Trial Outcomes & Findings for A Study to Assess the Bioequivalence of Dapagliflozin/Metformin XR Fixed-dose Combination Tablets in Healthy Subjects (NCT NCT02637037)

Results Overview

To evaluate the Bioequivalence for Dapagliflozin and Metformin following administration Dapagliflozin/Metformin XR 5/500 mg and 10/1000 mg Manufactured at Mt. Vernon plant, US, Compared to Humacao plant, Puerto Rico, in the Fasted or Fed state.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

80 participants

Primary outcome timeframe

Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period

Results posted on

2018-03-13

Participant Flow

This study was conducted at PAREXEL International, Early Phase Clinical Unit Baltimore, United States of America. Subjects were randomized into 4-period, 4-treatment (per study part) crossover (4 sequences containing 4 treatments) in fed and fasted state.

Sequences 1, 2, 3 and 4 Part 1: ABCD, BADC, ABDC, BACD Part 2: EFGH, FEHG, EFHG, FEGH (A = test, fed; B = reference, fed; C = test, fasted; D = reference, fasted; E = test, fed; F = reference, fed; G = test, fasted; H = reference, fasted) A total of 80 subjects were randomized into the study

Participant milestones

Participant milestones
Measure	Part 1 Sequences 1, 2, 3 and 4- each sequence had 10 subjects; Part 1: ABCD, BADC, ABDC, BACD (A = test, fed; B = reference, fed; C = test, fasted; D = reference, fasted) Part 1: Test: Dapagliflozin/metformin XR mg manufactured at Mount Vernon plant (1 x 5/500 mg); Reference: Dapagliflozin/metformin XR mg manufactured at Humacao plant (1 x 5/500 mg)	Part 2 Sequences 1, 2, 3 and 4 - each sequence had 10 subjects Part 2: EFGH, FEHG, EFHG, FEGH (E = test, fed; F = reference, fed; G = test, fasted; H = reference, fasted) Part 2: Test: Dapagliflozin/metformin XR manufactured at Mount Vernon plant (1 x 10/1000 mg); Reference: Dapagliflozin/metformin XR manufactured at Humacao plant (1 x 10/1000 mg)
Overall Study STARTED	40	40
Overall Study COMPLETED	36	39
Overall Study NOT COMPLETED	4	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 1 Sequences 1, 2, 3 and 4- each sequence had 10 subjects; Part 1: ABCD, BADC, ABDC, BACD (A = test, fed; B = reference, fed; C = test, fasted; D = reference, fasted) Part 1: Test: Dapagliflozin/metformin XR mg manufactured at Mount Vernon plant (1 x 5/500 mg); Reference: Dapagliflozin/metformin XR mg manufactured at Humacao plant (1 x 5/500 mg)	Part 2 Sequences 1, 2, 3 and 4 - each sequence had 10 subjects Part 2: EFGH, FEHG, EFHG, FEGH (E = test, fed; F = reference, fed; G = test, fasted; H = reference, fasted) Part 2: Test: Dapagliflozin/metformin XR manufactured at Mount Vernon plant (1 x 10/1000 mg); Reference: Dapagliflozin/metformin XR manufactured at Humacao plant (1 x 10/1000 mg)
Overall Study Positive drug screen at admission	1	0
Overall Study Withdrawal by Subject	2	1
Overall Study Adverse Event	1	0

Baseline Characteristics

A Study to Assess the Bioequivalence of Dapagliflozin/Metformin XR Fixed-dose Combination Tablets in Healthy Subjects

