Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000230459
Ethics application status
Approved
Date submitted
22/01/2025
Date registered
31/03/2025
Date last updated
17/08/2025
Date data sharing statement initially provided
31/03/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1 Randomized, Double-Blind, Placebo-Controlled Study With A Food Effect Assessment To Evaluate The Safety, Tolerability, And Pharmacokinetics Of Single Ascending Doses And Multiple Ascending Doses Of PX578 In Healthy Adult Participants (Part A & B)
Scientific title
A Phase 1 Randomized, Double-Blind, Placebo-Controlled Study With A Food Effect Assessment To Evaluate The Safety, Tolerability, And Pharmacokinetics Of Single Ascending Doses And Multiple Ascending Doses Of PX578 In Healthy Adult Participants (Part A & B)
Secondary ID [1] 313363 0
PX578-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Mitochondrial disease 335719 0
Condition category
Condition code
Human Genetics and Inherited Disorders 332286 332286 0 0
Other human genetics and inherited disorders
Neurological 333037 333037 0 0
Other neurological disorders
Musculoskeletal 333038 333038 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This Phase I healthy volunteer study will assess the safety, tolerability and pharmacokinetics (PK) of PX578 in healthy participants and will be conducted in 2 parts:

Part A:
Single ascending dose (SAD) evaluation of PX578 oral capsule or placebo will be administered a single dose on Day 1 at up to 6 fixed dose levels (in a total of 6 cohorts) in the range from 100 mg for Cohort 1, 250 mg for Cohort 2 and 500 mg for Cohort 3. For Cohorts 4, 5 and 6 the dose will be determined by the Safety Review Committee (SRC) based on safety, tolerability and PK data from previous cohorts up to a maximum dose of 1500 mg.

Part B:
Multiple ascending dose (MAD) evaluation PX578 oral capsule or placebo will be administered twice daily for 10 days at up to 6 fixed dose levels (in a total of 6 cohorts) . The dose for all cohorts will be determined by the SRC based on safety, tolerability and PK data from previous cohorts up to a maximum dose of 1500 mg.
Participants will be dosed at the site and will receive study drug directly from the Investigator or designee, under medical supervision. Drug administration will be recorded and any discrepancies with the dosing regimen will be documented and explained in the eCRF and the source documents. The dose of study drug and study participant identification will be confirmed at the time of dosing by a member of the study site staff other than the person administering the study drug.
Intervention code [1] 329948 0
Treatment: Drugs
Comparator / control treatment
Placebo capsule identical in appearance to study drug and containing 100% microcrystalline cellulose.
Control group
Placebo

Outcomes
Primary outcome [1] 339862 0
Composite Primary Outcome: To assess the safety and tolerability of PX578 when administered as single ascending oral doses in healthy adult participants
Timepoint [1] 339862 0
Adverse events will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5-point scale and assessed continuously as observed and reviewed daily from Day 1 until Day 8 End of Study/Early Termination Visit (EoS/ETV). Vital signs (blood pressure assessed using digital sphygmomanometer, heart rate and respiratory rate assessed using pulse oximeter, and temperature assessed using digital thermometer) will be assessed from Screening, pre-dose Day 1, 1, 2, 3, 4, 6, 8, 10 and 12 hrs post-dose, Day 2 24 hrs post-dose, Day 3 48 hrs post-dose, Day 4 72 hrs post-dose and Day 8 (EoS/ETV). ECG's will be conducted in triplicate at Screening, Day -1, pre-dose Day 1, 3 and 8 hrs post-dose, Day 2 24 hrs post-dose, Day 3 post-dose, Day 4 post-dose and ETV. Clinical laboratory blood and urine samples will be collected at Screening, Day -1, pre-dose Day 1, 2, 3, 4, 5, 6, 7, 8, 9 and Day 10 and post-dose Day 11, 12 and Day 17 (EoS/ETV).
Primary outcome [2] 339863 0
Composite Primary Outcome: To assess the safety and tolerability of PX578 when administered as multiple ascending oral doses in healthy adult participants
Timepoint [2] 339863 0
Adverse events will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5-point scale and assessed continuously as observed and reviewed daily from Screening until Day 17 End of Study/Early Termination Visit (EoS/ETV). Vital signs (blood pressure assessed using digital sphygmomanometer, heart rate and respiratory rate assessed using pulse oximeter, and temperature assessed using digital thermometer) will be assessed from Screening, pre-first dose Day 1, 1, 2, 3, 4, 6, 8 and 10 hrs post-first dose, Day 1 2 and 4 hrs post-second dose, anytime on Days 2, 3, 4, 5, 6, 7, 8 and 9, pre-first dose Day 10 1, 2, 3, 4, 6, 8 and 10 hrs post-first dose, anytime on Day 11, Day 12 and Day 17 (EoS/ETV). ECG's will be conducted in triplicate at Screening, Day -1, pre-dose Day 1, 3, 8 and 24 hrs post-dose, anytime on Days 2, 3, 4, 5, 6, 7, 8 and 9, pre-dose Day 10, 3, 8 and 24 hrs post-dose, anytime on Day 11, Day 12 and Day 17 (EoS/ETV). Clinical laboratory blood and urine samples will be collected at Screening, Day -1, pre-dose Day 1, Day 2 post-dose, Day 3 post-dose, Day 4 and Day 8 (EoS/ETV).
Secondary outcome [1] 441695 0
To assess the PK profile in plasma following single doses of PX578 in healthy adult participants
Timepoint [1] 441695 0
Blood samples will be collected pre-dose Day 1 - 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12 and 16 hrs post-dose, Day 2 - 24, 30 and 36 hrs post-dose and Day 3 48 hrs post-dose.
Secondary outcome [2] 441696 0
To assess the PK profile in plasma following multiple doses of PX578 in healthy adult participants
Timepoint [2] 441696 0
Blood samples will be collected pre-dose Day 1 - 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 hrs post-dose, pre-dose Days 2, 4, 6 and Day 8, pre-dose Day 10 - 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12 and 16 hrs post-dose, Day 11 - 24, 30 and 36 hrs post-dose and Day 12 48 hrs post-dose.
Secondary outcome [3] 441800 0
Exploratory Outcome: To evaluate the presence and PK of potential PX578 metabolites in plasma from healthy adult participants (Part A)
Timepoint [3] 441800 0
Blood samples will be collected pre-dose Day 1 - 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12 and 16 hrs post-dose, Day 2 - 24, 30 and 36 hrs post-dose and Day 3 48 hrs post-dose.
Secondary outcome [4] 441801 0
Exploratory Outcome: To evaluate the presence and PK of potential PX578 metabolites in plasma from healthy adult participants (Part B)
Timepoint [4] 441801 0
Blood samples will be collected pre-dose Day 1 - 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 hrs post-dose, pre-dose Days 2, 4, 6 and Day 8, pre-dose Day 10 - 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12 and 16 hrs post-dose, Day 11 - 24, 30 and 36 hrs post-dose and Day 12 48 hrs post-dose.

