Trial Outcomes & Findings for Coenzyme Q10 in Huntington's Disease (HD) (NCT NCT00608881)

NCT ID: NCT00608881

Last Updated: 2016-03-30

Results Overview

The primary outcome variable at the start of the trial was the change in TFC score from baseline to Month 60. The Data and Safety Monitoring Board recommended to the trial leadership that they reconsider how they accommodate missing data from subjects who die in their primary analysis of the change in TFC score. Based on these recommendations, the trial leadership changed the primary analysis to that of a joint rank approach. TFC consists of five ordinally scaled items assessing a person's capacity with: (1) occupation; (2) financial affairs; (3) domestic responsibilities; (4) activities of daily living; and (5) independent living. Total score ranges from zero (worst) to 13 (best).

• Recruitment status: TERMINATED
• Study phase: PHASE3
• Target enrollment: 609 participants
• Primary outcome timeframe: 5 years
• Results posted on: 2016-03-30

Participant Flow

Participant milestones

Measure	A - Coenzyme Q10 2400 mg/Day Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo Randomized to placebo placebo: an inactive substance
Overall Study STARTED	303	306
Overall Study COMPLETED	224	240
Overall Study NOT COMPLETED	79	66

Reasons for withdrawal

Measure	A - Coenzyme Q10 2400 mg/Day Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo Randomized to placebo placebo: an inactive substance
Overall Study Death	22	13
Overall Study Adverse Event	5	3
Overall Study Lost to Follow-up	28	14
Overall Study Withdrawal by Subject	18	29
Overall Study Physician Decision	5	5
Overall Study Institutionalized	1	2

Baseline Characteristics

Coenzyme Q10 in Huntington's Disease (HD)

Baseline characteristics by cohort

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance	Total n=609 Participants Total of all reporting groups
Age, Continuous	50.5 years STANDARD_DEVIATION 11.9 • n=5 Participants	50.7 years STANDARD_DEVIATION 11.6 • n=7 Participants	50.6 years STANDARD_DEVIATION 11.7 • n=5 Participants
Sex: Female, Male Female	149 Participants n=5 Participants	164 Participants n=7 Participants	313 Participants n=5 Participants
Sex: Female, Male Male	154 Participants n=5 Participants	142 Participants n=7 Participants	296 Participants n=5 Participants

PRIMARY outcome

Timeframe: 5 years

The primary outcome variable at the start of the trial was the change in TFC score from baseline to Month 60. The Data and Safety Monitoring Board recommended to the trial leadership that they reconsider how they accommodate missing data from subjects who die in their primary analysis of the change in TFC score. Based on these recommendations, the trial leadership changed the primary analysis to that of a joint rank approach. TFC consists of five ordinally scaled items assessing a person's capacity with: (1) occupation; (2) financial affairs; (3) domestic responsibilities; (4) activities of daily living; and (5) independent living. Total score ranges from zero (worst) to 13 (best).

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Joint Rank (Combination of Time to Death (for Subjects Who Died) and Change in Total Functional Capacity Score (TFC) From Baseline to Month 60 (for Subjects Who Survived))	303.3 rank Standard Deviation 173.1	306.7 rank Standard Deviation 179.0

SECONDARY outcome

Timeframe: Baseline and Month 60

TFC consists of five ordinally scaled items assessing a person's capacity with: (1) occupation; (2) financial affairs; (3) domestic responsibilities; (4) activities of daily living; and (5) independent living. Total score ranges from zero (worst) to 13 (best).

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Change in Total Functional Capacity (TFC) Score From Baseline to Month 60	-4.53 units on a scale Standard Error 0.25	-4.76 units on a scale Standard Error 0.24

SECONDARY outcome

Timeframe: Baseline and Month 60

The functional assessment checklist includes 25 questions about common daily tasks. A score of 1 is given for each "yes" reply and a score of 0 is given for each "no" reply (scale range is 0-25). Higher scores indicate better functioning.

