FIH, Phase 1 To Evaluate Safety, Tolerability & PK of NST-6179
Research type
Research Study
Full title
A Phase 1, First Time in Human Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of NST-6179 in Healthy Subjects and Patients Requiring Home Parenteral Nutrition (HPN) for Short Bowel Syndrome
IRAS ID
295389
Contact name
Jim Bush
Contact email
Sponsor organisation
NorthSea Therapeutics B.V
Eudract number
2021-000839-31
Clinicaltrials.gov Identifier
Clinicaltrials.gov Identifier
REC Reference, 21/NE/0062
Duration of Study in the UK
0 years, 8 months, 5 days
Research summary
Summary of Research
The purpose of this study is to determine the safety, tolerability and concentration profile of the study drug in the blood when given both as single doses in part A and multiple doses in Part B. This part of the study will be conducted in healthy male and female participants at Covance Clinical Research Unit. There is a part C which will be conducted in patients with Intestinal failure-associated liver disease (IFALD). This part will not be conducted at Covance Clinical Research Unit and will need an approved substantial amendment before this study can be conducted.
This will be a partly double-blind, randomised, placebo-controlled, single and multiple oral dose study conducted in 3 parts. Part A and Part B will be double-blind, randomised, placebo-controlled, with participants receiving single (Part A) and multiple (Part B) oral doses. Part C will be open-label, non-randomised with patients receiving a single oral dose.
Part A will comprise a double-blind, single-ascending dose, sequential-group design incorporating a food-effect evaluation.
Potential participants will be screened to assess their eligibility to enter the study within 28 days prior to the first dose administration. Each participant will participate in 1 treatment period only, except for Group A3, where each subject will participate in 2 treatment periods separated by a minimum of 7 days. It is the intent to conduct the assessment of the effect of food in Group A3, however, based on emerging data this may be conducted in a different dose group in Part A.
Part B will comprise a double-blind, multiple-ascending dose, sequential-group study design. Part B may start in parallel with Part A.
Summary of Results
2. SYNOPSIS
Title of study: A Phase 1, First Time in Human Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of NST-6179 in Healthy Subjects
Investigational product: NST-6179Sponsor: NorthSea Therapeutics B.V.
Investigator: Dr Jim Bush, MBChB, PhD, MRCS, FFPM, GFMD. This study was conducted at 1 site in the United Kingdom.Publications: None
Period of study: 11 November 2021 (date of first informed consent) to 27 May 2022 (date of final poststudy observation).
Phase of development: Clinical Phase 1
Objectives:
The primary objective was to assess the safety and tolerability of single and multiple oral doses of NST-6179 in healthy male and female subjects.The secondary objective was to evaluate the single and multiple oral dose pharmacokinetics (PK) of NST-6179 in healthy male and female subjects.
The exploratory objectives were:
• to collect data to assess the relationship between NST-6179 concentrations and QT interval corrected for heart rate (QTc) in healthy male and female subjects
• to evaluate the metabolite profile of NST-6179 in healthy male and female subjects
• to evaluate the effect of pharmacogenomics (PGx) on the PK of NST-6179 in healthy male and female subjects.Methodology:
This was a double-blind, randomised, placebo-controlled, ascending single and multiple oral dose study conducted in 2 parts. Part A comprised a double-blind, single-ascending dose, sequential-group design and Part B comprised a double-blind, multiple-ascending dose, sequential-group study design.Number of subjects (planned and analysed):
In Part A, it was originally planned to study 48 subjects in 6 groups (Groups A1 to A6), with each group consisting of 8 subjects. Overall, 40 subjects were studied in 5 groups (Groups A1 to A5), with each group consisting of 8 subjects.In Part B, it was originally planned to study 40 subjects in 4 groups (Groups B1 to B4), with each group consisting of 10 subjects. Overall, 30 subjects were studied in 3 groups
(Groups B1 to B3), with each group consisting of 10 subjects.Data for all subjects were included in the safety population, and all subjects who received at least 1 dose of NST-6179 were included in the PK population.
Diagnosis and main criteria for inclusion:
Healthy subjects of any race, aged between 18 and 65 years, inclusive, and with a body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive.
Test product, dose and mode of administration, batch number:Doses of 50 mg, 200 mg, 400 mg, 600 mg, and 1000 mg were administered orally as capsules in the fasted state. The batch numbers used were: PD21010 (10 mg capsule) and PD20044 (100 mg capsule).
