Trial Outcomes & Findings for Effects of Once and Twice Daily Dosing Regimen of Ertugliflozin (PF-04971729, MK-8835) In Participants With Type 2 Diabetes (MK-8835-040) (NCT NCT01054300)

Last Updated: 2019-11-21

Results Overview

Urine for analysis of glucose was collected at prespecified intervals. Each participant emptied his/her bladder just before dosing, and the collection started after the morning dose (collection times: 0-4 hours, 4-8 hours, 8-12 hours, and 12-24 hours after the morning dose). The average amount of urinary glucose excreted from 0 to 24 hours after the morning dose is presented in the table below.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

52 participants

Primary outcome timeframe

0 to 24 hours after the morning dose

Results posted on

2019-11-21

Participant Flow

Participant milestones

Participant milestones
Measure	Cohort 1: Ertu 2 mg/Pbo→Ertu 1 mg/Ertu 1 mg Period 1: Ertugliflozin (Ertu) 2 mg in the AM and placebo (Pbo) in the PM for 1 day. Period 2: Ertu 1 mg in the AM and Ertu 1 mg in the PM for 1 day. There was a \>= 7 day washout period between Period 1 and Period 2.	Cohort 1: Ertu 1 mg/Ertu 1 mg→Ertu 2 mg/Pbo Period 1: Ertu 1 mg in the AM and Ertu 1 mg in the PM for 1 day. Period 2: Ertu 2 mg in the AM and Pbo in the PM for 1 day. There was a \>= 7 day washout period between Period 1 and Period 2.	Cohort 2: Ertu 4 mg/Pbo→Ertu 2 mg/Ertu 2 mg Period 1: Ertu 4 mg in the AM and Pbo in the PM for 1 day. Period 2: Ertu 2 mg in the AM and Ertu 2 mg in the PM for 1 day. There was a \>= 7 day washout period between Period 1 and Period 2.	Cohort 2: Ertu 2 mg/Ertu 2 mg→Ertu 4 mg/P Period 1: Ertu 2 mg in the AM and Ertu 2 mg in the PM for 1 day. Period 2: Ertu 4 mg in the AM and Pbo in the PM for 1 day. There was a \>= 7 day washout period between Period 1 and Period 2.
Period 1 STARTED	13	13	13	13
Period 1 COMPLETED	12	13	13	13
Period 1 NOT COMPLETED	1	0	0	0
Period 2 STARTED	12	13	13	13
Period 2 COMPLETED	12	13	12	13
Period 2 NOT COMPLETED	0	0	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1: Ertu 2 mg/Pbo→Ertu 1 mg/Ertu 1 mg Period 1: Ertugliflozin (Ertu) 2 mg in the AM and placebo (Pbo) in the PM for 1 day. Period 2: Ertu 1 mg in the AM and Ertu 1 mg in the PM for 1 day. There was a \>= 7 day washout period between Period 1 and Period 2.	Cohort 1: Ertu 1 mg/Ertu 1 mg→Ertu 2 mg/Pbo Period 1: Ertu 1 mg in the AM and Ertu 1 mg in the PM for 1 day. Period 2: Ertu 2 mg in the AM and Pbo in the PM for 1 day. There was a \>= 7 day washout period between Period 1 and Period 2.	Cohort 2: Ertu 4 mg/Pbo→Ertu 2 mg/Ertu 2 mg Period 1: Ertu 4 mg in the AM and Pbo in the PM for 1 day. Period 2: Ertu 2 mg in the AM and Ertu 2 mg in the PM for 1 day. There was a \>= 7 day washout period between Period 1 and Period 2.	Cohort 2: Ertu 2 mg/Ertu 2 mg→Ertu 4 mg/P Period 1: Ertu 2 mg in the AM and Ertu 2 mg in the PM for 1 day. Period 2: Ertu 4 mg in the AM and Pbo in the PM for 1 day. There was a \>= 7 day washout period between Period 1 and Period 2.
Period 1 Adverse Event	1	0	0	0
Period 2 Withdrawal by Subject	0	0	1	0

