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Study on Safety, Tolerability and Prelimenary Efficacy of LNA043 in Patients Undergoing Autologous Chondrocyte Implantation (ACI)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03334812
Recruitment Status : Terminated (This study was terminated early based on an interim analysis of 14 subjects, which demonstrated a favorable safety and tolerability profile.)
First Posted : November 7, 2017
Results First Posted : April 17, 2020
Last Update Posted : April 17, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE October 16, 2017
First Posted Date  ICMJE November 7, 2017
Results First Submitted Date  ICMJE April 1, 2020
Results First Posted Date  ICMJE April 17, 2020
Last Update Posted Date April 17, 2020
Actual Study Start Date  ICMJE October 18, 2017
Actual Primary Completion Date April 5, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 5, 2020)
  • Change From Baseline in GAG Content [ Time Frame: Baseline, Week 4 ]
    Sodium MRI-based measurements of change from baseline in glycosaminoglycan (GAG) content were assessed from both defective sites and a nearby healthy cartilage region (as a reference tissue). Specifically, the ratio of normalized sodium signal in the surgically created defect (SCD or donor site) to healthy non-weight bearing region (HNWB), i.e. SCD/HNWB and the defect to be treated (DTBT or main lesion) to healthy weight bearing region (HWB), i.e. DTBT/HWB was of major interest
  • Bi-layer Collagen Organization Based on MRI Measurements [ Time Frame: Week 4 ]
    MRI T2 maps were generated and zonal T2 ratios (superficial layer T2 / deep layer T2) were calculated to assess the collagen fiber organization in the surgically created defect (SCD) and defect to be treated (DTBT) cartilage regions.
Original Primary Outcome Measures  ICMJE
 (submitted: November 2, 2017)
  • Cartilage GAG content based on MRI measurements [ Time Frame: 4 weeks ]
    Efficacy of a single LNA043 i.a. injection in regenerating hyaline cartilage tissue at the donor sites of patients undergoing autologous chondrocyte implantation (ACI)
  • Bi-layer Collagen Organization Based on MRI Measurements [ Time Frame: 4 weeks ]
    Efficacy of a single LNA043 i.a. injection in regenerating hyaline cartilage tissue at the donor sites of patients undergoing autologous chondrocyte implantation (ACI)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 5, 2020)
  • Change From Baseline in International Cartilage Repair Society (ICRS) Scoring [ Time Frame: Week 4 ]
    Extent of the repair tissue at the donor site before surgery. Each criterion was evaluated based on the visual analog scale and graded from 0 (best) to 100 (worst).
  • Percentage of Donor Site Refilling Based on MRI Measurements. [ Time Frame: Baseline, Week 4, Week 12 and Week 28 ]
    Extent of filling of the donor site over a longer term. Percentage change from baseline in refilling of cartilage defect based on 7T MRI for donor Region.
  • Change From Baseline in GAG Content [ Time Frame: Baseline, Week 12 and Week 28 ]
    Sodium MRI-based measurements of change from baseline in glycosaminoglycan (GAG) content was assessed from both defective sites and a nearby healthy cartilage region (as a reference tissue). Specifically, the ratio of normalized sodium signal in the surgically created defect (SCD or donor site) to healthy non-weight bearing region (HNWB), i.e. SCD/HNWB was of major interest
  • Bi-layer Collagen Organization Based on MRI Measurements [ Time Frame: Week 12 and Week 28 ]
    MRI T2 maps were generated and zonal T2 ratios (superficial layer T2 / deep layer T2) were calculated to assess the collagen fiber organization in the SCD cartilage region.
  • PK Profile of LNA043 and of AngPTL3 in Serum Cmax [ Time Frame: 4 weeks ]
    Local and systemic pharmacokinetics (PK) of LNA043 following a single i.a. administration
  • PK Profile of LNA043 and of AngPTL3 in Serum AUC [ Time Frame: 4 weeks ]
    Local and systemic pharmacokinetics (PK) of LNA043 following a single i.a. administration
  • Number of Participants With Anti-LNA043 Antibodies in Serum [ Time Frame: Baseline, Week 1, Week 4, Week 12 and Week 28 ]
    Potential immunogenicity of LNA043
Original Secondary Outcome Measures  ICMJE
 (submitted: November 2, 2017)
  • ICRS II histology scoring and percentage of donor site filling based on MRI measurements [ Time Frame: 4 weeks ]
    Extent and quality of the repair tissue at the donor site before surgery
  • Percentage of donor site filling based on MRI measurements. [ Time Frame: 12 and 28 weeks ]
    Extent and quality of filling of the donor site over a longer term
  • PK Profile of LNA043 and of AngPTL3 in Serum Cmax [ Time Frame: 4 weeks ]
    Local and systemic pharmacokinetics (PK) of LNA043 following a single i.a. administration
  • Presence and characterization of anti-LNA043 antibodies in serum [ Time Frame: Day 1, 8, 29, 85 and 197 ]
    Potential immunogenicity of LNA043
  • Cartilage GAG content based on MRI measurements. [ Time Frame: 12 and 28 weeks ]
    Extent and quality of filling of the donor site over a longer term
  • Bi-layer collagen organization based on MRI measurements. [ Time Frame: 12 and 28 weeks ]
    Extent and quality of filling of the donor site over a longer term
  • PK Profile of LNA043 and of AngPTL3 in Serum AUC [ Time Frame: 4 weeks ]
    Local and systemic pharmacokinetics (PK) of LNA043 following a single i.a. administration
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study on Safety, Tolerability and Prelimenary Efficacy of LNA043 in Patients Undergoing Autologous Chondrocyte Implantation
Official Title  ICMJE A Randomized, Placebo-controlled, Patient and Investigator Blinded, Single Dose, Proof of Concept Study Investigating the Safety, Tolerability and Preliminary Efficacy of Intra-articular LNA043 in Regenerating the Articular Cartilage of the Knee at Donor Sites in Patients Undergoing Autologous Chondrocyte Implantation
Brief Summary The purpose of this study was to assess safety, tolerability, pharmacokinetics and preliminary efficacy of a single intra-articular (i.a.) administration of LNA043 in regenerating the articular cartilage of the knee, in a standardized clinical scenario of acute cartilage defect. The study aimed at characterizing the mechanism of action of LNA043
Detailed Description

