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Trial registered on ANZCTR


Registration number
ACTRN12621001082897
Ethics application status
Approved
Date submitted
25/06/2021
Date registered
16/08/2021
Date last updated
16/08/2021
Date data sharing statement initially provided
16/08/2021
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-0796 in Healthy Volunteers.
Scientific title
A randomised, placebo-controlled single and multiple ascending dose study to test the safety, tolerability, pharmacokinetics and pharmacodynamics of NT-0796 in healthy volunteers
Secondary ID [1] 304584 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Inflammation 322518 0
Inflammatory and Immune System 322519 0
Condition category
Condition code
Inflammatory and Immune System 320155 320155 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Up to eighty (88) healthy men or women of non-child-bearing potential (WNCBP) will be enrolled in this study
This study comprises up to 7 SAD cohorts and up to 4 MAD cohorts.
For all of the SAD cohorts and 3 of the MAD cohorts, 8 participants will be enrolled and will be randomly allocated to receive placebo (2 participants) or active NT-0796 (6 participants) in a double-blind manner. One of the MAD cohorts (likely the 3rd MAD cohort, but the exact cohort to be decided upon by the DEC) will enrol 8 participants to NT-0796 (open-label).

For the blinded cohorts NT-0796 will be provided to the subjects in a blinded manner in liquid formation. Placebo liquid formation to match NT-0796 will be administered. Placebo will be indistinguishable from active treatment.

Dosing of the IP is oral, all dosing will be completed in a controlled unit where participants remain for the duration of treatment period.

The planned doses for the study are as follows:
SAD Cohorts dose ranging from 1mg to 1000mg. The current planned dose schedule is:
Cohort 1 - 1mg
Cohort 2 - 3mg
Cohort 3 - 10 mg
Cohort 4 - 30mg
Cohort 5 - 100mg
Cohort 6 - 300mg
Cohort 7 is currently an optional cohort.
The SAD dosing escalation shall be decided by a dose escalation committee upon review of the safety and PK data of previous SAD Cohorts.

MAD Cohorts dosing plan shall be decided by a dose escalation committee and upon reviewing the SAD Cohort data.
Intervention code [1] 320957 0
Treatment: Drugs
Comparator / control treatment
Placebo liquid formation to match NT-0796 will be administered. Placebo will be indistinguishable from active treatment.
Control group
Placebo

Outcomes
Primary outcome [1] 328033 0
To evaluate the safety and tolerability of NT-0796 in healthy volunteers.
Timepoint [1] 328033 0
Treatment-emergent (serious) adverse events ((S)AEs) from study dosing until end of study (4 weeks after enrolment) utilising:
- Clinical laboratory tests (For SAD Cohorts Days 2, 7, 10, 14 & 17; For MAD Cohorts Days 2, 3, 4, 7, 10, 14, 16, 21 & 28).
o Haematology
o Chemistry
o Urinalysis
o Coagulation
o Thyroid function tests
- Vital signs (For SAD Cohorts timepoints, 0.5, 1, 2, 4, 6, 8, 12, 24 hours post dose and Days 2, 7 & 14: For MAD Cohorts timepoints 2, 4 & 8 hours post dose on Days 1 to 3 and Day 14, and on Days 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 21 & 28)
o Pulse Rate (bpm)
o Systolic blood pressure (mmHg)
o Diastolic blood pressure (mmHg)
o Respiratory Rate (breaths/min)
- Electrocardiogram (ECG) (For SAD Cohorts timepoints, 0.5, 1, 2, 4, 6, 12 & 24 hours post dose and on Day 7; For MAD Cohorts on Days 1, 2, 3, 4, 7, 9, 11, 14, 15, 16, 21 & 28)
o Heart Rate (HR) (bpm), PR-, QRS-, and QTcF-intervals
o Morphological abnormalities
- Holter ECG
- Physical examination
- Weight
Secondary outcome [1] 397289 0
To evaluate the pharmacokinetic (PK) profile of NT-0796 in healthy volunteers after the administration of single ascending (SAD) and multiple ascending doses (MAD).
PK Paramaters to be assessed include • AUCinf, AUClast, CL/F, Cmax, t1/2, tmax, Vz/F.
These shall be assessed from Serum and Urine samples.
Timepoint [1] 397289 0
After the administration of single ascending and multiple ascending doses
SAD PK Timepoints: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 & 48 hours post dose.
MAD PK Timepoints: Days 1 and 14 Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 & 12 hours post dose and single PK draws on Days 2 through 6, 8, 9, 10, 11, 12, 13, 15, 16, 21 and 28. Day 7, pre-dose, 1 and 4 hours post dose. And if MAD Q12 dosing PK Day 7, pre-dose, 1, 4, 12 post AM dose.
Secondary outcome [2] 397290 0
To evaluate the pharmacodynamic (PD) properties of NT-0796 in healthy volunteers after single ascending and multiple ascending doses based on ex vivo inflammasome challenges.
PD parameters to be assessed include: IL-1ß, IL-18, IL-6, TNFa
These shall be assessed from Serum samples.
Timepoint [2] 397290 0
After single ascending and multiple ascending doses based on ex vivo inflammasome challenges.
SAD PD Timepoints: Pre-dose, 1, 4, 8, 12, 24 & 48 hours post dose.
MAD PD Timepoints: Day 1 Pre-dose, 1, 4, hours post dose and on Days 7 & 14.

