Nebulised rt-PA for ARDS due to COVID-19 – The PACA trial [COVID-19]
Research type
Research Study
Full title
A pilot, open label, phase II clinical trial of nebulised recombinant tissue-Plasminogen Activator (rt-PA)in patients with COVID-19 ARDS: The Plasminogen Activator COVID-19 ARDS (PACA) trial\n\n
IRAS ID
282600
Contact name
Pratima Chowdary
Contact email
Sponsor organisation
University College London
Eudract number
2020-001640-26
Clinicaltrials.gov Identifier
Duration of Study in the UK
0 years, 9 months, 0 days
Research summary
Research Summary
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. We believe that 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.\nThe 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.\n\nWe propose to use 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.\n \nThe first 12 consented patients will receive nebulised rt-PA in addition to standard of care (SOC). The second group of 12 patients will receive SOC alone as a comparison. \nWe will look at the improvement of oxygen levels over time and safety will be be monitored throughout. We will also take blood samples to measure markers of clotting and inflammation in both groups. \n\nFrom the end of the treatment phase (after Day 3) both groups will be followed up in accordance with SOC.\n
Summary of Results
The purpose of this study was to see if giving a drug called recombinant tissue plasminogen activator (rtPA) a clot busting agent could improve people’s health when they have a condition known as acute respiratory distress syndrome (ARDS) caused by COVID19 infection. It was hoped rtPA (the study drug) could help the lungs recover quicker by attempting to break down the clots that can form in the air pockets of the lungs when people have COVID19 ARDS. These clots decrease the capacity of these air pockets for air and also slow the transfer of oxygen from air to blood across lining of the air pockets. We tested rtPA because it is a type of drug called a 'thrombolytic' agent or clot-busting drug, which means it breaks down blood clots in the blood vessels and outside of the blood vessels.
The study drug is normally given by injection into the bloodstream to dissolve the clot in the blood vessels, for example following a stroke or acute heart attack. However, when given in this way, the study drug has a risk of bleeding and may not get into the lung lining. So in this study we gave the drug in ‘nebulised’ form meaning it was inhaled directly into the lungs as the clots without red cells are now forming in the air pockets.
We gave the study drug, alongside the best current care, to see if it improved oxygen levels in the blood and ultimately improved survival of patients with severe COVID 19 infection. The other purpose of the study was to test if the study drug was safe and tolerated by people with severe COVID-19. To do this we monitored patients’ oxygen saturation (levels of oxygen in their blood) did blood tests and assessed any symptoms or problems they had during the study, including any bleeding events.Patients who took part in the study were those who were hospitalised because they developed a severe form of a lung disease called acute respiratory distress syndrome (ARDS) caused by COVID19 infection. These patients needed oxygen support, and some required the help of ventilators, i.e. machines that help with breathing and oxygenation.
The total daily dose in Cohort 1 was 40 mg (10 mg four times a day). In Cohort 2 the total daily dose was dependent on the type of ventilatory support the patients were on – those patients on invasive mechanical ventilation received a total daily dose of 60 mg (20 mg three times a day); those patients on non-invasive oxygen support were given a total dose of 60 mg for the first 2 days and then 40 mg (20 mg twice a day) for the remaining dosing days. Cohort 1 initially received study drug for up to three days. Following an amendment, from the sixth patient onwards, treatment up to a maximum of 14 days was allowed. Cohort 2 received study drug for up to 14 days.
Recruitment for the first study group (C1) took place over 14 weeks from 23rd April to 30th July 2020, during the first COVID-19 surge in the UK, with 9 patients being recruited to receive the study drug together with standard of care (SOC). We also recruited 18 control patients with COVID19 who were matched to the study patients by age, ventilation and oxygen type, severity of disease, gender, and ethnicity. This recruitment of matched historical controls (MHC) was done retrospectively in October 2020 through review of medical records. The recruitment of these control patients was to help us find out if any improvements seen in the trial patients was due to the study drug.
