Trial Outcomes & Findings for A Study to Assess the Safety and Efficacy of Omarigliptin (MK-3102) in Participants With Type 2 Diabetes Mellitus (T2DM) and Inadequate Glycemic Control (MK-3102-011) (NCT NCT01717313)

Results Overview

A1C (%) is used to report average blood glucose levels over prolonged periods of time. Because it was discovered that in another omarigliptin study (MK-3102-028, NCT01814748) subjects had taken metformin (prohibited per protocol, and taken without investigator knowledge), after unblinding of Phase A of this study, an analysis of metformin levels was performed on stored Week 18 blood samples. Of the subjects not rescued with metformin prior to Week 18, 10% in the omarigliptin group and 20% in the placebo group had levels showing that they were taking metformin (prohibited per protocol). The use of prohibited metformin disproportionately by the placebo group may have resulted in a smaller than expected treatment effect for efficacy outcome measures (see post-hoc analysis).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

329 participants

Primary outcome timeframe

Baseline and Week 24

Results posted on

2018-09-10

Participant Flow

The double-blind treatment period included a 24-week placebo-controlled (omarigliptin/omarigliptin-matching placebo) period (Phase A) and a 30-week active-controlled period with blinded metformin/metformin matching placebo (Phase B).

Participant milestones

Participant milestones
Measure	Omarigliptin Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Phase A (Weeks 0 to 24) STARTED	165	164
Phase A (Weeks 0 to 24) COMPLETED	147	151
Phase A (Weeks 0 to 24) NOT COMPLETED	18	13
Interphase STARTED	147	151
Interphase COMPLETED	146	151
Interphase NOT COMPLETED	1	0
Phase B (Weeks 24 to 54) STARTED	146	151
Phase B (Weeks 24 to 54) COMPLETED	134	135
Phase B (Weeks 24 to 54) NOT COMPLETED	12	16

Reasons for withdrawal

Reasons for withdrawal
Measure	Omarigliptin Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Phase A (Weeks 0 to 24) Death	0	1
Phase A (Weeks 0 to 24) Lost to Follow-up	1	3
Phase A (Weeks 0 to 24) Withdrawal by Subject	12	6
Phase A (Weeks 0 to 24) Adverse Event	4	2
Phase A (Weeks 0 to 24) Non-Compliance with Study Drug	1	1
Interphase Completed Phase A Did Not Enter Phase B	1	0
Phase B (Weeks 24 to 54) Study Terminated by Sponsor	4	4
Phase B (Weeks 24 to 54) Withdrawal by Subject	7	9
Phase B (Weeks 24 to 54) Lost to Follow-up	1	3

Baseline Characteristics

A Study to Assess the Safety and Efficacy of Omarigliptin (MK-3102) in Participants With Type 2 Diabetes Mellitus (T2DM) and Inadequate Glycemic Control (MK-3102-011)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Omarigliptin n=165 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Total n=329 Participants Total of all reporting groups
Age, Continuous	57.4 Years STANDARD_DEVIATION 9.2 • n=5 Participants	57.0 Years STANDARD_DEVIATION 9.7 • n=7 Participants	57.2 Years STANDARD_DEVIATION 9.5 • n=5 Participants
Sex: Female, Male Female	70 Participants n=5 Participants	67 Participants n=7 Participants	137 Participants n=5 Participants
Sex: Female, Male Male	95 Participants n=5 Participants	97 Participants n=7 Participants	192 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Week 24

Population: The Full Analysis Set (FAS) population was comprised of all participants who received at least one dose of study treatment and have a baseline measurement for the analysis endpoint and a post-randomization measurement for the analysis endpoint after at least one dose of study treatment.

