Study Investigating the Safety, Tolerability, PK and Food Effect of BEN8744.

Healthy Volunteer Study Clinical Trial

Official title:

A Randomised, Double-blind, Placebo-controlled, Phase 1 First-in-human Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Food Effect of Single- and Multiple-ascending Doses of BEN8744 in Healthy Subjects.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT06118385
• Other study ID #: BB-8744-1001
• Status: Completed
• Phase: Phase 1
• Start date: August 30, 2023
• Est. completion date: March 18, 2024

Study information

• Verified date: April 2024
• Source: BenevolentAI Bio
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

BEN8744 is an experimental new medicine for treating inflammatory bowel diseases such as Ulcerative Colitis.

The study will test single and repeated doses of BEN8744 or placebo by mouth. BEN8744 is a first in human study, so will start with a small dose and the dose will be increased as the study progresses. The goal is to find out its side effects and blood levels when taken by mouth and whether food affects the blood levels.

This is a 3-part study (Parts A, B and C) in up to 108 healthy people, aged 18-65.

Part A, will include up to 64 participants, single doses of BEN8744 or placebo. They'll take about 2 weeks to finish the study, stay on the ward for 4 nights and 5 days in a row and make 2 outpatient visits.

Part B, will include up to 12 participants, single doses of BEN8744 with and without food. They'll take up to 3 weeks to finish the study, stay on the ward for 4 nights and 5 days in a row on 2 occasions, and make 2 outpatient visits.

Part C will include up to 32 participants repeat doses of the BEN8744 or placebo for 14 days. They'll take about 4 weeks to complete the study, stay on the ward for 17 nights and 18 days in a row and make 2 outpatient visits.

Description:

This first time in human, study will investigate the safety, tolerability, pharmacokinetics (PK) of BEN8744 after single and multiple ascending oral doses in healthy subjects, in both the fed and fasted state. The results of this study will be used to select doses for subsequent studies in patients. This is an exploratory study in healthy volunteers, with no anticipated therapeutic benefit to the participants; involvement of patients, service users or members of the public in the design of the trial is not appropriate.

Primary objectives Part A: To assess the safety and tolerability of single ascending oral doses of BEN8744 in healthy subjects Part B: To characterise the effect of food on the pharmacokinetic profile of at least 1 dose of BEN8744 Part C: To assess the safety and tolerability of multiple ascending oral doses of BEN8744 in healthy subjects

Secondary objectives Part A: To assess the PK profile of BEN8744 after single oral doses in healthy subjects Part B: To assess the safety and tolerability of a single dose of BEN8744 following high-fat food intake relative to fasting conditions in healthy subjects Part C: To assess the PK profile of BEN8744 after repeated oral doses in healthy subjects

Exploratory objective

Part B (and optional in Part C):

To measure BEN8744 in urine and determine renal clearance in healthy subjects. Exploratory characterisation of BEN8744 and its metabolites in plasma, urine, and faeces.

For part A

• Up to 64 subjects, 5 cohorts + 3 optional, 6 active, 2 placebo.

• Subjects will receive a single dose of BEN8744 or placebo, as capsules, after an overnight fast of at least 10 h.

• At each dose level, 6 subjects will receive BEN8744 and 2 will receive matching placebo in an overall ratio of 3:1.

• The starting dose for Group 1 is 2 mg BEN8744 or placebo. It is intended that subsequent cohorts will receive higher doses. The planned doses are:

A1- 2mg A2- 6mg A3- 20mg A4- 60mg A5- 100mg A6 (optional) - 120mg

For Part B

• Up to 12 subjects, 1 cohorts + 1 optional, 2 sessions fasted/fed.

• Each subject in Part B will have 2 study sessions (Sessions 1 and 2), in which they will receive a single dose of BEN8744, by mouth.

• Each subject will receive BEN8744 after an overnight fast of at least 10 h in one session, and after an FDA high-fat breakfast (1,013 kcal, 59.2 g fat [of which 28.1 g saturated fat) in the other session; the order will be randomised 1:1.

• A subject's doses will be separated by a washout of at least 7 days (or 5 half-lives as determined in Part A, whichever is longer).

• Subjects dosed on the same day may be dosed at intervals of at least 10 min.

For Part C:

• Up 32 subjects, 3 cohorts + 1 optional, 6 active, 2 placebo.

