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Clinical Trial Results:
A 26-Week, Multicentre, Randomised, Placebo-Controlled, Double-Blind, Parallel-Group, Phase III Trial with a 26-Week Safety Extension Period Evaluating the Safety and Efficacy of Dapagliflozin 5 and 10 mg, and Saxagliptin 2.5 and 5 mg in Paediatric Patients with Type 2 Diabetes Mellitus Who Are Between 10 and Below 18 Years of Age

Summary
EudraCT number	2015-005042-66
Trial protocol	FI GB PL IT RO
Global end of trial date	03 Jan 2024

Results information
Results version number	v1(current)
This version publication date	19 Jun 2024
First version publication date	19 Jun 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

D1680C00019

ISRCTN number

US NCT number

NCT03199053

WHO universal trial number (UTN)

Sponsor organisation name

AstraZeneca

Sponsor organisation address

One Medimmune Way, Gaithersburg, United States, MD 20878

Public contact

Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com

Scientific contact

Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

03 Jan 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

03 Jan 2024

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study was to determine if there was a greater mean reduction from Baseline in HbA1c achieved after 26 weeks of oral double-blind add-on therapy of dapagliflozin (5 mg or 10 mg [all doses and regimens combined]) or saxagliptin (2.5 mg or 5 mg [all doses and regimens combined]) compared to placebo in paediatric patients with type 2 diabetes mellitus (T2DM) and HbA1c levels of 6.5 to 10.5% on diet and exercise and metformin (IR or XR), insulin, or metformin (IR or XR) plus insulin.

Protection of trial subjects

This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Conference on Harmonisation/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca policy on Bioethics.

Background therapy

Evidence for comparator

Participants were randomised to receive dapagliflozin 5 mg or saxagliptin 2.5 mg (low-dose) or placebo administered orally once daily. At Week 14, participants initially randomised to dapagliflozin or saxagliptin with Week 12 glycated haemoglobin (HbA1c) values < 7% remained on low-dose dapagliflozin or saxagliptin. Participants with Week 12 HbA1c values ≥ 7% were re-randomised in a 1:1 ratio to continue on low-dose treatment or to uptitrate to dapagliflozin 10 mg or saxagliptin 5 mg administered orally once daily (high-dose). At Week 14, all participants randomised to placebo continued on placebo. To maintain blinding, all participants underwent a dummy second randomisation process that was undistinguishable from the actual second randomisation.

Actual start date of recruitment

11 Oct 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

12 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 1

Country: Number of subjects enrolled

Australia: 1

Country: Number of subjects enrolled

Brazil: 14

Country: Number of subjects enrolled

Colombia: 2

Country: Number of subjects enrolled

Finland: 1

Country: Number of subjects enrolled

India: 10

Country: Number of subjects enrolled

Israel: 7

Country: Number of subjects enrolled

Italy: 9

Country: Number of subjects enrolled

Malaysia: 31

Country: Number of subjects enrolled

Mexico: 80

Country: Number of subjects enrolled

New Zealand: 5

Country: Number of subjects enrolled

Philippines: 6

Country: Number of subjects enrolled

Poland: 2

Country: Number of subjects enrolled

Russian Federation: 2

Country: Number of subjects enrolled

Korea, Republic of: 7

Country: Number of subjects enrolled

Taiwan: 5

Country: Number of subjects enrolled

Thailand: 3

Country: Number of subjects enrolled

Türkiye: 14

Country: Number of subjects enrolled

Ukraine: 4

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

United States: 37

Worldwide total number of subjects

245

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

235

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A total of 245 participants were randomised from 94 sites in 21 countries. Participants were initially randomised in a 1:1:1 ratio to receive dapagliflozin 5 mg, saxagliptin 2.5 mg, or placebo. 11 participants were excluded from analysis due to GCP considerations at the site they originated from (see limitations and caveats for further details).

Screening details

An initial 26-week short-term (ST) period was followed by a 26-week long-term (LT) safety extension period. The study drug was discontinued at Week 52, after which participant continued in the Non-treatment Follow-up Period until Week 104.

Period 1 title

ST Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Subject

Are arms mutually exclusive

Yes

Dapagliflozin

Arm description

Participants were randomised to receive dapagliflozin administered orally once daily in the ST treatment period. In the LT treatment period, participants who were receiving background medication with insulin only or insulin and metformin (not eligible for the third randomisation) continued with their randomised study drug assigned after the second randomisation. A subset of eligible participants (on background treatment with metformin only and who had HbA1c < 7.5% at Week 26 or Week 32) were grouped into 2 separate strata for saxagliptin and dapagliflozin, and then randomised 1:1 within each of the strata to either continue or discontinue background medication with metformin at either Week 32 or Week 40. For participants randomised to withdraw background treatment with metformin, those receiving high-dose treatment continued to receive high-dose treatment, whereas those currently receiving low-dose treatment had their doses uptitrated to high-dose treatment.

Arm type

Experimental

Investigational medicinal product name

Dapagliflozin

Investigational medicinal product code

Other name

Forxiga

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Tablets, oral, once daily.

Saxagliptin

Arm description

Participants were randomised to receive saxagliptin administered orally once daily in the ST treatment period. In the LT treatment period, participants who were receiving background medication with insulin only or insulin and metformin (not eligible for the third randomisation) continued with their randomised study drug assigned after the second randomisation. A subset of eligible participants (on background treatment with metformin only and who had HbA1c < 7.5% at Week 26 or Week 32) were grouped into 2 separate strata for saxagliptin and dapagliflozin, and then randomised 1:1 within each of the strata to either continue or discontinue background medication with metformin at either Week 32 or Week 40. For participants randomised to withdraw background treatment with metformin, those receiving high-dose treatment continued to receive high-dose treatment, whereas those currently receiving low-dose treatment had their doses uptitrated to high-dose treatment.

Arm type

Experimental

Investigational medicinal product name

Saxagliptin

Investigational medicinal product code

Other name

Onglyza

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Tablets, oral, once daily.

Placebo

Arm description

Participants were randomised to receive placebo administered orally once daily in the ST treatment period. In the LT treatment period, participants who were receiving background medication with insulin only or insulin and metformin (not eligible for the third randomisation) continued with their randomised study drug assigned after the second randomisation. At either Week 32 or Week 40 eligible participants receiving placebo (on background treatment with metformin only and who had HbA1c < 7.5% at Week 26 or Week 32) were randomised 1:1:1 to either withdraw background medication with metformin and switch to active treatment with either saxagliptin 5 mg or dapagliflozin 10 mg or to remain on background medication with metformin and continue with placebo.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Tablets, oral, once daily.

Number of subjects in period 1	Dapagliflozin	Saxagliptin	Placebo
Started	81	88	76
Week 14 no uptitration randomisation	39 ^[1]	36 ^[2]	0 ^[3]
Week 14 uptitration randomisation	42 ^[4]	52 ^[5]	0 ^[6]
Completed	76	83	68
Not completed	5	5	8
Consent withdrawn by subject	2	4	6
Lost to follow-up	2	-	1
Withdrawal by parent/guardian	1	1	1

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Inclusive of participants that were eligible for background medication discontinuation only.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Inclusive of participants that were not eligible for background medication discontinuation only.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Eligible participants were randomised 1:1:1 to either withdraw background medication with metformin and switch to active treatment with either saxagliptin 5 mg or dapagliflozin 10 mg or to remain on background medication with metformin and continue with placebo.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Inclusive of participants that were not eligible for background medication discontinuation only.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Inclusive of participants that were eligible for background medication discontinuation only.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Inclusive of participants that were eligible for background medication discontinuation only.

Period 2 title

LT Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Dapagliflozin

Arm description

Arm type

Experimental

Investigational medicinal product name

Dapagliflozin

Investigational medicinal product code

Other name

Forxiga

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Tablets, oral, once daily.

Saxagliptin

Arm description

Arm type

Experimental

Investigational medicinal product name

Saxagliptin

Investigational medicinal product code

Other name

Onglyza

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Tablets, oral, once daily.

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Tablets, oral, once daily.

Investigational medicinal product name

Saxagliptin

Investigational medicinal product code

Other name

Onglyza

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Tablets, oral, once daily.

Investigational medicinal product name

Dapagliflozin

Investigational medicinal product code

Other name

Forxiga

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Tablets, oral, once daily.

Number of subjects in period 2	Dapagliflozin	Saxagliptin	Placebo
Started	76	83	68
Randomised Withdrawal Patients Data Set	13 ^[7]	25 ^[8]	8 ^[9]
Excluded Withdrawal Patients Data Set	68 ^[10]	63 ^[11]	68
Randomised to Continue Metformin	6 ^[12]	12 ^[13]	2 ^[14]
Randomised Metformin Withdrawal	7 ^[15]	13 ^[16]	6 ^[17]
Completed	75	79	61
Not completed	1	4	7
Consent withdrawn by subject	1	3	3
Miscellaneous	-	-	2
Lost to follow-up	-	1	1
Withdrawal by parent/guardian	-	-	1

Notes
[7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants were re-randomised in a 1:1 ratio to continue on low-dose treatment or to uptitrate to high-dose treatment.
[8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Eligible participants were randomised 1:1 within each of the strata to either continue or discontinue background medication with metformin.
[9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Eligible participants were randomised 1:1:1 to either withdraw background medication with metformin and switch to active treatment with either saxagliptin 5 mg or dapagliflozin 10 mg or to remain on background medication with metformin and continue with placebo.
[10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Eligible participants were randomised 1:1 within each of the strata to either continue or discontinue background medication with metformin.
[11] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Eligible participants were randomised 1:1 within each of the strata to either continue or discontinue background medication with metformin.
[12] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants were re-randomised in a 1:1 ratio to continue on low-dose treatment or to uptitrate to high-dose treatment.
[13] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants were re-randomised in a 1:1 ratio to continue on low-dose treatment or to uptitrate to high-dose treatment.
[14] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants randomised into the placebo arm were not eligible for uptitration randomisation.
[15] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Five participants withdrew following the LT Period, prior to starting the Non-treatment Follow-up Period.
[16] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants were re-randomised in a 1:1 ratio to continue on low-dose treatment or to uptitrate to high-dose treatment.
[17] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Participants randomised into the placebo arm were not eligible for uptitration randomisation.

Period 3 title

Non-treatment Follow-up Period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Dapagliflozin

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Saxagliptin

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Placebo

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 3 ^[18]	Dapagliflozin	Saxagliptin	Placebo
Started	74	77	59
Completed	67	68	52
Not completed	7	9	7
Consent withdrawn by subject	2	1	-
Miscellaneous	-	1	-
Lost to follow-up	3	4	5
Withdrawal by parent/guardian	2	3	2

Notes
[18] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Five participants withdrew following the LT Period, prior to starting the Non-treatment Follow-up Period.

Baseline characteristics

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Reporting group title

Dapagliflozin

Reporting group description

Reporting group title

Saxagliptin

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	Dapagliflozin	Saxagliptin	Placebo	Total
Number of subjects	81	88	76	245
Age categorical
Units: Subjects
≥ 10 and < 15 years	38	43	35	116
≥ 15 and < 18 years	43	45	41	129
Age Continuous
Units: years
arithmetic mean (standard deviation)	14.4 ( 2.00 )	14.5 ( 1.75 )	14.7 ( 1.64 )	-
Sex: Female, Male
Units:
Female	49	53	44	146
Male	32	35	32	99
Race/Ethnicity, Customized
Units: Subjects
White	42	50	32	124
Black or African American	7	4	3	14
Asian	18	23	24	65
Native Hawaiian or Other Pacific Islander	0	0	3	3
American Indian or Alaska Native	11	7	12	30
Other	3	4	2	9
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	45	43	34	122
Not Hispanic or Latino	36	45	42	123
Unknown or Not Reported	0	0	0	0
Mean Baseline HbA1c
Units: Percentage HbA1c
arithmetic mean (standard deviation)	8.22 ( 1.459 )	8.02 ( 1.431 )	7.96 ( 1.629 )	-

End points

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Reporting group title

Dapagliflozin

Reporting group description

Reporting group title

Saxagliptin

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

Dapagliflozin

Reporting group description

Reporting group title

Saxagliptin

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

Dapagliflozin

Reporting group description

Reporting group title

Saxagliptin

Reporting group description

Reporting group title

Placebo

Reporting group description

Subject analysis set title

Dapagliflozin 5 mg/10 mg (weighted)

Subject analysis set type

Full analysis

Subject analysis set description

Participants were randomised to receive dapagliflozin 5 mg administered orally once daily (low-dose). At Week 14, participants with Week 12 HbA1c values < 7% remained on low-dose dapagliflozin (weight = 1). Participants with Week 12 HbA1c values ≥ 7% were re-randomised in a 1:1 ratio to continue on low-dose treatment (weight = 0) or to uptitrate to dapagliflozin 10 mg administered orally once daily (high-dose) (weight = 2). After completion of the ST treatment period, participants could enter the LT treatment period.

Subject analysis set title

Saxagliptin 2.5 mg/5 mg (weighted)

Subject analysis set type

Full analysis

Subject analysis set description

Participants were randomised to receive saxagliptin 2.5 mg administered orally once daily (low-dose). At Week 14, participants with Week 12 HbA1c values < 7% remained on low-dose saxagliptin (weight = 1). Participants with Week 12 HbA1c values ≥ 7% were re-randomised in a 1:1 ratio to continue on low-dose treatment (weight = 0) or to uptitrate to saxagliptin 5 mg administered orally once daily (high-dose) (weight = 2). After completion of the ST treatment period, participants could enter the LT treatment period.

Subject analysis set title

Placebo (weight = 1)

Subject analysis set type

Full analysis

Subject analysis set description

Participants were randomised to receive placebo administered orally once daily. At Week 14, all participants continued on placebo. To maintain blinding, all participants underwent a dummy second randomisation process that was undistinguishable from the actual second randomisation. After completion of the ST treatment period, participants could enter the LT treatment period.

Subject analysis set title

Dapagliflozin 10 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants were randomised to receive dapagliflozin 5 mg administered orally once daily (low-dose). At Week 14, participants with Week 12 HbA1c values ≥ 7% were re-randomised in a 1:1 ratio to continue on low-dose treatment or to uptitrate to dapagliflozin 10 mg administered orally once daily (high-dose). After completion of the ST treatment period, participants could enter the LT treatment period.

Subject analysis set title

Dapagliflozin 5 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants were randomised to receive dapagliflozin 5 mg administered orally once daily (low-dose). At Week 14, participants with Week 12 HbA1c values < 7% remained on low-dose dapagliflozin. Participants with Week 12 HbA1c values ≥ 7% were re-randomised in a 1:1 ratio to continue on low-dose treatment or to uptitrate to dapagliflozin 10 mg administered orally once daily (high-dose). After completion of the ST treatment period, participants could enter the LT treatment period.

Subject analysis set title

Saxagliptin 5 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants were randomised to receive saxagliptin 2.5 mg administered orally once daily (low-dose). At Week 14, participants with Week 12 HbA1c values ≥ 7% were re-randomised in a 1:1 ratio to continue on low-dose treatment or to uptitrate to saxagliptin 5 mg administered orally once daily (high-dose). After completion of the ST treatment period, participants could enter the LT treatment period.

Subject analysis set title

Saxagliptin 2.5 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants were randomised to receive saxagliptin 2.5 mg administered orally once daily (low-dose). At Week 14, participants with Week 12 HbA1c values < 7% remained on low-dose saxagliptin. Participants with Week 12 HbA1c values ≥ 7% were re-randomised in a 1:1 ratio to continue on low-dose treatment or to uptitrate to saxagliptin 5 mg administered orally once daily (high-dose). After completion of the ST treatment period, participants could enter the LT treatment period.

Primary: Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26

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End point title

Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26 ^[1]

End point description

End point type

Primary

End point timeframe

Baseline and Week 26

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All arms in the baseline period could not be reported here due to the adjusted mean placebo results.

End point values	Dapagliflozin	Placebo
Number of subjects analysed	75	70
Units: Percentage HbA1c
arithmetic mean (standard error)	-0.62 ( 0.218 )	0.41 ( 0.218 )

Comparison between groups

Comparison groups

Dapagliflozin v Placebo

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-1.03

Confidence interval

level

95%

sides

2-sided

lower limit

-1.57

upper limit

-0.49

Variability estimate

Standard error of the mean

Dispersion value

0.274

Primary: Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26

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End point title

Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26 ^[2]

End point description

End point type

Primary

End point timeframe

Baseline and Week 26

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All arms in the baseline period could not be reported here due to the adjusted mean placebo results.

End point values	Saxagliptin	Placebo
Number of subjects analysed	82	70
Units: Percentage HbA1c
arithmetic mean (standard error)	0.06 ( 0.198 )	0.50 ( 0.202 )

Comparison between groups

Comparison groups

Saxagliptin v Placebo

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.078

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-0.44

Confidence interval

level

95%

sides

2-sided

lower limit

-0.93

upper limit

0.05

Variability estimate

Standard error of the mean

Dispersion value

0.251

Secondary: Dapagliflozin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

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End point title

Dapagliflozin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

End point description

Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline HbA1c as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Dapagliflozin participants were weighted as follows: participants who had HbA1c < 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c >= 7% at Week 12 and continued on the low-dose were assigned a weight of 0; participants who had HbA1c >= 7% at Week 12 and received the high-dose were assigned a weight of 2; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1. Randomised Participants Data Set: consisted of all randomised participants who receive at least one dose of study medication during the treatment period. Includes participants with available data only.

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Dapagliflozin 5 mg/10 mg (weighted)	Placebo (weight = 1)
Number of subjects analysed	54	70
Units: Percentage HbA1c
arithmetic mean (standard error)	-0.42 ( 0.214 )	0.43 ( 0.207 )

Comparison between groups

Comparison groups

Dapagliflozin 5 mg/10 mg (weighted) v Placebo (weight = 1)

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-0.86

Confidence interval

level

95%

sides

2-sided

lower limit

-1.44

upper limit

-0.27

Variability estimate

Standard error of the mean

Dispersion value

0.3

Secondary: Saxagliptin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

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End point title

Saxagliptin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

End point description

Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline HbA1c as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Saxagliptin participants were weighted as follows: participants who had HbA1c < 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c >= 7% at Week 12 and continued on the low-dose were assigned a weight of 0; participants who had HbA1c >= 7% at Week 12 and received the high-dose were assigned a weight of 2; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1. Randomised Participants Data Set: consisted of all randomised participants who receive at least one dose of study medication during the treatment period. Includes participants with available data only.

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Saxagliptin 2.5 mg/5 mg (weighted)	Placebo (weight = 1)
Number of subjects analysed	58	70
Units: Percentage HbA1c
arithmetic mean (standard error)	-0.04 ( 0.190 )	0.47 ( 0.200 )

Comparison between groups

Comparison groups

Saxagliptin 2.5 mg/5 mg (weighted) v Placebo (weight = 1)

Number of subjects included in analysis

128

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.067

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-0.51

Confidence interval

level

95%

sides

2-sided

lower limit

-1.05

upper limit

0.04

Variability estimate

Standard error of the mean

Dispersion value

0.277

Secondary: Dapagliflozin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

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End point title

Dapagliflozin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

End point description

Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline HbA1c as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Dapagliflozin participants were weighted as follows: participants who had HbA1c < 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c >= 7% at Week 12 and continued on the low-dose were assigned a weight of 2; participants who had HbA1c >= 7% at Week 12 and received the high-dose were assigned a weight of 0; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1. Randomised Participants Data Set: consisted of all randomised participants who receive at least one dose of study medication during the treatment period. Includes participants with available data only.

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Dapagliflozin 5 mg/10 mg (weighted)	Placebo (weight = 1)
Number of subjects analysed	56	70
Units: Percentage HbA1c
arithmetic mean (standard error)	-0.79 ( 0.202 )	0.40 ( 0.205 )

Comparison between groups

Comparison groups

Dapagliflozin 5 mg/10 mg (weighted) v Placebo (weight = 1)

Number of subjects included in analysis

126

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-1.19

Confidence interval

level

95%

sides

2-sided

lower limit

-1.76

upper limit

-0.62

Variability estimate

Standard error of the mean

Dispersion value

0.29

Secondary: Saxagliptin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

Top of page

End point title

Saxagliptin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

End point description

Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline HbA1c as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Saxagliptin participants were weighted as follows: participants who had HbA1c < 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c >= 7% at Week 12 and continued on the low-dose were assigned a weight of 2; participants who had HbA1c >= 7% at Week 12 and received the high-dose were assigned a weight of 0; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1. Randomised Participants Data Set: consisted of all randomised participants who receive at least one dose of study medication during the treatment period. Includes participants with available data only.

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Saxagliptin 2.5 mg/5 mg (weighted)	Placebo (weight = 1)
Number of subjects analysed	57	70
Units: Percentage HbA1c
arithmetic mean (standard error)	0.07 ( 0.188 )	0.47 ( 0.194 )

Comparison between groups

Comparison groups

Saxagliptin 2.5 mg/5 mg (weighted) v Placebo (weight = 1)

Number of subjects included in analysis

127

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.146

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-0.39

Confidence interval

level

95%

sides

2-sided

lower limit

-0.92

upper limit

0.14

Variability estimate

Standard error of the mean

Dispersion value

0.27

Secondary: Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26

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End point title

Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 ^[3]

End point description

End point type

Secondary

End point timeframe

Baseline and Week 26

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All arms in the baseline period could not be reported here due to the adjusted mean placebo results.

End point values	Dapagliflozin	Placebo
Number of subjects analysed	75	68
Units: mmol/L
arithmetic mean (standard error)	-0.57 ( 0.374 )	0.51 ( 0.384 )

Comparison between groups

Comparison groups

Dapagliflozin v Placebo

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.024

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-1.08

Confidence interval

level

95%

sides

2-sided

lower limit

-2.02

upper limit

-0.14

Variability estimate

Standard error of the mean

Dispersion value

0.479

Secondary: Dapagliflozin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

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End point title

Dapagliflozin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

End point description

Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline FPG as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Dapagliflozin participants were weighted as follows: participants who had HbA1c < 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c >= 7% at Week 12 and continued on the low-dose were assigned a weight of 0; participants who had HbA1c >= 7% at Week 12 and received the high-dose were assigned a weight of 2; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1. Randomised Participants Data Set: consisted of all randomised participants who receive at least one dose of study medication during the treatment period. Includes participants with available data only.

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Dapagliflozin 5 mg/10 mg (weighted)	Placebo (weight = 1)
Number of subjects analysed	54	68
Units: mmol/L
arithmetic mean (standard error)	-0.34 ( 0.365 )	0.70 ( 0.369 )

Comparison between groups

Comparison groups

Dapagliflozin 5 mg/10 mg (weighted) v Placebo (weight = 1)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.047

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-1.04

Confidence interval

level

95%

sides

2-sided

lower limit

-2.07

upper limit

-0.01

Variability estimate

Standard error of the mean

Dispersion value

0.525

Secondary: Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in FPG at Week 26

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End point title

Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in FPG at Week 26 ^[4]

End point description

End point type

Secondary

End point timeframe

Baseline and Week 26

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All arms in the baseline period could not be reported here due to the adjusted mean placebo results.

End point values	Saxagliptin	Placebo
Number of subjects analysed	80	68
Units: mmol/L
arithmetic mean (standard error)	0.08 ( 0.413 )	0.19 ( 0.428 )

Comparison between groups

Comparison groups

Saxagliptin v Placebo

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.833

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-1.15

upper limit

0.92

Variability estimate

Standard error of the mean

Dispersion value

0.528

Secondary: Saxagliptin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

Top of page

End point title

Saxagliptin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

End point description

Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline FPG as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Saxagliptin participants were weighted as follows: participants who had HbA1c < 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c >= 7% at Week 12 and continued on the low-dose were assigned a weight of 0; participants who had HbA1c >= 7% at Week 12 and received the high-dose were assigned a weight of 2; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1. Randomised Participants Data Set: consisted of all randomised participants who receive at least one dose of study medication during the treatment period. Includes participants with available data only.

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Saxagliptin 2.5 mg/5 mg (weighted)	Placebo (weight = 1)
Number of subjects analysed	57	68
Units: mmol/L
arithmetic mean (standard error)	0.18 ( 0.331 )	0.73 ( 0.359 )

Comparison between groups

Comparison groups

Saxagliptin 2.5 mg/5 mg (weighted) v Placebo (weight = 1)

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.268

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-0.54

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

0.42

Variability estimate

Standard error of the mean

Dispersion value

0.49

Secondary: Dapagliflozin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

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End point title

Dapagliflozin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

End point description

Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline FPG as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Dapagliflozin participants were weighted as follows: participants who had HbA1c < 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c >= 7% at Week 12 and continued on the low-dose were assigned a weight of 2; participants who had HbA1c >= 7% at Week 12 and received the high-dose were assigned a weight of 0; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1. Randomised Participants Data Set: consisted of all randomised participants who receive at least one dose of study medication during the treatment period. Includes participants with available data only.

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Dapagliflozin 5 mg/10 mg (weighted)	Placebo (weight = 1)
Number of subjects analysed	56	68
Units: mmol/L
arithmetic mean (standard error)	-0.56 ( 0.347 )	0.56 ( 0.363 )

Comparison between groups

Comparison groups

Dapagliflozin 5 mg/10 mg (weighted) v Placebo (weight = 1)

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.026

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-1.12

Confidence interval

level

95%

sides

2-sided

lower limit

-2.11

upper limit

-0.13

Variability estimate

Standard error of the mean

Dispersion value

0.505

Secondary: Saxagliptin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

Top of page

End point title

Saxagliptin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

End point description

Data was analysed with an ANCOVA model with treatment, sex, age group and background antidiabetes medication as factors and Baseline FPG as covariate. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Saxagliptin participants were weighted as follows: participants who had HbA1c < 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c >= 7% at Week 12 and continued on the low-dose were assigned a weight of 2; participants who had HbA1c >= 7% at Week 12 and received the high-dose were assigned a weight of 0; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1. Randomised Participants Data Set: consisted of all randomised participants who receive at least one dose of study medication during the treatment period. Includes participants with available data only.

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Saxagliptin 2.5 mg/5 mg (weighted)	Placebo (weight = 1)
Number of subjects analysed	55	68
Units: mmol/L
arithmetic mean (standard error)	0.63 ( 0.424 )	0.34 ( 0.446 )

Comparison between groups

Comparison groups

Saxagliptin 2.5 mg/5 mg (weighted) v Placebo (weight = 1)

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.644

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

0.29

Confidence interval

level

95%

sides

2-sided

lower limit

-0.92

upper limit

1.5

Variability estimate

Standard error of the mean

Dispersion value

0.618

Secondary: Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

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End point title

Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

End point description

A logistic regression model adjusting for sex, age group, background antidiabetes medication and Baseline HbA1c was used. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Randomised Participants Data Set: consisted of all randomised participants who receive at least one dose of study medication during the treatment period. Includes participants with Baseline HbA1c >= 7% and available data only.

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Dapagliflozin	Saxagliptin	Placebo
Number of subjects analysed	64	61	50
Units: Percentage of participants
number (not applicable)	26.6	21.3	10.0

Comparison between groups

Comparison groups

Saxagliptin v Placebo

Number of subjects included in analysis

111

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.114

Method

Regression, Logistic

Parameter type

Adjusted Odds Ratio

Point estimate

2.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

8.6

Comparison between groups

Comparison groups

Dapagliflozin v Placebo

Number of subjects included in analysis

114

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.019

Method

Regression, Logistic

Parameter type

Adjusted Odds Ratio

Point estimate

3.8

Confidence interval

level

95%

sides

2-sided

lower limit

1.2

upper limit

11.7

Secondary: Low-dose/High-dose Versus Placebo (Weighted): Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

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End point title

Low-dose/High-dose Versus Placebo (Weighted): Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

End point description

A weighted logistic regression model adjusting for sex, age group, background antidiabetes medication and Baseline HbA1c was used. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Participants were weighted as follows: participants who had HbA1c < 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c >= 7% at Week 12 and continued on the low-dose were assigned a weight of 0; participants who had HbA1c >= 7% at Week 12 and received the high-dose were assigned a weight of 2; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1. Randomised Participants Data Set: consisted of all randomised participants who receive at least one dose of study medication during the treatment period. Includes participants with Baseline HbA1c >= 7% and available data only.

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Dapagliflozin 5 mg/10 mg (weighted)	Saxagliptin 2.5 mg/5 mg (weighted)	Placebo (weight = 1)
Number of subjects analysed	44	41	50
Units: Percentage of participants
number (not applicable)	27.3	24.4	10.0

Comparison between groups

Comparison groups

Saxagliptin 2.5 mg/5 mg (weighted) v Placebo (weight = 1)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.175

Method

Weighted Logistic Regression

Parameter type

Adjusted Odds Ratio

Point estimate

2.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

7.4

Comparison between groups

Comparison groups

Dapagliflozin 5 mg/10 mg (weighted) v Placebo (weight = 1)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.042

Method

Weighted Logistic Regression

Parameter type

Adjusted Odds Ratio

Point estimate

3.5

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

11.4

Secondary: Low-dose Versus Placebo (Weighted): Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

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End point title

Low-dose Versus Placebo (Weighted): Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

End point description

A weighted logistic regression model adjusting for sex, age group, background antidiabetes medication and Baseline HbA1c was used. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Participants were weighted as follows: participants who had HbA1c < 7% at Week 12 and remained on low-dose were assigned a weight of 1; participants who had HbA1c >= 7% at Week 12 and continued on the low-dose were assigned a weight of 2; participants who had HbA1c >= 7% at Week 12 and received the high-dose were assigned a weight of 0; all participants who do not undergo second randomisation were assigned a weight of 1. Placebo participants were assigned a weight of 1. Randomised Participants Data Set: consisted of all randomised participants who receive at least one dose of study medication during the treatment period. Includes participants with Baseline HbA1c >= 7% and available data only.

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Dapagliflozin 5 mg/10 mg (weighted)	Saxagliptin 2.5 mg/5 mg (weighted)	Placebo (weight = 1)
Number of subjects analysed	45	38	50
Units: Percentage of participants
number (not applicable)	35.6	28.9	10.0

Comparison between groups

Comparison groups

Saxagliptin 2.5 mg/5 mg (weighted) v Placebo (weight = 1)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.042

Method

Weighted Logistic Regression

Parameter type

Adjusted Odds Ratio

Point estimate

3.8

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

13.5

Comparison between groups

Comparison groups

Dapagliflozin 5 mg/10 mg (weighted) v Placebo (weight = 1)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.009

Method

Weighted Logistic Regression

Parameter type

Adjusted Odds Ratio

Point estimate

4.4

Confidence interval

level

95%

sides

2-sided

lower limit

1.4

upper limit

13.2

Secondary: Low-dose Versus Uptitration to the High Dose: Adjusted Mean Change From Baseline in HbA1c at Week 26

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End point title

Low-dose Versus Uptitration to the High Dose: Adjusted Mean Change From Baseline in HbA1c at Week 26

End point description

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Dapagliflozin 10 mg	Dapagliflozin 5 mg	Saxagliptin 5 mg	Saxagliptin 2.5 mg
Number of subjects analysed	19	21	25	24
Units: Percentage HbA1c
arithmetic mean (standard error)	-0.74 ( 0.368 )	-0.71 ( 0.384 )	-0.16 ( 0.361 )	0.07 ( 0.372 )

Comparison between groups

Comparison groups

Saxagliptin 5 mg v Saxagliptin 2.5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.64

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

0.74

Variability estimate

Standard error of the mean

Dispersion value

0.495

Comparison between groups

Comparison groups

Dapagliflozin 10 mg v Dapagliflozin 5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.955

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

0.94

Variability estimate

Standard error of the mean

Dispersion value

0.496

Secondary: Low-dose Versus Uptitration to the High Dose: Adjusted Mean Change From Baseline in FPG at Week 26

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End point title

Low-dose Versus Uptitration to the High Dose: Adjusted Mean Change From Baseline in FPG at Week 26

End point description

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Dapagliflozin 10 mg	Dapagliflozin 5 mg	Saxagliptin 5 mg	Saxagliptin 2.5 mg
Number of subjects analysed	19	21	25	23
Units: mmol/L
arithmetic mean (standard error)	-1.62 ( 0.689 )	-0.98 ( 0.683 )	-2.38 ( 0.734 )	-0.56 ( 0.763 )

Comparison between groups

Comparison groups

Dapagliflozin 10 mg v Dapagliflozin 5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.476

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-0.64

Confidence interval

level

95%

sides

2-sided

lower limit

-2.39

upper limit

1.12

Variability estimate

Standard error of the mean

Dispersion value

0.896

Comparison between groups

Comparison groups

Saxagliptin 5 mg v Saxagliptin 2.5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.075

Method

ANCOVA

Parameter type

Adjusted mean difference

Point estimate

-1.81

Confidence interval

level

95%

sides

2-sided

lower limit

-3.81

upper limit

0.18

Variability estimate

Standard error of the mean

Dispersion value

1.017

Secondary: Dapagliflozin Low-dose Versus Uptitration to the High Dose: Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

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End point title

Dapagliflozin Low-dose Versus Uptitration to the High Dose: Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

End point description

A Fisher's exact test was used and unadjusted difference in percentage of participants and Clopper-Pearson CIs presented using imputed data. Missing Week 26 data was handled based on MI-WO within each arm using the data from placebo participants with Week 26 data. Uptitration Randomised Participants Data Set: consisted of the subset of randomised participants who were up-titration randomised because their HbA1c is greater than or equal to 7% at Week 12 (regardless of rescue medication initiation). Includes participants with available data only.

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Dapagliflozin 10 mg	Dapagliflozin 5 mg
Number of subjects analysed	19	20
Units: Percentage of participants
number (not applicable)	5.3	25.0

Comparison between groups

Comparison groups

Dapagliflozin 10 mg v Dapagliflozin 5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.182

Method

Fisher exact

Parameter type

Unadjusted Difference in Percentage

Point estimate

-19.7

Confidence interval

level

95%

sides

2-sided

lower limit

-44.5

upper limit

5.7

Secondary: Saxagliptin Low-dose Versus Uptitration to the High Dose: Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

Top of page

End point title

Saxagliptin Low-dose Versus Uptitration to the High Dose: Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

End point description

End point type

Secondary

End point timeframe

Baseline and Week 26

End point values	Saxagliptin 5 mg	Saxagliptin 2.5 mg
Number of subjects analysed	23	20
Units: Percentage of participants
number (not applicable)	8.7	15.0

Comparison between groups

Comparison groups

Saxagliptin 5 mg v Saxagliptin 2.5 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.65

Method

Fisher exact

Parameter type

Unadjusted Difference in Percentage

Point estimate

-6.3

Confidence interval

level

95%

sides

2-sided

lower limit

-29.8

upper limit

16.5

Adverse events

Top of page

Timeframe for reporting adverse events

All-cause mortality: Up to Week 104 Serious and other adverse events (AEs): Up to 52 Weeks + 30 days (Week 56)

Adverse event reporting additional description

Treated Participants Data Set: consisted of all participants who received at least one dose of study medication. As pre-specified in the statistical analysis plan, AEs data for participants continuing on metformin following third randomization and for participants who were not eligible for the third randomization were not collected separately.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Weeks 1 to 14: Saxagliptin 2.5 mg

Reporting group description

Participants were randomised to receive saxagliptin 2.5 mg administered orally once daily (low-dose).

Reporting group title

Weeks 14 to 26: Saxagliptin 5 mg

Reporting group description

At Week 14, participants with Week 12 HbA1c values ≥ 7% were re-randomised in a 1:1 ratio to continue on low-dose treatment or to uptitrate to saxagliptin 5 mg administered orally once daily (high-dose).

Reporting group title

Weeks 1 to 14: Dapagliflozin 5 mg

Reporting group description

Participants were randomised to receive dapagliflozin 5 mg administered orally once daily (low-dose).

Reporting group title

Weeks 14 to 26: Dapagliflozin 5 mg

Reporting group description

At Week 14, participants with Week 12 HbA1c values < 7% remained on low-dose dapagliflozin. Participants with Week 12 HbA1c values ≥ 7% were re-randomised in a 1:1 ratio to continue on low-dose treatment or to uptitrate to dapagliflozin 10 mg administered orally once daily (high-dose).

Reporting group title

Weeks 32/40 to 56: Dapagliflozin 10 mg + Metformin Withdrawal

Reporting group description

After completion of the ST treatment period, participants could enter the LT treatment period. A subset of eligible participants (on background treatment with metformin only and who had HbA1c < 7.5% at Week 26 or Week 32) were grouped into 2 separate strata for dapagliflozin, and then randomised 1:1 within each of the strata to either continue or discontinue background medication with metformin at either Week 32 or Week 40. For participants randomised to withdraw background treatment with metformin, those receiving high-dose treatment continued to receive high-dose treatment, whereas those currently receiving low-dose treatment had their doses uptitrated to high-dose treatment.

Reporting group title

Weeks 14 to 26: Saxagliptin 2.5 mg

Reporting group description

At Week 14, participants with Week 12 HbA1c values < 7% remained on low-dose saxagliptin. Participants with Week 12 HbA1c values ≥ 7% were re-randomised in a 1:1 ratio to continue on low-dose treatment or to uptitrate to saxagliptin 5 mg administered orally once daily (high-dose).

Reporting group title

Weeks 26 to 56: Dapagliflozin 5 mg

Reporting group description

After completion of the ST treatment period, participants could enter the LT treatment period. Participants who were receiving background medication with insulin only or insulin and metformin (not eligible for the third randomisation) continued with their randomised study drug assigned after the second randomisation. A subset of eligible participants (on background treatment with metformin only and who had HbA1c < 7.5% at Week 26 or Week 32) were grouped into 2 separate strata for saxagliptin and dapagliflozin, and then randomised 1:1 within each of the strata to either continue or discontinue background medication with metformin at either Week 32 or Week 40. Participants who were randomized to continue background medication with metformin continued with their current dose of dapagliflozin.

Reporting group title

Weeks 26 to 56: Dapagliflozin 10 mg

Reporting group description

Reporting group title

Weeks 14 to 26: Dapagliflozin 10 mg

Reporting group description

At Week 14, participants with Week 12 HbA1c values ≥ 7% were re-randomised in a 1:1 ratio to continue on low-dose treatment or to uptitrate to dapagliflozin 10 mg administered orally once daily (high-dose).

Reporting group title

Weeks 32 or 40 to 56: Placebo

Reporting group description

Participants who were receiving background medication with insulin only or insulin and metformin (not eligible for the third randomisation) continued with their randomised study drug assigned after the second randomisation. At either Week 32 or Week 40 eligible participants receiving placebo were randomised 1:1:1 to either withdraw background medication with metformin and switch to active treatment with either saxagliptin 5 mg or dapagliflozin 10 mg or to remain on background medication with metformin and continue with placebo.

Reporting group title

W32/40 to 56: Placebo to Dapagliflozin + Metformin Withdrawal

Reporting group description

At either Week 32 or Week 40 eligible participants receiving placebo were randomised 1:1:1 to either withdraw background medication with metformin and switch to active treatment with either saxagliptin 5 mg or dapagliflozin 10 mg or to remain on background medication with metformin and continue with placebo.

Reporting group title

Weeks 26 to 56: Saxagliptin 2.5 mg

Reporting group description

Reporting group title

Weeks 26 to 56: Saxagliptin 5 mg

Reporting group description

Reporting group title

Weeks 32/40 to 56: Saxagliptin 5 mg + Metformin Withdrawal

Reporting group description

After completion of the ST treatment period, participants could enter the LT treatment period. A subset of eligible participants (on background treatment with metformin only and who had HbA1c < 7.5% at Week 26 or Week 32) were grouped into 2 separate strata for saxagliptin, and then randomised 1:1 within each of the strata to either continue or discontinue background medication with metformin at either Week 32 or Week 40. For participants randomised to withdraw background treatment with metformin, those receiving high-dose treatment continued to receive high-dose treatment, whereas those currently receiving low-dose treatment had their doses uptitrated to high-dose treatment.

Reporting group title

Weeks 1 to 14: Placebo

Reporting group description

Participants were randomised to receive placebo administered orally once daily.

Reporting group title

Weeks 14 to 26: Placebo

Reporting group description

At Week 14, all participants continued on placebo. To maintain blinding, all participants underwent a dummy second randomisation process that was undistinguishable from the actual second randomisation.

Reporting group title

Week 56 to 104: Non-treatment Follow-up Period

Reporting group description

Safety monitoring continued in the Non-treatment Follow-up Period quarterly between the Week 56 and Week 104 visits.

Reporting group title

W32/40 to 56: Placebo to Saxagliptin + Metformin Withdrawal

Reporting group description

Reporting group title

Weeks 26 to 32 or 40: Placebo

Reporting group description

After completion of the ST treatment period, participants could enter the LT treatment period. Participants who were receiving background medication with insulin only or insulin and metformin (not eligible for the third randomisation) continued with their randomised study drug assigned after the second randomisation. At either Week 32 or Week 40 eligible participants receiving placebo were randomised 1:1:1 to either withdraw background medication with metformin and switch to active treatment with either saxagliptin 5 mg or dapagliflozin 10 mg or to remain on background medication with metformin and continue with placebo.

Weeks 1 to 14: Saxagliptin 2.5 mg

Weeks 14 to 26: Saxagliptin 5 mg

Weeks 1 to 14: Dapagliflozin 5 mg

Weeks 14 to 26: Dapagliflozin 5 mg

Weeks 32/40 to 56: Dapagliflozin 10 mg + Metformin Withdrawal

Weeks 14 to 26: Saxagliptin 2.5 mg

Weeks 26 to 56: Dapagliflozin 5 mg

Weeks 26 to 56: Dapagliflozin 10 mg

Weeks 14 to 26: Dapagliflozin 10 mg

Weeks 32 or 40 to 56: Placebo

W32/40 to 56: Placebo to Dapagliflozin + Metformin Withdrawal

Weeks 26 to 56: Saxagliptin 2.5 mg

Weeks 26 to 56: Saxagliptin 5 mg

Weeks 32/40 to 56: Saxagliptin 5 mg + Metformin Withdrawal

Weeks 1 to 14: Placebo

Weeks 14 to 26: Placebo

Week 56 to 104: Non-treatment Follow-up Period

W32/40 to 56: Placebo to Saxagliptin + Metformin Withdrawal

Weeks 26 to 32 or 40: Placebo

Total subjects affected by serious adverse events

subjects affected / exposed

2 / 88 (2.27%)

0 / 26 (0.00%)

1 / 81 (1.23%)

0 / 55 (0.00%)

0 / 7 (0.00%)

1 / 61 (1.64%)

5 / 55 (9.09%)

1 / 21 (4.76%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

3 / 61 (4.92%)

1 / 26 (3.85%)

0 / 13 (0.00%)

1 / 76 (1.32%)

1 / 70 (1.43%)

0 / 210 (0.00%)

0 / 3 (0.00%)

3 / 70 (4.29%)

number of deaths (all causes)

number of deaths resulting from adverse events

Investigations

Glycosylated haemoglobin increased

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

1 / 55 (1.82%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Transaminases increased

subjects affected / exposed

1 / 88 (1.14%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

0 / 55 (0.00%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Splenic rupture

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

1 / 55 (1.82%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Accidental overdose

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

1 / 55 (1.82%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Presyncope

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

0 / 55 (0.00%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

1 / 70 (1.43%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Lymphadenitis

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

1 / 55 (1.82%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Abdominal pain lower

subjects affected / exposed

1 / 88 (1.14%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

0 / 55 (0.00%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Abdominal pain upper

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

0 / 55 (0.00%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

1 / 70 (1.43%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastritis

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

0 / 55 (0.00%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

1 / 26 (3.85%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Reproductive system and breast disorders

Ovarian cyst

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

1 / 81 (1.23%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

0 / 55 (0.00%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Haematuria

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

0 / 55 (0.00%)

1 / 21 (4.76%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Appendicitis

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

0 / 55 (0.00%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

1 / 61 (1.64%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastroenteritis

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

1 / 55 (1.82%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urinary tract infection

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

1 / 55 (1.82%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

COVID-19

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

1 / 61 (1.64%)

0 / 55 (0.00%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Diabetic ketoacidosis

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

0 / 55 (0.00%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

1 / 70 (1.43%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Euglycaemic diabetic ketoacidosis

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

1 / 55 (1.82%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

0 / 61 (0.00%)

0 / 26 (0.00%)

0 / 13 (0.00%)

0 / 76 (0.00%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

0 / 70 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyperglycaemia

subjects affected / exposed

0 / 88 (0.00%)

0 / 26 (0.00%)

0 / 81 (0.00%)

0 / 55 (0.00%)

0 / 7 (0.00%)

0 / 61 (0.00%)

0 / 55 (0.00%)

0 / 21 (0.00%)

0 / 53 (0.00%)

0 / 3 (0.00%)

2 / 61 (3.28%)

0 / 26 (0.00%)

0 / 13 (0.00%)

1 / 76 (1.32%)

0 / 70 (0.00%)

0 / 210 (0.00%)

0 / 3 (0.00%)

1 / 70 (1.43%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Weeks 1 to 14: Saxagliptin 2.5 mg	Weeks 14 to 26: Saxagliptin 5 mg	Weeks 1 to 14: Dapagliflozin 5 mg	Weeks 14 to 26: Dapagliflozin 5 mg	Weeks 32/40 to 56: Dapagliflozin 10 mg + Metformin Withdrawal	Weeks 14 to 26: Saxagliptin 2.5 mg	Weeks 26 to 56: Dapagliflozin 5 mg	Weeks 26 to 56: Dapagliflozin 10 mg	Weeks 14 to 26: Dapagliflozin 10 mg	Weeks 32 or 40 to 56: Placebo	W32/40 to 56: Placebo to Dapagliflozin + Metformin Withdrawal	Weeks 26 to 56: Saxagliptin 2.5 mg	Weeks 26 to 56: Saxagliptin 5 mg	Weeks 32/40 to 56: Saxagliptin 5 mg + Metformin Withdrawal	Weeks 1 to 14: Placebo	Weeks 14 to 26: Placebo	Week 56 to 104: Non-treatment Follow-up Period	W32/40 to 56: Placebo to Saxagliptin + Metformin Withdrawal	Weeks 26 to 32 or 40: Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	37 / 88 (42.05%)	10 / 26 (38.46%)	35 / 81 (43.21%)	14 / 55 (25.45%)	2 / 7 (28.57%)	18 / 61 (29.51%)	26 / 55 (47.27%)	8 / 21 (38.10%)	4 / 21 (19.05%)	2 / 53 (3.77%)	1 / 3 (33.33%)	23 / 61 (37.70%)	12 / 26 (46.15%)	3 / 13 (23.08%)	39 / 76 (51.32%)	24 / 70 (34.29%)	0 / 210 (0.00%)	1 / 3 (33.33%)	29 / 70 (41.43%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Vascular disorders
Hot flush
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Hypertension
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	1 / 55 (1.82%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Surgical and medical procedures
Adenoidectomy
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Nasal septal operation
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Tonsillectomy
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Sphenoid sinus operation
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Pain
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Fatigue
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1
Drug intolerance
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	1 / 21 (4.76%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Chest pain
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	1	0	0	0	0
Pyrexia
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	2 / 76 (2.63%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	2 / 70 (2.86%)
occurrences all number	1	0	1	0	0	0	1	0	0	0	0	0	0	0	2	1	0	0	3
Swelling face
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Immunisation reaction
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Hypersensitivity
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Reproductive system and breast disorders
Amenorrhoea
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Dysmenorrhoea
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	1 / 55 (1.82%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	2 / 21 (9.52%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	2 / 76 (2.63%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	2	0	0	1	0	1	0	2	0	0	0	0	0	0	2	0	0	0	2
Premenstrual pain
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Vulvovaginal pruritus
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	1 / 13 (7.69%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	1
Cough
subjects affected / exposed	0 / 88 (0.00%)	1 / 26 (3.85%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	1 / 53 (1.89%)	0 / 3 (0.00%)	0 / 61 (0.00%)	1 / 26 (3.85%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	2 / 70 (2.86%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	0	1	0	0	1	0	0	2
Epistaxis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	1 / 13 (7.69%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	1	2	0	0	0	0
Nasal congestion
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0	0	0	0	0	0	1	0	0	0	0
Nasal obstruction
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Nasal septum deviation
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Obstructive airways disorder
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	4	0	0	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	1 / 26 (3.85%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	1	0	0	0	0
Rhinitis allergic
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Rhinorrhoea
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	1 / 26 (3.85%)	0 / 13 (0.00%)	1 / 76 (1.32%)	2 / 70 (2.86%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	2	0	1	0	0	0	1	0	0	0	0	0	4	0	1	2	0	0	0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Anxiety disorder
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Anxiety
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	1 / 55 (1.82%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Generalised anxiety disorder
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Insomnia
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Nervousness
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Persistent depressive disorder
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Tic
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	2 / 76 (2.63%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	2 / 70 (2.86%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2	0	0	0	2
Albumin urine present
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Aspartate aminotransferase increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	2 / 76 (2.63%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2	0	0	0	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Bacterial test
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Blood cholesterol increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Blood glucose increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0
Blood glucose normal
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Blood parathyroid hormone increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Blood pressure increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Blood triglycerides increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1	0	0	1
C-telopeptide increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Crystal urine present
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2	0	0	0	1
Glycosylated haemoglobin increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	2 / 70 (2.86%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2
Hepatic enzyme increased
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Low density lipoprotein increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Liver function test increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Mean cell haemoglobin concentration decreased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Transaminases increased
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0	0	0	0	0	0	1	0	0	0	0
Mean cell haemoglobin decreased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Urine albumin/creatinine ratio increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0
Weight increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	1 / 26 (3.85%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0	0	0	1	0	0	1	0	0	0
White blood cells urine positive
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
SARS-CoV-2 test positive
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Vitamin D decreased
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	2 / 81 (2.47%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	2 / 76 (2.63%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	2	0	0	0	0	0	0	0	0	0	0	0	2	0	0	0	1
Injury, poisoning and procedural complications
Limb injury
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Radius fracture
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Road traffic accident
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Scratch
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Skin abrasion
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	1	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Tooth fracture
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Thermal burn
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	1 / 53 (1.89%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Wound complication
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Animal bite
subjects affected / exposed	0 / 88 (0.00%)	1 / 26 (3.85%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Closed globe injury
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Fall
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Joint dislocation
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Ligament sprain
subjects affected / exposed	1 / 88 (1.14%)	1 / 26 (3.85%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	1 / 3 (33.33%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0	0	1	0	0	0	0	1	0	0	0
Cardiac disorders
Left ventricular hypertrophy
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Tachycardia
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Wolff-Parkinson-White syndrome
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	1 / 55 (1.82%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Headache
subjects affected / exposed	2 / 88 (2.27%)	0 / 26 (0.00%)	6 / 81 (7.41%)	5 / 55 (9.09%)	0 / 7 (0.00%)	1 / 61 (1.64%)	2 / 55 (3.64%)	2 / 21 (9.52%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	2 / 70 (2.86%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	2	0	7	5	0	1	2	3	0	0	0	1	0	0	2	4	0	0	1
Peripheral sensory neuropathy
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Somnolence
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Syncope
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Tremor
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Iron deficiency anaemia
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1
Lymphadenopathy
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Eye disorders
Cataract
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Conjunctivitis allergic
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	1 / 21 (4.76%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0
Ocular hyperaemia
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 88 (2.27%)	0 / 26 (0.00%)	2 / 81 (2.47%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	1 / 21 (4.76%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	2 / 76 (2.63%)	2 / 70 (2.86%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	2	0	2	0	0	0	0	0	1	0	0	0	0	0	2	3	0	0	0
Abdominal pain upper
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	2 / 55 (3.64%)	0 / 21 (0.00%)	1 / 21 (4.76%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	1	0	0	0	2	0	1	0	0	0	0	0	0	0	0	0	1
Aphthous ulcer
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	1 / 26 (3.85%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Colitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	1 / 26 (3.85%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Diarrhoea
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	3 / 81 (3.70%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	1 / 21 (4.76%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	3 / 76 (3.95%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	2 / 70 (2.86%)
occurrences all number	1	0	3	0	0	0	1	0	1	0	0	1	0	0	3	1	0	0	2
Gastritis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	1 / 55 (1.82%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	1	0	1	0	0	0	0	0	0	0	0	0	1	0	0	0
Food poisoning
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Irritable bowel syndrome
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	1 / 55 (1.82%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Nausea
subjects affected / exposed	3 / 88 (3.41%)	0 / 26 (0.00%)	3 / 81 (3.70%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	3 / 70 (4.29%)
occurrences all number	3	0	4	0	0	0	1	0	0	0	0	1	0	0	0	0	0	0	3
Tooth impacted
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Toothache
subjects affected / exposed	0 / 88 (0.00%)	2 / 26 (7.69%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	1 / 21 (4.76%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	1 / 26 (3.85%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	2	0	0	0	0	1	1	0	0	0	1	1	0	0	0	0	0	0
Vomiting
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	3 / 81 (3.70%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	1	0	3	0	0	0	1	0	0	0	0	0	0	0	2	0	0	0	2
Hepatobiliary disorders
Hepatic steatosis
subjects affected / exposed	2 / 88 (2.27%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	2	0	1	0	0	0	1	0	0	0	0	0	0	0	1	0	0	0	0
Hepatomegaly
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Hypertransaminasaemia
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 88 (0.00%)	1 / 26 (3.85%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	1	1	0	0	0	1	0	0	0	0	1	0	0	0	0	0	0	0
Alopecia
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Dermatitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Dermatitis allergic
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Erythema
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Eczema
subjects affected / exposed	0 / 88 (0.00%)	1 / 26 (3.85%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Dermatitis contact
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Dermatitis atopic
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Hyperhidrosis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Ingrowing nail
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	1	0	0	0
Ingrown hair
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	1 / 26 (3.85%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Pruritus
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Rash
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	0	0	1	0	0	0	0	0	0	0
Seborrhoeic dermatitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Rash maculo-papular
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Renal and urinary disorders
Diabetic nephropathy
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Dysuria
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Haematuria
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Microalbuminuria
subjects affected / exposed	2 / 88 (2.27%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	1 / 26 (3.85%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	2	0	0	0	0	0	1	0	0	0	0	1	1	0	0	0	0	0	0
Nocturia
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Nephropathy
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Nephrolithiasis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Pollakiuria
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Polyuria
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Proteinuria
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Renal colic
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Endocrine disorders
Hypoparathyroidism
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Hypothyroidism
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Primary hypothyroidism
subjects affected / exposed	0 / 88 (0.00%)	1 / 26 (3.85%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	2 / 70 (2.86%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	2	0	0	0
Back pain
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	1 / 26 (3.85%)	0 / 13 (0.00%)	2 / 76 (2.63%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1	1	0	2	0	0	0	1
Joint swelling
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Musculoskeletal pain
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Neck pain
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	1 / 21 (4.76%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Myalgia
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Pain in extremity
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	2 / 70 (2.86%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2	1	0	0	2
Infections and infestations
Acute sinusitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Asymptomatic bacteriuria
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Bronchitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	1 / 55 (1.82%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	0 / 21 (0.00%)	1 / 21 (4.76%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	1	0	0	0	0	0	0	0	0	0	0
Balanitis candida
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Cellulitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Conjunctivitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Chronic sinusitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Croup infectious
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Ear infection
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	2 / 70 (2.86%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2
Cystitis
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Fungal balanitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Fungal foot infection
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Fungal skin infection
subjects affected / exposed	0 / 88 (0.00%)	1 / 26 (3.85%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Fungal infection
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Gastritis viral
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	1 / 55 (1.82%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Gastroenteritis
subjects affected / exposed	2 / 88 (2.27%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	1 / 21 (4.76%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	2	0	1	0	0	1	0	1	0	0	0	0	0	0	0	0	0	0	0
Gastrointestinal infection
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	1 / 26 (3.85%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Influenza
subjects affected / exposed	2 / 88 (2.27%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	3 / 61 (4.92%)	3 / 55 (5.45%)	0 / 21 (0.00%)	1 / 21 (4.76%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	1 / 26 (3.85%)	0 / 13 (0.00%)	2 / 76 (2.63%)	2 / 70 (2.86%)	0 / 210 (0.00%)	0 / 3 (0.00%)	2 / 70 (2.86%)
occurrences all number	2	0	1	0	0	3	3	0	1	0	0	1	1	0	2	2	0	0	2
Hordeolum
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	1 / 26 (3.85%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	1	0	0	0	0
Hand-foot-and-mouth disease
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Nail infection
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	1 / 55 (1.82%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	2 / 88 (2.27%)	0 / 26 (0.00%)	1 / 81 (1.23%)	2 / 55 (3.64%)	0 / 7 (0.00%)	1 / 61 (1.64%)	1 / 55 (1.82%)	1 / 21 (4.76%)	0 / 21 (0.00%)	1 / 53 (1.89%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	2 / 13 (15.38%)	2 / 76 (2.63%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	3 / 70 (4.29%)
occurrences all number	2	0	1	2	0	1	1	1	0	1	0	0	0	2	2	0	0	0	4
Norovirus infection
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Otitis externa
subjects affected / exposed	0 / 88 (0.00%)	1 / 26 (3.85%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Otitis media
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	1 / 26 (3.85%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Otitis media bacterial
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Pharyngitis
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	2 / 76 (2.63%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	1	0	0	0	1	0	0	0	0	0	0	0	2	1	0	0	0
Pericoronitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Paronychia
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Pharyngotonsillitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	1 / 7 (14.29%)	0 / 61 (0.00%)	1 / 55 (1.82%)	1 / 21 (4.76%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	1	0	1	0	1	1	0	0	0	0	0	0	1	0	0	0	1
Respiratory tract infection
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Rhinitis
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	3 / 81 (3.70%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	1	0	3	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Respiratory tract infection viral
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Soft tissue infection
subjects affected / exposed	0 / 88 (0.00%)	1 / 26 (3.85%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Subcutaneous abscess
subjects affected / exposed	1 / 88 (1.14%)	1 / 26 (3.85%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Tinea versicolour
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	1	0	0	0
Tinea cruris
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Tonsillitis
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	1 / 7 (14.29%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Tonsillitis bacterial
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Tooth abscess
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Tooth infection
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Urinary tract infection
subjects affected / exposed	3 / 88 (3.41%)	1 / 26 (3.85%)	3 / 81 (3.70%)	0 / 55 (0.00%)	0 / 7 (0.00%)	1 / 61 (1.64%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	3 / 61 (4.92%)	1 / 26 (3.85%)	0 / 13 (0.00%)	4 / 76 (5.26%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	5 / 70 (7.14%)
occurrences all number	3	1	3	0	0	1	1	0	0	0	0	3	1	0	5	0	0	0	6
Upper respiratory tract infection
subjects affected / exposed	2 / 88 (2.27%)	1 / 26 (3.85%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	4 / 61 (6.56%)	1 / 26 (3.85%)	0 / 13 (0.00%)	2 / 76 (2.63%)	2 / 70 (2.86%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	2	1	1	0	0	0	1	0	0	0	0	4	1	0	2	2	0	0	2
Viral infection
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	1 / 21 (4.76%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1	0	0	0
Viral pharyngitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Viral upper respiratory tract infection
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1	0	0	1	0	0	0	0
Vulvovaginal candidiasis
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1	0	0	1	0	0	0	0
COVID-19
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	4 / 61 (6.56%)	0 / 26 (0.00%)	1 / 13 (7.69%)	2 / 76 (2.63%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	4	0	1	2	1	0	0	1
Metabolism and nutrition disorders
Diabetic ketoacidosis
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Diabetes mellitus
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	1 / 26 (3.85%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	1	0	0	0	0
Dyslipidaemia
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Hyperglycaemia
subjects affected / exposed	0 / 88 (0.00%)	1 / 26 (3.85%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	1 / 21 (4.76%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	1	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	1
Hypercholesterolaemia
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Hypertriglyceridaemia
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	4 / 81 (4.94%)	1 / 55 (1.82%)	0 / 7 (0.00%)	1 / 61 (1.64%)	0 / 55 (0.00%)	1 / 21 (4.76%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	1 / 61 (1.64%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	2 / 70 (2.86%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	1	0	4	1	0	1	0	1	0	0	0	1	0	0	1	2	0	0	0
Hypermagnesaemia
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	1 / 76 (1.32%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Hyperuricaemia
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	1 / 81 (1.23%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	3 / 76 (3.95%)	1 / 70 (1.43%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	4	1	0	0	0
Hypoglycaemia
subjects affected / exposed	1 / 88 (1.14%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	1 / 61 (1.64%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	2	0	0	0	0	1	1	0	0	0	0	0	0	0	0	0	0	0	0
Metabolic disorder
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	0 / 55 (0.00%)	0 / 7 (0.00%)	0 / 61 (0.00%)	0 / 55 (0.00%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	1 / 70 (1.43%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Obesity
subjects affected / exposed	0 / 88 (0.00%)	0 / 26 (0.00%)	0 / 81 (0.00%)	1 / 55 (1.82%)	0 / 7 (0.00%)	0 / 61 (0.00%)	1 / 55 (1.82%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	0 / 26 (0.00%)	0 / 13 (0.00%)	0 / 76 (0.00%)	0 / 70 (0.00%)	0 / 210 (0.00%)	0 / 3 (0.00%)	0 / 70 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Vitamin D deficiency
subjects affected / exposed	4 / 88 (4.55%)	0 / 26 (0.00%)	2 / 81 (2.47%)	1 / 55 (1.82%)	0 / 7 (0.00%)	1 / 61 (1.64%)	2 / 55 (3.64%)	0 / 21 (0.00%)	0 / 21 (0.00%)	0 / 53 (0.00%)	0 / 3 (0.00%)	0 / 61 (0.00%)	1 / 26 (3.85%)	0 / 13 (0.00%)	5 / 76 (6.58%)	1 / 70 (1.43%)	0 / 210 (0.00%)	1 / 3 (33.33%)	2 / 70 (2.86%)
occurrences all number	4	0	2	1	0	1	2	0	0	0	0	0	1	0	5	1	0	1	2