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; health status is verified by absence of evidence of any clinically significant acute disease, or 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 (defined as no menses for 12 months without an alternative medical cause; a high follicle- stimulating hormone [FSH] level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy [HRT]);
4. Male volunteers agree to use barrier protection when they engage in sexual relations with women of child-bearing potential (WOCBP), pregnant or lactating women for the duration of their participation in the study and until 90 days after end of study (EOS); they also agree to request their female partners to use an effective method of contraception if they are WOCBP, pregnant or lactating;
5. Body mass index (BMI) between 18.0 and 34.0 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. Has the intention to be reachable by mobile phone or e-mail during the whole study period;
Minimum age
18 Years
Maximum age
55 Years
Gender
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 acute 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 consecutive 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. History of any psychiatric condition that may affect participation in the study or preclude compliance with the protocol;
10. History of convulsions or severe head trauma;
11. Recent (within the last three years) and/or recurrent history of autonomic dysfunction (e.g. recurrent episodes of fainting, palpitations, etc.);
12. History of frequent headaches (either severe in nature or requiring continuous daily treatment or treatment more than three times per week on average) and/or chronic, ongoing migraines;
13. History of malignancy (with the exception of localised basal cell carcinoma of the skin);
14. History of asthma (with the exception of fully resolved childhood asthma);
15. History of porphyria;
16. Any previous organ transplantation or donation;
17. Any surgical or medical condition with the potential to affect drug absorption (e.g. gastrectomy, bowel disease), distribution, metabolism or excretion;
18. Any history of arrhythmias or documented prolonged QTcF- interval (greater than 450 msec in males, greater than 470 msec in females), any previous episode of syncope thought to be of cardiac origin, or a family history of long QT syndrome or unexplained sudden death;
19. Clinically significant ECG abnormalities at screening, admission to the clinical research unit (CRU) or baseline prior to IMP administration including but not limited to:
• PR-interval greater than 220 msec
• QRS duration greater than 120 msec
• QT-interval greater than 500 msec
• QTcF-interval greater than 450 msec in males, greater than 470 msec in females
• pathologic Q wave
• significant ST-T wave changes
• second or third-degree A-V heart block
The ECG reading may be repeated in assessing this criterion if the investigator believes that the values from the original reading were erroneous;
20. Resting vital signs (measured after 5 minutes in the supine position) at screening, admission to the clinical research unit (CRU) or baseline prior to IMP administration as follows:
• Tympanic body temperature greater than or equal to 38.0 °C
• SBP less than or equal to 90 or greater than or equal to 140 mmHg
• DBP less than or equal to 50 or greater than or equal to 90 mmHg
• Pulse rate less than or equal to 40 or greater than or equal to 100 bpm
Vital signs measurement may be repeated once in assessing this criterion if the investigator believes that the values from the original measurement were erroneous;
21. Symptomatic postural hypotension at screening, irrespective of the decrease in blood pressure, or asymptomatic postural hypotension at screening defined as a decrease in systolic blood pressure equal to 20 mmHg 2 minutes after changing from a supine to standing position;
22. Clinically significant laboratory abnormalities at screening or baseline, as judged by the Investigator; minor deviations from the normal range may be accepted, if judged by the Investigator (and following consultation with the Sponsor’s Medical Monitor if required) to have no clinical relevance;
23. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening, or other known infection requiring parenteral systemic antibiotic therapy within three months prior to the study (a short course of oral antibiotics is permitted);
24. A history of ongoing, chronic, or recurrent infectious disease;
25. Use of any prescription medications within 14 days or 5 half- lives (whichever is longer) of study drug administration or use of over-the-counter [OTC] medications or herbal supplements within 7 days or 5 half-lives (whichever is longer) of study drug administration, or an anticipated requirement for use of these during the course of the study. Nutritional supplements may be permitted but must be discussed with the Sponsor’s Medical Monitor prior to subject enrolment;
26. Receipt of any vaccination, other than an influenza and/or SARS-CoV-2 vaccine, within 3 months of IMP administration;
27. Receipt of a SARS-CoV-2 vaccine within 1 month of IMP administration. Subjects must not receive a SARS-CoV-2 vaccine within 1 month of completion of trial follow-up;
28. Participation in an investigational drug, vaccine or device study within 3 months of final dosing or prior to first dosing, or plans to participate in other investigational drug, vaccine or device research during the study period. Subjects must have completed follow-up of any prior investigational drug, vaccine or device study prior to screening for this trial;
29. Previous participation in a study with an investigational drug or device involving the dosing of a biological targeted at any immune pathway within one year of final dosing prior to screening;
30. Planned surgery for any time between screening and completion of study follow-up;
31. History of abuse of addictive substances (alcohol, illegal substances) in the 3 years prior to screening or current use of more than 14 units alcohol per week, drug abuse, or regular user of sedatives, hypnotics, tranquilizers, or any other addictive agent;
32. Positive test for drugs of abuse at screening or admission (day -1);
33. Use of alcohol during the 24 hours prior to screening and/or an unwillingness to abstain from alcohol consumption for at least 24 hours prior to admission and each ambulant study visit, and for the duration of the admission period. At other times throughout the study, subjects may not consume more than 2 units of alcohol daily (one unit is 10 grams of alcohol). Subjects may undergo an alcohol breath test at the discretion of the Investigator;
34. Smoking more than 2 cigarettes per week (or equivalent, including other nicotine-based products) within 30 days prior to study drug administration and/or unwillingness to abstain from the use of these during the study;
35. Habitual excessive xanthine consumption (equivalent to greater than 800mg caffeine per day). Decaffeinated beverages are permitted;
36. Inability to abstain from xanthine-containing foods and beverages from 8 hours prior to dosing until 24 hours post dose for SAD cohorts, or from 8 hours prior to dosing until 6 hours post dose on Days 1, 7 and 14 for participants in the MAD cohorts;
37. Any nutrients known to modulate CYP enzyme 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;
38. Strenuous physical activity (e.g., heavy lifting, weight or fitness training) is not permitted from 48 hours prior to each study day until collection of the final safety blood sample. Light ambulatory activities (e.g. walking at normal pace) are permitted;
39. Donation (or loss) of whole blood of 400 ml or more during the 56 days prior to IMP administration and no plan to donate whole blood for 4 weeks after the last study-related blood draw;
40. Donation of plasma or platelets during the 14 days prior to IMP administration and no plan to donate platelets for 4 weeks after the last study-related blood draw;
41. 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
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 23839 0
New Zealand
State/province [1] 23839 0

