First-in-human, Safety, Tolerability and Pharmacokinetics Study of LRX712 in Osteoarthritic Patients

A Randomized, Placebo Controlled, Subject and Investigator Blinded, first-in- Human, Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics After Intra-articular Injection of LRX712 Into the Knee of Osteoarthritic Patients

This study is designed to evaluate, for the first time in humans, safety and tolerability of single ascending doses of intra-articular (i.a.) injections of LRX712 into the knee of patients with moderate osteoarthritis (OA), in order to support the further clinical development. This study will also allow establishment of the systemic and local pharmacokinetics (PK) of LRX712 and the exploration of biomarkers of cartilage breakdown and regeneration in OA patients.

Study Overview

• Status: Completed
• Conditions: Patients With Moderate Knee Osteoarthritis (30 - 65 Years)
• Intervention / Treatment: Drug: LRX712; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands, 2333 CL
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female patients, 30 to 65 years of age inclusive, and in good health as determined by medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening.
• At screening, and at baseline vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the subject has rested for at least three minutes, and again (when required) after three minutes in the standing position as outlined in the SOM.

Sitting vital signs should be guided by the following ranges:

• body temperature between 35.0-37.5 °C
• systolic blood pressure 90-139 mm Hg
• diastolic blood pressure 50-89 mm Hg
• pulse rate, 40 - 90 bpm • Subjects must weigh at least 50 kg to participate in the study, and must have a body mass index (BMI) within the range of 18 - 32 kg/m2. BMI = Body weight (kg) / [Height (m)]

Exclusion Criteria:

• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant.
• Pregnant or nursing (lactating) women
• Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations

• A history of clinically significant ECG abnormalities, or any of the following ECG abnormalities at screening and baseline

  • PR > 200 msec
  • QRS complex > 120 msec
  • QTcF > 450 msec (males)
  • QTcF > 460 msec (females)
• Known family history or known presence of long QT syndrome

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: LRX712; LRX712 given intra-articularly	Drug: LRX712; Ascending single dose on Day 1
PLACEBO_COMPARATOR: Placebo; Placebo given intra-articularly	Drug: Placebo; Ascending single dose on Day 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) of LRX712 after a single intra-articular (i.a.) injection in Osteoarthritic (OA) patients	To evaluate Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) of LRX712 after a single i.a. injection in osteoarthritic patients	Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Reach the Maximum Plasma Concentration (Tmax)	To evaluate LRX712 and metabolite MAE344 pharmacokinetics in plasma - Time to Reach the Maximum Plasma Concentration (Tmax)	pre-dose to 29 days post-dose
Maximum Observed Plasma Concentration (Cmax)	To evaluate LRX712 and metabolite MAE344 pharmacokinetics in plasma - Maximum Observed Plasma Concentration (Cmax)	pre-dose to 29 days post-dose
Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast)	To evaluate LRX712 and metabolite MAE344 pharmacokinetics in plasma - Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast)	pre-dose to 29 days post-dose
Area under the plasma concentration-time curve from time zero to infinity (AUCinf)	To evaluate LRX712 and metabolite MAE344 pharmacokinetics in plasma - Area under the plasma concentration-time curve from time zero to infinity (AUCinf)	pre-dose to 29 days post-dose
Half-life (T1/2)	To evaluate LRX712 and metabolite MAE344 pharmacokinetics in plasma - Half-life (T1/2)	pre-dose to 29 days post-dose
CL/F - Total clearance	To evaluate LRX712 and metabolite MAE344 pharmacokinetics in plasma - CL/F - Total clearance	pre-dose to 29 days post-dose
Vz/F - Volume of Distribution	To evaluate LRX712 and metabolite MAE344 pharmacokinetics in plasma - Vz/F - Volume of Distribution	pre-dose to 29 days post-dose

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CLRX712X2101 can be found on the Novartis Clinical Trial Results Website
• A Plain Language Trial Summary is available on novartisclinicatrials.com

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 20, 2017
• Primary Completion (ACTUAL): March 26, 2019
• Study Completion (ACTUAL): March 26, 2019

Study Registration Dates

• First Submitted: November 17, 2017
• First Submitted That Met QC Criteria: November 27, 2017
• First Posted (ACTUAL): November 28, 2017

Study Record Updates

• Last Update Posted (ACTUAL): December 11, 2020
• Last Update Submitted That Met QC Criteria: December 9, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Safety; Cartilage; Osteoarthritic patients
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee
• Other Study ID Numbers: CLRX712X2101

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