parallel randomized trial

PIONEER 7

Efficacy and Safety of Oral Semaglutide Using a Flexible Dose Adjustment Based on Clinical Evaluation Versus Sitagliptin in Subjects With Type 2 Diabetes Mellitus

Type 2 diabetes (adults)NCT02849080S001153

Design

Randomized: 504
Start year: 2016
Treatment: 104 weeks, follow-up 109 weeks
Countries: multinational
Sponsor: Novo Nordisk (industry)
Eligibility: age 18 or more; HbA1c 7.5 to 9.5 percent; one or two oral glucose lowering drugs

Conduct and analysis

Blinding: open label
Sequence generation: not reported
Allocation concealment: central
Outcome adjudication: yes
Primary estimand: treatment policy
Analysis population: randomized
Missing data: multiple imputation pattern mixture

Arms

Arm	Treatment	Background	Randomized	Analyzed	Completed treatment
A1	Semaglutide oral once daily (original tablet), flexible dose: 3, 7 or 14 mg adjusted by HbA1c and tolerability Oral semaglutide flexible dosing	metformin, sulfonylurea, SGLT2 inhibitor or thiazolidinedione; lifestyle: not reported	253	253	177
A2	Sitagliptin Sitagliptin 100 mg, main phase	one or two oral glucose lowering drugs; lifestyle: not reported	251	251
A3	Semaglutide oral once daily (original tablet), flexible dose: 3, 7 or 14 mg adjusted by HbA1c and tolerability Oral semaglutide flexible dosing switch part	main phase background plus any main phase rescue; lifestyle: not reported	100	100
A4	Sitagliptin Continued sitagliptin 100 mg, extension	background drugs including prior rescue; lifestyle: not reported	98	98

Baseline characteristics

As printed in the trial reports or registry, per arm or for the whole trial.

Characteristic	Statistic	Semaglutide oral once daily (original tablet), flexible dose: 3, 7 or 14 mg adjusted by HbA1c and tolerability A1	Sitagliptin A2	Semaglutide oral once daily (original tablet), flexible dose: 3, 7 or 14 mg adjusted by HbA1c and tolerability A3	Sitagliptin A4
age	mean (years)	57	58	58	58
age	sd (years)	10	10	10	10
asian	n	34	38	17	17
asian	percent	13.4		17.0	17.3
black	n	22	25	6	10
black	percent	8.7		6.0	10.2
bmi	mean (kg/m2)	31.5		31.0	30.6
bmi	sd (kg/m2)	6.5		5.4	5.9
diabetes duration	mean (years)	8.6		8.1	9.6
diabetes duration	sd (years)	6.3		5.4	6.4
egfr	mean (mL/min/1.73 m2)	95.9		91.9	92.9
female	n	108	111	43	43
female	percent	42.7		43.0	43.9
hba1c	mean (percent)	8.3		7.4	7.5
hba1c	sd (percent)	0.6		1.0	0.9
hispanic	n	48	57	16	19
hispanic	percent	19.0		16.0	19.4
other race other	n	2	2
other race other	percent	0.8
weight	mean (kg)	88.9		85.8	86.9
weight	sd (kg)	19.6		15.4	20.4
white	n	195	186	77	71
white	percent	77.1		77.0	72.4

Analyses this trial contributes to

Results

191 adjudicated result lines, grouped by outcome. Open an outcome to see its values.

