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Report of the first seven agents in the I-SPY COVID trial: a phase 2,
open label, adaptive platform randomised controlled trial

I-SPY COVID Consortium. EClinicalMedicine. 2023 Apr.Show details Abstract PubMed PMID Full text linksCite

Abstract

Background: An urgent need exists to rapidly screen potential therapeutics for severe COVID-19 or other emerging pathogens associated with high morbidity and mortality.

Methods: Using an adaptive platform design created to rapidly evaluate investigational agents, hospitalised patients with severe COVID-19 requiring ≥6 L/min oxygen were randomised to either a backbone regimen of dexamethasone and remdesivir alone (controls) or backbone plus one open-label investigational agent. Patients were enrolled to the arms described between July 30, 2020 and June 11, 2021 in 20 medical centres in the United States. The platform contained up to four potentially available investigational agents and controls available for randomisation during a single time-period. The two primary endpoints were time-to-recovery (<6 L/min oxygen for two consecutive days) and mortality. Data were evaluated biweekly in comparison to pre-specified criteria for graduation (i.e., likely efficacy), futility, and safety, with an adaptive sample size of 40-125 individuals per agent and a Bayesian analytical approach. Criteria were designed to achieve rapid screening of agents and to identify large benefit signals. Concurrently enrolled controls were used for all analyses. https://clinicaltrials.gov/ct2/show/NCT04488081.

Findings: The first 7 agents evaluated were cenicriviroc (CCR2/5 antagonist; n = 92), icatibant (bradykinin antagonist; n = 96), apremilast (PDE4 inhibitor; n = 67), celecoxib/famotidine (COX2/histamine blockade; n = 30), IC14 (anti-CD14; n = 67), dornase alfa (inhaled DNase; n = 39) and razuprotafib (Tie2 agonist; n = 22). Razuprotafib was dropped from the trial due to feasibility issues. In the modified intention-to-treat analyses, no agent met pre-specified efficacy/graduation endpoints with posterior probabilities for the hazard ratios [HRs] for recovery ≤1.5 between 0.99 and 1.00. The data monitoring committee stopped Celecoxib/Famotidine for potential harm (median posterior HR for recovery 0.5, 95% credible interval [CrI] 0.28-0.90; median posterior HR for death 1.67, 95% CrI 0.79-3.58).

Interpretation: None of the first 7 agents to enter the trial met the prespecified criteria for a large efficacy signal. Celecoxib/Famotidine was stopped early for potential harm. Adaptive platform trials may provide a useful approach to rapidly screen multiple agents during a pandemic.

Funding: Quantum Leap Healthcare Collaborative is the trial sponsor. Funding for this trial has come from: the COVID R&D Consortium, Allergan, Amgen Inc., Takeda Pharmaceutical Company, Implicit Bioscience, Johnson & Johnson, Pfizer Inc., Roche/Genentech, Apotex Inc., FAST Grant from Emergent Venture George Mason University, The DoD Defense Threat Reduction Agency (DTRA), The Department of Health and Human ServicesBiomedical Advanced Research and Development Authority (BARDA), and The Grove Foundation. Effort sponsored by the U.S. Government under Other Transaction number W15QKN-16-9-1002 between the MCDC, and the Government.

Keywords: Acute lung injury; Clinical trial; Respiratory insufficiency; SARS-CoV-2.

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Conflict of interest statement

