Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000736640
Ethics application status
Approved
Date submitted
7/06/2023
Date registered
7/07/2023
Date last updated
22/09/2024
Date data sharing statement initially provided
7/07/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
An open-label, multiple dose study to compare the single-dose
and steady-state pharmacokinetics of a 40 mg PHA-022121
extended-release (XR) tablet administered once daily between
healthy Japanese, Chinese, and Caucasian volunteers.
Scientific title
An open-label, multiple dose study to compare the single-dose
and steady-state pharmacokinetics of a 40 mg PHA-022121
extended-release (XR) tablet administered once daily between
healthy Japanese, Chinese, and Caucasian volunteers.
Secondary ID [1] 309798 0
PHA022121-C019 (Sponsor Number)
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hereditary Angioedema (HAE) 330232 0
Condition category
Condition code
Human Genetics and Inherited Disorders 327103 327103 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The following treatment will be given to all subjects:
• Multiple oral doses of 40 mg PHA-022121 (PHVS719 XR tablet) once daily on Days 1 to
5.
Water intake (except for the water to be given to swallow the XR tablets) will not be allowed for at least 1 hour prior to dosing. At 2 hours after dosing, subjects have to drink 150 mL. With lunch (4 hours post dose), subjects have to drink 250 mL Afterwards, water intake is ad libitum.
Dosing takes place under fasting conditions, subjects should fast for at least 10 hours. Fasting will be continued for at least 4 hours after dosing on Day 1 and 5 only.
On Day 1 to Day 5, lunch will be served 4 hours post daily dose, and dinner will be provided approximately 10-12 hours post daily dose.
Subjects will be admitted to the clinical site on Day -1. Plasma concentrations of PHA-022121 and its metabolites (e.g. M2-D) will be determined at pre-dose, over a 24-hour evaluation period after dosing on Day 1, and over a 72-hour evaluation period after dosing on Day 5.
Subjects will be discharged from the clinical site on Day 8 on the condition that all required assessments have been performed and there are no medical reasons for a prolonged stay. The clinical study will be completed with an end-of-study visit (ESV), which will take place between 5 and 9 days after the last treatment-defined assessment (or after early withdrawal).
The study duration is maximally 9 days (including Day -1), screening and ESV not included.
Safety and tolerability will be assessed throughout the study from signing off the informed consent form (ICF) onwards until the subject’s last study-related activity

Rationale of intervention is
1. To compare the single-dose and steady-state pharmacokinetics of PHA-022121 and its
metabolites (e.g. M2-D) after oral administration of a 40 mg XR PHA-022121 tablet
(PHVS719 XR tablet) once daily.
2. To investigate the safety and tolerability of multiple oral doses of PHA-022121 (PHVS719
XR tablet) in healthy Japanese, Chinese, and Caucasian volunteers
Intervention code [1] 326250 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 334966 0
To compare the single-dose and steady-state pharmacokinetics of PHA-022121 and its
metabolites (e.g. M2-D) after oral administration of a 40 mg XR PHA-022121 tablet
(PHVS719 XR tablet) once daily.

For PHA 022121 and its metabolites (e.g. M2-D) on Day 1 and 5:
• Cmax, tmax, AUC0-12, AUC0-24, AUClast (Day 1 only), t1/2, lambda z, Vz/F and CL/F (latter two only for PHA 022121 on Day 5), RA(Cmax) and RA(AUC) (the latter two only for Day 5)
• Ratio Cmax, M2-D/PHA 022121,
• Ratio AUC0 24, M2 D/PHA 022121
Timepoint [1] 334966 0
Blood samples:
Day 1: pre-dose, 0.25h (15min), 0.5h, 1h, 1.5h, 2h,3h,4h,5h,6h,7h,8h, 9h,10h,11h, 12h,13h,14h,16h,18h,19h,20h
Day 2: pre-dose
Day3: pre-dose
Day4: pre-dose
Day 5 to Day 8: pre-dose, 0.25h (15min), 0.5h, 1h, 1.5h, 2h,3h,4h,5h,6h,7h,8h, 9h,10h,11h, 12h,13h,14h,16h,18h,19h,20h, 24h, 36h, 48h, 72h
Secondary outcome [1] 422561 0
To investigate the safety and tolerability of multiple oral doses of PHA-022121 (PHVS719
XR tablet) in healthy Japanese, Chinese, and Caucasian volunteers