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1 n=40 Participants Sequences 1, 2, 3 and 4- each sequence had 10 subjects; Part 1: ABCD, BADC, ABDC, BACD (A = test, fed; B = reference, fed; C = test, fasted; D = reference, fasted) Part 1: Test: Dapagliflozin/metformin XR mg manufactured at Mount Vernon plant (1 x 5/500 mg); Reference: Dapagliflozin/metformin XR mg manufactured at Humacao plant (1 x 5/500 mg)	Part 2 n=40 Participants Sequences 1, 2, 3 and 4 - each sequence had 10 subjects Part 2: EFGH, FEHG, EFHG, FEGH (E = test, fed; F = reference, fed; G = test, fasted; H = reference, fasted) Part 2: Test: Dapagliflozin/metformin XR manufactured at Mount Vernon plant (1 x 10/1000 mg); Reference: Dapagliflozin/metformin XR manufactured at Humacao plant (1 x 10/1000 mg)	Total n=80 Participants Total of all reporting groups
Age, Continuous	35.4 Years STANDARD_DEVIATION 10.38 • n=5 Participants	38.1 Years STANDARD_DEVIATION 9.71 • n=7 Participants	36.5 Years STANDARD_DEVIATION 10.04 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Sex: Female, Male Male	39 Participants n=5 Participants	37 Participants n=7 Participants	76 Participants n=5 Participants

PRIMARY outcome

Timeframe: Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period

Population: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.

To evaluate the Bioequivalence for Dapagliflozin and Metformin following administration Dapagliflozin/Metformin XR 5/500 mg and 10/1000 mg Manufactured at Mt. Vernon plant, US, Compared to Humacao plant, Puerto Rico, in the Fasted or Fed state.

Outcome measures

Outcome measures
Measure	Treatment A n=40 Participants Fed - 5/500 mg - Dapagliflozin/metformin XR mg manufactured at Mount Vernon plant	Treatment B n=38 Participants Fed - 5/500 mg - Dapagliflozin/metformin XR mg manufactured at Humacao plant	Treatment C n=37 Participants Fasted - 5/500 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment D n=36 Participants Fasted - 5/500 mg - Dapagliflozin/metformin XR manufactured at Humacao plant	Treatment E n=37 Participants Fed - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment F n=39 Participants Fed - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Humacao plant	Treatment G n=39 Participants Fasted - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment H n=39 Participants Fasted - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Humacao plant
Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State Dapagliflozin	236.3 h*ng/mL Geometric Coefficient of Variation 21.06	248.6 h*ng/mL Geometric Coefficient of Variation 20.79	251.6 h*ng/mL Geometric Coefficient of Variation 21.20	258.2 h*ng/mL Geometric Coefficient of Variation 18.35	471.9 h*ng/mL Geometric Coefficient of Variation 27.46	486.9 h*ng/mL Geometric Coefficient of Variation 26.47	504.4 h*ng/mL Geometric Coefficient of Variation 27.22	516.6 h*ng/mL Geometric Coefficient of Variation 27.15
Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State Metformin	5484 h*ng/mL Geometric Coefficient of Variation 24.69	5465 h*ng/mL Geometric Coefficient of Variation 27.87	4398 h*ng/mL Geometric Coefficient of Variation 29.41	4460 h*ng/mL Geometric Coefficient of Variation 29.69	8403 h*ng/mL Geometric Coefficient of Variation 27.90	8015 h*ng/mL Geometric Coefficient of Variation 31.65	7727 h*ng/mL Geometric Coefficient of Variation 30.82	7578 h*ng/mL Geometric Coefficient of Variation 35.76

PRIMARY outcome

Timeframe: Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period

Population: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.

To evaluate the Bioequivalence for Dapagliflozin and Metformin following administration Dapagliflozin/Metformin XR 5/500 mg and 10/1000 mg Manufactured at Mt. Vernon plant, US, Compared to Humacao plant, Puerto Rico, in the Fasted or Fed state

