A study to evaluate the safety, tolerability and processing by the body of RO7440688 in healthy volunteers

ISRCTN	ISRCTN15492429
DOI	https://doi.org/10.1186/ISRCTN15492429
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Protocol serial number	GC42880
Sponsor	Genentech, Inc
Funder	Genentech

Submission date: 05/02/2021
Registration date: 10/03/2021
Last edited: 08/04/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Circulatory System

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Current plain English summary as of 05/11/2021:
Background and study aims
The aim of this study is to test a new drug RO744068 compared with placebo at different doses, to find out if it is safe and to understand the way people process the drug. A placebo looks like a drug but has no active ingredient.

Who can participate?
Healthy male and female volunteers aged 18 to 65 years, inclusive

What does the study involve?
Participants are randomly assigned to receive either RO744068 or placebo as a single dose or multiple doses to determine the safety and the way people process the drug. The total maximum study duration for participants is about 50 days.

What are the possible benefits and risks of participating?
Participants are not expected to receive any direct benefits from the study, but the information that is learned may help other people in the future. RO744068 has not yet been tested in humans. This is the first trial of RO744068 in humans. For this reason, the side effects of this drug are not known at this time.

Where is the study run from?
Christchurch Clinical Studies Trust (New Zealand)

When is the study starting and how long is it expected to run for?
March 2021 to March 2022

Who is funding the study?
Genentech, Inc. (USA)

Who is the main contact?
global-roche-genentech-trials@gene.com

Previous plain English summary:
Background and study aims
The aim of this study is to test a new drug RO744068 compared with placebo at different doses, to find out if it is safe and to understand the way people process the drug. A placebo looks like a drug but has no active ingredient.

Who can participate?
Healthy male and female volunteers aged 18 to 65 years, inclusive

What does the study involve?
Participants are randomly assigned to receive either RO744068 or placebo as a single dose or multiple doses to determine the safety of the drug. The total maximum study duration for participants is about 50 days.

What are the possible benefits and risks of participating?
Participants are not expected to receive any direct benefits from the study, but the information that is learned may help other people in the future. RO744068 has not yet been tested in humans. This is the first trial of RO744068 in humans. For this reason, the side effects of this drug are not known at this time.

Where is the study run from?
Christchurch Clinical Studies Trust (New Zealand)

When is the study starting and how long is it expected to run for?
March 2021 to December 2021

Who is funding the study?
Genentech, Inc. (USA)