Baseline Characteristics

Effects of Once and Twice Daily Dosing Regimen of Ertugliflozin (PF-04971729, MK-8835) In Participants With Type 2 Diabetes (MK-8835-040)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 n=26 Participants Period 1: participants received a total daily dose of ertugliflozin 2 mg for 1 day; Period 2: participants received a total daily dose of ertugliflozin 2 mg for 1 day	Cohort 2 n=26 Participants Period 1: participants received a total daily dose of ertugliflozin 4 mg; Period 2: participants received a total daily dose of ertugliflozin 4 mg for 1 day	Total n=52 Participants Total of all reporting groups
Age, Customized 18 - 44 years	7 Participants n=5 Participants	7 Participants n=7 Participants	14 Participants n=5 Participants
Age, Customized 45 - 64 years	17 Participants n=5 Participants	18 Participants n=7 Participants	35 Participants n=5 Participants
Age, Customized 65 years or older	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Sex: Female, Male Male	22 Participants n=5 Participants	23 Participants n=7 Participants	45 Participants n=5 Participants

PRIMARY outcome

Timeframe: 0 to 24 hours after the morning dose

Population: Analysis population included randomized participants who received assigned dose and had urine collection during all of the collection time frames between 0 and 24 hours following the morning dose.

Outcome measures

Outcome measures
Measure	Cohort 1: Ertugliflozin 1 mg Twice Daily n=25 Participants Participants received ertugliflozin 1 mg twice daily for 1 day	Cohort 1: Ertugliflozin 2 mg Once Daily n=25 Participants Participants received ertugliflozin 2 mg once daily for 1 day	Cohort 2: Ertugliflozin 2 mg Twice Daily n=24 Participants Participants received ertugliflozin 2 mg twice daily for 1 day	Cohort 2: Ertugliflozin 4 mg Once Daily n=24 Participants Participants received ertugliflozin 4 mg once daily for 1 day
Cumulative Urinary Glucose Excretion Over 0 to 24 Hours	69.45 Grams 90% Confidence Interval 9.08 • Interval 54.2 to 84.7	70.43 Grams 90% Confidence Interval 9.08 • Interval 55.19 to 85.68	78.29 Grams 90% Confidence Interval 9.77 • Interval 61.87 to 94.72	80.54 Grams 90% Confidence Interval 9.81 • Interval 64.05 to 97.02

PRIMARY outcome

Timeframe: At 0-4 hrs, 4-8 hrs, 8-12 hrs, and 12-24 hrs after the AM dose (up to 24 hours)

Population: Analysis population included randomized participants who received assigned dose and had urine collection during the specific time frame.

Urine for analysis of glucose was collected at prespecified intervals. Each participant emptied his/her bladder just before dosing, and the collection started after the morning dose (collection times: 0-4 hours, 4-8 hours, 8-12 hours, and 12-24 hours after the morning dose). The average amount of urinary glucose excreted during the pre-specified time frame is presented in the table below.

Outcome measures

Outcome measures
Measure	Cohort 1: Ertugliflozin 1 mg Twice Daily n=25 Participants Participants received ertugliflozin 1 mg twice daily for 1 day	Cohort 1: Ertugliflozin 2 mg Once Daily n=26 Participants Participants received ertugliflozin 2 mg once daily for 1 day	Cohort 2: Ertugliflozin 2 mg Twice Daily n=25 Participants Participants received ertugliflozin 2 mg twice daily for 1 day	Cohort 2: Ertugliflozin 4 mg Once Daily n=26 Participants Participants received ertugliflozin 4 mg once daily for 1 day
Urinary Glucose Excretion by Time Period 0 to 4 hours post dose	12.88 Grams Standard Deviation 14.66	14.03 Grams Standard Deviation 11.63	14.66 Grams Standard Deviation 11.81	16.34 Grams Standard Deviation 10.16
Urinary Glucose Excretion by Time Period 4 to 8 hours post dose	15.42 Grams Standard Deviation 12.00	17.87 Grams Standard Deviation 12.60	16.97 Grams Standard Deviation 11.64	19.78 Grams Standard Deviation 14.02
Urinary Glucose Excretion by Time Period 8 to 12 hours post dose	14.47 Grams Standard Deviation 8.84	11.99 Grams Standard Deviation 7.70	14.30 Grams Standard Deviation 10.52	12.91 Grams Standard Deviation 6.93
Urinary Glucose Excretion by Time Period 12 to 24 hours post dose	26.76 Grams Standard Deviation 20.10	26.31 Grams Standard Deviation 21.11	31.47 Grams Standard Deviation 22.71	32.94 Grams Standard Deviation 21.08

PRIMARY outcome

Timeframe: Up to 24 hours

Population: Analysis population included randomized participants who received study drug and had mean plasma glucose measurements during all of the specific collection time frames.

Blood was collected during each treatment period at pre-dose (fasted) on Day 1 (Hour 0) and post-dose (fed) on Day 1 at 0.5, 1, 2, 3, 4, 5, 5.5, 6, 7, 8, 10, 12, 12.5, 13, 14, 15, 16, 18, and 24 hours.

