Nebulised Rt-PA for ARDS Due to COVID-19

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).