Trial Outcomes & Findings for Evaluate Carotid Artery Plaque Composition by Magnetic Resonance Imaging in People Receiving Cholesterol Medication (NCT NCT00715273)

Last Updated: 2022-06-07

Results Overview

The primary endpoint of this study is carotid plaque lipid composition identified by MRI. The determination of plaque lipid content for each carotid artery will be performed using the automated interactive system. These measurements will be performed from the MRI scans at four time points blinded to time sequence of MRI examinations, patient treatment, lipid levels and clinical course. Volume Measurements: Contours were placed around the lumen, outer-wall boundaries, and plaque features of carotid artery. (Arterial wall area) = (outer-wall area) - (lumen area). Volume calculated as: area x 2 mm (slice thickness). Tissue volume/wall volume x (100%) is presented as percentage. Annualized change presented mm\^3/year (for volume) and as percentage change/year.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

217 participants

Primary outcome timeframe

Measured at Years 1, 2, and 3

Results posted on

2022-06-07

Participant Flow

Participant milestones

Participant milestones
Measure	1 - Single Therapy Group Participants will receive atorvastatin, placebo niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the single therapy group. Atorvastatin: 10 to 80 mg of atorvastatin each day Placebo Niacin: Placebo niacin each day Placebo Colesevelam: Placebo colesevelam each day	2 - Double Therapy Group Participants will receive atorvastatin, niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the double therapy group. Atorvastatin: 10 to 80 mg of atorvastatin each day Niacin: 2000 mg of niacin each day Placebo Colesevelam: Placebo colesevelam each day	3 - Triple Therapy Group Participants will receive atorvastatin, niacin, and colesevelam. The treatment target for LDL-C will be ≤60 mg/dl for the triple therapy group Atorvastatin: 10 to 80 mg of atorvastatin each day Niacin: 2000 mg of niacin each day Colesevelam: 3.8 g of colesevelam each day
Overall Study STARTED	71	73	73
Overall Study COMPLETED	63	65	68
Overall Study NOT COMPLETED	8	8	5

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Evaluate Carotid Artery Plaque Composition by Magnetic Resonance Imaging in People Receiving Cholesterol Medication

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	1 - Single Therapy Group n=71 Participants Participants will receive atorvastatin, placebo niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the single therapy group. Atorvastatin: 10 to 80 mg of atorvastatin each day Placebo Niacin: Placebo niacin each day Placebo Colesevelam: Placebo colesevelam each day	2 - Double Therapy Group n=73 Participants Participants will receive atorvastatin, niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the double therapy group. Atorvastatin: 10 to 80 mg of atorvastatin each day Niacin: 2000 mg of niacin each day Placebo Colesevelam: Placebo colesevelam each day	3 - Triple Therapy Group n=73 Participants Participants will receive atorvastatin, niacin, and colesevelam. The treatment target for LDL-C will be ≤60 mg/dl for the triple therapy group Atorvastatin: 10 to 80 mg of atorvastatin each day Niacin: 2000 mg of niacin each day Colesevelam: 3.8 g of colesevelam each day	Total n=217 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	60 Participants n=5 Participants	62 Participants n=7 Participants	60 Participants n=5 Participants	182 Participants n=4 Participants
Age, Categorical >=65 years	11 Participants n=5 Participants	11 Participants n=7 Participants	13 Participants n=5 Participants	35 Participants n=4 Participants
Sex: Female, Male Female	28 Participants n=5 Participants	30 Participants n=7 Participants	30 Participants n=5 Participants	88 Participants n=4 Participants
Sex: Female, Male Male	43 Participants n=5 Participants	43 Participants n=7 Participants	43 Participants n=5 Participants	129 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	9 Participants n=5 Participants	12 Participants n=7 Participants	10 Participants n=5 Participants	31 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	62 Participants n=5 Participants	61 Participants n=7 Participants	63 Participants n=5 Participants	186 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants	11 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	3 Participants n=7 Participants	2 Participants n=5 Participants	5 Participants n=4 Participants
Race (NIH/OMB) White	65 Participants n=5 Participants	65 Participants n=7 Participants	64 Participants n=5 Participants	194 Participants n=4 Participants
Race (NIH/OMB) More than one race	3 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	6 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment United States	71 participants n=5 Participants	73 participants n=7 Participants	73 participants n=5 Participants	217 participants n=4 Participants
Family history of premature cardiovascular disease, n (%)	34 Participants n=5 Participants	36 Participants n=7 Participants	36 Participants n=5 Participants	106 Participants n=4 Participants
History of myocardial infarction, n (%)	25 Participants n=5 Participants	26 Participants n=7 Participants	31 Participants n=5 Participants	82 Participants n=4 Participants
Established coronary artery disease, n (%)	62 Participants n=5 Participants	60 Participants n=7 Participants	67 Participants n=5 Participants	189 Participants n=4 Participants
Hypertension, n (%)	42 Participants n=5 Participants	44 Participants n=7 Participants	44 Participants n=5 Participants	130 Participants n=4 Participants
Diabetes, n (%)	10 Participants n=5 Participants	13 Participants n=7 Participants	9 Participants n=5 Participants	32 Participants n=4 Participants
Current smoking, n (%)	13 Participants n=5 Participants	17 Participants n=7 Participants	15 Participants n=5 Participants	45 Participants n=4 Participants

