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Safety of Nebulized Combination Therapy BromAc® in COVID-19 Respiratory Disease

Primary Purpose

COVID-19 Pneumonia, COVID-19, Ventilator Associated Pneumonia

Status
Not yet recruiting
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Bromelains
Acetylcysteine
Sponsored by
Mucpharm Pty Ltd
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID-19 Pneumonia focused on measuring mucolytic, COVID-19, COVID-19 pneumonia, Ventilator associated pneumonia, Secondary bacterial infections

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Aged 18 years to 75 years old
  • Admitted to hospital for management of COVID-19 with moderate or severe disease
  • Positive testing by virologic test (i.e. SARS-CoV-2 based qRT-PCR)
  • Clinical signs suggestive of moderate or severe disease such as oxygen saturation (SpO2) less than 93% on room air or where the participant requires oxygen support such as nasal cannulas, mask, non-rebreather mask, high flow nasal cannulas

Exclusion Criteria:

  • Patients that have critical disease and are mechanically ventilated
  • Undergoing other airway administered mucolytic therapy for e.g. dornase alfa within 24 hours, or are enrolled in another clinical trial for COVID-19
  • Have known allergy, anaphylaxis or intolerance to pineapples, papain, bromeliads, sulphur, eggs or Acetylcysteine or any other serious allergy or intolerance to fruits or food products or any other serious allergy or allergen triggered asthma, such as dust or pollen
  • Have other serious comorbidities where inclusion in the trial will subject the participant to a higher risk of adverse events, including participants with asthma (existing severe lung disease such as COPD, bronchiectasis and cystic fibrosis are not exclusion criteria)
  • Pregnant women are excluded from this study because BromAc has unknown but a potential risk for adverse events in nursing infants secondary to treatment of the mother
  • Participants with psychiatric illness/social situations that would limit compliance with study requirements.
  • Are unable to give fully informed and educated consent or are unable to comply with the standard follow up procedures of a clinical trial

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    BromAc

    Arm Description

    BromAc (Bromelain and Acetylcysteine combination) will be administered three times (3x) per day for five (5) days in a dose escalation format via inhalation using an approved vibrating mesh nebuliser (Aerogen Pro). Dose escalation concentration levels are BromAc 125ug/20mg/ml, 250ug/20mg/ml, 375ug/20mg/ml. All levels will receive 5ml of BromAc.

    Outcomes

    Primary Outcome Measures

    Evaluate the treatment-emergent adverse events (AEs) of BromAc therapy following nebulised delivery
    The safety and tolerability of BromAc will be assessed by characterising the symptoms or side effects of treatment (treatment-emergent adverse events) by the Common Toxicity Criteria for Adverse Events (CTCAE) v4.0

    Secondary Outcome Measures

    Proportion of participants that proceed to invasive ventilation for deterioration of COVID-19 (need for mechanical ventilation)
    To assess the proportion of patients following commencement of BromAc that proceed to mechanical ventilation for COVID-19
    World Health Organisation (WHO) modified ordinal scale clinical score
    Determine the clinical score by improvement or deterioration based on World Health Organisation Modified Ordinal Scale for COVID-19 over 28-days
    Improvement or deterioration in oxygenation
    Assess the improvement or deterioration in percentage of oxygen saturation (SpO2) whilst hospitalised vs the fraction of inspired oxygen (SpO2/FiO2 ratio)
    All-cause mortality
    Determine the all-cause mortality of patients enrolled over 28 days
    Dose related toxicities
    Determine the tolerated dose of BromAc within the therapeutic range for COVID-19 sputum mucolysis delivered by nebuliser
    Treatment-emergent serious adverse events (SAEs)
    Assess the proportion of participants with treatment-emergent serious adverse events (SAEs) by Common Toxicity Criteria for Adverse Events (CTCAE) v4.0

    Full Information

    First Posted
    February 22, 2022
    Last Updated
    February 25, 2022
    Sponsor
    Mucpharm Pty Ltd
    Collaborators
    St George Hospital, Australia
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05258682
    Brief Title
    Safety of Nebulized Combination Therapy BromAc® in COVID-19 Respiratory Disease
    Official Title
    Safety of Nebulized Combination Therapy BromAc® in COVID-19 Respiratory Disease: a Phase 1 Study
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    February 2022
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    May 1, 2022 (Anticipated)
    Primary Completion Date
    September 30, 2022 (Anticipated)
    Study Completion Date
    October 30, 2022 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Mucpharm Pty Ltd
    Collaborators
    St George Hospital, Australia

