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1.
Influenza Other Respir Viruses ; 16(3): 542-551, 2022 May.
Article in English | MEDLINE | ID: covidwho-1784668

ABSTRACT

BACKGROUND: Zanamivir is a neuraminidase inhibitor effective against influenza A and B viruses. In 2009, GlaxoSmithKline (GSK) began clinical development of intravenous (IV) zanamivir and initiated a global Compassionate Use Program (CUP) in response to the evolving H1N1 global pandemic. The goal of the CUP was to provide zanamivir to critically ill patients with limited treatment options. METHODS: Zanamivir was administered to patients with suspected or confirmed influenza infection who were not suitable for other approved antiviral treatments. Reporting of serious adverse events (SAEs) was mandatory and recorded in the GSK safety database. A master summary tracking sheet captured requests and patient characteristics. A case report form was available for detailing medical conditions, dosing, treatment duration, and clinical outcomes. RESULTS: In total, 4,033 requests were made for zanamivir treatment of hospitalized patients from 38 countries between 2009 and 2019; ≥95% patients received zanamivir via the IV route. Europe had the highest number of requests (n = 3,051) followed by North America (n = 713). At least 20 patients were aged ≤6 months, of whom 12 were born prematurely. The GSK safety database included 466 patients with ≥1 SAE, of whom 374 (80%) had a fatal outcome. Drug-related SAEs were reported in 41 (11%) patients, including hepatic failure (n = 6 [2%]) and acute kidney injury (n = 5 [1%)]. CONCLUSIONS: The CUP facilitated global access to zanamivir prior to product approval. No new safety concerns were identified in the CUP compared with IV zanamivir clinical studies.


Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza, Human , Antiviral Agents/adverse effects , Compassionate Use Trials , Enzyme Inhibitors/adverse effects , Humans , Infant , Influenza, Human/drug therapy , Neuraminidase , Oseltamivir/therapeutic use , Zanamivir/adverse effects
2.
MAbs ; 14(1): 2014296, 2022.
Article in English | MEDLINE | ID: covidwho-1624515

ABSTRACT

In this 13th annual installment of the annual 'Antibodies to Watch' article series, we discuss key events in commercial antibody therapeutics development that occurred in 2021 and forecast events that might occur in 2022. Regulatory review of antibody therapeutics that target the SARS-CoV-2 coronavirus proceeded at an unprecedented pace in 2021, resulting in both emergency use authorizations and full approvals for sotrovimab, regdanvimab, REGEN-COV2, as well as others, in numerous countries. As of November 1, a total of 11 antibody therapeutics had been granted first approvals in either the United States or European Union in 2021 (evinacumab, dostarlimab loncastuximab tesirine, amivantamab, aducanumab, tralokinumab, anifrolumab, bimekizumab, tisotumab vedotin, regdanvimab, REGEN-COV2). The first global approvals of seven products, however, were granted elsewhere, including Japan (pabinafusp alfa), China (disitamab vedotin, penpulimab, zimberelimab), Australia (sotrovimab, REGEN-COV2), or the Republic of Korea (regdanvimab). Globally, at least 27 novel antibody therapeutics are undergoing review by regulatory agencies. First actions by the Food and Drug Administration on the biologics license applications for faricimab, sutimlimab, tebentafusp, relatlimab, sintilimab, ublituximab and tezepelumab are expected in the first quarter of 2022. Finally, our data show that, with antibodies for COVID-19 excluded, the late-stage commercial clinical pipeline of antibody therapeutics grew by over 30% in the past year. Of those in late-stage development, marketing applications for at least 22 may occur by the end of 2022.


Subject(s)
Antibodies, Monoclonal , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/immunology , Antibodies, Viral/therapeutic use , Antibody Specificity , Antigens, Viral/immunology , Asia , Australia , COVID-19/immunology , COVID-19/prevention & control , COVID-19/therapy , Clinical Trials as Topic , Compassionate Use Trials , Drug Approval , European Union , Forecasting , Humans , SARS-CoV-2/immunology , United States , United States Food and Drug Administration
3.
PLoS One ; 16(12): e0261478, 2021.
Article in English | MEDLINE | ID: covidwho-1598396

