Trial Outcomes & Findings for Study To Compare Single Dose Of Three Modified Release Formulations Of PF-04937319 With Immediate Release Material-Sparing-Tablet (IR MST) Formulation Previously Studied In Adults With Type 2 Diabetes Mellitus. (NCT NCT02206607)

NCT ID: NCT02206607

Last Updated: 2016-03-04

Results Overview

AUCinf is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

39 participants

Primary outcome timeframe

0 (pre-dose) and 1, 2, 3, 4, 5, 6, 7, 8, 11, 12.5, 14, 16, 20, 24, 36, 48, and 72 hours post-dose

Results posted on

2016-03-04

Participant Flow

Prior to being enrolled in the 4 period crossover, participants were required to complete an open-label, sponsor-provided metformin period. 42 participants started the metformin period and of those 42 participants, 39 were enrolled in the 4 period crossover and received at least 1 dose PF-04937319.

Participant milestones

Participant milestones
Measure	Metformin Run-In Participants received open-label, sponsor-provided metformin tablet(s) orally at a dose in multiples of 500 mg (minimum dose 500 mg, maximum dose 2500 mg). Participants who met eligibility criteria on metformin were then randomized to 1 of 4 treatment sequences.	Sequence ADBC: PF-04937319 150+100 mg IR First Participants received immediate-release material sparing tablet (IR MST) administered orally at 150 mg with morning meal and 100 mg with lunch, followed by PF-04937319 modified-release formulation #3 (MR3) 330 mg, followed by PF-04937319 modified-release formulation #1 (MR1) 250 mg, followed by PF-04937319 modified-release formulation #2 (MR2) 300 mg. There was a 5 to 10-day washout between dosing across the 4 regimens.	Sequence BACD: PF-04937319 250 mg MR1 First Participants received PF-04937319 MR1 250 mg, followed by PF-04937319 150+100 mg IR, followed by PF-04937319 300 mg MR2, followed by PF-04937319 330 mg MR3. There was a 5 to 10-day washout between dosing across the 4 regimens.	Sequence CBDA: PF-04937319 300 mg MR2 First Participants received PF-04937319 300 mg MR2, followed by PF-04937319 250 mg MR1, followed by PF-04937319 330 mg MR3, followed by PF-04937319 150+100 mg IR. There was a 5 to 10-day washout between dosing across the 4 regimens.	Sequence DCAB: PF-04937319 330 mg MR3 First Participants received PF-04937319 330 mg MR3, followed by PF-04937319 300 mg MR2, followed by PF-04937319 150+100 mg IR, followed by PF-04937319 250 mg MR1. There was a 5 to 10-day washout between dosing across the 4 regimens.
Second Intervention Period STARTED	0	9	9	11	10
Open-Label Run-In STARTED	42	0	0	0	0
Open-Label Run-In COMPLETED	39	0	0	0	0
Open-Label Run-In NOT COMPLETED	3	0	0	0	0
First Intervention Period STARTED	0	9	9	11	10
First Intervention Period COMPLETED	0	9	9	11	10
First Intervention Period NOT COMPLETED	0	0	0	0	0
First Washout Period 5 to 10 Days STARTED	0	9	9	11	10
First Washout Period 5 to 10 Days COMPLETED	0	9	9	11	10
First Washout Period 5 to 10 Days NOT COMPLETED	0	0	0	0	0
Second Intervention Period COMPLETED	0	9	9	10	10
Second Intervention Period NOT COMPLETED	0	0	0	1	0
Second Washout Period 5 to 10 Days STARTED	0	9	9	10	10
Second Washout Period 5 to 10 Days COMPLETED	0	9	9	10	10
Second Washout Period 5 to 10 Days NOT COMPLETED	0	0	0	0	0
Third Intervention Period STARTED	0	9	9	10	10
Third Intervention Period COMPLETED	0	9	9	10	10
Third Intervention Period NOT COMPLETED	0	0	0	0	0
Third Washout Period 5 to 10 Days STARTED	0	9	9	10	10
Third Washout Period 5 to 10 Days COMPLETED	0	9	9	10	10
Third Washout Period 5 to 10 Days NOT COMPLETED	0	0	0	0	0
Fourth Intervention Period STARTED	0	9	9	10	10
Fourth Intervention Period COMPLETED	0	9	9	10	10
Fourth Intervention Period NOT COMPLETED	0	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Metformin Run-In Participants received open-label, sponsor-provided metformin tablet(s) orally at a dose in multiples of 500 mg (minimum dose 500 mg, maximum dose 2500 mg). Participants who met eligibility criteria on metformin were then randomized to 1 of 4 treatment sequences.	Sequence ADBC: PF-04937319 150+100 mg IR First Participants received immediate-release material sparing tablet (IR MST) administered orally at 150 mg with morning meal and 100 mg with lunch, followed by PF-04937319 modified-release formulation #3 (MR3) 330 mg, followed by PF-04937319 modified-release formulation #1 (MR1) 250 mg, followed by PF-04937319 modified-release formulation #2 (MR2) 300 mg. There was a 5 to 10-day washout between dosing across the 4 regimens.	Sequence BACD: PF-04937319 250 mg MR1 First Participants received PF-04937319 MR1 250 mg, followed by PF-04937319 150+100 mg IR, followed by PF-04937319 300 mg MR2, followed by PF-04937319 330 mg MR3. There was a 5 to 10-day washout between dosing across the 4 regimens.	Sequence CBDA: PF-04937319 300 mg MR2 First Participants received PF-04937319 300 mg MR2, followed by PF-04937319 250 mg MR1, followed by PF-04937319 330 mg MR3, followed by PF-04937319 150+100 mg IR. There was a 5 to 10-day washout between dosing across the 4 regimens.	Sequence DCAB: PF-04937319 330 mg MR3 First Participants received PF-04937319 330 mg MR3, followed by PF-04937319 300 mg MR2, followed by PF-04937319 150+100 mg IR, followed by PF-04937319 250 mg MR1. There was a 5 to 10-day washout between dosing across the 4 regimens.
Open-Label Run-In Withdrawal by Subject	3	0	0	0	0
Second Intervention Period Insufficient Clinical Response	0	0	0	1	0