All standard safety assessments including:
physical examination,
vital signs: Blood pressure (systolic and diastolic) and pulse rate will be obtained at least after 5 minutes of rest in a supine position. Orthostatic blood pressure is measured after at least 2 minutes of standing. The body temperature will be measured by Temporal Artery Body Temperature and recorded. The respiratory rate (number of breaths per minute) will be measured as well.
adverse events: By inpatient monitoring/clinical examination, continuously throughout the study from signing ICF until the last study related activity.
hematology, chemistry, urinalysis,
ECG: ECG will be taken in triplicate at screening. On all other time points, single measurements will be taken. ECGs may be repeated at the discretion of the Investigator to rule out erroneous readings. Will be obtained at least after 5 minutes of rest in a supine position.

Currently, there are no clearly identifiable events of special interest defined for PHA-022121. A total of eight Phase I studies have been completed in heathy volunteers, with no deaths, related SAEs, or pregnancies reported by the Investigators. In addition, all TEAEs were assessed as mild to moderate in severity and resolved. In addition, no clinically significant changes in laboratory parameters, vital signs, or ECG intervals were reported. Two Phase 2 studies are currently enrolling subjects with HAE.
Timepoint [1] 422561 0
-Physical examination: Screening
-Vital signs, ECG: Screening, Day -1, Day 1, 3,5,6,8 post dose and end of study visit (day 13-17).
-Hematology, chemistry, urinalysis: Screening, Day -1, Day 3, 8 post dose, end of study visit (day 13-17).
-Adverse events: Continuously throughout the study from signing ICF until the last study-related activity.