Who is the main contact?
global-roche-genentech-trials@gene.com

Contact information

Dr Clinical Trials
Scientific

1 DNA Way
South San Francisco
94080
United States of America

Phone	+1 888-662-6728
Email	global-roche-genentech-trials@gene.com

Study information

Primary study design	Interventional
Study design	Single-centre Phase I trial including a randomized single ascending dose, food effect, and multiple ascending dose study, and a non-randomized drug-drug interaction study
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	A phase I, randomized, double-blind, placebo-controlled, dose-escalation study to evaluate the safety, tolerability, and pharmacokinetics of single‑ and multiple‑ascending oral doses of RO7440688, the effect of food on the pharmacokinetics of RO7440688, and the effects of RO7440688 on midazolam pharmacokinetics in healthy volunteers
Study objectives	Current study hypothesis as of 05/11/2021: To assess safety, tolerability, and pharmacokinetics of RO7440688 when administered to healthy volunteers. Previous study hypothesis: To assess safety, tolerability, and pharmacokinetics of RO7440688 when administered to healthy volunteers in single or multiple doses
Ethics approval(s)	Not provided at time of registration
Health condition(s) or problem(s) studied	Cardiovascular disease
Intervention	Current intervention as of 05/11/2021: Participants will be randomized to the treatment arms via a blinded Randomization List. In the single-ascending dose (SAD) study, each cohort will evaluate oral administration of RO7440688 The initial dose of RO7440688 will be 150 mg and subsequent doses will be determined based on review of safety and PK data. In SAD and Food Effect stages, all participants will reside at the clinical research unit for 72 hours after dosing and return for a scheduled non-residential follow-up visit. MAD participants will reside at the clinical research unit through the completion of the 7 day dosing period through 72 hours after last dose and complete non-residential follow-up visits through Day 35. The drug-drug interaction cohort is not randomized. Participants will be administered midazolam and multiple doses of RO7440688 (these dose levels will be determined by MAD) and will remain in the clinical research unit through completion of the dosing period up through 24 hours after the last dose and complete residential follow-up visits through Day 38. Previous intervention: Participants will be randomized to the treatment arms via a blinded Randomization List. In the single-ascending dose (SAD) study, each cohort will evaluate oral administration of RO7440688 The initial dose of RO7440688 will be 150 mg and subsequent doses will be determined based on review of safety and PK data. In SAD and Food Effect stages, all participants will reside at the clinical research unit for 72 hours after dosing and return for a scheduled non-residential follow-up visit. MAD participants will reside at the clinical research unit through the completion of the 7 day dosing period through 72 hours after last dose and complete non-residential follow-up visits through Day 35.
Intervention type	Drug
Phase	Phase I
Drug / device / biological / vaccine name(s)	RO7440688
Primary outcome measure(s)	1. Incidence of adverse events (DAIDS toxicity grading scale) throughout the study 2. Vital signs (respiratory rate, pulse rate, and systolic and diastolic blood pressure, and temperature) measured at baseline and daily post-dose (Day 1-15 in the SAD and Food Effect cohorts, and Day 1- 35 in the MAD cohorts) 3. Clinical laboratory test results, including chemistry panel, hematology panel, lipid panel, coagulation panel, methemoglobin level and urinalysis measured at baseline and post dose (Day 1-15 in SAD and Food Effect cohorts, and Day 1-35 in the MAD cohorts) 4. ECG abnormalities as measured by 12-lead ECG throughout the course of the study (Day 1-15 in the SAD and Food Effect cohorts, and Day 1- 35 in the MAD cohorts)
Key secondary outcome measure(s)	Current secondary outcome measures as of 05/11/2021: 1. Pharmacokinetics (PK) of RO7440688 following a single and multiple doses, and the effect of food on the PK of RO7440688 following a single dose, on the basis of plasma concentrations of RO7440688 measured at specified timepoints. The following PK parameters will be calculated if data allow: 1.1. SAD stage: AUC0-24, AUC from time 0 to last quantifiable concentration (AUC0-last), AUC from time 0 to infinity (AUC0-inf), percentage of AUC extrapolated (AUC%extrap), Cmax, tmax, apparent clearance (CL/F), apparent volume of distribution during elimination phase (Vz/F), elimination rate constant (λZ), and apparent half-life (t1/2) 1.2. MAD stage: AUC0-tau, Cmax, tmax, Ctrough, average concentration at steady state (Cave,ss), peak/trough fluctuation at steady state, accumulation ratios (ARs) for Cmax and AUC0-tau on the last versus first day of dosing, CL/F, Vz/F, apparent steady-state volume of distribution (Vss/F), λZ, and t1/2 1.3. Food effect stage: AUC0-24, AUC0-last, AUC0-inf, AUC%extrap, Cmax, tmax, CL/F, Vz/F, λZ, t1/2, relative bioavailability of RO7440688 following a high-fat breakfast versus fasted based on AUC and Cmax, and relative bioavailability of RO7440688 following a low-fat breakfast versus fasted based on AUC and Cmax (if appropriate) 1.4 Drug-Drug Interaction stage: plasma pharmacokinetics of midazolam and its metabolite 1-hydroxy midazolam including, but not limited to AUC0-t, AUC0-inf, Cmax, tmax, CL/F, t1/2 For SAD/food effect cohorts, PK will be collected on Day 1 (predose, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h post-dose), Day 2 (24h post-dose), Day 3 (48h post-dose), Day 4 (72 post-dose), and anytime during clinic visit on Day 15. For MAD cohorts, PK will be collected on Day 1 (predose, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h post-dose), Day 2 (pre-dose), Day 3 (pre-dose), Day 5 (pre-dose), Day 7 (predose, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h post-dose), Day 8 (24h after final dose), Day 9 (48h after final dose), Day 10 (72h after final dose), and anytime during clinic visit on Day 14. For DDI cohorts, PK will be collected on Day 1 (predose, 30 m, 1, 2, 3, 4, 6, 8, 12, 16, 20 hpost-dose), Day 2 (24 h post-Day 1 dose), Day 7-9 (predose), Day 10 (same as Day 1), Day 11 (24 h post-final dose) Previous secondary outcome measures: 1. Pharmacokinetics (PK) of RO7440688 following a single and multiple doses, and the effect of food on the PK of RO7440688 following a single dose, on the basis of plasma concentrations of RO7440688 measured at specified timepoints. The following PK parameters will be calculated if data allow: 1.1. SAD stage: AUC0-24, AUC from time 0 to last quantifiable concentration (AUC0-last), AUC from time 0 to infinity (AUC0-inf), percentage of AUC extrapolated (AUC%extrap), Cmax, tmax, apparent clearance (CL/F), apparent volume of distribution during elimination phase (Vz/F), elimination rate constant (λZ), and apparent half-life (t1/2) 1.2. MAD stage: AUC0-tau, Cmax, tmax, Ctrough, average concentration at steady state (Cave,ss), peak/trough fluctuation at steady state, accumulation ratios (ARs) for Cmax and AUC0-tau on the last versus first day of dosing, CL/F, Vz/F, apparent steady-state volume of distribution (Vss/F), λZ, and t1/2 1.3. Food effect stage: AUC0-24, AUC0-last, AUC0-inf, AUC%extrap, Cmax, tmax, CL/F, Vz/F, λZ, t1/2, relative bioavailability of RO7440688 following a high-fat breakfast versus fasted based on AUC and Cmax, and relative bioavailability of RO7440688 following a low-fat breakfast versus fasted based on AUC and Cmax (if appropriate) For SAD/food effect cohorts, PK will be collected on Day 1 (predose, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h post-dose), Day 2 (24h post-dose), Day 3 (48h post-dose), Day 4 (72 post-dose), and anytime during clinic visit on Day 15. For MAD cohorts, PK will be collected on Day 1 (predose, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h post-dose), Day 2 (pre-dose), Day 3 (pre-dose), Day 5 (pre-dose), Day 7 (predose, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h post-dose), Day 8 (24h after final dose), Day 9 (48h after final dose), Day 10 (72h after final dose), and anytime during clinic visit on Day 14.
Completion date	21/03/2022

