ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12621000644864

Ethics application status

Approved

Date submitted

31/03/2021

Date registered

28/05/2021

Date last updated

8/11/2022

Date data sharing statement initially provided

28/05/2021

Type of registration

Retrospectively registered

Titles & IDs

Public title

A Phase 1, Randomised, Double-Blind Placebo-Controlled, First in Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Doses of ANPA-0073 in Healthy Volunteers

Scientific title

Secondary ID [1]

ANPA-0073-01

Universal Trial Number (UTN)

U1111-1265-6060

Trial acronym

Linked study record

Health condition

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

Pulmonary Arterial Hypertension

Condition category

Condition code

Cardiovascular

Hypertension

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a randomised, double-blind, placebo-controlled, ascending dose, multi-cohort study. The study will be conducted in 2 parts: a single ascending dose (SAD) part (Part A) followed by a multiple ascending dose (MAD) part (Part B).

In part A, 64 healthy volunteers will be enrolled in a total of 8 cohorts testing single incremental doses of oral capsules at the following dose levels: 2mg, 5mg, 25mg, 50mg, 100mg, 200mg, 400mg and 600mg strengths of ANPA-0073.

Each cohort will enrol 8 participants with 6 participants randomised to receive ANPA-0073 and 2 participants randomised to receive placebo.

In addition, cohort 4 will be a food effect cohort: a single 50mg oral dose of ANPA-0073 or placebo will be administered on Day 1 under fasted conditions and another dose administered on Day 4 under fed conditions (total of 2 doses). Participants will receive a single 50mg oral dose of ANPA-0073 or placebo after consumption of a high-fat, high-calorie breakfast, based on the example meal provided in the US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) December 2002 Guidance for Industry – Food-Effect Bioavailability and Fed Bioequivalence Studies. Eg, Approximately 50 percent of the total calories of the meal are derived from fat and the meal is approximately 800 to 1000 calories. The meal should derive approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively.

In part B, 32 healthy volunteers will be enrolled in a total of 4 cohorts to receive a once daily dose of ANPA-0073 or placebo for seven consecutive days. Up to 4 dose levels (from 75 mg to 600 mg) will be evaluated in Part B. For Cohorts 1-4, ANPA-0073 dose administration will be once daily. The proposed dose for MAD cohort 1 is 75mg, MAD cohort 2 is 150mg, MAD cohort 3 is 300mg and MAD cohort 4 is 500mg.

Each MAD cohort will enrol 8 participants with 6 participants randomised to receive ANPA-0073 and 2 participants randomised to receive placebo.

In both parts, the SRC should make a recommendation as to whether the next dose should be escalated or reduced, or additional subjects should be dosed in a same dose level of a cohort.

Cohorts will be separated by approximately 5 to 10 days from the last participant visit in one cohort to the first participant visit in the next cohort. The actual time between cohorts is dependent on the time taken to obtain safety and PK data for the SRC to review at the SRC meetings.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Placebo. Oral capsules of matching composition and appearance to the investigational product, but containing microcrystalline cellulose instead of the active drug substance

Control group

Placebo

Outcomes

Primary outcome [1]

To assess the safety and tolerability of single oral doses of ANPA-0073 in healthy adult volunteers relative to placebo, as assessed by physical examination, vital signs (systolic and diastolic blood pressure assessed using a digital blood pressure monitor, Heart Rate assessed using a pulse oximeter, body temperature (oral or tympanic) and respiratory rate), safety labs (blood and urinalysis), 12-lead ECG and adverse events which will be monitored daily

Timepoint [1]

