Nebulised Rt-PA for ARDS Due to COVID-19

• Status: Recruiting
• Trial end date: 2021-04-30
• Target enrollment: 0
• Participant gender: All

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.

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University College, London
• Treatments: Plasminogen; Tissue Plasminogen Activator

Criteria

Inclusion Criteria (cohorts 1 and 2):

1. Patients with COVID-19 confirmed by PCR

2. ≥16 years and < 70 yrs

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 > 24 hrs but less than seven days

5. Patients on NIV must meet all 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 >24 hours and being actively treated

3. 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):

1. Females who are pregnant

2. Patients receiving anticoagulation with therapeutic doses

3. Concurrent involvement in another experimental investigational medicinal product

4. Known allergies to the IMP or excipients of IMP

5. A pre-existing bleeding disorder (e.g. severe haemophilia)

6. Pre-existing severe cardiopulmonary disease (e.g. incurable lung cancer, severe chronic obstructive lung disease, cardiomyopathy, heart failure or impaired contractility7. Fibrinogen < 2.0 g/L at time of screening

8. Patients considered inappropriate for critical care (prior decision re ceiling of care established)

9. Patients with active bleeding in the preceding 7 days

10. 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