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Trial registered on ANZCTR


Registration number
ACTRN12622001572752
Ethics application status
Approved
Date submitted
7/12/2022
Date registered
20/12/2022
Date last updated
18/09/2023
Date data sharing statement initially provided
20/12/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Randomized, Blinded, Placebo-Controlled, First-in-Human, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of APR002 Administered by Inhalation in Healthy Volunteers
Scientific title
A Phase 1, Randomized, Blinded, Placebo-Controlled, First-in-Human, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of APR002 Administered by Inhalation in Healthy Volunteers
Secondary ID [1] 308328 0
APR002-NEB-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 328117 0
Condition category
Condition code
Respiratory 325174 325174 0 0
Other respiratory disorders / diseases
Infection 325473 325473 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a randomised, Sponsor-open label, Investigator/participant-blinded, placebo-controlled, single ascending dose (SAD) study in Healthy Volunteers (HVs).

Forty-eight evaluable healthy, adult participants will be enrolled in total.

Six SAD cohorts of 8 HVs are planned. The dose levels to be evaluated are 10, 30, 100, 300, 1000, 3000 µg. Six volunteers in each cohort will receive APR002 and 2 will receive matched placebo. A single dose of study drug will be administered by inhalation. Participants will fast for at least 8 hours before dosing and 4 hours after dosing. Water will be restricted 1 hour prior to and 1 hour after dosing, but will be allowed ad libitum at all other times. Cohorts may be added or removed.

Sentinel dosing will be used for each SAD cohort. The first 2 participants (1 active:1 placebo) in each cohort will receive either APR002 or placebo in parallel, followed by a minimum 24- hour observation period to ensure adequate evaluation of safety and tolerability prior to administering the same dose of APR002 or placebo to the remaining participants within the cohort (remaining 5 active:1 placebo for a total of 6 active:2 placebo, includes replacements participants).

Dosing of the remaining participants will proceed in a staggered fashion with no more than 3 participants being dosed at a time and having an approximate 24-hour observation period before the next group of participants is dosed. Each dose cohort will be based on all the results from all participants in all previous cohorts.

The Trudell AeroEclipse® II BAN will be utilised to administer the APR002 or placebo per the manufacturer’s guidance. The nebuliser is intended to administer prescribed aerosolised medication to spontaneously breathing participants. The device will be paired with the PARI BOY® Classic compressor and an AeroEclipse® exhalation filtered mouthpiece.

The administration of the timed doses will be monitored by counting the breath actuations of the nebuliser. A check of the residual in the nebuliser will be performed to ensure that the participants have inhaled the study drug. Once a participant has completed their administration the nebuliser will be weighed.
Intervention code [1] 324779 0
Treatment: Drugs
Comparator / control treatment
Sodium Chloride 0.9% will be supplied by the pharmacy in a liquid form for inhalation (placebo)
Control group
Placebo

Outcomes
Primary outcome [1] 332994 0
To determine the safety and tolerability of APR002 when administered as oral inhalation, single dose at escalating dose levels in healthy participants.

- Incidence, severity, and relationship of adverse events (AEs)
- Changes from baseline in clinical laboratory results
- Changes from baseline in vital signs (including changes from baseline in oxygen saturation (SpO2)
- Changes in ECGs
- Comparison of baseline handheld spirometry to post-dose results
- Change from baseline in physical examination findings
Timepoint [1] 332994 0
Adverse events assessed using the National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 on Day -1 (Check-in), Day 1, Day 2, Day 3 (Check-out) and Day 14.

Clinical Laboratory Evaluations (serum chemistry, haematology coagulation and urinalysis): Blood and Urine samples collected at Screening, Day -1 (Check-in), Day 2, Day 3 (Discharge) and at various unscheduled timepoints, if deemed necessary by the Investigator.