Assessed during Single Ascending Dose (Part A) cohorts 1, 2, 3, 5, 6, 7 and 8 at the following timepoints: - Full physical examination at Screening and Day 7; symptom directed physical examination at Day -1, Day 1 pre-dose and at 2,3 and 4 days after drug administration; - Vital signs at Screening, Day -1, Day 1 pre-dose and at 30 mins, 2 hr, 6 hr, and 12 hr post-dose, and 1, 2, 3, 4 and 7 days after drug administration; - Safety labs at Screening, Day -1, Days 1 6 hr post-dose and 2, 3and 7 days after drug administration; - ECG at Screening, Day -1, Day 1 pre-dose and 2 hr, 6 hr, and 12 hr post-dose, and 2, 3, 4 and 7 days after drug administration; Assessed during Single Ascending Dose (Part A) cohort 4 at the following timepoints: - Full physical examination at Screening and Day 10; symptom directed physical examination at Day -1, Day 1 pre-dose; 2 and 3 days after drug administration, Day 4 pre-dose and 5, 6, 7 days after drug administration; - Vital signs at Screening, Day -1, Day 1 pre-dose and at 30 mins, 2 hr, 6 hr, and 12 hr post-dose; 2 and 3 days after drug administration, Day 4 pre-dose and at 30 mins, 2 hr, 6 hr, and 12 hr post-dose and 5, 6, 7 and 10 days after drug administration; - Safety labs at Screening, Day -1, Days 1 6 hr post-dose; 2 and 3 days after drug administration, Day 4 at 6 hr post-dose and 5,6 and 10 days after drug administration - ECG at Screening, Day -1, Day 1 pre-dose and at 2 hr, 6 hr, and 12 hr post-dose; 2 and 3 days after drug administration, Day 4 pre-dose and at 2 hr, 6 hr, and 12 hr post-dose and 5, 6, 7 and 10 days after drug administration; Adverse events from the day of study drug administration through to study completion or early termination and throughout the post-study follow-up period for serious adverse events (i.e. until resolution, stabilization or the participant is lost to follow-up)

Primary outcome [2]

To assess the safety and tolerability of 7-day repeat oral doses of ANPA 0073 in healthy adult volunteers relative to placebo, as assessed by physical examination, vital signs (systolic and diastolic blood pressure assessed using a digital blood pressure monitor, Heart Rate heart rate assessed using a pulse oximeter, body temperature (oral or tympanic) and respiratory rate), safety labs (blood and urinalysis), 12-lead ECG, change from baseline in body weight and adverse events which will be monitored daily

Timepoint [2]

Assessed during Multiple Ascending Dose (Part B) at the following timepoints:
-Full physical examination at Screening and Day 14; symptom directed physical examination at Day -1, Day 1 pre-dose and on days 2, 3, 4, 5, 6; Day 7 pre-dose and 1 and 2 days after last dose of study drug;
- Vital signs at screening, Day -1, Day 1 pre-dose and at 30min, 2 hr, 6 hr, and 12 hr post-dose; on Days 2, 3, 4, 5, 6; Day 7 pre-dose and at 30min, 2 hr, 6 hr, and 12 hr post-dose and 1, 2 and 7 days after last dose of study drug;
- ECG at Screening, Day -1, Day 1 pre-dose and at 2 hr, 6 hr, and 12 hr post-dose and on Days 2, 3, 4, 5, 6; Day 7 pre-dose and at 2 hr, 6 hr, and 12 hr post-dose and 1, 2 and 7 days after last dose of study drug
- Safety labs at screening, Day -1, Day 1 6 hr post-dose and on Days 2, 4 and 1 and 7 days after last dose of study drug
- Adverse events from the day of study drug administration through to study completion or early termination and throughout the post-study follow-up period for serious adverse events (i.e. until resolution, stabilization or the participant is lost to follow-up)

Secondary outcome [1]

To assess the pharmacokinetics (PK) of ANPA-0073 in plasma following administration of single and 7-day repeat oral doses in healthy adult volunteers. Plasma PK endpoints include (but are not limited to): Maximum observed concentration (Cmax) Time to Cmax (Tmax) Trough concentrations (Part B only) Area under the concentration-time curve from 0 to time of last quantifiable concentration (AUC0-t) Area under the concentration-time curve from 0 to infinity (AUC0-inf), Area under the concentration-time curve from 0 to tau, where tau = 12 hours for QD and tau = 24 hours for BID (AUCtau) (Part B only), Apparent terminal elimination half-life (t1/2), Terminal elimination rate constant, Total apparent body clearance (CL/F) following oral administration, Apparent volume of distribution (Vz/F) (Part A only), Apparent steady state volume of distribution (Vss/F) following multiple oral administration (Part B only)

Timepoint [1]