Reference therapy, dose and mode of administration, batch number:
Placebo capsules were administered orally in the fasted state. The batch number used was: PD20042.
Duration of treatment:
In Part A, single doses were administered in each group.
In Part B, multiple doses were administered once daily (QD) for 14 days.
Endpoints:
Pharmacokinetics:
Blood and urine samples were collected for the measurement of plasma and urinary concentrations of NST-6179. The PK outcome endpoints of NST-6179 for Part A (single-ascending dose in healthy subjects) were as follows:
• area under the concentration-time curve (AUC) from time 0 to infinity (AUC0-∞)
• area under the concentration-time curve from time 0 to infinity normalised by dose (DAUC0-∞)
• area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-tlast)
• area under the concentration-time curve from time 0 to the time of the last quantifiable concentration normalised by dose (DAUC0-tlast)
• maximum observed concentration (Cmax)
• Cmax normalised by dose (DCmax)
• time of the maximum observed concentration (tmax)
• apparent terminal elimination half-life (t½)
• apparent total clearance (CL/F)
• apparent volume of distribution (Vz/F)• amount of drug excreted (Ae)
• percentage of dose excreted (fe)
• renal clearance (CLR).
The PK outcome endpoints of NST-6179 for Part B (multiple-ascending dose in healthy subjects) were as follows:
• area under the concentration-time curve over a dosing interval (AUC0-τ)
• area under the concentration-time curve over a dosing interval normalised by dose (DAUC0-τ)
• AUC0-∞ (Day 1 only)
• DAUC0-∞ (Day 1 only)
• Cmax
• DCmax
• tmax
• t½
• CL/F
• Vz/F
• minimum observed concentration (Cmin)
• observed accumulation ratio based on AUC0-τ (RAAUC0-τ)
• observed accumulation ratio based on Cmax (RACmax).
Safety:
Safety assessments included adverse events, vital signs, 12-lead electrocardiograms (ECGs), clinical laboratory evaluations, and physical examinations.Statistical methods:
Analysis populations:
The all subjects population included all subjects who signed the informed consent form (ICF) and had any study assessment recorded in the database per the protocol.The safety population included all subjects who received at least 1 dose of study treatment (NST-6179 or placebo).
The PK population included all subjects who received at least 1 dose of active study treatment (NST-6179) and had at least 1 valid PK concentration.
Statistical methodology:
For PK statistical methodology, all PK concentrations and parameters were listed. Summary tables, arithmetic mean (+ standard deviation [SD]) figures, overlaying individual figures, and individual figures by treatment and time postdose were provided for plasma PK concentrations. Summary tables by treatment were provided for all PK parameters, with the exception of diagnostic regression-related PK parameters. Separate summary tables by treatment and time interval were also provided for excretion parameters and cumulative excretion parameters.
A statistical analysis was conducted to investigate the dose proportionality of plasma
NST-6179 AUC0-tlast, AUC0-∞, and Cmax on Profile Day 1 for dose levels administered in the fasted state in Part A; AUC0-∞ and Cmax on Profile Day 1 and AUC0-τ and Cmax on Profile
Day 14 for QD (fasted) doses in Part B. The hypothesis testing was 2-sided and carried out on
0.05 significance level. The PK parameters were analysed using a power model, provided the data met criteria supporting linearity. For the power model, it was concluded that PK parameters were dose proportional for the dose range studied if the 95% confidence intervals (CIs) for the slope spanned 1.
