Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000958785
Ethics application status
Approved
Date submitted
30/06/2022
Date registered
6/07/2022
Date last updated
6/07/2022
Date data sharing statement initially provided
6/07/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase 1, Open-label, Two-Cohort Study of Orally Administered PAX-1 in Patients with Moderate COVID-19
Scientific title
Phase 1, Open-label, Two-Cohort Study of Orally Administered PAX-1 in Patients with Moderate COVID-19
Secondary ID [1] 307461 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 326853 0
Condition category
Condition code
Respiratory 324064 324064 0 0
Other respiratory disorders / diseases
Infection 324065 324065 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Phase I, open-label study involving 48 patients
- To evaluate the safety of two escalating doses of PAX-1 in patients with moderate COVID-19.
- To assess the efficacy and pharmacodynamic effects of PAX-1 in patients with moderate COVID-19.

- Investigational Product: PAX-1 (tablet, 2.5mg/tablet)
- Route of administration: Oral
- Frequency of administration: Twice (for 5mg/day dose) or three (for 7.5mg/day dose) times daily for ten days
- Cohorts:
1. 5 mg PAX-1 + Standard of care (SOC)
2. 7.5 mg PAX-1 + Standard of care (SOC)

- The first 20 enrolled patients will be treated with the lowest dose of PAX-1 (5 mg) + SOC.
- When all 20 patients have completed treatment, a Data and Safety Monitoring Board (DSMB) will convene to evaluate the safety profile of the dose.
- Enrolment of the 20 patients in the 7.5 mg + SOC cohort will begin if and only when the DSMB considers the safety profile of PAX-1 to be appropriate.
- Patients in all cohorts will be treated with PAX-1 for 10 days or until complete recovery, whichever occurs first.
- Patients in all cohorts will be treated concomitantly with SOC as per local practice and regulatory guidelines.
- All patients will ingest medications under clinical monitoring.
Intervention code [1] 323918 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331853 0
Incidence and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.

The most common drug-related adverse events with a daily dose of less than or equal to 7.5 mg of PAX-1 are nausea, vomiting, constipation, diarrhoea and decreased appetite.
Timepoint [1] 331853 0
Once daily for 10 days since enrolment, and on day 13 and day 28 (end of monitoring) since enrolment.
Primary outcome [2] 331857 0
Change of Electrocardiograms (ECG), particularly of QT length, incidence of Torsades de Pointes (TdP) and cardioversion.
Timepoint [2] 331857 0
Once daily for 10 days since enrolment, and on day 13 and day 28 (end of monitoring) since enrolment.
Primary outcome [3] 331858 0
Change from baseline in vital signs results.

- Vital signs (respiratory rate, pulse rate, temperature, systolic and diastolic blood pressure) will be assessed using sphygmomanometer (for blood pressure), thermometer (of body temperature), and an integrated digital monitor (for heart rate),
Timepoint [3] 331858 0
Once daily for 10 days since enrolment, and on day 13 and day 28 (end of monitoring) since enrolment.
Secondary outcome [1] 411404 0
Clinical failure at Day 10, defined as any of:
- Death
- Respiratory failure (patient requires intubation and
mechanical ventilation)
- Presence in the Intensive Care Unit (ICU)