Vital Signs: Blood pressure and heart rate is assessed using a sphygmomanometer, respiratory rate by pulse oximetry and temperature by thermometer. Assessed at Screening, Day 1 2hrs pre-dose, 0.5hrs, 1hr, 2hrs, 3hrs, 4hrs, 6hrs, 8hrs, 12hrs post-dose, Day 2 24hrs post-dose, Day 3 (Discharge) 48hrs post-dose and at various unscheduled timepoints, if deemed necessary by the Investigator. After discharge (Day 3), all participants are required to record their temperature in the participant diary daily from Day 3 (after discharge) through Day 14 with a supplied thermometer.

12-Lead ECG: ECG recordings will be obtained in triplicate at Screening, then single ECG on Day 1 within 2hrs pre-dose, 0.5hr, 2hrs, 6hrs post-dose, Day 3 (Discharge) 48hrs post-dose and at various unscheduled timepoints, if deemed necessary by the Investigator.

Handheld Spirometry will be assessed for comparison at Screening, Day 1 within 2hrs pre-dose, 0.5 hr, 1hr, 3hrs post-dose, Day 3 (Discharge) 48hrs post-dose

A complete physical examination will include, at a minimum, assessment of general
appearance; head, eyes, ears, nose, and throat (HEENT); mouth/dental (if required); neck
(including thyroid and nodes), cardiovascular, respiratory, gastrointestinal, renal,
neurological, musculoskeletal, skin, and other as needed and assessed at Screening and Day 3 with additional symptom-driven physical examinations performed at other times, if deemed necessary by the Investigator.
Secondary outcome [1] 415480 0
To characterize the plasma pharmacokinetics (PK) of APR002 in healthy participants following a single inhalation.

Summary of PK parameters of total APR002:
AUC0-t -The area under the concentration-time curve, from time 0 to the last observed non-zero concentration, as calculated by the linear trapezoidal method.
AUC0-inf - The area under the concentration-time curve from time 0 extrapolated to infinity. AUC0-inf is calculated as the sum of AUC0-t plus the ratio of the last measurable plasma concentration to the elimination rate constant.
Cmax - Maximum observed concentration.
Tmax - Time to reach Cmax. If the maximum value occurs at more than 1 timepoint, Tmax is defined as the first timepoint with this value.
terminal elimination half life (T1/2) - Apparent first-order terminal elimination half-life will be calculated as 0.693/Kel.
CL/F - Apparent total plasma clearance after oral (extravascular) administration, calculated as Dose/AUC0-inf.
Vz/F - Apparent volume of distribution during the terminal elimination phase after oral (extravascular) administration, calculated as Dose/(AUC0-inf x Kel).
Timepoint [1] 415480 0
PK plasma samples will be collected on Day 1 within 1hr pre-dose, 5mins post-dose, 15mins post-dose, 0.5hr post-dose, 1hr post-dose, 1.5hrs post-dose, 2hrs post-dose, 4hrs post-dose, 6hrs post-dose, 12hrs post-dose, Day 2 24hrs post-dose.
Secondary outcome [2] 415482 0
To make a preliminary assessment of biomarkers that might act as pharmacodynamics (PD) indicators of biological activity of APR002

Changes from baseline in peripheral blood biomarkers (e.g., cytokine profile, IFN-stimulated genes, and proteins including, but not limited to IP-10).
Timepoint [2] 415482 0
Peripheral blood samples will be collected on Day 1 within 1hr pre-dose, 4hrs post-dose, 6hrs post-dose, Day 2 24hrs post-dose, Day 3 48hrs post-dose.
Secondary outcome [3] 415483 0
To assess changes in peripheral blood biomarkers (e.g., cytokine profile, IFN-stimulated genes & proteins including, but not limited to IP-10)

Changes from baseline in peripheral blood biomarkers (e.g., cytokine profile, IFN-stimulated genes, and proteins including, but not limited to IP-10).
Timepoint [3] 415483 0
Peripheral blood samples will be collected on Day 1 within 1hr pre-dose, 4hrs post-dose, 6hrs post-dose, Day 2 24hrs post-dose, Day 3 48hrs post-dose.

