ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12620000788976

Ethics application status

Approved

Date submitted

30/07/2020

Date registered

5/08/2020

Date last updated

3/12/2020

Date data sharing statement initially provided

5/08/2020

Type of registration

Prospectively registered

Titles & IDs

Public title

Safety and efficacy of intranasal delivery of BromAc® (Bromelain & Acetylcysteine) in swab positive SARS-CoV-2 COVID-19 patients

Scientific title

Safety and efficacy of intranasal delivery of BromAc® (Bromelain & Acetylcysteine) in swab positive SARS-CoV-2 patients – a phase I, single-arm, dose escalation study

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1256-2985

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

SARS-CoV-2

COVID19

Condition category

Condition code

Infection

Other infectious diseases

Respiratory

Other respiratory disorders / diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a phase I study on the safety of a combination of Bromelain and Acetylcysteine (BromAc®), where 40 patients who are PCR-positive for SARS-CoV-2 that are otherwise well and remain in the outpatient setting will receive BromAc® as an intranasal spray. This drug is a product that combines these two existing products (Bromelain and Acetylcysteine), along with 5% glucose to be delivered into the nose via spray bottle delivery. The dose of the nose spray will vary based on dose escalation with Bromelain 25, 50, 75, 100 and 125ug/ml. The dose of Acetylcysteine will be 20mg/ml. Doses will be increased after every 10 patients with the first patient receiving dose level 2 (50ug Bromelain) if safe based on the number of dose limiting toxicities. Cohorts will commence one week apart. The nose spray will be administered four times per day for five days. The participant will be asked to electronically log administration of the drug and any symptoms or side effects. In addition, the patient will be assessed for symptoms and side effects on daily follow up phone calls as well as preliminary evidence of efficacy with daily RT-PCR for viral load.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

To characterise and evaluate the safety of BromAc® following nasopharyngeal delivery by symptom and side effect assessment on daily phone call follow up with a study investigator or nurse and electronic diary. Examples of potential side effects include nasal irritation, nose bleed, nasal dryness.

Timepoint [1]

Symptoms and side effects will be assessed daily during treatment (day 1-5) and follow up (day 6-19) via electronic symptom/side effect tracker and phone calls with a study investigator/nurse.

Primary outcome [2]

Determine the maximum tolerated dose (MTD) of BromAc® delivered by nasopharyngeal spray by dose escalation (25, 50, 75, 100 and 125ug/ml Bromelain and standard Acetylcysteine 20mg/ml). Toxicity will be monitored by modified toxicity probability interval, MTPI, design and graded according to the Common Terminology Criteria for Adverse Events criteria

Timepoint [2]

Toxicity will be assessed daily during treatment (day 1-5) and follow up (day 6-19) via electronic symptom/side effect tracker and phone calls with a study investigator/nurse.

Primary outcome [3]

Proportion of patients with treatment-emergent serious adverse events (SAEs) which will be identified by daily phone call follow up with a study investigator or nurse and electronic diary. Examples of potential adverse events effects include nose bleed, anaphylaxis.

Timepoint [3]

Symptoms and side effects will be assessed daily daily during treatment (day 1-5) and follow up (day 6-19) via electronic symptom/side effect tracker and phone calls with a study investigator/nurse.

Secondary outcome [1]

Time-weighted average change from baseline in viral titre as measured by quantitative reverse transcription quantitative polymerase chain reaction (RT-qPCR) in nasopharyngeal swab samples

Timepoint [1]

Baseline (diagnosis/pretreatment PCR) then second daily self-collect swabs for qRT-PCR until day 19 (baseline, day 2, 4, 6, etc to day 18).

Secondary outcome [2]

Time to negative RT-qPCR in NP swabs with no subsequent positive RT-qPCR

Timepoint [2]

Baseline (diagnosis/pretreatment PCR) then ssecond daily self-collect swabs for qRT-PCR until day 19 (baseline, day 2, 4, 6, etc to day 18).

Secondary outcome [3]

Proportion of patients with at least one COVID-19 related medically attended visit where the patient requires escalation of care such as emergency department presentation (though hospital medical records) or physician or patient reported.

