Nebulised Rt-PA for ARDS Due to COVID-19

NCT04356833 | Completed Phase 2 Results DMC

• 1 other identifier: 132151
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

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.

Conditions

COVID

Outcome Measures

Primary Outcomes (4)

• Efficacy - PaO2/FiO2 Ratio

  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.

  Day 14 and last value available on treatment (which could occur up to 14 days, death or discharge may have occurred within 14 days)

• Safety- Participants With Major Bleeding Events Directly Attributable to Study Drug

  Number of patients with major bleeding events assessed as related to the study drug summarised in each group.

  28 days

• Safety- Participants With Serious Adverse Events Causally Related to Treatment

  Number of Participants with serious adverse events causally related to treatment. Adverse events (other than bleeding events) were not recorded in the study.

  28 days

• Safety- Participants With Decrease in Fibrinogen Levels to < 1gm/L

  Number of participants with a decrease in fibrinogen levels to \< 1gm/L during the treatment period and 48 hours after the last dose.

  28 days

Secondary Outcomes (9)

• Lung Compliance

  Last value available on treatment (which could occur up to 14 days, death or discharge may have occurred within 14 days)

• Clinical Status as Determined by a 7-point WHO Ordinal Scale

  Day 28

• Sequential Organ Failure Assessment (SOFA) Score

  28 days (day 14 presented)

• Number of Oxygenation Free Days

  up to 28 days or death or discharge, whichever occurred first

• Number of Ventilator Free Days

  up to 28 days or death or discharge, whichever occured first

Study Arms (4)

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

EXPERIMENTAL

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.

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

Historical matched controls - cohort 1

NO INTERVENTION

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

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

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

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

EXPERIMENTAL

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.

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

Interventions

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

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.

Also known as: Cohort 1

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

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

Patients on IMV received 60mg daily over three doses for up to 14 days

Also known as: Cohort 2 IMV

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

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

NIV patients received 60mg daily over 3 doses for two days, followed by 12 days receiving 40mg daily over two doses.

Also known as: Cohort 2 NIV

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

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with COVID-19 (confirmed by PCR or radiologically)
• ≥16 years
• Willing and able to provide written informed consent or where patient doesn't have capacity, consent obtained from a legal representative
• Patients on IMV must meet both the following criteria:
• PaO2/FiO2 of ≤ 300 (definition of ARDS)
• Intubated \> 6 hrs
• Patients not intubated must meet the following criteria:
• PaO2/FiO2 ≤ 300 or equivalent imputed by non-linear calculation from SpO2/FiO2 (see look-up table in appendices)
• In-patient \>6 hours and being actively treated
• On support with non-invasive ventilation OR continuous positive airway pressure (CPAP) OR high flow OR standard oxygen therapy

You may not qualify if:

• Females who are pregnant
• Concurrent involvement in another experimental investigational medicinal product
• Known allergies to the IMP or excipients of IMP
• A pre-existing bleeding disorder (e.g. severe haemophilia) with no definitive treatment
• 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)
• Fibrinogen \< 2.0 g/L at time of screening
• Patients considered inappropriate for active treatment (e.g. being considered for palliative care)
• Patients with active bleeding in the preceding 7 days
• Patients who in the opinion of the investigator are not suitable
• Females who are pregnant
• Known allergies to the IMP or excipients of IMP
• Fibrinogen \< 1.5 g/L at time of screening
• Patients considered inappropriate for active treatment (e.g. being considered for palliative care)
• Patients who in the opinion of the investigator are not suitable

Sponsors & Collaborators

• University College, London: lead

Study Sites (1)

The Royal Free Hospital

London, NW3 2QG, United Kingdom

Location

Limitations and Caveats

Open label design with a small sample size, missing data and absence of a concurrent control group. A change in a patient's condition could result in an alteration in ventilation type post-enrolment, or in discharge. Furthermore, the P/F ratio was calculated by different methods: for those receiving NIRS, the P/F ratio was determined by converting SpO2 and oxygen flow rate, whereas the P/F ratio was readily available for IMV group.

Results Point of Contact

• Title: Professor Pratima Chowdary
• Organization: Royal Free London NHS Foundation Trust

p.chowdary@nhs.net

0207 794 0500

Study Officials

• Pratima Chowdary

  Royal Free London NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: phase II, open label, uncontrolled, repeated dose, pilot trial

Study Record Dates

• First Submitted: April 14, 2020
• First Posted: April 22, 2020
• Study Start: April 22, 2020
• Primary Completion: March 18, 2021
• Study Completion: March 18, 2021
• Last Updated: August 11, 2025
• Results First Posted: August 11, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)