Baseline Characteristics

Study To Compare Single Dose Of Three Modified Release Formulations Of PF-04937319 With Immediate Release Material-Sparing-Tablet (IR MST) Formulation Previously Studied In Adults With Type 2 Diabetes Mellitus.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=39 Participants Participants received at least 1 dose of PF-04937319.
Age, Continuous	57.7 years STANDARD_DEVIATION 7.1 • n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants
Sex: Female, Male Male	20 Participants n=5 Participants

PRIMARY outcome

Timeframe: 0 (pre-dose) and 1, 2, 3, 4, 5, 6, 7, 8, 11, 12.5, 14, 16, 20, 24, 36, 48, and 72 hours post-dose

Population: The pharmacokinetic (PK) parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of the PK parameters of interest measured and available in at least 1 period; number of participants analyzed (N) is number of evaluable participants for this outcome measure.

AUCinf is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time.

Outcome measures

Outcome measures
Measure	PF-04937319 150+100 mg IR n=38 Participants Participants received immediate-release material sparing tablet (IR MST) administered orally at 150 mg with morning meal and 100 mg with lunch. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 250 mg MR1 n=31 Participants Participants received modified-release formulation #1 administered orally at 250 mg tablet with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 300 mg MR2 n=37 Participants Participants received modified-release formulation#2 administered orally at 300 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 n=36 Participants Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUCinf]	10690 nanogramhour/milliliter (nghr/mL) Geometric Coefficient of Variation 26	3187 nanogramhour/milliliter (nghr/mL) Geometric Coefficient of Variation 59	2725 nanogramhour/milliliter (nghr/mL) Geometric Coefficient of Variation 35	3430 nanogramhour/milliliter (nghr/mL) Geometric Coefficient of Variation 37	—

PRIMARY outcome

Timeframe: 0 (pre-dose) and 1, 2, 3, 4, 5, 6, 7, 8, 11, 12.5, 14, 16, 20, and 24 hours post-dose

Population: The pharmacodynamic analysis included participants who had taken at least 1 dose of PF-04937319 and who had WMDG assessment for at least 1 modified-release formulation and the Reference (IR MST) formulation; n=number of participants evaluated in respective arms for category.

MWG was calculated as the area under the curve (AUC) for the full 24 hours expressed.

