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

Phase 1

Completed

• Conditions: Healthy Subjects
• Interventions: Drug: Placebo; Drug: nangibotide

• Registration Number: NCT03463044
• Lead Sponsor: Inotrem

Brief Summary

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

Detailed Description

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

Study Timeline

• Study Start: 2016-04-01
• Primary Completion: 2016-08-25
• Study Completion: 2016-08-25
• Study First Submitted: 2018-02-27
• Study First Submitted QC: 2018-03-12
• Study First Posted: 2018-03-13
• Results First Submitted: 2022-06-08
• Status Verified: 2025-01
• Results First Submitted QC: 2025-01-16
• Last Update Submitted: 2025-01-16
• Results First Posted: 2025-02-10
• Last Update Posted: 2025-02-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 27

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Matched placebo
MOTREM 4	nangibotide	Nangibotide dose 4
MOTREM 7	nangibotide	Nangibotide dose 7
MOTREM 1	nangibotide	nangibotide dose 1
MOTREM 3	nangibotide	Nangibotide dose 3
MOTREM 2	nangibotide	Nangibotide dose 2
MOTREM 8	nangibotide	Nangibotide dose 8
MOTREM 5	nangibotide	Nangibotide dose 5
MOTREM 6	nangibotide	Nangibotide dose 6

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Statistical Analysis of LR12 PK Parameters: t1/2	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).	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.
Statistical Analysis of LR12 PK Parameters: 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).	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).
Pharmacokinetics (Maximum Plasma Concentration)	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.	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).
Statistical Analysis of LR12 PK Parameters: 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.	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).
Statistical Analysis of LR12 PK Parameters: 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.	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).
Statistical Analysis of LR12 PK Parameters: AUC0-∞	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).	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%.
Statistical Analysis of LR12 PK Parameters: CL	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).	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.
Statistical Analysis of LR12 PK Parameters: Volume of Distribution (V)	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.	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.
Statistical Analysis of LR12 PK Parameters: t Last	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.	This PK parameter was calculated from measured plasma concentrations of LR12 and it represents the time of last observed concentration.

Trial Locations

Locations (1)

Richmond Pharmacology Ltd.; 🇬🇧 Croydon, United Kingdom