Trial Outcomes & Findings for Pioglitazone in Early Parkinson's Disease (NCT NCT01280123)

Last Updated: 2015-10-14

Results Overview

Change in total UPDRS score from baseline to 44 weeks (in subjects treated with rasagiline 1 mg/day or selegiline 10 mg/day). The Total UPDRS is the sum of parts I, II, and III. The possible range of the total UPDRS is from 0-176. Higher values indicate worse outcomes. The change is 44 weeks - baseline.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

210 participants

Primary outcome timeframe

44 weeks

Results posted on

2015-10-14

Participant Flow

Participant milestones

Participant milestones
Measure	15 mg Pioglitazone 15 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	45 mg Pioglitazone 45 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	Matching Placebo Placebo placebo: Placebo will contain microcrystalline cellulose. An over-encapsulation process will be conducted in accordance with Clinical Good Manufacturing Procedures (cGMP) regulations to create a dosage form for the active study drug that will be indistinguishable from the comparator (Placebo) capsule.
Overall Study STARTED	72	67	71
Overall Study COMPLETED	71	63	70
Overall Study NOT COMPLETED	1	4	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Pioglitazone in Early Parkinson's Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	15 mg Pioglitazone n=72 Participants 15 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	45 mg Pioglitazone n=67 Participants 45 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	Matching Placebo n=71 Participants Placebo placebo: Placebo will contain microcrystalline cellulose. An over-encapsulation process will be conducted in accordance with Clinical Good Manufacturing Procedures (cGMP) regulations to create a dosage form for the active study drug that will be indistinguishable from the comparator (Placebo) capsule.	Total n=210 Participants Total of all reporting groups
Age, Continuous	61.3 years STANDARD_DEVIATION 10.6 • n=5 Participants	58.8 years STANDARD_DEVIATION 9.2 • n=7 Participants	59.0 years STANDARD_DEVIATION 9.9 • n=5 Participants	59.7 years STANDARD_DEVIATION 9.9 • n=4 Participants
Sex/Gender, Customized Males	53 participants n=5 Participants	47 participants n=7 Participants	48 participants n=5 Participants	148 participants n=4 Participants
Sex/Gender, Customized Females	19 participants n=5 Participants	20 participants n=7 Participants	23 participants n=5 Participants	62 participants n=4 Participants
Race/Ethnicity, Customized Non-Latino whites	58 participants n=5 Participants	63 participants n=7 Participants	63 participants n=5 Participants	184 participants n=4 Participants
Race/Ethnicity, Customized Racial/Ethnic Minority	14 participants n=5 Participants	4 participants n=7 Participants	8 participants n=5 Participants	26 participants n=4 Participants
Years of education	17.1 years STANDARD_DEVIATION 3.1 • n=5 Participants	16.2 years STANDARD_DEVIATION 3.3 • n=7 Participants	16.8 years STANDARD_DEVIATION 3.0 • n=5 Participants	16.7 years STANDARD_DEVIATION 3.1 • n=4 Participants
Right-handed Yes	62 participants n=5 Participants	62 participants n=7 Participants	62 participants n=5 Participants	186 participants n=4 Participants
Right-handed No	10 participants n=5 Participants	5 participants n=7 Participants	9 participants n=5 Participants	24 participants n=4 Participants
Duration of PD symptoms (years)	2.3 years STANDARD_DEVIATION 1.9 • n=5 Participants	2.0 years STANDARD_DEVIATION 1.2 • n=7 Participants	2.3 years STANDARD_DEVIATION 2.3 • n=5 Participants	2.2 years STANDARD_DEVIATION 1.9 • n=4 Participants
Time since PD diagnosis (years)	0.8 years STANDARD_DEVIATION 0.7 • n=5 Participants	0.7 years STANDARD_DEVIATION 0.7 • n=7 Participants	0.8 years STANDARD_DEVIATION 0.7 • n=5 Participants	0.7 years STANDARD_DEVIATION 0.7 • n=4 Participants