ABSTRACT

The U.S. Food and Drug Administration (FDA) allows patients with serious illnesses to access investigational drugs for "compassionate use" outside of clinical trials through expanded access (EA) Programs. The federal Right-to-Try Act created an additional pathway for non-trial access to experimental drugs without institutional review board or FDA approval. This removal of oversight amplifies the responsibility of physicians, but little is known about the role of practicing physicians in non-trial access to investigational drugs. We undertook semi-structured interviews to capture the experiences and opinions of 21 oncologists all with previous EA experience at a major cancer center. We found five main themes. Participants with greater EA experience reported less difficulty accessing drugs through the myriad of administrative processes and drug company reluctance to provide investigational products while newcomers reported administrative hurdles. Oncologists outlined several rationales patients offered when seeking investigational drugs, including those with stronger health literacy and a good scientific rationale versus others who remained skeptical of conventional medicine. Participants reported that most patients had realistic expectations while some had unrealistic optimism. Given the diverse reasons patients sought investigational drugs, four factors-scientific rationale, risk-benefit ratio, functional status of the patient, and patient motivation-influenced oncologists' decisions to request compassionate use drugs. Physicians struggled with a "right-to-try" framing of patient access to experimental drugs, noting instead their own responsibility to protect patients' best interest in the uncertain and risky process of off-protocol access. This study highlights the willingness of oncologists at a major cancer center to pursue non-trial access to experimental treatments for patients while also shedding light on the factors they use when considering such treatment. Our data reveal discrepancies between physicians' sense of patients' expectations and their own internal sense of professional obligation to shepherd a safe process for patients at a vulnerable point in their care.


Subject(s)
COVID-19/drug therapy , Compassionate Use Trials , Drugs, Investigational/therapeutic use , Neoplasms/drug therapy , Oncologists/psychology , Therapies, Investigational , Drug Approval , Humans , Interviews as Topic , Motivation , Patient Rights , Physician-Patient Relations , United States
4.
Acta Paediatr ; 111(4): 834-841, 2022 04.
Article in English | MEDLINE | ID: covidwho-1583685

ABSTRACT

AIM: This paper describes the emergency, compassionate use of the COVID-19 vaccination for high-risk adolescents aged 12-15 years prior to approval by the American Food and Drugs Administration in May 2021. The target audience had underlying health conditions associated with severe disease and multisystem inflammatory syndrome in children (MIS-C) or severely immunosuppressed household members. METHODS: An orderly approval system was established in Israel for adolescents aged 12-15 years, based on a professional position paper and compassionate treatment regulations. From 12 February 2021, eligible adolescents were referred to the Israeli Ministry of Health for permission to vaccinate, via four health maintenance organisations. Data were collected about adverse events after vaccinations and the incidence of any cases of COVID-19. RESULTS: By 15 March 2021, the vaccine had been approved for 607 adolescents: 333 had received one dose, and 92 had received two doses. The median age was 14.6 years, and the major indication was obesity. Only one child tested positive for the virus, 4 days after vaccination, and no adverse effects were recorded. CONCLUSION: The emergency use of COVID-19 vaccination for 333 adolescents aged 12-15, 92 of them with 2 doses, based on a position paper and compassionate treatment regulations, did not result in any adverse effects. Since 27 July 2021, the same process was further applied in Israel among younger children, aged 5-11, preceding formal release of the clinical trial.


Subject(s)
COVID-19 Vaccines , COVID-19 , Adolescent , COVID-19/complications , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Child , Child, Preschool , Compassionate Use Trials , Humans , Israel , SARS-CoV-2 , Systemic Inflammatory Response Syndrome , United States , Vaccination
5.
PLoS Med ; 18(12): e1003872, 2021 12.
Article in English | MEDLINE | ID: covidwho-1581903

ABSTRACT

BACKGROUND: The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. METHODS AND FINDINGS: Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician-principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had-or were at risk of progression to-severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects. CONCLUSIONS: These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT#: NCT04338360.