Data for Clinical failure will be collected by telephone follow-up, electronic data capture (EDC) records, or audit of study records by the CRA.
Timepoint [1] 411404 0
Day 10 since enrolment
Secondary outcome [2] 411405 0
Clinical improvement, stable disease, or progression will be assessed and scored using the WHO ordinal scale at Day 10 as below:
0. Uninfected: no clinical or virologic evidence of infection
1. Ambulatory: no limitation of activities
2. Ambulatory: limitation of activities
3. Hospitalized with mild disease: no oxygen therapy
4. Hospitalized with mild disease: oxygen by mask or nasal prongs
5. Hospitalized with severe disease: non-invasive ventilation or high-flow oxygen
6. Hospitalized with severe disease: intubation and mechanical ventilation
7. Hospitalized with severe disease: ventilation + additional organ support: vasopressors, renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO)
8. Death
Timepoint [2] 411405 0
Day 10 since enrolment.
Secondary outcome [3] 411445 0
Clinical improvement, stable disease or progression assessed through the National Early Warning Score 2 (NEWS2).
Timepoint [3] 411445 0
Day 10 since enrolment.
Secondary outcome [4] 411446 0
Duration of supplemental oxygen will be assessed by reviewing medical record.
Timepoint [4] 411446 0
Monitored daily for the duration of hospital admission. Final outcome to be collected on Day 28 (end of monitoring).
Secondary outcome [5] 411447 0
Rate of overall survival at Day 10 assessed by medical record.
Timepoint [5] 411447 0
Day 10 since enrolment. Final outcome to be collected on Day 28 (end of monitoring).
Secondary outcome [6] 411448 0
Time to hospital discharge or “ready for discharge” (i.e. normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or greater than or equal to 2 L supplemental oxygen). Outcome will be assessed by reviewing medical record.
Timepoint [6] 411448 0
Monitored daily for the duration of hospital admission. Final outcome to be collected on Day 28 (end of monitoring).
Secondary outcome [7] 411449 0
Time to a negative reverse transcription-polymerase chain reaction (RT-PCR) result for SARS-CoV-2 in nasopharyngeal swabs.
Timepoint [7] 411449 0
To be assessed on screening day, Day 0, 3, 6, 9, 13 and 28 (end of monitoring) since enrolment. Final outcome to be collected on Day 28.
Secondary outcome [8] 411450 0
Pharmacodynamics:
Serum tumour necrosis factor (TNF)-a, interferon (IFN)-a, interleukin (IL)-1, IL-2, IL-6, IL-7, IL-10, C-reactive protein (CRP), granulocyte colony-stimulating factor (G-CSF), interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)1, macrophage inflammatory protein (MIP)1a levels.
Timepoint [8] 411450 0
On screening day, Day 0, 3, 6, 9, 13 and 28 (end of monitoring) since enrolment. Final outcome to be collected on Day 28.
Secondary outcome [9] 411474 0
Primary outcome:
Change from baseline in clinical laboratory test results (haematology and blood chemistry).

- Blood and serum samples will be collected from participants
Timepoint [9] 411474 0
Once daily for 10 days since enrolment, and on day 13 and day 28 (end of monitoring) since enrolment.

Eligibility
Key inclusion criteria
1. Signed written informed consent by any patient capable of giving consent.
2. Aged between 18 and 60 years.
3. Patient is currently hospitalized.
4. Diagnosis of moderate COVID-19 pneumonia according to WHO criteria (no signs of severe pneumonia [respiratory rate > 30 breaths/min on room air; severe respiratory distress; or SpO2 less than or equal to 93% on room air] and no need for supplemental oxygen) including a positive RT-PCR test for SARS-CoV-2 and lung involvement confirmed with lung imaging technique.
5. Able to take oral medication.
6. Able to comply with the study protocol.
7. Female patients must agree to use a highly effective method of contraception throughout the study and for up to 90 days after stopping treatment.
8. Male subjects should use a condom during treatment and for 90 days following the end of treatment. For a non-pregnant WOCBP partner, contraception recommendations should also be considered as described above.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients with ECG evidence of a QTcF > 450 ms in men and > 470 ms in women and patients with any other risk factors for torsade de pointes (TdP) (low left ventricular ejection fraction, left ventricular hypertrophy, ischemia, slow heart rate, and electrolyte abnormalities including hypokalaemia and hypomagnesemia).
2. Patients with uncontrolled cardiac disease.
3. Patients under treatment with drugs having a known risk of prolonging the QT interval and/or inducing TdP.*
4. Patients in treatment with drugs having a known risk of causing neutropenia.*
5. Patients with known or suspected hypersensitivity to sodium metaarsenite, related compounds or any of the excipients of PAX-1.
6. Suspected active bacterial, fungal, viral, or other infection (besides COVID-19)
7. Patients requiring supplemental oxygen at screening.
8. Patient in ICU at screening.
9. Immunosuppressive or immunomodulatory drugs (except for corticosteroids) within the past 3 months.
10. ALT or AST > 5 x ULN at screening.
11. ANC < 1000/µL at screening.
12. Platelet count < 50,000/ µL at screening.
13. Serum creatinine > 2 mg/dL (> 176.8 µmol/L) or estimated creatinine clearance < 30 ml/min measured or calculated by Cockroft Gault equation.
14. Pregnant or breastfeeding.
15. Treatment with an investigational drug within 5 half-lives or 30 days (whichever is longer) of screening.
16. Patients who in the opinion of the treating physician should not participate in this program (ex: severe acute respiratory distress syndrome, septicaemia).
* Concomitant treatments with a known risk of causing neutropenia, and/or of prolonging the QT interval and/or inducing TdP are prohibited during the study.

