Clinical trial NCT04368377: Enhanced Platelet Inhibition in Critically Ill Patients With COVID-19
Official title: Platelet Inhibition With GP IIb/IIIa Inhibitor in Critically Ill Patients With Coronavirus Disease 2019 (COVID-19). A Compassionate Use Protocol
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pneumonia, Viral
Corona Virus Infection
Respiratory Failure
Embolism and Thrombosis
Keywords: Covid-19
Pneumonia
Respiratory failure
Platelet inhibition
GP IIb/IIIa inhibitor
Thrombosis
Platelet disfunction
Lead sponsor: University of Milan
Sponsor class: OTHER
Collaborators: name: Fondazione "Un Cuore per Milano" - a no profit foundation
First posted: 2020-04-29
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Compassionate-use, proof of concept, interventional, prospective,
Primary purpose: TREATMENT

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).

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.

Eligibility 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

Primary outcomes:
measure: P/F ratio
timeFrame: At baseline and 24, 48 and 168 hours after treatment initiation
measure: PaO2 difference
timeFrame: At baseline and 24, 48 and 168 hours after treatment initiation
measure: A-a O2 difference
timeFrame: At baseline and 24, 48 and 168 hours after treatment initiation
Secondary outcomes:
measure: CPAP duration
timeFrame: From the first day of study drugs administration (T0) until day 7 post study drugs administration
measure: In-hospital change in intensity of the respiratory support
timeFrame: At baseline and 72 and 168 hours after treatment initiation
measure: PaCO2 difference
timeFrame: At baseline and 24, 48 and 168 hours after treatment initiation
measure: HCO3- difference
timeFrame: At baseline and 24, 48 and 168 hours after treatment initiation
measure: Lactate difference
timeFrame: At baseline and 24, 48 and 168 hours after treatment initiation
measure: Hb difference
timeFrame: At baseline and 24, 48 and 168 hours after treatment initiation
measure: Plt difference
timeFrame: At baseline and 24, 48 and 168 hours after treatment initiation
measure: Adverse effects
timeFrame: From the first day of study drugs administration until day 30 post study drugs administration
Other outcomes:
Locations:
city: Milano
country: Italy
facility: L. Sacco Hospital
state: Lombardia
Study officials:
References:
citation: 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.
citation: 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.