ABSTRACT
Rationale There are few treatment options for severe COVID-19 pneumonia. Opaganib is an oral treatment under investigation. Objective Evaluate opaganib treatment in hospitalized patients with severe COVID-19 pneumonia. Methods A randomized, placebo-controlled, double-blind phase 2/3 trial was conducted in 60 sites worldwide from August 2020 to July 2021. Patients received either opaganib (n=230; 500mg twice daily) or matching placebo (n=233) for 14 days. Main Outcome Measurements Primary outcome was the proportion of patients no longer requiring supplemental oxygen by day 14. Secondary outcomes included changes in the World Health Organization Ordinal Scale for Clinical Improvement, viral clearance, intubation, and mortality at 28- and 42-days. Main Results Pre-specified primary and secondary outcome analyses did not demonstrate statistically significant benefit (except for time to viral clearance). Post-hoc analysis revealed the fraction of inspired oxygen (FiO2) at baseline was prognostic for opaganib treatment responsiveness and corresponded to disease severity markers. Patients with FiO2 levels at or below the median value ([≤]60%) had better outcomes after opaganib treatment (n=117) compared to placebo (n=134). The proportion of patients with [≤]60% FIO2 at baseline that no longer required supplemental oxygen (at least 24 hours) by day 14 of opaganib treatment increased (76.9% vs 63.4%: p-value =0.033). There was a 62.6% reduction in intubation/mechanical ventilation (6.84% vs 17.91%; p-value=0.012) and a clinically meaningful 62% reduction in mortality (5.98% vs 16.7%; p-value=0.019) by day 42. No new safety concerns observed. Conclusions Post-hoc analysis supports opaganib benefit in COVID-19 severe pneumonia patients that require lower supplemental oxygen ([≤]60% FiO2). Further studies are warranted.
Subject(s)
COVID-19 , Pneumonia , Severe Acute Respiratory SyndromeABSTRACT
Background: To assess differences in the probability of COVID-19-related death between native Italians and immigrants hospitalised with COVID-19. Methods This was a retrospective study of prospectively collected data conducted at the ASST Fatebenefratelli-Sacco Hospital in Milan, Italy, between 21 February and 31 November 2020. Uni- and multivariable Cox proportional hazard models were used to assess the impact of the patients' origin on the probability of COVID-19-related death. Results The study population consisted of 1,179 COVID-19 patients: 921 Italians (78.1%) and 258 immigrants (21.9%) from Latin America (99, 38.4%), Asia (72, 27.9%), Africa (50, 19.4%) and central/eastern Europe (37, 14.3%). The Italians were older (p
Subject(s)
COVID-19ABSTRACT
Background The potential benefit of a combination therapy with lopinavir/ritonavir (LPV/r) and hydroxychloroquine (HCQ) on COVID-19 has been speculated. We explored the effect of the timing of LPV/r + HCQ initiation on the outcome of patients with COVID-19. Methods A retrospective cohort study was conducted on patients with COVID-19 who started treatment with LPV/r plus HCQ between February 21 and March 20, 2020, at Luigi Sacco Hospital in Milan, Italy. Over time cumulative incidence of clinical improvement was compared between patients who started treatment less than 5 days from the onset of symptoms [early treatment group (ET)] and those who initiated it later [delayed treatment group (DT)]. The association of LPV/r plus HCQ initiation timing on 30-day mortality was also assessed by univariate and multivariate logistic models. Results The study included 172 patients, prevalently males (72%) in their sixties, with a moderate (53.4%) or severe (34.9%) disease. Fourty-three (25%) patients were included in the ET group and and 129 (75%) in the DT group. Severity of disease did not significantly differ between the two groups. Conclusion Timing of LPV/r + HCQ initiation seems to have no impact on COVID-19 clinical course in terms of improvement and 30-day mortality. These findings rise doubts on the clincial efficacy of this regimen.
