PAD PoC: Study of LLG783 in Patients With Peripheral Artery Disease (PAD) and Intermittent Claudication

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03194776
• Collaborator: (none)
• Enrollment: 46
• Locations: 8
• Arms: 2
• Actual Duration (Months): 15.2
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This study is designed to determine whether LLG783 displays the clinical safety and efficacy profile, after multiple i.v. doses, to support further development in patients with PAD and intermittent claudication.

Condition or Disease	Intervention/Treatment	Phase
Peripheral Artery Disease (PAD); Intermittent Claudication	Drug: LLG783; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized, patient and investigator-blinded, placebo controlled, parallel group studyRandomized, patient and investigator-blinded, placebo controlled, parallel group study
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Patient and Investigator-blinded, Randomized, Placebo Controlled Study of LLG783 in Patients With Peripheral Artery Disease (PAD) and Intermittent Claudication
• Actual Study Start Date: Sep 20, 2017
• Actual Primary Completion Date: Sep 7, 2018
• Actual Study Completion Date: Dec 27, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LLG783 Patients will receive LLG783 i.v. infusion every 4 weeks for 12 weeks.	Drug: LLG783; LLG783 concentrate solution for infusion/injection suitable for i.v. administration as well as s.c. administration.
Placebo Comparator: Placebo Patients will receive placebo to LLG783 i.v. infusion every 4 weeks for 12 weeks.	Drug: Placebo; Placebo to LLG783 concentrate solution for infusion/injection suitable for i.v. administration as well as s.c. administration.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events (AEs), Drug-related AEs, Serious Adverse Events (SAEs) and Deaths [Up to 32 Weeks]

   An AE is any untoward medical occurrence (that is, any unfavorable and unintended sign, including abnormal laboratory findings, symptom or disease) in a participant after providing written informed consent for participation in the study until the end of study visit. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. An SAE is defined as any AE which is is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect in offspring, requires inpatient hospitalization or prolongation of existing hospitalization and is is medically significant.

2. Change From Baseline in Maximum Walking Distance (MWD) as Assessed by 6-minute Walk Test (6MWT) at Week 16 [Baseline, Week 16 (Day 113)]

   MWD was assessed by the 6MWT prior to dosing was used to evaluate functional capacity of peripheral artery disease (PAD) participants. 6MWT test included measurement of total distance walked in 6 minutes.

Secondary Outcome Measures

1. Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) [1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose and 1, 2 and 4 hours postdose on Day 85]

   AUCinf is defined as the area under the serum concentration-time curve from time zero to infinity.

2. Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) [1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85]

   AUClast is defined as the area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration.

3. Area Under the Serum Concentration-time Curve From Time Zero to Defined Time Point 't' (AUC[0-t]) [1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85]

   AUC(0-t)is defined as the area under the serum concentration-time curve from time zero to time 't' where is a defined time point after administration.

4. Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) [1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85]

   AUCtau is defined as the area under the serum concentration-time curve from time zero to the end of the dosing interval tau.

5. Observed Maximum Serum Concentration (Cmax) Following Drug Administration [1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85]

   Cmax is defined as the observed maximum serum concentration following drug administration.

6. Time to Reach the Maximum Concentration After Drug Administration (Tmax) [1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85]

   Tmax is defined as the time to reach the maximum concentration after drug administration.

7. Change From Baseline in Pain-free Walking Distance (PFWD) as Assessed by 6-minute Walk Test at Week 16 [Baseline, Week 16 (Day 113)]

   PFWD was defined as the distance walked up to the point of onset of claudication symptoms (pain) recorded during the 6MWT and was used to evaluate symptomatic functional capacity of PAD participants. The PFWD was measured as the distance walked up to the time/place where the participant first experiences symptoms typical of their claudication which included pain, cramps, or other discomfort in the buttocks, thighs, calves or feet that occurs during the 6MWT exercise period.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• claudication, as defined by pain with exertion in either leg;

• On stable medical therapy, including statins, aspirin, and antihypertensive medications (as medically indicated) unless individually contraindicated, for at least 4 weeks prior to the screening visit;

• Vital signs must be within the following ranges:

• body temperature between 35.0-37.5°C

• systolic blood pressure, 90-159 mm Hg

• diastolic blood pressure, 50-99 mm Hg

• pulse rate, 50 - 90 bpm

• Moderately impaired ambulatory function judged by the investigator to be due primarily to PAD and assessed by a maximum walk distance between 50 and 400 meters (inclusive of these values) at the screening 6-minute walk test (6MWT).

