Nebulised Rt-PA for ARDS Due to COVID-19

Study Overview
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Brief Summary
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Some patients infected with COVID-19 require hospitalisation and develop patients a severe form of a lung disease called respiratory distress syndrome (ARDS). In these patients, the lungs become severely inflamed because of the virus. The inflammation causes fluid from nearby blood vessels to leak into the tiny air sacs in the lungs, making breathing increasingly difficult. This fluid forms small clots in the air sacs, creating a barrier until the cells regenerate. In some patients, this clot does not disappear in a timely fashion or interferes with the development of the new cells. Furthermore, the small clots in the air sacs obstruct the air and oxygen getting deep into the lungs, interfering with proper ventilation. The trial will recruit patients with COVID-19 induced ARDS. Eligible patients (or if patients lack capacity, their legal representative) will be provided with an information sheet and informed consent will be sought. Eligibility will be mainly assessed via routine clinical assessments. Patients will receive a nebulised version of a type of drug called tissue plasminogen activator (rt-PA) that is inhaled using a nebuliser. This is normally a drug used to break down blood clots. In this situation though, it might be useful for stopping clots forming in the lungs, because these might lead to even more difficulties with breathing. The study will run two cohorts sequentially. In cohort 1, 9 consented patients received nebulised rtPA in addition to SOC. 6 patients were receiving IMV and 3 were receiving non invasive support with NIV or CPAP or high flow oxygen or standard oxygen therapy. As an observational arm, matched historical controls who received standard of care were also recruited at a ratio of 2 controls to every 1 treatment arm patient, resulting in 18 historical controls. Originally, the study aimed to recruit 12 patients with 6 on each ventilation type (IMV and non-invasive oxygen support). This would have resulted in 24 historical controls. After the first wave of COVID-19 cases decreased in August 2020 in the UK it became difficult to continue recruitment, so recruitment closed for cohort 1. With a second surge underway in early 2021, cohort 2 will aim to recruit more patients during this period to provide more data on the safety of rtPA. Fewer timepoints will be collected, which will allow for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rtPA will be utilised. 30 patients will be recruited in total, with an aim to recruit a minimum of 10 IMV patients and 10 patients on non-invasive oxygen support. To evaluate efficacy, the improvement of oxygen levels over time and safety will be be monitored throughout. Blood samples will be taken to measure markers of clotting and inflammation in both groups. From the end of the treatment phase both groups will be followed up in accordance with SOC for 28 days from the day of first dose of rtPA.