HbA1c change (28 lines; O01)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
52	A1	change	-1.4 percent			81	hypothetical; other; diabetes_duration:5_to_<10; R0021795:Figure 2
52	A1	change	-1.0 percent			98	hypothetical; other; hba1c:<8.0; R0021795:Figure 3
52	A1	change	-1.5 percent			126	hypothetical; other; hba1c:8.0_to_<9.0; R0021795:Figure 3
52	A1	change	-2.0 percent			29	hypothetical; other; hba1c:>=9.0; R0021795:Figure 3
52	A1	change	-1.3 percent	0.9		230	not stated; randomized; registry:outcomes
52	A1	change	-1.4 percent			26	hypothetical; other; age:<45; R0021795:Figure 1
52	A1	change	-1.5 percent			66	hypothetical; other; age:>=65; R0021795:Figure 1
52	A1	change	-1.4 percent			161	hypothetical; other; age:45_to_<65; R0021795:Figure 1
52	A1	change	-1.4 percent			83	hypothetical; other; diabetes_duration:<5; R0021795:Figure 2
52	A1	change	-1.3 percent			89	hypothetical; other; diabetes_duration:>=10; R0021795:Figure 2
52	A2	change	-0.6 percent			160	hypothetical; other; age:45_to_<65; R0021795:Figure 1
52	A2	change	-0.5 percent			72	hypothetical; other; diabetes_duration:5_to_<10; R0021795:Figure 2
52	A2	change	-0.7 percent			25	hypothetical; other; age:<45; R0021795:Figure 1
52	A2	change	-0.7 percent			94	hypothetical; other; diabetes_duration:>=10; R0021795:Figure 2
52	A2	change	-0.8 percent	1.0		238	not stated; randomized; registry:outcomes
52	A2	change	-1.5 percent			28	hypothetical; other; hba1c:>=9.0; R0021795:Figure 3
52	A2	change	-0.9 percent			71	hypothetical; other; age:>=65; R0021795:Figure 1
52	A2	change	-0.7 percent			120	hypothetical; other; hba1c:8.0_to_<9.0; R0021795:Figure 3
52	A2	change	-0.8 percent			86	hypothetical; other; diabetes_duration:<5; R0021795:Figure 2
52	A2	change	-0.5 percent			103	hypothetical; other; hba1c:<8.0; R0021795:Figure 3
52	A3	change	-0.2 percent	1.2		92	not stated; randomized; registry:outcomes
52	A3	change	-0.2 percent			100	treatment policy; randomized; R0023369:Results
52	A3 vs A4	md	-0.3 percent		-0.6 to 0.0		treatment policy; randomized; R0023369:Results
52	A3 vs A4	md	-0.4 percent		-0.7 to -0.2		hypothetical; randomized; R0023369:Results
52	A4	change	0.0 percent	1.0		96	not stated; randomized; registry:outcomes
52	A4	change	0.1 percent			98	treatment policy; randomized; R0023369:Results
104	A1	change	-1.4 percent	0.8			hypothetical; other; R0023369:Results
104	A1	change	-1.3 percent	1.0		180	not stated; other; registry:outcomes

Body weight change in kilograms (diabetes) (32 lines; O02)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
52	A1	change	-2.9 kg			126	hypothetical; other; hba1c:8.0_to_<9.0; R0021795:Figure 3
52	A1	change	-2.9 kg	4.0		253	hypothetical; randomized; registry:outcomes
52	A1 vs A2	md	-2.2 kg		-2.9 to -1.5		hypothetical; randomized; registry:outcomes
52	A1	change	-3.2 kg			29	hypothetical; other; hba1c:>=9.0; R0021795:Figure 3
52	A1	change	-3.0 kg			98	hypothetical; other; hba1c:<8.0; R0021795:Figure 3
52	A1	change	-3.3 kg			81	hypothetical; other; diabetes_duration:5_to_<10; R0021795:Figure 2
52	A1	change	-2.7 kg	3.9		253	treatment policy; randomized; registry:outcomes
52	A1 vs A2	md	-1.9 kg		-2.6 to -1.2		treatment policy; randomized; registry:outcomes
52	A1	change	-2.6 kg			83	hypothetical; other; diabetes_duration:<5; R0021795:Figure 2
52	A1	change	-3.0 kg			89	hypothetical; other; diabetes_duration:>=10; R0021795:Figure 2
52	A1	change	-3.1 kg			66	hypothetical; other; age:>=65; R0021795:Figure 1
52	A1	change	-3.1 kg			161	hypothetical; other; age:45_to_<65; R0021795:Figure 1
52	A1	change	-1.7 kg			26	hypothetical; other; age:<45; R0021795:Figure 1
52	A2	change	-0.8 kg			86	hypothetical; other; diabetes_duration:<5; R0021795:Figure 2
52	A2	change	-0.9 kg	3.6		251	hypothetical; randomized; registry:outcomes
52	A2	change	-0.7 kg	3.5		251	treatment policy; randomized; registry:outcomes
52	A2	change	0.4 kg			25	hypothetical; other; age:<45; R0021795:Figure 1
52	A2	change	-1.1 kg			71	hypothetical; other; age:>=65; R0021795:Figure 1
52	A2	change	-0.8 kg			160	hypothetical; other; age:45_to_<65; R0021795:Figure 1
52	A2	change	-0.9 kg			94	hypothetical; other; diabetes_duration:>=10; R0021795:Figure 2
52	A2	change	-0.6 kg			72	hypothetical; other; diabetes_duration:5_to_<10; R0021795:Figure 2
52	A2	change	-0.8 kg			103	hypothetical; other; hba1c:<8.0; R0021795:Figure 3
52	A2	change	-1.7 kg			28	hypothetical; other; hba1c:>=9.0; R0021795:Figure 3
52	A2	change	-0.5 kg			120	hypothetical; other; hba1c:8.0_to_<9.0; R0021795:Figure 3
52	A3	change	-2.6 kg	3.8		93	not stated; randomized; registry:outcomes
52	A3	change	-2.4 kg			100	treatment policy; randomized; R0023369:Results
52	A3 vs A4	md	-1.8 kg		-3.3 to -0.3		hypothetical; randomized; R0023369:Results
52	A3 vs A4	md	-1.5 kg		-2.8 to -0.1		treatment policy; randomized; R0023369:Results
52	A4	change	-0.9 kg			98	treatment policy; randomized; R0023369:Results
52	A4	change	-0.9 kg	5.4		97	not stated; randomized; registry:outcomes
104	A1	change	-3.7 kg	5.2		180	not stated; other; registry:outcomes
104	A1	change	-3.9 kg	5.2			hypothetical; other; R0023369:Results

HbA1c below 7 percent (14 lines; O03)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
52	A1 vs A2	or	5.54	3.54 to 8.68		hypothetical; randomized; registry:outcomes
52	A1	responders			123 / 253	hypothetical; randomized; registry:outcomes
52	A1	responders			134 / 253	treatment policy; randomized; registry:outcomes
52	A1 vs A2	or	4.40	2.89 to 6.70		treatment policy; randomized; registry:outcomes
52	A2	responders			60 / 251	treatment policy; randomized; registry:outcomes
52	A2	responders			52 / 251	hypothetical; randomized; registry:outcomes
52	A3	responders			44 / 92	treatment policy; randomized; R0023369:Table 3
52	A3 vs A4	or	3.97	1.73 to 9.07		hypothetical; randomized; R0023369:Table 3
52	A3	responders			40 / 76	hypothetical; randomized; R0023369:Table 3
52	A3 vs A4	or	2.65	1.35 to 5.22		treatment policy; randomized; R0023369:Table 3
52	A4	responders			26 / 96	treatment policy; randomized; R0023369:Table 3
52	A4	responders			20 / 70	hypothetical; randomized; R0023369:Table 3
104	A1	responders			101 / 180	treatment policy; other; R0023369:Supplement Table S2
104	A1	responders			91 / 150	hypothetical; other; R0023369:Supplement Table S2

Level 2 or 3 hypoglycemia (participants) (8 lines; O04)