Assessed during Single Ascending Dose (Part A) on Day 1 pre-dose, then within 15 mins, at 30 mins 1 hr, 1.5 hrs, 2 hr, 3 hr, 4 hr, 6hr, 8 hr, 10hr and 12 hr post-dose; Days 2, 3, and 4 days after drug administration, for Cohorts 1, 2, 3, 5, 6, 7 and 8. Assessed during Multiple Ascending Dose (Part B) on day 1 pre-dose, then within 15 mins, at 30 mins 1 hr, 1.5 hrs, 2 hr, 3 hr, 4 hr, 6hr, 8 hr, 10hr and 12 hr post-dose, pre-dose on Days 2, 3 and 5; Day 7 pre-dose, then within 15 mins, at 30 mins 1 hr, 1.5 hrs, 2 hr, 3 hr, 4 hr, 6hr, 8 hr, 10hr 12 hr and 24hr post-dose

Secondary outcome [2]

To assess the PK of ANPA-0073 in urine following administration of a single oral dose in healthy adult volunteers (Cohort 3 only). Urine PK endpoints include (but are not limited to):
Cumulative amount of unchanged drug excreted in urine (Ae)
Renal clearance (CLr)

Timepoint [2]

Assessed during Single Ascending Dose (Part A) from 10 pm to 0 h on Day -1, and 0 to 6 h, 6 to 12 h, 12 to 24 h, 24 to 48 h and 48 to 72 h post dose in cohort 3

Secondary outcome [3]

To assess the effect of food on the plasma PK of ANPA-073 following administration of a single oral dose in healthy adult volunteers under fasted and fed conditions (Cohort 4 only). Food effect PK endpoints include (but are not limited to):
Cmax
AUC0-inf
t1/2

Timepoint [3]

Assessed on Day 1 pre-dose, then within 15 mins, at 30 mins 1 hr, 1.5 hrs, 2 hr, 3 hr, 4 hr, 6hr, 8 hr, 10hr, 12 hr, 24 hr, 48 hr and 72 hr post-dose and on Day 4 pre-dose, then within 15 mins, at 30 mins 1 hr, 1.5 hrs, 2 hr, 3 hr, 4 hr, 6hr, 8 hr, 10hr, 12 hr, 24 hr, 48 hr and 72 hr post-dose

Secondary outcome [4]

To assess the pharmacodynamic (PD) effect of ANPA-0073 on echocardiographic parameters at or near maximum plasma concentration in healthy adult volunteers (in Part B only). Pharmacodynamic endpoints include:
Two-dimensional transthoracic echocardiography parameters including: left and right heart chamber volumes, such as left ventricular fractional area change (LVFAC), left ventricular (LV) eccentricity index, and tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular peak systolic velocity (TAS’).
Doppler echocardiographic parameters to evaluate LV function, including Tei index.
Measurement of LV and right ventricular (RV) strain using speckle tracking echocardiography.

Timepoint [4]

A transthoracic echocardiogram (including two-dimensional, Doppler, and speckle tracking), will be performed at screening and 1.5 hours (plus or minus 30 minutes) post-dose on Day 2 and again on Day 5 OR Day 6. The post-dose timepoint may be adjusted based on the Cmax data obtained from Part A SAD

Eligibility

Key inclusion criteria

1. Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects
2. Adult males and females, 18 to 55 years of age (inclusive) at screening
3. Body mass index more than 18.0 and less than 30.0 kg/m2, with a body weight (to 1 decimal place) more than 50 kg at screening
4. Be nonsmokers (including tobacco, e-cigarettes and marijuana) for at least 3 months prior to first study drug administration and have a negative test for cotinine at the screening visit and at check-in on Day -1
5. Medically healthy without clinically significant abnormalities (in the opinion of the Investigator) at the screening visit and prior to dosing at the timepoints indicated in the Schedules of Assessments (SoA), including:
a. Physical examination without any clinically significant findings
b. Systolic blood pressure in the range of 90 to 160 mmHg (inclusive) and diastolic blood pressure in the range of 50 to 95 mmHg (inclusive) after 5 minutes in supine position
c. Heart rate (HR) in the range of 40 to 100 bpm (inclusive) after 5 minutes rest in supine position
d. Body temperature (tympanic or oral) in the range 35.5 degrees C to 37.7 degrees C (inclusive)
e. No clinically significant findings in serum chemistry, haematology, coagulation and urinalysis tests
f. Triplicate 12-lead ECG (taken after the volunteer has been supine for at least 5 minutes) with a QT interval corrected using the Fridericia method (QTcF) less than 450 msec for males and less than 470 msec for females and no clinically significant abnormalities
6. Female volunteers must:
a. Be of nonchildbearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before screening) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause, and a follicle-stimulating hormone level more than 40 IU/L at the screening visit), or
b. If of childbearing potential, must agree not to donate ova, not to attempt to become pregnant and, if engaging in sexual intercourse with a male partner, must agree to use an acceptable method of contraception from signing the consent form until at least 30 days after the last dose of the study drug
7. Male volunteers must agree not to donate sperm and, if engaging in sexual intercourse with a female partner who could become pregnant, must agree to use an acceptable method of contraception from signing the consent form until at least 90 days after the last dose of study drug
8. Have suitable venous access for blood sampling
9. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions

Minimum age

18 Years

Maximum age

55 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

1. History or presence of significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or major surgery within the past 3 months determined by the PI to be clinically significant
2. Current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medications
3. Any history of malignant disease in the last 10 years (excludes surgically resected skin squamous cell or basal cell carcinoma)
4. Presence of clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia
5. Use of or plans to use systemic immunosuppressive (e.g., corticosteroids, methotrexate, azathioprine, cyclosporine) or immunomodulating medications (e.g., interferon) during the study or within 3 months prior to the first study drug administration
6. History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or a known arrythmia
7. Findings on transthoracic echocardiogram to have LV ejection fraction on less than 50%, more than mild mitral or aortic valvular regurgitation, or more than mild mitral or aortic valvular stenosis
8. Liver function test results elevated more than 1.5-fold above the upper limit of normal (ULN) for gamma glutamyl transferase (GGT), bilirubin (total, conjugated and unconjugated), alkaline phosphatase (ALP), aspartate aminotransferase (AST) or alanine aminotransferase (ALT). Volunteers with ALP and/or ALT/AST above the limits specified may be included, at the discretion of the Investigator, if the levels are unaccompanied by clinical signs and are determined to be normal variants
9. Positive test results for active human immunodeficiency virus (HIV-1 or HIV-2), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at the screening visit
10. Presence or having sequelae of gastrointestinal, liver (including Gilbert’s syndrome), kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs
11. Estimated creatinine clearance (CrCl) less than 60 mL/min using the Cockcroft-Gault formula or serum creatinine more than 1.5-fold above the ULN
12. History of substance abuse or alcohol abuse (defined as more than 10 standard drinks per week or regularly consuming more than 4 standard drinks on any one day; where 1 standard drink is 10 g of pure alcohol and is equivalent to 285 mL beer (4.9% Alc./Vol), 100 mL wine (12% Alc./Vol), 30 mL spirit (40% Alc./Vol) within 12 weeks prior to the screening visit
13. Positive drugs of abuse or alcohol breath test results at the screening visit or at check-in (Day -1).
14. Use of any prescription or over-the-counter medication (including herbal products, diet aids, and hormone supplements) within 10 days or 5 half-lives of the medication (whichever is longer) prior to the first study drug administration, except use of contraceptives and occasional use of paracetamol (doses of 500 mg up to every 6 hours or 2 g per day maximum for no more than 3 consecutive days)
15. Consumption of grapefruit or Seville orange (or products containing grapefruit or Seville orange) within 10 days prior to the first administration of study drug
16. Demonstrated clinically significant (required intervention, e.g., emergency room visit, epinephrine administration) allergic reactions (e.g., food, drug, or atopic reactions, asthmatic episodes) which, in the opinion of the Investigator, would interfere with the volunteer’s ability to participate in the trial
17. Known hypersensitivity to any of the study drug ingredients
18. Use of any vaccinations within 14 days prior to the first study drug administration
19. For women of childbearing potential, a positive serum pregnancy test at the screening visit or a positive urine pregnancy test (with confirmatory serum pregnancy test) at check-in (Day -1)
20. Females who are breastfeeding or planning to breast feed at any time during the study
21. Donation of blood or plasma within 30 days prior to first study drug administration, or loss of whole blood of more than 500 mL within 30 days prior to first study drug administration, or receipt of a blood transfusion within 1 year of first study drug administration
22. Participation in another clinical trial of an investigational drug within 60 days or 5 half-lives of the investigational agent (whichever is longer) prior to the first study drug administration
23. Any other condition or prior therapy that in the opinion of the Investigator would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements

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)