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Change in Functional Checklist Score From Baseline to Month 60	-7.93 units on a scale Standard Error 0.55	-8.02 units on a scale Standard Error 0.54

SECONDARY outcome

Timeframe: Baseline and Month 60

The independence scale assesses independence on a 0 to 100 scale with higher scores indicating better functioning.

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Change in Independence Scale Score From Baseline to Month 60	-26.30 units on a scale Standard Error 1.92	-24.86 units on a scale Standard Error 1.90

SECONDARY outcome

Timeframe: Baseline and Month 60

The motor section of the Unified Huntington's Disease Rating Scale (UHDRS) assesses motor features of Huntington disease with standardized ratings of oculomotor function, dysarthria, chorea, dystonia, gait, and postural stability. The total motor score is the sum of all the individual motor ratings, with higher scores (124) indicating more severe motor impairment than lower scores. The score ranges from 0 to 124.

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Change in Total Motor Score From Baseline to Month 60	18.06 units on a scale Standard Error 1.22	19.18 units on a scale Standard Error 1.18

SECONDARY outcome

Timeframe: Baseline and Month 60

The Unified Huntington's Disease Rating Scale (UHDRS) behavioral subscale assesses frequency and severity of psychiatric-related symptoms, including depressed mood, apathy, low self-esteem/guilt, suicidal thoughts, anxiety, irritable behavior, aggressive behavior, obsessional thinking, compulsive behavior, delusions, and hallucinations. A total score was calculated by summing up all the individual behavioral frequency items (range 0-56) with higher scores representing more severe behavioral impairment.

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Change in Behavioral Frequency Score From Baseline to Month 60	1.39 units on a scale Standard Error 0.55	1.43 units on a scale Standard Error 0.53

SECONDARY outcome

Timeframe: Baseline and Month 60

The Unified Huntington's Disease Rating Scale (UHDRS) behavioral subscale assesses frequency and severity of psychiatric-related symptoms, including depressed mood, apathy, low self-esteem/guilt, suicidal thoughts, anxiety, irritable behavior, aggressive behavior, obsessional thinking, compulsive behavior, delusions, and hallucinations. The total score is the sum of the product of the individual behavioral frequency and severity items (range 0-176) with higher scores representing more severe behavioral impairment.

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Change in Behavioral Frequency x Severity Score From Baseline to Month 60	4.29 units on a scale Standard Error 1.52	5.06 units on a scale Standard Error 1.46

SECONDARY outcome

Timeframe: Baseline and Month 60

The SDMT assesses attention, visuoperceptual processing, working memory, and cognitive/psychomotor speed. The score is the number of correctly paired abstract symbols and specific numbers in 90 seconds with higher scores indicating better cognitive functioning.

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Change in Symbol Digit Modalities Test (SDMT) From Baseline to Month 60	-10.95 units on a scale Standard Error 0.66	-11.36 units on a scale Standard Error 0.65

SECONDARY outcome

Timeframe: Baseline and Month 60

The verbal fluency test is typically considered a measure of executive function. The score is the number of correct words produced across three 1-minute trials.

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Change in Verbal Fluency Test From Baseline to Month 60	-5.07 units on a scale Standard Error 0.79	-4.47 units on a scale Standard Error 0.78

SECONDARY outcome

Timeframe: Baseline and Month 60

Stroop Interference Test - color naming score is the total number of correct colors identified in 45 seconds and reflects processing speed.

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Change in Stroop Interference Test - Color Naming From Baseline to Month 60	-14.21 units on a scale Standard Error 1.00	-14.51 units on a scale Standard Error 0.97

SECONDARY outcome

Timeframe: Baseline and Month 60

Stroop Interference Test - word reading score is the total number of correct words read in 45 seconds and reflects processing speed.

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Change in Stroop Interference Test - Word Reading From Baseline to Month 60	-15.25 units on a scale Standard Error 1.36	-19.13 units on a scale Standard Error 1.32

SECONDARY outcome

Timeframe: Baseline and Month 60

Stroop Interference Test - interference score is the total number of correct items identified in 45 seconds and reflects an executive measure of inhibitory ability.