Outcome measures

Outcome measures
Measure	Cohort 1: Ertugliflozin 1 mg Twice Daily n=23 Participants Participants received ertugliflozin 1 mg twice daily for 1 day	Cohort 1: Ertugliflozin 2 mg Once Daily n=25 Participants Participants received ertugliflozin 2 mg once daily for 1 day	Cohort 2: Ertugliflozin 2 mg Twice Daily n=23 Participants Participants received ertugliflozin 2 mg twice daily for 1 day	Cohort 2: Ertugliflozin 4 mg Once Daily n=24 Participants Participants received ertugliflozin 4 mg once daily for 1 day
24-hour Weighted Mean Plasma Glucose	173.6 mg/dL Standard Deviation 26.94	175.7 mg/dL Standard Deviation 29.88	169.1 mg/dL Standard Deviation 35.91	170.4 mg/dL Standard Deviation 41.26

PRIMARY outcome

Timeframe: At 0-5 hours, 5-12 hrs, and 12-18 hrs after the morning dose (up to 18 hours)

Population: Analysis population included randomized participants who received assigned dose and had postprandial plasma glucose measurements during the specific time frame.

The weighted mean postprandial glucose over the specified intervals were analyzed by cohort.

Outcome measures

Outcome measures
Measure	Cohort 1: Ertugliflozin 1 mg Twice Daily n=25 Participants Participants received ertugliflozin 1 mg twice daily for 1 day	Cohort 1: Ertugliflozin 2 mg Once Daily n=26 Participants Participants received ertugliflozin 2 mg once daily for 1 day	Cohort 2: Ertugliflozin 2 mg Twice Daily n=25 Participants Participants received ertugliflozin 2 mg twice daily for 1 day	Cohort 2: Ertugliflozin 4 mg Once Daily n=25 Participants Participants received ertugliflozin 4 mg once daily for 1 day
Weighted Mean Postprandial Plasma Glucose 0 to 5 hours	200.1 mg/dL Standard Deviation 38.27	187.2 mg/dL Standard Deviation 41.37	194.1 mg/dL Standard Deviation 46.87	189.9 mg/dL Standard Deviation 53.17
Weighted Mean Postprandial Plasma Glucose 5 to 12 hours	159.4 mg/dL Standard Deviation 25.76	159.8 mg/dL Standard Deviation 28.46	160.5 mg/dL Standard Deviation 42.14	161.5 mg/dL Standard Deviation 40.70
Weighted Mean Postprandial Plasma Glucose 12 to 18 hours	180.7 mg/dL Standard Deviation 35.98	190.7 mg/dL Standard Deviation 35.38	182.6 mg/dL Standard Deviation 40.79	181.9 mg/dL Standard Deviation 40.79

PRIMARY outcome

Timeframe: Up to 24 hours

Population: The protocol listed fasting plasma glucose as one of the endpoints of the study. However, given the assessment of weighted mean 24-hour plasma glucose and weighted mean postprandial glucose following the 3 meals on Day 1 of each period, analysis of fasting plasma glucose was not undertaken.

Blood samples were to be collected following a fast from all food and drink (except water) for at least 8 hours. Fasting Plasma Glucose was collected as part of the assessment of weighted mean 24-hour plasma glucose. As such, it was not specified as an endpoint in the Statistical Analysis Plan and was not analyzed or summarized separately.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Up to 24 hours (0 and 24 hours)

Population: Analysis population included randomized participants who received assigned dose and had fasting c-peptide measurements during the specific time frame.

The fasting c-peptide was analyzed by cohort using a mixed-effects model with sequence, period, and treatment as fixed effects and participant within sequence as a random effect.

Outcome measures

Outcome measures
Measure	Cohort 1: Ertugliflozin 1 mg Twice Daily n=25 Participants Participants received ertugliflozin 1 mg twice daily for 1 day	Cohort 1: Ertugliflozin 2 mg Once Daily n=26 Participants Participants received ertugliflozin 2 mg once daily for 1 day	Cohort 2: Ertugliflozin 2 mg Twice Daily n=25 Participants Participants received ertugliflozin 2 mg twice daily for 1 day	Cohort 2: Ertugliflozin 4 mg Once Daily n=26 Participants Participants received ertugliflozin 4 mg once daily for 1 day
Fasting C-peptide	2.82 ng/mL 90% Confidence Interval 1.148 • Interval 2.54 to 3.11	2.76 ng/mL 90% Confidence Interval 0.997 • Interval 2.47 to 3.04	3.00 ng/mL 90% Confidence Interval 0.916 • Interval 2.64 to 3.35	2.99 ng/mL 90% Confidence Interval 0.973 • Interval 2.64 to 3.34

PRIMARY outcome

Timeframe: Up to 16 days

Population: Analysis population includes all treated participants.

Outcome measures

Outcome measures
Measure	Cohort 1: Ertugliflozin 1 mg Twice Daily n=25 Participants Participants received ertugliflozin 1 mg twice daily for 1 day	Cohort 1: Ertugliflozin 2 mg Once Daily n=26 Participants Participants received ertugliflozin 2 mg once daily for 1 day	Cohort 2: Ertugliflozin 2 mg Twice Daily n=26 Participants Participants received ertugliflozin 2 mg twice daily for 1 day	Cohort 2: Ertugliflozin 4 mg Once Daily n=26 Participants Participants received ertugliflozin 4 mg once daily for 1 day
Number of Participants Experiencing an Adverse Event	5 Participants	8 Participants	3 Participants	5 Participants

PRIMARY outcome

Timeframe: Up to 8 days (Day 1 in each dosing period)

Population: Analysis population includes all treated participants.

An adverse event is any untoward medical occurrence in a clinical investigation participant administered a product or medical device. The table below includes all data collected since the first dose of study drug. Data include participants discontinued due to adverse events, participants with dose reduced or temporary discontinuation due to adverse events.

Outcome measures

Outcome measures
Measure	Cohort 1: Ertugliflozin 1 mg Twice Daily n=25 Participants Participants received ertugliflozin 1 mg twice daily for 1 day	Cohort 1: Ertugliflozin 2 mg Once Daily n=26 Participants Participants received ertugliflozin 2 mg once daily for 1 day	Cohort 2: Ertugliflozin 2 mg Twice Daily n=26 Participants Participants received ertugliflozin 2 mg twice daily for 1 day	Cohort 2: Ertugliflozin 4 mg Once Daily n=26 Participants Participants received ertugliflozin 4 mg once daily for 1 day
Number of Participants Discontinuing Study Drug Due to an Adverse Event	0 Participants	1 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: 0 predose, 0.5, 1, 2, 3, 4, 5, 5.5, 6, 7, 8, 10, 12, 18, 24 hours postdose

Population: All participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

Pharmacokinetic (PK) parameter of AUClast for study drug. Actual sample collection times (relative to the AM dose) were used for the pharmacokinetic analysis.

Outcome measures

Outcome measures
Measure	Cohort 1: Ertugliflozin 1 mg Twice Daily n=25 Participants Participants received ertugliflozin 1 mg twice daily for 1 day	Cohort 1: Ertugliflozin 2 mg Once Daily n=26 Participants Participants received ertugliflozin 2 mg once daily for 1 day	Cohort 2: Ertugliflozin 2 mg Twice Daily n=25 Participants Participants received ertugliflozin 2 mg twice daily for 1 day	Cohort 2: Ertugliflozin 4 mg Once Daily n=26 Participants Participants received ertugliflozin 4 mg once daily for 1 day
Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration (AUClast) for Ertugliflozin	131.8 ng*hr/mL Geometric Coefficient of Variation 26	132.7 ng*hr/mL Geometric Coefficient of Variation 28	272 ng*hr/mL Geometric Coefficient of Variation 19	270.5 ng*hr/mL Geometric Coefficient of Variation 20

PRIMARY outcome

Timeframe: 0 predose, 0.5, 1, 2, 3, 4, 5, 5.5, 6, 7, 8, 10, 12, 18, 24 hours postdose

Population: All participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

PK parameter of Cmax for study drug. Actual sample collection times (relative to the AM dose) were used for the pharmacokinetic analysis.

Outcome measures

Outcome measures
Measure	Cohort 1: Ertugliflozin 1 mg Twice Daily n=25 Participants Participants received ertugliflozin 1 mg twice daily for 1 day	Cohort 1: Ertugliflozin 2 mg Once Daily n=26 Participants Participants received ertugliflozin 2 mg once daily for 1 day	Cohort 2: Ertugliflozin 2 mg Twice Daily n=25 Participants Participants received ertugliflozin 2 mg twice daily for 1 day	Cohort 2: Ertugliflozin 4 mg Once Daily n=26 Participants Participants received ertugliflozin 4 mg once daily for 1 day
Maximum Plasma Concentration (Cmax) of Ertugliflozin	19.51 ng/mL Geometric Coefficient of Variation 39	26.98 ng/mL Geometric Coefficient of Variation 37	34.80 ng/mL Geometric Coefficient of Variation 23	50.83 ng/mL Geometric Coefficient of Variation 25

PRIMARY outcome

Timeframe: 0 predose, 0.5, 1, 2, 3, 4, 5, 5.5, 6, 7, 8, 10, 12, 18, 24 hours postdose

Population: All participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

PK parameter of Tmax for study drug. Actual sample collection times (relative to the AM dose) were used for the pharmacokinetic analysis.