Eligibility
Key inclusion criteria
1. Subject must sign an ICF indicating that the subject understands the purpose of the study
including the procedures required, potential risks involved, and is willing to participate in the study before starting any screening activities.
2. Subject must be healthy, between 18 to 65 years of age (inclusive)at the time of informed
consent.
3. Subject must have a body mass index (BMI; weight in kg divided by the square of height in meters) between 17.0 and 32.0 kg/m2, extremes included, and a body weight between 45.0 kg and100.0 kg (inclusive), at screening
4. A female subject may be enrolled if she is willing and able to adhere to the contraceptive
requirement as follows:
- documented to be surgically sterile or postmenopausal: Permanent sterilisation methods
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
- practicing true abstinence for at least 21 days prior to dosing and until 90 days after study
drug administration. The reliability of sexual abstinence needs to be evaluated if it is the
preferred and usual lifestyle of the subject.
- using two forms of medically acceptable and effective contraception:
1) where one should be a highly effective method such as a hormonal method (e.g.,
contraceptive implants, injectables, oral contraceptives), or a non-hormonal method
(e.g., intrauterine device), from Screening or at least 2 weeks prior to study drug
administration (whichever is earlier) until 90 days after the study follow-up visit,
2) and the other should be a physical barrier method.
Notes
- Two forms of above-mentioned contraception are not needed if the male partner is
sterilized.
- Contraception is not needed for same-sex contacts.
5. All female subjects must have a negative serum ß-human chorionic gonadotropin (ß-hCG)
pregnancy test at Screening and at Day -1 of each treatment period.
6. Subject must be willing and able to adhere to the prohibitions and restrictions as follows:
- Subject must remain at the clinical site throughout the study duration.
- Within 7 days before first study drug administration and throughout the study, the use of prescription and nonprescription medication (including vitamins and herbal supplements) other than the study drug are prohibited.
- The use of paracetamol is allowed up to 72 hours prior to the first study drug administration (Day 1). After that and at the discretion of the Investigator, a maximum of 1000 mg dose per day paracetamol, will be allowed for the treatment of headache or other pain.
- The use of hormonal contraceptives or hormonal replacement therapy is allowed for female subjects of child-bearing potential or post-menopausal respectively.
- Subject must not consume food or beverages containing alcohol or quinine (e.g., tonic water, bitter lemon, etc.) from 48 hours prior to admission to the clinical site and during clinical site confinement.
- Subject must not consume grapefruit or grapefruit juice, pomelo juice, star fruit, or Seville orange products starting from 72 hours before the first PK sample is drawn and during clinical site confinement.
- Subject must refrain from any methylxanthine containing products, (e.g., chocolate bars or chocolate beverages, coffee, teas, colas, etc.) from 48 hours before administration of study drug and during clinical site confinement.
- Subjects are advised not to consume food containing poppy seeds or codeine starting 72 hours before screening or 72 hours before admission to clinical site (in order to avoid false positive urine drug test).
- Subjects must consume standard institutional meals during confinement to the clinical site. Excessive food consumption will not be permitted.
- Subjects must refrain from the use of nicotine-containing substances, including tobacco products (e.g., cigarettes, e cigarettes, cigars, chewing tobacco, gum, or patch) while confined to the clinical site.
- If a subject has had a febrile illness 5 days before the first study drug administration, the first administration of study drug should be postponed until body temperature has been normalized for at least 72 hours.
- Subjects should avoid strenuous exercise (e.g., long distance running equal to 5 km/day, weight-lifting, or any physical activity to which the subject is not accustomed) and sunbathing from 96 hours before admission to the clinical site and while confined to the clinical site.
- Subjects must avoid donating blood for at least 60 days after completion of the study and are advised not to participate in an investigational drug study for at least 30 days after completion of the study.
- A female subject may be enrolled if she is willing and able to adhere to the contraceptive requirement as specified as follows:
- documented to be surgically sterile or postmenopausal: Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
- practicing true abstinence for at least 21 days prior to dosing and until 90 days after study drug administration. The reliability of sexual abstinence needs to be evaluated if it is the preferred and usual lifestyle of the subject.
- using two forms of medically acceptable and effective contraception:
1) where one should be a highly effective method such as a hormonal method (e.g., contraceptive implants, injectables, oral contraceptives), or a non-hormonal method (e.g., intrauterine device), from Screening or at least 2 weeks prior to study drug administration (whichever is earlier) until 90 days after the study follow-up visit,
2) and the other should be a physical barrier method.
Notes:
- Two forms of above-mentioned contraceptions are not needed if the male partner is sterilized.
- Contraception is not needed for same-sex contacts.

7. Subject must be healthy on the basis of a medical evaluation that reveals the absence of any
clinically relevant abnormality at screening per Investigator discretion.


Cohort 1: Japanese subjects (in addition) defined as follows
8. Japanese subjects are defined as first- or second- or third-generation Japanese of full Japanese parentage. No specific distribution among the generations is required.

Cohort 2: Chinese subjects (in addition) defined as follows
9. Chinese subjects are defined as first- or second- or third-generation Chinese of full Chinese parentage. No specific distribution among the generations is required.

