Trial Outcomes & Findings for Comparison of Glycemic Control in Obese Diabetics Using Three Different Pen Needles (NCT NCT01231984)

NCT ID: NCT01231984

Last Updated: 2024-09-19

Results Overview

Subjects' glycemic control was assessed by comparing hemoglobin A1c (HbA1c) levels measured at the end of each 12 week Study Period (e.g., at Visit 5 or Visit 7) to the HbA1c measured at the start of that Study Period, i.e. the baseline (Visit 3) for Period 1 and the Period 1/2 crossover (Visit 5) for Period 2. Analysis included only subjects with HbA1C values at baseline (Visit 3) and at the end of Study Period 1 (Visit 5) and end of Period 2 (Visit 7).

Recruitment status

COMPLETED

Study phase

Target enrollment

293 participants

Primary outcome timeframe

Over each 12 week study period

Results posted on

2024-09-19

Participant Flow

A total of 380 subjects were screened from the current diabetic patient population at 10 research centers in the US. Of those, 293 subjects met eligibility criteria and were enrolled in the wash-in period.

Subjects who successfully completed the wash-in period and agreed to participate were further randomized into one of the study arms. Specifically, 274 of 293 subjects who were enrolled in the wash-in period completed the wash-in period and were randomized into one of the two study arms.

Participant milestones

Participant milestones
Measure	4 mm First (4 vs.8) Subjects randomized to this sequence used the 4mm PN for the first 12 weeks (Period 1), then switched to the 8 mm PN for the next 12 weeks (Period 2).	8 mm First (4 vs.8) Subjects randomized to this sequence used the 8mm PN for the first 12 weeks (Period 1), then switched to the 4 mm PN for the next 12 weeks (Period 2).	4 mm First (4 vs.12.7) Subjects randomized to this sequence used the 4mm PN for the first 12 weeks (Period 1), then switched to the 12.7 mm PN for the next 12 weeks (Period 2).	12.7 mm First ( 4 vs.12.7) Subjects randomized to this sequence used the 12.7 mm PN for the first 12 weeks (Period 1), then switched to the 4 mm PN for the next 12 weeks (Period 2).
Study Period 1 STARTED	69	70	66	69
Study Period 1 COMPLETED	57	63	59	60
Study Period 1 NOT COMPLETED	12	7	7	9
Study Period 2 STARTED	57	63	59	60
Study Period 2 COMPLETED	54	61	59	56
Study Period 2 NOT COMPLETED	3	2	0	4

Reasons for withdrawal

Reasons for withdrawal
Measure	4 mm First (4 vs.8) Subjects randomized to this sequence used the 4mm PN for the first 12 weeks (Period 1), then switched to the 8 mm PN for the next 12 weeks (Period 2).	8 mm First (4 vs.8) Subjects randomized to this sequence used the 8mm PN for the first 12 weeks (Period 1), then switched to the 4 mm PN for the next 12 weeks (Period 2).	4 mm First (4 vs.12.7) Subjects randomized to this sequence used the 4mm PN for the first 12 weeks (Period 1), then switched to the 12.7 mm PN for the next 12 weeks (Period 2).	12.7 mm First ( 4 vs.12.7) Subjects randomized to this sequence used the 12.7 mm PN for the first 12 weeks (Period 1), then switched to the 4 mm PN for the next 12 weeks (Period 2).
Study Period 1 Withdrawal by Subject	0	0	0	1
Study Period 1 Lost to Follow-up	1	1	1	0
Study Period 1 Did not continue to meet I/E Criteria	2	2	2	2
Study Period 1 Screen Failure	0	0	0	1
Study Period 1 Non-compliance with study requirements	5	0	2	1
Study Period 1 Protocol Violation	3	4	2	3
Study Period 1 Adverse Event	1	0	0	0
Study Period 1 Other	0	0	0	1
Study Period 2 Withdrawal by Subject	1	1	0	0
Study Period 2 Lost to Follow-up	1	0	0	3
Study Period 2 Did not continue to meet I/E Criteria	1	1	0	1

Baseline Characteristics

Comparison of Glycemic Control in Obese Diabetics Using Three Different Pen Needles

