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Trial registered on ANZCTR


Registration number
ACTRN12622001067763
Ethics application status
Approved
Date submitted
28/07/2022
Date registered
2/08/2022
Date last updated
17/10/2022
Date data sharing statement initially provided
2/08/2022
Date results information initially provided
2/08/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
A first-in-human, randomized, double-blind, placebo-controlled, single ascending dose and multiple ascending dose (SAD/MAD) study of ENN0403 in healthy subjects
Scientific title
A Phase 1, first-in-human, 2-part, randomized, double-blind, placebo-controlled, parallel-group, single ascending dose and multiple ascending dose (SAD/MAD) study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ENN0403 in healthy adult subjects.
Secondary ID [1] 307645 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Nonalcoholic steatohepatitis (NASH) 327150 0
Diabetic retinopathy 327223 0
Pulmonary fibrosis 327224 0
Condition category
Condition code
Inflammatory and Immune System 324287 324287 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment Drug: ENN0403 oral capsules
1. Part A, Single Ascending Dose (SAD) Arms: Part A evaluates single-dose administration of ENN0403 at dose levels 1, 4, 10, 20 and 30 mg respectively in cohort A1-A5. The dose level of 20 mg has also been evaluated in a preliminary Food Effect (FE) study in cohort A6. While cohrot A1-A5 will receive a single dose of investigational drug under fasted state (after an overnight fast of at least 10 hours prior to dosing), cohort A6 will receive a high calorie (approximately 800 to 1000 calories) and high-fat (approximately 50% of total caloric content of the meal) breakfast meal following an overnight fast of at least 10 hours; the investigational drug will be administered 30 minutes after the start of the meal.
2. Part B, Multiple Ascending Dose (MAD) Arms: Part B evaluates multiple dose administration of ENN0403 at 6, 12, and 20 mg once daily (QD) for 14 consecutive days, respectively in cohort B1-B3.

Each cohort included 8 subjects (6 receiving ENN0403 and 2 receiving placebo). Each subject will be enrolled in only 1 cohort and receive only one dose regimen in this study.
Dosing will be escalated in a sequential fashion, contingent on a review of safety, tolerability, and available PK data of the previous dose level by a Safety Review Committee (SRC). The MAD study will commence only after SRC review of the data from Cohort A3 in Part A (SAD study) and cumulative data from previous completed cohorts. Further dose level decisions for Part B will be guided by the emerging safety, tolerability, PK, and PD data from Part A as well as completed cohorts of Part B.

All dose administrations will be performed at the study site under the supervision of appropriately trained staff. A hand and mouth check will be performed following each dose administration to make sure the dose has been swallowed. The details of investigational drug administration will be recorded in both the source documents and eCRF(electronic Case Report Form).
Intervention code [1] 324101 0
Treatment: Drugs
Comparator / control treatment
Treatment Drug: ENN0403 placebo oral capsules; placebo will contain excipients only, with powder-in-capsule using hard gelatin capsules (identical in appearance to ENN0403 capsules) outside.
1. Part A, SAD Arms: Single dose administration of ENN0403 placebo capsules at 1, 4, 10, 20 and 30 mg respectively in cohort A1-A5. The dose level of 20 mg has also been evaluated in a preliminary Food Effect (FE) study in cohort A6, for which 20 mg placebo capsules will be administrated.
2. Part B, MAD Arms: Multiple dose administration of ENN0403 placebo capsules at 6, 12, and 20 mg once daily (QD) for 14 consecutive days, respectively in cohort B1-B3.
Control group
Placebo

Outcomes
Primary outcome [1] 332099 0
To evaluate the safety and tolerability of ENN0403 following single and multiple dose
administration in healthy adult subjects. The safety parameters to be assessed include
AEs/SAEs, and changes in clinical laboratory tests, vital signs, 12-lead ECG, and physical
examinations from baseline.

Adverse events will be reported by the subject. The Investigator and any designees are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE. Events meeting the AE definition include:
• Any abnormal laboratory test results (hematology, coagulation, clinical chemistry, or urinalysis) or other safety assessments (eg, ECG, vital signs measurements, or physical examinations), including those that worsen from baseline, considered clinically significant in the medical and scientific judgment of the Investigator.
• Exacerbation of a chronic or intermittent preexisting condition including either an increase in frequency and/or intensity of the condition.
• New conditions detected or diagnosed after IP administration although it may have been present before the start of the study.
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either IP or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae. Severity categories of AE assessment include mild, moderate and severe, as defined below-
• Mild: An AE that is easily tolerated by the subject, causes minimal discomfort, and does not interfere with everyday activities.
• Moderate: An AE that is sufficiently discomforting to interfere with normal everyday activities; intervention may be needed.
• Severe: An AE that prevents normal everyday activities; treatment or other intervention usually needed.