Eligibility
Key inclusion criteria
1. The participant is a healthy adult male or female. The health status is verified by absence of evidence of any clinical significant active or uncontrolled chronic disease following a detailed medical history (specific attention to prior asthma or AR); a complete physical examination; vital signs; blood sampling of hematology, chemistry, and virology; urinalysis, and urine drug testing. In the case of uncertain or questionable results, tests performed during screening may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant for healthy participants.
2. The participant is aged 18 to 55 years, inclusive at the time of consent.
3. The participant weighs at least 45 kg (99 lb) and has a body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive at Screening.
4. A male participant who is nonsterilized and sexually active with a female partner of
childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 90 days after the dose of study drug.
5. A female participant of childbearing potential* who is sexually active with a nonsterilized male partner agrees to use adequate contraception from the time of signing the informed consent, throughout the duration of the study, and for 30 days after the dose of study drug.
*Females of non-childbearing potential may be enrolled. Female participants of childbearing potential must follow protocol specified contraception guidance.
6. Continuous non-smoker who has not used tobacco/nicotine-containing products for at
least 3 months prior to the first dosing based on participant self-reporting.
7. Medically healthy (i.e., with no clinically significant medical history, physical examination, laboratory profiles, vital signs or ECGs, as deemed by the Investigator or designee), including according to the following:
- Seated blood pressure is greater than or equal to 90/50 mmHg and less than or equal to 140/90 mmHg at the Screening Visit and check-in at rest for 5 minutes.
- Seated heart rate/pulse is greater than or equal to 40 bpm and less than or equal to 99 bpm at the Screening Visit and
check-in at rest for 5 minutes. Heart rate/pulse below 50 bpm to be discussed with the Medical Monitor before study inclusion.
- QTcF intervals are less than or equal to 470 msec (females) / less than or equal to 450 msec (males) at the Screening
Visit and check-in.
- Estimated creatinine clearance is greater than or equal to 80 mL/min at the Screening Visit, calculated utilizing the Cockcroft & Gault formula.
- ALT and AST are less than or equal to upper limit of normal (ULN) at the Screening Visit and check-in, if ALT/AST is less than or equal to 1.5 × ULN, discussion between the Sponsor and Investigator must occur before inclusion.
- Total bilirubin is less than or equal to 1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if total bilirubin is fractionated and direct bilirubin <35%) at the Screening Visit and check-in.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the Screening Visit or expected during the conduct of the study.
2. History or presence of clinically significant medical (e.g., chronic obstructive pulmonary disease, asthma, COVID-19, etc.) or psychiatric condition or disease in the opinion of the Investigator or designee. For example, pulmonary function test results should
be within normal range, FEV1 % Predicted: 80 to 120%, FVC % Predicted: 80 to 120%, FEV1/FVC % Predicted: 85 to 110%.
3. History of any illness that, in the opinion of the Investigator or designee, might confound the results of the study or poses an additional risk to the participant by their participation in the study.
4. History of unexplained syncope.
5. History or presence of acute porphyria at the Screening Visit.
6. Lymphoma, leukemia, or any malignancy within the past 5 years of the Screening Visit except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years or breast cancer within the past
10 years of the Screening Visit.
7. Clinically significant cardiac disease (e.g., myocardial infarction, stroke, unstable angina, claudication) within 6 months prior to check-in.
8. History of clinically significant hepatic impairment.
9. Current or chronic history of liver disease, including but not limited to hepatitis virus infections, drug- or alcohol-related liver disease, nonalcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson’s disease, ?-1 antitrypsin deficiency, primary biliary
cholangitis, primary sclerosing cholangitis, or any other liver disease considered clinically significant by the Investigator.
10. Known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones).
11. Participant has had previous episodes of seizures or convulsion (lifetime), including absence seizure and febrile convulsion.
12. Participant or any immediate family member has a history of epilepsy (including febrile convulsions).