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    COVID-19 has multiple facets including cytokine storm, thromboembolism and gelatinous secretions. It is known that oxygen exchange is the main problem in patients with COVID-19 and hypoxia is one of the most serious, in which patients succumb to acute respiratory distress syndrome (ARDS). In other severe respiratory disease such as ventilator associated pneumonia (VAP), formation of biofilm in the endotracheal tube causes infection to spread to the lungs, resulting in respiratory decline and high mortality. The development of gelatinous sputum plugs correlates with negative outcome. Both groups of patients still have limited therapy options. BromAc is a potent mucolytic, biofilm degrader, cleaves the glycoproteins of the SARS-CoV-2 virus (antiviral), and down regulates cytokines and chemokine in COVID-19 sputum. The investigators seek to examine the safety and attempt to gain preliminary efficacy of nebulised BromAc in moderate to severe COVID-19 and other mucus producing, severe, respiratory diseases.
    Detailed Description
    It is well known that oxygen exchange is a major problem in patients with COVID-19 and hypoxia is one of the most serious effects, where patients succumb from acute respiratory distress syndrome (ARDS). The development of mucinous sputum plugs in individuals infected with SARS-CoV-2 is variable in the early stages of the disease. In addition, 30-40% of patients who are in hospital have expectoration production, and in a recent study on pulmonary pathology in patients with COVID-19, subsequent tests revealed markedly increased levels of MUC1 and MUC5AC in sputum and tracheal aspirates. Currently, there are few therapeutic agents of limited efficacy to treat or avoid the complications of COVID-19 and none directed against airway mucus. An Australian pharmaceutical company has developed BromAc for the palliative treatment of highly mucinous tumors of the appendix and lung. This drug is composed of bromelain and acetylcysteine. During pre-clinical development, the sponsor found that BromAc® rapidly dissolved and removed tumour mucin, making it a potent mucolytic. BromAc® in combination have the ability, as shown in pre-clinical studies, to remove the mucin protective framework expressed by cancer including MUC1, MUC2, MUC4, MUC5AC and MUC16. The sponsor has shown the mechanism of action of BromAc - to break peptide and glycosidic linkages and disulphide bonds in tumour produced and respiratory mucin. In an in vitro study by the sponsor with Vero and CALU-3 cells infected by SARS-CoV-2 (MOI 1 to -4) and treated with BromAc, it was found that the drug was able to reduce the virus's ability to infect cells, demonstrating an antiviral potential for SARS-CoV-2, with 99.99% reduction in viral infectivity at low concentrations. In addition to the anti-viral effect, BromAc is a potent mucolytic. In laboratory studies, BromAc (125ug or 250ug/ml plus 20mg/ml Acetylcysteine) resulted in complete dissolution of severe COVID-19 sputum after a single application within 30 minutes. BromAc significantly down-regulated cytokines and chemokines in comparison to Acetylcysteine alone or control, specifically those important to COVID-19 cytokine storm CCL2, CCL3, IL-6, CXCL10. In vivo safety models in two species have received nebulised and intranasal BromAc up to 500ug/20mg/ml three times daily for five days, with no evidence of respiratory or systemic toxicity clinically or on histology. This project will evaluate the mucolytic and anti-inflammatory effect of BromAc in patients with moderate to severe COVID-19 that are not on mechanical ventilation. The investigators believe that BromAc may have a role clinically in removing the proteinaceous material from the bronchi and alveoli allowing improved ventilation, gas exchange and transfer and aim to study whether this is a potential treatment for these patients. This therapy if safe may reduce the need for ventilation or improve the outcome of ventilation (reduced pressure, faster time to extubation, reduced secondary lung injury, reduced deaths), which will be assessed in future studies.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    COVID-19 Pneumonia, COVID-19, Ventilator Associated Pneumonia, COVID-19 Acute Respiratory Distress Syndrome
    Keywords
    mucolytic, COVID-19, COVID-19 pneumonia, Ventilator associated pneumonia, Secondary bacterial infections