PRIMARY outcome

Timeframe: Measured at Years 1, 2, and 3

Population: Analysis group was limited from total study population due to the need for detectable lipid-rich necrotic core (LRNC) measurement at study baseline.

Outcome measures

Outcome measures
Measure	1 - Single Therapy Group n=60 Participants Participants will receive atorvastatin, placebo niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the single therapy group. Atorvastatin: 10 to 80 mg of atorvastatin each day Placebo Niacin: Placebo niacin each day Placebo Colesevelam: Placebo colesevelam each day	2 - Double Therapy Group n=61 Participants Participants will receive atorvastatin, niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the double therapy group. Atorvastatin: 10 to 80 mg of atorvastatin each day Niacin: 2000 mg of niacin each day Placebo Colesevelam: Placebo colesevelam each day	3 - Triple Therapy Group n=61 Participants Participants will receive atorvastatin, niacin, and colesevelam. The treatment target for LDL-C will be ≤60 mg/dl for the triple therapy group Atorvastatin: 10 to 80 mg of atorvastatin each day Niacin: 2000 mg of niacin each day Colesevelam: 3.8 g of colesevelam each day
Annualized LRNC Volume Change in Carotid Plaque Composition, as Assessed by MRI	-4.6 mm^3/year Standard Error 5.0	-15.1 mm^3/year Standard Error 3.2	-9.4 mm^3/year Standard Error 3.0

PRIMARY outcome

Timeframe: Measured at Years 1, 2, and 3

Population: Analysis group was limited from total study population due to the need for detectable lipid-rich necrotic core (LRNC) measurement at study baseline.

Outcome measures

Outcome measures
Measure	1 - Single Therapy Group n=60 Participants Participants will receive atorvastatin, placebo niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the single therapy group. Atorvastatin: 10 to 80 mg of atorvastatin each day Placebo Niacin: Placebo niacin each day Placebo Colesevelam: Placebo colesevelam each day	2 - Double Therapy Group n=61 Participants Participants will receive atorvastatin, niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the double therapy group. Atorvastatin: 10 to 80 mg of atorvastatin each day Niacin: 2000 mg of niacin each day Placebo Colesevelam: Placebo colesevelam each day	3 - Triple Therapy Group n=61 Participants Participants will receive atorvastatin, niacin, and colesevelam. The treatment target for LDL-C will be ≤60 mg/dl for the triple therapy group Atorvastatin: 10 to 80 mg of atorvastatin each day Niacin: 2000 mg of niacin each day Colesevelam: 3.8 g of colesevelam each day
Annualized LRNC and Wall Volume Changes in Carotid Plaque Composition, as Assessed by MRI LRNC change	-1.6 percentage change/year Standard Error 1.1	-3.6 percentage change/year Standard Error 0.8	-2.8 percentage change/year Standard Error 0.7
Annualized LRNC and Wall Volume Changes in Carotid Plaque Composition, as Assessed by MRI Wall Volume change	-0.6 percentage change/year Standard Error 0.5	-1.4 percentage change/year Standard Error 0.4	-1.2 percentage change/year Standard Error 0.5

SECONDARY outcome

Timeframe: Measured at Years 3, 4, and 5

Any cardiovascular events such as death from any cause, nonfatal myocardial infarction, stroke, and revascularization procedures (PCI or CABG) due to unstable ischemia will be recorded and verified.

