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Clinical Trial Results:
A Multi-Center, Randomised, Double-Blind, Active-Controlled, Parallel Group, Phase III Trial to Evaluate the Safety and Efficacy of Saxagliptin 5 mg Co-administered with Dapagliflozin 5 mg compared to Saxagliptin 5 mg or Dapagliflozin 5 mg all given as Add-on therapy to Metformin in Patients with Type 2 Diabetes who have Inadequate Glycaemic Control on Metformin Alone

Summary
EudraCT number	2015-005406-11
Trial protocol	DE CZ
Global end of trial date	15 Jul 2017

Results information
Results version number	v1(current)
This version publication date	22 Jul 2018
First version publication date	22 Jul 2018
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

D1683C00005

ISRCTN number

US NCT number

NCT02681094

WHO universal trial number (UTN)

Sponsor organisation name

AstraZeneca

Sponsor organisation address

Södertälje, Södertälje, Sweden, S-151 85

Public contact

Information Centre, AstraZeneca AB, Information Centre, AstraZeneca AB, +1 800 2369933, information.centre@astrazeneca.com

Scientific contact

Global Clinical Leader, AstraZeneca, +46 766 346712, clinicaltrialtransparency@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?

Analysis stage

Final

Date of interim/final analysis

15 Jul 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

15 Jul 2017

Global end of trial reached?

Yes

Global end of trial date

15 Jul 2017

Was the trial ended prematurely?

Main objective of the trial

To demonstrate the superiority of the change from baseline glycated haemoglobin (HbA1c) achieved with the co-dministered saxagliptin 5 mg and dapagliflozin 5 mg to either agent individually after 24 weeks

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 Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples. At each site, subject was given full and adequate oral and written information about the nature, purpose, possible benefit and risk of the study. Subject was given opportunity to ask questions and time to consider the information provided. Subjects signed informed consent form (ICF) before conducting any procedure specifically for the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

26 Feb 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 100

Country: Number of subjects enrolled

United States: 299

Country: Number of subjects enrolled

Czech Republic: 101

Country: Number of subjects enrolled

Germany: 65

Country: Number of subjects enrolled

Mexico: 109

Country: Number of subjects enrolled

Russian Federation: 196

Worldwide total number of subjects

870

EEA total number of subjects

166

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)

Adults (18-64 years)

652

From 65 to 84 years

217

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 119 sites in 6 countries: Canada, Czech Republic, Germany, Mexico, Russia, and United States (US). Approximately 900 subjects were to be randomized. Subjects with Type 2 Diabetes (T2DM) inadequately controlled on metformin alone were randomized in this study.

Screening details

Subjects had screening (Visit 0) at 1 week prior to enrolment to screen the eligibility based on non-fasting sample of Glycated haemoglobin (Hb A1c); results of HbA1c determined enrolment based on inclusion/exclusion criteria. An abbreviated informed consent form was signed and review of concomitant or other medications/therapies were performed.

Period 1 title

1 - Modified full analysis set

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Subject

Blinding implementation details

Randomized subjects received orally once daily (QD) dapagliflozin 5 mg and saxagliptin 5 mg film coated tablets as an add-on to metformin (≥1500 mg/day orally)

Are arms mutually exclusive

Yes

Dapagliflozin + Saxagliptin + Metformin

Arm description

Randomized participants received orally once daily (QD) dapagliflozin 5 mg and saxagliptin 5 mg film coated tablets as an add-on to metformin (≥1500 mg/day orally)

Arm type

Experimental

Investigational medicinal product name

Dapagliflozin + Saxagliptin + Metformin

Investigational medicinal product code

Other name

Dapagliflozin: Farxiga™ Saxagliptin: ONGLYZA

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Dapagliflozin 5 mg and saxagliptin 5 mg tablets as an add-on to metformin (≥1500 mg/day orally) tablet QD orally

Dapagliflozin + Metformin

Arm description

Randomized participants received orally QD dapagliflozin 5 mg film coated tablet and placebo for saxagliptin as an add-on to metformin (≥1500 mg/day orally)