This was a non-confirmatory, patient and investigator blinded, randomized, placebo-controlled, parallel group, single dose study in patients with cartilage lesions undergoing autologous cartilage implantation (ACI). Participants were treated only on one occasion (Day 1) with a single i.a. injection that was performed under arthroscopic visualization and followed up for 28 weeks.

Originally approximately 22 patients were planned to be enrolled in two cohorts (LNA043 20 mg and LNA043 40 mg). The study was terminated before any patient was randomized into the LNA043 40 mg cohort

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Knee Cartilage Lesion
Intervention  ICMJE
  • Biological: LNA043
    LNA043 Single dose
  • Biological: placebo to LNA043
    placebo to LNA043 single dose
Study Arms  ICMJE
  • Experimental: LNA043 20mg/ml
    LNA043 20mg/ml single dose
    Intervention: Biological: LNA043
  • Placebo Comparator: Matching placebo to 20mg
    Matching placebo to 20mg/3ml, single dose
    Intervention: Biological: placebo to LNA043
  • Experimental: LNA043 40mg/ml
    LNA043 40mg/ml single dose
    Intervention: Biological: LNA043
  • Placebo Comparator: Matching placebo to 40mg
    Matching placebo to 40mg/4ml, single dose
    Intervention: Biological: placebo to LNA043
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: April 5, 2020)
14
Original Estimated Enrollment  ICMJE
 (submitted: November 2, 2017)
22
Actual Study Completion Date  ICMJE April 5, 2019
Actual Primary Completion Date April 5, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Written informed consent must be obtained before any assessment is performed
  • Patient is ≥18 and≤ 50 years old at time of screening
  • Patient has a body mass index (BMI) <30 kg/m2 at screening
  • Patient has a localized articular cartilage defect of the knee and is scheduled for an ACI procedure
  • Able to communicate well with the investigator, to understand and comply with the requirements of the study.

Exclusion Criteria:

  • Patient has radiologically apparent degenerative joint disease in the target knee as determined by Kellgren and Lawrence grade ≥2 based on X-ray evaluation performed within 6 months from screening
  • Patient has unstable knee joint or insufficiently reconstructed ligaments, based on medical history and physical examination by the investigator.
  • Patient scheduled for a concomitant articular surgical procedure (e.g., anterior cruciate ligament reconstruction) other than debridement or partial meniscectomy
  • Patient has malalignment (valgus- or varus-deformity) in the target knee ≥ 5° based on based on X-ray evaluation performed within 6 months from screening.at screeningmedical history. In suspected cases, the mechanical axis must be established radiographically through complete leg imaging during standing and in postero-anterior projection.
  • Patient has a known autoimmune disease, inflammatory arthropathy (including but not limited to rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, CPPD, gout), active acute or chronic infection of the joint, recent Lyme disease to the knee, systemic cartilage disorder, or a known systemic connective tissue disease.
  • Patient has had surgical treatment of the target knee using autologous osteochondral transplantation/mosaicplasty within 12 months prior to screening (Note: prior diagnostic arthroscopy with debridement and lavage, meniscal surgery, microfracture, anterior cruciate ligament reconstruction, and extra-articular surgery e.g., high-tibial osteotomy are acceptable).
  • Patient is unable to undergo magnetic resonance imaging (MRI) or presents absolute contraindications to MRI (e.g., metallic implants, metallic foreign bodies, pacemaker, defibrillator).
  • Patient taking medications prohibited by the protocol: corticosteroids by any route (except topical) from 4 weeks prior to screening; nonsteroidal anti-inflammatories or aspirin (greater than 100 mg per day) within 2 weeks prior to screening; paracetamol greater than 3000 mg per day within 2 weeks prior to screening; glucosamine or chondroitin sulfate within 2 weeks prior to screening; any local treatment i.a. into the knee within 3 months from screening.
  • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 15 days after stopping of investigational drug.
  • Regular smokers (use of tobacco/nicotine products in the previous 3 months > 5 cigarettes/day). Urine cotinine levels will be measured during screening for all subjects. Regular smokers will be defined as any subject who reports tobacco use of > 5 cigarettes/day and/or who has a urine cotinine ≥ 500 ng/mL.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03334812
Other Study ID Numbers  ICMJE CLNA043X2201
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Novartis
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP