ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12623000476639

Ethics application status

Approved

Date submitted

26/04/2023

Date registered

11/05/2023

Date last updated

26/08/2024

Date data sharing statement initially provided

11/05/2023

Type of registration

Prospectively registered

Titles & IDs

Public title

Phase 1, Randomized, Placebo-controlled, Double-blind, Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) Study to Evaluate the Safety, Tolerability and Pharmacokinetics of NB-4746 in Healthy Volunteers

Scientific title

Secondary ID [1]

CL-4746-23-01

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Amyotrophic lateral sclerosis (ALS)

Condition category

Condition code

Neurological

Neurodegenerative diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a single center, double-blind randomized placebo-controlled study to assess the safety, tolerability and pharmacokinetics of NB-4746 in healthy volunteers.

A total of 66 subjects will be enrolled sequentially into 6 ascending single dose and 3 ascending multiple dose cohorts. Subjects will only be allowed to enrol in one cohort.

Part A - Single Escalating Dose:
Study participants will be randomly assigned to receive a single dose of NB-4746 or placebo administered as an oral solution on day 1. There will be 6 ascending dose cohorts in Part A with 7 participants per cohort. The proposed dose levels for cohorts 1 through to 6 are 50, 100, 175, 300, 450 and 600mg as a single oral dose. Participants must fast for at least 10 hours prior to administration. Administration will occur under supervision.

Sentinel dosing will occur within each cohort, whereby on Day 1, the first 2 subjects will receive NB-4746 or placebo as assigned per the 1:1 randomization schedule. A minimum of 48 hours following sentinel dosing, following safety assessment by the Principal Investigator (PI), the remaining 5 subjects in each cohort will be randomly assigned to receive NB-4746 or placebo in a 4:1 ratio.

A Safety Review Committee (SRC) will review the safety and 24-hour PK data together in a blinded manner and approve or deny escalation to the next higher dose. Each follow-on cohort will not commence dosing until a minimum of 6 subjects from the prior cohort have completed their in-house/confinement period.

Part B - Multiple Ascending Doses:
Study participants will be randomly assigned to receive multiple doses of NB-4746 or placebo administered as an oral solution for 10 days. NB-4746 or placebo will be administered once on day 1 (single dose in the morning (AM)), twice a day (BID) 12 hours apart on days 2 to 9, and a single dose in the morning (AM) of day 10. There will be 3 ascending dose cohorts in Part B with 8 participants per cohort. The proposed dose levels for cohorts 1 through to 3 are 100, 250 and 400mg, but may be revised depending on the results of part A. Participants must fast for at least 10 hours prior to administration. Administration will occur under supervision.

Sentinel dosing will occur within each cohort, whereby on Day 1, the first 2 subjects will receive NB-4746 or placebo for 10 days in a 1:1 randomization ratio. A minimum of 48 hours following the second (PM) dose of study drug on Day 3 in these 2 “sentinel” subjects and following safety assessment by the PI, the remaining 6 subjects in each cohort will be randomly assigned to receive NB-4746 or placebo for 10 days in a 5:1 ratio starting on day 6 with the morning dose.

Prior to the initiation the second and subsequent dosing cohorts, the SRC will review the blinded safety and PK data (if available) from a minimum of 3 days of dosing to determine if a dose escalation to the next higher can occur. Each follow-on cohort will not commence dosing until a minimum of 7 subjects from the prior cohort have completed their in-house/confinement period.

Part C - Cerebrospinal Fluid (CSF) cohort
Part C is a standalone cohort to estimate central nervous system (CNS) exposure of NB-47476 by measuring CSF concentrations. All participants in the CSF cohort will receive the study drug (NB-4746). Upon confirmation of eligibility, approximately 4 participants will receive a single dose of study drug on Day 1, at the same dose as SAD cohort 4 (250mg). All participants will remain at the research site from days -1 to day 4 post-dose, and CSF sampling will occur on day 1.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Study participants randomized to receive placebo will have the placebo administered as an oral solution by the study staff in an identical manner to NB-4746.

The placebo formulation will be an oral solution that is identical in terms of taste and appearance to the active formulation including pH adjustment, but without NB-4746.