Vital signs measurements will include tympanic body temperature, pulse rate, and blood pressure. Blood pressure and pulse rate will be assessed with a completely automated device; manual techniques will be used only if an automated device is not available.
Timepoint [1] 332099 0
1. Single Ascending Dose arms: Day -1 (the day before dosing) to Day 8 (7 days post-dose)
Clinical laboratory tests will be assessed on Day -1, Day 2, Day 4 and Day 8.
Complete physical examinations will be assessed at screening and Day 8, while symptom-directed physicial examinations will be assessed at all visits.
Vital signs will be assessed on Day -1, Day 1, Day 2, Day 4 and Day 8.
12-Lead ECG will be assessed on Day -1, Day 1, Day 2, Day 4 and Day 8.
AEs/SAEs will be assessed at all timepoints.

2. Multiple Ascending Dose arms: Day -1 to Day 21 (7 days post-last dose)
Clinical laboratory tests will be assessed on Day 2, Day 4, Day 6, Day 8, Day 10, Day 12, Day 15 and Day 21.
Complete physical examinations will be assessed at screening and Day 21, while symptom-directed physicial examinations will be assessed at all visits.
Vital signs will be assessed on Day -1, Day 1, Day2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 10, Day 12, Day 14, Day 15, Day 17 and Day 21.
12-Lead ECG will be assessed on Day -1, Day 1, Day2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 10, Day 12, Day 14, Day 15, Day 17 and Day 21.
AEs/SAEs will be assessed at all timepoints.
Secondary outcome [1] 412207 0
To characterize the plasma PK profile and determine dose proportionality of ENN0403 following single and multiple dose administration in healthy adult subjects.
• Characterize plasma concentration-time profile of ENN0403.
• The assessed plasma PK parameters are:
o Part A (SAD): Cmax, AUC0-inf, AUC0-last, Tmax, MRT, Kel, t1/2, CL/F, and Vz/F.
o Part B (MAD): Css,max, Css,av, Css,min, AUC0-tau, AUC0-last, Tmax, MRTss, Kel, t1/2, CL/F, Vz/F, Rac(Cmax), Rac(AUC0-tau), and DF.
• A regression power model, relating log-transformed Cmax and AUC parameters to log-transformed dose, will be used to investigate dose proportionality.
Timepoint [1] 412207 0
Single Ascending Dose arms: blood samples collected at pre-dose, 0.25,0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 and 72 hours post-dose.

Multiple Ascending Dose arms: blood samples collected at Day 1 and Day 7 pre-dose,0.25, 0.5, 1, 1.5,2, 4, 6, 8, 12 and 24 hours (sample to be collected prior to dosing on Days 2 and 8) post-dose; Day 14 , pre-dose,0.25, 0.5, 1, 1.5,2, 4, 6, 8, 12, 24 (Day 15) and 72 hours(Day17) post-dose.
Secondary outcome [2] 412484 0
To evaluate the PD effect of ENN0403 on target engagement activity in plasma following single and multiple dose administration in healthy adult subjects; this is assessed as an exploratory outcome, via evaluating change in plasma target engagement (%) activity from baseline and exposure-response relationship.
Timepoint [2] 412484 0
PD blood sampling timepoints: Part A, SAD: predose, and 15 min, 30 min, 1h, 1.5h, 2h, 4h, 6h, 8h, 12h, 24h, 72h, 168h postdose. Part B, MAD: 1) Days 1 and 7: predose, and 30 min, 1.5h, 4h postdose 2) Days 2 and 8: 24h post Day 1 and Day 7 dose (sample to be collected prior to dosing on Days 2 and 8) 3) Day 14: predose, and 4h postdose 4) Day 15: 24h postdose 5) Day 17: 72h postdose 6) Day 21: 168h postdose