Timepoint [3]

Daily for 19 days

Secondary outcome [4]

Proportion of patients admitted to a hospital due to COVID-19 where the patient requires escalation of care such as emergency department presentation (though hospital medical records) or physician or patient reported.

Timepoint [4]

Daily for 19 days

Eligibility

Key inclusion criteria

• Aged 18 years or older
• Swab positive for SARS-CoV-2 based on RT-PCR (patients must be identified and commence treatment within 3 days of the positive result)
• Diagnostic PCR or pre-treatment PCR must have viral load titre measurement
• Swabbed within 48 hours of symptom onset
• Remain generally well and as an outpatient in isolation in their home
• Are considered suitable for the trial based on ability to follow protocol and provide informed consent
• Are within a 50km radius of a study centre for ensuring adherence to trial procedures and follow up

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

• Have symptoms from SARS-CoV-2 that warrant admission to hospital, require supplemental oxygen therapy or are an inpatient in a hospital for SARS-CoV-2
• Are unwilling to undergo repeat swab for PCR viral load
• On anti-viral therapy for SARS-CoV-2 (for e.g. Remdesivir, Interferon-beta1alpha) or are enrolled in another clinical trial for SARS-CoV-2
• Have known allergy (anaphylaxis) to pineapples, papain, bromeliads, sulphur, eggs or Acetylcysteine that cannot be managed with steroids or antihistamine prophylaxis or any other serious unrelated allergy
• Have a coagulation disorder of any kind or are on anticoagulant or anti-platelet therapy that cannot be withheld for the treatment period
• ECOG >2
• Have other serious comorbidities where inclusion in the trial will subject the patient to a higher risk of adverse events, including patients with uncontrolled intercurrent illness
• 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. Breastfeeding should be discontinued if the mother is treated with BromAc®
• Patients 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

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Single group

Other design features

Phase

Phase 1

Type of endpoint/s

Safety

Statistical methods / analysis

Participants will receive study drug at one of five dose levels in a single dose group. The starting dose is the Level 2. Dose escalation will be conducted by using an improved mTPI design to determine the MTD. A total of about 2 to 40 patients will be enrolled. The safety analysis will include the following:
• Patients who have received at least 1 dose, even if incomplete, of study drug will be used for all safety analyses and for some efficacy analyses.
• DLT-evaluable analysis set: The DLT-evaluable analysis set will include patients who receive all 5 days of the drug (20 doses) during week 1 of the study. The DLT-evaluable population in the dose escalation cohorts will be used to determine the MTD.
To evaluate the safety and tolerability, the frequency and severity of adverse events (AE), SAEs will be characterised by type of adverse event and grade. The maximum grade of toxicity for each category of interest will be recorded for each evaluable patient and the summary results will be tabulated by category and grade. Attribution of SAEs to treatment (unrelated, unlikely, possible, probable, or definite) will also be reported.
For the secondary efficacy points, the time to viral clearance and viral load titre measurements will be assessed by subgroup (dose level). The rates with corresponding exact 95% CI will be calculated and compared to their corresponding historical control rates by both clearance and progression to hospitalisation for management of disease. A data-driven Hochberg test will be used for multiplicity consideration.

The distribution of time-to-event will be characterized by median and quartiles, with the corresponding Kaplan-Meier estimate and 95% CI if data allows. Log-rank test was used to assess the difference among clinical and/or pathologic characteristics. To the extent possible from the available data, Cox proportional hazards regression will be used to assess in exploratory fashion whether the rate of response varied among groups, and whether disease progression towards hospitalisation varied among the subgroups.

Descriptive statistics will be provided for selected demographics, safety, efficacy, biomarker and other changes as appropriate. Descriptive statistics on continuous data will include means, medians, standard deviations, and ranges, while categorical data will be summarised using frequency counts and percentages. A parametric or non-parametric statistical test as appropriate may be conducted in exploratory fashion.

