Safety, Tolerability and Pharmacokinetic Profiles of MOTREM (LR12) in Healthy Male Subjects

A Phase I, Randomised, Placebo Controlled Study to Assess the Safety, Tolerability and Pharmacokinetic Profiles of Ascending, Single, Intravenous Doses of MOTREM (LR12) in Healthy Male Subjects

This was a single center, randomized, placebo-controlled study with a sequential i.v. dose escalation cohorts design, to assess safety, tolerability and pharmacokinetics of MOTREM (nangibotide) in healthy volunteers

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: Placebo; Drug: nangibotide

Detailed Description

This was a dose escalation study in healthy volunteers to evaluate the safety and pharmacokinetics of nangibotide in humans

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Croydon, United Kingdom
    • Richmond Pharmacology Ltd.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• healthy male
• ≥18 to ≤45 years old
• Body mass index (BMI) between 18-30 kg/m² inclusive
• Written informed consent to participate.

Main Exclusion Criteria:

• Any clinically relevant acute or chronic diseases
• Any history of drug or alcohol abuse
• Any History of clinical significant disease as determined by medical history, physical examination or other evaluations.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matched placebo	Drug: Placebo; Placebo; Other Names: matched placebo
Experimental: MOTREM 1; nangibotide dose 1	Drug: nangibotide; Continous i.v. infusion; Other Names: LR12; MOTREM
Experimental: MOTREM 2; Nangibotide dose 2	Drug: nangibotide; Continous i.v. infusion; Other Names: LR12; MOTREM
Experimental: MOTREM 3; Nangibotide dose 3	Drug: nangibotide; Continous i.v. infusion; Other Names: LR12; MOTREM
Experimental: MOTREM 4; Nangibotide dose 4	Drug: nangibotide; Continous i.v. infusion; Other Names: LR12; MOTREM
Experimental: MOTREM 5; Nangibotide dose 5	Drug: nangibotide; Continous i.v. infusion; Other Names: LR12; MOTREM
Experimental: MOTREM 6; Nangibotide dose 6	Drug: nangibotide; Continous i.v. infusion; Other Names: LR12; MOTREM
Experimental: MOTREM 7; Nangibotide dose 7	Drug: nangibotide; Continous i.v. infusion; Other Names: LR12; MOTREM
Experimental: MOTREM 8; Nangibotide dose 8	Drug: nangibotide; Continous i.v. infusion; Other Names: LR12; MOTREM