Outcome measures

Outcome measures
Measure	Treatment A n=40 Participants Fed - 5/500 mg - Dapagliflozin/metformin XR mg manufactured at Mount Vernon plant	Treatment B n=38 Participants Fed - 5/500 mg - Dapagliflozin/metformin XR mg manufactured at Humacao plant	Treatment C n=37 Participants Fasted - 5/500 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment D n=36 Participants Fasted - 5/500 mg - Dapagliflozin/metformin XR manufactured at Humacao plant	Treatment E n=39 Participants Fed - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment F n=40 Participants Fed - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Humacao plant	Treatment G n=39 Participants Fasted - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment H n=39 Participants Fasted - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Humacao plant
AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. Dapagliflozin	228.1 h*ng/mL Geometric Coefficient of Variation 20.43	239.1 h*ng/mL Geometric Coefficient of Variation 21.10	243.4 h*ng/mL Geometric Coefficient of Variation 20.93	248.8 h*ng/mL Geometric Coefficient of Variation 17.92	454.7 h*ng/mL Geometric Coefficient of Variation 27.15	472.1 h*ng/mL Geometric Coefficient of Variation 26.72	490.9 h*ng/mL Geometric Coefficient of Variation 27.30	505.1 h*ng/mL Geometric Coefficient of Variation 26.80
AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. Metformin	5307 h*ng/mL Geometric Coefficient of Variation 26.54	5205 h*ng/mL Geometric Coefficient of Variation 28.59	4211 h*ng/mL Geometric Coefficient of Variation 28.71	4212 h*ng/mL Geometric Coefficient of Variation 27.22	8040 h*ng/mL Geometric Coefficient of Variation 27.82	7798 h*ng/mL Geometric Coefficient of Variation 32.77	7456 h*ng/mL Geometric Coefficient of Variation 30.57	7401 h*ng/mL Geometric Coefficient of Variation 34.75

PRIMARY outcome

Timeframe: Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period

Population: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.

To evaluate the Bioequivalence for Dapagliflozin and Metformin following administration Dapagliflozin/Metformin XR 5/500 mg and 10/1000 mg Manufactured at Mt. Vernon plant, US, Compared to Humacao plant, Puerto Rico, in the Fasted or Fed state

Outcome measures

Outcome measures
Measure	Treatment A n=40 Participants Fed - 5/500 mg - Dapagliflozin/metformin XR mg manufactured at Mount Vernon plant	Treatment B n=38 Participants Fed - 5/500 mg - Dapagliflozin/metformin XR mg manufactured at Humacao plant	Treatment C n=37 Participants Fasted - 5/500 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment D n=36 Participants Fasted - 5/500 mg - Dapagliflozin/metformin XR manufactured at Humacao plant	Treatment E n=39 Participants Fed - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment F n=40 Participants Fed - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Humacao plant	Treatment G n=39 Participants Fasted - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment H n=39 Participants Fasted - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Humacao plant
Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State Dapagliflozin	39.69 ng/mL Geometric Coefficient of Variation 26.42	41.33 ng/mL Geometric Coefficient of Variation 18.49	65.28 ng/mL Geometric Coefficient of Variation 25.49	67.41 ng/mL Geometric Coefficient of Variation 24.95	87.48 ng/mL Geometric Coefficient of Variation 30.14	90.14 ng/mL Geometric Coefficient of Variation 32.09	125.6 ng/mL Geometric Coefficient of Variation 30.77	132.7 ng/mL Geometric Coefficient of Variation 28.31
Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State Metformin	510.2 ng/mL Geometric Coefficient of Variation 22.23	503.4 ng/mL Geometric Coefficient of Variation 22.16	563.2 ng/mL Geometric Coefficient of Variation 30.27	573.9 ng/mL Geometric Coefficient of Variation 28.55	982.6 ng/mL Geometric Coefficient of Variation 28.11	975.5 ng/mL Geometric Coefficient of Variation 27.89	1016 ng/mL Geometric Coefficient of Variation 35.36	998.5 ng/mL Geometric Coefficient of Variation 36.05

SECONDARY outcome

Timeframe: Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period

Population: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.

To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states.

Outcome measures

Outcome measures
Measure	Treatment A n=40 Participants Fed - 5/500 mg - Dapagliflozin/metformin XR mg manufactured at Mount Vernon plant	Treatment B n=38 Participants Fed - 5/500 mg - Dapagliflozin/metformin XR mg manufactured at Humacao plant	Treatment C n=37 Participants Fasted - 5/500 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment D n=36 Participants Fasted - 5/500 mg - Dapagliflozin/metformin XR manufactured at Humacao plant	Treatment E n=39 Participants Fed - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment F n=40 Participants Fed - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Humacao plant	Treatment G n=39 Participants Fasted - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment H n=39 Participants Fasted - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Humacao plant
Time to Reach Maximum Plasma Concentration (t Max) Dapagliflozin	2.50 Hour Interval 1.0 to 4.0	3.00 Hour Interval 1.0 to 4.0	1.00 Hour Interval 0.5 to 2.98	1.00 Hour Interval 0.48 to 2.92	2.00 Hour Interval 0.98 to 4.0	2.00 Hour Interval 0.98 to 4.0	1.00 Hour Interval 0.5 to 1.98	1.00 Hour Interval 0.48 to 3.0
Time to Reach Maximum Plasma Concentration (t Max) Metformin	6.00 Hour Interval 4.0 to 11.95	6.00 Hour Interval 3.98 to 12.03	4.00 Hour Interval 2.0 to 6.0	4.00 Hour Interval 2.0 to 6.03	4.00 Hour Interval 3.98 to 7.98	4.00 Hour Interval 3.98 to 6.02	4.00 Hour Interval 1.0 to 6.0	4.00 Hour Interval 1.98 to 6.0