Eligibility
Key inclusion criteria
1. Capable of giving signed informed consent
2. 18 to 55 years old (inclusive)
3. BMI of 18 to 30 kg/m2 (inclusive); body weight >50 to <100 kg for male subjects or >45 to <100 kg for female subjects
4. Computerized (12-lead) ECG recording without signs of clinically relevant pathology or
showing no clinically relevant deviations as judged by the PI
5. Test negative for COVID-19
6. Test negative for HBsAg, anti-HBc, anti-hepatitis C virus (HCV) antibodies, anti-human immunodeficiency virus (HIV) 1 and 2 antibodies, and tuberculosis.
9. Have a negative urine drug screen and a negative alcohol breath test.
10. Nonsmoker or occasional smoker and willingness to refrain from smoking during study.
11. Ability and willingness to abstain from alcohol during study.
13. not pregnant, not breastfeeding; apply contraception methods for child-bearing potential subjects.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease in the opinion of the Investigator within 12 months prior to Screening.
2. Any disease or take any medication that affects IP absorption, distribution, metabolism, and excretion.
3. Family history of sudden death or of congenital prolongation of the QTc interval or known congenital prolongation of the QTc interval or any clinical condition known to prolong the QTc interval.
4. Presence of malignancy including hematological malignancies. Subjects with a history of basal cell or squamous cell carcinoma that has been treated with no evidence of recurrence within 3 years of Screening will be allowed for inclusion, as judged by the Investigator.
5. Any current active infections, including localized infections, or any recent history (within 1 week prior to IP administration) of active infections, cough or fever; or a history of recurrent or chronic infections.
6. In the 12-lead ECG assessment, QTcF >450 ms for male subjects or >470 ms for female subjects.
7. Estimated glomerular filtration rate <90 mL/min (using the Cockcroft-Gault formula) at Screening.
8. ALT or aspartate aminotransferase >1.5 × ULN.
9. Have received any live vaccines (bacterial or viral) within 12 weeks prior to Screening or intend to receive a live vaccine during the study period or within 30 days after the last dose of the IP.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



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

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
17/02/2021
Date of last participant enrolment
Anticipated
Actual
22/03/2022
Date of last data collection
Anticipated
Actual
16/05/2022
Sample size
Target
72
Accrual to date
Final
69
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 311907 0
Commercial sector/Industry
Name [1] 311907 0
EnnovaBio Australia Pharmaceuticals Pty Ltd
Country [1] 311907 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
EnnovaBio Australia Pharmaceuticals Pty Ltd
Address
Level 17, HWT Tower, 40 City Road SOUTHBANK, VIC.3006
Country
Australia
Secondary sponsor category [1] 313391 0
None
Name [1] 313391 0
Address [1] 313391 0
Country [1] 313391 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311343 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 311343 0
123 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 311343 0
Australia
Date submitted for ethics approval [1] 311343 0
Approval date [1] 311343 0
28/01/2021
Ethics approval number [1] 311343 0

Summary
Brief summary
This is a FIH, randomized, double-blind, placebo-controlled, dose-escalation study to investigate the safety, tolerability, PK, and PD of ENN0403 after single and multiple oral dose administration in healthy adult subjects. The study will include 2 parts which will proceed in a parallel staggered manner: Part A, a single ascending dose (SAD) study and Part B, a multiple ascending dose (MAD) study.

Approximately 80 healthy adult subjects will be enrolled at a single site in Australia, in up to 6 cohorts in Part A (SAD study), including a Food Effect (FE) study, and up to 4 cohorts in Part B (MAD study). Part A is for the single dose use of IP, while Part B is once daily use for 14 consecutive days. Each cohort will include 8 subjects (6 receiving ENN0403 and 2 receiving placebo). Each subject will be enrolled in only 1 cohort and receive only one dose regimen in this study.

Dosing will be escalated in a sequential fashion, contingent on a review of safety, tolerability, and available PK data of the previous dose level by a Safety Review Committee (SRC). The proposed dose levels/dosing frequency of ENN0403 may be adjusted over the course of the whole study and cohorts may be added or removed depending on the emerging safety, tolerability, and available PK data.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 120782 0
Dr Sepehr Shakib
Address 120782 0
CMAX Clinical Research Pty Ltd
Level 5, 18a North Terrace Adelaide SA 5000
Country 120782 0
Australia
Phone 120782 0
+61 882222763
Fax 120782 0
Email 120782 0
Sepehr.shakib@sa.gov.au
Contact person for public queries
Name 120783 0
Dr Sepehr Shakib
Address 120783 0
CMAX Clinical Research Pty Ltd
Level 5, 18a North Terrace Adelaide SA 5000
Country 120783 0
Australia
Phone 120783 0
+61 882222763
Fax 120783 0
Email 120783 0
Sepehr.shakib@sa.gov.au
Contact person for scientific queries
Name 120784 0
Dr Jianyong Shou
Address 120784 0
EnnovaBio Australia Pharmaceuticals Pty Ltd
Level 17, HWT Tower, 40 City Road, Southbank, Victoria 3006, Australia.
Country 120784 0
Australia
Phone 120784 0
+61 0416 186 052
Fax 120784 0
Email 120784 0
jianyong.shou@ennovabio.com

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.