To assess potential predictive factors for response to treatment or time-to-event, logistic and Cox proportional hazards regression will be used to examine patients’ demographic, clinical, pathologic characteristics (including blood levels, viral titre, etc.), respectively. All such exploratory data analyses will be essentially descriptive and hypothesis generating in nature.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

4/01/2021

Actual

Date of last participant enrolment

Anticipated

3/04/2021

Actual

Date of last data collection

Anticipated

17/04/2021

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Royal Melbourne Hospital - Royal Park campus - Parkville

Recruitment postcode(s) [1]

3052 - Parkville

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Mucpharm Pty Ltd

Address [1]

1353 High Street
Malvern Victoria 3144

Country [1]

Australia

Primary sponsor type

Commercial sector/Industry

Name

Mucpharm Pty Ltd

Address

1353 High Street
Malvern Victoria 3144

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Melbourne Health - Melbourne Health Human Research Ethics Committee

Ethics committee address [1]

Level 2
South West
300 Grattan Street
Parkville Victoria 3050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

09/09/2020

Approval date [1]

02/11/2020

Ethics approval number [1]

HREC/67339/MH-2020

Summary

Brief summary

Since December 2019, we have been facing our third severe acute respiratory syndrome (SARS) due to a coronavirus in 18 years, known as SARS-CoV-2. There are currently few therapeutic agents and of only limited efficacy. The large majority of patients are diagnosed with a mild form of the virus. The SARS-CoV-2 virus, with its clinical syndrome known as COVID-19, is made up of spike protein (S), nucleocapsid protein (N) that contains the RNA, membrane protein (M) and the envelope protein (E). The spike protein that is responsible for initiating internalization of the virus genome into human lung cells protrudes on the outer surface and is a number of amino acids and glycoproteins. Recent insights strongly support the theory that the nose is the primary site of infection, from where the infection is prone to progress to the lung, suggesting the potential for early nasal-directed treatment.
Bromelain and Acetylcysteine (BromAc®) is a palliative treatment for highly mucinous tumours of the appendix due to its ability to remove glycosidic linkages and disulphide bonds. Bromelain is already known to remove the spike protein and haemagglutinin of similar viruses, including Semliki Forest virus, Sindbis virus, mouse gastrointestinal coronavirus, hemagglutinating encephalomyelitis virus and H1i1 influenza viruses, rendering these non-infective, Acetylcysteine has already been used as an anti-viral. It inhibits influenza A and induced production of pro-inflammatory molecules in lung epithelial cells. In a murine model of lethal influenza infection, an increased survival was seen in the acetylcysteine combination with oseltamivir group (100% vs 60%). 
We predicted and have now shown that BromAc® can disrupt and completely cleave the glycoproteins of the SARS-CoV-2 virus, which have a detrimental effect on the virus, rendering it non-infective. 
We believe that BromAc® may be suitable in clinical application with delivery intranasally in swab PCR positive SARS-CoV-2 outpatients. This drug has the potential to reduce infectivity of those with SARS-CoV-2, potentially reducing exposure to close contacts and progression of the disease into COVID19 syndrome, and act as a prophylactic to prevent the virus from binding to host cells.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

A/Prof Daniel Steinfort

Address

Royal Melbourne Hospital
Department of Respiratory Medicine
300 Grattan Street
Parkville VIC 3050

Country

Australia

Phone

+61393427807

Fax

daniel.steinfort@mh.org.au

Contact person for public queries

Name

Sarah Valle

Address

Level 3 Pitney Building
St George Hospital
Short Street
Kogarah NSW 2217

Country

Australia

Phone

+61 291132070

Fax

s.valle@unsw.edu.au

Contact person for scientific queries

Name

Sarah Valle

Address

Level 3 Pitney Building
St George Hospital
Short Street
Kogarah NSW 2217

Country

Australia

Phone

+61 291132070

Fax

s.valle@unsw.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

Individual patient data will not be available publicly, however data from this study will be assessed and reported in manuscript form.

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Dimensions AI	The Combination of Bromelain and Acetylcysteine (BromAc) Synergistically Inactivates SARS-CoV-2	2021	https://doi.org/10.3390/v13030425

N.B. These documents automatically identified may not have been verified by the study sponsor.

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