Exclusion Criteria:

• Pregnant or nursing (lactating) women;

• Patients who meet any of the following PAD related criteria:

• Patients actively attending and participating in a supervised exercise rehabilitation program (patients who have already completed such a program and remain symptomatic may be included).

• Patients with any condition other than PAD that limits walking ability.

• Known inflammatory disease of the arteries (other than atherosclerosis; e.g. Thromboangiitis obliterans).

• Clinical evidence of critical limb ischemia including new or non-healing ulcers (felt secondary to critical limb ischemia), new or recent onset of resting pain in the lower extremities particularly at night (felt secondary to critical limb ischemia) and/or gangrene of the lower extremities (Fontaine stage III-IV) .

• 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 150 days after stopping of investigational drug.

• Any of the following concomitant cardiovascular or metabolic conditions or diseases:

• Myocardial infarction within 6 months of screening.

• Stroke within 6 months of screening.

• History of clinically significant ventricular arrhythmias, according to the discretion of the investigator, within 6 months of screening.

• Significant ECG abnormalities, according to the discretion of the investigator, at screening.

• History of sustained and clinically significant supraventricular arrhythmias (e.

1. associated with hemodynamic compromise) within 6 months of screening.

• Chronic heart failure New York Heart Association Class III or IV.

• Known presence of aortic aneurysm > 5 cm.

• Uncontrolled diabetes as defined by a random fasting glucose level of 13 mmol/L or 240 mg/dL or a HbA1c greater than 9% as measured at screening. Diabetes should be treated as appropriate during the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Jacksonville	Florida	United States	32216
2	Novartis Investigative Site	Columbus	Ohio	United States	43215
3	Novartis Investigative Site	Kiel	Schleswig-Holstein	Germany	24105
4	Novartis Investigative Site	Berlin		Germany	10117
5	Novartis Investigative Site	Berlin		Germany	10787
6	Novartis Investigative Site	Magdeburg		Germany	39112
7	Novartis Investigative Site	Taipei		Taiwan	10002
8	Novartis Investigative Site	Taipei		Taiwan	11217

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Nov 1, 2017
• Statistical Analysis Plan - Feb 8, 2019

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03194776
• Other Study ID Numbers: CLLG783X2201; 2017-000706-37
• First Posted: Jun 21, 2017
• Last Update Posted: Jan 5, 2021
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: PAD; peripheral artery/arterial disease; peripheral vascular disease; leg pain; claudication; leg pain with exercise; exercise test; walk test
• Additional relevant MeSH terms: Peripheral Arterial Disease; Intermittent Claudication

Study Results

Participant Flow

Pre-assignment Detail	A total of 46 subjects with clinical evidence of PAD and intermittent claudication were enrolled and randomized in this study.

Arm/Group Title	LLG783 6mg/kg	Placebo
Arm/Group Description	Participants received LLG783 6 milligram per kilogram (mg/kg) as intravenous (IV) infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.	Participants received placebo as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.
Period Title: Overall Study
STARTED	23	23
COMPLETED	23	23
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	LLG783 6mg/kg	Placebo	Total
Arm/Group Description	Participants received LLG783 6 mg/kg as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.	Participants received placebo as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.	Total of all reporting groups
Overall Participants	23	23	46
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.0 (7.1)	66.3 (6.9)	66.7 (6.9)
Sex: Female, Male (Count of Participants)
Female	8 34.8%	5 21.7%	13 28.3%
Male	15 65.2%	18 78.3%	33 71.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	23 100%	23 100%	46 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Maximum walking distance (MWD) (meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters]	317.3 (62.0)	311.3 (84.0)	314.3 (73.0)
Pain Free Walking Distance (PWFD) (meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters]	160.7 (79.4)	156.0 (86.7)	158.3 (82.3)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events (AEs), Drug-related AEs, Serious Adverse Events (SAEs) and Deaths
Description	An AE is any untoward medical occurrence (that is, any unfavorable and unintended sign, including abnormal laboratory findings, symptom or disease) in a participant after providing written informed consent for participation in the study until the end of study visit. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. An SAE is defined as any AE which is is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect in offspring, requires inpatient hospitalization or prolongation of existing hospitalization and is is medically significant.
Time Frame	Up to 32 Weeks

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants that received any study treatment.

