parallel randomized trial

PIONEER 12

China Multi-regional Clinical Trial: Efficacy and Safety of Oral Semaglutide Versus Sitagliptin in Subjects With Type 2 Diabetes Mellitus Treated With Metformin

Type 2 diabetes (adults)NCT04017832S000522

Design

Randomized: 1,441
Start year: 2019
Treatment: 26 weeks, follow-up 31 weeks
Countries: China, Taiwan, Hong Kong, Brazil, Czech Republic, Romania, Serbia, South Africa (90 sites)
Sponsor: Novo Nordisk A/S (industry)
Eligibility: adults with type 2 diabetes on metformin, HbA1c 7.0 to 10.5 percent

Conduct and analysis

Blinding: double blind
Sequence generation: not reported
Allocation concealment: central
Outcome adjudication: yes
Primary estimand: hypothetical
Analysis population: full analysis
Missing data: MMRM

Arms

Arm	Treatment	Background	Randomized	Analyzed	Completed treatment
A1	Semaglutide 3 mg oral once daily (original tablet) Oral semaglutide 3 mg	metformin; lifestyle: not reported	361	361	331
A2	Semaglutide 7 mg oral once daily (original tablet) Oral semaglutide 7 mg	metformin; lifestyle: not reported	360	360	329
A3	Semaglutide 14 mg oral once daily (original tablet) Oral semaglutide 14 mg	metformin; lifestyle: not reported	361	361	307
A4	Sitagliptin Sitagliptin 100 mg	metformin; lifestyle: not reported	359	359	344

Baseline characteristics

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

Characteristic	Statistic	Semaglutide 3 mg oral once daily (original tablet) A1	Semaglutide 7 mg oral once daily (original tablet) A2	Semaglutide 14 mg oral once daily (original tablet) A3	Sitagliptin A4
age	mean (years)	53	53	54	53
age	sd (years)	11	11	10	11
asian	n	272	270	271	271
asian	percent	75.3	75.0	75.1	75.5
black	n	8	14	5	11
black	percent	2.2	3.9	1.4	3.1
bmi	mean (kg/m2)	28.9	28.8	28.4	28.2
bmi	sd (kg/m2)	6.0	5.6	5.0	5.3
diabetes duration	mean (years)	5.8	5.2	5.9	5.6
diabetes duration	sd (years)	5.4	4.9	5.2	4.9
egfr	mean (mL/min/1.73 m2)	103	103	103	105
egfr	sd (mL/min/1.73 m2)	14	16	14	13
female	n	152	147	146	156
female	percent	42.1	40.8	40.4	43.5
hba1c	mean (percent)	8.1	8.1	8.1	8.2
hba1c	sd (percent)	0.9	0.9	0.9	0.9
other race other	n	8	11	18	18
other race other	percent	2.2	3.1	5.0	5.0
sbp	mean (mmHg)	131	132	130	130
sbp	sd (mmHg)	16	15	14	14
waist	mean (cm)	98.6	97.8	97.2	97.3
waist	sd (cm)	13.9	13.1	12.2	13.1
weight	mean (kg)	80.8	80.1	79.0	78.3
weight	sd (kg)	19.3	17.7	16.7	17.6
white	n	73	65	67	59
white	percent	20.2	18.1	18.6	16.4