A1C (%) is used to report average blood glucose levels over prolonged periods of time. Because it was discovered that in another omarigliptin study (MK-3102-028, NCT01814748) subjects had taken metformin (prohibited per protocol, and taken without investigator knowledge), after unblinding of Phase A of this study, an analysis of metformin levels was performed on stored Week 18 blood samples. Of the subjects not rescued with metformin prior to Week 18, 10% in the omarigliptin group and 20% in the placebo group had levels showing that they were taking metformin (prohibited per protocol). The use of prohibited metformin disproportionately by the placebo group may have resulted in a smaller than expected treatment effect for efficacy outcome measures (see post-hoc analysis).

Outcome measures

Outcome measures
Measure	Omarigliptin n=165 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Change From Baseline in Hemoglobin A1c (A1C) at Week 24 (Phase A, FAS Population)	-0.49 Percent Interval -0.73 to -0.24	-0.10 Percent Interval -0.34 to 0.14

PRIMARY outcome

Timeframe: Up to 27 weeks

Population: The All-Participants-as-Treated (APaT) population included all participants who received at least one dose of study drug.

An adverse event is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of preexisting conditions. This analysis may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin).

Outcome measures

Outcome measures
Measure	Omarigliptin n=165 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Percentage of Participants Who Experienced at Least One Adverse Event in Phase A (Excluding Data After Glycemic Rescue, Safety Population)	41.8 Percentage of participants	50.0 Percentage of participants

PRIMARY outcome

Timeframe: Up to 24 weeks

Population: The APaT population included all participants who received at least one dose of study drug.

An adverse event is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of preexisting conditions. This analysis may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin).

Outcome measures

Outcome measures
Measure	Omarigliptin n=165 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Percentage of Participants Who Discontinued From the Study Drug Due to an Adverse Event in Phase A (Excluding Data After Glycemic Rescue, Safety Population)	2.4 Percentage of participants	1.8 Percentage of participants

PRIMARY outcome

Timeframe: Up to 57 weeks

Population: The APaT population included all participants who received at least one dose of study drug.

An adverse event is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of preexisting conditions. This analysis may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin).

Outcome measures

Outcome measures
Measure	Omarigliptin n=165 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Percentage of Participants Who Experienced at Least One Adverse Event (Phase A + Phase B, Excluding Data After Glycemic Rescue, Safety Population)	54.5 Percentage of participants	60.4 Percentage of participants

PRIMARY outcome

Timeframe: Up to 57 weeks

Population: The APaT population included all participants who received at least one dose of study drug.

An adverse event is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of preexisting conditions. This analysis may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin).

Outcome measures

Outcome measures
Measure	Omarigliptin n=165 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Percentage of Participants Who Discontinued From the Study Drug Due to an Adverse Event (Phase A + Phase B, Excluding Data After Glycemic Rescue, Safety Population)	3.0 Percentage of participants	2.4 Percentage of participants

SECONDARY outcome

Timeframe: Week 24

Population: The FAS population was comprised of all participants who received at least one dose of study treatment and have a baseline measurement for the analysis endpoint and a post-randomization measurement for the analysis endpoint after at least one dose of study treatment, and estimated using standard multiple imputation techniques.

A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). The percentage of participants who achieved A1C values \<7.0% (53 mmol/mol) in the FAS population at Week 24. Because it was discovered that in another omarigliptin study (MK-3102-028, NCT01814748) subjects had taken metformin (prohibited per protocol, and taken without investigator knowledge), after unblinding of Phase A of this study, an analysis of metformin levels was performed on stored Week 18 blood samples. Of the subjects not rescued with metformin prior to Week 18, 10% in the omarigliptin group and 20% in the placebo group had levels showing that they were taking metformin (prohibited per protocol). The use of prohibited metformin disproportionately by the placebo group may have resulted in a smaller than expected treatment effect for efficacy outcome measures (see post-hoc analysis).

Outcome measures

Outcome measures
Measure	Omarigliptin n=165 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Percentage of Participants Who Achieve an A1C Goal of <7% (53 mmol/Mol) at Week 24 (Phase A, FAS Population)	36.5 Percentage of participants Interval 29.3 to 44.5	16.3 Percentage of participants Interval 11.3 to 22.9

SECONDARY outcome

Timeframe: Week 24

Population: The FAS population was comprised of all participants who received at least one dose of study treatment and have a baseline measurement for the analysis endpoint and a post-randomization measurement for the analysis endpoint after at least one dose of study treatment, and estimated using standard multiple imputation techniques.