Eligibility
Key inclusion criteria
1. Must provide 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. Healthy male or female participant, 18-55 years of age at the time of signing informed consent.
3. Both male and female participants must agree to follow contraceptive requirements and gamete donation restrictions during the Screening period and for 90 days following the last dose of study drug.
4. A body mass index (BMI) of between 18 and 32 kg/m2 at Screening with a minimum body weight of 45 kg.
5. Hematocrit or hemoglobin levels within normal limits for age and sex at Screening and on Day -1, prior to dose administration.
6. Be willing and able to comply with all study assessments and adhere to the protocol schedule, procedures, and restrictions
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Clinically-significant medical history or ongoing chronic illness that, in the opinion of the study Investigator, would jeopardize the safety of the participant or compromise the integrity of the data derived from their participation in this study.
2. Clinically-significant infection of any kind requiring systemic antimicrobial therapy or hospitalization within 4 weeks prior to the first dose of study drug.
3. Clinically-significant abnormal findings at Screening on physical examination, ECG, or laboratory testing in the opinion of the Investigator.
4. QTcF > 470 ms (females) or > 450 ms (males) at Screening or Day -1 based on the mean of triplicate ECGs.
5. Liver test results during Screening or at check-in day (Day -1) that are above the upper limit of normal (ULN) for gamma-glutamyl transferase, bilirubin (total), aspartate aminotransferase (AST) or alanine aminotransferase (ALT), unless a diagnosis of Gilbert syndrome. For history of Gilbert syndrome, the limit is extended to 2-fold above the ULN.
6. Positive test results for hepatitis B surface antigen (HBsAg), hepatitis C (HCV) antibody or human immunodeficiency virus (HIV) antibody at Screening. Participants who are positive for HCV antibody but do not have active HCV (ie, test negative for HCV RNA on a polymerase chain reaction [PCR] test) are eligible for the study.
7. Estimated glomerular filtration rate (eGFR) <90 ml/min/1.73 m2 at Screening using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 formula.
8. History of active malignancy within 3 years prior to Screening, except basal cell carcinoma of the skin, curatively resected squamous cell carcinoma of the skin, cervical carcinoma in situ curatively treated or low-grade prostate adenocarcinoma for which appropriate management is observation alone.
9. History of surgery or hospitalization within 3 months prior to Screening, or surgery planned during the study.
10. History of hypersensitivity, allergic or anaphylactic reactions to the study drug ingredients or other therapeutic proteins.
11. History of drug or alcohol abuse (as defined by the Investigator) within 5 years prior to Screening, a positive urine drug or alcohol test at Screening or Day -1, or an unwillingness to abstain from drugs of abuse throughout the study, or from alcohol for 48 hours prior to Day -1 and for the duration of the study.
12. Participant smokes more than 5 cigarettes or equivalent nicotine-containing products per day, and/or is unwilling to abstain from smoking or the use of nicotine-containing products for 72 hours prior to check-in on Day -1 and throughout the study.
Note: 1 average cigar equals approximately 5 average cigarettes; 1 average pipe session equals approximately 5 average cigarettes; 1 average nicotine liquid vape session equals 1 average e-cigarette equals 1 average cigarette.
13. Has a positive urine screen for cotinine at Day -1.
14. Unwilling to abstain from caffeine containing products for 24 hours prior to Day -1 and for the duration of the study.
15. Unwilling to abstain from eating cruciferous vegetables, charcoal-grilled meats, and poppy seeds for 48 hours prior to Day -1 and for the duration of the study.
16. Unwilling to refrain from consumption of Seville oranges, grapefruit or grapefruit juice, [pomelos, exotic citrus fruits, grapefruit hybrids, or their juices] within 14 days of Day -1 and for the duration of the study.
17. Substance abuse, mental illness, or any reason that makes it unlikely in the judgment of the Investigator for the participant to be able to comply fully with study procedures.
18. Females who are pregnant (positive pregnancy test at Screening or during the study), lactating, or, if having reproductive potential, are considered potentially unreliable with respect to contraceptive practice.
19. Use of prescription medication (with the exception of oral contraceptives) within 7 days or 5 half-lives prior to initiation of study drug dosing (whichever is longer) and for the duration of the study.
20. Participant is using medications which are exogenous modulators of CYP pathways as identified in the Flockhart table (Flockhart Table)
21. Participant has taken over-the-counter medications including herbal/dietary supplements, protein powders/creatinine, or homeopathic preparations within 7 days prior to initiation of study drug dosing (within 28 days of Day -1 or 10 half lives, whichever is longer, for St John’s Wort). Prophylactic doses of vitamin/mineral supplements and occasional paracetamol or ibuprofen are allowed.
22. Participation in any clinical study of an investigational drug or investigational device within 30 days or 5 half-lives of the investigational drug (whichever is longer) prior to Day 1.
23. Administration of any live, attenuated vaccines within 30 days and all other vaccinations within 14 days prior to initiation of study drug dosing.
24. Participant has donated or lost greater than or equal to 400 mL blood in the 6 weeks prior to Day 1.
25. Participant is unable to swallow oral medication.
26. Participant has an inability to follow a standardized meal schedule and diet or inability to fast, as required by the study protocol.
NOTE: Potential study participants with abnormal laboratory values may be rescreened once for specific laboratory tests within the Screening period (up to 4 weeks prior to dosing) before being designated a Screen failure. Repeat values within the normal range must be confirmed at Day -1 for inclusion.