Detailed Description
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This is a phase II, open label, single centre, uncontrolled, repeated dose, pilot trial of nebulised rt-PA in patients with COVID-19 ARDS. The study will recruit patients requiring either IMV or NIV. Eligible patients (or if patients lack capacity, their legal representative) will be provided with an information sheet and informed consent will be sought. Eligibility will be assessed via routine clinical assessments, which may have been done prior to consent. The only exceptions are a pregnancy test (blood or urine), and possibly any assessments that were not done as per routine care. These must be done following consent, and all screening assessments must have been done during the 24-hour period before dosing with rt-PA. The first 12 consented patients will receive nebulised rt-PA in addition to SOC. As an observational arm, matched historical controls who received standard of care were also recruited at a ratio of 2 controls to every 1 treatment arm patient, to ensure that any changes are not entirely due to disease resolution. In the treatment group, 6 patients will be receiving IMV and another six will be receiving NIV. This consituted cohort 1. For patients in the rt-PA group, 10 mg of rt-PA dissolved in 5 ml of diluent will be given every 6 hrs for 3 days (this was extended to 14 days with a subsequent amendment). Dose modifications will not be permitted. Efficacy will be assessed by the monitoring of arterial oxygen saturation. With a second surge underway in early 2021, cohort 2 will aim to recruit more patients during this period to provide more data on the safety of rtPA. Fewer timepoints will be collected, which will allow for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rtPA will be utilised. Patients on IMV will receive 60mg daily over three doses for 14 days, NIV patients will receive 60mg daily for over 3 doses for two days, followed by 12 days receiving 40mg daily over two doses. 30 patients will be recruited to cohort 2 in total, with an aim to recruit a minimum of 10 IMV patients and 10 patients on non-invasive oxygen support. Safety monitoring will be performed by assessment of the incidence and severity of bleeding events, and by the monitoring of plasma fibrinogen levels and routine coagulation parameters. Additional samples will be taken for exploratory assessment of potential biomarkers, including (but not restricted to) PAI- 1, alpha 2 antiplasmin and a range of inflammatory cytokines and coagulation proteins. All other monitoring will be done as per SOC. From the end of the treatment phase (after Day 14) patients will be followed up in accordance with SOC for 28 days from the day of first dose of rtPA. A statistically powered randomised controlled trial (RCT) would be ideal to define the magnitude of benefit and impact on overall survival and is the typical design in patients with ARDS. Although there is clinical data on the safety of nebulised rt-PA, but there is no clinical data in this clinical condition to facilitate a sample size calculation. There is data from a small RCT that has used another fibrinolytic agent, but the doses are not comparable. When a patient is randomised to receive no treatment, this precludes participation in other interventional studies which might decrease the risk of mortality. The most recent figures suggest a 50% mortality in patients receiving IMV there is 50% mortality. Currently there is a concerted effort to introduce multiple therapies based on our understanding of the pathophysiologic basis of disorder. Further, if this pilot study shows significant effect in a subset of patients, there would be justification to progress to a statistically powered RCT. In the event of major adverse drug reactions or minor improvement in the oxygenation as assessed by PaO2/FiO2 , there are minimal gains to be had with a larger randomised control study. Although there is extensive experience with the use of nebulised rt-PA in the context of the underlying inflammation, safety measures been included. A gap of 24hrs will be maintained between first and second patient. At 24hrs if patient 1 has no evidence of major pulmonary bleeding suggesting exaggerated alveolar fibrinolysis and no evidence of fibrinogen reduction of more than 50%, suggestive of systemic absorption a second patient will be dosed. Both patients will be evaluated for 72 hrs for major pulmonary bleeding and if no bleeding is noticed than the rest of the cohort can be recruited after the review of the safety data by the trial management group comprised of the investigators. If there are any concerns with the data this will be referred to the DMC for review. If the safety profile is acceptable, dosing of the third and subsequent patients in the rt-PA group will resume with no required interval between patients. Efficacy will be described as a relative improvement in PaO2/FiO2 (or SaO2/FiO2) ratio assessed at day 5 and day 7 after start of treatment. A Data Monitoring Committee (DMC) will be set-up to review safety data within the trial along with the final study results and advise on progressing from a pilot study to a randomised control trial based on the safety and efficacy data that is collected. The DMC will receive weekly reports on bleeding complications, both major and minor along with fibrinogen levels. If at any time a patient has major pulmonary bleeding, further dosing of patients will be stopped and an adhoc DMC review will be arranged before resuming dosing (see section 12.2 Data Monitoring Committee).

Official Title
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A Pilot, Open Label, Phase II Clinical Trial of Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA)

Conditions
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COVID

Intervention / Treatment
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* Drug: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1
* Drug: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 IMV
* Drug: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 NIV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (cohorts 1 and 2): Patients with COVID-19 confirmed by PCR ≥16 years and < 70 yrs Willing and able to provide written informed consent or where patient doesn't have capacity, consent obtained from a legal representative Patients on IMV must meet both the following criteria: PaO2/FiO2 of ≤ 300 (definition of ARDS) Intubated > 24 hrs but less than seven days Patients on NIV must meet all the following criteria: PaO2/FiO2 ≤ 300 or equivalent imputed by non-linear calculation from SpO2/FiO2 (see look-up table in appendices) In-patient >24 hours and being actively treated On non-invasive ventilator support with continuous positive airway pressure (CPAP) OR high flow oxygen (HFO >15L/min) with venturi or mask Exclusion Criteria (cohort 1): Females who are pregnant Patients receiving anticoagulation with therapeutic doses Concurrent involvement in another experimental investigational medicinal product Known allergies to the IMP or excipients of IMP A pre-existing bleeding disorder (e.g. severe haemophilia) Pre-existing severe cardiopulmonary disease (e.g. incurable lung cancer, severe chronic obstructive lung disease, cardiomyopathy, heart failure or impaired contractility <estimated 40% LVEF or RVEF ) Fibrinogen < 2.0 g/L at time of screening Patients considered inappropriate for critical care (prior decision re ceiling of care established) Patients with active bleeding in the preceding 7 days Patients who in the opinion of the investigator are not suitable Exclusion Criteria (cohort 2): Females who are pregnant Known allergies to the IMP or excipients of IMP Fibrinogen < 1.5 g/L at time of screening Patients considered inappropriate for active treatment (e.g. being considered for palliative care) Patients who in the opinion of the investigator are not suitable