Control group

Placebo

Outcomes

Primary outcome [1]

To evaluate the safety and tolerability of single escalating oral doses of NB 4746 in healthy subjects.
Safety will be measured by routine clinical and laboratory procedures including blood samples to assess hematology, liver function, renal function and blood chemistry; urinalysis; physical examination; 24 hour urine collection; collection of vital signs including measurement of blood pressure measured using an automated sphygmomanometer, heart rate, respiratory rate and temperature; ECG and recording treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) in accordance with Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Timepoint [1]

Following enrolment into the study and administration of the first dose of study drug participants will undergo vital signs measurements comprising temperature, heart rate, respiratory rate and blood pressure at 0.5, 1, 2, 4 and 8 hours post dose on day 1, 24 hours post dose on day 2, 48 hours post dose on day 3 and 72 hours post dose on day 4 and EOS (End of Study/day 8). A complete physical examination will occur on day 4 and EOS, a focused physical examination will be performed on day 1 (predose), day 2 and day 3 if clinically indicated. Clinical laboratory tests including chemistry, hematology and urinalysis will be collected during screening and on day 1 (predose), 24 hours post dose on day 2, day 4 and EOS. Serum electrolyte levels will be collected pre-dose, 0.5, 1, 2, 4, 8 and 24-hours post-dose on day 1. Triplicate 12-lead ECG recordings will be obtained during screening, on day 1 (predose), 0.5, 1, 2, 4, 8 hours post dose on day 1, 24 hours post dose on day 2, 48 hours post dose on day 3, and 72 hours post dose on day 4 and EOS. 24-hour urine collection will be conducted on days 1, 2 and 3. All AE and SAE information will be collected from signing of the informed consent form until the EOS visit.

Primary outcome [2]

To evaluate the safety and tolerability of multiple escalating oral doses of NB 4746 in healthy subjects.
Safety will be measured by routine clinical and laboratory procedures including blood samples to assess hematology, liver function, renal function and blood chemistry; urinalysis; physical examination; 24 hour urine collection; collection of vital signs including measurement of blood pressure measured using an automated sphygmomanometer, heart rate, respiratory rate and temperature; ECG and recording treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) in accordance with Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Timepoint [2]

Following enrolment into the study and administration of the first dose of study drug participants will undergo vital signs measurements comprising temperature, heart rate, respiratory rate and blood pressure at 1, 2, 4, 8 and 12 hours post dose on day 1, 3, 7 and 10; 24 hours after day 10 dosing, day 14 and EOS (day 18). A complete physical examination will occur on day 14 and EOS, a focused physical examination will be performed on day 1 (predose), days 3, 5, 7 and day 10 if clinically indicated and body weight measured on days 2, 4, 7 and 10. Clinical laboratory tests including chemistry, hematology and urinalysis will be collected during screening and predose on day 1, 3, 7, 10, 14 and at EOS. Serum electrolyte levels will be collected 2 hours post AM dose from Days 1-10 (inclusive). Triplicate 12-lead ECG recordings will be obtained during screening, predose and 1, 2, 4, 8 and 12 hours post dose (AM dose) on days 1, 3, 7, and 10; 24 hours after day 10 dosing, on day 14, and at EOS. ECG will also be obtained pre-dose and 2 hours post AM dose on days 2, 4,5, 6, 8 and 9. 24-hour urine collection will be conducted daily on days 1 to 13. All AE and SAE information will be collected from signing of the informed consent form until the EOS visit.

Primary outcome [3]

To evaluate the safety and tolerability of a single 250mg dose of NB-4746 in healthy subjects. Safety will be measured by routine clinical and laboratory procedures including blood samples to assess hematology, liver function, renal function and blood chemistry; urinalysis; physical examination; collection of vital signs including measurement of blood pressure measured using an automated sphygmomanometer, heart rate, respiratory rate and temperature; Electrocardiogram (ECG) and recording treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) in accordance with Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Timepoint [3]

Primary outcome [4]

Timepoint [4]

Following enrolment into the study and administration of the first dose of study drug participants will undergo vital signs measurements comprising temperature, heart rate, respiratory rate and blood pressure at 0.5, 1, 2, 4 and 8 hours post dose on day 1, 24 hours post dose on day 2, 48 hours post dose on day 3 and 72 hours post dose on day 4 and EOS (End of Study/day 8). A complete physical examination will occur on day 4 and EOS, a focused physical examination will be performed on day 1 (predose), day 2 and day 3 if clinically indicated. Clinical laboratory tests including chemistry, hematology and urinalysis will be collected during screening and on day 1 (predose), 24 hours post dose on day 2, day 4 and EOS. Serum electrolyte levels will be collected pre-dose, 0.5, 1, 2, 4, 8 and 24-hours post-dose on day 1. Triplicate 12-lead ECG recordings will be obtained during screening, on day 1 (predose), 0.5, 1, 2, 4, 8 hours post dose on day 1. All AE and SAE information will be collected from signing of the informed consent form until the EOS visit.