Outcome measures

Outcome measures
Measure	1 - Single Therapy Group n=71 Participants Participants will receive atorvastatin, placebo niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the single therapy group. Atorvastatin: 10 to 80 mg of atorvastatin each day Placebo Niacin: Placebo niacin each day Placebo Colesevelam: Placebo colesevelam each day	2 - Double Therapy Group n=73 Participants Participants will receive atorvastatin, niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the double therapy group. Atorvastatin: 10 to 80 mg of atorvastatin each day Niacin: 2000 mg of niacin each day Placebo Colesevelam: Placebo colesevelam each day	3 - Triple Therapy Group n=73 Participants Participants will receive atorvastatin, niacin, and colesevelam. The treatment target for LDL-C will be ≤60 mg/dl for the triple therapy group Atorvastatin: 10 to 80 mg of atorvastatin each day Niacin: 2000 mg of niacin each day Colesevelam: 3.8 g of colesevelam each day
Composite of Cardiovascular Endpoints: Number of Participants With Cardiovascular Disease Death, Non-fatal Heart Attack, Stroke, and Worsening Ischemia Requiring Medical Interventions Composite Measured at Year 5 (cumulative)	9 Participants	11 Participants	9 Participants
Composite of Cardiovascular Endpoints: Number of Participants With Cardiovascular Disease Death, Non-fatal Heart Attack, Stroke, and Worsening Ischemia Requiring Medical Interventions Composite Measured at Year 3	6 Participants	6 Participants	7 Participants
Composite of Cardiovascular Endpoints: Number of Participants With Cardiovascular Disease Death, Non-fatal Heart Attack, Stroke, and Worsening Ischemia Requiring Medical Interventions Composite Measured at Year 4 (cumulative)	7 Participants	11 Participants	9 Participants

Adverse Events

1 - Single Therapy Group

Serious events: 26 serious events

Other events: 34 other events

Deaths: 7 deaths

2 - Double Therapy Group

Serious events: 20 serious events

Other events: 40 other events

Deaths: 7 deaths

3 - Triple Therapy Group

Serious events: 20 serious events

Other events: 32 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

Xue-Qiao Zhao

University of Washington

Phone: 206-744-8305

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	1 - Single Therapy Group n=71 participants at risk Participants will receive atorvastatin, placebo niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the single therapy group. Atorvastatin: 10 to 80 mg of atorvastatin each day Placebo Niacin: Placebo niacin each day Placebo Colesevelam: Placebo colesevelam each day	2 - Double Therapy Group n=73 participants at risk Participants will receive atorvastatin, niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the double therapy group. Atorvastatin: 10 to 80 mg of atorvastatin each day Niacin: 2000 mg of niacin each day Placebo Colesevelam: Placebo colesevelam each day	3 - Triple Therapy Group n=73 participants at risk Participants will receive atorvastatin, niacin, and colesevelam. The treatment target for LDL-C will be ≤60 mg/dl for the triple therapy group Atorvastatin: 10 to 80 mg of atorvastatin each day Niacin: 2000 mg of niacin each day Colesevelam: 3.8 g of colesevelam each day
Cardiac disorders Percutaneous coronary intervention	14.1% 10/71 • Number of events 13 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	8.2% 6/73 • Number of events 10 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	11.0% 8/73 • Number of events 8 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Vascular disorders Peripheral artery revascularization	2.8% 2/71 • Number of events 3 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	2.7% 2/73 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	4.1% 3/73 • Number of events 3 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer	2.8% 2/71 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	4.1% 3/73 • Number of events 3 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	5.5% 4/73 • Number of events 4 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Cardiac disorders Myocardial infarction	4.2% 3/71 • Number of events 3 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	5.5% 4/73 • Number of events 4 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	5.5% 4/73 • Number of events 4 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
General disorders Stroke	2.8% 2/71 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	1.4% 1/73 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	0.00% 0/73 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Surgical and medical procedures Coronary artery bypass graft surgery	1.4% 1/71 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	2.7% 2/73 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	1.4% 1/73 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Cardiac disorders Hospitalized for worsening ischemia	9.9% 7/71 • Number of events 9 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	9.6% 7/73 • Number of events 9 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	6.8% 5/73 • Number of events 6 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Vascular disorders Hospitalized for transient ischemic attack	2.8% 2/71 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	2.7% 2/73 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	1.4% 1/73 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Cardiac disorders Hospitalized for heart failure	1.4% 1/71 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	0.00% 0/73 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	1.4% 1/73 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Death - Cancer	1.4% 1/71 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	2.7% 2/73 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	2.7% 2/73 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Cardiac disorders Death - myocardial infarction	1.4% 1/71 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	1.4% 1/73 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	0.00% 0/73 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Cardiac disorders Death - Coronary artery disease	2.8% 2/71 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	1.4% 1/73 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	0.00% 0/73 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
General disorders Death - Intentional self-harm	0.00% 0/71 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	0.00% 0/73 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	1.4% 1/73 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Respiratory, thoracic and mediastinal disorders Death - Idiopathic Pulmonary Fibrosis	0.00% 0/71 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	1.4% 1/73 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	0.00% 0/73 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
General disorders Death - Other/Multiple/Unknown	4.2% 3/71 • Number of events 3 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	2.7% 2/73 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	0.00% 0/73 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Musculoskeletal and connective tissue disorders Diseased or injured hip joint requiring replacement	0.00% 0/71 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	1.4% 1/73 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	2.7% 2/73 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.

Measure	1 - Single Therapy Group n=71 participants at risk Participants will receive atorvastatin, placebo niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the single therapy group. Atorvastatin: 10 to 80 mg of atorvastatin each day Placebo Niacin: Placebo niacin each day Placebo Colesevelam: Placebo colesevelam each day	2 - Double Therapy Group n=73 participants at risk Participants will receive atorvastatin, niacin, and placebo colesevelam. The treatment target for LDL-C will be ≤80 mg/dl for the double therapy group. Atorvastatin: 10 to 80 mg of atorvastatin each day Niacin: 2000 mg of niacin each day Placebo Colesevelam: Placebo colesevelam each day	3 - Triple Therapy Group n=73 participants at risk Participants will receive atorvastatin, niacin, and colesevelam. The treatment target for LDL-C will be ≤60 mg/dl for the triple therapy group Atorvastatin: 10 to 80 mg of atorvastatin each day Niacin: 2000 mg of niacin each day Colesevelam: 3.8 g of colesevelam each day
Endocrine disorders New onset Type 2 Diabetes Melitus	6.6% 4/61 • Number of events 4 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	8.3% 5/60 • Number of events 5 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	4.7% 3/64 • Number of events 3 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Infections and infestations Sinus infection	8.5% 6/71 • Number of events 6 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	0.00% 0/73 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	2.7% 2/73 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
General disorders Muscle aches	7.0% 5/71 • Number of events 5 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	1.4% 1/73 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	4.1% 3/73 • Number of events 3 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
General disorders Leg pain	2.8% 2/71 • Number of events 3 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	9.6% 7/73 • Number of events 7 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	8.2% 6/73 • Number of events 6 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Surgical and medical procedures Diseased or injured knee joint requiring surgery	8.5% 6/71 • Number of events 6 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	4.1% 3/73 • Number of events 3 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	4.1% 3/73 • Number of events 3 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
General disorders Headache	7.0% 5/71 • Number of events 5 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	8.2% 6/73 • Number of events 6 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	2.7% 2/73 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
General disorders Dizziness	1.4% 1/71 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	12.3% 9/73 • Number of events 12 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	2.7% 2/73 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Renal and urinary disorders Kidney stone	2.8% 2/71 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	0.00% 0/73 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	5.5% 4/73 • Number of events 5 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Blood and lymphatic system disorders Anemia	1.4% 1/71 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	5.5% 4/73 • Number of events 4 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	1.4% 1/73 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Gastrointestinal disorders Gastroenteritis	2.8% 2/71 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	6.8% 5/73 • Number of events 5 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	5.5% 4/73 • Number of events 4 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Infections and infestations Upper respiratory infection	12.7% 9/71 • Number of events 13 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	15.1% 11/73 • Number of events 11 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	11.0% 8/73 • Number of events 10 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Infections and infestations Influenza	4.2% 3/71 • Number of events 4 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	11.0% 8/73 • Number of events 10 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	4.1% 3/73 • Number of events 3 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Musculoskeletal and connective tissue disorders Back pain	2.8% 2/71 • Number of events 2 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	4.1% 3/73 • Number of events 3 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	9.6% 7/73 • Number of events 7 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Cardiac disorders Angina	4.2% 3/71 • Number of events 4 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	12.3% 9/73 • Number of events 12 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	8.2% 6/73 • Number of events 8 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.
Respiratory, thoracic and mediastinal disorders Pneumonia	7.0% 5/71 • Number of events 5 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	1.4% 1/73 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.	1.4% 1/73 • Number of events 1 • Period of time from study baseline visit until subject completion. Subject followed for up to 168 months in open label follow-up period.