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Trial registered on ANZCTR


Registration number
ACTRN12620000685910
Ethics application status
Approved
Date submitted
21/05/2020
Date registered
17/06/2020
Date last updated
19/08/2021
Date data sharing statement initially provided
17/06/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A First-In-Human study to evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Ascending Doses of NT-0167 in Healthy Volunteers.
Scientific title
A randomized, double-blind, placebo-controlled single and multiple ascending dose study to test the safety, tolerability, pharmacokinetics and pharmacodynamics of NT-0167 in healthy volunteers
Secondary ID [1] 301333 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Inflammation 317536 0
Condition category
Condition code
Inflammatory and Immune System 315627 315627 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Up to eighty (80) healthy men or women of non-child-bearing potential (WNCBP) will be enrolled in this study in up to six SAD and up to four MAD cohorts comprising 8 subjects each. Subjects within each cohort will be randomised to receive either NT-0167 (6 subjects) or placebo (2 subjects). All SAD cohorts and the first MAD cohort will be started with sentinel dosing. Subjects that were enrolled into one of the SAD cohorts will take
part in a further, single dose, food effect, cross-over cohort.

One of the SAD cohorts will have a second study period in which the same NT-0167 dose will be repeated for evaluation of pharmacokinetics under fed conditions. This will be determined before the subjects of that particular SAD cohort start with the fasted study part. The food cohort will be scheduled to ensure that, for each participant, the fed dose of the IMP is administered at least 14 days after the corresponding fasted dose.

NT-0167 will be provided to the subjects in a blinded manner in capsules. Placebo capsules to match NT-0167 will be administered. Placebo will be indistinguishable from active treatment. All doses are for oral administration under direct observation in the Phase 1 unit. The dose shall be administered per below for each cohort:
SAD
Cohort 1, 10 mg, fasted
Cohort 2, 30 mg, fasted
Cohort 3, 100 mg, fasted
Cohort 4a, 300 mg, fasted
Cohort 4b, 300 mg, fed
Cohort 5, 1000 mg, fasted
Cohort 6, 2000 mg, fasted

MAD
Cohort 1, 100 mg, fasted, daily for 14 days
Cohort 2, 300 mg, fasted, daily for 14 days
Cohort 3, 1000 mg, fasted, daily for 14 days
Cohort 4, 2000 mg, fasted, daily for 14 days

Fasted condition: No food from -8h pre-dose until 4h post-dose; water is permitted, except 1 hour pre-dosing until 1 hour post-dosing.

Fed condition: Subjects have to be fasted from 8 hours prior to dose administration except for the standardized high fat meal which will commence 45 minutes prior to dosing and should be consumed within 30 minutes. Fasting then continues until 4 hours post-dose. Water intake is allowed ad libitum during the fasting period, except from 1 hour prior to dosing until 1 hour post-dose.

For the MAD cohorts the once or twice daily for 14 days, frequency will be determined by PK parameters in SAD Cohorts, and confirmed by the dose escalation committee.
Intervention code [1] 317629 0
Treatment: Drugs
Comparator / control treatment
Placebo capsules to match NT-0167 will be administered. Placebo will be indistinguishable from active treatment.
Control group
Placebo