Arm type

Experimental

Investigational medicinal product name

Dapagliflozin + Metformin

Investigational medicinal product code

Other name

Dapagliflozin: Forxiga™

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Dapagliflozin 5 mg and placebo for saxagliptin as an add-on to metformin (≥1500 mg/day orally) tablet QD orally

Saxagliptin + Metformin

Arm description

Randomized participants received orally QD saxagliptin 5 mg film coated tablet and placebo for dapagliflozin as an add-on to metformin (≥1500 mg/day orally)

Arm type

Experimental

Investigational medicinal product name

Saxagliptin + Metformin

Investigational medicinal product code

Other name

Saxagliptin: ONGLYZA

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Saxagliptin 5 mg and placebo for dapagliflozin as an add-on to metformin (≥1500 mg/day orally) tablet QD orally

Number of subjects in period 1	Dapagliflozin + Saxagliptin + Metformin	Dapagliflozin + Metformin	Saxagliptin + Metformin
Started	290	289	291
Completed	290	289	291

Period 2 title

2 -Modified Enrolled subjects set

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Dapagliflozin + Saxagliptin + Metformin

Arm description

Randomized participants received orally once daily (QD) dapagliflozin 5 mg and saxagliptin 5 mg film coated tablets as an add-on to metformin (≥1500 mg/day orally)

Arm type

Experimental

Investigational medicinal product name

Dapagliflozin + Saxagliptin + Metformin

Investigational medicinal product code

Other name

Dapagliflozin: Farxiga™ Saxagliptin: ONGLYZA

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Dapagliflozin 5 mg and saxagliptin 5 mg tablets as an add-on to metformin (≥1500 mg/day orally) tablet QD orally

Dapagliflozin + Metformin

Arm description

Randomized participants received orally QD dapagliflozin 5 mg film coated tablet and placebo for saxagliptin as an add-on to metformin (≥1500 mg/day orally)

Arm type

Experimental

Investigational medicinal product name

Dapagliflozin + Metformin

Investigational medicinal product code

Other name

Dapagliflozin: Farxiga™

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Dapagliflozin 5 mg and placebo for saxagliptin as an add-on to metformin (≥1500 mg/day orally) tablet QD orally

Saxagliptin + Metformin

Arm description

Randomized participants received orally QD saxagliptin 5 mg film coated tablet and placebo for dapagliflozin as an add-on to metformin (≥1500 mg/day orally)

Arm type

Experimental

Investigational medicinal product name

Saxagliptin + Metformin

Investigational medicinal product code

Other name

Saxagliptin: ONGLYZA

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Saxagliptin 5 mg and placebo for dapagliflozin as an add-on to metformin (≥1500 mg/day orally) tablet QD orally

Number of subjects in period 2	Dapagliflozin + Saxagliptin + Metformin	Dapagliflozin + Metformin	Saxagliptin + Metformin
Started	293	294	296
Completed treatment	273	276	283
Completed	256	255	243
Not completed	37	39	53
Severe non-compliance to protocol	2	-	1
Lack of therapeutic response	1	5	14
Subject decision	7	10	9
Adverse event, non-fatal	10	4	1
Not specified	6	6	7
Study-specific discontinuation criteria	11	13	20
No treatment given	-	1	1

Period 3 title

3 - Enrolled subjects set

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Dapagliflozin + Saxagliptin + Metformin

Arm description

Randomized participants received orally once daily (QD) dapagliflozin 5 mg and saxagliptin 5 mg film coated tablets as an add-on to metformin (≥1500 mg/day orally)

Arm type

Experimental

Investigational medicinal product name

Dapagliflozin + Saxagliptin + Metformin

Investigational medicinal product code

Other name

Dapagliflozin: Farxiga™ Saxagliptin: ONGLYZA

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Dapagliflozin 5 mg and saxagliptin 5 mg tablets as an add-on to metformin (≥1500 mg/day orally) tablet QD orally