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Change in Stroop Interference Test - Interference From Baseline to Month 60	-7.57 units on a scale Standard Error 0.81	-8.61 units on a scale Standard Error 0.79

SECONDARY outcome

Timeframe: 5 years

TFC consists of five ordinally scaled items assessing a person's capacity with: (1) occupation; (2) financial affairs; (3) domestic responsibilities; (4) activities of daily living; and (5) independent living. Total score ranges from zero (worst) to 13 (best).

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Time to a Two-Point Decline in TFC Score or Death	553 days to event Interval 545.0 to 728.0	549 days to event Interval 395.0 to 726.0

SECONDARY outcome

Timeframe: 5 years

TFC consists of five ordinally scaled items assessing a person's capacity with: (1) occupation; (2) financial affairs; (3) domestic responsibilities; (4) activities of daily living; and (5) independent living. Total score ranges from zero (worst) to 13 (best).

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Time to a Three-Point Decline in TFC Score or Death	917 days to event Interval 760.0 to 1092.0	911 days to event Interval 737.0 to 1092.0

SECONDARY outcome

Timeframe: 5 years

Outcome measures

Measure	A - Coenzyme Q10 2400 mg/Day n=303 Participants Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 Participants Randomized to placebo placebo: an inactive substance
Number Completing Study at Assigned Dosage Level	98 participants completing study on drug	108 participants completing study on drug