NA reports institutional research funding from the Defense Threat Reduction Agency (DTRA), and the Department of HHS Biomedical Advanced Research and Development Authority (BARDA); reports grants from the National Institute of Health (NIH); and reports honoraria from Young Investigators Respiratory Disease Forum. JRB reports institutional research funding from Quantum Leap Healthcare Collaborative and the National Institute of Health (NIH); reports payment or honoraria from Sedana Medical, Hamilton Medical, and BioMarck Pharmaceuticals; and serves as an associate editor of Critical Care. PB serves as a contracted consulted for Auris Health and Johnson & Johnson; and reports payment for expert testimony from University of Minnesota Physicians Group. EB reports institutional research funding from Quantum Leap Healthcare Collaborative. CSC reports grants or institutional funding from the National Institute of Health (NIH), Roche-Genenetch, and Quantum Leap Healthcare Collaborative; and reports consulting feed from Cellenkos, Vasomune, Gen1e Life Sciences, and NGM Bio. LE is an unpaid Board Member at Quantum Leap Healthcare Collaborative. DCF reports institutional research funding from Quantum Leap Healthcare Collaborative and the National Institute of Health (NIH); reports consulting fees from Cytovale; and reports participation on a Data Safety Monitoring Board for Medpace. SG reports institutional research funding from Quantum Leap Healthcare Collaborative; reports participation on a Scientific Advisory Board and holds stock in Respana Therapeutics. KDL reports institutional research funding from the Defense Threat Reduction Agency (DTRA), and the Department of HHS Biomedical Advanced Research and Development Authority (BARDA). TRM reports consulting fees from Novartis Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, the Bill and Melinda Gates Foundation, and the National Heart, Lung and Blood Institute. MM reports consulting fees from Gilead Pharmaceuticals, Johnson & Johnson, Novartis Pharmaceuticals, Citius Pharmaceuticals, and Pliant Therapeutics; and reports institutional funding from Roche Genentech, the Department of Defense, Quantum Leap Healthcare Collaborative, Regenerative Medicine, the National Institute of Health (NIH), the National Heart, Lung, and Blood Institute, and National Institute of Allergy and Infectious Diseases. NJM reports institutional research funding from Quantum Leap Healthcare Collaborative and the Marcus Foundation; reports grants from the National Institute of Health (HL137006, HL137915, HL155804, GM115553), and BioMarch Inc. (BIO-11006); reports honoraria from University of Pittsburgh, Department of Critical Care Grand Rounds, and NYU Langone Pulmonary Critical Care Grand Rounds, Brown University Investigators in Respiratory Diseases, ViralED and Penn Center for AIDS Research, and University of Colorado Pulmonary Research Excellence Conference; reports travel support from the Aspen Lung Conference; and reports participation on a Data Safety Monitoring Board for the Careful Ventilation in ARDS Trial (CAVIARDS), and NHLBI Observational Study Monitoring Board for SPIROMICS II. DWR reports institutional research funding from the National Institute of Health (NIH), National Heart, Lung and Blood Institute and Quantum Leap Healthcare Collaborative; reports travel support from the National Institute of Health (NIH), National Heart, Lung and Blood Institute, and Department of Veteran’s Affairs; and holds stock in Achieve Life Sciences. KWT reports royalties from UpToDate; reports payment for expert testimony from Bencoe & Lacour Law PC, and Jakeway Injury Law; and holds stock in Johnson & Johnson, Gilead Sciences, Bristol-Myer Squibb, Pfizer, and Doximity. AR reports grant from the Agency for Healthcare Research and Quality (T32HS026121). KWG reports grants from the National Institute of Health (ACTIV4-HT/NECTAR, NEXIS-FLAME R32). JPR reports institutional research funding from Quantum Leap Healthcare Collaborative and the National Institute of Health (HL155159). JD reports grant funding from the National Heart, Lung, and Blood Institute (T32HL116271). GRSB reports grant funding from the National Institute of Health and the Veterans Administration. BDS reports grants from the National Institute of Health (R01HL149883, R01HL153122, P01HL154998, P01AG049665, U19AI135964); reports participating in an Advisory Board, and owns stock in Zoe Biosciences; and reports patent, “Compositions and Methods to Accelerate Resolution of Acute Lung Inflammation,” (US 10, 905, 706 B2). JL reports personal fees from Quantum Leap Healthcare Collaborative for serving as Chair of the Safety Working Group for the ISPY COVID Trial. PH and ID are full time employees of Quantum Leap Healthcare Collaborative. All other authors declare no competing interests.

Figures

Fig. 1 Consort flow chart of the…

Fig. 1

Fig. 2 Time-to-Recovery, Modified Intention-To-Treat Population. Aalen-Johansen…

Fig. 2

Fig. 3 Survival Over Time, Modified Intention-To-Treat…

Fig. 3

Fig. 4 Progression to Mechanical Ventilation or…

Fig. 4

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  5. Calfee C. Clinical trial design during and beyond the pandemic: the I-SPY COVID trial. Nat Med. 2022;28(1):9–11. – PMC – PubMed
  6. Files D.C., Matthay M.A., Calfee C.S., et al. I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations. BMJ Open. 2022;12(6) – PMC– PubMed
  7. Beigel J.H., Tomashek K.M., Dodd L.E., et al. Remdesivir for the treatment of Covid-19 – final report. N Engl J Med. 2020;383(19):1813–1826. – PMC – PubMed
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  13. Matthay M.A., Thompson B.T., Ware L.B. The Berlin definition of acute respiratory distress syndrome: should patients receiving high-flow nasal oxygen be included? Lancet Respir Med. 2021;9(8):933–936. – PMC – PubMed
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Associated data

  • ClinicalTrials.gov/NCT04488081

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Clinical trial design during and beyond the pandemic: the I-SPY COVID trial

Clinical trial design during and beyond the pandemic: the I-SPY COVID trial – PubMed

The COVID-19 pandemic and a reflection on the conduct of clinical trials in times of war???

The COVID-19 pandemic and a reflection on the conduct of clinical trials in times of war – PubMed

Lancet Respir Med. 2021 Aug; 9(8): 933–936. 

The Berlin definition of acute respiratory distress syndrome: should patients receiving high-flow nasal oxygen be included?

Published online 2021 Apr 27. doi: 10.1016/S2213-2600(21)00105-3

PMCID: PMC8075801

PMID: 33915103

Michael A Matthay, Prof, MD,a,* B Taylor Thompson, Prof, MD,b and  Lorraine B Ware, Prof, MDc

Author information Copyright and License information PMC Disclaimer

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Abstract

The 2012 Berlin definition of acute respiratory distress syndrome (ARDS) provided validated support for three levels of initial arterial hypoxaemia that correlated with mortality in patients receiving ventilatory support. Since 2015, high-flow nasal oxygen (HFNO) has become widely used as an effective therapeutic support for acute respiratory failure, most recently in patients with severe COVID-19. We propose that the Berlin definition of ARDS be broadened to include patients treated with HFNO of at least 30 L/min who fulfil the other criteria for the Berlin definition of ARDS. An expanded definition would make the diagnosis of ARDS more widely applicable, allowing patients at an earlier stage of the syndrome to be recognised, independent of the need for endotracheal intubation or positive-pressure ventilation, with benefits for the testing of early interventions and the study of factors associated with the course of ARDS. We identify key questions that could be addressed in refining an expanded definition of ARDS, the implementation of which could lead to improvements in clinical practice and clinical outcomes for patients.