Secondary outcome [1]

To estimate the pharmacokinetic (PK) profile of NB-4746 after single, escalating oral doses in healthy subjects.

Plasma PK parameters include Cmax (maximum plasma concentration), tmax (time to maximum plasma concentration), AUC0-inf (area under the curve from time 0 to infinity), AUC0-last (area under the curve to the last concentration), AUC0-12 (area under the curve from time 0 to 12 hours), AUC0-24 (area under the curve from time 0 to 24 hours), Terminal half-life (t½), CL/F (apparent clearance following oral administration).

Timepoint [1]

Sampling for PK plasma parameters will occur at the following time points: predose, 05, 1, 2, 4, 6, 8, 12, 16, 24, 32, 40, 48, 56 and 72 hours post dose.

Secondary outcome [2]

To estimate the PK profile of NB-4746 after multiple escalating oral doses in healthy subjects.

Plasma PK parameters include Cmax (maximum plasma concentration), tmax (time to maximum plasma concentration), AUC0-inf (area under the curve from time 0 to infinity), AUC0-last (area under the curve to the last concentration), AUC0-12 (area under the curve from time 0 to 12 hours), AUC0-24 (area under the curve from time 0 to 24 hours), Terminal half-life (t½), CL/F (apparent clearance following oral administration).

Timepoint [2]

Sampling for PK plasma parameters will occur at the following time points: predose, 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 post dose on day 1; predose and 2 hours after first daily dose on days 3, 5, and 7; and predose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 32, 48, 56, 72, 80, and 96 hours post dose on day 10.

Secondary outcome [3]

To estimate the urinary excretion of unchanged drug (NB-4746) after multiple escalating oral doses in healthy subjects.

Parameters include Ae0-24 (amount excreted from time 0 to 24 hours) on day 9.

Timepoint [3]

Urine will be analyzed for drug levels (amount excreted) on Day 9.

Secondary outcome [4]

To determine markers of CYP3A activity after multiple escalating oral doses in healthy subjects.

Urine 6beta-OH cortisol/cortisol ratio will be examined.

Timepoint [4]

Urine will be analyzed for 6beta-OH cortisol/cortisol ratio (a CYP3A activity marker) on Day -1, and Day 1 and Day 10 from the 24-hour urine collection.

Secondary outcome [5]

To estimate the PK profile of NB-4746 after a single 250mg dose in healthy subjects. Plasma PK parameters include Cmax (maximum plasma concentration), tmax (time to maximum plasma concentration), AUC0-inf (area under the curve from time 0 to infinity), AUC0-last (area under the curve to the last concentration), AUC0-12 (area under the curve from time 0 to 12 hours), AUC0-24 (area under the curve from time 0 to 24 hours), Terminal half-life (t½), CL/F (apparent clearance following oral administration).

Timepoint [5]

Secondary outcome [6]

Timepoint [6]

Sampling for PK plasma parameters will occur at the following time points: predose, 05, 1, 2, 4, 6, 8, 12, 16, 24, 32, 40, 48, 56 and 72 hours post dose.

Secondary outcome [7]

To estimate the CNS exposure to NB-4746 after a single 250mg dose in healthy participants. CSF/plasma NB-4746 concentration ratio and absolute CSF concentration of NB-4746 will be examined.

Timepoint [7]

Sampling for PK plasma parameters will occur at the following time points: predose, 05, 1, 2, 4, 6, 8, 12, 16, 24, 32, 40, 48, 56 and 72 hours post dose.

Secondary outcome [8]

To estimate the CNS exposure to NB-4746 after a single 250mg dose in healthy participants. CSF/plasma NB-4746 concentration ratio and absolute CSF concentration of NB-4746 will be examined.

