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

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ClinicalTrials.gov Identifier: NCT04356833
Recruitment Status : Recruiting
First Posted : April 22, 2020
Last Update Posted : April 6, 2021
Sponsor:
Information provided by (Responsible Party):
University College, London

Brief 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.


Condition or disease Intervention/treatment Phase
COVID Drug: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1 Drug: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 IMV Drug: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 NIV Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: phase II, open label, single centre, uncontrolled, repeated dose, pilot trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot, Open Label, Phase II Clinical Trial of Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA)
Actual Study Start Date : April 22, 2020
Estimated Primary Completion Date : April 30, 2021
Estimated Study Completion Date : April 30, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Alteplase

Arm Intervention/treatment
Experimental: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - 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 66 hrs, in addition to standard of care for COVID-19 acute respiratory distress syndrome (ARDS). 6 patients will be receiving Invasive mechanical ventilation and another six will be receiving Non Invasive ventilation.
Drug: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1
Patients in the cohort 1 rt-PA group will receive the first dose as soon as possible after registration. 10mg rt-PA in 5mL diluent will be administered by nebulisation every 6 hours for 14 days, resulting in a total daily dose of 40mg.

No Intervention: Historical matched controls - cohort 1

Matched historical controls who received standard of care were also recruited at a ratio of 2 controls to every 1 treatment arm patient. Matching will be done according to the following criteria in the order stated:

  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
Experimental: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - cohort 2
In cohort 2, 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.
Drug: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 IMV
Patients on IMV will receive 60mg daily over three doses for 14 days

Drug: nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 NIV
NIV patients will receive 60mg daily for over 3 doses for two days, followed by 12 days receiving 40mg daily over two doses.




Primary Outcome Measures :
  1. treatment efficacy - Change in PaO2/FiO2 ratio [ Time Frame: across 19 days ]
    Change in PaO2/FiO2 ratio from baseline (same day as start of treatment but prior to start of treatment), daily during treatment (14 days treatment), 3 days post end of treatment and 5 days post end of treatment.

  2. Safety as measured by bleeds [ Time Frame: 28 days ]
    Incidence and severity of major bleeding events

  3. Safety as measured by other (non-bleed related) adverse events [ Time Frame: 28 days ]

    Incidence and severity of adverse events

    More than 1 treatment-emergent serious adverse event (SAE) during and up to 24 hours of the treatment


  4. Safety as measured by fibrinogen levels [ Time Frame: 72 hours ]
    Decrease in fibrinogen levels over 72 hrs post initiation of treatment (>50%).


Secondary Outcome Measures :
  1. Changes in lung compliance (defined as tidal volume / (peak inspiratory pressure - PEEP)) [ Time Frame: across 19 days ]
    Changes in respiratory compliance from from baseline (same day as start of treatment but prior to start of treatment) and absolute values at day 5 (96 hrs ± 2 hrs), day 7 (144 hrs ± 4hrs), end of treatment, 3 and 5 days post end of treatment

  2. Clinical status as determined by a 7 point ordinal scale [ Time Frame: 7 days ]

    Clinical status as assessed by a 7-point WHO ordinal scale at baseline and daily up to 5 days post end of treatment and at day 28, discharge or death (whichever comes first).

    1. Limitation of activities
    2. Hospitalized, no oxygen therapy
    3. Oxygen by mask or nasal prongs
    4. Non-invasive ventilation or high-flow oxygen
    5. Intubation and mechanical ventilation
    6. Ventilation+ additional organ support (vasopressor, RRT, ECMO)
    7. Death

  3. Sequential Organ Failure Assessment (SOFA) score [ Time Frame: 7 days ]
    Mean daily Sequential Organ Failure Assessment (SOFA) score at baseline through up to day 7 (done daily)

  4. Follow up period - oxygen free days [ Time Frame: 28 days ]
    Duration of oxygenation free days, up to 28 days or death or discharge, whichever occurs first.

  5. Follow up period - ventilator free days [ Time Frame: 28 days ]
    In follow up period, ventilator free days, up to 28 days or death or discharge, whichever occurs first.

  6. Follow up period - intensive care stay [ Time Frame: 28 days ]
    In follow up period, intensive care stay, up to 28 days or death or discharge, whichever occurs first.

  7. New oxygen via ventilation use - incidence [ Time Frame: 28 days ]
    Incidence of either new oxygen use via ventilation in the first 28 days. These include non-invasive ventilation or high flow oxygen devices

  8. New oxygen via ventilation use - duration [ Time Frame: 28 days ]
    Total duration of new oxygen use via ventilation in the first 28 days. These include non-invasive ventilation or high flow oxygen devices.

  9. Incidence of new mechanical ventilation use [ Time Frame: 28 days ]
    Incidence of new mechanical ventilation use during in the first 28 days

  10. Duration of new mechanical ventilation use [ Time Frame: 28 days ]
    Duration of new mechanical ventilation use during in the first 28 days

  11. In hospital mortality [ Time Frame: 28 days ]
    In hospital mortality



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   16 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 contractility <estimated 40% LVEF or RVEF )
  7. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04356833


Contacts
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Contact: Mark Phillips 0208 016 8111 mark.phillips12@nhs.net

Locations
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United Kingdom
Barnet Hospital Completed
London, United Kingdom
The Royal Free Hospital Recruiting
London, United Kingdom
Contact: Mark Phillips         
Principal Investigator: Pratima Chowdary         
Sponsors and Collaborators
University College, London
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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT04356833    
Other Study ID Numbers: 132151
First Posted: April 22, 2020    Key Record Dates
Last Update Posted: April 6, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Plasminogen
Tissue Plasminogen Activator
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action