Total Unified Parkinson's Disease Rating Scale (UPDRS)	23.8 units on a scale STANDARD_DEVIATION 9.9 • n=5 Participants	21.2 units on a scale STANDARD_DEVIATION 8.8 • n=7 Participants	21.7 units on a scale STANDARD_DEVIATION 8.7 • n=5 Participants	22.2 units on a scale STANDARD_DEVIATION 9.2 • n=4 Participants
UPDRS mental	0.8 units on a scale STANDARD_DEVIATION 0.9 • n=5 Participants	0.8 units on a scale STANDARD_DEVIATION 0.9 • n=7 Participants	0.9 units on a scale STANDARD_DEVIATION 1.1 • n=5 Participants	0.8 units on a scale STANDARD_DEVIATION 1.0 • n=4 Participants
UPDRS motor	17.7 units on a scale STANDARD_DEVIATION 7.7 • n=5 Participants	15.0 units on a scale STANDARD_DEVIATION 7.1 • n=7 Participants	15.3 units on a scale STANDARD_DEVIATION 6.5 • n=5 Participants	15.8 units on a scale STANDARD_DEVIATION 7.1 • n=4 Participants
UPDRS ADL	5.9 units on a scale STANDARD_DEVIATION 3.2 • n=5 Participants	5.5 units on a scale STANDARD_DEVIATION 2.9 • n=7 Participants	5.5 units on a scale STANDARD_DEVIATION 3.0 • n=5 Participants	5.6 units on a scale STANDARD_DEVIATION 3.0 • n=4 Participants
Ambulatory capacity	1.1 units on a scale STANDARD_DEVIATION 0.9 • n=5 Participants	0.8 units on a scale STANDARD_DEVIATION 0.8 • n=7 Participants	1.1 units on a scale STANDARD_DEVIATION 0.9 • n=5 Participants	1.0 units on a scale STANDARD_DEVIATION 0.9 • n=4 Participants
Schwab and England Activities of Daily Living scale (SEADL)	93.8 units on a scale STANDARD_DEVIATION 4.9 • n=5 Participants	94.1 units on a scale STANDARD_DEVIATION 5.0 • n=7 Participants	93.9 units on a scale STANDARD_DEVIATION 5.0 • n=5 Participants	93.9 units on a scale STANDARD_DEVIATION 4.9 • n=4 Participants
Parkinson's Disease Questionnaire 39 (PDQ-39) Summary Index	8.5 units on a scale STANDARD_DEVIATION 8.1 • n=5 Participants	8.1 units on a scale STANDARD_DEVIATION 5.9 • n=7 Participants	10.6 units on a scale STANDARD_DEVIATION 7.9 • n=5 Participants	9.1 units on a scale STANDARD_DEVIATION 7.4 • n=4 Participants
Geriatric Depression Scale (GDS)	1.4 units on a scale STANDARD_DEVIATION 1.4 • n=5 Participants	1.1 units on a scale STANDARD_DEVIATION 1.3 • n=7 Participants	1.8 units on a scale STANDARD_DEVIATION 1.9 • n=5 Participants	1.4 units on a scale STANDARD_DEVIATION 1.6 • n=4 Participants
Mattis-Dementia Rating scale	138.6 units on a scale STANDARD_DEVIATION 8.2 • n=5 Participants	138.8 units on a scale STANDARD_DEVIATION 10.2 • n=7 Participants	138 units on a scale STANDARD_DEVIATION 11.4 • n=5 Participants	138.4 units on a scale STANDARD_DEVIATION 9.9 • n=4 Participants
rasagiline/selegiline use rasagiline use	60 participants n=5 Participants	57 participants n=7 Participants	60 participants n=5 Participants	177 participants n=4 Participants
rasagiline/selegiline use selegiline use	12 participants n=5 Participants	10 participants n=7 Participants	11 participants n=5 Participants	33 participants n=4 Participants

PRIMARY outcome

Timeframe: 44 weeks

Outcome measures

Outcome measures
Measure	15 mg Pioglitazone n=72 Participants 15 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	45 mg Pioglitazone n=67 Participants 45 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	Matching Placebo n=71 Participants Placebo placebo: Placebo will contain microcrystalline cellulose. An over-encapsulation process will be conducted in accordance with Clinical Good Manufacturing Procedures (cGMP) regulations to create a dosage form for the active study drug that will be indistinguishable from the comparator (Placebo) capsule.
Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline to 44 Weeks	4.42 units on a scale Standard Error 0.95	5.13 units on a scale Standard Error 0.99	6.25 units on a scale Standard Error 0.96

SECONDARY outcome

Timeframe: 44 weeks

This is the sum of the 5 UPDRS questions regarding ambulatory capacity: falling, freezing, walking, gait, postural stability. Ambulatory Capacity is calculated as the sum of items 13-15, 29, 30 of the Unified Parkinson's Disease Rating Scale (UPDRS). It ranges from 0-20. Higher scores are worse. Change is 44 weeks - baseline.

