Trial Outcomes & Findings for Safety and Efficacy of Bexagliflozin Compared to Glimepiride as Add-on Therapy to Metformin in Type 2 Diabetes Subjects (NCT NCT02769481)

Last Updated: 2021-05-27

Results Overview

The primary objective is to demonstrate that bexagliflozin is non-inferior to glimepiride by evaluating the treatment effect on HbA1c reduction at week 60 in subjects whose T2DM is inadequately controlled by metformin. The least square mean (LSM) change from baseline to Week 60 was analyzed using a mixed model repeated measures (MMRM) analysis of covariance model (ANCOVA).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

426 participants

Primary outcome timeframe

Baseline and Week 60

Results posted on

2021-05-27

Participant Flow

Participant milestones

Participant milestones
Measure	Bexagliflozin Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride for the duration of the study. Bexagliflozin tablets: 20 mg Glimepiride capsules: Placebo, inactive capsule to match the active comparator	Glimepiride Subjects will receive a glimepiride capsule, 2, 4 or 6 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study. Bexagliflozin: Placebo, inactive tablet to match the active comparator Glimepiride capsules: 2, 4 or 6 mg
Overall Study STARTED	213	213
Overall Study Study Complete at Week 60	193	192
Overall Study COMPLETED	180	177
Overall Study NOT COMPLETED	33	36

Reasons for withdrawal

Reasons for withdrawal
Measure	Bexagliflozin Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride for the duration of the study. Bexagliflozin tablets: 20 mg Glimepiride capsules: Placebo, inactive capsule to match the active comparator	Glimepiride Subjects will receive a glimepiride capsule, 2, 4 or 6 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study. Bexagliflozin: Placebo, inactive tablet to match the active comparator Glimepiride capsules: 2, 4 or 6 mg
Overall Study Protocol Violation	1	0
Overall Study Adverse Event	3	6
Overall Study Entry Criteria Not Met	1	2
Overall Study Withdrawal by Subject	14	16
Overall Study Lost to Follow-up	9	9
Overall Study Physician Decision	0	1
Overall Study Terminated by Sponsor	1	0
Overall Study Death	0	1
Overall Study Undefined	4	1

Baseline Characteristics

Safety and Efficacy of Bexagliflozin Compared to Glimepiride as Add-on Therapy to Metformin in Type 2 Diabetes Subjects

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bexagliflozin n=213 Participants Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride for the duration of the study. Bexagliflozin tablets: 20 mg Glimepiride capsules: Placebo, inactive capsule to match the active comparator	Glimepiride n=213 Participants Subjects will receive a glimepiride capsule, 2, 4 or 6 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study. Bexagliflozin: Placebo, inactive tablet to match the active comparator Glimepiride capsules: 2, 4 or 6 mg	Total n=426 Participants Total of all reporting groups
Age, Continuous	59.5 years STANDARD_DEVIATION 9.06 • n=5 Participants	59.7 years STANDARD_DEVIATION 10.35 • n=7 Participants	59.6 years STANDARD_DEVIATION 9.71 • n=5 Participants
Sex: Female, Male Female	95 Participants n=5 Participants	83 Participants n=7 Participants	178 Participants n=5 Participants
Sex: Female, Male Male	118 Participants n=5 Participants	130 Participants n=7 Participants	248 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	46 Participants n=5 Participants	47 Participants n=7 Participants	93 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	167 Participants n=5 Participants	166 Participants n=7 Participants	333 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	9 Participants n=5 Participants	4 Participants n=7 Participants	13 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
Race (NIH/OMB) White	198 Participants n=5 Participants	204 Participants n=7 Participants	402 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment United States	65 participants n=5 Participants	63 participants n=7 Participants	128 participants n=5 Participants
Region of Enrollment Poland	74 participants n=5 Participants	79 participants n=7 Participants	153 participants n=5 Participants
Region of Enrollment Germany	28 participants n=5 Participants	29 participants n=7 Participants	57 participants n=5 Participants
Region of Enrollment Spain	46 participants n=5 Participants	42 participants n=7 Participants	88 participants n=5 Participants
Height	166.7 cm STANDARD_DEVIATION 11.13 • n=5 Participants	167.1 cm STANDARD_DEVIATION 9.53 • n=7 Participants	166.9 cm STANDARD_DEVIATION 10.35 • n=5 Participants
Body Weight at Baseline	87.95 kg STANDARD_DEVIATION 19.122 • n=5 Participants	90.23 kg STANDARD_DEVIATION 17.616 • n=7 Participants	89.09 kg STANDARD_DEVIATION 18.399 • n=5 Participants
BMI	31.45 kg/m^2 STANDARD_DEVIATION 4.861 • n=5 Participants	32.22 kg/m^2 STANDARD_DEVIATION 5.155 • n=7 Participants	31.83 kg/m^2 STANDARD_DEVIATION 5.019 • n=5 Participants
Systolic Blood Pressure at Baseline	133.3 mm Hg STANDARD_DEVIATION 14.88 • n=5 Participants	134.2 mm Hg STANDARD_DEVIATION 14.37 • n=7 Participants	133.8 mm Hg STANDARD_DEVIATION 14.62 • n=5 Participants
Systolic Blood Pressure Categories < 140 mm Hg	135 Participants n=5 Participants	138 Participants n=7 Participants	273 Participants n=5 Participants
Systolic Blood Pressure Categories > 140 mm Hg	78 Participants n=5 Participants	75 Participants n=7 Participants	153 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Week 60

Population: The intention-to-treat population was used for the analysis. Subjects with a value at baseline and at week 60 were analyzed.