Timepoint [8]

CSF samples will be collected 2 hours post dose on day 1.

Eligibility

Key inclusion criteria

- Male and post-menopausal females aged >/=18 years and < /=65 years old at the time of signing informed consent.
- Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring (ECG).
- Nonsmoker and/or ex-smoker who has discontinued smoking and/or the use of nicotine containing products for at least 3 months prior to first dose of study drug.
- Body mass index within the range 18 to 30 kg/m2 inclusive.
- Females must be either postmenopausal for >/=1 year (or with FSH >/=40 mIU/mL at screening if postmenopausal for < 1 year) or surgically sterile (having undergone bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 6 months. However, to protect against the transfer of the study drug in any bodily fluids, male partners of female subjects (whether postmenopausal or surgically sterile) must use a barrier form (e.g., condom) of contraception until the end of the study visit (EOS) or 7 days after the last dose of study drug in case of early termination.
- Males with female partners of childbearing potential will agree to use barrier contraceptive (i.e., condom) and their female partners must use a highly effective method of contraception from screening to 90 days after the last dose of study drug. Males must also refrain from sperm donations during this time period. Males who are abstinent will not be required to use a contraceptive method unless they become sexually active. Males in a same sex relationship must also use a barrier form of contraception against the transfer of the study drug in any bodily fluids until the end of the study visit (EOS) or 7 days after the last dose of study drug in case of early termination.

Minimum age

18 Years

Maximum age

65 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

- History or presence of significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrinological, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data.
- Subjects with a history of pancreatitis or with prior cholecystectomy.
- Any significant chronic medical illness, as determined by the investigator.
- Mentally or legally incapacitated, has significant emotional problems at screening or expected during the conduct of the study, or has a history of a clinically significant psychiatric disorder within the last 5 years. Note: normal healthy volunteers who have had situational depression may be enrolled in the study at the discretion of the Investigator.
- The subject has a history of severe drug allergy or hypersensitivity or food allergy, including anaphylaxis.
- The subject has had surgery or trauma with significant blood loss within the last 3 months prior to the first dose of study drug.
- The subject has donated more than 1 unit (500 mL) of blood within 4 weeks prior to the first dose of study drug. .
- Abnormal vital signs that are considered to be clinically significant by the investigator.
- Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years. Fully resected basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with no evidence of recurrence for 1 year are permitted.
- Breast cancer within the past 10 years.
- Clinically significant laboratory abnormality at the screening visit or before the administration of the first dose of study drug.
- Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of asymptomatic gallstones).
- QTcF interval (QT with Fredericia’s correction) > 450 msec in males and > 470 msec in females (based on the mean of triplicate measurements taken at screening).
- Females of childbearing potential, irrespective of contraceptive measures taken.
- Inability to tolerate oral medications.
- Past or intended use of over-the-counter or prescription medication (including herbal medications) within 14 days before dosing.
- Live vaccine(s) within 1 month before Screening or plans to receive such vaccines during the study.
- Treatment with biologic agents (such as monoclonal antibodies including marketed drugs) within 3 months or 5 half-lives (whichever is longer) before dosing.
- Current participation in any other investigational drug study or receipt of an investigational drug within 30 days or 5 half-lives (whichever is longer) before Screening.
- Positive prestudy drug or alcohol screen.
- Positive human immunodeficiency virus (HIV) or hepatitis C antibody test (HCV), or hepatitis B surface antigen (HBsAg) at screening or 3 months before enrollment.
- Regular alcohol consumption within 6 months before the study defined, current evidence of substance dependence or self-reported alcoholic intake > 2 drinks/day for female subjects and > 3 drinks/day for male subjects.
- Use of tobacco products (e.g., cigarettes, e-cigarettes, cigars, smokeless tobacco) confirmed by a positive cotinine test on Day -1.
- Regular use of known drugs of abuse or a history of drug abuse within 12 months prior to screening.

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)

A computerized randomization list will be created by an unblinded statistician or designee. Subjects will be randomized to receive either NB-4746 or placebo.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

In part A subjects will be randomized 5:2 to receive NB-4746 or placebo.

In part B subjects will be randomized 6:2 to receive NB-4746 or placebo.