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Introduction

Definitions of clinical syndromes are not immutable and should be updated as needed to match the needs of patients, clinicians, and investigators. The definition of acute respiratory distress syndrome (ARDS) has been revised several times since its original description in 1967.1, 2 In 1988, Murray and colleagues3proposed an expanded definition of ARDS that specified a four-point lung injury score (ranging from 0 to 4) that included the degree of hypoxaemia, static respiratory compliance, the level of positive end-expiratory pressure (PEEP), and the extent of radiographic pulmonary infiltrates. In 1994, the American–European Consensus Conference provided a revised definition of ARDS that designated patients with a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) of 300 mm Hg or less as having acute lung injury, and reserved the term ARDS for patients with more severe hypoxaemia (PaO2/FiO2 ≤200 mm Hg).4 In 2012, the Berlin definition of ARDS recommended that the term be expanded to include patients with an initial PaO2/FiO2 of 201–300 mm Hg who were receiving invasive or non-invasive ventilation with a tight-fitting mask and PEEP or continuous positive airway pressure (CPAP) of at least 5 cm H2O; this group was designated as having mild ARDS. PaO2/FiO2 of 101–200 mm Hg defined moderate ARDS and PaO2/FiO2 of 100 mm Hg or less was termed severe ARDS.5This recommendation was validated in a patient-level meta-analysis of 4188 patients, in which mortality was 27%, 35%, and 45% in the mild, moderate, and severe PaO2/FiO2 groups,5and has since been prospectively confirmed.6The Berlin definition also specified the following criteria: first, that respiratory failure should have developed within 1 week of a known clinical insult; second, that respiratory failure should not be fully explained by cardiac failure, with the recommendation for additional testing such as echocardiography to exclude hydrostatic oedema, if needed; and third, that chest imaging should include bilateral opacities not fully explained by effusions, atelectasis, or nodules. In 2016, Riviello and colleagues7proposed the Kigali modification of the Berlin definition, to respond to patient needs in resource-limited settings. This modification specified that bilateral opacities could be documented by either ultrasonography or chest radiograph, and that oxygenation criteria could be met with a pulse oximetric oxygen saturation (SpO2)/FiO2 ratio of less than or equal to 315 without the requirement for PEEP.

Key messages

  • •Definitions of ARDS have evolved since the first description of the syndrome in 1967: key advances include the 1988 proposal of an acute lung injury score, which provided a semi-quantitative scoring of lung injury that was useful for clinical research; and the 1994 American–European Consensus Conference definition of ARDS, which was used in several successful clinical trials, including those of lung-protective ventilation, prone positioning, and a fluid-conservative management strategy
  • •The 2012 Berlin definition of ARDS simplified the terminology, clarified several criteria, and provided validated support for three strata of initial arterial hypoxaemia (PaO2/FiO2 categories of ≤100, 101–200, and 201–300 mm Hg), which correlated with mortality (45%, 35%, and 27%, respectively)
  • •Since 2015, HFNO has become widely used as an effective therapeutic support for acute respiratory failure, most recently in patients with severe COVID-19
  • •We propose that the Berlin definition of ARDS be broadened to include patients treated with HFNO of at least 30 L/min who fulfil the other criteria for the Berlin definition of ARDS
  • •This broadened definition would make the diagnosis of ARDS more widely applicable, focusing on patients with sufficient clinical lung injury to require high levels of oxygen support, independent of the need for endotracheal intubation or positive-pressure ventilation
  • •An expanded definition of ARDS, including HFNO, would be valuable in addressing the needs of patients in clinical practice and through clinical research, including clinical trials

ARDS=acute respiratory distress syndrome. HFNO=high-flow nasal oxygen. PaO2/FiO2=ratio of partial pressure of arterial oxygen to fraction of inspired oxygen.

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Patients receiving HFNO

Now, in 2021, we propose a further modification to the clinical definition of ARDS to include patients treated with high-flow nasal oxygen (HFNO) who otherwise meet the Berlin criteria for ARDS. Since the landmark study by Frat and colleagues,8 HFNO has become widely used in critically ill patients to provide support for hypoxaemic respiratory failure that was not previously feasible with supplemental oxygen supplied by face mask or standard nasal cannula. HFNO provides heated and humidified oxygen that can be delivered at high flow rates, ranging from 10 to 60 L/min, thus increasing FiO2 to levels in the range of 80–90% (figure ). In addition, in most patients, HFNO provides a modest flow-dependent level of end-expiratory airway pressure (2–5 cm H2O) that inflates atelectatic distal airspaces similar to low levels of PEEP in mechanically ventilated patients.9, 10 HFNO also increases carbon dioxide excretion and diminishes work of breathing.8, 11, 12, 13, 14 During the COVID-19 pandemic, HFNO has been widely used to support patients with bilateral pulmonary infiltrates and hypoxaemia due to SARS-CoV-2 pneumonia,15, 16, 17 including those managed in resource-limited settings18 and patients with severe COVID-19-associated ARDS managed in the prone position,19 who typically meet all other Berlin diagnostic criteria for ARDS other than the requirement for invasive or non-invasive mechanical ventilation.