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
Other
Other design features
The first 20 enrolled patients will be treated with the lowest dose of PAX-1 cohort.
When all 20 patients have completed treatment, DSMB will convene to evaluate the safety profile of the dose.
Enrolment of the 20 patients in the escalated dose of PAX-1 cohort will begin if and only when the DSMB considers the safety profile of PAX-1 to be appropriate.
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Planned number of subjects: A total of 48 patients (at least 40 subjects with a dropout rate of 20% ) are planned to be enrolled.
Given that the primary objective of the study is to investigate the safety of two escalating doses of PAX-1, the sample size of 20 patients in each cohort is based on the probability of occurrence of at least one event with an incidence of 10% in the population sample. With a sample size of 20, the probability of observing at least one event will be 0.88 when the probability of an event is 0.1.

Statistical Analysis Plan (SAP) will be produced between finalization of the CRF and database lock. This will include detailed descriptions of all statistical methodology to be utilized, planned analyses, together with master table and listing shells and outline figures for reporting. The SAP will be approved and signed prior to clean file.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/09/2022
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
48
Accrual to date
Final
Recruitment outside Australia
Country [1] 24856 0
Pakistan
State/province [1] 24856 0

Funding & Sponsors
Funding source category [1] 311733 0
Commercial sector/Industry
Name [1] 311733 0
Komipharm International Australia Pty Ltd
Country [1] 311733 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Komipharm International Australia Pty Ltd
Address
11 Monterey Rd Dandenong South Victoria 3175
Country
Australia
Secondary sponsor category [1] 313193 0
None
Name [1] 313193 0
Address [1] 313193 0
Country [1] 313193 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311181 0
National Institute of Health IRB
Ethics committee address [1] 311181 0
National Institutes of Health (NIH) Park Road, Chak Shahzad, Islamabad, Pakistan
Ethics committee country [1] 311181 0
Pakistan
Date submitted for ethics approval [1] 311181 0
26/07/2021
Approval date [1] 311181 0
20/09/2021
Ethics approval number [1] 311181 0
Ethics committee name [2] 311184 0
National Bioethics Committee
Ethics committee address [2] 311184 0
NBC Secretariat PHRC
Shahrah-e-Jamhuriat, G-5/2
Islamabad
Ethics committee country [2] 311184 0
Pakistan
Date submitted for ethics approval [2] 311184 0
23/09/2021
Approval date [2] 311184 0
02/11/2021
Ethics approval number [2] 311184 0

Summary
Brief summary
This purpose of this Phase I study is to evaluate the safety, efficacy and pharmacodynamic effects of two escalating doses of PAX-1 in patients with moderate COVID-19.

This study is being performed to address an unmet urgent clinical need for an effective treatment for COVID-19 infection. It is hoped that this treatment is shown to be safe and effective with potential implications for treatment of COVID-19.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 120238 0
Prof Aamir Ikram
Address 120238 0
National Institutes of Health, (Isolation Hospital and Infectious Treatment Centre - IHITC), Park Road, Chak Shahzad, Islamabad.
Country 120238 0
Pakistan
Phone 120238 0
+92 51 9255117
Fax 120238 0
Email 120238 0
[email protected]
Contact person for public queries
Name 120239 0
Prof Aamir Ikram
Address 120239 0
National Institutes of Health, (Isolation Hospital and Infectious Treatment Centre - IHITC), Park Road, Chak Shahzad, Islamabad.
Country 120239 0
Pakistan
Phone 120239 0
+92 51 9255117
Fax 120239 0
Email 120239 0
[email protected]
Contact person for scientific queries
Name 120240 0
Prof Aamir Ikram
Address 120240 0
National Institutes of Health, (Isolation Hospital and Infectious Treatment Centre - IHITC), Park Road, Chak Shahzad, Islamabad.
Country 120240 0
Pakistan
Phone 120240 0
+92 51 9255117
Fax 120240 0
Email 120240 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Only aggregate data will be available


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
No additional documents have been identified.