Outcome measures

Outcome measures
Measure	PF-04937319 150+100 mg IR n=36 Participants Participants received immediate-release material sparing tablet (IR MST) administered orally at 150 mg with morning meal and 100 mg with lunch. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 250 mg MR1 n=36 Participants Participants received modified-release formulation #1 administered orally at 250 mg tablet with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 300 mg MR2 n=36 Participants Participants received modified-release formulation#2 administered orally at 300 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 n=36 Participants Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.
Change From Reference in Weighted-Mean-Daily-Glucose (WMDG) on Day 1 Observed (n=36,33,32,35)	159.47 milligrams per deciliter (mg/dL) Standard Deviation 42.949	176.24 milligrams per deciliter (mg/dL) Standard Deviation 42.648	170.85 milligrams per deciliter (mg/dL) Standard Deviation 38.928	180.47 milligrams per deciliter (mg/dL) Standard Deviation 50.099	—
Change From Reference in Weighted-Mean-Daily-Glucose (WMDG) on Day 1 Change From Reference (36,33,32,35)	NA milligrams per deciliter (mg/dL) Standard Deviation NA No measure type or method of dispersion was calculated, as the 'PF-04937319 150+100 mg IR' arm is the Reference.	15.55 milligrams per deciliter (mg/dL) Standard Deviation 19.358	15.96 milligrams per deciliter (mg/dL) Standard Deviation 17.122	20.15 milligrams per deciliter (mg/dL) Standard Deviation 20.005	—

SECONDARY outcome

Timeframe: 0 (pre-dose) and 1, 2, 3, 4, 5, 6, 7, 8, 11, 12.5, 14, 16, 20, 24, 36, 48, and 72 hours post-dose

Population: The PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of the PK parameters of interest measured and available in at least 1 period.

Outcome measures

Outcome measures
Measure	PF-04937319 150+100 mg IR n=38 Participants Participants received immediate-release material sparing tablet (IR MST) administered orally at 150 mg with morning meal and 100 mg with lunch. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 250 mg MR1 n=39 Participants Participants received modified-release formulation #1 administered orally at 250 mg tablet with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 300 mg MR2 n=39 Participants Participants received modified-release formulation#2 administered orally at 300 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 n=38 Participants Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.
Maximum Observed PF-04937319 Plasma Concentration (Cmax)	641.2 ng/mL Geometric Coefficient of Variation 22	161.8 ng/mL Geometric Coefficient of Variation 37	171.3 ng/mL Geometric Coefficient of Variation 24	236.2 ng/mL Geometric Coefficient of Variation 24	—

SECONDARY outcome

Timeframe: 0 (pre-dose) and 1, 2, 3, 4, 5, 6, 7, 8, 11, 12.5, 14, 16, 20, 24, 36, 48, and 72 hours post-dose

Outcome measures

Outcome measures
Measure	PF-04937319 150+100 mg IR n=38 Participants Participants received immediate-release material sparing tablet (IR MST) administered orally at 150 mg with morning meal and 100 mg with lunch. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 250 mg MR1 n=39 Participants Participants received modified-release formulation #1 administered orally at 250 mg tablet with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 300 mg MR2 n=39 Participants Participants received modified-release formulation#2 administered orally at 300 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 n=38 Participants Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.
PF-04937319 Plasma Concentration at 5 Hours After Morning Dose (C5)	413.2 ng/mL Geometric Coefficient of Variation 26	124.3 ng/mL Geometric Coefficient of Variation 43	154.3 ng/mL Geometric Coefficient of Variation 29	202.1 ng/mL Geometric Coefficient of Variation 30	—

SECONDARY outcome

Timeframe: 0 (pre-dose) and 1, 2, 3, 4, 5, 6, 7, 8, 11, 12.5, 14, 16, 20, 24, 36, 48, and 72 hours post-dose

Outcome measures

Outcome measures
Measure	PF-04937319 150+100 mg IR n=38 Participants Participants received immediate-release material sparing tablet (IR MST) administered orally at 150 mg with morning meal and 100 mg with lunch. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 250 mg MR1 n=39 Participants Participants received modified-release formulation #1 administered orally at 250 mg tablet with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 300 mg MR2 n=39 Participants Participants received modified-release formulation#2 administered orally at 300 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 n=38 Participants Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.
PF-04937319 Plasma Concentration at 16 Hours After Morning Dose (C16)	324.7 ng/mL Geometric Coefficient of Variation 34	74.49 ng/mL Geometric Coefficient of Variation 57	58.88 ng/mL Geometric Coefficient of Variation 37	77.92 ng/mL Geometric Coefficient of Variation 37	—