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Sorry. But for me it looks like a modern gas chamber

Figure

Proposed expansion of the Berlin definition of ARDS

ARDS=acute respiratory distress syndrome. HFNO=high-flow nasal oxygen. PaO2/FiO2=ratio of partial pressure of arterial oxygen to fraction of inspired oxygen.

Several studies have reported that non-ventilated patients who otherwise meet the diagnostic criteria for ARDS have characteristics and outcomes similar to those of patients with ARDS. For example, Kangelaris and colleagues20 reported that non-ventilated patients who otherwise met the criteria for ARDS had the same 60-day mortality outcomes as ventilated patients with ARDS. Another study found that patients with hypoxaemia and bilateral infiltrates who were treated with HFNO had patterns of elevated plasma biomarkers of inflammation and injury similar to those of patients with ARDS who were mechanically ventilated.21 Additionally, Coudroy and colleagues22 reported that almost all patients with bilateral pulmonary infiltrates and a PaO2/FiO2 of 300 mm Hg or less under standard oxygen support fulfilled ARDS criteria by oxygenation and chest radiographic criteria without meeting the Berlin criteria for positive-pressure ventilation. These studies and others suggest that the severity of hypoxaemia is more important than the method used for oxygen delivery, supporting the concept that the diagnosis of ARDS should not depend on the presence of an endotracheal tube or positive-pressure ventilation in adults23, 24, 25, 26 or in children.27

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An expanded definition of ARDS

We propose that the use of HFNO at a rate of at least 30 L/min be added as an additional criterion for the diagnosis of ARDS. There are other modifications that could be considered (panel ). Given the more indolent progression of hypoxaemia and respiratory failure in COVID-19 compared with other causes of ARDS,17 a revised definition of ARDS could also consider a latency longer than 7 days from identification of the ARDS risk factor, as specified by the Berlin definition, perhaps up to 14 days. Oxygenation and radiographic criteria for the diagnosis of ARDS would be the same as in the Berlin definition, although the addition of SpO2/FiO2 of less than or equal to 315 should be considered, as in the Kigali modification,7given its increasing use both clinically and in research settings since it was originally validated.28 Would it be reasonable to consider a wider range of patients who have severe hypoxaemia on high FiO2 delivered with lower flow rates, as suggested decades ago, before the HFNO era?29 Should the radiographic criteria for bilateral opacities be reconsidered? One recent study indicated that mechanically ventilated patients from the LUNG SAFE study had the same mortality with opacities in two quadrants, independent of whether the infiltrates were bilateral or unilateral.30

Panel

Questions to address in considering an expanded definition of ARDS

The proposal to include patients receiving HFNO in an expanded definition of ARDS could be evaluated in several forums. Areas of uncertainty and other potential modifications to the Berlin definition are listed below. These questions could be addressed in randomised controlled trials or observational studies that include patients recruited at an early stage of respiratory failure.

  • •Is an HFNO cutoff of 30 L/min optimal?
  • •Should the latency period for the inciting clinical disorder be increased to 14 days rather than 7 days, a point that is especially relevant to viral pneumonia and COVID-19?
  • •Should the use of a SpO2/FiO2 ratio of less than or equal to 315 be formally integrated as an oxygenation criterion?
  • •Should the radiographic criteria be modified to include two quadrants, independent of whether the infiltrates are bilateral or unilateral?

ARDS=acute respiratory distress syndrome. HFNO=high-flow nasal oxygen. SpO2/FiO2=ratio of pulse oximetric oxygen saturation to fraction of inspired oxygen.

What would be the advantages of adding HFNO of at least 30 L/min to the definition of ARDS? First, the addition would explicitly recognise that many HFNO-supported patients have acute respiratory failure and acute lung injury from a non-cardiogenic cause of pulmonary oedema, regardless of the presence of an endotracheal tube. Second, it would emphasise that these patients are excellent candidates for the testing of treatments for acute lung injury and ARDS in an earlier phase of respiratory failure, allowing treatment to begin before the patient is intubated and mechanically ventilated. This approach is being taken in the US I-SPY COVID trial (NCT04488081)31—a national, randomised, platform trial that is testing several pharmacological agents for COVID-19-associated ARDS in patients who meet the Berlin definition either with mechanical ventilation or with HFNO support—and with other trials that are being designed as part of ACTIV-3 (NCT04501978) in the US National Institutes of Health Operation Warp Speed.32, 33 Third, because HFNO provides end-expiratory support of 2–5 cm H2O, our proposal would be concordant, to an extent, with the current criterion in the Berlin definition that requires at least 5 cm H2O PEEP or CPAP. Fourth, from an epidemiological perspective, the inclusion of these patients would more comprehensively identify those with ARDS at an earlier stage of the syndrome, and would include more patients in resource-limited settings, as was recommended with the Kigali modification of the Berlin definition of ARDS.7Fifth, the addition of HFNO would make the definition of ARDS more widely applicable by focusing on all patients who have sufficient clinical lung injury to require high levels of oxygen support. Sixth, although the optimum use of HFNO and the optimum timing of intubation for ARDS remain unclear, randomised trials with a broader definition of ARDS would help to determine whether the use of HFNO reduces the use of invasive mechanical ventilation.15 Finally, other investigators have already concluded that ARDS is present in many patients being treated with HFNO, suggesting that this modification is already overdue.21, 24, 25