Dapagliflozin + Metformin

Arm description

Randomized participants received orally QD dapagliflozin 5 mg film coated tablet and placebo for saxagliptin as an add-on to metformin (≥1500 mg/day orally)

Arm type

Experimental

Investigational medicinal product name

Dapagliflozin + Metformin

Investigational medicinal product code

Other name

Dapagliflozin: Farxiga™

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Dapagliflozin 5 mg and placebo for saxagliptin as an add-on to metformin (≥1500 mg/day orally) tablet QD orally

Saxagliptin + Metformin

Arm description

Randomized participants received orally QD saxagliptin 5 mg film coated tablet and placebo for dapagliflozin as an add-on to metformin (≥1500 mg/day orally)

Arm type

Experimental

Investigational medicinal product name

Saxagliptin + Metformin

Investigational medicinal product code

Other name

Saxagliptin: ONGLYZA

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Saxagliptin 5 mg and placebo for dapagliflozin as an add-on to metformin (≥1500 mg/day orally) tablet QD orally

Number of subjects in period 3	Dapagliflozin + Saxagliptin + Metformin	Dapagliflozin + Metformin	Saxagliptin + Metformin
Started	301	302	302
Completed treatment	281	284	289
Completed	261	261	248
Not completed	40	41	54
Severe non-compliance to protocol	2	-	1
Study specific discontinuation criteria	14	15	21
Lack of therapeutic response	1	5	14
Subject decision	7	10	9
Adverse event, non-fatal	10	4	1
Not specified	6	6	7
No treatment given	-	1	1

Baseline characteristics

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Reporting group title

Dapagliflozin + Saxagliptin + Metformin

Reporting group description

Randomized participants received orally once daily (QD) dapagliflozin 5 mg and saxagliptin 5 mg film coated tablets as an add-on to metformin (≥1500 mg/day orally)

Reporting group title

Dapagliflozin + Metformin

Reporting group description

Randomized participants received orally QD dapagliflozin 5 mg film coated tablet and placebo for saxagliptin as an add-on to metformin (≥1500 mg/day orally)

Reporting group title

Saxagliptin + Metformin

Reporting group description

Randomized participants received orally QD saxagliptin 5 mg film coated tablet and placebo for dapagliflozin as an add-on to metformin (≥1500 mg/day orally)

Reporting group values	Dapagliflozin + Saxagliptin + Metformin	Dapagliflozin + Metformin	Saxagliptin + Metformin	Total
Number of subjects	290	289	291	870
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	212	219	221	652
From 65-84 years	78	69	70	217
85 years and over	0	1	0	1
Age Continuous
Units: Years
arithmetic mean (standard deviation)	57.2 ( 10.68 )	55.9 ( 10.94 )	57.0 ( 9.94 )	-
Sex: Female, Male
Units: Subjects
Female	148	137	134	419
Male	142	152	157	451
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	1	3	0	4
Asian	9	9	6	24
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	10	17	24	51
White	265	257	258	780
More than one race	0	0	0	0
Unknown or Not Reported	5	3	3	11
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	99	95	99	293
Not Hispanic or Latino	191	194	192	577
Unknown or Not Reported	0	0	0	0

End points

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Reporting group title

Dapagliflozin + Saxagliptin + Metformin

Reporting group description

Randomized participants received orally once daily (QD) dapagliflozin 5 mg and saxagliptin 5 mg film coated tablets as an add-on to metformin (≥1500 mg/day orally)

Reporting group title

Dapagliflozin + Metformin

Reporting group description

Randomized participants received orally QD dapagliflozin 5 mg film coated tablet and placebo for saxagliptin as an add-on to metformin (≥1500 mg/day orally)

Reporting group title

Saxagliptin + Metformin

Reporting group description

Randomized participants received orally QD saxagliptin 5 mg film coated tablet and placebo for dapagliflozin as an add-on to metformin (≥1500 mg/day orally)

Reporting group title

Dapagliflozin + Saxagliptin + Metformin

Reporting group description

Randomized participants received orally once daily (QD) dapagliflozin 5 mg and saxagliptin 5 mg film coated tablets as an add-on to metformin (≥1500 mg/day orally)

Reporting group title

Dapagliflozin + Metformin

Reporting group description

Randomized participants received orally QD dapagliflozin 5 mg film coated tablet and placebo for saxagliptin as an add-on to metformin (≥1500 mg/day orally)

Reporting group title

Saxagliptin + Metformin

Reporting group description

Randomized participants received orally QD saxagliptin 5 mg film coated tablet and placebo for dapagliflozin as an add-on to metformin (≥1500 mg/day orally)

Reporting group title

Dapagliflozin + Saxagliptin + Metformin

Reporting group description

Randomized participants received orally once daily (QD) dapagliflozin 5 mg and saxagliptin 5 mg film coated tablets as an add-on to metformin (≥1500 mg/day orally)

Reporting group title

Dapagliflozin + Metformin

Reporting group description

Randomized participants received orally QD dapagliflozin 5 mg film coated tablet and placebo for saxagliptin as an add-on to metformin (≥1500 mg/day orally)

Reporting group title

Saxagliptin + Metformin

Reporting group description

Randomized participants received orally QD saxagliptin 5 mg film coated tablet and placebo for dapagliflozin as an add-on to metformin (≥1500 mg/day orally)

Primary: Change from baseline in HbA1c at Week 24

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End point title

Change from baseline in HbA1c at Week 24

End point description

To demonstrate the superiority of the change from baseline HbA1c achieved with the co-administered saxagliptin 5 mg and dapagliflozin 5 mg to either agent individually after 24 weeks. Results were presented for the modified full analysis set. Note: Baseline was defined as the last assessment on or prior to the date of the first dose of the study medication.

End point type

Primary

End point timeframe

At week 24

End point values	Dapagliflozin + Saxagliptin + Metformin	Dapagliflozin + Metformin	Saxagliptin + Metformin
Number of subjects analysed	284	280	288
Units: Percentage (%)
least squares mean (standard error)	-1.03 ( 0.0558 )	-0.63 ( 0.0560 )	-0.69 ( 0.0551 )

Dapa + Saxa + Met Versus Dapa + Met

Comparison groups

Dapagliflozin + Saxagliptin + Metformin v Dapagliflozin + Metformin

Number of subjects included in analysis

564

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LS mean difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.55

upper limit

-0.24

Dapa + Saxa + Met Versus Saxa + Met

Comparison groups

Dapagliflozin + Saxagliptin + Metformin v Saxagliptin + Metformin

Number of subjects included in analysis

572

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LS mean difference

Point estimate

-0.34

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

-0.19

Secondary: Proportion of subjects achieving HbA1c <7.0% at 24 weeks

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End point title

Proportion of subjects achieving HbA1c <7.0% at 24 weeks

End point description

To demonstrate the effect of the co-administered saxagliptin 5 mg and dapagliflozin 5 mg to either agent individually on proportion of patients achieving therapeutic glycaemic response after 24 weeks. Therapeutic glycaemic response was defined as an HbA1c value at Week 24 <7.0% irrespective of whether subject received rescue medication. Subjects who did not had an HbA1c measurement at Week 24 were regarded as non-responders. Results were presented for the modified full analysis set.

End point type

Secondary

End point timeframe

After week 24

End point values	Dapagliflozin + Saxagliptin + Metformin	Dapagliflozin + Metformin	Saxagliptin + Metformin
Number of subjects analysed	290	289	291
Units: Percentages of response rate
number (not applicable)
Responder\|	124	63	83
Response rate\|	42.8	21.8	28.5
Adjusted response rate\|	41.6	21.8	29.8

Dapa + Saxa + Met Versus Dapa + Met

Comparison groups

Dapagliflozin + Saxagliptin + Metformin v Dapagliflozin + Metformin

Number of subjects included in analysis

579

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Method of Zhang, Tsiatis, and Davidian

