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Enhanced Platelet Inhibition in Critically Ill Patients With COVID-19 (PIC-19)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04368377
Recruitment Status : Completed
First Posted : April 29, 2020
Last Update Posted : April 29, 2020
Sponsor:
Collaborator:
Fondazione "Un Cuore per Milano" - a no profit foundation
Information provided by (Responsible Party):
Pierachille Santus, MD, PhD, University of Milan

Brief Summary:
This is a compassionate use, proof of concept, phase IIb, prospective, interventional, pilot study in which the investigators will evaluate the effects of compassionate-use treatment with IV tirofiban 25 mcg/kg, associated with acetylsalicylic acid IV, clopidogrel PO and fondaparinux 2.5 mg s/c, in patients affected by severe respiratory failure in Covid-19 associated pneumonia who underwent treatment with continuous positive airway pressure (CPAP).

Condition or disease Intervention/treatment Phase
Pneumonia, Viral Corona Virus Infection Respiratory Failure Embolism and Thrombosis Drug: Tirofiban Injection Drug: Clopidogrel Drug: Acetylsalicylic acid Drug: Fondaparinux Phase 2

Detailed Description:

It is a investigator-initiated, compassionate use, prospective, phase 2b, non randomized, open-label, proof of concept study in which the investigators will evaluate the effects of compassionate-use treatment with IV tirofiban, associated with acetylsalicylic acid PO, clopidogrel PO and fondaparinux 2.5 mg s/c, in patients affected by severe respiratory failure in Covid-19 associated pneumonia who underwent treatment with continuous positive airway pressure (CPAP).

Patients will be treated with:

  1. 25 microgram per kilogram of body weight tirofiban as bolus IV injection (3 minutes) followed by continuous infusion at a rate of 0,15 microgram/kg/minute for 48 hours.
  2. acetylsalicylic acid 250 mg IV before starting tirofiban, and this will be continued at a dose of 75mg daily for 30 days.
  3. a loading dose of clopidogrel 300 mg PO, followed by 75mg daily for 30 days
  4. concurrent fondaparinux 2.5 mg s/c per day for the duration of the in hospital stay.

1) Demographics, body mass index, comorbidities, SOFA score, APACHE II score, Glasgow Coma Scale will be assessed the day the patient is admitted to the IRCU.

2) Blood gas analysis parameters (PaO2, PaCO2, HCO3-, lactates, SaO2, pH), Alveolar-arterial gradient, P/F ratio, respiratory rate, arterial blood pressure, heart rate and Chest X ray or Chest CT scan will be collected at admittance following the standard operating procedures of the IRCU for COVID-19 patients. The same measurement as detailed in 2) will be repeated 1 hour before and 1, 24, 48 and 168 hours after the loading bolus of tirofiban.

Moreover, at admittance, participating patients will undergo a complete blood count, serum dosage of: creatinine, blood urea nitrogen (BUN), procalcitonin, c-reactive protein, Prothrombin Time (PT), Partial Thromboplastin Time (PTT), D-Dimer, fibrinogen, bilirubin, lactate dehydrogenase (LDH), aspartate transaminase (AST). The same assessment will be repeated the same morning and 24, 48 and 168 hours after the loading dose of tirofiban.

During hospital stay patients will receive continuous vital sign monitoring including: electrocardiogram tracing, blood arterial pressure, peripheral oxygen saturation and heart rate. Neurological status, signs of active bleeding or the occurrence of adverse effects will be monitored during the whole hospital stay.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Compassionate-use, proof of concept, interventional, prospective,
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Platelet Inhibition With GP IIb/IIIa Inhibitor in Critically Ill Patients With Coronavirus Disease 2019 (COVID-19). A Compassionate Use Protocol
Actual Study Start Date : April 6, 2020
Actual Primary Completion Date : April 23, 2020
Actual Study Completion Date : April 23, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Tirofiban
  1. Patients will receive 25 microgram per kilogram of body weight tirofiban as bolus IV injection (3 minutes) followed by continuous infusion at a rate of 0.15 microgram/kg/minute for 48 hours.
  2. Patients will receive acetylsalicylic acid 250 mg IV before starting tirofiban, and this will be continued at a dose of 75 mg daily for 30 days.
  3. Patients will receive a loading dose of clopidogrel 300 mg PO, followed by 75 mg daily for 30 days
  4. Patents will receive concurrent fondaparinux 2.5 mg s/c per day for the duration of the hospital stay
Drug: Tirofiban Injection
Patients will receive 25 microgram per kilogram of body weight tirofiban as bolus IV injection (3 minutes) followed by continuous infusion at a rate of 0,15 microgram/kg//minute for 48 hours.
Other Names:
  • Ibisqus
  • Agrastat

Drug: Clopidogrel
Patients will receive a loading dose of clopidogrel 300 mg PO, followed by 75mg daily for 30 days
Other Name: Plavix

Drug: Acetylsalicylic acid
Patients will receive acetylsalicylic acid 250 mg IV before starting tirofiban, and this will be continued at a dose of 75mg daily for 30 days.
Other Name: Cardirene

Drug: Fondaparinux
Patients will receive concurrent fondaparinux 2.5mg s/c per day for the duration of the in hospital stay
Other Name: Arixtra




Primary Outcome Measures :
  1. P/F ratio [ Time Frame: At baseline and 24, 48 and 168 hours after treatment initiation ]
    Change in ratio between partial pressure of oxygen in arterial blood, measured by means of arterial blood gas analysis, and inspired oxygen fraction at baseline and after study treatment

  2. PaO2 difference [ Time Frame: At baseline and 24, 48 and 168 hours after treatment initiation ]
    Change in partial pressure of oxygen in arterial blood, measured by means of arterial blood gas analysis, at baseline and after study treatment

  3. A-a O2 difference [ Time Frame: At baseline and 24, 48 and 168 hours after treatment initiation ]
    Change in alveolar-arterial gradient of oxygen at baseline and after study treatment. Arterial alveolar gradient will be calculated using the following parameters derived from arterial blood gas analysis: partial pressure of oxygen in arterial blood and partial pressure of carbon dioxide in arterial blood.