Challenges and opportunities

Are there disadvantages to expanding the Berlin definition of ARDS to include HFNO? Conceivably, some patients might be included who would not meet the criterion of a PaO2/FiO2 ratio of less than 300 mm Hg, since FiO2 can only be estimated with HFNO. However, this would be unlikely if a simple bedside estimate of FiO2 were included along with a measure of either PaO2, as was done in the trial of Frat and colleagues,8 or SpO2.28

Expanding the definition to include HFNO should not obscure the need to rule out left heart failure or a primary pulmonary process such as an autoimmune disease or acute eosinophilic pneumonia.34 The need to make these diagnostic distinctions would be the same whether the patient was being mechanically ventilated or being treated with HFNO. Also, some patients treated with HFNO might have declined intubation and mechanical ventilation or have a do-not-resuscitate restriction. However, such patients might have ARDS and their personal preference for limits on further respiratory support, such as intubation, should not impede an appropriate diagnosis.

Steps need to be taken to evaluate our proposal, to review it critically, and potentially to implement it in clinical research and clinical practice. We recognise the need for empirical validation of the optimum cutoff for HFNO flow rates. We have proposed 30 L/min partly because most of the beneficial effects of HFNO—including favourable effects on oxygenation, lung mechanics, end-expiratory lung volume, and respiratory drive—are achieved with flow of at least 30 L/min.12, 14 This and other uncertainties could be considered in several forums—including regional, national, or international conferences, or journals devoted at least in part to critical care medicine—and possibly at a consensus conference to address the scope and the specifics of an expanded definition of ARDS.

In conclusion, we recommend that the Berlin definition of ARDS be modified to include patients treated with HFNO of at least 30 L/min and propose that this would be an advance for patients with lung injury who require high levels of oxygen support, and for the clinicians and investigators caring for them. We welcome responses from the global community of investigators and clinicians caring for critically ill patients.

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Declaration of interests

MAM receives fees as a consultant for Novartis and Citius Pharmaceuticals, outside of the present work. BTT receives fees as a consultant for Bayer, Novartis, and Thetis, outside of the present work. LBW receives fees as a consultant for Boehringer and Citius, outside of the present work.

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Contributors

MAM wrote the original draft. BTT and LBW edited subsequent versions and contributed to the figure, panels, and selection of references.

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References

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Covid-19:
Researcher blows the whistle
on data integrity issues in
Pfizer’s vaccine trial

For researchers who were testing Pfizer’s vaccine at several sites in Texas during that autumn, speed may have come at the cost of data integrity and patient safety.

A regional director who was employed at the research organisation Ventavia Research Group has told The BMJ that the company falsified data, unblinded patients, employed inadequately trained vaccinators, and was slow to follow up on adverse events reported in Pfizer’s pivotal phase III trial.

Staff who conducted quality control checks were overwhelmed by the volume of problems they were finding.

After repeatedly notifying Ventavia of these problems, the regional director, Brook Jackson , emailed a complaint to the US Food and Drug Administration (FDA).

Jackson has provided The BMJ with dozens of internal company documents, photos, audio recordings, and emails.

Read the full investigation:

Covid-19: Researcher blows the whistle on data integrity issues in Pfizer’s vaccine trial

https://www.bmj.com/content/375/bmj.n2635

More Harm Than Good

Dr. David Martin at EU Parliament in Strasbourg:Expert Panel about WHO’s power grab!Wed, Sept. 13th

https://m.youtube.com/watch?v=nd6wuWTg9mw

Independent MP Derek Sloan holds a news conference on Parliament Hill to raise concerns about the censorship of doctors and scientists as well as medical information related to vaccines. The Ontario MP has been highly critical of lockdowns that have been in place due to the COVID-19 pandemic, and also sponsored a petition questioning the safety of COVID-19 vaccines. He is joined by a trio of doctors and scientists. (June 17, 2021)

Concerns Over Censorship of Doctors and Scientists

Guidance Agenda: Guidance Documents CBER is Planning to Publish During Calendar Year 2024 (Updated January 2024)

https://www.fda.gov/media/120341/download

Hospital Operations Toolkit for COVID-19 Patient Care Policies/Processes: Crisis Standards of Care

Note: This resource was last reviewed in September 2021.

This toolkit was designed as a single source of information for hospital emergency managers and planners preparing to manage large numbers of patients during the COVID-19 pandemic. Some information may be applicable to other hospital personnel and non-hospital settings. The toolkit is comprised of four primary sections and covers considerations from before patients arrive at a hospital to after they are discharged and is designed for users to easily navigate to desired information. All content may be accessed from this landing page and each section links back to this page.

Because information about the pandemic is rapidly evolving, toolkit content may not accurately reflect the landscape at the time the document is referenced. If you are a clinician treating a patient, please refer to the National Institutes of Health Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. If you have tools, templates, or other resources to contribute to this toolkit, please contact our Assistance Center.