Arm	Statistic	Events / N	Detail
A1	events	14 / 253	while on treatment; safety; registry:outcomes
A1	events	0 / 253	while on treatment; safety; R0023369:Supplement Table 5
A1	events	18 / 253	while on treatment; safety; R0023369:Supplement Table 5
A2	events	14 / 250	while on treatment; safety; registry:outcomes
A3	events	0 / 100	while on treatment; safety; R0023369:Supplement Table 5
A3	events	2 / 100	while on treatment; safety; R0023369:Supplement Table 5
A4	events	0 / 97	while on treatment; safety; R0023369:Supplement Table 5
A4	events	4 / 97	while on treatment; safety; R0023369:Supplement Table 5

Systolic blood pressure change (9 lines; O05)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
52	A1	change	-3 mmHg	14		206	not stated; randomized; registry:outcomes
52	A2	change	-2 mmHg	15		225	not stated; randomized; registry:outcomes
52	A3 vs A4	md	-5 mmHg		-9 to -1		while on treatment; safety; R0023369:Supplement Table S11
52	A3	change	-3 mmHg	15		87	not stated; randomized; registry:outcomes
52	A3	change	-3 mmHg			100	while on treatment; safety; R0023369:Supplement Table 11
52	A4	change	2 mmHg	15		93	not stated; randomized; registry:outcomes
52	A4	change	2 mmHg			97	while on treatment; safety; R0023369:Supplement Table 11
104	A1	change	-3 mmHg	14		176	while on treatment; other; R0023369:Supplement Table 9
104	A1	change	-3 mmHg	14		180	treatment policy; other; R0023369:Supplement Table S9

Percent body weight change (12 lines; O10)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
52	A1	percent change	-2.99 percent	4.42		233	not stated; randomized; registry:outcomes
52	A2	percent change	-0.76 percent	3.91		239	not stated; randomized; registry:outcomes
52	A3	percent change	-2.9 percent			100	treatment policy; randomized; R0023369:Supplement Table S10
52	A3 vs A4	md	-2.1 percent		-3.5 to -0.7		treatment policy; randomized; R0023369:Supplement Table S10
52	A3	percent change	-3.12 percent	4.50		93	not stated; randomized; registry:outcomes
52	A3	percent change	-3.3 percent			100	hypothetical; randomized; R0023369:Supplement Table S10
52	A3 vs A4	md	-2.5 percent		-4.1 to -1.0		hypothetical; randomized; R0023369:Supplement Table S10
52	A4	percent change	-0.8 percent			98	hypothetical; randomized; R0023369:Supplement Table S10
52	A4	percent change	-0.70 percent	5.27		97	not stated; randomized; registry:outcomes
52	A4	percent change	-0.7 percent			98	treatment policy; randomized; R0023369:Supplement Table S10
104	A1	percent change	-4.36 percent	5.98		154	hypothetical; other; R0023369:Supplement Table S2
104	A1	percent change	-4.03 percent	5.75		180	treatment policy; other; R0023369:Supplement Table S2

Weight loss of 5 percent or more (11 lines; O11A)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
52	A1	responders			63 / 233	not stated; randomized; registry:outcomes
52	A2	responders			29 / 239	not stated; randomized; registry:outcomes
52	A3	responders			31 / 93	treatment policy; randomized; R0023369:Table 3
52	A3	responders			30 / 79	hypothetical; randomized; R0023369:Table 3
52	A3 vs A4	or	3.65	1.60 to 8.33		hypothetical; randomized; R0023369:Table 3
52	A3 vs A4	or	3.20	1.51 to 6.78		treatment policy; randomized; R0023369:Table 3
52	A4	responders			7 / 72	hypothetical; randomized; R0023369:Table 3
52	A4	responders			12 / 97	treatment policy; randomized; R0023369:Table 3
104	A1	responders			58 / 154	hypothetical; other; R0023369:Supplement Table S2
104	A1	responders			64 / 180	treatment policy; other; R0023369:Supplement Table S2
104	A1	responders			61 / 180	not stated; other; registry:outcomes

Weight loss of 10 percent or more (2 lines; O11B)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
52	A1	responders				15 / 233	not stated; randomized; registry:outcomes
52	A2	responders				5 / 239	not stated; randomized; registry:outcomes