Outcome measures

Outcome measures
Measure	Bexagliflozin n=193 Participants Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride for the duration of the study. Bexagliflozin tablets: 20 mg Glimepiride capsules: Placebo, inactive capsule to match the active comparator	Glimepiride n=191 Participants Subjects will receive a glimepiride capsule, 2, 4 or 6 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study. Bexagliflozin: Placebo, inactive tablet to match the active comparator Glimepiride capsules: 2, 4 or 6 mg
Change From Baseline in HbA1c at Week 60	-0.70 percentage of glycated hemoglin Standard Error 0.058	-0.66 percentage of glycated hemoglin Standard Error 0.058

SECONDARY outcome

Timeframe: Baseline and 60 weeks

Population: Number of subjects with a value at baseline and at the specified visit

Least squares (LS) mean treatment difference between the bexagliflozin group and placebo group in the change of body weight in subjects with baseline BMI ≥ 25 kg/m2 at week 60 is analyzed using ANCOVA.

Outcome measures

Outcome measures
Measure	Bexagliflozin n=182 Participants Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride for the duration of the study. Bexagliflozin tablets: 20 mg Glimepiride capsules: Placebo, inactive capsule to match the active comparator	Glimepiride n=182 Participants Subjects will receive a glimepiride capsule, 2, 4 or 6 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study. Bexagliflozin: Placebo, inactive tablet to match the active comparator Glimepiride capsules: 2, 4 or 6 mg
Change From Baseline in Body Weight at Week 60 for Subjects With Baseline BMI ≥ 25 kg/m2	-3.71 kg Standard Error 0.285	0.59 kg Standard Error 0.284

SECONDARY outcome

Timeframe: Baseline and 60 weeks

Least squares (LS) mean treatment difference between the bexagliflozin group and placebo group in the change of SBP in subjects with baseline SBP ≥ 140 mmHg at week 60 is analyzed using ANCOVA.

Outcome measures

Outcome measures
Measure	Bexagliflozin n=74 Participants Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride for the duration of the study. Bexagliflozin tablets: 20 mg Glimepiride capsules: Placebo, inactive capsule to match the active comparator	Glimepiride n=68 Participants Subjects will receive a glimepiride capsule, 2, 4 or 6 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study. Bexagliflozin: Placebo, inactive tablet to match the active comparator Glimepiride capsules: 2, 4 or 6 mg
Change From Baseline in Systolic Blood Pressure (SBP) at Week 60 for Subjects With Baseline SBP ≥ 140 mmHg	-13.48 mm Hg Standard Error 1.404	-6.95 mm Hg Standard Error 1.460

SECONDARY outcome

Timeframe: During the 96 week treatment period

Population: Subjects with post-baseline assessment.

The difference in proportion of subjects with ≥ 1 severe or documented symptomatic hypoglycemia events in the bexagliflozin group compared with glimepiride group over 96 weeks is analyzed using a logistic regression model. The full model included region, baseline HbA1c value, background treatment status (metformin or metformin + OHA), eGFR at baseline ≥ 90 or \< 90 mL min 1 per 1.73 m2), treatment as a fixed effect covariate.

Outcome measures

Outcome measures
Measure	Bexagliflozin n=213 Participants Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride for the duration of the study. Bexagliflozin tablets: 20 mg Glimepiride capsules: Placebo, inactive capsule to match the active comparator	Glimepiride n=212 Participants Subjects will receive a glimepiride capsule, 2, 4 or 6 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study. Bexagliflozin: Placebo, inactive tablet to match the active comparator Glimepiride capsules: 2, 4 or 6 mg
Difference in Proportion of Subjects With ≥ 1 Severe or Documented Symptomatic Hypoglycemia Events Over 96 Weeks	0.02 Proportion of participants Interval 0.01 to 0.05	0.15 Proportion of participants Interval 0.1 to 0.22

SECONDARY outcome

Timeframe: Baseline to Week 60

Population: The intention-to-treat population was used for the analysis. Subjects with a value at baseline and at week 60 were analyzed.

Superiority of bexagliflozin over glimepiride in HbA1c reduction from baseline to week 60 will be declared if the upper bound of 95% CI is less than 0.