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)
All study participants who sign an informed consent form at Screening will receive a unique sequential number (a Screening Number). Participants to be dosed in either Part A or Part B will be assigned a randomization number prior to dose administration on Day 1 in accordance with the randomization schedule. The randomization schedules will be maintained under controlled access. A sealed envelope that contains the study drug assignment for each participant will be provided to the Investigator. The sealed envelope will be retained by the Investigator (or representative) in a secured area.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The allocation to PX578 or placebo will be performed using a block randomization algorithm and will be documented in the study randomization schedule.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
22/04/2025
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
112
Accrual to date
0
Final
Recruitment outside Australia
Country [1] 26730 0
New Zealand
State/province [1] 26730 0
Christchurch

Funding & Sponsors
Funding source category [1] 317804 0
Commercial sector/Industry
Name [1] 317804 0
Pretzel Therapeutics Inc.
Country [1] 317804 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Pretzel Therapeutics Inc.
Address
Country
United States of America
Secondary sponsor category [1] 320133 0
Commercial sector/Industry
Name [1] 320133 0
Avance Clinical Pty Ltd
Address [1] 320133 0
Country [1] 320133 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316487 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 316487 0
Ethics committee country [1] 316487 0
New Zealand
Date submitted for ethics approval [1] 316487 0
13/12/2024
Approval date [1] 316487 0
03/03/2025
Ethics approval number [1] 316487 0

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

Contacts
Principal investigator
Name 138054 0
Dr Christopher Wynne
Address 138054 0
New Zealand Clinical Research, Level 3, 264 Antigua Street, Christchurch 8011, New Zealand
Country 138054 0
New Zealand
Phone 138054 0
+64 272443963
Fax 138054 0
Email 138054 0
[email protected]
Contact person for public queries
Name 138055 0
Christopher Wynne
Address 138055 0
New Zealand Clinical Research, Level 3, 264 Antigua Street, Christchurch 8011, New Zealand
Country 138055 0
New Zealand
Phone 138055 0
+64 272443963
Fax 138055 0
Email 138055 0
[email protected]
Contact person for scientific queries
Name 138056 0
Christopher Wynne
Address 138056 0
New Zealand Clinical Research, Level 3, 264 Antigua Street, Christchurch 8011, New Zealand
Country 138056 0
New Zealand
Phone 138056 0
+64 272443963
Fax 138056 0
Email 138056 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No


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.