Acute kidney injury (5 lines; O121)

Arm	Statistic	Events / N	Detail
A1	events	0 / 253	not stated; safety; acute kidney injury; registry:adverse_events
A1	events	2 / 253	while on treatment; safety; R0023369:Supplement Table 6
A2	events	0 / 250	not stated; safety; acute kidney injury; registry:adverse_events
A3	events	0 / 100	while on treatment; safety; R0023369:Supplement Table 6
A4	events	0 / 97	while on treatment; safety; R0023369:Supplement Table 6

All cause mortality (5 lines; O20)

Arm	Statistic	Events / N	Detail
A1	events	0 / 253	not stated; safety; registry:adverse_events
A1	events	0 / 253	treatment policy; safety; R0023369:Table 2
A2	events	2 / 250	not stated; safety; registry:adverse_events
A3	events	0 / 100	treatment policy; safety; R0023369:Table 2
A4	events	0 / 97	treatment policy; safety; R0023369:Table 2

Hospitalization for heart failure (3 lines; O23)

Arm	Statistic	Events / N	Detail
A1	events	0 / 253	treatment policy; safety; R0023369:Supplement Table 6
A3	events	0 / 100	treatment policy; safety; R0023369:Supplement Table 6
A4	events	1 / 97	treatment policy; safety; R0023369:Supplement Table 6

SF-36 physical component summary change (5 lines; O24A)

Week	Arm	Statistic	Estimate	SE or SD	Events / N	Detail
52	A1	change	1.51 points	6.39	253	not stated; randomized; registry:outcomes
52	A2	change	0.74 points	5.81	251	not stated; randomized; registry:outcomes
52	A3	change	0.66 points	6.06	93	not stated; randomized; registry:outcomes
52	A4	change	-0.43 points	5.36	97	not stated; randomized; registry:outcomes
104	A1	change	1.33 points	6.96	180	not stated; other; registry:outcomes

Physical functioning (any instrument) (5 lines; O24B)

Week	Arm	Statistic	Estimate	SE or SD	Events / N	Detail
52	A1	change	1.54 points	7.92	253	not stated; randomized; registry:outcomes
52	A2	change	-0.03 points	7.16	251	not stated; randomized; registry:outcomes
52	A3	change	1.14 points	8.55	93	not stated; randomized; registry:outcomes
52	A4	change	-0.97 points	6.71	97	not stated; randomized; registry:outcomes
104	A1	change	1.44 points	8.48	180	not stated; other; registry:outcomes

Health related quality of life total score (any instrument) (5 lines; O24C)

Week	Arm	Statistic	Estimate	SE or SD	Events / N	Detail
52	A1	change	5.39 points	6.84	253	not stated; randomized; registry:outcomes
52	A2	change	4.70 points	7.23	251	not stated; randomized; registry:outcomes
52	A3	change	0.20 points	5.14	100	not stated; randomized; registry:outcomes
52	A4	change	-0.06 points	5.62	98	not stated; randomized; registry:outcomes
104	A1	change	5.81 points	7.11	180	not stated; other; registry:outcomes

Serious adverse events (5 lines; O25)

Arm	Statistic	Events / N	Detail
A1	events	36 / 253	while on treatment; safety; R0023369:Table 2
A1	events	24 / 253	not stated; safety; registry:adverse_events
A2	events	24 / 250	not stated; safety; registry:adverse_events
A3	events	9 / 100	while on treatment; safety; R0023369:Table 2
A4	events	7 / 97	while on treatment; safety; R0023369:Table 2

Discontinuation due to adverse events (3 lines; O26)

Arm	Statistic	Events / N	Detail
A1	events	23 / 253	while on treatment; safety; R0023369:Table 2
A3	events	6 / 100	while on treatment; safety; R0023369:Table 2
A4	events	0 / 97	while on treatment; safety; R0023369:Table 2

Nausea (5 lines; O27A)

