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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03334812
• Collaborator: (none)
• Enrollment: 14
• Locations: 2
• Arms: 4
• Actual Duration (Months): 17.5
• Patients Per Site: 7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Knee Cartilage Lesion	Biological: LNA043; Biological: placebo to LNA043	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Oct 18, 2017
• Actual Primary Completion Date: Apr 5, 2019
• Actual Study Completion Date: Apr 5, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LNA043 20mg/ml LNA043 20mg/ml single dose	Biological: LNA043; LNA043 Single dose
Placebo Comparator: Matching placebo to 20mg Matching placebo to 20mg/3ml, single dose	Biological: placebo to LNA043; placebo to LNA043 single dose
Experimental: LNA043 40mg/ml LNA043 40mg/ml single dose	Biological: LNA043; LNA043 Single dose
Placebo Comparator: Matching placebo to 40mg Matching placebo to 40mg/4ml, single dose	Biological: placebo to LNA043; placebo to LNA043 single dose

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in GAG Content [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

2. Bi-layer Collagen Organization Based on MRI Measurements [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.

Secondary Outcome Measures

1. Change From Baseline in International Cartilage Repair Society (ICRS) Scoring [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).

2. Percentage of Donor Site Refilling Based on MRI Measurements. [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.

3. Change From Baseline in GAG Content [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

4. Bi-layer Collagen Organization Based on MRI Measurements [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.

5. PK Profile of LNA043 and of AngPTL3 in Serum Cmax [4 weeks]

   Local and systemic pharmacokinetics (PK) of LNA043 following a single i.a. administration

6. PK Profile of LNA043 and of AngPTL3 in Serum AUC [4 weeks]

   Local and systemic pharmacokinetics (PK) of LNA043 following a single i.a. administration

7. Number of Participants With Anti-LNA043 Antibodies in Serum [Baseline, Week 1, Week 4, Week 12 and Week 28]

   Potential immunogenicity of LNA043

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Wien		Austria	1090
2	Novartis Investigative Site	Wien		Austria	1180

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 24, 2018
• Statistical Analysis Plan - Feb 18, 2020

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03334812
• Other Study ID Numbers: CLNA043X2201
• First Posted: Nov 7, 2017
• Last Update Posted: Oct 7, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: cartilage lesion, ACI

Study Results

Participant Flow

Recruitment Details	All patients were recruited from 3 clinical sites in Austria.
Pre-assignment Detail	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
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

Baseline Characteristics

Arm/Group Title	LNA043 20mg	Matching Placebo to 20mg	Total
Arm/Group Description	LNA043 20mg/3ml single dose	Matching placebo to 20mg/3ml, single dose	Total of all reporting groups
Overall Participants	9	5	14
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.0 (6.16)	39.4 (7.40)	34.0 (7.60)
Sex: Female, Male (Count of Participants)
Female	3 33.3%	5 100%	8 57.1%
Male	6 66.7%	0 0%	6 42.9%
Race/Ethnicity, Customized (Count of Participants)
White	9 100%	5 100%	14 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in GAG Content
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

Outcome Measure Data

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
Arm/Group Description	LNA043 20mg/3ml single dose	Matching placebo to 20mg/3ml, single dose
Measure Participants	7	2
SCD/HNWB	0.24 (0.06)	0.06 (0.12)
DTBT/HWB	0.08 (0.04)	0.09 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LNA043 20mg, Matching Placebo to 20mg
	Comments	SCD/HNWB
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1219
	Comments
	Method	Mixed Effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.18
	Confidence Interval	(2-Sided) 95%; -0.15 to 0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LNA043 20mg, Matching Placebo to 20mg
	Comments	DTBT/HWB
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5438
	Comments
	Method	Mixed Effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.28 to 0.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Bi-layer Collagen Organization Based on MRI Measurements
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

Outcome Measure Data

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
Arm/Group Description	LNA043 20mg/3ml single dose	Matching placebo to 20mg/3ml, single dose
Measure Participants	7	4
Mean (Standard Error) [Ratio]	1.01 (0.07)	0.95 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LNA043 20mg, Matching Placebo to 20mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3067
	Comments
	Method	Mixed Effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.19 to 0.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in International Cartilage Repair Society (ICRS) Scoring
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

Outcome Measure Data

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
Arm/Group Description	LNA043 20mg/3ml single dose	Matching placebo to 20mg/3ml, single dose
Measure Participants	8	4
Abnormal Calcification/Ossification	98.75 (1.05)	100.00 (1.48)
Cell Morphology	61.43 (14.14)	56.67 (21.60)
Chondrocyte clustering	85.71 (8.37)	85.00 (12.78)
Inflammation	92.50 (2.15)	98.75 (3.04)
Matrix Staining	57.14 (12.17)	25.00 (18.59)
Overall assessment	49.29 (12.23)	55.00 (18.68)
Tissue Morphology	71.43 (7.78)	65.00 (11.88)
Vascularisation in repaired tissue	66.25 (12.88)	77.50 (18.21)
Basal Integration	82.86 (10.64)	90.00 (16.26)
Formation of a Tidemark	65.71 (18.15)	63.33 (27.72)
Mid/Deep zone assessment	50.00 (14.56)	56.67 (22.24)
Subcondral bone abnormalities/marrow fibrosis	73.75 (13.45)	77.50 (19.01)
Surface Architecture	57.86 (11.33)	80.00 (17.31)
Surface/Superficial assessment	56.43 (11.42)	83.33 (17.44)