Adverse Events

A - Coenzyme Q10 2400 mg/Day

Serious events: 76 serious events

Other events: 276 other events

Deaths: 0 deaths

B - Placebo

Serious events: 83 serious events

Other events: 280 other events

Deaths: 0 deaths

Serious adverse events

Measure	A - Coenzyme Q10 2400 mg/Day n=303 participants at risk Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 participants at risk Randomized to placebo placebo: an inactive substance
Respiratory, thoracic and mediastinal disorders ACUTE RESPIRATORY FAILURE	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Renal and urinary disorders RENAL FAILURE	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.65% 2/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Reproductive system and breast disorders UTERINE PROLAPSE	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Blood and lymphatic system disorders NEUTROPENIA	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Cardiac disorders ANGINA UNSTABLE	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Cardiac disorders ATRIAL FIBRILLATION	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Cardiac disorders CARDIAC ARREST	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Cardiac disorders CORONARY ARTERY DISEASE	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Cardiac disorders CORONARY ARTERY OCCLUSION	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Cardiac disorders MYOCARDIAL INFARCTION	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.98% 3/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Congenital, familial and genetic disorders HUNTINGTON'S DISEASE	0.66% 2/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.65% 2/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Ear and labyrinth disorders VERTIGO	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Eye disorders RETINAL DETACHMENT	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Gastrointestinal disorders COLITIS	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Gastrointestinal disorders CROHN'S DISEASE	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Gastrointestinal disorders DIARRHOEA	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Gastrointestinal disorders DYSPHAGIA	0.66% 2/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.65% 2/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Gastrointestinal disorders HAEMORRHOIDS	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Gastrointestinal disorders INTESTINAL OBSTRUCTION	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Gastrointestinal disorders LARGE INTESTINAL OBSTRUCTION	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Gastrointestinal disorders PEPTIC ULCER	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Gastrointestinal disorders SMALL INTESTINAL OBSTRUCTION	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Gastrointestinal disorders VOMITING	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
General disorders CHEST PAIN	0.66% 2/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
General disorders DRUG WITHDRAWAL SYNDROME	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
General disorders NON-CARDIAC CHEST PAIN	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Hepatobiliary disorders CHOLECYSTITIS	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Hepatobiliary disorders CHOLELITHIASIS	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Immune system disorders DRUG HYPERSENSITIVITY	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations ABSCESS	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations ARTHRITIS INFECTIVE	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations BACTERAEMIA	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations CELLULITIS	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations DIVERTICULITIS	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.65% 2/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations GASTROENTERITIS	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations NECROTISING FASCIITIS	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations PNEUMONIA	0.66% 2/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	1.6% 5/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations SEPSIS	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations SKIN GRAFT INFECTION	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations STAPHYLOCOCCAL BACTERAEMIA	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations STAPHYLOCOCCAL INFECTION	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations URINARY TRACT INFECTION	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.65% 2/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications ACCIDENTAL OVERDOSE	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications ANKLE FRACTURE	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications COMMINUTED FRACTURE	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications CONCUSSION	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications FACIAL BONES FRACTURE	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications FALL	0.99% 3/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	1.6% 5/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications FEMUR FRACTURE	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications FIBULA FRACTURE	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications FRACTURE	0.66% 2/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications HIP FRACTURE	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.65% 2/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications INJURY	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications INTENTIONAL OVERDOSE	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications LIMB TRAUMATIC AMPUTATION	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications ROAD TRAFFIC ACCIDENT	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications SPINAL COMPRESSION FRACTURE	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications SUBDURAL HAEMATOMA	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	1.6% 5/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications TIBIA FRACTURE	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications TRAUMATIC FRACTURE	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications UPPER LIMB FRACTURE	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications WRIST FRACTURE	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Metabolism and nutrition disorders DEHYDRATION	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Metabolism and nutrition disorders DIABETIC KETOACIDOSIS	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Metabolism and nutrition disorders HYPERGLYCAEMIA	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Metabolism and nutrition disorders HYPONATRAEMIA	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Musculoskeletal and connective tissue disorders NECK PAIN	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.65% 2/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Musculoskeletal and connective tissue disorders NOSE DEFORMITY	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Musculoskeletal and connective tissue disorders OSTEOARTHRITIS	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Musculoskeletal and connective tissue disorders OSTEOPOROSIS	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Musculoskeletal and connective tissue disorders RHABDOMYOLYSIS	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) BASAL CELL CARCINOMA	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) BRAIN NEOPLASM	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) BREAST CANCER	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.65% 2/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) CARCINOID TUMOUR	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) COLON CANCER METASTATIC	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) GLIOMA	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) INFLAMMATORY CARCINOMA OF THE BREAST	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) LUNG NEOPLASM MALIGNANT	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) MANTLE CELL LYMPHOMA	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) PROSTATE CANCER	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) UTERINE LEIOMYOMA	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Nervous system disorders CEREBROVASCULAR ACCIDENT	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Nervous system disorders CHOREA	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Nervous system disorders CONVULSION	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.65% 2/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Nervous system disorders HAEMORRHAGE INTRACRANIAL	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Nervous system disorders LOSS OF CONSCIOUSNESS	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.65% 2/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Nervous system disorders PARKINSONISM	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Nervous system disorders SYNCOPE	0.99% 3/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.65% 2/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Nervous system disorders TOXIC ENCEPHALOPATHY	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Nervous system disorders TRANSIENT ISCHAEMIC ATTACK	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders ABNORMAL BEHAVIOUR	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders AGGRESSION	0.66% 2/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.65% 2/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders AGITATION	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders ANXIETY	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders COMPLETED SUICIDE	1.3% 4/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders CONFUSIONAL STATE	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders DELIRIUM	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders DELUSION	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.65% 2/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders DEPRESSION	0.66% 2/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	2.0% 6/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders HALLUCINATION, AUDITORY	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders MAJOR DEPRESSION	0.66% 2/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders PANIC ATTACK	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders PARANOIA	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders PSYCHOTIC BEHAVIOUR	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders PSYCHOTIC DISORDER	0.66% 2/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders SUICIDAL BEHAVIOUR	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders SUICIDAL IDEATION	0.99% 3/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	2.3% 7/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders SUICIDE ATTEMPT	3.3% 10/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	2.6% 8/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Renal and urinary disorders NEPHROLITHIASIS	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Respiratory, thoracic and mediastinal disorders ASPIRATION	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Respiratory, thoracic and mediastinal disorders ASTHMA	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Respiratory, thoracic and mediastinal disorders BRONCHIECTASIS	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Respiratory, thoracic and mediastinal disorders COUGH	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Respiratory, thoracic and mediastinal disorders PNEUMONIA ASPIRATION	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Respiratory, thoracic and mediastinal disorders UPPER AIRWAY OBSTRUCTION	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Surgical and medical procedures CORONARY ARTERY BYPASS	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Surgical and medical procedures DEEP BRAIN STIMULATION	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Surgical and medical procedures HAEMORRHOID OPERATION	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Surgical and medical procedures HERNIA REPAIR	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Surgical and medical procedures HIP ARTHROPLASTY	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Surgical and medical procedures HYSTERECTOMY	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Surgical and medical procedures KNEE ARTHROPLASTY	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Surgical and medical procedures SHOULDER ARTHROPLASTY	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Surgical and medical procedures SPINAL LAMINECTOMY	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Surgical and medical procedures SURGERY	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Surgical and medical procedures THYROIDECTOMY	0.00% 0/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.33% 1/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Vascular disorders HYPOTENSION	0.66% 2/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Vascular disorders ILIAC ARTERY OCCLUSION	0.33% 1/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	0.00% 0/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.