Arm/Group Title	LLG783 6mg/kg	Placebo
Arm/Group Description	Participants received LLG783 6 mg/kg as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.	Participants received placebo as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.
Measure Participants	23	23
AEs	18 78.3%	17 73.9%
Drug-related AEs	4 17.4%	4 17.4%
SAEs	1 4.3%	2 8.7%
Death	0 0%	0 0%

2. Primary Outcome

Title	Change From Baseline in Maximum Walking Distance (MWD) as Assessed by 6-minute Walk Test (6MWT) at Week 16
Description	MWD was assessed by the 6MWT prior to dosing was used to evaluate functional capacity of peripheral artery disease (PAD) participants. 6MWT test included measurement of total distance walked in 6 minutes.
Time Frame	Baseline, Week 16 (Day 113)

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set included all participants with available PD data, who received any study treatment and experienced no protocol deviations with relevant impact on PD data. Here 'N' (overall number of participants analyzed) signifies number of participants evaluable for this endpoint.

Arm/Group Title	LLG783 6mg/kg	Placebo
Arm/Group Description	Participants received LLG783 6 mg/kg as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.	Participants received placebo as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.
Measure Participants	22	19
Least Squares Mean (80% Confidence Interval) [meter (m)]	19.10	36.84

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LLG783 6mg/kg, Placebo
	Comments	Statistical analysis was done by mixed effect model repeat measurement (MMRM) model analysis.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.2612
	Comments	P-value of <= 0.2 was considered significant.
	Method	two-sided test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.74
	Confidence Interval	(2-Sided) 80%; -38.03 to 2.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf)
Description	AUCinf is defined as the area under the serum concentration-time curve from time zero to infinity.
Time Frame	1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose and 1, 2 and 4 hours postdose on Day 85

Outcome Measure Data

Analysis Population Description

PK analysis set: Participants with at least 1 available valid PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data. N (overall number of participants analyzed) = participants evaluable for this outcome measure and 'n' (number analyzed) = participants evaluable at specified time points.

Arm/Group Title	LLG783 6 mg/kg
Arm/Group Description	Participants received LLG783 6 mg/kg as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.
Measure Participants	20
Day 1	2110 (21.1)
Day 85	4860 (39.1)

4. Secondary Outcome

Title	Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast)
Description	AUClast is defined as the area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration.
Time Frame	1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set included all participants with at least one available valid PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data.

Arm/Group Title	LLG783 6 mg/kg
Arm/Group Description	Participants received LLG783 6 mg/kg as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.
Measure Participants	23
Day 1	1660 (33.6)
Day 85	4930 (38.9)

5. Secondary Outcome

Title	Area Under the Serum Concentration-time Curve From Time Zero to Defined Time Point 't' (AUC[0-t])
Description	AUC(0-t)is defined as the area under the serum concentration-time curve from time zero to time 't' where is a defined time point after administration.
Time Frame	1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85

Outcome Measure Data

Analysis Population Description

PK analysis set included all participants with at least one available valid PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data.

Arm/Group Title	LLG783 6 mg/kg
Arm/Group Description	Participants received LLG783 6 mg/kg as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.
Measure Participants	23
Day 1	1640 (34.1)
Day 85	3130 (34.7)

6. Secondary Outcome

Title	Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau)
Description	AUCtau is defined as the area under the serum concentration-time curve from time zero to the end of the dosing interval tau.
Time Frame	1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LLG783 6 mg/kg
Arm/Group Description	Participants received LLG783 6 mg/kg as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.
Measure Participants	23
Day 1	1640 (34.1)
Day 85	3130 (34.7)

7. Secondary Outcome

Title	Observed Maximum Serum Concentration (Cmax) Following Drug Administration
Description	Cmax is defined as the observed maximum serum concentration following drug administration.
Time Frame	1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85

Outcome Measure Data

Analysis Population Description

PK analysis set included all participants with at least one available valid PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data.