Cohort 3: Caucasian subjects (in addition)
10. Subjects must be Caucasian, which is identified as of European, Middle Eastern, or North African descent.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Subject has a history of current clinically significant medical illness including (but not limited to) cardiac arrhythmias or other cardiac disease, hematologic disease, lipid abnormalities, significant pulmonary disease, including bronchospastic respiratory disease, diabetes mellitus, hepatic or renal insufficiency (estimated creatinine clearance < 90 mL/min/1.73m2 at screening, calculated by Crockfault-Gault formula), thyroid disease, neurologic or psychiatric
disease, infection, or any other illness, that in the investigator’s and/or sponsor’s medical
monitor opinion should exclude the subject or that could interfere with the interpretation of the study results.
2. Subject has one of the following laboratory abnormalities at screening as defined by the
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, 27 November 2017
and in accordance with the normal ranges of the clinical laboratory if no gradings are available.
-Serum creatinine elevation grade 1 or greater than (>1.1 x upper limit of normal range [ULN])
-Hemoglobin below lower limit of normal range (LLN), per Investigator discretion
-Platelet count below LLN, per Investigator discretion
-Absolute neutrophil count lowering grade 1 or greater than and equal to (1.5 109/L)
-Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > (greater than) ULN
-Total bilirubin > (greater than) ULN
-Any other toxicity grade 2 or above, except for grade 2 elevations for triglycerides, low density lipoprotein (LDL) cholesterol and/or total cholesterol.

3. Subject underwent surgery or has a medical condition that might significantly affect absorption of medicines (e.g., stomach bypass, cholecystectomy, etc.) as judged by the Investigator.
4. Subject has clinically significant abnormal values for hematology, clinical chemistry or
urinalysis at screening or at admission to the clinical site on Day -1 as judged by the
investigator.
5. Subject, at screening, has a positive test of human immunodeficiency virus (HIV) 1 and 2
antibodies, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibodies.
6. Subject has a history of heart arrhythmias, tachycardia at rest, or history of risk factors for
Torsade de Pointes syndrome (e.g., hypokalemia, family history of long QT syndrome, etc.).
7. Subject has known allergies, hypersensitivity, or intolerance to PHA-022121’s excipients.
8. Subject received a known potent inhibitor of cytochrome CYP3A activity (e.g., erythromycin, clarithromycin, ketoconazole or itraconazole) within 30 days before the first dose of the study drug is scheduled.
9. Subject received a strong inducer of CYP3A activity (e.g., rifampin, St. John’s Wort) within
30 days before the first dose of study drug is scheduled.
10. Subject used any prescription or nonprescription medication (including vitamins and herbal supplements) within 7 days before first study drug administration is scheduled. The use of paracetamol (maximum 1000 mg per day) is allowed up to 72 hours prior to the first study drug administration (Day 1). The use of hormonal contraceptives is allowed for female
subjects with child-bearing potential and the use of hormonal replacement therapy is allowed for post-menopausal female subjects.
11. Subject has an average intake of more than 21 units of alcohol per week for males or 14 unites of alcohol for females. One (1) unit of alcohol equals approximately 250 mL of beer, 100 mL of wine, or 35mL of spirits.
12. Subject has a history of drug or alcohol abuse according to Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-V) criteria within 6 months before screening or is currently abusing alcohol.
13. Subject has a positive test result for alcohol or drugs of abuse including Amphetamines (AMP), Methamphetamines (MET), Methadone (MTD), Barbiturates (BAR), Benzodiazepines (BZO), Cocaine (COC), Opiates (OPI), Methylenedioxymethamphetamine (MDMA), Phencyclidine (PCP), and Tetrahydrocannabinol (THC) at screening or on Day -1.
14. Subject drinks on average more than approximately 500 mg caffeine per day (for example, as contained in 8 xanthine containing drinks).
15. Subject refuses to refrain from smoking while admitted in the clinic.
16. Subject smokes more than 5 cigarettes or equivalent per day.
17. Subject has a lack of adequate venous access for study required laboratory testing and PK sampling.
18. Subject has a current and ongoing history of urinary retention.
19. Female subject who is pregnant or breast-feeding at screening or Day -1, or plans to become pregnant during the study and up to 90 days after the last study drug administration.
20. Subject has received
• an investigational drug (including investigational vaccines) or used an invasive
investigational medical device within 30 days before the planned first study drug
administration, or 5 times the half-life of the drug (if known), whichever is longer;
• or is currently enrolled in an investigational study;
• or has been exposed to more than three new investigational agents within 12 months
prior to study drug administration.
21. Subject has donated blood or blood products or had substantial loss of blood (more than 500 mL) within 60 days before the planned first study drug administration.
22. Subject has preplanned surgery or procedures that would interfere with the conduct of the study.
23. Vulnerable subjects (e.g., subjects who are not capable of giving consent and persons who have been committed to an institution by way of official or judicial order, or incarcerated individuals).
24. Subject is an employee of the investigator or clinical site, with direct involvement in the
proposed study or other studies under the direction of that investigator or clinical site, as well as family members of the employees or the investigator, or subject is an employee of the sponsor.
25. Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

