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

Platelet Inhibition With GP IIb/IIIa Inhibitor in Critically Ill Patients With Coronavirus Disease 2019 (COVID-19). A Compassionate Use Protocol

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).

Study Overview

• Status: Completed
• Conditions: Pneumonia, Viral; Embolism and Thrombosis; Respiratory Failure; Corona Virus Infection
• Intervention / Treatment: Drug: Tirofiban Injection; Drug: Clopidogrel; Drug: Acetylsalicylic acid; Drug: Fondaparinux

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Lombardia
    • Milano, Lombardia, Italy, 20157
      • L. Sacco Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
P/F ratio	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	At baseline and 24, 48 and 168 hours after treatment initiation
PaO2 difference	Change in partial pressure of oxygen in arterial blood, measured by means of arterial blood gas analysis, at baseline and after study treatment	At baseline and 24, 48 and 168 hours after treatment initiation
A-a O2 difference	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.	At baseline and 24, 48 and 168 hours after treatment initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CPAP duration	Number of days on continuous positive end expiratory pressure (CPAP)	From the first day of study drugs administration (T0) until day 7 post study drugs administration
In-hospital change in intensity of the respiratory support	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	At baseline and 72 and 168 hours after treatment initiation
PaCO2 difference	Difference in partial pressure of carbon dioxide in arterial blood, measured by means of arterial blood gas analysis, at baseline and after study treatment	At baseline and 24, 48 and 168 hours after treatment initiation
HCO3- difference	Difference in concentration of bicarbonate in arterial blood, measured by means of arterial blood gas analysis, at baseline and after study treatment	At baseline and 24, 48 and 168 hours after treatment initiation
Lactate difference	Difference in concentration of lactate in arterial blood, measured by means of arterial blood gas analysis, at baseline and after study treatment	At baseline and 24, 48 and 168 hours after treatment initiation
Hb difference	Difference in hemoglobin concentration in blood samples, measured by means of blood chemistry test, at baseline and after study treatment.	At baseline and 24, 48 and 168 hours after treatment initiation
Plt difference	Difference in platelet concentration in blood samples, measured by means of blood chemistry test, at baseline and after study treatment.	At baseline and 24, 48 and 168 hours after treatment initiation
Adverse effects	Any major or minor adverse effect occuring during and after the administration of the study drug (e.g. bleeding)	From the first day of study drugs administration until day 30 post study drugs administration

Collaborators and Investigators

• Sponsor: University of Milan
• Collaborators: Fondazione "Un Cuore per Milano" - a no profit foundation

Publications and helpful links

General Publications

• Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.
• Flumignan RL, Tinoco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD013739. doi: 10.1002/14651858.CD013739.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 6, 2020
• Primary Completion (ACTUAL): April 23, 2020
• Study Completion (ACTUAL): April 23, 2020

Study Registration Dates

• First Submitted: April 23, 2020
• First Submitted That Met QC Criteria: April 28, 2020
• First Posted (ACTUAL): April 29, 2020

Study Record Updates

• Last Update Posted (ACTUAL): April 29, 2020
• Last Update Submitted That Met QC Criteria: April 28, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Pneumonia; Covid-19; Thrombosis; Respiratory failure; Platelet inhibition; GP IIb/IIIa inhibitor; Platelet disfunction
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; COVID-19; Coronavirus Infections; Embolism; Respiratory Insufficiency; Pneumonia; Thrombosis; Pneumonia, Viral; Embolism and Thrombosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Aspirin; Clopidogrel; Tirofiban; Fondaparinux; PENTA
• Other Study ID Numbers: 18275/2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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