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Trial registered on ANZCTR


Registration number
ACTRN12622000657729
Ethics application status
Approved
Date submitted
7/01/2022
Date registered
4/05/2022
Date last updated
25/08/2022
Date data sharing statement initially provided
4/05/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I, Open Label Study to Evaluate the Drug-Drug Interaction (DDI) of ANPA-0073 and Sildenafil in Healthy Subjects
Scientific title
A Phase I, Open Label Study to Evaluate the Drug-Drug Interaction (DDI) of ANPA-0073 and Sildenafil in Healthy Subjects
Secondary ID [1] 306104 0
ANPA-0073-02
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary arterial hypertension (PAH) 324772 0
Condition category
Condition code
Cardiovascular 322222 322222 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
ANPA-0073 oral capsules at the dose strength of 100 mg will be used in this study. Commercially available sildenafil oral tablets (brand name: Viagra®) at the dose strength of 50 mg will be used in this study.

This study will assess the effect of ANPA-0073 on the PK of sildenafil (and vice versa) using a single sequence, 3-period design.

On Day 1 (Period 1), participants will receive a single dose of 50 mg sildenafil. On Days 2-7 (Period 2), participants will receive ANPA-0073, 300-500mg once daily at about the same time(s) each day. On Day 8 (Period 3) participants will receive concurrent administration of a single dose of ANPA-0073 (dose level TBC) and a single dose of 50 mg sildenafil.

Participants will receive study drugs (ANPA-0073 capsules and sildenafil tablets) orally with noncarbonated room temperature water (approximately 240 mL) under the supervision of site staff.

The dose level of ANPA-0073, and final dosing schedule (i.e. once or twice daily
administration) to be used in this study will be determined from emerging safety and PK data from the ongoing ANPA-0073-01 study. The dose level of ANPA-0073 will not exceed that which has been shown to be safe and well tolerated in the ANPA-0073-01 study. Participants will be discharged on Day 11.
Intervention code [1] 322524 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 330000 0
To determine the effect of ANPA-0073 on the pharmacokinetics (PK) of sildenafil (a CYP3A4substrate), including its active N-demethylated metabolite UK-103 320, and to determine the effect of sildenafil on the PK of ANPA-0073.

The primary PK parameters of interest include Cmax, Tmax, t1/2, AUC0-last, AUC0-inf, Lambda-z, CL/Fand Vz/F for plasma.
Timepoint [1] 330000 0
Timepoints measured to determine the effect of ANPA-0073 on the pharmacokinetics (PK) of sildenafil:

Day 1: pre-drug administration and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-drug administration
Day 8: pre-drug administration and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours post-drug administration
Early termination, if appropriate

Timepoints measured to determine the effect of sildenafil on the PK of ANPA-0073:

Day 2: pre-drug administration and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-drug administration
Day 6: pre-drug administration
Day 7: pre-drug administration and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-drug administration
Day 8: pre-drug administration and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours post-drug administration
Early termination, if appropriate
Secondary outcome [1] 404538 0
These will be addressed as a composite.

To assess the safety and tolerability of ANPA-0073 in the presence of sildenafil in healthy adult volunteers.

Safety and tolerability endpoints include:
• Incidence, severity and relationship of Adverse Events/Serious Adverse Events (including withdrawals due to Adverse Events) assessed by clinical examination and participant self-report. Known/Possible adverse events include: dizziness (1 participant), increased creatinine kinase enzymes which could be an indication of reversible muscle damage (1 participant), fast heartbeat (1 participant), heart palpitations (1 participant), a delay in conduction of electrical signals in the heart (1 participant), and headache (1 participant). These side effects were all mild in nature.
• Change from baseline in vital signs and body weight. Observed values and changes from baseline for vital signs (systolic and diastolic BP, HR, body temperature, and RR) and body weight. Blood pressure and heart rate is assessed using a sphygmomanometer, body temperature by thermometer and body weight by sphygmomanometerm digital scales.
• Change from baseline in electrocardiogram (ECG) parameters. The following ECG parameters will be analysed: PR interval, QT interval, QRS duration, QTcF and ventricular HR. Observed values and changes from baseline. For QTcF, the number of participants with values greater than 450, and 480, and 500 msec or an increase from baseline of at least 30 and 60 msec will also be presented,
• Change from baseline in clinical laboratory parameters (haematology, serum chemistry, coagulation and urinalysis).
Timepoint [1] 404538 0
Assessed at the following timepoints:
Incidence, severity and relationship of AEs/SAEs - Day -1, Day 1,2,3,4,5,6,7,8, pre and post dose, Day 9, Day 10 and Day 11. Follow up, Day 15 - End of Study visit, Early Termination.
Vital signs & ECG: Screening, Day -1, Day 1 Pre-dose, 2 and 6 hours post dose, Day 2 24 hours post dose, Day 2: 2 and 6 hours post dose, Day 3,4,5 & 6 pre-dose, Day 7 pre-dose, Day 8 (ANPA-0073 and sildenafil) pre-dose, 2 and 6 hours post dose, Day 9 24 hours post final dose, Day 10 48 hours post final dose, Day 11 72 hours post final dose, Day 15 - End of Study Visit, Early Termination
Body weight: Screening, Day 11, BMI to be calculated using the height value recorded at screening.
Clinical Laboratory Samples: Screening, Day -1, Day 2 24 hours post dose, Day 3 and 5 pre-dose, Day 7, Day 9 24 hours post final dose, Day 11 72 hours post final dose, Day 15 - End of Study Visit, Early Termination.