Outcomes
Primary outcome [1] 323864 0
To evaluate the safety and tolerability of NT-0167 in healthy volunteers
Timepoint [1] 323864 0
Treatment-emergent (serious) adverse events ((S)AEs) from study dosing until end of study utilising:
- Clinical laboratory tests
o Haematology
o Chemistry
o Urinalysis
o Coagulation
o Thyroid function tests
- Vital signs
o Pulse Rate (bpm)
o Systolic blood pressure (mmHg)
o Diastolic blood pressure (mmHg)
o Respiratory Rate (breaths/min)
- Electrocardiogram (ECG)
o Heart Rate (HR) (bpm), PR-, QRS-, and QTcF-intervals
o Morphological abnormalities
- Holter ECG (not in Food cohort)
- Physical examination
- Weight (only during MAD cohorts)
A follow up visit will occur (SAD Day 8 +/- 2 days post IP administration, MAD Day 21 +/- 2 days post last IP administration) to mark the “end of study” participation of the subjects enrolled and dosed in the study.
SAD
Clinical Laboratory tests are collected at Screening, Day-1, 24h, and 48h post dose and the Day 8 follow up visit.
Vital Signs are collected (Pulse Rate, HR, BP, RR) Screening, Day -1, baseline, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h post dose and at the Day 8 follow up visit
ECG is collected Screening, Day -1, baseline, 0.5h, 1h, 2h, 8h, 12h, 24h post dose and at the Day 8 follow up visit
Holter Monitoring - Baseline continuous until 24hours post administration of the dose.
Physical Exam- Screening, Day -1, 24 hours post dose and Day 8 follow up (symptom directed exam)
MAD
Clinical Laboratory tests are collected at Screening, Day-1, 24h post dose, Days 2, 3, 4, 7, 10, 14, 16 and follow up Day 21
Vital Signs are collected (Pulse Rate, HR, BP, RR) Screening, Day -1 and follow up Day 8
Pre-dose, 2, 4, 8 hours post-dose on Days 1, 2, and 3
Vital Signs pre-dose only Days 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15 and 16
Vital Signs (Pre-dose, 2, 4, 8 and 24 hours post-dose) Day 14
ECG is collected Screening, Day -1, baseline, Days 1, 2, 3, 4, 7, 9, 11, 14, 15, 16 and at the Day 21 follow up
Holter Monitoring Days 1, 2, 7 and 14
Physical Exam Screening Day -1, Day 14, and Day 21 follow up (symptom directed exam)
Secondary outcome [1] 383080 0
To evaluate the pharmacokinetic profile of NT-0167 in healthy volunteers.


The specific pharmacokinetic parameters assessed, are to be: AUCinf, AUClast, CL/F, Cmax, t1/2, tlag, tmax, Vz/F

The mode of assessment is a serum assay.
Timepoint [1] 383080 0
After the administration of single ascending and multiple ascending doses.

SAD- The PK samples will be collected at Baseline, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h and 48 hours post dose
MAD
PK sample (Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 h post dose for Day 1
Single PK sample at Pre-dose (trough) Days 2-13 and at the Day 21 Follow up visit
Day 14 PK sampling Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h post-dose
Secondary outcome [2] 383081 0
To evaluate the pharmacodynamic properties of NT-0167 in healthy volunteers.

The specific pharmacodynamic parameters to be assessed include serum levels of these cytokines: IL-1ß, IL-18, IL-6, TNFa.

This is a Serum ex vivo LPS/ATP stimulation assay.
Timepoint [2] 383081 0
After single ascending and multiple ascending doses based on ex vivo inflammasome challenges.
SAD PD sample collection will be pre-dose, 3h, 6h, and 24h post dose.
MAD PD sample collection will be pre-dose, 3h, 6h on Days 1, 7 and 14 and 24h and 48h post dose on Day 14.
Secondary outcome [3] 383082 0
To evaluate the effect of food on the PK profile and tolerability of NT-0167.

The specific pharmacokinetic parameters assessed will be AUCinf, AUClast, CL/F, Cmax, t1/2, tlag, tmax, Vz/F, this will be done using a serum and urine assay.
Timepoint [3] 383082 0
After a single dose administration within the Food Cohort.

Serum PK will be collected -15 min pre dose, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, and 48h post dose

Urine PK collections will be Predose, 0-4h, 4-8h, 8-12h, 12-24h post dose in pooled collections


