Trial Outcomes & Findings for Assessing the Effect of Met DR on Plasma Glucose and PK in Subjects With T2DM (NCT NCT01804842)

Last Updated: 2016-10-21

Results Overview

AUC (0-24) = Area under the curve from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

26 participants

Primary outcome timeframe

Times points to create the AUC (0-24) were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner.

Results posted on

2016-10-21

Participant Flow

Participant milestones

Participant milestones
Measure	Sequence 1: ABC Treatment A = 1000 mg Met DR qAM Treatment B = 1000 mg Met DR qPM Treatment C = 500 mg Met DR BID	Sequence 2: BCA Treatment A = 1000 mg Met DR qAM Treatment B = 1000 mg Met DR qPM Treatment C = 500 mg Met DR BID	Sequence 3: CAB Treatment A = 1000 mg Met DR qAM Treatment B = 1000 mg Met DR qPM Treatment C = 500 mg Met DR BID
Overall Study STARTED	9	8	9
Overall Study Completed Treatment A	9	6	8
Overall Study Completed Treatment B	8	8	8
Overall Study Completed Treatment C	7	7	9
Overall Study COMPLETED	6	6	8
Overall Study NOT COMPLETED	3	2	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Sequence 1: ABC Treatment A = 1000 mg Met DR qAM Treatment B = 1000 mg Met DR qPM Treatment C = 500 mg Met DR BID	Sequence 2: BCA Treatment A = 1000 mg Met DR qAM Treatment B = 1000 mg Met DR qPM Treatment C = 500 mg Met DR BID	Sequence 3: CAB Treatment A = 1000 mg Met DR qAM Treatment B = 1000 mg Met DR qPM Treatment C = 500 mg Met DR BID
Overall Study Adverse Event	1	1	0
Overall Study Lost to Follow-up	1	0	0
Overall Study Non-Compliance	1	1	0
Overall Study Personal Reason	0	0	1

Baseline Characteristics

Assessing the Effect of Met DR on Plasma Glucose and PK in Subjects With T2DM

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sequence 1: ABC n=9 Participants Treatment A = 1000 mg Met DR qAM Treatment B = 1000 mg Met DR qPM Treatment C = 500 mg Met DR BID	Sequence 2: BCA n=8 Participants Treatment A = 1000 mg Met DR qAM Treatment B = 1000 mg Met DR qPM Treatment C = 500 mg Met DR BID	Sequence 3: CAB n=9 Participants Treatment A = 1000 mg Met DR qAM Treatment B = 1000 mg Met DR qPM Treatment C = 500 mg Met DR BID	Total n=26 Participants Total of all reporting groups
Age, Continuous	51.2 years STANDARD_DEVIATION 11.73 • n=5 Participants	51.9 years STANDARD_DEVIATION 13.47 • n=7 Participants	49.7 years STANDARD_DEVIATION 8.49 • n=5 Participants	50.9 years STANDARD_DEVIATION 10.90 • n=4 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	6 Participants n=7 Participants	4 Participants n=5 Participants	16 Participants n=4 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants	10 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	7 Participants n=5 Participants	6 Participants n=7 Participants	5 Participants n=5 Participants	18 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	8 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants	8 Participants n=7 Participants	8 Participants n=5 Participants	24 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
BMI	32.3 kg/m^2 STANDARD_DEVIATION 3.73 • n=5 Participants	31.6 kg/m^2 STANDARD_DEVIATION 3.93 • n=7 Participants	30.7 kg/m^2 STANDARD_DEVIATION 1.58 • n=5 Participants	31.5 kg/m^2 STANDARD_DEVIATION 3.17 • n=4 Participants
Diabetes Management Diet and Exercise Only	1 participants n=5 Participants	4 participants n=7 Participants	2 participants n=5 Participants	7 participants n=4 Participants
Diabetes Management Metformin Alone	7 participants n=5 Participants	3 participants n=7 Participants	7 participants n=5 Participants	17 participants n=4 Participants
Diabetes Management Metformin and DPP-4 Inhibitors	1 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	2 participants n=4 Participants
Fasting Serum Glucose	161.2 mg/dL STANDARD_DEVIATION 29.94 • n=5 Participants	177.6 mg/dL STANDARD_DEVIATION 84.17 • n=7 Participants	165.0 mg/dL STANDARD_DEVIATION 54.02 • n=5 Participants	167.6 mg/dL STANDARD_DEVIATION 57.04 • n=4 Participants
HbA1c	7.34 % STANDARD_DEVIATION 1.038 • n=5 Participants	7.13 % STANDARD_DEVIATION 1.107 • n=7 Participants	7.36 % STANDARD_DEVIATION 1.022 • n=5 Participants	7.28 % STANDARD_DEVIATION 1.017 • n=4 Participants

PRIMARY outcome

Timeframe: Times points to create the AUC (0-24) were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner.

Population: Evaluable Population

Outcome measures

Outcome measures
Measure	500 mg Met DR BID n=12 Participants Two doses of 500 mg metformin delayed-release Met DR: metformin delayed-release tablets	1000 mg Met DR qAM n=12 Participants One dose of 1000 mg metformin delayed-release in the morning Met DR: metformin delayed-release tablets	1000 mg Met DR qPM n=12 Participants One dose of 1000 mg metformin delayed-release in the evening Met DR: metformin delayed-release tablets
AUC (0-24) of Plasma Metformin	7771 ng*h/mL Standard Error 619	5559 ng*h/mL Standard Error 433	7757 ng*h/mL Standard Error 604

PRIMARY outcome

Timeframe: Times points to determine Cmax were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner.