In response to the rapidly evolving COVID-19 pandemic, the National Institutes of Health assembled a panel of experts to provide practical recommendations for health care providers and issued the first version of the Coronavirus Disease 2019 (COVID-19) Treatment Guidelines on April 21, 2020. For close to 4 years, the COVID-19 Treatment Guidelines Panel (the Panel) has critically reviewed the growing body of research data on COVID-19 and used that information to develop and revise their recommendations for treating patients with this disease. The Panel has released a total of 72 versions of the Guidelines.

The federal COVID-19 Public Health Emergency ended in May 2023, and several professional societies currently provide COVID-19 treatment guidelines for their medical specialties or subspecialties. Accordingly, this will be the final update of the COVID-19 Treatment Guidelines.

The Panel members hope these Guidelines have been of value to health care providers, and they appreciate the support and input they have received over the past 4 years.

The COVID-19 Treatment Guidelines website will remain available until August 16, 2024, and will provide a downloadable PDF of the final version of the Guidelines.

February 29, 2024

In preparation for this final version of the Guidelines, the Panel reviewed all the sections that were not updated on December 20, 2023. The information in these sections is current as of February 2024. 

The Viral Rebound and Symptom Recurrence subsections in Therapeutic Management of Nonhospitalized Adults With COVID-19 and Ritonavir-Boosted Nirmatrelvir (Paxlovid) have been updated with new references. The Panel noted that concerns about the recurrence of symptoms or viral rebound should not be a reason to avoid using antiviral therapy when indicated.

The Panel updated the discussion on the role of remdesivir in adults with COVID-19 who require mechanical ventilation or extracorporeal membrane oxygenation in Therapeutic Management of Hospitalized Adults With COVID-19.

In Therapeutic Management of Nonhospitalized Children With COVID-19, the vaccination status categories that determine a child’s risk level for progression to severe disease have been changed from “Unvaccinated,” “Primary Series,” and “Up to Date” to “Not Up to Date” and “Up to Date.” Chronic kidney disease and pregnancy were added to the list of risk factors that are associated with progression to severe COVID-19.

Other sections that were reviewed for this final version of the Guidelines can be found in:

Guideline PDFs

Source https://www.covid19treatmentguidelines.nih.gov/about-the-guidelines/whats-new/

https://asprtracie.hhs.gov/hospital-toolkit-covid-19
https://files.asprtracie.hhs.gov/documents/healthcare-operations-speaker-series–speed.pdf

Tools/Resources

Baseball Cards?

Casirivimab + Imdevimab Baseball Cards

Casirivimab (a.k.a. REGN10933) Injection (120 mg/ml)
MUST ADMINISTER WITH IMDEVIMAB (a.k.a. REGN10987)

Manufacturer: Regeneron Pharmaceuticals, Inc. 

Distributor: AmerisourceBergen (a.k.a. ABC); c19therapies@amerisourcebergen.com 

Product: Component of 2-drug monoclonal antibody cocktail for outpatient infusion 

Emergency Use Authorization (EUA): 11/21/20 

Units: Supplied in 2 volumes 

  • 1332 mg/11.1 ml single-dose vial in carton (10 ml from 1 vial needed for patient course)
  • 300 mg/2.5 ml single-dose vials in cartons (10 ml; 2.5 ml from each of 4 vials needed for patient course)

Note: Some cartons and vials of casirivimab may be instead labeled REGN10933 

Casirivimab1332 mg/11.1 ml carton (a.ka. REGN10933 product label

 
Example: 1332 mg/ 11.1 ml carton 

Casirivimab 300 mg/2.5 ml Carton (a.ka. REGN10933 product label

 
Example: 300 mg/2.5 ml carton


Storage: Keep in carton until use. Unopened vials must be stored at refrigerated temperature (2oC–8oC / 36°F–46°F) until use. Do not freeze, shake, or expose to direct light.

Earliest Expiration Date of Units Shipped: 06/2022

Single Vial w/ Carton Dimensions: 1.7”(d) x 1.8”(w) x 2.8”(h)
Single Vial w/ Carton Weight: 1.5 oz. for 1332 mg/11.1 ml vial; 0.9 oz. for 300 mg/2.5 ml vial

Case: A full case contains 24 vials in cartons
Case Dimensions: 9.6”(d) x 7.4”(w) x 4.6”(h)
Case Weight: 2.7 lb. for 1332mg/11.1 ml vials; 1.8 lb. for 300 mg/2.5 ml vials 

Administration: (Detailed guidelines are available.)

  1. Inject 10 ml (1200 mg) casirivimab
  2. Inject 10 ml (1200 mg) imdevimab
  3. Infuse final volume (270 ml) containing cocktail of 2 monoclonal antibodies over at least 60 min

https://www.fda.gov/media/143891/download

HHS-ASPR Resources

  • T

• mAb Administration Baseball Cards (review Resource/Links as well)

• Bamlanivimab: https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Bamlanivimab/Pages/Bamlanivimab-Baseball-Card.aspx

• Casirivimab/Imdevimab: https://www.phe.gov/emergency/events/COVID19/investigation-MCM/cas_imd/Pages/Casirivimab-Imdevimab-Baseball-Cards.aspx

• Administration playbooks

• Federal Response mAb Playbook: https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Documents/COVID-Therapeutics-playbook_1Feb2021.pdf

This is outrageous!