Outcome measures

Outcome measures
Measure	Cohort 1: Ertugliflozin 1 mg Twice Daily n=25 Participants Participants received ertugliflozin 1 mg twice daily for 1 day	Cohort 1: Ertugliflozin 2 mg Once Daily n=26 Participants Participants received ertugliflozin 2 mg once daily for 1 day	Cohort 2: Ertugliflozin 2 mg Twice Daily n=25 Participants Participants received ertugliflozin 2 mg twice daily for 1 day	Cohort 2: Ertugliflozin 4 mg Once Daily n=26 Participants Participants received ertugliflozin 4 mg once daily for 1 day
Time Taken to Reach the Maximum Observed Plasma Concentration (Tmax) of Ertugliflozin	6.00 hours Interval 0.5 to 12.0	1.00 hours Interval 0.5 to 5.5	6.00 hours Interval 0.5 to 8.0	1.00 hours Interval 0.5 to 6.0

Adverse Events

Cohort 1: Ertugliflozin 1 mg Twice Daily

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Cohort 1: Ertugliflozin 2 mg Once Daily

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Cohort 2: Ertugliflozin 2 mg Twice Daily

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Cohort 2: Ertugliflozin 4 mg Once Daily

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Institution will provide manuscripts, abstracts, or the full text of any other intended disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer at least 30 days before they are submitted for publication or otherwise disclosed. If any patent action is required to protect intellectual property rights, Institution agrees to delay the disclosure for a period not to exceed an additional 60 days.
Publication restrictions are in place

Restriction type: OTHER

Measure	Cohort 1: Ertugliflozin 1 mg Twice Daily n=25 participants at risk Participants received ertugliflozin 1 mg twice daily for 1 day	Cohort 1: Ertugliflozin 2 mg Once Daily n=26 participants at risk Participants received ertugliflozin 2 mg once daily for 1 day	Cohort 2: Ertugliflozin 2 mg Twice Daily n=26 participants at risk Participants received ertugliflozin 2 mg twice daily for 1 day	Cohort 2: Ertugliflozin 4 mg Once Daily n=26 participants at risk Participants received ertugliflozin 4 mg once daily for 1 day
Eye disorders Eye pain	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
Eye disorders Vision blurred	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
Gastrointestinal disorders Abdominal pain	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)
Gastrointestinal disorders Constipation	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
Gastrointestinal disorders Diarrhoea	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	11.5% 3/26 • Number of events 3 • Up to 16 days (including 7-day follow-up for each period)
Gastrointestinal disorders Dry mouth	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
Gastrointestinal disorders Dyspepsia	4.0% 1/25 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
Gastrointestinal disorders Flatulence	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
Gastrointestinal disorders Nausea	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)
Gastrointestinal disorders Vomitting	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
General disorders Fatigue	4.0% 1/25 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
Infections and infestations Wound infection	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)
Metabolism and nutrition disorders Increased appetite	4.0% 1/25 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
Musculoskeletal and connective tissue disorders Back pain	4.0% 1/25 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
Musculoskeletal and connective tissue disorders Pain in extremity	4.0% 1/25 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
Nervous system disorders Dizziness	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
Nervous system disorders Headache	12.0% 3/25 • Number of events 3 • Up to 16 days (including 7-day follow-up for each period)	11.5% 3/26 • Number of events 3 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	7.7% 2/26 • Number of events 2 • Up to 16 days (including 7-day follow-up for each period)
Nervous system disorders Presyncope	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
Renal and urinary disorders Pollakiuria	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)
Respiratory, thoracic and mediastinal disorders Postnasal drip	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)
Skin and subcutaneous tissue disorders Ecchymosis	0.00% 0/25 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	3.8% 1/26 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)
Skin and subcutaneous tissue disorders Skin irritation	4.0% 1/25 • Number of events 1 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)	0.00% 0/26 • Up to 16 days (including 7-day follow-up for each period)