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

11 Oct 2016

The original study design was entirely revised in accordance with Food and Drug Administration (FDA)-specified preferred study objectives and design.

04 Apr 2017

Protocol revised to reflect cessation of Bristol-Myers Squibb’s role in the study, and the specified preferred objectives and procedures following European Medicines Agency and FDA review. A post treatment visit was also added at Week 104.

04 Oct 2018

Protocol revised to reflect modifications in study design based on recommendations from FDA, i.e., addition of randomised withdrawal of background medication in a subset of eligible participants from the active treatment groups, and randomised withdrawal of background medication or switch to active treatment in a subset of eligible participants in the placebo group. Collection of vital status removed.

27 Jun 2019

Protocol revised to reflect modifications in study design, i.e., extension of the screening period and change in the screening/retesting design, update of safety concerns and monitoring of AEs of interest, revision of fasting blood glucose, growth, bone and maturation marker measurements, as well as Tanner staging schedules in participants who discontinued study drug early, and clarification of initiation or uptitration of insulin at the Rescue Visit and AE/serious AE collection until study completion. In addition, correction of the study drug dispensation schedule was incorporated and some common language added or revised in several sections for harmonisation across all AstraZeneca clinical study protocols.

24 Sep 2020

Protocol revised to specify that visits should be delayed to maintain an interval of at least 12 weeks between the Week 14 and Week 26 visits and between the third randomisation visit (for participants undergoing third randomisation) and the Week 52 visit in case the Week 14 or third randomisation visit was delayed. This change was instituted because HbA1c is derived from the average of the blood glucose fluctuation in the preceding 3 months and therefore, approximately 12 weeks of exposure to a new dose is needed to demonstrate efficacy. Short- and long-term period study visits could be delayed by a maximum of 11 months in total. If the duration of study drug administration was longer than 52 (+1) weeks, the safety follow-up period was to be shortened such that the complete study duration did not exceed 104 weeks. The Week-104 visit was not to be delayed. If more than 12 weeks elapsed between the HbA1c collection at Week 26 and the third randomisation at Week 32, or the HbA1c collection at Week 32 and the third randomisation at Week 40, the participant was not to go through this randomisation since the HbA1c value would no longer be reliable to ascertain eligibility for the third randomisation.

07 Feb 2022

Following changes made to the protocol: To allow for flexibility in scheduling, the window period for the Week 104 post-dose visit was modified from “± 7 days” to “-28 days to +7 days” from the original scheduled date. Based on discussions with FDA, the primary objective was modified to assess the effect of all doses and regimens combined for each drug vs placebo. In line with this, the primary and secondary objectives were reordered and updated. The reordering was done to make overall analysis (all doses for each treatment) as the primary objective. The secondary objectives were updated to follow the order/hierarchy of overall, followed by low-dose/high-dose regimen testing, followed by low-dose regimen testing. Corresponding to the change in primary objective, the primary analysis was updated as: “The primary analysis will be performed using an analysis of covariance (ANCOVA)”. Other key changes: Based on discussions with FDA, the analyses were updated to use a fully alpha of 0.05 to test each drug vs placebo rather than the current split into 0.025. For power analysis, the assumption of an effect size of 0.75% rather than 0.5% was used.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Due to legal dispute, the source documents could not be accessed for 11 participants at 1 site. All data from this site were excluded as documented in the statistical analysis plan.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26

Primary: Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26

Primary: Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26

Primary: Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in HbA1c at Week 26

Secondary: Dapagliflozin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

Secondary: Dapagliflozin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

Secondary: Saxagliptin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

Secondary: Saxagliptin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

Secondary: Dapagliflozin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

Secondary: Dapagliflozin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

Secondary: Saxagliptin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

Secondary: Saxagliptin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in HbA1c at Week 26

Secondary: Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26

Secondary: Dapagliflozin Versus Placebo: Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26

Secondary: Dapagliflozin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

Secondary: Dapagliflozin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

Secondary: Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in FPG at Week 26

Secondary: Saxagliptin Versus Placebo: Adjusted Mean Change From Baseline in FPG at Week 26

Secondary: Saxagliptin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

Secondary: Saxagliptin Low-dose/High-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

Secondary: Dapagliflozin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

Secondary: Dapagliflozin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

Secondary: Saxagliptin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

Secondary: Saxagliptin Low-dose Versus Placebo (Weighted): Adjusted Mean Change From Baseline in FPG at Week 26

Secondary: Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

Secondary: Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

Secondary: Low-dose/High-dose Versus Placebo (Weighted): Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

Secondary: Low-dose/High-dose Versus Placebo (Weighted): Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

Secondary: Low-dose Versus Placebo (Weighted): Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

Secondary: Low-dose Versus Placebo (Weighted): Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

Secondary: Low-dose Versus Uptitration to the High Dose: Adjusted Mean Change From Baseline in HbA1c at Week 26

Secondary: Low-dose Versus Uptitration to the High Dose: Adjusted Mean Change From Baseline in HbA1c at Week 26

Secondary: Low-dose Versus Uptitration to the High Dose: Adjusted Mean Change From Baseline in FPG at Week 26

Secondary: Low-dose Versus Uptitration to the High Dose: Adjusted Mean Change From Baseline in FPG at Week 26

Secondary: Dapagliflozin Low-dose Versus Uptitration to the High Dose: Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

Secondary: Dapagliflozin Low-dose Versus Uptitration to the High Dose: Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

Secondary: Saxagliptin Low-dose Versus Uptitration to the High Dose: Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

Secondary: Saxagliptin Low-dose Versus Uptitration to the High Dose: Percentage of Participants with Baseline HbA1c ≥ 7% who achieved HbA1c < 7% at Week 26

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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