SECONDARY outcome

Timeframe: Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period

Population: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.

To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states.

Outcome measures

Outcome measures
Measure	Treatment A n=40 Participants Fed - 5/500 mg - Dapagliflozin/metformin XR mg manufactured at Mount Vernon plant	Treatment B n=38 Participants Fed - 5/500 mg - Dapagliflozin/metformin XR mg manufactured at Humacao plant	Treatment C n=37 Participants Fasted - 5/500 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment D n=36 Participants Fasted - 5/500 mg - Dapagliflozin/metformin XR manufactured at Humacao plant	Treatment E n=39 Participants Fed - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment F n=40 Participants Fed - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Humacao plant	Treatment G n=39 Participants Fasted - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment H n=39 Participants Fasted - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Humacao plant
Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] Dapagliflozin	14.01 Hour (h) Standard Deviation 6.747	14.65 Hour (h) Standard Deviation 7.245	13.73 Hour (h) Standard Deviation 6.203	16.55 Hour (h) Standard Deviation 8.260	14.88 Hour (h) Standard Deviation 6.272	14.42 Hour (h) Standard Deviation 5.778	14.72 Hour (h) Standard Deviation 5.641	15.11 Hour (h) Standard Deviation 5.998
Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] Metformin	13.48 Hour (h) Standard Deviation 7.873	12.87 Hour (h) Standard Deviation 6.587	11.91 Hour (h) Standard Deviation 7.351	13.52 Hour (h) Standard Deviation 8.760	14.18 Hour (h) Standard Deviation 7.718	13.74 Hour (h) Standard Deviation 6.984	14.38 Hour (h) Standard Deviation 8.241	15.94 Hour (h) Standard Deviation 9.671

SECONDARY outcome

Timeframe: Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period

Population: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.

To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states.

Outcome measures

Outcome measures
Measure	Treatment A n=40 Participants Fed - 5/500 mg - Dapagliflozin/metformin XR mg manufactured at Mount Vernon plant	Treatment B n=38 Participants Fed - 5/500 mg - Dapagliflozin/metformin XR mg manufactured at Humacao plant	Treatment C n=37 Participants Fasted - 5/500 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment D n=36 Participants Fasted - 5/500 mg - Dapagliflozin/metformin XR manufactured at Humacao plant	Treatment E n=39 Participants Fed - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment F n=40 Participants Fed - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Humacao plant	Treatment G n=39 Participants Fasted - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Mount Vernon plant	Treatment H n=39 Participants Fasted - 10/1000 mg - Dapagliflozin/metformin XR manufactured at Humacao plant
Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] Dapagliflozin	421.3 L/h Standard Deviation 194.2	424.4 L/h Standard Deviation 217.3	412.7 L/h Standard Deviation 220.5	454.6 L/h Standard Deviation 202.6	476.5 L/h Standard Deviation 224	433.3 L/h Standard Deviation 196.1	441.7 L/h Standard Deviation 191.7	421.4 L/h Standard Deviation 163.1
Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] Metformin	2030 L/h Standard Deviation 1407	2133 L/h Standard Deviation 1891	2104 L/h Standard Deviation 1309	2803 L/h Standard Deviation 2066	3357 L/h Standard Deviation 2549	3324 L/h Standard Deviation 2713	3635 L/h Standard Deviation 2648	3212 L/h Standard Deviation 2079

SECONDARY outcome

Timeframe: Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period

Population: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.

To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states.