SECONDARY outcome

Timeframe: 0 (pre-dose) and 1, 2, 3, 4, 5, 6, 7, 8, 11, 12.5, 14, 16, 20, 24, 36, 48, and 72 hours post-dose

Outcome measures

Outcome measures
Measure	PF-04937319 150+100 mg IR n=38 Participants Participants received immediate-release material sparing tablet (IR MST) administered orally at 150 mg with morning meal and 100 mg with lunch. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 250 mg MR1 n=39 Participants Participants received modified-release formulation #1 administered orally at 250 mg tablet with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 300 mg MR2 n=39 Participants Participants received modified-release formulation#2 administered orally at 300 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 n=38 Participants Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.
PF-04937319 Plasma Concentration at 24 Hours After Morning Dose (C24)	171.1 ng/dL Geometric Coefficient of Variation 37	56.04 ng/dL Geometric Coefficient of Variation 64	39.38 ng/dL Geometric Coefficient of Variation 52	48.17 ng/dL Geometric Coefficient of Variation 47	—

SECONDARY outcome

Timeframe: 0 (pre-dose) and 1, 2, 3, 4, 5, 6, 7, 8, 11, 12.5, 14, 16, 20, 24, 36, 48, and 72 hours post-dose

Cmax/C24 is the ratio of maximum to approximate trough concentration, where Cmax is the overall maximum observed plasma concentration and C24 is the plasma concentration at 24 hours after the morning dose.

Outcome measures

Outcome measures
Measure	PF-04937319 150+100 mg IR n=38 Participants Participants received immediate-release material sparing tablet (IR MST) administered orally at 150 mg with morning meal and 100 mg with lunch. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 250 mg MR1 n=39 Participants Participants received modified-release formulation #1 administered orally at 250 mg tablet with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 300 mg MR2 n=39 Participants Participants received modified-release formulation#2 administered orally at 300 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 n=38 Participants Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.
Ratio of Maximum to Approximate Trough PF-04937319 Concentration (Cmax/C24)	3.748 ratio Geometric Coefficient of Variation 33	2.887 ratio Geometric Coefficient of Variation 49	4.350 ratio Geometric Coefficient of Variation 48	4.903 ratio Geometric Coefficient of Variation 43	—

SECONDARY outcome

Timeframe: 0 (pre-dose) and 1, 2, 3, 4, 5, 6, 7, 8, 11, 12.5, 14, 16, 20, 24, 36, 48, and 72 hours post-dose

Outcome measures

Outcome measures
Measure	PF-04937319 150+100 mg IR n=38 Participants Participants received immediate-release material sparing tablet (IR MST) administered orally at 150 mg with morning meal and 100 mg with lunch. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 250 mg MR1 n=39 Participants Participants received modified-release formulation #1 administered orally at 250 mg tablet with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 300 mg MR2 n=39 Participants Participants received modified-release formulation#2 administered orally at 300 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 n=38 Participants Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.
Time to Reach Maximum Observed PF-04937319 Plasma Concentration (Tmax)	8.00 hours Interval 3.0 to 15.2	6.00 hours Interval 4.0 to 48.0	5.00 hours Interval 1.0 to 7.07	5.00 hours Interval 3.0 to 7.0	—

SECONDARY outcome

Timeframe: 0 (pre-dose) and 1, 2, 3, 4, 5, 6, 7, 8, 11, 12.5, 14, 16, 20, 24, 36, 48, and 72 hours post-dose

Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)

Outcome measures

Outcome measures
Measure	PF-04937319 150+100 mg IR n=38 Participants Participants received immediate-release material sparing tablet (IR MST) administered orally at 150 mg with morning meal and 100 mg with lunch. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 250 mg MR1 n=39 Participants Participants received modified-release formulation #1 administered orally at 250 mg tablet with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 300 mg MR2 n=39 Participants Participants received modified-release formulation#2 administered orally at 300 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 n=38 Participants Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.
Area Under the Curve From Time Zero to Last Quantifiable PF-04937319 Concentration (AUClast)	10560 ng*hr/mL Geometric Coefficient of Variation 26	3287 ng*hr/mL Geometric Coefficient of Variation 55	2644 ng*hr/mL Geometric Coefficient of Variation 34	3369 ng*hr/mL Geometric Coefficient of Variation 34	—

SECONDARY outcome

Timeframe: 0 (pre-dose) and 1, 2, 3, 4, 5, 6, 7, 8, 11, 12.5, 14, 16, 20, 24, 36, 48, and 72 hours post-dose

t1/2 is the time measured for the plasma concentration to decrease by one half.

