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

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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 )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Knee Cartilage Lesion
Interventions Biological: LNA043
Biological: placebo to LNA043
Enrollment 14
Recruitment Details All patients were recruited from 3 clinical sites in Austria.
Pre-assignment Details The original set up of this trial was for 2 cohorts of LNA043 (20 mg and 40 mg). The trial was terminated before any patient in the LNA043 40 mg cohort was randomized
Arm/Group Title LNA043 20mg Matching Placebo to 20mg LNA043 40mg Matching Placebo to 40mg
Hide Arm/Group Description LNA043 20mg/3ml single dose Matching placebo to 20mg/3ml, single dose LNA043 40mg/4ml single dose Matching placebo to 40mg/4ml, single dose
Period Title: Overall Study
Started 9 5 0 0
Completed 9 5 0 0
Not Completed 0 0 0 0
Arm/Group Title LNA043 20mg Matching Placebo to 20mg Total
Hide Arm/Group Description LNA043 20mg/3ml single dose Matching placebo to 20mg/3ml, single dose Total of all reporting groups
Overall Number of Baseline Participants 9 5 14
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 9 participants 5 participants 14 participants
31.0  (6.16) 39.4  (7.40) 34.0  (7.60)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 5 participants 14 participants
Female
3
  33.3%
5
 100.0%
8
  57.1%
Male
6
  66.7%
0
   0.0%
6
  42.9%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 5 participants 14 participants
White
9
 100.0%
5
 100.0%
14
 100.0%
1.Primary Outcome
Title Change From Baseline in GAG Content
Hide Description 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
Time Frame Baseline, Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacodynamic analysis set. Subjects with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data.
Arm/Group Title LNA043 20mg Matching Placebo to 20mg
Hide Arm/Group Description:
LNA043 20mg/3ml single dose
Matching placebo to 20mg/3ml, single dose
Overall Number of Participants Analyzed 7 2
Least Squares Mean (Standard Error)
Unit of Measure: Ratio
SCD/HNWB 0.24  (0.06) 0.06  (0.12)
DTBT/HWB 0.08  (0.04) 0.09  (0.09)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LNA043 20mg, Matching Placebo to 20mg
Comments SCD/HNWB
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1219
Comments [Not Specified]
Method Mixed Effect Model Repeat Measurement
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.18
Confidence Interval (2-Sided) 95%
-0.15 to 0.51
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection LNA043 20mg, Matching Placebo to 20mg
Comments DTBT/HWB
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5438
Comments [Not Specified]
Method Mixed Effect Model Repeat Measurement
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.01
Confidence Interval (2-Sided) 95%
-0.28 to 0.25
Estimation Comments [Not Specified]
2.Primary Outcome
Title Bi-layer Collagen Organization Based on MRI Measurements
Hide Description 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.
Time Frame Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacodynamic analysis set. Subjects with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data.
Arm/Group Title LNA043 20mg Matching Placebo to 20mg
Hide Arm/Group Description:
LNA043 20mg/3ml single dose
Matching placebo to 20mg/3ml, single dose
Overall Number of Participants Analyzed 7 4
Mean (Standard Error)
Unit of Measure: Ratio
1.01  (0.07) 0.95  (0.09)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LNA043 20mg, Matching Placebo to 20mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3067
Comments [Not Specified]
Method Mixed Effect Model Repeat Measurement
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.06
Confidence Interval (2-Sided) 95%
-0.19 to 0.31
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline in International Cartilage Repair Society (ICRS) Scoring
Hide Description 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).
Time Frame Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacodynamic analysis set. Subjects with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data.