4. Secondary Outcome

Title	Percentage of Donor Site Refilling Based on MRI Measurements.
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

Outcome Measure Data

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
Arm/Group Description	LNA043 20mg/3ml single dose	Matching placebo to 20mg/3ml, single dose
Measure Participants	8	4
Week 4	64.38 (7.80)	38.15 (11.03)
Week 12	60.25 (14.55)	32.44 (19.09)
Week 28 (EOS)	86.53 (11.09)	62.73 (14.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LNA043 20mg, Matching Placebo to 20mg
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0404
	Comments
	Method	Mixed Effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	26.23
	Confidence Interval	(2-Sided) 95%; -3.86 to 56.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LNA043 20mg, Matching Placebo to 20mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1381
	Comments
	Method	Mixed Effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	27.82
	Confidence Interval	(2-Sided) 95%; -26.5 to 82.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.1168
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	23.80
	Confidence Interval	(2-Sided) 96%; -19.3 to 66.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in GAG Content
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

Outcome Measure Data

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
Arm/Group Description	LNA043 20mg/3ml single dose	Matching placebo to 20mg/3ml, single dose
Measure Participants	7	4
SCD/HNWB - Week 12	0.14 (0.07)	0.15 (0.09)
SCD/HNWB - Week 28	0.33 (0.10)	0.14 (0.14)

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
Statistical Test of Hypothesis	p-Value	0.5175
	Comments
	Method	Mixed Effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.1476
	Comments
	Method	Mixed Effect Model Repeat Measurement
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; -0.22 to 0.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Bi-layer Collagen Organization Based on MRI Measurements
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

Outcome Measure Data

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
Arm/Group Description	LNA043 20mg/3ml single dose	Matching placebo to 20mg/3ml, single dose
Measure Participants	6	4
Week 12	1.44 (0.15)	1.57 (0.18)
Week 28	1.33 (0.11)	1.45 (0.14)

7. Secondary Outcome

Title	PK Profile of LNA043 and of AngPTL3 in Serum Cmax
Description	Local and systemic pharmacokinetics (PK) of LNA043 following a single i.a. administration
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set

Arm/Group Title	LNA043 20mg	Matching Placebo to 20mg
Arm/Group Description	LNA043 20mg/3ml single dose	Matching placebo to 20mg/3ml, single dose
Measure Participants	8	5
LNA043	57.4 (22.1)
AngPTL3	22.9 (9.03)	26.6 (7.62)

8. Secondary Outcome

Title	PK Profile of LNA043 and of AngPTL3 in Serum AUC
Description	Local and systemic pharmacokinetics (PK) of LNA043 following a single i.a. administration
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set

Arm/Group Title	LNA043 20mg	Matching Placebo to 20mg
Arm/Group Description	LNA043 20mg/3ml single dose	Matching placebo to 20mg/3ml, single dose
Measure Participants	8	5
LNA043	821 (349)
AngPTL3	3130 (1440)	3030 (1060)

9. Secondary Outcome

Title	Number of Participants With Anti-LNA043 Antibodies in Serum
Description	Potential immunogenicity of LNA043
Time Frame	Baseline, Week 1, Week 4, Week 12 and Week 28

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	LNA043 20mg	Matching Placebo to 20mg
Arm/Group Description	LNA043 20mg/3ml single dose	Matching placebo to 20mg/3ml, single dose
Measure Participants	9	5
YES	0 0%	0 0%
NO	9 100%	5 100%
YES	0 0%	0 0%
NO	9 100%	5 100%
YES	0 0%	0 0%
NO	9 100%	5 100%
YES	0 0%	0 0%
NO	9 100%	5 100%
YES	0 0%	0 0%
NO	9 100%	5 100%

Adverse Events

Time Frame	Adverse events were collected from the dose of study treatment until up to 28 weeks post treatment
Arm/Group Title	LNA043 20mg		Placebo
Arm/Group Description	LNA043 20mg		Placebo
All Cause Mortality
	LNA043 20mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/5 (0%)
Serious Adverse Events
	LNA043 20mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	LNA043 20mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/9 (44.4%)		4/5 (80%)
Ear and labyrinth disorders
Vertigo	1/9 (11.1%)		0/5 (0%)
Endocrine disorders
Thyroid mass	0/9 (0%)		1/5 (20%)
Gastrointestinal disorders
Nausea	0/9 (0%)		2/5 (40%)
General disorders
Influenza like illness	1/9 (11.1%)		0/5 (0%)
Infections and infestations
Nasopharyngitis	0/9 (0%)		1/5 (20%)
Urinary tract infection	0/9 (0%)		1/5 (20%)
Injury, poisoning and procedural complications
Contusion	1/9 (11.1%)		0/5 (0%)
Fall	1/9 (11.1%)		0/5 (0%)
Traumatic haematoma	1/9 (11.1%)		0/5 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/9 (11.1%)		0/5 (0%)
Joint range of motion decreased	0/9 (0%)		1/5 (20%)
Nervous system disorders
Headache	2/9 (22.2%)		0/5 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.