A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). The percentage of participants who achieved A1C values \<6.5% (48 mmol/mol) in the FAS population at Week 24. Because it was discovered that in another omarigliptin study (MK-3102-028, NCT01814748) subjects had taken metformin (prohibited per protocol, and taken without investigator knowledge), after unblinding of Phase A of this study, an analysis of metformin levels was performed on stored Week 18 blood samples. Of the subjects not rescued with metformin prior to Week 18, 10% in the omarigliptin group and 20% in the placebo group had levels showing that they were taking metformin (prohibited per protocol). The use of prohibited metformin disproportionately by the placebo group may have resulted in a smaller than expected treatment effect for efficacy outcome measures (see post-hoc analysis).

Outcome measures

Outcome measures
Measure	Omarigliptin n=165 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Percentage of Participants Who Achieve an A1C Goal of <6.5% (48 mmol/Mol) at Week 24 (Phase A, FAS Population)	16.4 Percentage of participants Interval 11.4 to 23.1	5.0 Percentage of participants Interval 2.5 to 9.6

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: The FAS population was comprised of all participants who received at least one dose of study treatment and have a baseline measurement or a post-randomization measurement for the analysis endpoint after at least one dose of study treatment.

Blood glucose was measured on a fasting basis (collected after an 10-hour fast). FPG is expressed as mg/dL. This change from baseline reflects the FPG level at Week 24 minus the FPG level at Week 0. Because it was discovered that in another omarigliptin study (MK-3102-028, NCT01814748) subjects had taken metformin (prohibited per protocol, and taken without investigator knowledge), after unblinding of Phase A of this study, an analysis of metformin levels was performed on stored Week 18 blood samples. Of the subjects not rescued with metformin prior to Week 18, 10% in the omarigliptin group and 20% in the placebo group had levels showing that they were taking metformin (prohibited per protocol). The use of prohibited metformin disproportionately by the placebo group may have resulted in a smaller than expected treatment effect for efficacy outcome measures (see post-hoc analysis).

Outcome measures

Outcome measures
Measure	Omarigliptin n=165 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Phase A, FAS Population)	-12.8 mg/dL Interval -25.2 to -0.3	-2.5 mg/dL Interval -15.0 to 10.1

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: The FAS population was comprised of all participants who received at least one dose of study treatment and have a baseline measurement or a post-randomization measurement for the analysis endpoint after at least one dose of study treatment.

Blood glucose was measured 2 hours after a meal (2-hour PMG). 2-hour PMG is expressed as mg/dL. This change from baseline in 2-hour PMG reflects the Week 24 2-hour PMG minus the Week 0 2-hour PMG. Because it was discovered that in another omarigliptin study (MK-3102-028, NCT01814748) subjects had taken metformin (prohibited per protocol, and taken without investigator knowledge), after unblinding of Phase A of this study, an analysis of metformin levels was performed on stored Week 18 blood samples. Of the subjects not rescued with metformin prior to Week 18, 10% in the omarigliptin group and 20% in the placebo group had levels showing that they were taking metformin (prohibited per protocol). The use of prohibited metformin disproportionately by the placebo group may have resulted in a smaller than expected treatment effect for efficacy outcome measures (see post-hoc analysis).

Outcome measures

Outcome measures
Measure	Omarigliptin n=106 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=102 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Change From Baseline in 2-hour Post Meal Glucose (PMG) at Week 24 (Phase A, FAS Population)	-25.6 mg/dL Interval -56.0 to 4.8	-13.9 mg/dL Interval -43.5 to 15.6

SECONDARY outcome

Timeframe: Baseline and Week 54

Population: The FAS population was comprised of all participants who received at least one dose of study treatment and have a baseline measurement or a post-randomization measurement for the analysis endpoint after at least one dose of study treatment.