Eligibility

Participant type(s)	Healthy volunteer
Age group	Mixed
Lower age limit	18 Years
Upper age limit	65 Years
Sex	All
Target sample size at registration	116
Total final enrolment	67
Key inclusion criteria	1. Age ≥18 years and ≤65 years 2. Ability to comply with the study protocol, in the investigator’s judgment 3. Use of contraceptive measures
Key exclusion criteria	Current participant exclusion criteria as of 05/11/2021: 1. Pregnant or breastfeeding, or intending to become pregnant during the study or within 14 days of last study drug dose for subjects in the SAD and food effect stages and 28 days for subjects in the MAD and DDI stages 2. No comorbid conditions that may interfere with the evaluation of an investigational medical product 3. No history or evidence of substance abuse that would pose a risk to participants safety, interfere with the conduct of the study, or have an impact on the study results 4. History of severe allergic or anaphylactic reactions to human, humanized, or Current treatment with medications that are well known to prolong the QT Previous participant exclusion criteria: 1. Pregnant or breastfeeding, or intending to become pregnant during the study or within 14 days of last study drug dose for subjects in the SAD and food effect stages and 28 days for subjects in the MAD stage 2. No comorbid conditions that may interfere with the evaluation of an investigational medical product 3. No history or evidence of substance abuse that would pose a risk to participants safety, interfere with the conduct of the study, or have an impact on the study results 4. History of severe allergic or anaphylactic reactions to human, humanized, or Current treatment with medications that are well known to prolong the QT
Date of first enrolment	20/04/2021
Date of final enrolment	11/12/2021

Locations

Countries of recruitment

New Zealand

Study participating centre

Christchurch Clinical Studies Trust

Level 4 - 264 Antigua St.
Christchurch
8011
New Zealand

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not expected to be made available
IPD sharing plan	The datasets generated during and/or analysed during the current study are not expected to be made available due to confidentiality.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article		23/07/2023	08/04/2024	Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

08/04/2024: Publication reference and total final enrolment added.
22/07/2022: The following changes have been made:
1. The recruitment end date has been changed from 20/02/2022 to 11/12/2021.
2. The overall trial end date has been changed from 01/03/2022 to 21/03/2022.
15/11/2021: The following changes have been made:
1. The study design has been changed from "Single-centre Phase I randomized double-blind placebo-controlled" to "Single-centre Phase I trial including a randomized single ascending dose, food effect, and multiple ascending dose study, and a non-randomized drug-drug interaction study".
2. The overall trial end date has been changed from 30/11/2021 to 01/03/2022 and the plain English summary has been updated to reflect this change.
05/11/2021: The following changes have been made:
1. The recruitment end date has been changed from 31/10/2021 to 20/02/2022.
2. The scientific title has been changed from "A phase I, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of single‑ and multiple‑ascending doses of oral RO7440688 and the effect of food on the pharmacokinetics of RO7440688 in healthy volunteers" to "A phase I, randomized, double-blind, placebo-controlled, dose-escalation study to evaluate the safety, tolerability, and pharmacokinetics of single‑ and multiple‑ascending oral doses of RO7440688, the effect of food on the pharmacokinetics of RO7440688, and the effects of RO7440688 on midazolam pharmacokinetics in healthy volunteers".
3. The study hypothesis has been updated.
4. The intervention has been updated.
5. The secondary outcome measures have been updated.
6. The participant exclusion criteria have been updated.
7. The plain English summary has been updated.
01/03/2021: Trial’s existence confirmed by Health and Disability Ethics Committees (New Zealand)