Eligibility
Key inclusion criteria
Healthy Volunteers may be included if they satisfy at least the following key criteria:
1. Body mass index greater than or equal to 18.0 and less than or equal to 30.0 kg/m2, with a body weight (to 1 decimal place) greater than or equal to 45 kg at screening.
2. Be non-smokers (including tobacco and e-cigarettes) for at least 3 months prior to first study drug administration and have a negative test for carbon monoxide (breath test) at the screening visit and at check-in on Day -1.
3. Medically healthy without clinically significant abnormalities (in the opinion of the Investigator) at the screening visit and prior to dosing at the timepoints
4. 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 greater than 40 IU/L at the screening visit), or
b. If of childbearing potential (and not exclusively in same-sex relationships), 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.
5. 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.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Healthy volunteers will be excluded if there is evidence of any of the following at the screening visit or prior to dosing at the timepoints
1. History or presence of significant cardiovascular, pulmonary, hepatic, renal, haematological,gastrointestinal, endocrine, immunologic, psychiatric, dermatologic or neurological disease , including anyacute 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 antiviralmedications.
3. Any history of malignant disease in the last 10 years (excludes surgically resected skin squamous cell orbasal cell carcinoma).
4. Presence of clinically relevant immunosuppression from, but not limited to, immunodeficiencyconditions 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 priorto the first study drug administration.
6. History of risk factors for torsade de pointes (including a family history of long QT syndrome or suddencardiac death) or a known arrythmia.
7. History of substance abuse or alcohol abuse (defined as more than 10 standard drinks per week orregularly consuming more than 4 standard drinks on any one day; where 1 standard drink is 10 g of purealcohol 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.
8. Positive drugs of abuse or alcohol breath test results at the screening visit or at check-in (Day -1).
9. Use of any prescription or over-the-counter medication (including herbal products, diet aids, andhormone supplements) within 10 days or 5 half-lives of the medication (whichever is longer) prior to thefirst study drug administration, except use of contraceptives and occasional use of paracetamol (doses of500 mg up to every 6 hours or 2 g per day maximum for no more than 3 consecutive days) or ibuprofen (upto a maximum of 4 doses of 200 mg per day).
10. Demonstrated clinically significant (required intervention, e.g., emergency room visit, epinephrineadministration) allergic reactions (e.g., food, drug, or atopic reactions, asthmatic episodes) which, in theopinion of the Investigator, would interfere with the volunteer’s ability to participate in the trial.
11. Have received any vaccinations within 14 days prior to the first study drug administration.
12. For women of childbearing potential, a positive serum pregnancy test at the screening visit or a positiveurine pregnancy test (with confirmatory serum pregnancy test) at check-in (Day -1).
13. Females who are breastfeeding or planning to breast feed at any time during the study.
14. Participation in another clinical trial of where an investigational drug was administered, within 5 half-lives of the investigational agent (whichever is longer) prior to the first study drug administration.

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 design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Sponsor Annapurna Bio Pty Ltd. has terminated activities related to this study as the clinical development strategy for ANPA-0073 is being re-evaluated
Date of first participant enrolment
Anticipated
19/05/2022
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
16
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 21417 0
Scientia Clinical Research - Randwick
Recruitment postcode(s) [1] 36309 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 310456 0
Commercial sector/Industry
Name [1] 310456 0
Annapurna Bio Pty Ltd (the Australian entity of Shouti, Inc)
Country [1] 310456 0
Australia
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] 311601 0
None
Name [1] 311601 0
Address [1] 311601 0
Country [1] 311601 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310090 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 310090 0
123 Glen Osmond Rd, Eastwood SA 5063
Ethics committee country [1] 310090 0
Australia
Date submitted for ethics approval [1] 310090 0
16/02/2022
Approval date [1] 310090 0
07/04/2022
Ethics approval number [1] 310090 0

Summary
Brief summary
This study will assess the effect of ANPA-0073 on the PK of sildenafil (and vice versa) using a single sequence, 3-period design.
Participants will receive a single dose of 50 mg sildenafil on Day 1, ANPA-0073 on each Day 2 to 7, single dose of 50 mg sildenafil + single dose of ANPA-0073 on Day 8.
The total maximum study duration for participants is 44 days, inclusive of screening and visit windows. For each participant, the confinement period will commence on Day -1, with dosing commencing on Day 1 and continuing to Day 8, and discharge on Day 11. Participants will return to the clinic on Day 15 (± 1 day) for a final EoS visit.
It is anticipated that ANPA-0073 will help treat patients with pulmonary arterial hypertension (PAH),. The results from this study will form the basis for further evaluation of ANPA 0073 and dose and formulation selection for future studies.
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 116430 0
Dr Christopher Argent
Address 116430 0
Scientia Clinical Research Ltd, Bright Building, Levels 5 & 6, corner High & Avoca Street, Randwick, 2031 NSW
Country 116430 0
Australia
Phone 116430 0
+61 2 9382 5800
Fax 116430 0
Email 116430 0
christopher.argent@scientiaclinicalresearch.com.au
Contact person for public queries
Name 116431 0
Mr Michael Pelayo
Address 116431 0
Annapurna Bio, Inc
611 Gateway Boulevard, Suite 223, South San Francisco, CA 94080
Country 116431 0
United States of America
Phone 116431 0
+1 628 200 8547
Fax 116431 0
Email 116431 0
michael.pelayo@shoutipharma.com
Contact person for scientific queries
Name 116432 0
Dr Christopher Argent
Address 116432 0
Scientia Clinical Research Ltd, Bright Building, Levels 5 & 6, corner High & Avoca Street, Randwick, 2031 NSW
Country 116432 0
Australia
Phone 116432 0
+61 2 9382 5800
Fax 116432 0
Email 116432 0
christopher.argent@scientiaclinicalresearch.com.au

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.