Subject(s)
COVID-19/therapy , Compassionate Use Trials/methods , Health Services Needs and Demand/statistics & numerical data , Hospital Distribution Systems/organization & administration , Registries , Transfusion Reaction/complications , Transfusion Reaction/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/epidemiology , Female , Humans , Immunization, Passive/adverse effects , Immunization, Passive/methods , Inpatients , Male , Medically Underserved Area , Middle Aged , Pandemics , Patient Safety , SARS-CoV-2 , Treatment Outcome , United States
6.
Clin Infect Dis ; 73(11): e3996-e4004, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1562033

ABSTRACT

BACKGROUND: Remdesivir is efficacious for severe coronavirus disease 2019 (COVID-19) in adults, but data in pregnant women are limited. We describe outcomes in the first 86 pregnant women with severe COVID-19 who were treated with remdesivir. METHODS: The reported data span 21 March to 16 June 2020 for hospitalized pregnant women with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 infection and room air oxygen saturation ≤94% whose clinicians requested remdesivir through the compassionate use program. The intended remdesivir treatment course was 10 days (200 mg on day 1, followed by 100 mg for days 2-10, given intravenously). RESULTS: Nineteen of 86 women delivered before their first dose and were reclassified as immediate "postpartum" (median postpartum day 1 [range, 0-3]). At baseline, 40% of pregnant women (median gestational age, 28 weeks) required invasive ventilation, in contrast to 95% of postpartum women (median gestational age at delivery 30 weeks). By day 28 of follow-up, the level of oxygen requirement decreased in 96% and 89% of pregnant and postpartum women, respectively. Among pregnant women, 93% of those on mechanical ventilation were extubated, 93% recovered, and 90% were discharged. Among postpartum women, 89% were extubated, 89% recovered, and 84% were discharged. Remdesivir was well tolerated, with a low incidence of serious adverse events (AEs) (16%). Most AEs were related to pregnancy and underlying disease; most laboratory abnormalities were grade 1 or 2. There was 1 maternal death attributed to underlying disease and no neonatal deaths. CONCLUSIONS: Among 86 pregnant and postpartum women with severe COVID-19 who received compassionate-use remdesivir, recovery rates were high, with a low rate of serious AEs.


Subject(s)
COVID-19 , Pregnancy Complications, Infectious , Adenosine Monophosphate/analogs & derivatives , Adult , Alanine/analogs & derivatives , COVID-19/drug therapy , Compassionate Use Trials , Female , Humans , Infant , Pregnancy , Pregnancy Complications, Infectious/drug therapy , Pregnant Women , SARS-CoV-2
7.
Viruses ; 13(12)2021 12 03.
Article in English | MEDLINE | ID: covidwho-1554959

ABSTRACT

Eculizumab, a terminal complement (C5)-inhibiting monoclonal antibody, was administered in five mechanically ventilated patients in life-threatening condition due to COVID-19-related acute respiratory distress syndrome (ARDS) between 23 March 2020 and 3 April 2020. Their clinical progress was monitored. The primary endpoint was mortality. One patient was excluded while two passed away. The remaining two patients survived. At the time of this study, the mortality rate in mechanically ventilated COVID-19 patients suffering from ARDS receiving the standard of care as their therapeutic regimen was reportedly as high as 97%. This pilot study demonstrates a 50% mortality rate in patients receiving eculizumab therapy.


Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19/immunology , COVID-19/mortality , Compassionate Use Trials , Complement System Proteins , Adolescent , Adult , Aged , Aged, 80 and over , Critical Illness , Female , Humans , Male , Middle Aged , Pilot Projects , Respiratory Distress Syndrome , SARS-CoV-2 , Young Adult
9.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(8): 909-914, 2021 Aug 28.
Article in English, Chinese | MEDLINE | ID: covidwho-1439638

ABSTRACT

Compassionate use may play an important role in responding to major public health emergencies. The Jinyintan Hospital in Wuhan launched the III phase of clinical trials of antiviral drug-remdesivir on February 6, 2020. As an unapproved drug, remdesivir raised great concerns about compassionate use in China. Compassionate use is therapeutic use of unauthorized drugs outside of clinical trials. It is used for critically ill patients with life-threatening diseases and no effective treatment means in China. Patients voluntarily apply to their medical institutions. The Center for Drug Evaluation, National Medical Products Administration shall conduct scientific and reasonable review, approval, and supervision on patients' application for compassionate medication. By analyzing and comparing the current situation of compassionate use at home and abroad, it is expected to provide thinking for the development of compassionate use system in China.