Subject(s)
COVID-19ABSTRACT
Objective. To describe the radiographic key patterns on CXR in patients with SARS-CoV-2 infection, assessing the prevalence of radiographic signs of interstitial pneumonia. To evaluate pattern variation between a baseline and a follow-up CXR.Materials and methods. 1117 patients tested positive for SARS-CoV-2 infection were retrospectively enrolled from four centers in Lombardy region. All patients underwent a CXR at presentation. Follow-up CXR was performed when clinically indicated.Two radiologists in each center reviewed CXR images and classified them as suggestive or not for interstitial pneumonia, recording the presence of ground-glass opacity (GGO), reticular pattern or consolidation and their distribution.Pearson’s chi-square test for categorical variables and McNemar test (chi-square for paired data) were performed.Results. Patients mean age 63.3 years, 767 were males (65.5%). The main result is the large proportion of positive CXR in COVID-19 patients.Baseline CXR was positive in 940 patients (80.3%), with significant differences in age and sex distribution between patients with positive and negative CXR. 382 patients underwent a follow-up CXR. The most frequent pattern on baseline CXR was the GGO (66.1%), on follow-up was consolidation (53.4%). The most common distributions were peripheral and middle-lower lung zone.Conclusions. We described key-patterns and their distribution on CXR in a large cohort of COVID-19 patients: GGO was the most frequent finding on baseline CXR, while we found an increase in the proportion of lung consolidation on follow-up CXR. CXR proved to be a reliable tool in our cohort obtaining positive results in 80.3% of the baseline cases.
Subject(s)
COVID-19 , Lung Diseases, InterstitialABSTRACT
Background: Italy was the first European country hit by the COVID-19 pandemic and has the highest number of recorded COVID-19 deaths in Europe. Methods: This prospective cohort study of the correlates of the risk of death in COVID-19 patients was conducted at the Infectious Diseases and Intensive Care units of Luigi Sacco Hospital, Milan, Italy. The clinical characteristics of all the COVID-19 patients hospitalised in the early days of the epidemic (21 February -19 March 2020) were recorded upon admission, and the time-dependent probability of death was evaluated using the Kaplan-Meier method (censored as of 20 April 2020). Cox proportional hazard models were used to assess the factors independently associated with the risk of death. Results: Forty-eight (20.6%) of the 233 patients followed up for a median of 40 days (interquartile range 33-47) died during the follow-up. Most were males (69.1%) and their median age was 61 years (IQR 50-72). The time-dependent probability of death was 19.7% (95% CI 14.6-24.9%) 30 days after hospital admission. Age (adjusted hazard ratio [aHR] 2.08, 95% CI 1.48-2.92 per ten years more) and obesity (aHR 3.04, 95% CI 1.42-6.49) were independently associated with an increased risk of death, which was also associated with critical disease (aHR 8.26, 95% CI 1.41-48.29), C-reactive protein levels (aHR 1.17, 95% CI 1.02-1.35 per 50 mg/L more) and creatinine kinase levels above 185 U/L (aHR 2.58, 95% CI 1.37-4.87) upon admission. Conclusions: Case-fatality rate of patients hospitalized with COVID-19 in the early days of the Italian epidemic was about 20%. Our study adds evidence to the notion that older age, obesity and more advanced illness are factors associated to an increased risk of death among patients hospitalized with COVID-19.
Subject(s)
Critical Illness , Obesity , Death , COVID-19ABSTRACT
Condition:
COVID-19Intervention:
Drug: Favipiravir;Other: PlaceboPrimary outcome:
Time from randomization to clinical recoveryCriteria:
Inclusion Criteria:
1. Voluntarily participating in the clinical study; fully understanding and being fully
informed of the study and having signed the Informed Consent Form (ICF); willingness
and capability to complete all the study procedures;
2. Age 18-75 years (inclusive) at the time of signing ICF;
3. Being confirmed with COVID-19-Moderate type according to Competent Authority and
Italian Ministry of Health guidelines and to the recommendations reported in Appendix
1 to the present protocol. Based on comprehensive analysis and judgement taking into
account both the epidemiological history and clinical manifestations, the diagnosis is
to be confirmed for suspected cases/clinically diagnosed cases with all of the
following etiological evidences:
- Positivity in RT-PCR 2019-nCov test on respiratory tract specimens;
- High homology with known gene sequence of 2019-nCov in viral gene sequencing on
respiratory tract specimens; Note: The above criterion would be subject to any
update of the Competent Authority and Italian Ministry of Health guidelines and
to the recommendations reported in Appendix 1 to the present protocol. In case
any new etiologically detection methods/criteria or any new detectable specimens
become available after confirmed diagnosis, the new methods or new specimens may
or may not be used at the discretion of the investigator.