Eligibility
Key inclusion criteria
1. Signed informed consent and willing and able to comply with the study protocol;
2. Healthy men or women of non-child bearing potential (WNCBP), 18 to 55 years of age (inclusive) at screening. The health status is verified by absence of evidence of any clinically significant active or uncontrolled chronic disease following a detailed medical history, a complete physical examination including vital signs, laboratory measurements, and 12-lead ECG;
3. Female subjects must be of non-childbearing potential in accordance with one of the following definitions:
• Surgically sterile (by hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy) as documented by a surgical report or by ultrasound, or
• Post-menopausal (age-appropriate spontaneous amenorrhoea for equal to or greater than 12 months and follicle-stimulating hormone (FSH) equal to or greater than 40 IU/mL together with the absence of oral contraceptive use for greater than 12 months);
4. Male volunteers agree to use barrier protection when they engage in sexual relations with women of child-bearing potential (WOCBP) or lactating women for the duration of their participation in the study and until 90 days after EOS.
5. Body mass index (BMI) between 18 and 32 kg/m2, inclusive, and with a minimum bodyweight of 50 kg;
6. Has the ability to communicate well with the Investigator and willing to comply with the study restrictions.
7. Have the intention to be reachable by mobile phone or e-mail during the whole study period.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Lactating females;
2. Female volunteers with a positive pregnancy test at screening or baseline prior to IMP administration;
3. Evidence (including symptoms, physical signs, and/or laboratory values) of any active or chronic disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study, or that would pose an unacceptable risk to the subject in the opinion of the investigator;
4. Any confirmed or suspected disease or condition associated with immune system impairment, including auto-immune diseases, HIV, asplenia or recurrent severe infections.
5. Use of chronic (more than 14 days) immunosuppressant or immunomodulatory drugs within the 6 months prior to IMP administration, or isolated (non-chronic) use within 30 days prior to IMP administration;
6. Any history of severe allergic reaction(s);
7. Any confirmed drug hypersensitivity reactions (including skin reactions or anaphylaxis), or other known clinically significant allergies;
8. History of clinically significant systemic disorders including haematological, renal, endocrine, gastrointestinal, hepatic, cardiovascular, pulmonary, dermatological and neurological disorders, or other conditions which could interfere with the interpretation of the study results or compromise the health of the volunteers;
9. Any history of psychiatric condition that may affect participation in the study or preclude compliance with the protocol;
10. Receipt of any vaccination, other than an influenza vaccine, within 3 months of IMP administration.
11.. Participation in an investigational drug, vaccine or device study within 3 months prior to first dosing or plans to participate in other investigational drug, vaccine or device research during the study period.
12. Any nutrients known to modulate CYP enzymes activity (e.g., grapefruit or Seville orange containing products or quinine containing drinks (tonic water or bitter lemon)) will not be permitted from 5 days before dosing until the final PK sample is collected;
13. Donation (or loss) of whole blood of 400 ml or more during the 12 weeks prior to IMP administration;
14.. Donation of plasma or platelets during the 8 weeks prior to IMP administration;
15.. Any other known factor, condition, or disease that, in the opinion of the Investigator, might interfere with treatment compliance, study conduct or interpretation of the results, or may compromise volunteer safety.

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
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Safety concerns
Date of first participant enrolment
Anticipated
24/06/2020
Actual
24/06/2020
Date of last participant enrolment
Anticipated
Actual
20/08/2020
Date of last data collection
Anticipated
30/11/2020
Actual
30/11/2020
Sample size
Target
80
Accrual to date
Final
41
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 305766 0
Commercial sector/Industry
Name [1] 305766 0
NodThera
Country [1] 305766 0
United Kingdom
Primary sponsor type
Commercial sector/Industry
Name
NodThera
Address
Suite 8, Mansion House, Chesterfold Research Park, Little Chesterford, Saffron Walden, CB10 1XL
Country
United Kingdom
Secondary sponsor category [1] 306204 0
Commercial sector/Industry
Name [1] 306204 0
Clinical Network Services Pty Ltd
Address [1] 306204 0
Level 2, 381 MacArthur Ave, Hamilton, Queensland, 4007
Country [1] 306204 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306040 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 306040 0
Ethics committee country [1] 306040 0
Australia
Date submitted for ethics approval [1] 306040 0
06/05/2020
Approval date [1] 306040 0
02/06/2020
Ethics approval number [1] 306040 0
238/20

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

Contacts
Principal investigator
Name 102514 0
Dr Jason Lickliter
Address 102514 0
Centre for Clinical Studies, Nucleus Network Ltd
5th Floor, Burnet Building, AMREP Precinct,
89 Commercial Rd, Melbourne, VIC, 3004
Country 102514 0
Australia
Phone 102514 0
+61 3 9076 8960
Fax 102514 0
Email 102514 0
j.lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 102515 0
Jessica Faggian
Address 102515 0
Centre for Clinical Studies, Nucleus Network Ltd
5th Floor, Burnet Building, AMREP Precinct,
89 Commercial Rd, Melbourne, VIC, 3004
Country 102515 0
Australia
Phone 102515 0
+61 3 9076 8958
Fax 102515 0
Email 102515 0
J.Faggian@nucleusnetwork.com.au
Contact person for scientific queries
Name 102516 0
Jason Lickliter
Address 102516 0
Centre for Clinical Studies, Nucleus Network Ltd
5th Floor, Burnet Building, AMREP Precinct,
89 Commercial Rd, Melbourne, VIC, 3004
Country 102516 0
Australia
Phone 102516 0
+61 3 9076 8960
Fax 102516 0
Email 102516 0
j.lickliter@nucleusnetwork.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


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.