Subject(s)
Compassionate Use Trials , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Clinical Trials, Phase III as Topic , Humans
10.
Viruses ; 13(9)2021 09 14.
Article in English | MEDLINE | ID: covidwho-1411074

ABSTRACT

Presently, the use of convalescent plasma and hyperimmunoglobulin obtained from individuals who have recovered from coronavirus disease 2019 (COVID-19) has proved to potentially provide passive antibody-based immunity, thereby leading to several clinical trials to develop an immune-based COVID-19 treatment. However, the therapeutic efficacy of hyperimmunoglobulin in critically ill patients with COVID-19 remains unknown. On 23 October 2020, we first administered GC5131 in a compassionate-use program to critically ill patients at the Kyungpook National University, Chilgok Hospital, Korea. Since then, five more critically ill patients were treated with GC5131 in this compassionate-use program in our hospital up until 17 December 2020. We retrospectively reviewed the clinical responses of six critically ill patients diagnosed with COVID-19 who received the hyperimmunoglobulin concentrate, GC5131, which was produced by the Green Cross Corporation. After the administration of GC5131, five patients died due to an exacerbation of COVID-19 pneumonia. GC5131 was ineffective when administered to critically ill patients with COVID-19. Nevertheless, we propose that to expect a therapeutic effect from GC5131, it should be administered as early as possible to avoid the excessive inflammatory response phase in patients with severe and advanced COVID-19 infection. This step was difficult to achieve in the real world due to the time required for decision making and the process of the compassionate-use program.


Subject(s)
COVID-19/drug therapy , COVID-19/therapy , COVID-19/virology , Critical Illness , Immunoglobulins/therapeutic use , SARS-CoV-2/drug effects , Aged , COVID-19/diagnosis , Compassionate Use Trials , Female , Humans , Immunization, Passive , Male , Republic of Korea , Treatment Outcome
12.
J Clin Invest ; 130(9): 4791-4797, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-1365265

ABSTRACT

BACKGROUNDConvalescent plasma is the only antibody-based therapy currently available for patients with coronavirus disease 2019 (COVID-19). It has robust historical precedence and sound biological plausibility. Although promising, convalescent plasma has not yet been shown to be safe as a treatment for COVID-19.METHODSThus, we analyzed key safety metrics after transfusion of ABO-compatible human COVID-19 convalescent plasma in 5000 hospitalized adults with severe or life-threatening COVID-19, with 66% in the intensive care unit, as part of the US FDA expanded access program for COVID-19 convalescent plasma.RESULTSThe incidence of all serious adverse events (SAEs), including mortality rate (0.3%), in the first 4 hours after transfusion was <1%. Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n = 4), transfusion-associated circulatory overload (n = 7), transfusion-related acute lung injury (n = 11), and severe allergic transfusion reactions (n = 3). However, only 2 of 36 SAEs were judged as definitely related to the convalescent plasma transfusion by the treating physician. The 7-day mortality rate was 14.9%.CONCLUSIONGiven the deadly nature of COVID-19 and the large population of critically ill patients included in these analyses, the mortality rate does not appear excessive. These early indicators suggest that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19.TRIAL REGISTRATIONClinicalTrials.gov NCT04338360.FUNDINGMayo Clinic, Biomedical Advanced Research and Development Authority (75A50120C00096), National Center for Advancing Translational Sciences (UL1TR002377), National Heart, Lung, and Blood Institute (5R35HL139854 and R01 HL059842), National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK07352), Natural Sciences and Engineering Research Council of Canada (PDF-532926-2019), National Institute of Allergy and Infectious Disease (R21 AI145356, R21 AI152318, and AI152078), Schwab Charitable Fund, United Health Group, National Basketball Association, Millennium Pharmaceuticals, and Octapharma USA Inc.


Subject(s)
Betacoronavirus , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19 , Compassionate Use Trials , Coronavirus Infections/epidemiology , Coronavirus Infections/mortality , Female , Humans , Immunization, Passive/adverse effects , Immunization, Passive/mortality , Male , Middle Aged , Pandemics , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Safety , Transfusion Reaction/epidemiology , Transfusion Reaction/etiology , Transfusion-Related Acute Lung Injury/epidemiology , Transfusion-Related Acute Lung Injury/etiology , United States/epidemiology , United States Food and Drug Administration , Young Adult
13.
Minerva Anestesiol ; 87(10): 1080-1090, 2021 10.
Article in English | MEDLINE | ID: covidwho-1337893