Arm/Group Title	LLG783 6 mg/kg
Arm/Group Description	Participants received LLG783 6 mg/kg as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.
Measure Participants	23
Day 1	203 (40.0)
Day 85	268 (39.8)

8. Secondary Outcome

Title	Time to Reach the Maximum Concentration After Drug Administration (Tmax)
Description	Tmax is defined as the time to reach the maximum concentration after drug administration.
Time Frame	1 hour predose and 1, 2 and 4 hours postdose on Day 1; 0 hour predose on Day 29 and 57; 0 hour predose and 1, 2 and 4 hours postdose on Day 85

Outcome Measure Data

Analysis Population Description

PK analysis set included all participants with at least one available valid PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data.

Arm/Group Title	LLG783 6 mg/kg
Arm/Group Description	Participants received LLG783 6 mg/kg as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.
Measure Participants	23
Day 1	0.0833
Day 85	0.0833

9. Secondary Outcome

Title	Change From Baseline in Pain-free Walking Distance (PFWD) as Assessed by 6-minute Walk Test at Week 16
Description	PFWD was defined as the distance walked up to the point of onset of claudication symptoms (pain) recorded during the 6MWT and was used to evaluate symptomatic functional capacity of PAD participants. The PFWD was measured as the distance walked up to the time/place where the participant first experiences symptoms typical of their claudication which included pain, cramps, or other discomfort in the buttocks, thighs, calves or feet that occurs during the 6MWT exercise period.
Time Frame	Baseline, Week 16 (Day 113)

Outcome Measure Data

Analysis Population Description

PD analysis set included all participants with available PD data, who received any study treatment and experienced no protocol deviations with relevant impact on PD data. Here 'N' (overall number of participants analyzed) signifies number of participants evaluable for this outcome measure.

Arm/Group Title	LLG783 6mg/kg	Placebo
Arm/Group Description	Participants received LLG783 6 mg/kg as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.	Participants received placebo as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.
Measure Participants	22	19
Least Squares Mean (80% Confidence Interval) [meters]	44.77	57.09