Funding & Sponsors
Funding source category [1] 308949 0
Commercial sector/Industry
Name [1] 308949 0
NodThera
Address [1] 308949 0
Suite 8, Mansion House, Chesterfold Research Park, Little Chesterford, Saffron Walden, CB10 1XL
Country [1] 308949 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] 309871 0
Commercial sector/Industry
Name [1] 309871 0
Novotech (New Zealand) Limited
Address [1] 309871 0
Level 6, 3 Ferncroft Street Grafton, Auckland 1010

Country [1] 309871 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308837 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 308837 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 308837 0
New Zealand
Date submitted for ethics approval [1] 308837 0
25/06/2021
Approval date [1] 308837 0
21/07/2021
Ethics approval number [1] 308837 0
21/STH/162

Summary
Brief summary

This project is testing the safety, tolerability, pharmacokinetics (PK, the amount of study drug in your blood)
and pharmacodynamics (PD, how the study drug affects your body) of both single and multiple oral doses of a
new drug called NT-0796.
Up to eighty eight (88) healthy men or women of non-child-bearing potential (WNCBP), aged between 18-55 will be
enrolled in this study in up to seven SAD and up to four MAD cohorts comprising 8 subjects each.
This study will enrol approximately 88 participants, in two parts:
Part A: will involve a single ascending (increasing) dose (SAD) where approximately 56 participants (7 groups
of 8) will be randomised (assigned randomly, like flipping a coin) to receive a single dose of the study drug or
placebo. The placebo will look the same as the study drug but will not contain any medicine.
Part B: will involve a multiple ascending (increasing) dose (MAD) where approximately 32 participants (4
groups of 8) will receive one dose of the study drug or placebo daily for 14 consecutive days (14 doses in
total).
The study is placebo controlled, meaning that some participants will receive capsule(s) containing the active
study drug, and some will receive capsule(s) containing placebo.
For Part A your total participation will last about 8 weeks, of which you will spend 4 days (3 nights) in the clinic.
For Part B your total participation will last about 10 weeks, of which you will spend 17 days (16 nights) in the
clinic.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112066 0
Dr Chris Wynne
Address 112066 0
Christchurch Clinical Studies Trust Ltd
264 Antigua Street
Christchurch 8011
Country 112066 0
New Zealand
Phone 112066 0
+64 33729477
Fax 112066 0
Email 112066 0
chris.wynne@nzcr.co.nz
Contact person for public queries
Name 112067 0
Ms Jo Sanders
Address 112067 0
Christchurch Clinical Studies Trust Ltd
264 Antigua Street
Christchurch 8011
Country 112067 0
New Zealand
Phone 112067 0
+64 33729477
Fax 112067 0
Email 112067 0
jo.sanders@nzcr.co.nz
Contact person for scientific queries
Name 112068 0
Dr Chris Wynne
Address 112068 0
Christchurch Clinical Studies Trust Ltd
264 Antigua Street
Christchurch 8011
Country 112068 0
New Zealand
Phone 112068 0
+64 33729477
Fax 112068 0
Email 112068 0
chris.wynne@nzcr.co.nz

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 other documents available
Summary results
No Results