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
3 cohorts:
- Cohort 1: twelve (12) Japanese healthy adult;
- Cohort 2: twelve (12) Chinese healthy adult;
- Cohort 3: twelve (12) Caucasian healthy adult.
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
This is an exploratory study and no sample size calculation was performed. Based on PHA-022121 Phase I data, 10 subjects per arm was sufficient to adequately describe PK profiles. The sample size of 12 enrolled subjects per cohort to have at least 10 subjects per cohort
completing the study is a customary sample size employed in Phase I ethno-bridging
pharmacokinetic studies of similar design and objectives, and it is considered sufficient to fulfill the objectives of the study.

Descriptive statistics will be calculated for the plasma concentrations of PHA-022121 and its
metabolites and for the derived PK parameters, as applicable. Plasma concentration data per cohort at each time point will be summarized with mean, median, minimum, maximum, standard deviation (SD), percent coefficient of variation, and geometric mean for all subjects who receive study drug.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
21/08/2023
Actual
25/09/2023
Date of last participant enrolment
Anticipated
3/11/2023
Actual
4/01/2024
Date of last data collection
Anticipated
11/11/2023
Actual
4/01/2024
Sample size
Target
36
Accrual to date
Final
36
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 24882 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 40531 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 313981 0
Commercial sector/Industry
Name [1] 313981 0
Pharvaris Netherlands B.V.
Country [1] 313981 0
Netherlands
Primary sponsor type
Commercial sector/Industry
Name
Pharvaris Netherlands B.V.
Address
J.H. Oortweg 21
2333 CH Leiden
The Netherlands
Country
Netherlands
Secondary sponsor category [1] 315937 0
None
Name [1] 315937 0
Address [1] 315937 0
Country [1] 315937 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313118 0
Alfred Health Ethics & Research Governance
Ethics committee address [1] 313118 0
Ethics committee country [1] 313118 0
Australia
Date submitted for ethics approval [1] 313118 0
26/06/2023
Approval date [1] 313118 0
03/08/2023
Ethics approval number [1] 313118 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 127058 0
Dr Sam Lourdesan Francis
Address 127058 0
Nucleus Network Melbourne
Level 5, Burnet Tower, 89 Commercial Rd, Melbourne 3004, Victoria
Country 127058 0
Australia
Phone 127058 0
+61 03 8593 9800
Fax 127058 0
Email 127058 0
[email protected]
Contact person for public queries
Name 127059 0
Emily Jochim
Address 127059 0
Pharvaris Netherlands B.V.
Leiden Bio Science Park
J.H. Oortweg 21
2333 CH Leiden
The Netherlands
Country 127059 0
United States of America
Phone 127059 0
+16173124434
Fax 127059 0
Email 127059 0
[email protected]
Contact person for scientific queries
Name 127060 0
Raf Crabbe
Address 127060 0
Pharvaris Netherlands B.V.
Leiden Bio Science Park
J.H. Oortweg 21
2333 CH Leiden
The Netherlands
Country 127060 0
Netherlands
Phone 127060 0
+41 79 470 09 44
Fax 127060 0
Email 127060 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


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.