• Each subject will receive daily doses of BEN8744 or placebo, by mouth, for 14 days.

• Doses will be taken once or twice daily in the fasted state, unless emerging data indicate they should be taken in the fed state.

• Part C will not start until at least 3 dose levels have been completed in Part A and may also be conducted in parallel with Part B.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 76
• Est. completion date: March 18, 2024
• Est. primary completion date: March 14, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Male or female healthy volunteer in good health

2. Aged 18-65 years

3. Body mass index 18.0-30.9 and weight = 50 kg

Exclusion Criteria:

1. Woman who is pregnant or lactating, or pre-menopausal woman who is sexually active and not using a reliable method of contraception

Related Conditions & MeSH terms

• Healthy Volunteer Study

Intervention

Drug:
• BEN8744
Formulated powder in capsule for oral administration. Supplied as filled Size 0 Swedish Orange capsule. Doses: 2mg, 10mg and 40mg.
• Matching Placebo
Formulated powder in capsule for oral administration. Supplied as filled Size 0 Swedish Orange capsule. Doses: 2mg, 10mg and 40mg.

Locations

Country	Name	City	State
United Kingdom	Hammersmith Medicines Research	London

Sponsors (1)

Lead Sponsor	Collaborator
BenevolentAI Bio

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Observer's Assessment of Alertness/Sedation scale (OAAS/S) (Part A only)	In the OAAS/S, the investigator or their delegate will score the subject's level of alertness on a scale of minimum 0 to maximum 5, where 0 is absence of response to stimulus, and 5 is readily responsive to the subject's name in a normal tone.	Immediately before each PK blood sample up to 72 hours after dosing.
Primary	Visual analogue scale (VAS) (Part A only)	In the VAS, subjects will complete a self-reported post-dosing questionnaire. Subjects will be asked to grade their alertness on a linear scale from 0 (very alert) to 100 (very drowsy).	Immediately before each PK blood sample up to 72 hours after dosing.
Primary	Columbia-Suicide Severity Rating Scale (C-SSRS; Part C only)	The C-SSRS is a suicidal ideation rating scale used to evaluate suicidality. The questionnaire will be administered by the investigator or their delegate. Answers will be listed in a "yes" and "no" format i,e, no score calculated.	Day 17 and Day 24 +/-2 days (follow up)
Primary	Cmax (PK Part B)	Maximum (peak) plasma concentration. Obtained directly from the concentration-time data.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours) in each treatment session.
Primary	tmax (PK Part B)	Time to reach maximum (peak) plasma concentration. Obtained directly from the concentration-time data.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours) in each treatment session.
Primary	AUC24 (PK Part B)	Area under the plasma concentration-time curve from time zero to time 24 h.Calculated using the trapezoidal method.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours) in each treatment session.
Primary	AUC72 (PK Part B)	Area under the plasma concentration-time curve from time zero to time 72 h. Calculated using the trapezoidal method.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours) in each treatment session.
Primary	AUClast (PK Part B)	Area under the plasma concentration-time curve from time zero to time of last measurable concentration. Calculated using the trapezoidal method.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours) in each treatment session.
Primary	AUCinf (PK Part B)	Area under the plasma concentration-time curve from time zero to infinity. Calculated using the trapezoidal method for the interval 0 to tlast.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours) in each treatment session.
Primary	%AUCextrap (PK Part B)	Percentage of AUC8 extrapolated from tlast to infinity.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours) in each treatment session.
Primary	t1/2 (PK Part B)	Terminal half-life. Calculated from the terminal slope of the log concentration-time curve.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours) in each treatment session.
Primary	Terminal Rate Constant (PK Part B)	Estimated by linear regression of logarithmically transformed concentration versus time data.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours) in each treatment session.
Primary	CL/F (PK Part B)	Apparent total clearance from plasma after oral administration.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours) in each treatment session.
Primary	VZ/F (PK Part B)	Apparent volume of distribution during terminal phase after non-intravenous administration.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours) in each treatment session.
Secondary	Cmax (PK Part A)	Maximum (peak) plasma concentration. Obtained directly from the concentration-time data.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours).
Secondary	tmax (PK Part A)	Time to reach maximum (peak) plasma concentration. Obtained directly from the concentration-time data.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours).
Secondary	AUC24 (PK Part A)	Area under the plasma concentration-time curve from time zero to time 24 h. Calculated using the trapezoidal method.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours).