13. Participant has a history of clinically significant neurological abnormalities including known abnormal electroencephalography at screening or brain injury including traumatic injury, perinatal cerebropathy and postnatal brain damage, blood-brain barrier abnormality, and angioma cavernous.
14. Participant has a history of cerebral arteriosclerosis.
15. Participant has a condition that can potentially reduce drug clearance (e.g., renal or hepatic insufficiency).
16. Clinically significant acute illness or infection within 14 days prior to check-in.
17. Major surgical procedure within 3 months prior to check-in.
18. History or known presence of hypersensitivity or idiosyncratic reaction to the study drug(s) or related compounds.
19. History or presence of alcohol or drug abuse within the past 2 years prior to the first dosing.
20. Positive urine drug or breath alcohol results at the Screening Visit or check-in.
21. Drinks alcohol in excess of 14 glasses/units per week, with 1 unit = 8 ounces (240 mL) beer, 1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine. The participant has history of alcoholism, alcohol abuse (a current alcohol consumption of more than 2 drinks per day [a drink is defined as 5 oz (~150 mL) of wine, 12 oz (~355 mL) of beer, or 1 oz (~30 mL) of hard liquor]).
22. Current smoker or a history of smoking within 3 months of screening, or a total pack year history of >5 pack years. [number of pack years = (number of cigarettes per day/20) x number of years smoked]. The participant has used any tobacco- or nicotine-containing
products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 3 months prior to screening, or has positive urine cotinine test (defined as greater than or equal to 100 ng/mL) at screening, or is unwilling to forgo the use of tobacco- or nicotine-containing products throughout the study.
23. Is a heavy caffeine drinker (i.e., consumes >5 cups/glasses of caffeinated beverages [e.g., coffee, tea, cola, energy drinks] per day for 3 or more days consecutively within the past 3 months).
24. Has a positive pregnancy test at the Screening Visit or check-in, or is lactating.
25. Is planning to become pregnant or father a child from the Screening Visit and throughout the study.
26. Positive results at the Screening Visit for HIV, hepatitis B surface antigen (HbsAg), HCV, or on Screening or Day 1 for COVID-19
27. Unable to refrain from or anticipates the use of:
Any drugs, including prescription and non-prescription medications, herbal remedies, or vitamin supplements beginning 14 days prior to the first dosing. Thyroid hormone replacement medication will be allowed.
28. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or designee, within the 30 days prior to the first dosing.
29. Donation of blood or significant blood loss within 56 days prior to the first dosing. The participant has donated 1 pint or more of blood or had a significant blood loss within 1 month (inclusive) prior to screening. The participant has received blood products within 2
months (inclusive) prior to check-in.
30. Plasma donation within 7 days prior to the first dosing.
31. Participant has poor peripheral venous access.
32. Participation in another clinical study within 30 days or 5 half-lives prior to dosing. The 30-day window will be derived from the date of the last dosing in the previous study to the first dosing of the current study.
33. Participant is pregnant or lactating or intending to become pregnant before, during, or within 30 days after the dose of study drug or intending to donate ova during such time period.
34. If male, participant intends to donate sperm during the course of this study or within 90 days after the dose of study drug.
35. Participant has a risk of suicide per the C-SSRS (a score of 4 or 5 on ideation or any suicidal behavior) or according to the Investigator’s clinical judgment, has made a suicide attempt in the previous 6 months, or has a history of deliberate self-harm in the past 6 months.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Within each dose group, eligible participants will be randomised to either active drug or
placebo according to a randomisation schedule generated by the Sponsor or designee. As the appearance of placebo is the same as APR002, the study blind will be maintained during the administration procedure.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Each participant will be assigned a unique identification number upon the Screening Visit.
Participants who complete the study screening assessments and meet all the eligibility criteria will be assigned a unique randomisation identification number at the time of the first dosing, different from the screening number, and will receive the corresponding product, according to a randomization scheme.

