control group. The instruments were used: mental health continuum-MHC, revised impact scale-IES-r, generalized anxiety disorder-GAD-7, and Patient health questionnaire PHQ-9, before and after eight weeks. The main results indicated only a time effect, with a significant increase in global MHC scores, emotional well-being, social well-being, and psychological well-being, as well as detected a significant reduction in global IES-R scores, intrusion, avoidance, and hyperarousal, in addition to a reduction in GAD-7 and PHQ-9 scores (p < 0.05). In conclusion, it was possible to identify those psychoeducational interventions that effectively reduced anxiety, depression, and post-traumatic stress symptoms in post-COVID-19 patients, regardless of symptomatology, in addition to the control group. However, moderate and severe post-COVID-19 patients need to be monitored continuously since the results of these groups did not follow the response pattern of the mild and control groups.
-
10.
Clinical efficacy of Jingyin granules, a Chinese patent medicine, in treating patients infected with coronavirus disease 2019.
Chen, B, Yu, X, Zhang, L, Huang, W, Lyu, H, Xu, Y, Shen, J, Yuan, W, Fang, M, Li, M, et al
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2023;:154496
-
-
Free full text
-
Abstract
BACKGROUND Jingyin granules (JY), one patented Chinese herbal formula, have been advised for treating coronavirus disease 2019 (COVID-19) in China. As of now, the safety and effectiveness of JY in treating COVID-19 patients were still to be evaluated. PURPOSE To investigate the safety and clinical effectiveness of JY in treating mild COVID-19 patients. STUDY DESIGN We carried out a prospective cohort study, as the highly infectious COVID-19 omicron variant ranged in Shanghai (ClinicalTrial.gov registration number: ChiCTR2200058692). METHODS Participants infected with COVID-19, who were diagnosed as mild cases, were assigned to receive either JY (JY group) or traditional Chinese medicine placebo (placebo group) orally for 7 days. The primary clinical indicators were the RNA negative conversion rate (NCR) and the incidence of severe cases. The secondary clinical indicators were the negative conversion time (NCT), inpatient length of stay (ILOS), and the disappearance rates of clinical symptoms. RESULTS Nine hundred participants were recruited in this clinical trial study, and 830 patients met the eligibility criteria. Seven hundred and ninety-one patients, accomplished the following-up assessment, including 423 cases of JY group and 368 cases of placebo group. NCR in JY group at 7-day posttreatment was considerably greater compared with placebo group (89.8% [380/423] vs 82.6% [304/368], P = 0.003). None of the patients with mild COVID-19 developed into severe cases. The median NCT of SARS-CoV-2 and ILOS in JY group were lesser than that in placebo group (4.0 [3.0,6.0]vs 5.0 [4.0,7.0] days, P < 0.001; 6.0 [4.0, 8.0] vs 7.0 [5.0, 9.0] days, P < 0.001). In both groups, the obvious improvement in clinical symptoms was observed, but the difference was not significant. In the subgroup of age ≤ 60 years, JY promoted SARS-CoV-2 RNA negative conversion (HR=1.242; 95% CI: 1.069-1.444, P < 0.001). No patients in both groups were reported as the case of serious adverse event. CONCLUSION JY maybe the potential medicine for treating mild COVID-19 patients, which had beneficial effects on increasing NCR, and shortening NCT and ILOS.