A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Thus, this change from baseline reflects the Week 54 A1C minus the Week 0 A1C. The results of the study at Week 54 may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin).

Outcome measures

Outcome measures
Measure	Omarigliptin n=165 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Change From Baseline in A1C at Week 54 (Phase A + Phase B, FAS Population)	-0.40 Percent Interval -0.67 to -0.13	-0.80 Percent Interval -1.07 to -0.53

SECONDARY outcome

Timeframe: Week 54

Population: The FAS population was comprised of all participants who received at least one dose of study treatment and have a baseline measurement for the analysis endpoint and a post-randomization measurement for the analysis endpoint after at least one dose of study treatment, and estimated using standard multiple imputation techniques.

The percentage of participants who achieved A1C values \<7.0% (53 mmol/mol) in the FAS population at Week 54. The results of the study at Week 54 may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin).

Outcome measures

Outcome measures
Measure	Omarigliptin n=165 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Percentage of Participants Who Achieve an A1C Goal of <7% (53 mmol/Mol) at Week 54 (Phase A + Phase B, FAS Population)	33.8 Percentage of participants Interval 26.8 to 41.5	43.8 Percentage of participants Interval 36.2 to 51.7

SECONDARY outcome

Timeframe: Week 54

Population: The FAS population was comprised of all participants who received at least one dose of study treatment and have a baseline measurement for the analysis endpoint and a post-randomization measurement for the analysis endpoint after at least one dose of study treatment, and estimated using standard multiple imputation techniques.

A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). The percentage of participants who achieved A1C values \<6.5% (48 mmol/mol) in the FAS population at Week 54. The results of the study at Week 54 may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin).

Outcome measures

Outcome measures
Measure	Omarigliptin n=165 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Percentage of Participants Who Achieve an A1C Goal of <6.5% at Week 54 (Phase A + Phase B, FAS Population)	14.5 Percentage of participants Interval 9.7 to 21.2	20.6 Percentage of participants Interval 14.8 to 28.0

SECONDARY outcome

Timeframe: Baseline and Week 54

Population: The FAS population was comprised of all participants who received at least one dose of study treatment and have a baseline measurement or a post-randomization measurement for the analysis endpoint after at least one dose of study treatment.

Blood glucose was measured on a fasting basis (collected after an 10-hour fast). FPG is expressed as mg/dL. This change from baseline reflects the FPG level at Week 54 minus the FPG level at Week 0. The results of the study at Week 54 may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin).

Outcome measures

Outcome measures
Measure	Omarigliptin n=165 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Change From Baseline in FPG at Week 54 (Phase A + Phase B, FAS Population)	-8.3 mg/dL Interval -19.8 to 3.2	-21.1 mg/dL Interval -32.7 to -9.5

POST_HOC outcome

Timeframe: Baseline and Week 24

Population: The Per-Protocol population excluded participants from the FAS population who either had \<75% drug compliance or used a prohibited medication (including metformin).

A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Thus, this change from baseline reflects the Week 24 A1C minus the Week 0 A1C. A post-hoc sensitivity analysis was performed that excluded participants in both treatment groups who were found to have used prohibited metformin (see results above for a description of the use of prohibited metformin).

Outcome measures

Outcome measures
Measure	Omarigliptin n=149 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=131 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Change From Baseline in A1C at Week 24 (Phase A, Per-Protocol Population)	-0.54 Percent Interval -0.68 to -0.39	-0.00 Percent Interval -0.17 to 0.16

POST_HOC outcome

Timeframe: Baseline and Week 24

Population: The Per-Protocol population excluded participants from the FAS population who either had \<75% drug compliance or used a prohibited medication (including metformin).

Blood glucose was measured on a fasting basis (collected after an 10-hour fast). FPG is expressed as mg/dL. This change from baseline reflects the FPG level at Week 24 minus the FPG level at Week 0. A post-hoc sensitivity analysis was performed that excluded participants in both treatment groups who were found to have used prohibited metformin (see results above for a description of the use of prohibited metformin).