Arm/Group Title LNA043 20mg Matching Placebo to 20mg
Hide Arm/Group Description:
LNA043 20mg/3ml single dose
Matching placebo to 20mg/3ml, single dose
Overall Number of Participants Analyzed 8 4
Mean (Standard Error)
Unit of Measure: Unit on a scale
Abnormal Calcification/Ossification Number Analyzed 8 participants 4 participants
98.75  (1.05) 100.00  (1.48)
Cell Morphology Number Analyzed 7 participants 3 participants
61.43  (14.14) 56.67  (21.60)
Chondrocyte clustering Number Analyzed 7 participants 3 participants
85.71  (8.37) 85.00  (12.78)
Inflammation Number Analyzed 8 participants 4 participants
92.50  (2.15) 98.75  (3.04)
Matrix Staining Number Analyzed 7 participants 3 participants
57.14  (12.17) 25.00  (18.59)
Overall assessment Number Analyzed 7 participants 3 participants
49.29  (12.23) 55.00  (18.68)
Tissue Morphology Number Analyzed 7 participants 3 participants
71.43  (7.78) 65.00  (11.88)
Vascularisation in repaired tissue Number Analyzed 8 participants 4 participants
66.25  (12.88) 77.50  (18.21)
Basal Integration Number Analyzed 7 participants 3 participants
82.86  (10.64) 90.00  (16.26)
Formation of a Tidemark Number Analyzed 7 participants 3 participants
65.71  (18.15) 63.33  (27.72)
Mid/Deep zone assessment Number Analyzed 7 participants 3 participants
50.00  (14.56) 56.67  (22.24)
Subcondral bone abnormalities/marrow fibrosis Number Analyzed 8 participants 4 participants
73.75  (13.45) 77.50  (19.01)
Surface Architecture Number Analyzed 7 participants 3 participants
57.86  (11.33) 80.00  (17.31)
Surface/Superficial assessment Number Analyzed 7 participants 3 participants
56.43  (11.42) 83.33  (17.44)
4.Secondary Outcome
Title Percentage of Donor Site Refilling Based on MRI Measurements.
Hide Description 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.
Time Frame Baseline, Week 4, Week 12 and Week 28
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacodynamic analysis set. Subjects with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data.
Arm/Group Title LNA043 20mg Matching Placebo to 20mg
Hide Arm/Group Description:
LNA043 20mg/3ml single dose
Matching placebo to 20mg/3ml, single dose
Overall Number of Participants Analyzed 8 4
Least Squares Mean (Standard Error)
Unit of Measure: Percent
Week 4 Number Analyzed 8 participants 4 participants
64.38  (7.80) 38.15  (11.03)
Week 12 Number Analyzed 7 participants 4 participants
60.25  (14.55) 32.44  (19.09)
Week 28 (EOS) Number Analyzed 5 participants 4 participants
86.53  (11.09) 62.73  (14.52)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LNA043 20mg, Matching Placebo to 20mg
Comments Week 4
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0404
Comments [Not Specified]
Method Mixed Effect Model Repeat Measurement
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 26.23
Confidence Interval (2-Sided) 95%
-3.86 to 56.32
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection LNA043 20mg, Matching Placebo to 20mg
Comments Week 12
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1381
Comments [Not Specified]
Method Mixed Effect Model Repeat Measurement
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 27.82
Confidence Interval (2-Sided) 95%
-26.5 to 82.10
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection LNA043 20mg, Matching Placebo to 20mg
Comments Week 28 (EOS)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1168
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 23.80
Confidence Interval (2-Sided) 96%
-19.3 to 66.89
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Change From Baseline in GAG Content
Hide Description 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
Time Frame Baseline, Week 12 and Week 28
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacodynamic analysis set. Subjects with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data.
Arm/Group Title LNA043 20mg Matching Placebo to 20mg
Hide Arm/Group Description:
LNA043 20mg/3ml single dose
Matching placebo to 20mg/3ml, single dose
Overall Number of Participants Analyzed 7 4
Least Squares Mean (Standard Error)
Unit of Measure: Ratio
SCD/HNWB - Week 12 Number Analyzed 7 participants 4 participants
0.14  (0.07) 0.15  (0.09)
SCD/HNWB - Week 28 Number Analyzed 6 participants 3 participants
0.33  (0.10) 0.14  (0.14)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LNA043 20mg, Matching Placebo to 20mg
Comments SCD/HNWB - Week 12
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5175
Comments [Not Specified]
Method Mixed Effect Model Repeat Measurement
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.01
Confidence Interval (2-Sided) 95%
-0.26 to 0.25
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection LNA043 20mg, Matching Placebo to 20mg
Comments SCD/HNWB - Week 28
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1476
Comments [Not Specified]
Method Mixed Effect Model Repeat Measurement
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.19
Confidence Interval (2-Sided) 95%
-0.22 to 0.60
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Bi-layer Collagen Organization Based on MRI Measurements
Hide Description 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.
Time Frame Week 12 and Week 28
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacodynamic analysis set. Subjects with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data.