Outcome measures

Outcome measures
Measure	15 mg Pioglitazone n=72 Participants 15 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	45 mg Pioglitazone n=67 Participants 45 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	Matching Placebo n=71 Participants Placebo placebo: Placebo will contain microcrystalline cellulose. An over-encapsulation process will be conducted in accordance with Clinical Good Manufacturing Procedures (cGMP) regulations to create a dosage form for the active study drug that will be indistinguishable from the comparator (Placebo) capsule.
Change in Ambulatory Capacity From Baseline to 44 Weeks	0.39 units on a scale Interval 0.16 to 0.61	0.38 units on a scale Interval 0.07 to 0.7	0.4 units on a scale Interval 0.17 to 0.64

SECONDARY outcome

Timeframe: 44 weeks

The modified Schwab and England Activities of Daily Living is a single question ranging from 0-100% with anchors for each 10% interval. Higher scores are better (100% completely independent- 0% vegetative).

Outcome measures

Outcome measures
Measure	15 mg Pioglitazone n=72 Participants 15 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	45 mg Pioglitazone n=67 Participants 45 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	Matching Placebo n=71 Participants Placebo placebo: Placebo will contain microcrystalline cellulose. An over-encapsulation process will be conducted in accordance with Clinical Good Manufacturing Procedures (cGMP) regulations to create a dosage form for the active study drug that will be indistinguishable from the comparator (Placebo) capsule.
Change in Schwab and England Scale From Baseline to 44 Weeks	-2.12 units on a scale Interval -3.47 to -0.78	-2.52 units on a scale Interval -3.95 to -1.09	-1.84 units on a scale Interval -3.49 to -0.18

SECONDARY outcome

Timeframe: 44 weeks

The Parkinson's Disease Questionnaire (PDQ-39) is a short, 39 item measure of quality of life in subjects with Parkinson's disease. The questionnaire covers 8 aspects of quality of life: mobility, activities of daily living, emotional well-being, stigma, social support, cognitions, communication and bodily discomfort. The total score ranges from 0 (never have difficulty) to 100 (always have difficulty). Lower scores reflect better quality of life.

Outcome measures

Outcome measures
Measure	15 mg Pioglitazone n=72 Participants 15 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	45 mg Pioglitazone n=67 Participants 45 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	Matching Placebo n=71 Participants Placebo placebo: Placebo will contain microcrystalline cellulose. An over-encapsulation process will be conducted in accordance with Clinical Good Manufacturing Procedures (cGMP) regulations to create a dosage form for the active study drug that will be indistinguishable from the comparator (Placebo) capsule.
Change in Parkinson's Disease Questionnaire (PDQ-39) From Baseline to 44 Weeks	2.03 units on a scale Interval 0.47 to 3.59	2.08 units on a scale Interval 0.32 to 3.84	0.08 units on a scale Interval -1.59 to 1.76

SECONDARY outcome

Timeframe: 44 weeks

The Mattis dementia rating scale is a psychometric instrument designed to assess the extent and nature of dementia. Mattis Dementia Rating scale (DRS-2) raw score is the sum of 5 raw sub-scores (attention has possible 37 points, initiation/perseveration has possible 37 points, construction has possible 6 points, conceptualization has possible 39 points, memory has possible 25 points). Total range is 0-144. Higher scores are better.

