Nebulised Rt-PA for ARDS Due to COVID-19

Phase 2

Completed

Conditions: COVID

Interventions: 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

Registration Number: NCT04356833

Lead Sponsor: University College, London

Brief Summary: Some patients infected with COVID-19 develop a severe form of a lung disease called acute 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. In some patients, these clots do not disappear in a timely fashion. Furthermore, the small clots in the air sacs obstruct the air and oxygen getting deep into the lungs, interfering with ventilation. The trial recruited patients with COVID-19 induced ARDS. Eligible patients (or if patients lack capacity, their legal representative) were provided with an information sheet and informed consent was sought. Eligibility was mainly assessed via routine clinical assessments. Patients received a nebulised version of a type of drug called tissue plasminogen activator (rt-PA) that was inhaled using a nebuliser. This is normally a drug used to break down blood clots. In the nebulised form, we hypothesised that it may be useful for stopping clots forming in the lungs. The study ran two cohorts sequentially. In cohort 1, 9 consented patients received nebulised rtPA in addition to SOC. As an observational arm, matched historical controls who received SOC were also recruited at a ratio of 2 controls to every 1 treatment arm patient, resulting in 18 historical controls. After the first wave of COVID-19 cases decreased in August 2020 in the UK, it became difficult to continue recruiting, so recruitment was closed for cohort 1. With a second surge in early 2021, cohort 2 opened with the aim to recruit more patients to provide more data on the safety of rt-PA. In cohort 2, fewer timepoints were collected, which allowed for more rapid recruitment without compromising safety monitoring. A more flexible dosing regimen for rtPA was utilised. 26 patients were recruited in total, 12 in the IMV arm and 14 in the NIV/NIRS arm. To evaluate drug efficacy, the improvement of oxygen levels over time and safety were monitored throughout. Blood samples were taken to measure markers of clotting and inflammation in both cohorts. From the end of the treatment phase, both groups were followed up in accordance with SOC up to a maximum of 28 days, starting from the day of first dose of rt-PA.

Detailed Description: This is a phase II, open label, uncontrolled, repeated dose, pilot trial of nebulised rt-PA in patients with COVID-19 ARDS.

The study recruited patients requiring either invasive mechanical ventilation (IMV) or non-invasive ventilation/non-invasive respiratory support (NIV/NIRS) between April 2020 and February 2021. Eligible patients (or if patients lacked capacity, their legal representative) were provided with an information sheet and informed consent was sought. Eligibility was assessed via routine clinical assessments, which may have been done prior to consent. The only exceptions were pregnancy tests (blood or urine), and possibly any assessments that were not done as per routine care. If required, these would have been done following consent, and all screening assessments must have been done during the 24-hour period before dosing with rt-PA.

In the rt-PA treatment group of cohort 1, 9 consented patients received nebulised rt-PA in addition to standard of care (SOC). Out of the 9 patients, 6 were on the IMV arm and another 3 were on the NIV arm. As an observational arm, matched historical controls who received only SOC were also recruited at a ratio of 2 controls to every 1 treatment arm patient, to ensure that any changes were not entirely due to disease resolution. A total of 18 patients were recruited to the historical matched control arm of cohort 1. Therefore a total of 27 patient constituted cohort 1.

For patients in the treatment group, 10 mg of rt-PA dissolved in 5 ml of diluent was given every 6 hrs for 3 days. This was extended to up to 14 days with a subsequent protocol amendment. Dose modifications were not permitted. Efficacy was described as the change in PaO2/FiO2 ratio from baseline, daily during treatment, end of treatment, 3 days post end of treatment and 5 days post end of treatment.

With a second surge of COVID-19 in early 2021, cohort 2 was opened to recruit more patients to provide additional data on the safety of rt-PA. Fewer timepoints were collected, which allowed for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rt-PA was utilised. Patients on IMV received 60mg daily over three doses for up to 14 days. NIV patients received 60mg daily over 3 doses for two days, followed by 40mg daily over two doses for up to 12 days. A total of 26 patients were recruited in cohort 2, 12 on the IMV arm and 14 on the NIV/NIRS arm.

From the end of the treatment phase (after Day 14), patients were followed up in accordance with SOC for 28 days from the day of first dose of rtPA.

Safety monitoring was 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 were 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 was done as per SOC.

A Data Monitoring Committee (DMC) was 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 was to be collected. If a patient had major pulmonary bleeding at any time, further dosing of patients was to be stopped and an ad-hoc DMC review to be arranged before resuming dosing (see section 12.2 Data Monitoring Committee).

Although there is extensive experience with the use of nebulised rt-PA in the context of the underlying inflammation, safety measures were included in the study. A gap of 24hrs was maintained between the first and second patient. At 24hrs, if patient 1 had no evidence of major pulmonary bleeding suggesting exaggerated alveolar fibrinolysis and no evidence of fibrinogen reduction of more than 50% (suggestive of systemic absorption), then the second patient was to be dosed. Both patients were evaluated for 72 hrs post dose for any major pulmonary bleeding and if no bleeding was noticed, then the rest of the cohort were to be recruited after the review of the safety data by the trial management group comprised of the investigators. Any concerns with the data were referred to the DMC for review. If the safety profile was acceptable, dosing of the third and subsequent patients in the rt-PA group would resume with no required interval between patients.