Outcome measures

Outcome measures
Measure	Bexagliflozin n=193 Participants Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride for the duration of the study. Bexagliflozin tablets: 20 mg Glimepiride capsules: Placebo, inactive capsule to match the active comparator	Glimepiride n=191 Participants Subjects will receive a glimepiride capsule, 2, 4 or 6 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study. Bexagliflozin: Placebo, inactive tablet to match the active comparator Glimepiride capsules: 2, 4 or 6 mg
Superiority of Bexagliflozin Over Glimepiride in HbA1c Reduction at Week 60.	-0.70 percentage of glycated hemoglobin Standard Error 0.058	-0.66 percentage of glycated hemoglobin Standard Error 0.058

Adverse Events

Bexagliflozin

Serious events: 25 serious events

Other events: 98 other events

Deaths: 0 deaths

Glimepiride

Serious events: 26 serious events

Other events: 112 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Bexagliflozin n=213 participants at risk Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride for the duration of the study. Bexagliflozin tablets: 20 mg Glimepiride capsules: Placebo, inactive capsule to match the active comparator	Glimepiride n=213 participants at risk Subjects will receive a glimepiride capsule, 2, 4 or 6 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study. Bexagliflozin: Placebo, inactive tablet to match the active comparator Glimepiride capsules: 2, 4 or 6 mg
Metabolism and nutrition disorders Hypoglycemia	16.9% 36/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	33.3% 71/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Metabolism and nutrition disorders Diabetes mellitus inadequate control	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	8.0% 17/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Infections and infestations Nasopharyngitis	13.6% 29/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	13.6% 29/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Infections and infestations Urinary Tract Infection	11.7% 25/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	4.7% 10/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Infections and infestations Bronchitis	6.6% 14/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	7.5% 16/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Musculoskeletal and connective tissue disorders Back pain	2.8% 6/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	7.5% 16/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Musculoskeletal and connective tissue disorders Arthralgia	6.1% 13/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	1.9% 4/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).

Additional Information

Albert Collinson

Theracos Sub, LLC

Phone: (508) 630-2129

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Investigator has no publication right.
Publication restrictions are in place

Restriction type: OTHER

Measure	Bexagliflozin n=213 participants at risk Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride for the duration of the study. Bexagliflozin tablets: 20 mg Glimepiride capsules: Placebo, inactive capsule to match the active comparator	Glimepiride n=213 participants at risk Subjects will receive a glimepiride capsule, 2, 4 or 6 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study. Bexagliflozin: Placebo, inactive tablet to match the active comparator Glimepiride capsules: 2, 4 or 6 mg
Cardiac disorders Acute myocardial infarction	0.94% 2/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Cardiac disorders Myocardial ischemia	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.94% 2/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Cardiac disorders Acute coronary syndrome	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Cardiac disorders Angina unstable	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Cardiac disorders Bradycardia	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Cardiac disorders Cardiac failure congestive	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Cardiac disorders Myocardial infarction	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Cardiac disorders Myocarditis	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Cardiac disorders Palpitation	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Infections and infestations Pneumonia	0.94% 2/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.94% 2/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Infections and infestations Erysipelas	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Infections and infestations Otitis media chronic	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Infections and infestations Pyelonephritis acute	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Nervous system disorders Transient ischemic attack	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Nervous system disorders Carotid artery stenosis	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Nervous system disorders Cerebrovascular accident	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Nervous system disorders Ischemic stroke	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Nervous system disorders Nervous system disorder	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Nervous system disorders Thalamic infarction	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Musculoskeletal and connective tissue disorders Osteoarthritis	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Musculoskeletal and connective tissue disorders Osteochondrosis	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Musculoskeletal and connective tissue disorders Polyarthritis	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Musculoskeletal and connective tissue disorders Ankle fracture	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Musculoskeletal and connective tissue disorders Contusion	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Musculoskeletal and connective tissue disorders Muscle rupture	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Musculoskeletal and connective tissue disorders Tibia fracture	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Eye disorders Ectropion	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Eye disorders Entropion	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Eye disorders Retinal detachment	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Gastrointestinal disorders Faecaloma	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Gastrointestinal disorders Inguinal hernia	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Renal and urinary disorders Nephrolithiasis	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.94% 2/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Renal and urinary disorders Bladder disorder	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Hepatobiliary disorders Cholelithiasis	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal adenocarcinoma	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small cell lung cancer	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Reproductive system and breast disorders Genital hemorrhage	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Reproductive system and breast disorders Uterine prolapse	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Skin and subcutaneous tissue disorders Dermatitis	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Skin and subcutaneous tissue disorders Ecchymosis	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Congenital, familial and genetic disorders Phimosis	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Ear and labyrinth disorders Deafness unilateral	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
General disorders Non-cardiac chest pain	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Metabolism and nutrition disorders Hyponatremia	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
Vascular disorders Arterial occlusive disease	0.00% 0/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).	0.47% 1/213 • Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).