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	4 mm vs. 8 mm n=139 Participants Subjects randomized to this study arm first use either the 4mm PN or the 8mm PN for 12 weeks, then switched to the alternate PN for another 12 weeks. Order of PN use is randomly determined.	4 mm vs. 12.7 mm n=135 Participants Subjects randomized to this study arm first use either the 4mm PN or the 12.7mm PN for 12 weeks, then switch to the alternate PN for another 12 weeks. Order of PN use is randomly determined.	Total n=274 Participants Total of all reporting groups
Age, Continuous	57.5 years STANDARD_DEVIATION 10.6 • n=5 Participants	55.9 years STANDARD_DEVIATION 11.3 • n=7 Participants	56.7 years STANDARD_DEVIATION 11.0 • n=5 Participants
Sex: Female, Male Female	66 Participants n=5 Participants	66 Participants n=7 Participants	132 Participants n=5 Participants
Sex: Female, Male Male	73 Participants n=5 Participants	69 Participants n=7 Participants	142 Participants n=5 Participants
Region of Enrollment United States	139 participants n=5 Participants	135 participants n=7 Participants	274 participants n=5 Participants

PRIMARY outcome

Timeframe: Over each 12 week study period

Population: 115 subjects completed all main study visits. Two subjects were excluded from the 4 vs. 8 primary analysis due to protocol deviations. The total population size evaluated for the primary objective (4 vs. 8) is therefore 113.

Outcome measures

Outcome measures
Measure	4 mm First (4 vs. 8) n=54 Participants Subjects randomized to this sequence used the 4mm PN for the first 12 weeks (Period 1), then switched to the 8 mm PN for the next 12 weeks (Period 2).	8 mm First (4 vs. 8) n=59 Participants Subjects randomized to this sequence used the 8mm PN for the first 12 weeks (Period 1), then switched to the 4 mm PN for the next 12 weeks (Period 2).	12.7mm Needle Number of subjects enrolled who were assigned to use the 12.7mm PN.
Glycemic Control as Measured by HbA1c (4 mm vs. 8 mm) HbA1c at baseline (Visit 3)	7.59 HbA1c (%) Standard Deviation 0.86 • Interval -0.209 to 0.058	7.46 HbA1c (%) Standard Deviation 1.01 • Interval -0.19 to 0.0	—
Glycemic Control as Measured by HbA1c (4 mm vs. 8 mm) HbA1c end of Period 1 (Visit 5)	7.63 HbA1c (%) Standard Deviation 0.92	7.59 HbA1c (%) Standard Deviation 1.28	—
Glycemic Control as Measured by HbA1c (4 mm vs. 8 mm) HbA1c end of Period 2 (Visit 7)	7.78 HbA1c (%) Standard Deviation 1.23	7.59 HbA1c (%) Standard Deviation 1.23	—

PRIMARY outcome

Timeframe: Over each 12 week study period

Population: 115 subjects completed all main study visits. Two subjects were excluded from the 4 vs. 12.7 primary analysis due to protocol deviations. The total population size evaluated for this analysis is therefore 113.

Outcome measures

Outcome measures
Measure	4 mm First (4 vs. 8) n=57 Participants Subjects randomized to this sequence used the 4mm PN for the first 12 weeks (Period 1), then switched to the 8 mm PN for the next 12 weeks (Period 2).	8 mm First (4 vs. 8) n=56 Participants Subjects randomized to this sequence used the 8mm PN for the first 12 weeks (Period 1), then switched to the 4 mm PN for the next 12 weeks (Period 2).	12.7mm Needle Number of subjects enrolled who were assigned to use the 12.7mm PN.
Glycemic Control as Measured by HbA1c (4 mm vs. 12.7 mm) HbA1c Baseline (Visit 3)	7.57 HbA1c (%) Standard Deviation 0.96	7.45 HbA1c (%) Standard Deviation 0.88	—
Glycemic Control as Measured by HbA1c (4 mm vs. 12.7 mm) HbA1c end of Period 1 (Visit 5)	7.58 HbA1c (%) Standard Deviation 1.03	7.54 HbA1c (%) Standard Deviation 0.95	—
Glycemic Control as Measured by HbA1c (4 mm vs. 12.7 mm) HbA1c end of Period 2 (Visit 7)	7.73 HbA1c (%) Standard Deviation 1.18	7.51 HbA1c (%) Standard Deviation 0.97	—

SECONDARY outcome

Timeframe: Subjects were randomly assigned to use the BD Ultra-Fine™ 4mm pen needle for one - 12 week study period and either the BD Ultra-Fine™ 8mm pen needle or the BD Ultra-Fine™ 12.7mm pen needle for one - 12 week study period.