Secondary Outcome Measures :
  1. CPAP duration [ Time Frame: From the first day of study drugs administration (T0) until day 7 post study drugs administration ]
    Number of days on continuous positive end expiratory pressure (CPAP)

  2. In-hospital change in intensity of the respiratory support [ Time Frame: At baseline and 72 and 168 hours after treatment initiation ]
    Difference in intensity of the respiratory support (non invasive mechanical ventilation, CPAP, high flow nasal cannula (HFNC), Venturi Mask, nasal cannula, from higher to lower intensity, respectively) employed at baseline and at 72 and 168 hours after study treatment initiation

  3. PaCO2 difference [ Time Frame: At baseline and 24, 48 and 168 hours after treatment initiation ]
    Difference in partial pressure of carbon dioxide in arterial blood, measured by means of arterial blood gas analysis, at baseline and after study treatment

  4. HCO3- difference [ Time Frame: At baseline and 24, 48 and 168 hours after treatment initiation ]
    Difference in concentration of bicarbonate in arterial blood, measured by means of arterial blood gas analysis, at baseline and after study treatment

  5. Lactate difference [ Time Frame: At baseline and 24, 48 and 168 hours after treatment initiation ]
    Difference in concentration of lactate in arterial blood, measured by means of arterial blood gas analysis, at baseline and after study treatment

  6. Hb difference [ Time Frame: At baseline and 24, 48 and 168 hours after treatment initiation ]
    Difference in hemoglobin concentration in blood samples, measured by means of blood chemistry test, at baseline and after study treatment.

  7. Plt difference [ Time Frame: At baseline and 24, 48 and 168 hours after treatment initiation ]
    Difference in platelet concentration in blood samples, measured by means of blood chemistry test, at baseline and after study treatment.

  8. Adverse effects [ Time Frame: From the first day of study drugs administration until day 30 post study drugs administration ]
    Any major or minor adverse effect occuring during and after the administration of the study drug (e.g. bleeding)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Laboratory-confirmed SARS-CoV-2-related pneumonia, defined as positive nasal swab for SARS-CoV-2 infection or positive IgM serum title. A laboratory confirmed diagnosis must be associated with a clinically confirmed COVID-19 pneumonia, with a history of fever ≥ 3 days and multiple pulmonary infiltrates at the chest X-Ray
  • Acute de novo severe hypoxic respiratory failure, defined by means of arterial blood gas analysis performed in room air showing severe hypoxemia with an arterial partial pressure of oxygen (PaO2) to fraction of inspired oxygen (FiO2) ratio < 250 (according to the Berlin 2012 acute respiratory distress syndrome - ARDS - definition), requiring CPAP respiratory support
  • D-Dimer value ≥ 3 times the upper level of normal of the laboratory

Exclusion Criteria:

  • Ongoing bleeding or bleeding diathesis, contraindications for anticoagulation or increased bleeding risk or history of bleeding in the last eight weeks
  • Previous stroke or transient ischemic attack or any intracranial pathology in the last six months, major surgery or trauma within the previous six weeks
  • Laboratory confirmed Laboratory confirmed Glucose 6-Phosphate Dehydrogenase (G6PDH) deficiency.
  • Confirmed or suspected pregnancy or patients in childbearing age.
  • Previous known adverse effects or intolerance to the study drugs
  • Ongoing septic shock. Septic shock will be defined as the concomitant presence of sepsis (life-threatening organ dysfunction caused by a dysregulated host response to infection with a Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more) and need for vasopressors to maintain a mean arterial pressure of 65 mm Hg or greater and a serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia.
  • Need for surgery during hospitalization
  • Elevated risk of in hospital fall
  • Glasgow Coma Scale <15
  • Confirmed diagnosis of dementia or mental disability that jeopardizes the comprehension of the study protocol
  • Inability to sign the informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04368377


Locations
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Italy
L. Sacco Hospital
Milano, Lombardia, Italy, 20157
Sponsors and Collaborators
University of Milan
Fondazione "Un Cuore per Milano" - a no profit foundation
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Responsible Party: Pierachille Santus, MD, PhD, Professor of Respiratory Medicine, University of Milan
ClinicalTrials.gov Identifier: NCT04368377    
Other Study ID Numbers: 18275/2020
First Posted: April 29, 2020    Key Record Dates
Last Update Posted: April 29, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Pierachille Santus, MD, PhD, University of Milan:
Covid-19
Pneumonia
Respiratory failure
Platelet inhibition
GP IIb/IIIa inhibitor
Thrombosis
Platelet disfunction
Additional relevant MeSH terms:
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Coronavirus Infections
Severe Acute Respiratory Syndrome
Pneumonia, Viral
Pneumonia
Respiratory Insufficiency
Thrombosis
Embolism
Embolism and Thrombosis
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Vascular Diseases
Cardiovascular Diseases
Respiration Disorders
Virus Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Aspirin
PENTA
Tirofiban
Fondaparinux
Clopidogrel
Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action