Population: Evaluable Population

Cmax = maximum response from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C.

Outcome measures

Outcome measures
Measure	500 mg Met DR BID n=12 Participants Two doses of 500 mg metformin delayed-release Met DR: metformin delayed-release tablets	1000 mg Met DR qAM n=12 Participants One dose of 1000 mg metformin delayed-release in the morning Met DR: metformin delayed-release tablets	1000 mg Met DR qPM n=12 Participants One dose of 1000 mg metformin delayed-release in the evening Met DR: metformin delayed-release tablets
Cmax of Plasma Metformin	780 ng/mL Standard Error 71.7	868 ng/mL Standard Error 79.8	1035 ng/mL Standard Error 95.2

PRIMARY outcome

Timeframe: Times points to create the AUC (0-24) were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.75, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 18.5, 19, 19.5, 20, 21, 22, 23, and 24 hours relative to the time of the standardized dinner.

Population: Evaluable Population

Outcome measures

Outcome measures
Measure	500 mg Met DR BID n=12 Participants Two doses of 500 mg metformin delayed-release Met DR: metformin delayed-release tablets	1000 mg Met DR qAM n=12 Participants One dose of 1000 mg metformin delayed-release in the morning Met DR: metformin delayed-release tablets	1000 mg Met DR qPM n=12 Participants One dose of 1000 mg metformin delayed-release in the evening Met DR: metformin delayed-release tablets
AUC (0-24) of Plasma Glucose Pre-Treatment	4668 mg*h/dL Standard Error 581	4947 mg*h/dL Standard Error 615	4961 mg*h/dL Standard Error 617
AUC (0-24) of Plasma Glucose On-Treatment	4438 mg*h/dL Standard Error 552	4503 mg*h/dL Standard Error 560	4509 mg*h/dL Standard Error 561

PRIMARY outcome

Timeframe: Times points to determine Rmax were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.75, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 18.5, 19, 19.5, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner.

Population: Evaluable Population

Rmax (0-24) = maximum response from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C.

Outcome measures

Outcome measures
Measure	500 mg Met DR BID n=12 Participants Two doses of 500 mg metformin delayed-release Met DR: metformin delayed-release tablets	1000 mg Met DR qAM n=12 Participants One dose of 1000 mg metformin delayed-release in the morning Met DR: metformin delayed-release tablets	1000 mg Met DR qPM n=12 Participants One dose of 1000 mg metformin delayed-release in the evening Met DR: metformin delayed-release tablets
Rmax (0-24) of Plasma Glucose Pre-Treatment	279 mg/dL Standard Error 29.9	290 mg/dL Standard Error 31.1	302 mg/dL Standard Error 32.4
Rmax (0-24) of Plasma Glucose On-Treatment	263 mg/dL Standard Error 28.2	262 mg/dL Standard Error 28.1	273 mg/dL Standard Error 29.4

Adverse Events

1000 mg Met DR qAM

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

1000 mg Met DR qPM

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

500 mg Met DR BID

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Senior Director, Development

Elcelyx Therapeutics, Inc

Phone: 858-876-1814

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The results of the Study may be published by INSTITUTE, however the publication shall not disclose any SPONSOR Confidential Information, the INSTITUTE shall send the SPONSOR a copy of any such proposed publication 90 days prior to submission for publication, the INSTITUTE, on request of the SPONSOR, shall delete any SPONSOR Confidential Information in the proposed publication, and the INSTITUTE shall, on the SPONSOR's request, delay submission while the SPONSOR files applications for patents.
Publication restrictions are in place

Restriction type: OTHER

Measure	1000 mg Met DR qAM n=23 participants at risk One dose of 1000 mg metformin delayed-release in the morning Met DR: metformin delayed-release tablets	1000 mg Met DR qPM n=24 participants at risk One dose of 1000 mg metformin delayed-release in the evening Met DR: metformin delayed-release tablets	500 mg Met DR BID n=23 participants at risk Two doses of 500 mg metformin delayed-release Met DR: metformin delayed-release tablets
Renal and urinary disorders Urine Odour Abnormal	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Reproductive system and breast disorders Pruritus Genital	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Vascular disorders Pallor	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Cardiac disorders Palpitations	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Gastrointestinal disorders Abdominal Pain	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Gastrointestinal disorders Breath Odour	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Gastrointestinal disorders Constipation	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.2% 1/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Gastrointestinal disorders Diarrhoea	8.7% 2/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Gastrointestinal disorders Dry Mouth	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Gastrointestinal disorders Dyspepsia	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.2% 1/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Gastrointestinal disorders Nausea	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	8.7% 2/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Gastrointestinal disorders Vomiting	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	8.7% 2/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
General disorders Fatigue	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.2% 1/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
General disorders Thirst	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.2% 1/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
General disorders Vessel Puncture Site Bruise	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.2% 1/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
General disorders Vessel Puncture Site Pain	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	8.7% 2/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
General disorders Vessel Puncture Site Swelling	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Infections and infestations Urinary Tract Infection	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.2% 1/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Investigations Glomerular Filtration Rate Decreased	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Investigations Haemoglobin Decreased	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Nervous system disorders Dizziness	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Nervous system disorders Dizziness Postural	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Nervous system disorders Headache	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Nervous system disorders Presyncope	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Nervous system disorders Tremor	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.3% 1/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Psychiatric disorders Anxiety	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.2% 1/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.
Renal and urinary disorders Urinary Incontinence	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	4.2% 1/24 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.	0.00% 0/23 • Approximately 36 to 91 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment periods.