Safety data were presented using descriptive statistics. Determination of sample size:
No formal statistical assessment, in terms of sample size, was conducted as this is the first time NST-6179 is being administered to humans. However, the number of subjects in each part of the present study is common in early clinical pharmacology studies and was considered sufficient to achieve the objectives of the study.Summary - Conclusions:
Subject disposition:
Across both Part A and Part B, a total of 70 subjects were randomised, dosed, and completed the study in accordance with the protocol (and protocol amendments), with 40 subjects in Part A and 30 subjects in Part B.Pharmacokinetic results:
Following single and daily administration in the fasted state, all NST-6179 treated subjects were systemically exposed to NST-6179. Oral administration was characterised by a median tmax ranging from 1.25 to 2 hours postdose, tlast of 8 to 24 hours postdose, and estimates of plasma NST-6179 t½ in the range of 1 to 3 hours. NST-6179 exposure tended to increase in a manner that was proportional or slightly more than proportional to the increase in dose over the single dose range of 50 mg to 1000 mg on Day 1 (Part A) and following daily administration over the range of 200 mg to 1000 mg (Part B, Day 14). A 5-fold increase in dose from 200 mg to 1000 mg was associated with a 4- to 7-fold increase in AUC and Cmax. Renal clearance of unchanged NST-6179 was very low, with <0.1% of the dose recovered in urine collected up to 24, 48, or 72 hours postdose, consistent with potential metabolism prior to excretion. Where quantifiable (1000 mg QD), geometric mean Cmin values were consistent with predose levels from Day 4 to Day 12, demonstrating that steady-state plasma levels were likely achieved by Day 4. Following 14 days of daily administration, geometric mean accumulation ratios (AUC0-τ) were in the range of 1.10 to 1.20.Generally, there was low to moderate between-subject variability in AUCs and Cmax observed across all single- and multiple-ascending dose groups in this study, with inter-subject coefficient of variation (CVs) of <35% for AUC and <50% for Cmax (per statistical assessments of dose proportionality) and a trend toward higher variability for Cmax as compared to AUCs.
Safety results:
NST-6179 was considered safe and well-tolerated when administered as single oral doses up to 1000 mg and as multiple oral doses up to 1000 mg QD for 14 days.There were no deaths, serious adverse events (SAEs), and no subjects discontinued due to treatment-emergent adverse events (TEAEs).
In Part A, 10 subjects reported TEAEs following a single dose of NST-6179 up to 1000 mg and 4 subjects reported TEAEs following a single dose of placebo. With the exception of
1 TEAE, all TEAEs were mild and not considered treatment-related. The only TEAE reported in more than 1 subject was headache, and the only treatment-related TEAE was a single event of moderate headache reported in the 1000 mg NST-6179 dose group.In Part B, 16 subjects reported TEAEs following multiple doses of NST-6179 up to 1000 mg QD and 2 subjects reported TEAEs following multiple doses of placebo. The majority of all TEAEs were considered treatment-related; however, there was no apparent difference in relatedness of TEAEs between treatment groups.
Other safety assessments, including clinical laboratory evaluations, vital signs, 12-lead ECGs, telemetry, and physical examinations, were without findings of clinical significance, and there were no apparent dose- or treatment-related trends.
Conclusions:
• Single and multiple QD oral doses of NST-6179 up to 1000 mg were safe and well tolerated by the healthy subjects in this study.
• The majority of TEAEs were mild, and resolved without treatment. None of the subjects had a severe TEAE or SAE during the study and no subjects were discontinued due to a TEAE. Following single doses of NST-6179 up to 1000 mg, the majority of TEAEs were not considered by the investigator to be related to investigational medicinal product (IMP).
• The most common TEAEs were headache following single doses of NST-6179, and headache, diarrhoea, dizziness, abdominal pain upper, nausea, constipation, back pain, and limb discomfort following multiple doses of NST-6179 QD for 14 days.
• There were no treatment- or dose-related trends and no clinically significant findings in the clinical laboratory evaluations, vital signs data, 12-lead ECG data, or physical examination findings during the study.
• Following a single oral (fasted) dose of 50 mg to 1000 mg, NST-6179 appeared rapidly in plasma, with a median tmax of between 1.25 to 2 hours, and was eliminated with a geometric mean t½ of approximately 1 to 3 hours.• Following multiple 200 mg to 1000 mg QD oral doses for 14 days, NST-6179 showed minimal accumulation in plasma, with accumulation ratios of 1.10 to 1.20 for AUC0-τ. The geometric mean t½ estimates from Day 14 were in the range of 1 to 3 hours.
• Urinary excretion of unchanged NST-6179 was minimal following single or multiple doses of 50 mg to 1000 mg and represented <0.1% of the administered dose.• Systemic exposure to NST-6179 generally increased in a manner that was proportional or slightly more than proportional to the increase in dose, in terms of AUC and Cmax, following single doses over the range of 50 mg (or 200 mg) to 1000 mg, or daily doses of 200 mg to 1000 mg.
REC name
North East - York Research Ethics Committee
REC reference
21/NE/0062
Date of REC Opinion
28 May 2021
REC opinion
Further Information Favourable Opinion