Adverse Events

Time Frame	Adverse events were collected from first dose of study treatment until end of study treatment, plus 30 days post treatment, up to maximum duration of approximately 15 months.
Adverse Event Reporting Description	Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Arm/Group Title	LLG783 i.v. 6 mg/kg		Placebo
Arm/Group Description	Participants received LLG783 6 mg/kg as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.		Participants received placebo as IV infusion once every 4 weeks for a total of 4 doses over a period of 12 weeks.
All Cause Mortality
	LLG783 i.v. 6 mg/kg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/23 (0%)
Serious Adverse Events
	LLG783 i.v. 6 mg/kg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/23 (4.3%)		2/23 (8.7%)
Blood and lymphatic system disorders
Hypochromic anaemia	1/23 (4.3%)		0/23 (0%)
Gastrointestinal disorders
Gastritis haemorrhagic	0/23 (0%)		1/23 (4.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Small cell lung cancer	0/23 (0%)		1/23 (4.3%)
Other (Not Including Serious) Adverse Events
	LLG783 i.v. 6 mg/kg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/23 (78.3%)		16/23 (69.6%)
Blood and lymphatic system disorders
Anaemia	0/23 (0%)		1/23 (4.3%)
Hypochromic anaemia	1/23 (4.3%)		0/23 (0%)
Lymphadenopathy	0/23 (0%)		1/23 (4.3%)
Cardiac disorders
Atrial flutter	1/23 (4.3%)		0/23 (0%)
Bradycardia	0/23 (0%)		2/23 (8.7%)
Pericardial effusion	1/23 (4.3%)		0/23 (0%)
Sinus bradycardia	1/23 (4.3%)		0/23 (0%)
Gastrointestinal disorders
Abdominal pain	0/23 (0%)		1/23 (4.3%)
Diarrhoea	3/23 (13%)		1/23 (4.3%)
Nausea	1/23 (4.3%)		0/23 (0%)
Toothache	1/23 (4.3%)		0/23 (0%)
General disorders
Fatigue	2/23 (8.7%)		1/23 (4.3%)
Medical device site irritation	3/23 (13%)		0/23 (0%)
Oedema peripheral	2/23 (8.7%)		0/23 (0%)
Peripheral swelling	1/23 (4.3%)		0/23 (0%)
Infections and infestations
Bronchitis	1/23 (4.3%)		0/23 (0%)
Cystitis	1/23 (4.3%)		0/23 (0%)
Erysipelas	0/23 (0%)		1/23 (4.3%)
Infected bite	0/23 (0%)		1/23 (4.3%)
Nasopharyngitis	5/23 (21.7%)		4/23 (17.4%)
Paronychia	1/23 (4.3%)		0/23 (0%)
Root canal infection	0/23 (0%)		1/23 (4.3%)
Tooth abscess	1/23 (4.3%)		0/23 (0%)
Injury, poisoning and procedural complications
Arthropod bite	0/23 (0%)		1/23 (4.3%)
Contusion	0/23 (0%)		1/23 (4.3%)
Limb injury	1/23 (4.3%)		1/23 (4.3%)
Post procedural haemorrhage	0/23 (0%)		1/23 (4.3%)
Thermal burn	0/23 (0%)		1/23 (4.3%)
Investigations
Alanine aminotransferase increased	1/23 (4.3%)		0/23 (0%)
Aspartate aminotransferase increased	1/23 (4.3%)		0/23 (0%)
Blood creatinine increased	1/23 (4.3%)		0/23 (0%)
Blood pressure increased	1/23 (4.3%)		0/23 (0%)
Gamma-glutamyltransferase increased	1/23 (4.3%)		0/23 (0%)
Weight increased	1/23 (4.3%)		0/23 (0%)
Metabolism and nutrition disorders
Iron deficiency	0/23 (0%)		1/23 (4.3%)
Musculoskeletal and connective tissue disorders
Arthritis	1/23 (4.3%)		0/23 (0%)
Back pain	2/23 (8.7%)		1/23 (4.3%)
Joint effusion	1/23 (4.3%)		0/23 (0%)
Muscle spasms	0/23 (0%)		1/23 (4.3%)
Pain in extremity	1/23 (4.3%)		0/23 (0%)
Spinal pain	0/23 (0%)		1/23 (4.3%)
Nervous system disorders
Carpal tunnel syndrome	1/23 (4.3%)		0/23 (0%)
Dizziness	1/23 (4.3%)		0/23 (0%)
Headache	2/23 (8.7%)		2/23 (8.7%)
Neuralgia	1/23 (4.3%)		0/23 (0%)
Paraesthesia	0/23 (0%)		2/23 (8.7%)
Sciatica	1/23 (4.3%)		0/23 (0%)
Syncope	1/23 (4.3%)		0/23 (0%)
Psychiatric disorders
Adjustment disorder with depressed mood	1/23 (4.3%)		0/23 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/23 (4.3%)		1/23 (4.3%)
Cough	1/23 (4.3%)		0/23 (0%)
Haemoptysis	1/23 (4.3%)		0/23 (0%)
Nasal congestion	1/23 (4.3%)		0/23 (0%)
Oropharyngeal pain	1/23 (4.3%)		0/23 (0%)
Skin and subcutaneous tissue disorders
Pruritus	0/23 (0%)		1/23 (4.3%)
Stasis dermatitis	0/23 (0%)		1/23 (4.3%)
Vascular disorders
Hypertension	0/23 (0%)		1/23 (4.3%)
Peripheral arterial occlusive disease	3/23 (13%)		1/23 (4.3%)
Peripheral ischaemia	0/23 (0%)		1/23 (4.3%)
Spider vein	1/23 (4.3%)		0/23 (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 pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.