Arm	Statistic	Events / N	Detail
A1	events	53 / 253	not stated; safety; registry:adverse_events
A1	events	58 / 253	while on treatment; safety; R0023369:Table 2
A2	events	6 / 250	not stated; safety; registry:adverse_events
A3	events	17 / 100	while on treatment; safety; R0023369:Table 2
A4	events	4 / 97	while on treatment; safety; R0023369:Table 2

Vomiting (5 lines; O27B)

Arm	Statistic	Events / N	Detail
A1	events	14 / 253	not stated; safety; registry:adverse_events
A1	events	18 / 253	while on treatment; safety; R0023369:Table 2
A2	events	2 / 250	not stated; safety; registry:adverse_events
A3	events	7 / 100	while on treatment; safety; R0023369:Table 2
A4	events	2 / 97	while on treatment; safety; R0023369:Table 2

Diarrhea (5 lines; O27C)

Arm	Statistic	Events / N	Detail
A1	events	29 / 253	while on treatment; safety; R0023369:Table 2
A1	events	22 / 253	not stated; safety; registry:adverse_events
A2	events	8 / 250	not stated; safety; registry:adverse_events
A3	events	10 / 100	while on treatment; safety; R0023369:Table 2
A4	events	3 / 97	while on treatment; safety; R0023369:Table 2

Constipation (5 lines; O27D)

Arm	Statistic	Events / N	Detail
A1	events	7 / 253	not stated; safety; registry:adverse_events
A1	events	11 / 253	while on treatment; safety; R0023369:Table 2
A2	events	7 / 250	not stated; safety; registry:adverse_events
A3	events	5 / 100	while on treatment; safety; R0023369:Table 2
A4	events	1 / 97	while on treatment; safety; R0023369:Table 2

Discontinuation due to gastrointestinal adverse events (3 lines; O27E)

Arm	Statistic	Events / N	Detail
A1	events	15 / 253	while on treatment; safety; R0023369:Table 2
A3	events	4 / 100	while on treatment; safety; R0023369:Table 2
A4	events	0 / 97	while on treatment; safety; R0023369:Table 2

Gallbladder and biliary disease (2 lines; O28)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 253	not stated; safety; cholecystitis acute; registry:adverse_events
	A2	events				1 / 250	not stated; safety; cholecystitis acute; registry:adverse_events

Acute pancreatitis (3 lines; O29)

Arm	Statistic	Events / N	Detail
A1	events	0 / 253	while on treatment; safety; R0023369:Supplement Table 6
A3	events	0 / 100	while on treatment; safety; R0023369:Supplement Table 6
A4	events	0 / 97	while on treatment; safety; R0023369:Supplement Table 6

Thyroid cancer (any) (3 lines; O32B)

Arm	Statistic	Events / N	Detail
A1	events	0 / 253	treatment policy; safety; R0023369:Supplement Table 6
A3	events	0 / 100	treatment policy; safety; R0023369:Supplement Table 6
A4	events	0 / 97	treatment policy; safety; R0023369:Supplement Table 6

Diabetic retinopathy complications (3 lines; O33)

Arm	Statistic	Events / N	Detail
A1	events	13 / 253	treatment policy; safety; R0023369:Supplement Table 8
A3	events	4 / 100	treatment policy; safety; R0023369:Supplement Table 8
A4	events	2 / 97	treatment policy; safety; R0023369:Supplement Table 8

Intestinal obstruction or ileus (2 lines; O37B)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 253	not stated; safety; ileus; registry:adverse_events
	A2	events				1 / 250	not stated; safety; ileus; registry:adverse_events

Any cancer (3 lines; O39)

Arm	Statistic	Events / N	Detail
A1	events	11 / 253	treatment policy; safety; R0023369:Supplement Table 7
A3	events	2 / 100	treatment policy; safety; R0023369:Supplement Table 7
A4	events	0 / 97	treatment policy; safety; R0023369:Supplement Table 7