Arm/Group Title LNA043 20mg Matching Placebo to 20mg
Hide Arm/Group Description:
LNA043 20mg/3ml single dose
Matching placebo to 20mg/3ml, single dose
Overall Number of Participants Analyzed 6 4
Mean (Standard Error)
Unit of Measure: Ratio
Week 12 Number Analyzed 5 participants 4 participants
1.44  (0.15) 1.57  (0.18)
Week 28 Number Analyzed 6 participants 4 participants
1.33  (0.11) 1.45  (0.14)
7.Secondary Outcome
Title PK Profile of LNA043 and of AngPTL3 in Serum Cmax
Hide Description Local and systemic pharmacokinetics (PK) of LNA043 following a single i.a. administration
Time Frame 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set
Arm/Group Title LNA043 20mg Matching Placebo to 20mg
Hide Arm/Group Description:
LNA043 20mg/3ml single dose
Matching placebo to 20mg/3ml, single dose
Overall Number of Participants Analyzed 8 5
Mean (Standard Deviation)
Unit of Measure: ng/mL
LNA043 Number Analyzed 8 participants 0 participants
57.4  (22.1)
AngPTL3 Number Analyzed 8 participants 5 participants
22.9  (9.03) 26.6  (7.62)
8.Secondary Outcome
Title PK Profile of LNA043 and of AngPTL3 in Serum AUC
Hide Description Local and systemic pharmacokinetics (PK) of LNA043 following a single i.a. administration
Time Frame 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set
Arm/Group Title LNA043 20mg Matching Placebo to 20mg
Hide Arm/Group Description:
LNA043 20mg/3ml single dose
Matching placebo to 20mg/3ml, single dose
Overall Number of Participants Analyzed 8 5
Mean (Standard Deviation)
Unit of Measure: hr*ng/mL
LNA043 Number Analyzed 8 participants 0 participants
821  (349)
AngPTL3 Number Analyzed 8 participants 5 participants
3130  (1440) 3030  (1060)
9.Secondary Outcome
Title Number of Participants With Anti-LNA043 Antibodies in Serum
Hide Description Potential immunogenicity of LNA043
Time Frame Baseline, Week 1, Week 4, Week 12 and Week 28
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set
Arm/Group Title LNA043 20mg Matching Placebo to 20mg
Hide Arm/Group Description:
LNA043 20mg/3ml single dose
Matching placebo to 20mg/3ml, single dose
Overall Number of Participants Analyzed 9 5
Measure Type: Count of Participants
Unit of Measure: Participants
Day 1: anti-LNA043 antibodies present YES
0
   0.0%
0
   0.0%
NO
9
 100.0%
5
 100.0%
Day 8: anti-LNA043 antibodies present YES
0
   0.0%
0
   0.0%
NO
9
 100.0%
5
 100.0%
Day 29: anti-LNA043 antibodies present YES
0
   0.0%
0
   0.0%
NO
9
 100.0%
5
 100.0%
Day 85: anti-LNA043 antibodies present YES
0
   0.0%
0
   0.0%
NO
9
 100.0%
5
 100.0%
Day 197: anti-LNA043 antibodies present YES
0
   0.0%
0
   0.0%
NO
9
 100.0%
5
 100.0%
Time Frame Adverse events were collected from the dose of study treatment until up to 28 weeks post treatment
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title LNA043 20mg Placebo
Hide Arm/Group Description LNA043 20mg Placebo
All-Cause Mortality
LNA043 20mg Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/9 (0.00%)   0/5 (0.00%) 
Hide Serious Adverse Events
LNA043 20mg Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/9 (0.00%)   0/5 (0.00%) 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
LNA043 20mg Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   4/9 (44.44%)   4/5 (80.00%) 
Ear and labyrinth disorders     
Vertigo  1  1/9 (11.11%)  0/5 (0.00%) 
Endocrine disorders     
Thyroid mass  1  0/9 (0.00%)  1/5 (20.00%) 
Gastrointestinal disorders     
Nausea  1  0/9 (0.00%)  2/5 (40.00%) 
General disorders     
Influenza like illness  1  1/9 (11.11%)  0/5 (0.00%) 
Infections and infestations     
Nasopharyngitis  1  0/9 (0.00%)  1/5 (20.00%) 
Urinary tract infection  1  0/9 (0.00%)  1/5 (20.00%) 
Injury, poisoning and procedural complications     
Contusion  1  1/9 (11.11%)  0/5 (0.00%) 
Fall  1  1/9 (11.11%)  0/5 (0.00%) 
Traumatic haematoma  1  1/9 (11.11%)  0/5 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/9 (11.11%)  0/5 (0.00%) 
Joint range of motion decreased  1  0/9 (0.00%)  1/5 (20.00%) 
Nervous system disorders     
Headache  1  2/9 (22.22%)  0/5 (0.00%) 
1
Term from vocabulary, MedDRA (22.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
EMail: novartis.email@novartis.com
Layout table for additonal information
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT03334812    
Other Study ID Numbers: CLNA043X2201
First Submitted: October 16, 2017
First Posted: November 7, 2017
Results First Submitted: April 1, 2020
Results First Posted: April 17, 2020
Last Update Posted: April 17, 2020