ABSTRACT

BACKGROUND: COVID-19 patients developing the acute respiratory distress syndrome (ARDS) show increased production of pro-inflammatory cytokines, including interleukin-6 (IL-6). The use of humanized monoclonal antibody against interleukin-6 receptor (IL-6R) may represent a potential treatment strategy. We analyzed the effects of compassionate use of tocilizumab and sarilumab on clinical outcome of patients affected by ARDS due COVID-19. METHODS: This single-center, observational, exploratory study was performed during the acute phase of COVID-19 outbreak, between March 7th and April 21st, 2020 in a University Hospital in Rome, Italy. All consecutive adult patients admitted to the intensive care unit with laboratory-confirmed COVID-19 and fulfilling ARDS criteria were enrolled. Patients who were treated with anti-IL-6R therapy were compared to those who were not, as per clinical decision. Inverse probability weights were applied to weight individual's contribution to survival curves and in the multivariate regression model. RESULTS: Among 105 ARDS patients, 65 received compassionate treatment with anti-IL-6R therapy (43 [66%] Tocilizumab [Hoffmann-La Roche, Basel, Switzerland] and 22 [34%] Sarilumab, respectively], with oxygenation improvement. In the multivariable Cox proportional regression hazards model with propensity score inverse probability weighting, patients who received anti-IL-6R treatment had lower risk of death compared to those who did not, with a hazard ration of 0.34 [95% confidence interval 0.17-0.74], P=0.001. CONCLUSIONS: Our data suggested that immune modulator therapy based on anti-human IL-6 receptor monoclonal antibodies might lead to improved outcome in patients with ARDS due to COVID-19. These data support the need for confirmatory randomized trials to assess the effect of immune modulator therapies on mortality.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Adult , Compassionate Use Trials , Critical Illness , Humans , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2
14.
Pharmacol Res ; 158: 104950, 2020 08.
Article in English | MEDLINE | ID: covidwho-1318942

ABSTRACT

Patients affected by severe coronavirus induced disease-2019 (Covid-19) often experience hypoxemia due to alveolar involvement and endothelial dysfunction, which leads to the formation of micro thrombi in the pulmonary capillary vessels. Both hypoxemia and a prothrombotic diathesis have been associated with more severe disease and increased risk of death. To date, specific indications to treat this condition are lacking. This was a single center, investigator initiated, compassionate use, proof of concept, case control, phase IIb study (NCT04368377) conducted in the Intermediate Respiratory Care Unit of L. Sacco University Hospital in Milano, Italy. Our objective was to explore the effects of the administration of anti-platelet therapy on arterial oxygenation and clinical outcomes in patients with severe Covid-19 with hypercoagulability. We enrolled five consecutive patients with laboratory confirmed SARS-CoV-2 infection, severe respiratory failure requiring helmet continuous positive airway pressure (CPAP), bilateral pulmonary infiltrates and a pro-thrombotic state identified as a D-dimer > 3 times the upper limit of normal. Five patients matched for age, D-dimer value and SOFA score formed the control group. Beyond standard of care, treated patients received 25 µg/Kg/body weight tirofiban as bolus infusion, followed by a continuous infusion of 0.15 µg/Kg/body weight per minute for 48 hours. Before tirofiban, patients received acetylsalicylic acid 250 mg infusion and oral clopidogrel 300 mg; both were continued at a dose of 75 mg daily for 30 days. Fondaparinux2.5 mg/day sub-cutaneous was given for the duration of the hospital stay. All controls were receiving prophylactic or therapeutic dose heparin, according to local standard operating procedures. Treated patients consistently experienced a mean (SD) reduction in A-a O2 gradient of -32.6 mmHg (61.9, P = 0.154), -52.4 mmHg (59.4, P = 0.016) and -151.1 mmHg (56.6, P = 0.011; P = 0.047 vs. controls) at 24, 48 hours and 7 days after treatment. PaO2/FiO2 ratio increased by 52 mmHg (50, P = 0.172), 64 mmHg (47, P = 0.040) and 112 mmHg (51, P = 0.036) after 24, 48 hours and 7 days, respectively. All patients but one were successfully weaned from CPAP after 3 days. This was not true for the control group. No major adverse events were observed. Antiplatelet therapy might be effective in improving the ventilation/perfusion ratio in Covid-19 patients with severe respiratory failure. The effects might be sustained by the prevention and interference on forming clots in lung capillary vessels and by modulating megakaryocytes' function and platelet adhesion. Randomized clinical trials are urgently needed to confirm these results.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Hypoxia/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Pneumonia, Viral/drug therapy , Thrombophilia/drug therapy , Aged , Aspirin/therapeutic use , COVID-19 , Clopidogrel/therapeutic use , Compassionate Use Trials , Coronavirus Infections/complications , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Hypoxia/complications , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Proof of Concept Study , SARS-CoV-2 , Thrombophilia/blood , Thrombophilia/complications , Tirofiban/therapeutic use
15.
Pharmacol Res ; 158: 104899, 2020 08.
Article in English | MEDLINE | ID: covidwho-1318934

ABSTRACT

SARS-CoV-2 is causing an increasing number of deaths worldwide because no effective treatment is currently available. Remdesivir has shown in vitro activity against coronaviruses and is a possible antiviral treatment for SARS-CoV-2 infection. This prospective (compassionate), open-label study of remdesivir, which was conducted at Luigi Sacco Hospital, Milan, Italy, between February 23 and March 20, 2020, involved patients with SARS-CoV-2 pneumonia aged ≥18 years undergoing mechanical ventilation or with an oxygen saturation level of ≤94 % in air or a National Early Warning Score 2 of ≥4. The primary outcome was the change in clinical status based on a 7-category ordinal scale (1 = not hospitalised, resuming normal daily activities; 7 = deceased). The 35 patients enrolled from February 23 to March 20, 2020, included 18 in intensive care unit (ICU), and 17 in our infectious diseases ward (IDW). The 10-day course of remdesivir was completed by 22 patients (63 %) and discontinued by 13, of whom eight (22.8 %) discontinued because of adverse events. The median follow-up was 39 days (IQR 25-44). At day 28, 14 (82.3 %) patients from IDW were discharged, two were still hospitalized and one died (5.9 %), whereas in ICU 6 (33.3 %) were discharged, 8 (44.4 %) patients died, three (16.7 %) were still mechanically ventilated and one (5.6 %) was improved but still hospitalized. Hypertransaminasemia and acute kidney injury were the most frequent severe adverse events observed (42.8 % and 22.8 % of the cases, respectively). Our data suggest that remdesivir can benefit patients with SARS-CoV-2 pneumonia hospitalised outside ICU where clinical outcome was better and adverse events are less frequently observed. Ongoing randomised controlled trials will clarify its real efficacy and safety, who to treat, and when.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Betacoronavirus , Compassionate Use Trials/statistics & numerical data , Coronavirus Infections/drug therapy , Hospitalization/statistics & numerical data , Intensive Care Units/statistics & numerical data , Pneumonia, Viral/drug therapy , Acute Kidney Injury/chemically induced , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/therapeutic use , Aged , Alanine/adverse effects , Alanine/therapeutic use , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , COVID-19 , Coronavirus Infections/blood , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , SARS-CoV-2 , Transaminases/blood , Treatment Outcome
16.
Recenti Prog Med ; 112(5): 338-342, 2021 05.
Article in Italian | MEDLINE | ID: covidwho-1232488

ABSTRACT

The Italian Medicines Agency has started, since the first months of 2020, a monitoring of drug use during the covid-19 pandemic. This made it possible to identify specific trends in hospital and local purchases, such as the extensive use of off-label drugs with little evidence of efficacy during the first weeks of the epidemic, and to progressively assess the degree of implementation of regulatory and ministerial recommendations.Fin dalle prime fasi dell'emergenza covid-19 è emersa per l'Agenzia Italiana del Farmaco (AIFA) la necessità di monitorare in modo specifico l'uso dei farmaci utilizzati nel corso dell'epidemia. È infatti fondamentale, in un contesto caratterizzato da grande incertezza e da continui aggiornamenti delle linee guida, disporre di informazioni utili a una corretta lettura e interpretazione dei dati. È stato quindi realizzato un primo rapporto dell'Osservatorio Nazionale sull'Impiego dei Medicinali (OsMed) sull'uso dei farmaci utilizzati, a livello ospedaliero e territoriale, nella fase iniziale dell'epidemia1. Questo metteva a confronto i consumi relativi al periodo compreso tra marzo a maggio del 2020 con quelli del trimestre immediatamente precedente, da dicembre 2019 a febbraio 2020. In seguito, il 4 marzo 2021, è stato pubblicato un aggiornamento dei dati in riferimento alle fasi successive dell'epidemia2. Il monitoraggio ha preso in considerazione diverse categorie di farmaci, andando a valutare le oscillazioni negli acquisti in riferimento al progressivo aggiornamento degli indirizzi regolatori. I volumi osservati per ciascun farmaco sono stati standardizzati per 10.000 abitanti/die, andando a valutare le differenze pre- e post-covid-19 in termini di differenza assoluta, differenza percentuale e di p-value (p).


Subject(s)
COVID-19/drug therapy , Drug Utilization Review/statistics & numerical data , Off-Label Use/statistics & numerical data , Pandemics , COVID-19/epidemiology , Compassionate Use Trials , Humans , Italy/epidemiology , Time Factors
17.
Clin Infect Dis ; 72(9): e440-e441, 2021 05 04.
Article in English | MEDLINE | ID: covidwho-1221472
19.
Pediatrics ; 147(5)2021 05.
Article in English | MEDLINE | ID: covidwho-1197419

ABSTRACT

OBJECTIVES: Remdesivir shortens time to recovery in adults with severe coronavirus disease 2019 (COVID-19), but its efficacy and safety in children are unknown. We describe outcomes in children with severe COVID-19 treated with remdesivir. METHODS: Seventy-seven hospitalized patients <18 years old with confirmed severe acute respiratory syndrome coronavirus 2 infection received remdesivir through a compassionate-use program between March 21 and April 22, 2020. The intended remdesivir treatment course was 10 days (200 mg on day 1 and 100 mg daily subsequently for children ≥40 kg and 5 mg/kg on day 1 and 2.5 mg/kg daily subsequently for children <40 kg, given intravenously). Clinical data through 28 days of follow-up were collected. RESULTS: Median age was 14 years (interquartile range 7-16, range <2 months to 17 years). Seventy-nine percent of patients had ≥1 comorbid condition. At baseline, 90% of children required supplemental oxygen and 51% required invasive ventilation. By day 28 of follow-up, 88% of patients had a decreased oxygen-support requirement, 83% recovered, and 73% were discharged. Among children requiring invasive ventilation at baseline, 90% were extubated, 80% recovered, and 67% were discharged. There were 4 deaths, of which 3 were attributed to COVID-19. Remdesivir was well tolerated, with a low incidence of serious adverse events (16%). Most adverse events were related to COVID-19 or comorbid conditions. Laboratory abnormalities, including elevations in transaminase levels, were common; 61% were grades 1 or 2. CONCLUSIONS: Among 77 children treated with remdesivir for severe COVID-19, most recovered and the rate of serious adverse events was low.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/therapeutic use , Adolescent , Alanine/adverse effects , Alanine/therapeutic use , Antiviral Agents/adverse effects , COVID-19/diagnosis , Child , Child, Preschool , Compassionate Use Trials , Drug Therapy, Combination , Female , Hospitalization , Humans , Infant , Male , Oxygen Inhalation Therapy , Respiration, Artificial , SARS-CoV-2 , Severity of Illness Index , Treatment Outcome
20.
Pac Symp Biocomput ; 26: 38-49, 2021.
Article in English | MEDLINE | ID: covidwho-1124033

ABSTRACT

The coronavirus pandemic has placed renewed focus on expanded access (EA) programs to provide compassionate use exceptions to the waves of patients seeking medical care in treating the novel disease. While commendable, justifiable, and compassionate, EA programs are not designed to collect the necessary vital clinical data that can be later used in the New Drug Application process before the U.S. Food and Drug Administration (FDA). In particular, they lack the necessary rigor of properly crafted and controlled randomized controlled trials (RCT) which ensure that each patient closely monitored for side effects and other potential dangers associated with the drug, that the data is documented, stable and are traceable and that the patient population is well defined with the defined target condition. Overall, while RCTs is deemed to be of the most reliable methodologies within evidence-based medicine, morally, however, they are problematic in EA programs. Nevertheless, actionable data ought to be collected from EA patients. To this end, we look to the growing incorporation of real-world data real-world evidence as increasingly useful substitutes for data collected via RCTs, including the ethical, legal and social implications thereof. Finally, we suggest the use of digital twins as an additional method to derive causal inferences from real-world trials involving expanded access patients.


Subject(s)
Compassionate Use Trials , Pharmaceutical Preparations , Computational Biology , Humans , Randomized Controlled Trials as Topic , United States , United States Food and Drug Administration
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