Outcome measures

Outcome measures
Measure	15 mg Pioglitazone n=72 Participants 15 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	45 mg Pioglitazone n=67 Participants 45 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	Matching Placebo n=71 Participants Placebo placebo: Placebo will contain microcrystalline cellulose. An over-encapsulation process will be conducted in accordance with Clinical Good Manufacturing Procedures (cGMP) regulations to create a dosage form for the active study drug that will be indistinguishable from the comparator (Placebo) capsule.
Change in the Mattis Dementia Rating Scale (DRS-2)From Baseline to 44 Weeks	1.16 units on a scale Interval -1.26 to 3.58	2.11 units on a scale Interval -0.41 to 4.63	3.16 units on a scale Interval 0.66 to 5.65

SECONDARY outcome

Timeframe: 44 weeks

The Geriatric Depression Scale - 15 is a short 15 yes or no question instrument for assessing depression in the elderly. It has been found to be particularly useful in assessing depression in Parkinson's Disease. A score of 0 to 5 is normal. A score greater than 5 suggests depression.

Outcome measures

Outcome measures
Measure	15 mg Pioglitazone n=72 Participants 15 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	45 mg Pioglitazone n=67 Participants 45 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	Matching Placebo n=71 Participants Placebo placebo: Placebo will contain microcrystalline cellulose. An over-encapsulation process will be conducted in accordance with Clinical Good Manufacturing Procedures (cGMP) regulations to create a dosage form for the active study drug that will be indistinguishable from the comparator (Placebo) capsule.
Change in the 15-item Geriatric Depression Scale (GDS-15)From Baseline to 44 Weeks	0.13 units on a scale Interval -0.33 to 0.58	0.38 units on a scale Interval -0.1 to 0.85	0.18 units on a scale Interval -0.37 to 0.72

Adverse Events

15 mg Pioglitazone

Serious events: 6 serious events

Other events: 63 other events

Deaths: 0 deaths

45 mg Pioglitazone

Serious events: 9 serious events

Other events: 51 other events

Deaths: 0 deaths

Matching Placebo

Serious events: 3 serious events

Other events: 59 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Tanya Simuni, MD

Northwestern University

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	15 mg Pioglitazone n=72 participants at risk 15 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	45 mg Pioglitazone n=67 participants at risk 45 mg pioglitazone Pioglitazone: Oral capsules of Pioglitazone (15 mg capsules) either 15 mg/qd or 45 mg/qd or matching placebo 44 weeks: Subjects who are on stable dose of rasagiline 1 mg/day or selegiline 10 mg/day, for at least 8 weeks but no more than 8 months, will begin randomized dose of study drug. Subjects will titrate in a blinded fashion to 30 mg/day after 2 weeks and to 45 mg per day) 2 weeks later as tolerated. Subjects will be followed on study drug for 44 weeks.	Matching Placebo n=71 participants at risk Placebo placebo: Placebo will contain microcrystalline cellulose. An over-encapsulation process will be conducted in accordance with Clinical Good Manufacturing Procedures (cGMP) regulations to create a dosage form for the active study drug that will be indistinguishable from the comparator (Placebo) capsule.
Injury, poisoning and procedural complications Ankle fracture	1.4% 1/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Cardiac disorders Atrial fibrillation	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.4% 1/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Cardiac disorders Atrial flutter	1.4% 1/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
General disorders Chest pain	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.4% 1/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Psychiatric disorders Confusional state	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	3.0% 2/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Cardiac disorders Coronary artery stenosis	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.4% 1/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Metabolism and nutrition disorders Dehydration	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.5% 1/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.5% 1/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Vascular disorders Hypertension	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.4% 1/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.5% 1/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Musculoskeletal and connective tissue disorders Intervertebral disc degeneration	1.4% 1/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Gastrointestinal disorders Intestinal obstruction	1.4% 1/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.5% 1/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Cardiac disorders Myocardial infarction	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.5% 1/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Reproductive system and breast disorders Ovarian cyst ruptured	1.4% 1/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.5% 1/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	1.4% 1/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Musculoskeletal and connective tissue disorders Spondylolisthesis	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.5% 1/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Surgical and medical procedures Knee arthroplasty	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.4% 1/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Nervous system disorders Transient ischemic attack	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.5% 1/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Psychiatric disorders Disorientation	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.5% 1/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Nervous system disorders Dizziness	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.5% 1/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/72 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	1.5% 1/67 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"	0.00% 0/71 • All events during study period (defined as from signing consent to conclusion of study participation 44 weeks). Adverse event data was elicited by asking an open ended question "What unusual symptoms or medical problems have you experienced since the last visit?"