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: phase II, open label, single centre, uncontrolled, repeated dose, pilot trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - cohort 1<br>For patients in the rt-PA group, 10 mg of rt-PA dissolved in 5 ml of diluent will be given every 6 hrs for 66 hrs, in addition to standard of care for COVID-19 acute respiratory distress syndrome (ARDS). 6 patients will be receiving Invasive mechanical ventilation and another six will be receiving Non Invasive ventilation. | Drug: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1<br>* Patients in the cohort 1 rt-PA group will receive the first dose as soon as possible after registration. 10mg rt-PA in 5mL diluent will be administered by nebulisation every 6 hours for 14 days, resulting in a total daily dose of 40mg.<br>|
| No Intervention: Historical matched controls - cohort 1<br>Matched historical controls who received standard of care were also recruited at a ratio of 2 controls to every 1 treatment arm patient. Matching will be done according to the following criteria in the order stated: Ventilation and oxygen type (IMV and non-invasive oxygen support) Severity as determined by PaO2/FiO2 ratio Gender Age (+/- 2 years, up to a maximum of 10 years) Ethnicity | |
| Experimental: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - cohort 2<br>In cohort 2, fewer timepoints will be collected, which will allow for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rtPA will be utilised. 30 patients will be recruited in total, with an aim to recruit a minimum of 10 IMV patients and 10 patients on non-invasive oxygen support. | Drug: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 IMV<br>* Patients on IMV will receive 60mg daily over three doses for 14 days<br>Drug: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 NIV<br>* NIV patients will receive 60mg daily for over 3 doses for two days, followed by 12 days receiving 40mg daily over two doses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| treatment efficacy - Change in PaO2/FiO2 ratio | Change in PaO2/FiO2 ratio from baseline (same day as start of treatment but prior to start of treatment), daily during treatment (14 days treatment), 3 days post end of treatment and 5 days post end of treatment. | across 19 days | 
| Safety as measured by bleeds | Incidence and severity of major bleeding events | 28 days | 
| Safety as measured by other (non-bleed related) adverse events | Incidence and severity of adverse events More than 1 treatment-emergent serious adverse event (SAE) during and up to 24 hours of the treatment | 28 days | 
| Safety as measured by fibrinogen levels | Decrease in fibrinogen levels over 72 hrs post initiation of treatment (>50%). | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in lung compliance (defined as tidal volume / (peak inspiratory pressure - PEEP)) | Changes in respiratory compliance from from baseline (same day as start of treatment but prior to start of treatment) and absolute values at day 5 (96 hrs ± 2 hrs), day 7 (144 hrs ± 4hrs), end of treatment, 3 and 5 days post end of treatment | across 19 days | 
| Clinical status as determined by a 7 point ordinal scale | Clinical status as assessed by a 7-point WHO ordinal scale at baseline and daily up to 5 days post end of treatment and at day 28, discharge or death (whichever comes first). Limitation of activities Hospitalized, no oxygen therapy Oxygen by mask or nasal prongs Non-invasive ventilation or high-flow oxygen Intubation and mechanical ventilation Ventilation+ additional organ support (vasopressor, RRT, ECMO) Death | 7 days | 
| Sequential Organ Failure Assessment (SOFA) score | Mean daily Sequential Organ Failure Assessment (SOFA) score at baseline through up to day 7 (done daily) | 7 days | 
| Follow up period - oxygen free days | Duration of oxygenation free days, up to 28 days or death or discharge, whichever occurs first. | 28 days | 
| Follow up period - ventilator free days | In follow up period, ventilator free days, up to 28 days or death or discharge, whichever occurs first. | 28 days | 
| Follow up period - intensive care stay | In follow up period, intensive care stay, up to 28 days or death or discharge, whichever occurs first. | 28 days | 
| New oxygen via ventilation use - incidence | Incidence of either new oxygen use via ventilation in the first 28 days. These include non-invasive ventilation or high flow oxygen devices | 28 days | 
| New oxygen via ventilation use - duration | Total duration of new oxygen use via ventilation in the first 28 days. These include non-invasive ventilation or high flow oxygen devices. | 28 days | 
| Incidence of new mechanical ventilation use | Incidence of new mechanical ventilation use during in the first 28 days | 28 days | 
| Duration of new mechanical ventilation use | Duration of new mechanical ventilation use during in the first 28 days | 28 days | 
| In hospital mortality | In hospital mortality | 28 days |