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1, Phase 2
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    30 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    BromAc
    Arm Type
    Experimental
    Arm Description
    BromAc (Bromelain and Acetylcysteine combination) will be administered three times (3x) per day for five (5) days in a dose escalation format via inhalation using an approved vibrating mesh nebuliser (Aerogen Pro). Dose escalation concentration levels are BromAc 125ug/20mg/ml, 250ug/20mg/ml, 375ug/20mg/ml. All levels will receive 5ml of BromAc.
    Intervention Type
    Drug
    Intervention Name(s)
    Bromelains
    Other Intervention Name(s)
    Bromelain
    Intervention Description
    Bromelain combined with Acetylcysteine (BromAc), administered simultaneously.
    Intervention Type
    Drug
    Intervention Name(s)
    Acetylcysteine
    Other Intervention Name(s)
    N-Acetylcysteine
    Intervention Description
    Bromelain combined with Acetylcysteine (BromAc), administered simultaneously.
    Primary Outcome Measure Information:
    Title
    Evaluate the treatment-emergent adverse events (AEs) of BromAc therapy following nebulised delivery
    Description
    The safety and tolerability of BromAc will be assessed by characterising the symptoms or side effects of treatment (treatment-emergent adverse events) by the Common Toxicity Criteria for Adverse Events (CTCAE) v4.0
    Time Frame
    Following each nebulisation on days 1 to 5 and during follow up on days 6-15, 21, 28 and 60
    Secondary Outcome Measure Information:
    Title
    Proportion of participants that proceed to invasive ventilation for deterioration of COVID-19 (need for mechanical ventilation)
    Description
    To assess the proportion of patients following commencement of BromAc that proceed to mechanical ventilation for COVID-19
    Time Frame
    Daily for 60 days
    Title
    World Health Organisation (WHO) modified ordinal scale clinical score
    Description
    Determine the clinical score by improvement or deterioration based on World Health Organisation Modified Ordinal Scale for COVID-19 over 28-days
    Time Frame
    Daily for 28 days
    Title
    Improvement or deterioration in oxygenation
    Description
    Assess the improvement or deterioration in percentage of oxygen saturation (SpO2) whilst hospitalised vs the fraction of inspired oxygen (SpO2/FiO2 ratio)
    Time Frame
    Daily for up to 14 days
    Title
    All-cause mortality
    Description
    Determine the all-cause mortality of patients enrolled over 28 days
    Time Frame
    Daily for 28 days
    Title
    Dose related toxicities
    Description
    Determine the tolerated dose of BromAc within the therapeutic range for COVID-19 sputum mucolysis delivered by nebuliser
    Time Frame
    Following each nebulisation on days 1 to 5 and during follow up on days 6-15, 21, 28 and 60
    Title
    Treatment-emergent serious adverse events (SAEs)
    Description
    Assess the proportion of participants with treatment-emergent serious adverse events (SAEs) by Common Toxicity Criteria for Adverse Events (CTCAE) v4.0
    Time Frame
    Following each nebulisation on days 1 to 5 and during follow up on days 6-15, 21, 28 and 60

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Aged 18 years to 75 years old Admitted to hospital for management of COVID-19 with moderate or severe disease Positive testing by virologic test (i.e. SARS-CoV-2 based qRT-PCR) Clinical signs suggestive of moderate or severe disease such as oxygen saturation (SpO2) less than 93% on room air or where the participant requires oxygen support such as nasal cannulas, mask, non-rebreather mask, high flow nasal cannulas Exclusion Criteria: Patients that have critical disease and are mechanically ventilated Undergoing other airway administered mucolytic therapy for e.g. dornase alfa within 24 hours, or are enrolled in another clinical trial for COVID-19 Have known allergy, anaphylaxis or intolerance to pineapples, papain, bromeliads, sulphur, eggs or Acetylcysteine or any other serious allergy or intolerance to fruits or food products or any other serious allergy or allergen triggered asthma, such as dust or pollen Have other serious comorbidities where inclusion in the trial will subject the participant to a higher risk of adverse events, including participants with asthma (existing severe lung disease such as COPD, bronchiectasis and cystic fibrosis are not exclusion criteria) Pregnant women are excluded from this study because BromAc has unknown but a potential risk for adverse events in nursing infants secondary to treatment of the mother Participants with psychiatric illness/social situations that would limit compliance with study requirements. Are unable to give fully informed and educated consent or are unable to comply with the standard follow up procedures of a clinical trial
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Sarah J Valle, BN
    Phone
    61291132070
    Email
    sarah@mucpharm.com
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Frank MP van Haren, MD, PhD
    Organizational Affiliation
    St George Hospital, Director of Intensive Care
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No

    Learn more about this trial

    Safety of Nebulized Combination Therapy BromAc® in COVID-19 Respiratory Disease

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