Population: Of the 226 subjects who were considered for the Primary analysis, 107 subjects had at least one dose of insulin that was at least 40 units. The glycemic control of this sub-group of subjects was analyzed as in the Primary Analysis.The same analysis was performed for the high insulin dose subjects, with the two longer PN study arms pooled together.

Glycemic control was assessed as by difference between the subjects' HbA1c (%) at baseline (randomization, Visit 3) and at the end of each 12 week study period,in the same manner as for the primary outcome measures. The 95% confidence interval for the mean difference in HbA1c values between the 4mm PN and the longer PN will be estimated based on general linear models adjusting for baseline HbA1c.

Outcome measures

Outcome measures
Measure	4 mm First (4 vs. 8) n=52 Participants Subjects randomized to this sequence used the 4mm PN for the first 12 weeks (Period 1), then switched to the 8 mm PN for the next 12 weeks (Period 2).	8 mm First (4 vs. 8) n=55 Participants Subjects randomized to this sequence used the 8mm PN for the first 12 weeks (Period 1), then switched to the 4 mm PN for the next 12 weeks (Period 2).	12.7mm Needle Number of subjects enrolled who were assigned to use the 12.7mm PN.
Glycemic Control as Measured by HbA1c, in High Dose Insulin (at Least One Dose of ≥ 40 Units) Users HbA1c at Baseline (Visit 3)	7.77 HbA1C (%) Standard Deviation 0.92 • Interval -0.23 to 0.051	7.57 HbA1C (%) Standard Deviation 0.90	—
Glycemic Control as Measured by HbA1c, in High Dose Insulin (at Least One Dose of ≥ 40 Units) Users HbA1c end Period 1 (Visit 5)	7.76 HbA1C (%) Standard Deviation 1.03	7.62 HbA1C (%) Standard Deviation 0.97	—
Glycemic Control as Measured by HbA1c, in High Dose Insulin (at Least One Dose of ≥ 40 Units) Users HbA1c end Period 2 (Visit 7)	7.98 HbA1C (%) Standard Deviation 1.35	7.66 HbA1C (%) Standard Deviation 0.99	—

SECONDARY outcome

Timeframe: At the end of Study Period 2

Population: 115 subjects in the 4mm vs. 8 mm study arm completed all main study visits. Two of the 115 subjects were excluded from all primary and secondary analyses due to protocol deviations. The total number of subjects analyzed for perceived pain for this study was therefore 113.

At the end of second study period, subjects were asked to rate the level of pain experienced with study period 2 needle compared to the pen needle used in study period 1, using a 150 mm Visual Analog Scale (VAS). The VAS is a measure of the pain perceived with the needle they are using at that point in the study relative to the needle they used in Period 1. The VAS is anchored at the center (0mm) with "as painful" and at each extreme with "much less painful (-75mm) and "much more painful (+75mm); therefore a pain rating \< 0 indicates that the Period 2 needle was perceived as less painful than the Period 1 needle.

Outcome measures

Outcome measures
Measure	4 mm First (4 vs. 8) n=59 Participants Subjects randomized to this sequence used the 4mm PN for the first 12 weeks (Period 1), then switched to the 8 mm PN for the next 12 weeks (Period 2).	8 mm First (4 vs. 8) n=54 Participants Subjects randomized to this sequence used the 8mm PN for the first 12 weeks (Period 1), then switched to the 4 mm PN for the next 12 weeks (Period 2).	12.7mm Needle Number of subjects enrolled who were assigned to use the 12.7mm PN.
Injection Pain Scores (4 mm vs. 8 mm)	-31.53 mm Standard Error 5.3 • Interval -75.0 to 75.0	-19.17 mm Standard Error 4.85 • Interval -75.0 to 75.0	—

SECONDARY outcome

Timeframe: At the end of Study Period 2

Population: 115 subjects in the 4mm vs. 12 mm study arm completed all main study visits. One of the subjects was excluded from all primary and secondary analyses due to protocol deviations.