Outcome measures

Outcome measures
Measure	PF-04937319 150+100 mg IR n=38 Participants Participants received immediate-release material sparing tablet (IR MST) administered orally at 150 mg with morning meal and 100 mg with lunch. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 250 mg MR1 n=31 Participants Participants received modified-release formulation #1 administered orally at 250 mg tablet with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 300 mg MR2 n=37 Participants Participants received modified-release formulation#2 administered orally at 300 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 n=36 Participants Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.
Terminal Elimination Half-Life (t1/2)	8.648 hour Standard Deviation 2.7801	12.10 hour Standard Deviation 5.5922	13.52 hour Standard Deviation 6.9657	12.62 hour Standard Deviation 6.1783	—

SECONDARY outcome

Timeframe: Baseline up to 28 days after last study drug administration in Period 4

Population: The safety analysis population included all participants who received at least 1 dose of open-label, sponsor-provided metformin.

An AE was any untoward medical occurrence in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-SAEs.

Outcome measures

Outcome measures
Measure	PF-04937319 150+100 mg IR n=42 Participants Participants received immediate-release material sparing tablet (IR MST) administered orally at 150 mg with morning meal and 100 mg with lunch. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 250 mg MR1 n=38 Participants Participants received modified-release formulation #1 administered orally at 250 mg tablet with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 300 mg MR2 n=39 Participants Participants received modified-release formulation#2 administered orally at 300 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 n=39 Participants Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 n=38 Participants Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) AEs	2 participants	16 participants	11 participants	16 participants	10 participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) SAEs	0 participants	0 participants	0 participants	0 participants	0 participants

Adverse Events

Metformin Run-In

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

PF-04937319 150+100 mg IR

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

PF-04937319 250 mg MR1

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

PF-04937319 300 mg MR2

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

PF-04937319 330 mg MR3

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Metformin Run-In n=42 participants at risk Participants received open-label, sponsor-provided metformin tablet(s) orally at a dose in multiples of 500 mg (minimum dose 500 mg, maximum dose 2500 mg). Participants who met eligibility criteria on metformin were then randomized to 1 of 4 treatment regimens.	PF-04937319 150+100 mg IR n=38 participants at risk Participants received immediate-release material sparing tablet (IR MST) administered orally at 150 mg with morning meal and 100 mg with lunch. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 250 mg MR1 n=39 participants at risk Participants received modified-release formulation #1 administered orally at 250 mg tablet with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 300 mg MR2 n=39 participants at risk Participants received modified-release formulation#2 administered orally at 300 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.	PF-04937319 330 mg MR3 n=38 participants at risk Participants received modified-release formulation#3 administered orally at 330 mg with morning meal. There was a 5 to 10-day washout between dosing across the 4 regimens.
Gastrointestinal disorders Diarrhoea	0.00% 0/42 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/38 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/39 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.1% 2/39 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.3% 2/38 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Toothache	0.00% 0/42 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.3% 2/38 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.1% 2/39 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	2.6% 1/39 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	2.6% 1/38 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Infections and infestations Upper respiratory tract infection	0.00% 0/42 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/38 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	2.6% 1/39 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.1% 2/39 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/38 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/42 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	10.5% 4/38 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/39 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	2.6% 1/39 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	2.6% 1/38 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Nervous system disorders Headache	2.4% 1/42 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	18.4% 7/38 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.1% 2/39 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	7.7% 3/39 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.3% 2/38 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Respiratory, thoracic and mediastinal disorders Sinus congestion	0.00% 0/42 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/38 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	2.6% 1/39 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.1% 2/39 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/38 • Baseline up to 28 days after last study drug administration in Period 4 The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.

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