Other adverse events

Measure	A - Coenzyme Q10 2400 mg/Day n=303 participants at risk Randomized to active treatment (coenzyme Q10 2400 mg/day) coenzyme Q10: 4 - 300 mg CoQ chewable wafers taken orally twice a day	B - Placebo n=306 participants at risk Randomized to placebo placebo: an inactive substance
Gastrointestinal disorders CONSTIPATION	8.6% 26/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	7.2% 22/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Gastrointestinal disorders DIARRHOEA	11.9% 36/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	14.1% 43/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Gastrointestinal disorders DYSPHAGIA	8.3% 25/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	6.9% 21/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Gastrointestinal disorders NAUSEA	10.2% 31/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	7.8% 24/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Gastrointestinal disorders VOMITING	8.3% 25/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	7.5% 23/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
General disorders FATIGUE	6.3% 19/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	5.2% 16/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations BRONCHITIS	5.3% 16/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	6.2% 19/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations INFLUENZA	6.9% 21/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	5.6% 17/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations NASOPHARYNGITIS	8.9% 27/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	11.1% 34/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations SINUSITIS	4.6% 14/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	6.2% 19/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	7.6% 23/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	8.8% 27/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Infections and infestations URINARY TRACT INFECTION	10.9% 33/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	15.0% 46/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications CONTUSION	3.3% 10/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	6.9% 21/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications FALL	23.8% 72/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	27.5% 84/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Injury, poisoning and procedural complications LACERATION	4.6% 14/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	7.5% 23/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Investigations WEIGHT DECREASED	8.3% 25/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	10.8% 33/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Nervous system disorders BALANCE DISORDER	6.3% 19/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	6.9% 21/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Nervous system disorders CHOREA	12.2% 37/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	14.4% 44/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Nervous system disorders DIZZINESS	5.0% 15/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	5.2% 16/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Nervous system disorders HEADACHE	5.6% 17/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	4.6% 14/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders ANXIETY	11.9% 36/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	13.7% 42/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders DEPRESSION	20.1% 61/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	21.6% 66/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders INSOMNIA	11.6% 35/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	20.9% 64/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Psychiatric disorders IRRITABILITY	11.9% 36/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	12.4% 38/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.
Respiratory, thoracic and mediastinal disorders COUGH	4.3% 13/303 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.	6.2% 19/306 • 5 years Adverse events were assessed at each visit by recording all voluntary complaints of the subject and by assessment of clinical features. Subjects were questioned regarding the occurrence of any adverse event since the last visit. All adverse events were recorded on an Adverse Event Log case report form.

Additional Information

Dr. Merit Cudkowicz

Massachusetts General Hospital

Phone: 617-726-0813

Email: mcudkowicz@partners.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place