Parameter type

Risk difference (RD)

Point estimate

19.8

Confidence interval

level

95%

sides

2-sided

lower limit

12.7

upper limit

26.9

Dapa + Saxa + Met Versus Saxa + Met

Comparison groups

Dapagliflozin + Saxagliptin + Metformin v Saxagliptin + Metformin

Number of subjects included in analysis

581

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0018

Method

Method of Zhang, Tsiatis, and Davidian

Parameter type

Risk difference (RD)

Point estimate

11.7

Confidence interval

level

95%

sides

2-sided

lower limit

4.4

upper limit

19.1

Secondary: Change in fasting plasma glucose at 24 weeks

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End point title

Change in fasting plasma glucose at 24 weeks

End point description

To demonstrate the effect of the co-administered saxagliptin 5 mg and dapagliflozin 5mg to either agent individually on fasting plasma glucose after 24 weeks. Results were presented for the modified full analysis set. Note: Baseline was defined as the last assessment on or prior to the date of the first dose of the study medication.

End point type

Secondary

End point timeframe

After week 24

End point values	Dapagliflozin + Saxagliptin + Metformin	Dapagliflozin + Metformin	Saxagliptin + Metformin
Number of subjects analysed	284	278	287
Units: Milligrams per deciliter (mg/dL)
least squares mean (standard error)	-27.53 ( 2.1557 )	-19.95 ( 2.1738 )	-12.66 ( 2.1373 )

Dapa + Saxa + Met Versus Dapa + Met

Comparison groups

Dapagliflozin + Saxagliptin + Metformin v Dapagliflozin + Metformin

Number of subjects included in analysis

562

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0135

Method

Mixed models analysis

Parameter type

LS mean difference

Point estimate

-7.58

Confidence interval

level

95%

sides

2-sided

lower limit

-13.59

upper limit

-1.57

Dapa + Saxa + Met Versus Saxa + Met

Comparison groups

Dapagliflozin + Saxagliptin + Metformin v Saxagliptin + Metformin

Number of subjects included in analysis

571

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LS mean difference

Point estimate

-14.88

Confidence interval

level

95%

sides

2-sided

lower limit

-20.85

upper limit

-8.91

Secondary: Change in total body weight at 24 weeks

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End point title

Change in total body weight at 24 weeks ^[1]

End point description

To demonstrate the effect of the co-administered saxagliptin 5 mg and dapagliflozin 5 mg to saxagliptin 5 mg on total body weight after 24 weeks. Results were presented for the modified full analysis set. Note: Baseline was defined as the last assessment on or prior to the date of the first dose of the study medication.

End point type

Secondary

End point timeframe

After week 24

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: 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.

End point values	Dapagliflozin + Saxagliptin + Metformin	Saxagliptin + Metformin
Number of subjects analysed	284	288
Units: Kilograms (Kg)
least squares mean (standard error)	-2.01 ( 0.1829 )	-0.41 ( 0.1815 )

Dapa + Saxa + Met Versus Saxa + Met

Comparison groups

Dapagliflozin + Saxagliptin + Metformin v Saxagliptin + Metformin

Number of subjects included in analysis

572

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LS mean difference

Point estimate

-1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.11

upper limit

-1.09

Adverse events

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Timeframe for reporting adverse events

At enrolment, throughout the treatment period and end of treatment /early termination.

Adverse event reporting additional description

Adverse event (AE; both serious and non-serious) - undesirable medical condition (symptoms [eg, nausea], signs [eg, tachycardia]/ abnormal investigation results [eg, laboratory findings])/deterioration of pre-existing medical condition following/during exposure to a pharmaceutical product, whether/not considered causally related to the product

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Dapagliflozin + Saxagliptin + Metformin

Reporting group description

Randomized subjects received orally once daily (QD) dapagliflozin 5 mg and saxagliptin 5 mg film coated tablets as an add-on to metformin (≥1500 mg/day orally)

Reporting group title

Saxagliptin + Metformin

Reporting group description

Randomized subjects received orally QD saxagliptin 5 mg film coated tablet and placebo for dapagliflozin as an add-on to metformin (≥1500 mg/day orally)

Reporting group title

Dapagliflozin + Metformin

Reporting group description

Randomized subjects received orally QD dapagliflozin 5 mg film coated tablet and placebo for saxagliptin as an add-on to metformin (≥1500 mg/day orally)

Serious adverse events	Dapagliflozin + Saxagliptin + Metformin	Saxagliptin + Metformin	Dapagliflozin + Metformin
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 293 (2.39%)	7 / 295 (2.37%)	8 / 293 (2.73%)
number of deaths (all causes)	1	0	2
number of deaths resulting from adverse events	0	0	0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 293 (0.00%)	1 / 295 (0.34%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 293 (0.00%)	1 / 295 (0.34%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	1 / 293 (0.34%)	0 / 295 (0.00%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	1 / 293 (0.34%)	0 / 295 (0.00%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Sternal fracture
subjects affected / exposed	1 / 293 (0.34%)	0 / 295 (0.00%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 293 (0.00%)	0 / 295 (0.00%)	1 / 293 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Arteritis
subjects affected / exposed	1 / 293 (0.34%)	0 / 295 (0.00%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	1 / 293 (0.34%)	0 / 295 (0.00%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina unstable
subjects affected / exposed	1 / 293 (0.34%)	0 / 295 (0.00%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 293 (0.34%)	0 / 295 (0.00%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 293 (0.00%)	0 / 295 (0.00%)	1 / 293 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Tachycardia
subjects affected / exposed	0 / 293 (0.00%)	0 / 295 (0.00%)	1 / 293 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular arrhythmia
subjects affected / exposed	0 / 293 (0.00%)	0 / 295 (0.00%)	1 / 293 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 293 (0.00%)	0 / 295 (0.00%)	2 / 293 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basal ganglia haemorrhage
subjects affected / exposed	0 / 293 (0.00%)	0 / 295 (0.00%)	1 / 293 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbosacral radiculopathy
subjects affected / exposed	0 / 293 (0.00%)	1 / 295 (0.34%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 293 (0.34%)	0 / 295 (0.00%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 293 (0.00%)	1 / 295 (0.34%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 293 (0.00%)	0 / 295 (0.00%)	1 / 293 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 293 (0.00%)	1 / 295 (0.34%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 293 (0.00%)	1 / 295 (0.34%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	1 / 293 (0.34%)	0 / 295 (0.00%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	0 / 293 (0.00%)	1 / 295 (0.34%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 293 (0.00%)	0 / 295 (0.00%)	1 / 293 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Osteomyelitis
subjects affected / exposed	0 / 293 (0.00%)	1 / 295 (0.34%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 293 (0.00%)	1 / 295 (0.34%)	0 / 293 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 293 (0.00%)	0 / 295 (0.00%)	1 / 293 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	0 / 293 (0.00%)	0 / 295 (0.00%)	1 / 293 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	Dapagliflozin + Saxagliptin + Metformin	Saxagliptin + Metformin	Dapagliflozin + Metformin
Total subjects affected by non serious adverse events
subjects affected / exposed	41 / 293 (13.99%)	29 / 295 (9.83%)	39 / 293 (13.31%)
Investigations
Glomerular filtration rate decreased
subjects affected / exposed	12 / 293 (4.10%)	5 / 295 (1.69%)	11 / 293 (3.75%)
occurrences all number	13	5	11
Gastrointestinal disorders
Nausea
subjects affected / exposed	6 / 293 (2.05%)	3 / 295 (1.02%)	5 / 293 (1.71%)
occurrences all number	6	3	5
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	7 / 293 (2.39%)	0 / 295 (0.00%)	1 / 293 (0.34%)
occurrences all number	8	0	1
Infections and infestations
Urinary tract infection
subjects affected / exposed	7 / 293 (2.39%)	5 / 295 (1.69%)	3 / 293 (1.02%)
occurrences all number	7	5	4
Viral upper respiratory tract infection
subjects affected / exposed	5 / 293 (1.71%)	8 / 295 (2.71%)	9 / 293 (3.07%)
occurrences all number	5	8	10
Influenza
subjects affected / exposed	3 / 293 (1.02%)	3 / 295 (1.02%)	9 / 293 (3.07%)
occurrences all number	3	3	9
Upper respiratory tract infection
subjects affected / exposed	3 / 293 (1.02%)	6 / 295 (2.03%)	4 / 293 (1.37%)
occurrences all number	4	6	4

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Were there any global substantial amendments to the protocol? Yes

08 Jan 2016

Amendment 1: - Information on ketoacidosis was added to the Benefit/risk and ethical assessment of the clinical study protocol (CSP). - The differentiation between treatment discontinuation from study withdrawal was clarified. - Additional reasons for discontinuation of the study were included in the CSP. - The CSP was clarified with regards to allowing HbA1c re-testing at screening under specific conditions.

18 Jan 2016

Amendment 2: - Section 3.9.1 was updated to clearly differentiate treatment discontinuation from study withdrawal by removing ‘Lost to follow-up’ since this was one of the reason for study withdrawal. - The sections on diabetic ketoacidosis (DKA) and DKA adjudication were removed and to be updated after the review from FDA regarding the relevant text to be added in CSP. - Management of maternal exposure cases was clarified. If a subject became pregnant during the course of study all study medication was to be discontinued immediately. Subject was to be continued in the study as per original visit schedule.

04 Aug 2016

Amendment 3: - Inclusion criteria: FPG criteria were described in mmol/L, and male condom with spermicidal gel was added as an acceptable birth control method. - Exclusion criteria: criterion 8(a) was updated and mentioned as a 8(b) to exclude any exposure of DPP-4 and SGLT-2 inhibitor within 8 weeks prior to enrolment. - Methods for unblinding: pharmacists were removed from the list of persons having access to individual treatment codes. - Study-specific discontinuation criteria: a note was added to withhold study medication when eGFR <60 mL/min/1.73 m2 (by MDRD) until retest eGFR result were available only for randomization visit. – Study Plan: footnote 'k' was added to clarify that rescue medication should also be returned for rescued subjects at Visit 4 & 5. Footnote 'h' was updated to make it clear on pregnancy testing. Visit window for enrolment visit was changed to be consistent with footnote 'c'. Return study medication was added. Study Medication Compliance Review marked for Visit 3. Collect unused study medication/supplies was removed - Enrolment visit: review of the patient diary was removed. - Treatment period visits: provision of patient diary & instructions was removed, and study medication were dispensed and returned at Visit 4. - Description of the time period for collection of AEs: discontinuation visit was deleted. - The reference for the hypoglycaemia classification was updated. - Specific reporting requirements for liver test abnormalities accompanied by jaundice/hyperbilirubinemia, opportunistic infections & severe hypersensitivity were removed. - Treatment compliance evaluation: an upper limit of ≤120% of the prescribed dose was added. - Guidance on management of sustained elevated liver safety abnormalities (CSP Appendix D): a correction was made indicating that subject had to be discontinued from study medication and not from study. - Guidance on actions required in cases of increases in liver biochemistry & evaluation of Hy’s Law was added.

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.

None reported

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Baseline characteristics

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End points

End points

Primary: Change from baseline in HbA1c at Week 24

Primary: Change from baseline in HbA1c at Week 24

Secondary: Proportion of subjects achieving HbA1c <7.0% at 24 weeks

Secondary: Proportion of subjects achieving HbA1c <7.0% at 24 weeks

Secondary: Change in fasting plasma glucose at 24 weeks

Secondary: Change in fasting plasma glucose at 24 weeks

Secondary: Change in total body weight at 24 weeks

Secondary: Change in total body weight at 24 weeks

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