At the end of second study period, subjects were asked to rate the level of pain experienced with study period 2 needle compared to the pen needle used in study period 1, using a 150 mm Visual Analog Scale (VAS). The VAS is a measure of the pain perceived with the needle they are using at that point in the study relative to the needle they used the previous period. The VAS is anchored at the center (0mm) with "as painful" and at each extreme with "much less painful (-75mm) and "much more painful (+75mm); therefore a negative pain rating means the period 2 needle was perceived as less painful than the period 1 needle.

Outcome measures

Outcome measures
Measure	4 mm First (4 vs. 8) n=56 Participants Subjects randomized to this sequence used the 4mm PN for the first 12 weeks (Period 1), then switched to the 8 mm PN for the next 12 weeks (Period 2).	8 mm First (4 vs. 8) n=58 Participants Subjects randomized to this sequence used the 8mm PN for the first 12 weeks (Period 1), then switched to the 4 mm PN for the next 12 weeks (Period 2).	12.7mm Needle Number of subjects enrolled who were assigned to use the 12.7mm PN.
Injection Pain Scores (4 mm vs. 12 mm)	-27.72 mm Standard Error 5.47 • Interval -75.0 to 75.0	3.10 mm Standard Error 5.01 • Interval -75.0 to 75.0	—

SECONDARY outcome

Timeframe: During Study Period 1 (12 weeks) and Study Period 2 (12 weeks)

Population: Two hundred seventy-four subjects were randomized into the study. Data from all subjects randomized were included in the analysis of subjects with serious, unexplained hypoglycemic events.

Subjects were asked to record hypoglycemic events in his/her diary anytime his/her blood glucose (BG) was below 50mg/dL, s/he had signs/symptoms of hypoglycemia, or s/he required medical attention for treatment. Hypoglycemia was defined as serious when the subject required the assistance of another person to be treated, or when the hypoglycemic event met the per-protocol definition of a Serious Adverse Event. An unexplained episode was defined as one with no known cause (for example, the subject skipped a meal or exercised vigorously).

Outcome measures

Outcome measures
Measure	4 mm First (4 vs. 8) n=274 Participants Subjects randomized to this sequence used the 4mm PN for the first 12 weeks (Period 1), then switched to the 8 mm PN for the next 12 weeks (Period 2).	8 mm First (4 vs. 8) n=139 Participants Subjects randomized to this sequence used the 8mm PN for the first 12 weeks (Period 1), then switched to the 4 mm PN for the next 12 weeks (Period 2).	12.7mm Needle n=135 Participants Number of subjects enrolled who were assigned to use the 12.7mm PN.
Number of Serious, Unexplained Hypoglycemic Events, Reported as Number of Events by Needle.	1 Adverse Events	2 Adverse Events	0 Adverse Events

SECONDARY outcome

Timeframe: During Study Period 1 (12 weeks) and Study Period 2 (12 weeks)

Subjects were asked to record hyperglycemic events in his/her diary anytime his/her blood glucose (BG) was above 400mg/dL, or s/he required medical attention for treatment for hyperglycemia. Hyperglycemia was defined as serious when the subject required the assistance of another person to be treated, or when the hyperglycemic event met the per-protocol definition of a Serious Adverse Event. An unexplained episode was defined as one with no known cause (for example, the subject missed an insulin dose). Subjects were asked to record these events in a diary.

Outcome measures

Outcome measures
Measure	4 mm First (4 vs. 8) n=274 Participants Subjects randomized to this sequence used the 4mm PN for the first 12 weeks (Period 1), then switched to the 8 mm PN for the next 12 weeks (Period 2).	8 mm First (4 vs. 8) n=139 Participants Subjects randomized to this sequence used the 8mm PN for the first 12 weeks (Period 1), then switched to the 4 mm PN for the next 12 weeks (Period 2).	12.7mm Needle n=135 Participants Number of subjects enrolled who were assigned to use the 12.7mm PN.
Number of Serious, Unexplained Hyperglycemic Events, Reported as Number of Events by Needle.	0 Adverse Events	0 Adverse Events	0 Adverse Events

