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

Sponsor

University of Milan (Other)

Overall Status

Completed

CT.gov ID

NCT04368377

Collaborator

Fondazione "Un Cuore per Milano" - a no profit foundation (Other)

Enrollment

Location

Arm

Actual Duration (Days)

Patients Per Site Per Month

Study Details

Study Description

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:

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.
acetylsalicylic acid 250 mg IV before starting tirofiban, and this will be continued at a dose of 75mg daily for 30 days.
a loading dose of clopidogrel 300 mg PO, followed by 75mg daily for 30 days
concurrent fondaparinux 2.5 mg s/c per day for the duration of the in hospital stay.

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.
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.

Study Design

Study Type:

Interventional

Actual Enrollment :

5 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Compassionate-use, proof of concept, interventional, prospective,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 :

Apr 6, 2020

Actual Primary Completion Date :

Apr 23, 2020

Actual Study Completion Date :

Apr 23, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tirofiban 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. 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. Patients will receive a loading dose of clopidogrel 300 mg PO, followed by 75 mg daily for 30 days 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 Names: 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 Names: Cardirene Drug: Fondaparinux Patients will receive concurrent fondaparinux 2.5mg s/c per day for the duration of the in hospital stay Other Names: Arixtra

Arm

Intervention/Treatment

Experimental: Tirofiban

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. 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. Patients will receive a loading dose of clopidogrel 300 mg PO, followed by 75 mg daily for 30 days 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 Names:

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 Names:

Cardirene

Drug: Fondaparinux

Patients will receive concurrent fondaparinux 2.5mg s/c per day for the duration of the in hospital stay

Other Names:

Arixtra

Outcome Measures

Primary Outcome Measures

P/F ratio [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
PaO2 difference [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
A-a O2 difference [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

CPAP duration [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)
In-hospital change in intensity of the respiratory support [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
PaCO2 difference [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
HCO3- difference [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
Lactate difference [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
Hb difference [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.
Plt difference [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.
Adverse effects [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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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