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, there is no 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 were 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. Currently there is a concerted effort to introduce multiple therapies based on our understanding of the pathophysiologic basis of the 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 35

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - cohort 1	Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1	Patients in the rt-PA group received the first dose as soon as possible after registration. Initial dosing regime: 10 mg of rt-PA dissolved in 5 ml of diluent given every 6 hrs (resulting in a total daily dose of 40mg) for a maximum of 66 hrs, in addition to standard of care for COVID-19 acute respiratory distress syndrome (ARDS). Following protocol amendment, dosing duration was increased from 3 days to up to 14 days of rt-PA treatment. Six patients were receiving Invasive mechanical ventilation and 3 were receiving non-invasive ventilation.
Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - cohort 2 IMV	Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 IMV	In cohort 2, fewer timepoints were collected, which allowed for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rtPA was utilised. Patients on IMV received 60mg daily over three doses for up to 14 days
Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - cohort 2 NIV	Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 NIV	n cohort 2, fewer timepoints were collected, which allowed for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rtPA was utilised. Patients on NIV received 60mg daily for over 3 doses for two days, followed by 12 days receiving 40mg daily over two doses.

Primary Outcome Measures

Name	Time	Method
Efficacy - PaO2/FiO2 Ratio	Day 14 and last value available on treatment (which could occur up to 14 days, death or discharge may have occurred within 14 days)	PaO2/FiO2 measured at multiple timepoints: baseline, during treatment, end of treatment, 3 days post end of treatment and 5 days post end of treatment. For Cohort 1, all available values were extracted per day and summarised every 4 hours (± 2h). For Cohort 2, up to six values were extracted per days including the worst ratio over the preceding day; Cohort 2 included only the lowest value for the day. PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure to fractional inspired oxygen. It is a widely used clinical indicator of hypoxaemia and is used to classify severity of acute respiratory distress syndrome. Limited data was observed due to patient discharge or death: Day 14 is presented below, and the last value available on treatment regardless of the duration of treatment (death or discharge may have occurred within 14 days) was summarised post-hoc. Summarized values were rounded to the nearest integer.
Safety- Participants With Major Bleeding Events Directly Attributable to Study Drug	28 days	Number of patients with major bleeding events assessed as related to the study drug summarised in each group.
Safety- Participants With Serious Adverse Events Causally Related to Treatment	28 days	Number of Participants with serious adverse events causally related to treatment. Adverse events (other than bleeding events) were not recorded in the study.
Safety- Participants With Decrease in Fibrinogen Levels to < 1gm/L	28 days	Number of participants with a decrease in fibrinogen levels to \< 1gm/L during the treatment period and 48 hours after the last dose.

Secondary Outcome Measures

Name	Time	Method
Clinical Status as Determined by a 7-point WHO Ordinal Scale	Day 28	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). 1. Limitation of activities 2. Hospitalized, no oxygen therapy 3. Oxygen by mask or nasal prongs 4. Non-invasive ventilation or high-flow oxygen 5. Intubation and mechanical ventilation 6. Ventilation+ additional organ support (vasopressor, RRT, ECMO) 7. Death
Number of Days of New Mechanical Ventilation Use During in the First 28 Days	28 days	incidence and number of days of new mechanical ventilation use during in the first 28 days was a secondary outcome measure as defined in the protocol.
Lung Compliance	Last value available on treatment (which could occur up to 14 days, death or discharge may have occurred within 14 days)	Changes in lung compliance (defined as tidal volume / (peak inspiratory pressure - PEEP) from baseline (same day as start of treatment but prior to start of treatment) was a secondary outcome as defined in the protocol. Limited data was observed due to patient discharge or death, therefore the last value available on treatment regardless of the duration of treatment (death or discharge may have occurred within 14 days) was summarised post-hoc and presented below. For cohort 2, the daily measurement coinciding with the worst PF ratio (as close as possible in date and time) was used for the summaries.
Sequential Organ Failure Assessment (SOFA) Score	28 days (day 14 presented)	The Sequential Organ Failure Assessment (SOFA) is a morbidity severity score and mortality estimation tool developed from a large sample of ICU patients throughout the world. The SOFA was designed to focus on organ dysfunction and morbidity, with less of an emphasis on mortality prediction. It requires the following (worst value within past 24 hours): FiO2, PaO2, Mechanical ventilation, Platelets, Bilirubin, Glasgow coma scale, Mean arterial pressure, Vasopressors, Creatinine, Urine output, and can be calculated by entering the results above into an online tool: https://clincalc.com/IcuMortality/SOFA.aspx. The SOFA Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems. A higher value for each organ system is associated with higher mortality, and here total score was used. The total possible score ranges from 0 to 24.
Number of Oxygenation Free Days	up to 28 days or death or discharge, whichever occurred first	Number of oxygen free days, up to 28 days or death or discharge, whichever occured first.
Number of Ventilator Free Days	up to 28 days or death or discharge, whichever occured first	Number of ventilator free days, up to 28 days or death or discharge, whichever occured first
Intensive Care Stay	28 days	Intensive care stay, up to 28 days or death or discharge, whichever occurs first, was a secondary outcome as defined in the protocol. However, due to protocol amendments, difficulties in collecting this data, differences in study design between cohort 1 and cohort 2 and limited comparability of this outcome measure between groups, results are presented but have limited interpretation and should not be used or compared. For cohort 1, the number of days in ICU were limited to the 1st admission.
Number of Days of Non-invasive Ventilation Use	Day 28	Number of days of new oxygen use, non-invasive ventilation or high flow oxygen devices
In-hospital Mortality	28 days	In-hospital mortality.

Trial Locations

Locations (1): The Royal Free Hospital
🇬🇧
London, United Kingdom
The Royal Free Hospital
🇬🇧London, United Kingdom
Mark Phillips
Contact
Pratima Chowdary
Principal Investigator