This is the so called scientific racism against every one who is >65 old and has a BMI over 35!!!

https://web.archive.org/web/20210325090519if_/https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Documents/COVID-Therapeutics-playbook_1Feb2021.pdf

• Lilly Playbook: https://www.covid19.lilly.com/assets/pdf/bamlanivimab/lilly-antibodies-playbook.pdf

• Regeneron Guidebook: https://www.regeneroneua.com/Content/pdf/treatment-covid19-eua-guide-book.pdf

Unclassified//For Public Use

30

Tools/Resources (cont.)

• Reimbursement information

• CMS Reimbursement rates: https://www.cms.gov/medicare/medicare-part-b-drug-average-sales-price/covid-19-vaccines-and-monoclonal-antibodies

• HRSA FAQs for COVID-19 Claims Reimbursement: https://www.hrsa.gov/coviduninsuredclaim/frequently-asked-questions

• General guidance

• HHS/ASPR Website: https://www.phe.gov/

• CombatCOVID official website: https://combatcovid.hhs.gov/

• mAb product locator tool: https://protect-public.hhs.gov/pages/therapeutics-distribution/

• Bamlanivimab FAQ: https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Bamlanivimab/Pages/bamlanivimab-faq.aspx

• Casirivimab + Imdevimab FAQ: https://www.phe.gov/emergency/events/COVID19/investigation-MCM/cas_imd/Pages/faq.aspx

• FAQ for non-hospital sites: https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Pages/FAQs-mAB.aspx

• mAb Infusion Center Model: https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Documents/Monoclonal-Antibody-Infusion-Center-Model-508.pdf

31

Unclassified//For Public Use

Tools/Resources (cont.)

• More information

• HHS / ASPR Office Call Sessions (Tue 1-1:30PM EST, Thu 2-2:30PM EST)

• Open forum for state and territorial health officer, health care providers and sties of care to reach out on questions for administration of therapies

• https://hhsasproea.zoomgov.com/j/1604329034?pwd=dGRwZTBETTJzWFliQW83TXZSOFVNQT09

• MeetingID:1604329034 • Passcode: 897674

• ECHO – Outpatient Therapeutics Mini-Series (Wed 12-1PM EST) for clinical overview and examples of administration models

• https://hsc.unm.edu/echo/institute-programs/covid-19-response/us-covid19/hhs-aspr/miniseries.html

• Regional Emergency Coordinators: https://www.phe.gov/Preparedness/responders/rec/Pages/default.aspx

• Contact: COVID19Therapeutics@hhs.gov

How did we get here?

Gates Foundation Hired PR Firm to Manipulate UN Over Gene Drives

Launching the Decade of Vaccines – https://www.gatesfoundation.org/Media-Center/Press-Releases/2010/12/Global-Health-Leaders-Launch-Decade-of-Vaccines-Collaboration

Event 201 – https://www.centerforhealthsecurity.org/event201/

Event 201 Explained in Detail – https://www.youtube.com/watch?v=AoLw-Q8X174&feature=youtu.be&t=493

Mayors Challenge – https://www.bloomberg.org/program/government-innovation/mayors-challenge/

Implementing a National COVID-19 Testing Action Plan – https://www.rockefellerfoundation.org/wp-content/uploads/2020/04/TheRockefellerFoundation_WhitePaper_Covid19_4_22_2020.pdf

Implementing a Digital Immunity Proof Certificate – https://www.youtube.com/watch?time_continue=23&v=LsNfyzuDvQ0&feature=emb_title

Implementing the COVI-Pass – https://covipass.com/

Implementing the “Trust Stamp” Vaccine Record and Payment System – https://citizentruth.org/africa-to-become-testing-ground-for-trust-stamp-vaccine-record-and-payment-system/

Efficiently delivering vaccines to millions of children, tracking identity and immunisation records in a digitised manner and incentivising the delivery of vaccines – https://www.gavi.org/investing-gavi/funding/donor-profiles/mastercard

Why “We need to develop genetic engineering technologies and techniques (mRNA software)to be able to write circuitry for cells and predictably program biology the same way in which we write a software and program computers.” Execute Order. https://www.whitehouse.gov/briefing-room/presidential-actions/2022/09/12/executive-order-on-advancing-biotechnology-and-biomanufacturing-innovation-for-a-sustainable-safe-and-secure-american-bioeconomy/

Wireless Personal Communications (2021)

Nano‐Sensor Modelling for Intra‐Body Nano‐Networks https://doi.org/10.1007/s11277-021-08171-2

Techniques of EMG signal analysis: detection, processing, classification and applications https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1455479/

INHALATION EXPOSURE TO CARBON NANOTUBES (CNT) AND CARBON NANOFIBERS (CNF): METHODOLOGY AND DOSIMETRY – PMC

https://lawcat.berkeley.edu/record/1119251

https://particleandfibretoxicology.biomedcentral.com/counter/pdf/10.1186/s12989-016-0168-y.pdf?pdf=button%20sticky

COVID Vax Ingredients Exposed: Graphene, Nanometals, PEG and Parasites Platelets and hemostatic proteins are co-localized with chronic neuroinflammation surrounding implanted intracortical microelectrodes – PubMed

https://patents.google.com/patent/CA2028849A1/en

Nanobills S. 189 AN ACT authorize appropriations for nanoscience, nanoengineering, and nanotechnology research, and for other pur- poses.