Adverse Events

4mm Needle

Serious events: 9 serious events

Other events: 91 other events

Deaths: 0 deaths

8mm Needle

Serious events: 1 serious events

Other events: 36 other events

Deaths: 0 deaths

12.7mm Needle

Serious events: 7 serious events

Other events: 29 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	4mm Needle n=274 participants at risk	8mm Needle n=127 participants at risk	12.7mm Needle n=147 participants at risk
Metabolism and nutrition disorders Hypoglycaemic Conditions NEC	21.9% 60/274 • Number of events 209 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	19.7% 25/127 • Number of events 91 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	13.6% 20/147 • Number of events 83 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Metabolism and nutrition disorders Hyperglycaemic Conditions NEC	6.2% 17/274 • Number of events 63 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	6.3% 8/127 • Number of events 20 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	4.8% 7/147 • Number of events 30 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Respiratory, thoracic and mediastinal disorders Upper Respiratory Tract Infections NEC	5.1% 14/274 • Number of events 14 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	2.4% 3/127 • Number of events 3 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	1.4% 2/147 • Number of events 2 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.

Additional Information

Laurence Hirsch, MD

Becton Dickinson

Phone: 201-847-6513

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The PI and Clinical Center will not publish the results pursuant to the Protocol without sponsor review and opportunity to comment on the publication or oral presentation. Abstracts and synopsis of oral presentations must be received by sponsor 30 days, and journal submissions 60 days, prior to submission. The data generated pursuant to the Protocol will be the property of the sponsor and may be used in any manner by the sponsor as it may determine in its sole discretion.
Publication restrictions are in place

Restriction type: OTHER

Measure	4mm Needle n=274 participants at risk	8mm Needle n=127 participants at risk	12.7mm Needle n=147 participants at risk
Metabolism and nutrition disorders Diabetic Complications Opthalmic	0.36% 1/274 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/147 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Gastrointestinal disorders Diaphragmatic Hernias	0.36% 1/274 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/147 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Gastrointestinal disorders Gastric and Gastroenteric Infections	0.36% 1/274 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/147 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Gastrointestinal disorders Gastrointestinal and Abdominal Pains (Excl Oral and Throat)	0.00% 0/274 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.68% 1/147 • Number of events 2 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Metabolism and nutrition disorders General Nutritional Disorder	0.00% 0/274 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.68% 1/147 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Cardiac disorders Heart Failure NEC	0.36% 1/274 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/147 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Metabolism and nutrition disorders Hypoglycaemic Conditions NEC	0.36% 1/274 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/147 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Ear and labyrinth disorders Inner Ear Signs and Symptoms	0.36% 1/274 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/147 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Gastrointestinal disorders Intestinal Ulceration and Perforation	0.36% 1/274 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/147 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Cardiac disorders Ischaemic Coronary Artery Disorders	0.36% 1/274 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/147 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Musculoskeletal and connective tissue disorders Joint Related Signs and Symptoms	0.36% 1/274 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/147 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Injury, poisoning and procedural complications Lower Limb Fractures and Dislocations	0.36% 1/274 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/147 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Infections and infestations Lower Respiratory Tract and Lung Infections	0.00% 0/274 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.68% 1/147 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Respiratory, thoracic and mediastinal disorders Lower Respiratory Tract Infection NEC	0.36% 1/274 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/147 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Gastrointestinal disorders Nausea and Vomiting Symptoms	0.36% 1/274 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/147 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Injury, poisoning and procedural complications Non-Site Specific Injuries	0.00% 0/274 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.68% 1/147 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic Neoplasms Malignant (Excl Islet Cell and Carcinoid)	0.00% 0/274 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.68% 1/147 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate Neoplasms Malignant	0.00% 0/274 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.68% 1/147 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid Neoplasms Malignant	0.00% 0/274 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.79% 1/127 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/147 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.
Renal and urinary disorders Urinary Abnormalities	0.00% 0/274 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.00% 0/127 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.	0.68% 1/147 • Number of events 1 • Adverse events that occurred during the wash-in period as well as during the two study periods were collected throughout each subject's participation in the study. Total time of participation could have been up to approximately eight months.