Note: Sputum specimen is preferred for RT-PCR test of 2019-nCov nucleic acid; the
specific type of respiratory tract specimen (e.g., nasopharyngeal swabs, sputum, lower
respiratory tract secretions) is to be selected based on the conditions of the local
laboratory.
The type of specimen and detection method for 2019-nCov should remain consistent for
the same subject receiving study treatment.
4. Chest imaging (CT as first option or X-ray if CT not possible)-documented pneumonia;
if CT cannot be performed, Pneumonia confirmed by X-ray may be used. The method of
chest imaging pneumonia diagnosis must be consistent all through the study period.
5. Patients with pyrexia (axillary =37? or oral =37.5?, or axillary or rectal=38?) or
either respiratory rate >24/min and <30/min or cough; For not hospitalized patients,
the Investigator should maintain the detection method consistent all through the study
period. In addition, the Investigator should maintain the data collection and quality
compliant with GCP requirements.
6. The interval between symptoms onset and randomization is no more than 10 days;
symptoms onset is primarily based on pyrexia, and can be based on cough or other
related symptoms for patients without experiencing pyrexia following onset;
7. For female subjects: evidence of post-menopause, or, for pre-menopause subjects,
negative pre-treatment serum or urine pregnancy test. Menopause is defined as
amenorrhea for at least 12 months without other medical cause, with the following
age-specific requirements:
- For female subjects aged <50 years: menopause for at least 12 months following
withdrawal of exogenous hormonal therapy, with LH or FSH within the
post-menopausal ranges, or having undergone any contraceptive surgery (bilateral
oophorectomy or hysterectomy);
- For female subjects aged =50 years: menopause for at least 12 months following
withdrawal of exogenous hormonal therapy, or having undergone
radiotherapy-induced oophorectomy with amenorrhea>1 year, or having undergone
chemotherapy-induced menopause with amenorrhea>1 year, or having undergone any
contraceptive surgery (bilateral oophorectomy or hysterectomy).
8. Eligible subjects of child-bearing age (male or female) must agree to take effective
contraceptive measures (including hormonal contraception, barrier methods or
abstinence) with his/her partner during the study period and for at least 7 days
following the last study treatment;
9. Not participating in any other interventional drug clinical studies before completion
of the present study.
Exclusion Criteria:
1. Where, in the opinion of the investigator, participation in this study will not be in
the best interest of the subject, or any other circumstances that prevent the subject
from participating in the study safely;
2. Refractory nausea, vomiting, or chronic gastrointestinal disorders, inability to
swallow the study drug or having undergone extensive bowel resection which may affect
adequate absorption of Favipiravir;
3. Severe liver disease: underlying liver cirrhosis or alanine aminotransferase
(ALT)/aspartate aminotransferase (AST) elevated over 5 times the ULN;
4. Gout/history of gout or hyperuricemia (above the ULN);
5. Oxygen saturation (SPO2)=93% or arterial oxygen partial pressure (PaO2)/ fraction of
inspired O2 (FiO2)=300 mmHg;
6. Known allergy or hypersensitivity to Favipiravir;
7. Known severe renal impairment [creatinine clearance (CcCl) <30 mL/min] or having
received continuous renal replacement therapy, hemodialysis or peritoneal dialysis;
CcCl is to be calculated by the following Cockcroft-Gault formula only when the serum
creatinine is>1.5×ULN
8. Possibility of the subject being transferred to a non-study hospital within 72h;
9. Pregnant or lactating women;
10. Having used Favipiravir or participated in any other interventional drug clinical
study within 30 days prior to first dose of study drug.
Note: Considering that COVID-19 requires immediate treatment, absence of severe
hepatic/renal disorders (e.g., cirrhosis, long-term dialysis) in the medical record can be
used as an evidence for eligibility determination. It is recommended that hepatic function
and creatinine be examined whenever possible.
ABSTRACT
This report describes the isolation, the molecular characterization and the phylogenetic analysis of the first three complete genomes of SARS-CoV-2 isolated from three patients involved in the first outbreak of COVID-19 in Lombardy, Italy. Early molecular epidemiological tracing suggests that SARS-CoV-2 was present in Italy weeks before the first reported cases of infection.