Klicke, um auf nanobills189.pdf zuzugreifen

Magnetic soft robotics to manipulate the extracellular matrix in vitro – PubMed

US Firm Integrates Nanotechnology, Blockchain For Covid-19 Immunity Passports!

US Firm Integrates Nanotechnology, Blockchain For Covid-19 Immunity Passports!

Archer Materials demonstrates multiplexing readout for its Biochip gFET

https://www.graphene-info.com/archer-materials-demonstrates-multiplexing-readout-its-biochip-gfet

QUANTUM DOTS „PCR“ „TESTS“

https://open.substack.com/pub/outraged/p/quantum-dots-pcr-tests?r=1pk0jl&utm_medium=ios&utm_campaign=post

https://www.theverge.com/2020/4/21/21230453/palantir-coronavirus-trump-contract-peter-thiel-tracking-hhs-protect-now

Palantir, The Peter Thiel-Backed $20 Billion Big Data Cruncher, Scores $17 Million Coronavirus Emergency Relief Deal https://www.forbes.com/sites/thomasbrewster/2020/04/11/palantir-the-peter-thiel-backed-20-billion-big-data-cruncher-scores-17-million-coronavirus-emergency-relief-deal/#589ca90f5ed1

See selected coverage on coronavirus pressure:

• Rome Declaration: Over 6,700 Doctors Sign Letter Rejecting Coronavirus Tyranny

• EXPOSED: The Top Five Lies about Monoclonal Antibody Treatment

• Blacklist Exposed: Top Seven Banned Coronavirus Questions

• Did America Fund the Pandemic?

• ALERT: Bill Gates’ Obsession With Population Control Should Discredit Him

• SCAM: Alabama Man Was Not Turned Away from 43 Hospitals Due to Unvaccinated Covid Patients Hogging Beds

• Flashback: Officials State that the Federal Government Cannot Impose a Vaccine Mandate (Video)

• Medical Tyranny: Hospitals Refuse Life-Saving Ivermectin – Families Fight for the Lives of their Loved Ones (Video)

• Exposed: CDC Rushed to Change Definition of ‘Vaccination’ After Israel Study Touts Natural Immunity over Vaccine

• UPDATE: Woman Loses Battle Against Ohio Hospital to Keep her Dying Husband on Ivermectin (Video)

• BAM: Famous Doctor Exposes FDA Ivermectin Lies

• BREAKING: FDA Leaders Quit After Democrat Pressure to Approve Booster Shots & Vaccines for Children

• Bombshell: Nobel Prize Winner Reveals – Covid Vaccine is ‘Creating Variants’

• Indoctrination: Teacher Exposed Tormenting Unmasked Children with Propaganda Video (Watch)

• Beware: Biden Targets Parents – Uses Taxpayer Dollars to Push Vaccine & Mask Propaganda (Video)

• Disinformation: Jen Psaki Falsely Refers to Covid Vaccines as ‘Approved’ (Videos)

• War on Free Speech: Indivisible Trains Digital Army to Target ‘Right-Wing Disinformation’

• WARNING: Globalists Launch War on Doctors Who Question State Vaccination and Coronavirus Narratives (Video)

• BREAKING: ‘Trusted News Initiative’ will Ban Posts Challenging Coronavirus Vaccine (Plot Exposed)

Cardiac side effects of RNA-based SARS-CoV-2 vaccines: Hidden cardiotoxic effects of mRNA-1273 and BNT162b2 on ventricular myocyte function and structure https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.16262

Italian study on vaccine effectiveness (VE) in kids reports effectiveness dropping to 21% after 43 days. And this is after applying the 14 days miscategorisation trick where the vaccinated are counted as unvaccinated. So in reality VE is much much lower. https://thelancet.com/journals/lancet/article/PIIS0140-6736(22)01185-0/fulltext…

Klicke, um auf weiss_intro.pdf zuzugreifen

Healthy people should wear masks only if caring for coronavirus patients, WHO says – https://nypost.com/2020/05/28/healthy-people-should-wear-masks-only-if-caring-for-coronavirus-patients-who-says/?fbclid=IwAR3xxJeYcTnI7OJTrqIskeP1rd31fUTbLac9–BWqrv3J_M0Tkwb9hws8KY

Covid-19: Researchers face wait for patient level data from Pfizer and Moderna vaccine trials

Misinformation Is the Biggest Threat to
Ending This Pandemic https://www.rockefellerfoundation.org/blog/misinformation-is-the-biggest-threat-to-ending-this-pandemic/

BREAKING! WHO Calls for Global Police to Arrest Journalists Who Speak out Against Pandemic Policies

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Eine Antwort zu „HUMANS WAS USED AS LAB MOUSES UNDER THE EMERGENCY SHILD”.

  1. Avatar von Why we not aware of the massive amount of damage from the scientific and medical community in the past? – JULIMINATION
    Why we not aware of the massive amount of damage from the scientific and medical community in the past? – JULIMINATION

    […] HUMANS WAS USED AS LAB MOUSES UNDER THE EMERGENCY SHILD […]

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