Allocation concealed. The compounding pharmacy holds the randomisation schedule and will prepare individual treatment doses labelled with the randomisation number and according to the randomisation schedule. The site will randomise participants and assign a randomisation number. Site pharmacy will dispense the individual dose to the correspondingly randomised participant

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

A computer generated randomisation schedule will be prepared by a statistician prior to preparation of individual study doses

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes

Intervention assignment

Other

Other design features

Sequential cohort study of single and multiple ascending doses of ANPA-0073-01 or placebo

Phase

Phase 1

Type of endpoint/s

Safety

Statistical methods / analysis

Safety and tolerability: Treatment-emergent adverse events (TEAEs) will be summarised by system organ class and preferred term for each dose group. Summaries of TEAEs by severity and relationship, TEAEs leading to death, serious TEAEs and for TEAEs leading to study withdrawal will also be presented.
Observed values and changes from baseline in vital signs, body weight, ECG parameters and continuous clinical laboratory parameters will be summarised at each scheduled timepoint by dose group using descriptive statistics (n, mean, standard deviation, minimum, maximum, median).
Pharmacokinetics: ANPA-0073 plasma concentrations at each timepoint will be listed and summarised by treatment using descriptive statistics (n, mean, standard deviation, coefficient of variation, minimum, maximum, median and geometric mean) for each dose group. Individual and mean ANPA-0073 plasma concentrations over time will be presented graphically with concentration displayed on a linear and logarithmic scale. A plot of mean plasma ANPA-0073 concentration for each dosing condition (fed vs fasted) will also be presented.
Pharmacokinetic parameters will be determined using noncompartmental methods and summarised by dose group using descriptive statistics (n, mean, standard deviation, coefficient of variation, minimum, maximum, median, geometric mean and geometric coefficient of variation).
The effect of food on the PK of ANPA-0073 (AUC0-inf, Cmax, and t1/2) will be examined.
Urine concentration-time data of ANPA-0073 will be used for the calculation of urine PK parameters. The pharmacokinetic parameters will be summarised by dose group using descriptive statistics

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

7/05/2021

Actual

7/05/2021

Date of last participant enrolment

Anticipated

29/04/2022

Actual

29/04/2022

Date of last data collection

Anticipated

11/05/2022

Actual

27/05/2022

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW

Recruitment hospital [1]

Scientia Clinical Research - Randwick

Recruitment postcode(s) [1]

2031 - Randwick

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Annapurna Bio Pty Ltd

Address [1]

c/o BDO Australia Ltd
Collins Square, Tower 4, Level 18
727 Collins Street
Docklands, VIC 3008, Australia

Country [1]

United States of America

Primary sponsor type

Commercial sector/Industry

Name

Avance Clinical Pty Ltd

Address

Level 1, 2 Ann Nelson Drive
Thebarton SA 5031

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry Limited Human Research Ethics Committee

Ethics committee address [1]

123 Glen Osmond Road Eastwood Adelaide
South Australia 5063

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

10/03/2021

Approval date [1]

20/04/2021

Ethics approval number [1]

Summary

Brief summary

This study aims to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of an experimental new drug, ANPA-0073 being developed for the treatment of Pulmonary arterial hypertension

Trial website

Trial related presentations / publications

Public notes

A COVID-19 PCR or antigen test may be performed, if clinically indicated, as determined by the Investigator. Participants with a positive result will not be allowed to continue in the study

Contacts

Principal investigator

Name

Dr Christopher Argent

Address

Scientia Clinical Research Ltd, Bright Building, Levels 5 & 6, corner High & Avoca Street, Randwick, 2031 NSW.

Country

Australia

Phone

+61 2 9382 5800

Fax

[email protected]

Contact person for public queries

Name

Lani Ibarra

Address

Annapurna Bio, Inc
611 Gateway Boulevard, Suite 223, South San Francisco, CA 94080, United States

Country

United States of America

Phone

+1 4158602352

Fax

[email protected]

Contact person for scientific queries

Name

Christopher Argent

Address

Scientia Clinical Research Ltd, Bright Building, Levels 5 & 6, corner High & Avoca Street, Randwick, 2031 NSW.

Country

Australia

Phone

+61 2 9382 5800

Fax

[email protected]

Data sharing statement

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

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

Source	Title	Year of Publication	DOI
Embase	AI-powered therapeutic target discovery.	2023	https://dx.doi.org/10.1016/j.tips.2023.06.010

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

Trial Review

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