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability: the Number of Subjects Experiencing Treatment Emergent Adverse Events	The number of subjects experiencing treatment emergent adverse events was collected to assess the safety and tolerability of MOTREM (LR12) in comparison with placebo.	30-44 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (Maximum Plasma Concentration)	Plasma concentrations of LR12 were measured by a validated liquid chromatography-mass spectrometry (LC-MS/MS) assay and analyzed using noncompartmental methods to obtain estimates of the pharmacokinetic parameter of Maximum Plasma Concentration (Cmax).	Maximum Plasma Concentration (Cmax) was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. Cmax is determined over a period of time starting from predose to 10h after start of the loading dose.
Statistical Analysis of LR12 PK Parameters: Steady State Concentration During the Maintenance Infusion (Cavg30-465)	Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of steady state concentration during the maintenance infusion (Cavg30-465).	Cavg30-465 was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. Cavg30-465 is determined over a period of time starting from predose to 10h after start of the loading dose.
Statistical Analysis of LR12 PK Parameters: t1/2	Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of terminal half-life (t1/2). Of note, apparent increase in half-life at increasing doses is explained by the detection of a slow elimination phase, which was below limit of quantification for the lower doses.	t1/2 was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. t1/2 is determined over a period of time starting from 7 h and 45 min to 10h after start of the loading dose (decaying period).
Statistical Analysis of LR12 PK Parameters: AUC0-t	Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of the area under the plasma concentration curve (h.ng/mL) from time zero (predose) to the time of last observed concentration (t) measured (which can go up to 10h post loading dose start) using a linear trapezoidal method (AUC0-t).	AUC0-t was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. AUC0-t is determined over a period of time starting time zero (predose) to the time of last observed concentration (t).
Statistical Analysis of LR12 PK Parameters: AUC0-∞	Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of AUC0-∞. AUC0-∞ represents the area under the plasma concentration-time curve (h.ng/mL) from time 0 to infinity (AUC0- ∞= AUC0-t + [Ct/ke], where Ct = the observed concentration of drug for the last sample on the PK profile in which drug was detected, and ke represents the terminal rate constant). The percentage of extrapolation of AUC0-∞ should not exceed 20%.	AUC0-∞ was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. AUC0-∞ is determined over a period of time starting time zero (predose) to infinity (cf. extrapolation formula in the above section).
Statistical Analysis of LR12 PK Parameters: CL	Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analyzed using noncompartmental methods to obtain estimates of the PK parameter of systemic clearance (CL). The systemic clearance was estimated using the formula: CL = K0/ Css where K0 is the perfusion rate (ng/kg/h) and Css is the concentration at the end of perfusion (C at 465 min). Of note, this narrow range of the clearance values indicates that the apparent increases in t1/2 and volume of distribution as a function of doses are not due to a non-linearity in the pharmacokinetics, but to the limit of quantification of the bioanalytical assay.	CL was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min (465 min). CL is calculated based on the perfusion rate (ng/kg/h) and the concentration at the end of perfusion (7h45min = 465min).
Statistical Analysis of LR12 PK Parameters: Volume of Distribution (V)	The volume of distribution was estimated according to the following equation: V= CL x MRT (mean residence time). However, regarding administration procedures, MRT could not be calculated precisely. Furthermore, in some cases MRT could not be estimated. Thus, the following formula was used V = CL / ke. The terminal rate constant (ke) was estimated by log-linear regression analysis on data points visually assessed to be on the terminal log-linear phase. Of note, it can be said that this apparent increase in V is also explained by the detection of a slow elimination phase, which was below limit of quantification for the lower doses.	V was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. V is derived from both CL and ke which are calculated from the LR12 concentration time curve from predose to 10h after loading dose start.
Statistical Analysis of LR12 PK Parameters: Tmax	Plasma concentrations of LR12 were measured by a validated LC-MS/MS assay and analysed using noncompartmental methods to obtain estimates of the PK parameter of the time at which Cmax is apparent, identified by inspection of the plasma drug concentration vs.time data by WinNonlin (tmax).	tmax was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. tmax is determined over a period of time starting from predose to 10h after start of the loading dose.
Statistical Analysis of LR12 PK Parameters: t Last	This PK parameter was calculated from measured plasma concentrations of LR12 and it represents the time of last observed concentration.	t last was assessed only for Groups 3-8 who received loading dose over 15 min and maintenance dose over 7 h and 45 min. t last is determined as the time of last observed concentration which can go up to 10h after loading dose start.

Collaborators and Investigators

• Sponsor: Inotrem
• Collaborators: Richmond Pharmacology Limited
• Investigators: Study Director: Valérie Cuvier, Inotrem

Publications and helpful links

General Publications

• Cuvier V, Lorch U, Witte S, Olivier A, Gibot S, Delor I, Garaud JJ, Derive M, Salcedo-Magguilli M. A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition. Br J Clin Pharmacol. 2018 Oct;84(10):2270-2279. doi: 10.1111/bcp.13668. Epub 2018 Jul 20.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2016
• Primary Completion (Actual): August 25, 2016
• Study Completion (Actual): August 25, 2016

Study Registration Dates

• First Submitted: February 27, 2018
• First Submitted That Met QC Criteria: March 12, 2018
• First Posted (Actual): March 13, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 16, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Anti-Inflammatory Agents; Nangibotide
• Other Study ID Numbers: MOT-C-104

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No