Recruitment for the second study group (C2) took place over four weeks between 21st January and 19th February 2021 with 26 patients recruited. As with cohort 1, all patients in cohort 2 received the study drug in addition to standard of care (SOC) treatment. The cohorts were divided into treatment arms, depending on the way the patients were receiving supplementary oxygen. Patients in the most severe conditions were intubated and were given oxygen in the form of invasive mechanical ventilation (IMV). Patients receiving non-invasive respiratory support (NIRS), or non-invasive ventilation (NIV) were given oxygen in several forms as clinically indicated. These included continuous positive airway pressure (CPAP), high flow nasal oxygen (HFNO) or conventional oxygen therapy using venturi or non-breathing masks. After receiving the first dose of the study drug, patients were followed until the end of study (EOS). EOS for both cohorts was day 28, or earlier in the event of death of discharge from the hospital.
The efficacy of the study drug was measured by recording the change in a ratio called the PaO2/FiO2 (P/F) ratio, where a ratio of less than 300 mmHg was indicative of ARDS.
In C1, a total of 27 patients were recruited; 9 patients received the study drug with SOC and 18 patients were recruited as MHC, receiving SOC only. In the study drug group, 6 patients were received IMV and 3 patients received NIRS. The P/F ratio increased during the 28-day study period in both the rt-PA and MHC groups, however, a higher mean P/F ratio of 50.6 was observed in the rt-PA group compared to the MHC group. Seven bleeding events occurred among four patients receiving rt-PA treatment, however, all bleeds were deemed unrelated to the treatment. The MHC group were not reviewed for bleeding events.
In C2, all 26 patients recruited received study drug with SOC; 12 were receiving IMV and 14 were receiving NIRS. In the IMV arm, the mean (SD) P/F ratio was 120 (28) the day before the first dose of rt-PA, a small increase in P/F ratio was seen for most patients by their last day of treatment, with a mean (SD) difference from baseline of 48 (126). In patients receiving NIRS, the mean (SD) P/F ratio was 126 (42) the day before the first dose of rt-PA, and an increase was seen for most patients by their last day of treatment, with a mean change (SD) of 114 (92). In total, 25 bleeding events were reported; 17 in the IMV group, and 8 in the NIRS group. These bleeds were reported as adverse events of special interest (AESI) and categorised as 18 mild, 5 moderate and 2 severe. Of these, 4 bleeding events in 3 patients were considered potentially related to the rt-PA treatment, with 1 being categorised as a severe AE and the other 3 as mild.
Patients were assessed for recovery using a WHO performance scale relating to activity levels. Recovery was defined as achieving a WHO ordinal score of ≤2 or discharge. Data for patients who did not recover or died were censored at Day 28. In C1, patients receiving rt-PA had a more rapid recovery compared to MHC patients. In C2, NIRS patients recovered more rapidly than IMV patients.
This study was the first clinical trial investigating the use of nebulised rt-PA (the study drug) in patients with COVID-19-related ARDS. The results of this pilot study using nebulised rt-PA demonstrated a favourable safety profile with no excess bleeding, even in patients receiving therapeutic anticoagulation. There were some bleeding events considered related to the study drug, but none serious. No patients had clinically significant decreases in levels of fibrinogen in their blood suggesting minimal absorption of the study drug into the bloodstream. There was some evidence of an improvement in respiratory efficiency as demonstrated by higher levels of oxygen in the blood, suggesting efficacy of the study drug. Whilst a statistically significant change was demonstrated in cohort 1 compared to controls, the small sample size means these results need to be seen as hypothesis-generating rather than confirmatory of treatment outcome.
Limitations of the study include its open label design (with no placebo) with a small sample size, missing data, and absence of a concurrent control group.Considering the findings, it would be worthwhile to investigate nebulised rt-PA in a larger randomised controlled trial so that the direct clinical impact of the therapy, such as the need for oxygen support, mechanical ventilation, requirement for admission to intensive care unit, and death rate could be rigorously evaluated. This intervention could be of value in older adults who are not ideal candidates for invasive ventilation.
REC name
South Central - Hampshire A Research Ethics Committee
REC reference
20/SC/0187
Date of REC Opinion
16 Apr 2020
REC opinion
Favourable Opinion