Nebulised Rt-PA for ARDS Due to COVID-19 (PACA)

University College London (UCL)

Status and phase: Completed; Phase 2

Conditions: COVID

Treatments: Drug: Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 IMV; Drug: Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1; Drug: Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 NIV

Study type: Interventional

Funder types: Other

Identifiers

NCT04356833

132151

Details and patient eligibility

About

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.

Full 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.

Enrollment: 35 patients

Sex: All

Ages: 16 to 70 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria (cohorts 1 and 2):

1. Patients with COVID-19 (confirmed by PCR or radiologically)

2. ≥16 years

3. Willing and able to provide written informed consent or where patient doesn't have capacity, consent obtained from a legal representative

4. Patients on IMV must meet both the following criteria:

   1. PaO2/FiO2 of ≤ 300 (definition of ARDS)
   2. Intubated > 6 hrs

5. Patients not intubated must meet the following criteria:

   1. PaO2/FiO2 ≤ 300 or equivalent imputed by non-linear calculation from SpO2/FiO2 (see look-up table in appendices)
   2. In-patient >6 hours and being actively treated
   3. On support with non-invasive ventilation OR continuous positive airway pressure (CPAP) OR high flow OR standard oxygen therapy

Exclusion Criteria (cohort 1):

1. Females who are pregnant
2. Concurrent involvement in another experimental investigational medicinal product
3. Known allergies to the IMP or excipients of IMP
4. A pre-existing bleeding disorder (e.g. severe haemophilia) with no definitive treatment
5. 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)
6. Fibrinogen < 2.0 g/L at time of screening
7. Patients considered inappropriate for active treatment (e.g. being considered for palliative care)
8. Patients with active bleeding in the preceding 7 days
9. Patients who in the opinion of the investigator are not suitable

Exclusion Criteria (cohort 2):

1. Females who are pregnant
2. Known allergies to the IMP or excipients of IMP
3. Fibrinogen < 1.5 g/L at time of screening
4. Patients considered inappropriate for active treatment (e.g. being considered for palliative care)
5. Patients who in the opinion of the investigator are not suitable

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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35 participants in 4 patient groups

Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - cohort 1

Experimental group

Description:

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.

Treatment:

Drug: Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1

Historical matched controls - cohort 1

No Intervention group

Description:

Historical matched controls were recruited at a ratio of 2 controls to every 1 rtPA + SOC arm patient, and were matched according to the following characteristics: 1. Ventilation and oxygen type (IMV and non-invasive oxygen support) 2. Severity as determined by PaO2/FiO2 ratio 3. Gender 4. Age (+/- 2 years, up to a maximum of 10 years) 5. Ethnicity

Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - cohort 2 IMV

Experimental group

Description:

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

Treatment:

Drug: Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 IMV

Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - cohort 2 NIV

Experimental group

Description:

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.

Treatment:

Drug: Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 NIV