Outcome measures

Outcome measures
Measure	Omarigliptin n=149 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=131 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Change From Baseline in FPG at Week 24 (Phase A, Per-Protocol Population)	-15.5 mg/dL Interval -22.5 to -8.4	-2.2 mg/dL Interval -10.9 to 6.4

POST_HOC outcome

Timeframe: Baseline and Week 24

Population: The Per Protocol population excluded participants from the FAS population who either had \<75% drug compliance or used a prohibited medication (including metformin).

Blood glucose was measured 2 hours after a meal (2-hour PMG). 2-hour PMG is expressed as mg/dL. This change from baseline in 2-hour PMG reflects the Week 24 2-hour PMG minus the Week 0 2-hour PMG. A post-hoc sensitivity analysis was performed that excluded participants in both treatment groups who were found to have used prohibited metformin (see results above for a description of the use of prohibited metformin).

Outcome measures

Outcome measures
Measure	Omarigliptin n=95 Participants Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=80 Participants Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Change From Baseline in 2-hour PMG at Week 24 (Phase A, Per-Protocol Population)	-40.1 mg/dL Interval -53.4 to -26.9	-19.6 mg/dL Interval -34.1 to -5.2

Adverse Events

Omarigliptin

Serious events: 8 serious events

Other events: 31 other events

Deaths: 0 deaths

Placebo to Omarigliptin

Serious events: 8 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Omarigliptin n=165 participants at risk Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 participants at risk Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Infections and infestations Nasopharyngitis	10.3% 17/165 • Number of events 21 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	7.3% 12/164 • Number of events 16 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Investigations Blood glucose increased	8.5% 14/165 • Number of events 14 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	7.9% 13/164 • Number of events 13 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/ presentation. Any information identified by the sponsor as confidential must be deleted prior to submission.
Publication restrictions are in place

Restriction type: OTHER

Measure	Omarigliptin n=165 participants at risk Omarigliptin 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.	Placebo to Omarigliptin n=164 participants at risk Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B.
Cardiac disorders Acute myocardial infarction	0.00% 0/165 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.61% 1/164 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Eye disorders Cataract	0.00% 0/165 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.61% 1/164 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Infections and infestations Pneumonia	0.61% 1/165 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.00% 0/164 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Injury, poisoning and procedural complications Tendon rupture	0.61% 1/165 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.00% 0/164 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Vulval cancer	0.00% 0/165 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.61% 1/164 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Renal and urinary disorders Calculus ureteric	0.00% 0/165 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	1.2% 2/164 • Number of events 2 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Renal and urinary disorders Urethral stenosis	0.61% 1/165 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.00% 0/164 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Vascular disorders Hypertension	0.61% 1/165 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.00% 0/164 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Cardiac disorders Angina unstable	0.61% 1/165 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.00% 0/164 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Cardiac disorders Atrial flutter	0.00% 0/165 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.61% 1/164 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
General disorders Non-cardiac chest pain	0.61% 1/165 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.00% 0/164 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Infections and infestations Appendicitis	0.61% 1/165 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.00% 0/164 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Injury, poisoning and procedural complications Fall	0.00% 0/165 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.61% 1/164 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Injury, poisoning and procedural complications Ilium fracture	0.00% 0/165 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.61% 1/164 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Injury, poisoning and procedural complications Rib fracture	0.00% 0/165 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.61% 1/164 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.00% 0/165 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.61% 1/164 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).
Nervous system disorders Syncope	0.61% 1/165 • Number of events 1 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).	0.00% 0/164 • Up to 57 weeks for serious adverse events (SAE, including 3-week follow-up) and up to 54 weeks for non-serious adverse events. SAE tables include data after glycemic rescue. Non-SAE tables exclude data after glycemic rescue. This analysis may have been confounded by use of prohibited metformin (see use of prohibited metformin).