Clinical trial NCT06118385: Study Investigating the Safety, Tolerability, PK and Food Effect of BEN8744.
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteer Study
Lead sponsor: BenevolentAI Bio
Sponsor class: INDUSTRY
First posted: 2023-11-07
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The trial will be in 3 parts: Part A will investigate single ascending oral doses of BEN8744; Part B is a 2-way crossover assessment of the effect of food on the PK of BEN8744; and Part C will investigate multiple ascending oral doses of BEN8744
Primary purpose: TREATMENT

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

The study will test single and repeated oral doses of BEN8744 or placebo. 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline in Observer's Assessment of Alertness/Sedation Scale (OAAS/S) (Part A)
timeFrame: From Baseline (predose on Day 1) through 72 hours postdose
measure: Change From Baseline in Visual Analogue Scale (VAS) (Part A)
timeFrame: From Baseline (predose on Day 1) through 72 hours postdose
measure: Cmax (PK Part B)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
measure: Tmax (PK Part B)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
measure: AUC24 (PK Part B)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose in each of the 2 treatment periods (fasted and fed)
measure: AUC72 (PK Part B)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
measure: AUClast (PK Part B)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
measure: AUCinf (PK Part B)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
measure: t1⁄2 (PK Part B)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
measure: Terminal Rate Constant (PK Part B)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
measure: CL/F (PK Part B)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
measure: VZ/F (PK Part B)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
measure: %AUCextrap (PK Part B)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
measure: Change From Baseline in Observer's Assessment of Alertness/Sedation Scale (OAAS/S) (Part C)
timeFrame: From Baseline (predose on Day 1) through 48 hours postdose
measure: Change From Baseline in Visual Analogue Scale (VAS) (Part C)
timeFrame: From Baseline (predose on Day 1) through 48 hours postdose
measure: Columbia-Suicide Severity Rating Scale (C-SSRS) (Part C)
timeFrame: Completed during screening and on Days 17 and 24
Secondary outcomes:
measure: Cmax (PK Part A)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
measure: Tmax (PK Part A)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
measure: AUC24 (PK Part A)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours postdose
measure: AUC72 (PK Part A)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
measure: AUClast (PK Part A)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
measure: AUCinf (PK Part A)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
measure: %AUCextrap (PK Part A)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
measure: t1⁄2 (PK Part A)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
measure: Terminal Rate Constant (PK Part A)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
measure: CL/F (PK Part A)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
measure: VZ/F (PK Part A)
timeFrame: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
measure: Change From Baseline in Observer's Assessment of Alertness/Sedation Scale (OAAS/S) (Part B)
timeFrame: From Baseline (predose on Day 1) through 72 hours postdose
measure: Change From Baseline in Visual Analogue Scale (VAS) (Part B)
timeFrame: From Baseline (predose on Day 1) through 72 hours postdose
measure: Cmax (PK Part C)
timeFrame: Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)
measure: Tmax (PK Part C)
timeFrame: Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)
measure: Ctrough (PK Part C)
timeFrame: Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)
measure: AUCtau (PK Part C)
timeFrame: Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)
measure: AUClast (PK Part C)
timeFrame: Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)
measure: AUC72 (PK Part C)
timeFrame: At 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14
measure: t1⁄2 (PK Part C)
timeFrame: Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)
measure: AUCinf (PK Part C)
timeFrame: Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)
measure: %AUCextrap (PK Part C)
timeFrame: Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)
measure: Terminal Rate Constant (PK Part C)
timeFrame: Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)
measure: CLSS/F (PK Part C)
timeFrame: Plasma concentrations measured at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14
measure: VZ/F (PK Part C)
timeFrame: Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)
measure: Rac(AUCtau) (PK Part C)
timeFrame: Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)
measure: Rac(Cmax) (PK Part C)
timeFrame: Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)
measure: SR(AUC) (PK Part C)
timeFrame: Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above)
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Hammersmith Medicines Research
Study officials:
affiliation: Hammersmith Medicine Research
name: Denisa Wilkes
role: PRINCIPAL_INVESTIGATOR
References: