Trial Outcomes & Findings for A Multi-Center, Randomized, Double-Blind, Phase III Trial to Evaluate the Safety and Efficacy of Saxagliptin Co-administered With Dapagliflozin Compared to Saxagliptin or Dapagliflozin All Given as add-on Therapy to Metformin in Subject With Type 2 Diabetes (NCT NCT02681094)

Last Updated: 2018-10-10

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

905 participants

Primary outcome timeframe

Baseline and week 24

Results posted on

2018-10-10

Participant Flow

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

All participants 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 was signed and review of concomitant or other medications/therapies were performed.

Participant milestones

Participant milestones
Measure	Dapagliflozin + Saxagliptin + Metformin 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)	Dapagliflozin + Metformin 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)	Saxagliptin + Metformin 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)
1 -Modified Enrolled Participants Set STARTED	293	294	296
1 -Modified Enrolled Participants Set Participants Completed Treatment Period	273	276	283
1 -Modified Enrolled Participants Set COMPLETED	256	255	243
1 -Modified Enrolled Participants Set NOT COMPLETED	37	39	53
2 - Enrolled Participants Set STARTED	301	302	302
2 - Enrolled Participants Set Participants Completed Treatment Period	281	284	289
2 - Enrolled Participants Set COMPLETED	261	261	248
2 - Enrolled Participants Set NOT COMPLETED	40	41	54

Reasons for withdrawal

Reasons for withdrawal
Measure	Dapagliflozin + Saxagliptin + Metformin 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)	Dapagliflozin + Metformin 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)	Saxagliptin + Metformin 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)
1 -Modified Enrolled Participants Set Participant decision	7	10	9
1 -Modified Enrolled Participants Set Adverse Event	10	4	1
1 -Modified Enrolled Participants Set Severe non-compliance to protocol	2	0	1
1 -Modified Enrolled Participants Set Lack of therapeutic response	1	5	14
1 -Modified Enrolled Participants Set Study-specific discontinuation criteria	11	13	20
1 -Modified Enrolled Participants Set Other	6	6	7
1 -Modified Enrolled Participants Set No treatment given	0	1	1
2 - Enrolled Participants Set Participant decision	7	10	9
2 - Enrolled Participants Set Adverse Event	10	4	1
2 - Enrolled Participants Set Severe non-compliance to protocol	2	0	1
2 - Enrolled Participants Set Lack of therapeutic response	1	5	14
2 - Enrolled Participants Set Study specific discontinuation criteria	14	15	21
2 - Enrolled Participants Set Other	6	6	7
2 - Enrolled Participants Set No treatment given	0	1	1

Baseline Characteristics

A Multi-Center, Randomized, Double-Blind, Phase III Trial to Evaluate the Safety and Efficacy of Saxagliptin Co-administered With Dapagliflozin Compared to Saxagliptin or Dapagliflozin All Given as add-on Therapy to Metformin in Subject With Type 2 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dapagliflozin + Saxagliptin + Metformin n=290 Participants 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)	Dapagliflozin + Metformin n=289 Participants 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)	Saxagliptin + Metformin n=291 Participants 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)	Total n=870 Participants Total of all reporting groups
Age, Continuous	57.2 Years STANDARD_DEVIATION 10.68 • n=5 Participants	55.9 Years STANDARD_DEVIATION 10.94 • n=7 Participants	57.0 Years STANDARD_DEVIATION 9.94 • n=5 Participants	56.7 Years STANDARD_DEVIATION 10.53 • n=4 Participants
Sex: Female, Male Female	148 Participants n=5 Participants	137 Participants n=7 Participants	134 Participants n=5 Participants	419 Participants n=4 Participants
Sex: Female, Male Male	142 Participants n=5 Participants	152 Participants n=7 Participants	157 Participants n=5 Participants	451 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	99 Participants n=5 Participants	95 Participants n=7 Participants	99 Participants n=5 Participants	293 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	191 Participants n=5 Participants	194 Participants n=7 Participants	192 Participants n=5 Participants	577 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	3 Participants n=7 Participants	0 Participants n=5 Participants	4 Participants n=4 Participants
Race (NIH/OMB) Asian	9 Participants n=5 Participants	9 Participants n=7 Participants	6 Participants n=5 Participants	24 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	10 Participants n=5 Participants	17 Participants n=7 Participants	24 Participants n=5 Participants	51 Participants n=4 Participants
Race (NIH/OMB) White	265 Participants n=5 Participants	257 Participants n=7 Participants	258 Participants n=5 Participants	780 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	11 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and week 24

Population: FAS: All randomized participants who took at least one dose of the study medication and had a baseline value for HbA1c. Analysis of the FAS was based on the randomized treatment. The modified FAS included all participants from FAS with the exception of participants from one site (excluded due to serious GCP violations).

Outcome measures

Outcome measures
Measure	Dapagliflozin + Saxagliptin + Metformin n=290 Participants 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)	Dapagliflozin + Metformin n=289 Participants 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)	Saxagliptin + Metformin n=291 Participants 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)
Change From Baseline in HbA1c at Week 24	-1.03 Percentage (%) Standard Error 0.0558	-0.63 Percentage (%) Standard Error 0.0560	-0.69 Percentage (%) Standard Error 0.0551

SECONDARY outcome

Timeframe: Baseline and week 24

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

Outcome measures

Outcome measures
Measure	Dapagliflozin + Saxagliptin + Metformin n=290 Participants 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)	Dapagliflozin + Metformin n=289 Participants 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)	Saxagliptin + Metformin n=291 Participants 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)
Proportion of Participants Achieving HbA1c <7.0% at 24 Weeks	124 Participants	63 Participants	83 Participants

SECONDARY outcome

Timeframe: Baseline and week 24

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.

Outcome measures

Outcome measures
Measure	Dapagliflozin + Saxagliptin + Metformin n=290 Participants 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)	Dapagliflozin + Metformin n=289 Participants 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)	Saxagliptin + Metformin n=291 Participants 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)
Change in Fasting Plasma Glucose at 24 Weeks	-27.53 Milligrams per deciliter (mg/dL) Standard Error 2.1557	-19.95 Milligrams per deciliter (mg/dL) Standard Error 2.1738	-12.66 Milligrams per deciliter (mg/dL) Standard Error 2.1373

SECONDARY outcome

Timeframe: Baseline and week 24

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.

Outcome measures

Outcome measures
Measure	Dapagliflozin + Saxagliptin + Metformin n=290 Participants 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)	Dapagliflozin + Metformin n=291 Participants 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)	Saxagliptin + Metformin 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)
Change in Total Body Weight at 24 Weeks	-2.01 Kilograms (Kg) Standard Error 0.1829	-0.41 Kilograms (Kg) Standard Error 0.1815	—

Adverse Events

Dapagliflozin + Saxagliptin + Metformin

Serious events: 7 serious events

Other events: 41 other events

Deaths: 1 deaths

Dapagliflozin + Metformin

Serious events: 8 serious events

Other events: 39 other events

Deaths: 2 deaths

Saxagliptin + Metformin

Serious events: 7 serious events

Other events: 29 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Dapagliflozin + Saxagliptin + Metformin n=293 participants at risk 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)	Dapagliflozin + Metformin n=293 participants at risk 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)	Saxagliptin + Metformin n=295 participants at risk 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)
Investigations Glomerular filtration rate decreased	4.1% 12/293 • Number of events 13 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.	3.8% 11/293 • Number of events 11 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.	1.7% 5/295 • Number of events 5 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.
Infections and infestations Urinary tract infection	2.4% 7/293 • Number of events 7 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.	1.0% 3/293 • Number of events 4 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.	1.7% 5/295 • Number of events 5 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.
Renal and urinary disorders Pollakiuria	2.4% 7/293 • Number of events 8 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.	0.34% 1/293 • Number of events 1 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.	0.00% 0/295 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.
Gastrointestinal disorders Nausea	2.0% 6/293 • Number of events 6 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.	1.7% 5/293 • Number of events 5 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.	1.0% 3/295 • Number of events 3 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.
Infections and infestations Viral upper respiratory tract infection	1.7% 5/293 • Number of events 5 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.	3.1% 9/293 • Number of events 10 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.	2.7% 8/295 • Number of events 8 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.
Infections and infestations Influenza	1.0% 3/293 • Number of events 3 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.	3.1% 9/293 • Number of events 9 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.	1.0% 3/295 • Number of events 3 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.
Infections and infestations Upper respiratory tract infection	1.0% 3/293 • Number of events 4 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.	1.4% 4/293 • Number of events 4 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.	2.0% 6/295 • Number of events 6 • From time of randomization, and throughout the treatment period and until end of treatment (Visit 5)/early termination + 4 days for non serious AEs and 30 days for SAEs. An undesirable medical condition could be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver)/abnormal results of an investigation (eg, laboratory findings, electrocardiogram). One participant was randomized but did not receive treatment in Dapagliflozin+Metformin and Saxagliptin + Metformin groups.

Additional Information

Global Clinical Leader

AstraZeneca

Phone: +46 766 346712

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee All clinical study findings and documents will be regarded as confidential. The investigator and members of his/her research team must not disclose such information without prior written approval from the sponsor.
Publication restrictions are in place

Restriction type: OTHER