Secondary	AUC72 (PK Part A)	Area under the plasma concentration-time curve from time zero to time 72 h. Calculated using the trapezoidal method.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours).
Secondary	AUClast (PK Part A)	Area under the plasma concentration-time curve from time zero to time of last measurable concentration. Calculated using the trapezoidal method.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours).
Secondary	AUCinf (PK Part A)	Area under the plasma concentration-time curve from time zero to infinity. Calculated using the trapezoidal method.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours).
Secondary	%AUCextrap (PK Part A)	Percentage of AUC8 extrapolated from tlast to infinity.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours).
Secondary	t1/2 (PK Part A)	Terminal half-life. Calculated from the terminal slope of the log concentration-time curve.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours).
Secondary	Terminal Rate Constant (PK Part A)	Estimated by linear regression of logarithmically transformed concentration versus time data.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours).
Secondary	CL/F (PK Part A)	Apparent total clearance from plasma after oral administration.	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours).
Secondary	VZ/F (PK Part A)	Apparent volume of distribution during terminal phase after non-intravenous administration	Day 1 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Day 2 (24 and 36 hours); on Day 3 (48 hours); and on Day 4 (72 hours).
Secondary	Observer's Assessment of Alertness/Sedation scale (OAAS/S) (Part B)	In the OAAS/S, the investigator or their delegate will score the subject's level of alertness on a scale of minimum 0 to maximum 5, where 0 is absence of response to stimulus, and 5 is readily responsive to the subject's name in a normal tone.	Frequently at specific timepoints immediately before PK blood samples up to 72h after dosing.
Secondary	Visual analogue scale (VAS) (Part B)	In the VAS, subjects will complete a self-reported post-dosing questionnaire. Subjects will be asked to grade their alertness on a linear scale from 0 (very alert) to 100 (very drowsy).	Immediately before each PK blood sample up to 72 hours after dosing.
Secondary	Cmax (PK Part C)	Maximum (peak) plasma concentration.Obtained directly from the concentration-time data.	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.
Secondary	tmax (PK Part C)	Time to reach maximum (peak) plasma concentration.Obtained directly from the concentration-time data.	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.
Secondary	Ctrough (PK Part C)	Trough plasma concentration. Trough plasma concentration (measured concentration at the end of a dosing interval at steady state [taken directly before next administration]) obtained directly from the concentration-time data.	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.
Secondary	AUCtau (PK Part C)	Area under the plasma concentration-time curve during a dosing interval (tau).Calculated using the trapezoidal method.	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.
Secondary	AUClast (PK Part C)	Area under the plasma concentration-time curve from time zero to time of last measurable concentration. Calculated using the trapezoidal method	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.
Secondary	AUC72 (PK Part C)	Area under the plasma concentration-time curve from time zero to time 72 h.	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.
Secondary	AUCinf (PK Part C)	Area under the plasma concentration-time curve from time zero to infinity. Calculated using the trapezoidal method for the interval 0 to tlast.	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.
Secondary	%AUCextrap (PK Part C)	Percentage of AUC8 extrapolated from tlast to infinity.	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.
Secondary	t1/2 (PK Part C)	Terminal half-life. Calculated from the terminal slope of the log concentration-time curve.	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.
Secondary	Terminal Rate Constant (PK Part C)	Estimated by linear regression of logarithmically transformed concentration versus time data	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.
Secondary	CLSS/F (PK Part C)	Apparent total clearance from plasma at steady state after non-intravenous administration.	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.
Secondary	VZ/F (PK Part C)	apparent volume of distribution after non-intravenous administration calculated at steady state	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.
Secondary	Rac(AUC) (PK Part C)	Accumulation ratio for AUC.Calculated from AUCtau at steady state and AUCtau after a single dose.	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.
Secondary	Rac(Cmax) (PK Part C)	Accumulation ratio for Cmax. Calculated from Cmax at steady state and Cmax after a single dose.	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.
Secondary	SR(AUC) (PK Part C)	Stationarity ratio for AUC. Stationarity ratio will be calculated from AUCt at steady state and AUC8 after single dose.	Once-daily dosing: Days 1 and 14 at predose and postdose at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours; on Days 2, 15, 16 and 17. Trough samples will be taken predose on Days 3, 5, 7, 9, 11, and 13.