If replacement participants are used, the replacement participant number will be 100 more
than the original (e.g., Participant No. 101 will replace Participant No. 001).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
The sample size chosen for this study was selected without statistical considerations.

Population for Analyses

Safety Population: All participants who received at study drug will be included in the safety
analysis.

PK Population: All participants who comply sufficiently with the protocol and display an
evaluable PK profile (e.g., exposure to treatment, availability of measurements and absence
of major protocol violations) will be included in the statistical analysis.

Detailed methodology for summary and statistical analyses of the data collected in this study will be documented in a Statistical Analysis Plan (SAP). The SAP will be prepared by the Sponsor/designee. This document may modify the plans outlined in the protocol; however, any major modifications of the primary endpoint’s definition and/or its analysis will also be reflected in a protocol amendment. Additional statistical analyses other than those described in this section may be performed if deemed appropriate.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Safety concerns
Date of first participant enrolment
Anticipated
14/02/2023
Actual
21/03/2023
Date of last participant enrolment
Anticipated
Actual
15/06/2023
Date of last data collection
Anticipated
Actual
28/06/2023
Sample size
Target
48
Accrual to date
Final
42
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 23565 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 38987 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 312573 0
Commercial sector/Industry
Name [1] 312573 0
Global Health Drug Discovery Institute (GHDDI)
Country [1] 312573 0
China
Primary sponsor type
Commercial sector/Industry
Name
Avance Clinical Pty Ltd
Address
Level 1, 2 Ann Nelson Drive, Thebarton
South Australia 5031
Country
Australia
Secondary sponsor category [1] 314276 0
None
Name [1] 314276 0
Address [1] 314276 0
Country [1] 314276 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311899 0
Bellberry Limited Human Research Ethics Committee
Ethics committee address [1] 311899 0
123 Glen Osmond Road,
Eastwood, SA, 5063
Ethics committee country [1] 311899 0
Australia
Date submitted for ethics approval [1] 311899 0
27/01/2022
Approval date [1] 311899 0
09/11/2022
Ethics approval number [1] 311899 0

Summary
Brief summary
The study will include a Screening Period, a Treatment Period, and a Follow-up Period.

Sequential groups of fasted participants will receive a single dose of inhalation administered APR002 at 6 increasing dose levels or placebo.

Staggered dosing will be employed with approximately 24 hours between dosing cohorts.
After all participants in a dose group have completed study procedures to Day 3 (48 hours
after dosing), a decision on dose escalation and enrolment of the next dose group will be
made based upon all available data, including the incidence and severity of reported AEs and safety laboratory test results collected after administration of APR002/placebo.

Escalation to the next dose level will occur in the absence of dose-limiting toxicity or other significant safety findings after agreement between the Sponsor, an independent Medical Monitor, and the Investigator.

Follow-up assessments will occur approximately 14 days after the dosing to inquire for any ongoing AEs or serious adverse events (SAEs), worsening of AEs or SAEs, or development of new AEs or SAEs, and concomitant medications taken since final dose. Follow-up will occur by telephone unless abnormal, clinically significant findings are observed upon discharge or at the Investigator’s discretion. Participants should then be brought back to the clinic for re-evaluation.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 122766 0
Prof Sepehr Shakib
Address 122766 0
CMAX Clinical Research
Level 5, 18a North Terrace Adelaide
South Australia 5000
Country 122766 0
Australia
Phone 122766 0
+61 411 100 278
Fax 122766 0
Email 122766 0
[email protected]
Contact person for public queries
Name 122767 0
Sepehr Shakib
Address 122767 0
CMAX Clinical Research
Level 5, 18a North Terrace Adelaide
South Australia 5000
Country 122767 0
Australia
Phone 122767 0
+61 411 100 278
Fax 122767 0
Email 122767 0
[email protected]
Contact person for scientific queries
Name 122768 0
Sepehr Shakib
Address 122768 0
CMAX Clinical Research
Level 5, 18a North Terrace Adelaide
South Australia 5000
Country 122768 0
Australia
Phone 122768 0
+61 411 100 278
Fax 122768 0
Email 122768 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
Privacy and intellectual property considerations


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.