Block randomization will be used to allow randomization of a sentinel pair (1 active, 1 placebo) to be dosed first within each cohort group. The sentinel's dosing and early post-dosing course will precede that of the remainder of the dose group, which will be randomized 4:1 (NB-4746 or placebo) for Part A and in a 5:1 ratio (NB-4746 or placebo) in part B. Dosing of the remainder of the group will be done after the PI or SRC decides to proceed after an observation period of the sentinel group.

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

Single ascending dose and multiple ascending dose cohorts.

Phase

Phase 1

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

The sample size for this study is 66 subjects (42 in Part A and 24 in Part B). The number of subjects in Part A was selected to allow sufficient evaluation of safety, tolerability and PK of the various single-dose regimens to be administered in this study and is consistent with standards of practice for Phase 1 studies.

For Part B, approximately 24 subjects (18 subjects receiving NB-4746, 6 subjects receiving placebo) were selected to allow sufficient evaluation of safety, tolerability, and PK of the various multiple-dose regimens to be administered in this study and is consistent with standards of practice for Phase 1 studies.

With 6 subjects receiving NB-4746 within a dose cohort, the probability of observing at least 1 dose limiting toxicity (DLT) event that occurs at a rate of 25% is 0.82. With 5 subjects receiving NB-4746 within a dose cohort, the probability of observing at least 1 DLT event that occurs at a rate of 25% is 0.76.

There are three analysis sets identified for the study. The Randomized Analysis Set will consist of all subjects randomized into the study. Subjects will be analyzed according to their randomized treatment, regardless of which treatment the subject actually received.

The Safety Analysis Set will consist of all subjects who receive any amount of study drug (NB-4746 or placebo). Subject will be analyzed according to the treatment they actually received, if this differs from that to which the subject was randomized.

The PK Analysis Set will consist of all subjects who receive any amount of active study drug (NB-4746) and have at least one evaluable PK parameter. Subjects will be analyzed according to the treatment they actually receive, if this differs from that to which the subject was randomized. Subjects with dosing deviations that could potentially affect the PK profile or protocol deviations deemed to impact the assessment of PK, will be excluded from the PK Set, at the discretion of the pharmacokineticist.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

29/05/2023

Actual

29/05/2023

Date of last participant enrolment

Anticipated

Actual

24/12/2023

Date of last data collection

Anticipated

Actual

28/02/2024

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Nucleus Network - Melbourne

Recruitment postcode(s) [1]

3004 - Melbourne

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Nura Bio Inc.

Address [1]

161 Oyster Point Boulevard, Suite 200,
South San Francisco
California 94080
USA

Country [1]

United States of America

Primary sponsor type

Commercial sector/Industry

Name

Nura Bio Inc.

Address

161 Oyster Point Boulevard, Suite 200,
South San Francisco
California 94080
USA

Country

United States of America

Secondary sponsor category [1]

Commercial sector/Industry

Name [1]

InClin Pty Ltd

Address [1]

210 / 25-29 Berry Street
North Sydney, NSW
Australia, 2060

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Alfred Hospital Ethics Committee

Ethics committee address [1]

55 Commercial Road,
Melbourne VIC 3004

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

24/03/2023

Approval date [1]

28/04/2023

Ethics approval number [1]

171/23 (HREC/95642/Alfred-2023)

Summary

Brief summary

This phase 1 study is a randomized, placebo-controlled, double-blind, trial of an oral drug called NB-4746 vs. placebo in normal healthy volunteers. The study will assess the safety and tolerability in single and multiple ascending dose cohorts.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Ofer Gonen

Address

Nucleus Network Melbourne,
Level 5, Burnet Tower
89 Commercial Road
Melbourne 3004, Victoria

Country

Australia

Phone

+61 431 614 515

Fax

[email protected]

Contact person for public queries

Name

Taylor Kilfoil

Address

InClin Pty Ltd.
210 / 25-29 Berry Street
North Sydney, NSW
Australia, 2060

Country

Australia

Phone

+61 408 880 403

Fax

[email protected]

Contact person for scientific queries

Name

Taylor Kilfoil

Address

InClin Pty Ltd.
210 / 25-29 Berry Street
North Sydney, NSW
Australia, 2060

Country

Australia

Phone

+61 408 880 403

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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.

Trial Review

Documents added manually

Documents added automatically