Analyses this trial contributes to

Results

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

HbA1c change (24 lines; O01)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
26	A1 vs A4	md	-2 mmol/mol		-4 to -1		treatment policy; full analysis; R0019776:Figure 2
26	A1 vs A4	md	-0.2 percent		-0.3 to -0.1		hypothetical; full analysis; R0019776:Results
26	A1 vs A4	md	-2 mmol/mol		-4 to -1		hypothetical; full analysis; region:china; R0019776:Figure 3
26	A1 vs A4	md	-2 mmol/mol		-4 to -1		treatment policy; full analysis; region:china; R0019776:Figure 3
26	A1	change	-0.8 percent				hypothetical; full analysis; R0019776:Results
26	A1	change	-0.8 percent	1.0			hypothetical; full analysis; registry:outcomes
26	A1	change	-0.8 percent	1.0		344	treatment policy; full analysis; registry:outcomes
26	A2	change	-1.3 percent				hypothetical; full analysis; R0019776:Results
26	A2 vs A4	md	-7 mmol/mol		-9 to -5		treatment policy; full analysis; R0019776:Figure 2
26	A2	change	-1.3 percent	1.0			hypothetical; full analysis; registry:outcomes
26	A2 vs A4	md	-0.7 percent		-0.8 to -0.6		hypothetical; full analysis; R0019776:Results
26	A2 vs A4	md	-7 mmol/mol		-9 to -6		treatment policy; full analysis; region:china; R0019776:Figure 3
26	A2	change	-1.3 percent	1.0		340	treatment policy; full analysis; registry:outcomes
26	A2 vs A4	md	-8 mmol/mol		-10 to -7		hypothetical; full analysis; region:china; R0019776:Figure 3
26	A3 vs A4	md	-9 mmol/mol		-11 to -7		treatment policy; full analysis; region:china; R0019776:Figure 3
26	A3	change	-1.6 percent				hypothetical; full analysis; R0019776:Results
26	A3	change	-1.6 percent	1.0			hypothetical; full analysis; registry:outcomes
26	A3 vs A4	md	-1.0 percent		-1.1 to -0.8		hypothetical; full analysis; R0019776:Results
26	A3 vs A4	md	-10 mmol/mol		-12 to -8		hypothetical; full analysis; region:china; R0019776:Figure 3
26	A3	change	-1.5 percent	1.0		332	treatment policy; full analysis; registry:outcomes
26	A3 vs A4	md	-10 mmol/mol		-11 to -8		treatment policy; full analysis; R0019776:Figure 2
26	A4	change	-0.7 percent	1.0		350	treatment policy; full analysis; registry:outcomes
26	A4	change	-0.6 percent				hypothetical; full analysis; R0019776:Results
26	A4	change	-0.7 percent	1.0			hypothetical; full analysis; registry:outcomes

Body weight change in kilograms (diabetes) (20 lines; O02)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
26	A1 vs A4	md	-0.9 kg		-1.4 to -0.5		treatment policy; full analysis; R0019776:Figure 4
26	A1 vs A4	md	-0.8 kg		-1.3 to -0.2		hypothetical; full analysis; region:china; R0019776:Figure 5
26	A1	change	-1.4 kg				hypothetical; full analysis; R0019776:Results
26	A1	change	-1.4 kg	3.0		322	hypothetical; full analysis; registry:outcomes
26	A1 vs A4	md	-0.9 kg		-1.4 to -0.4		hypothetical; full analysis; R0019776:Results
26	A1 vs A4	md	-0.8 kg		-1.3 to -0.3		treatment policy; full analysis; region:china; R0019776:Figure 5
26	A2 vs A4	md	-2.3 kg		-2.8 to -1.8		hypothetical; full analysis; R0019776:Results
26	A2 vs A4	md	-2.2 kg		-2.6 to -1.7		treatment policy; full analysis; R0019776:Figure 4
26	A2	change	-2.8 kg				hypothetical; full analysis; R0019776:Results
26	A2 vs A4	md	-1.9 kg		-2.4 to -1.4		treatment policy; full analysis; region:china; R0019776:Figure 5
26	A2 vs A4	md	-2.1 kg		-2.6 to -1.6		hypothetical; full analysis; region:china; R0019776:Figure 5
26	A2	change	-2.9 kg	3.3		319	hypothetical; full analysis; registry:outcomes
26	A3 vs A4	md	-2.6 kg		-3.1 to -2.1		treatment policy; full analysis; region:china; R0019776:Figure 5
26	A3	change	-3.8 kg				hypothetical; full analysis; R0019776:Results
26	A3	change	-3.8 kg	3.7		300	hypothetical; full analysis; registry:outcomes
26	A3 vs A4	md	-3.3 kg		-3.8 to -2.8		hypothetical; full analysis; R0019776:Results
26	A3 vs A4	md	-3.0 kg		-3.5 to -2.5		treatment policy; full analysis; R0019776:Figure 4
26	A3 vs A4	md	-3.0 kg		-3.5 to -2.5		hypothetical; full analysis; region:china; R0019776:Figure 5
26	A4	change	-0.5 kg	2.6		335	hypothetical; full analysis; registry:outcomes
26	A4	change	-0.5 kg				hypothetical; full analysis; R0019776:Results

HbA1c below 7 percent (14 lines; O03)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
26	A1 vs A4	or	1.2	0.9 to 1.7		treatment policy; full analysis; R0019776:Table 2
26	A1	responders			139 / 321	hypothetical; full analysis; R0019776:Table 2
26	A1 vs A4	or	1.3	0.9 to 1.8		hypothetical; full analysis; R0019776:Table 2
26	A1	responders			147 / 344	treatment policy; full analysis; R0019776:Table 2
26	A2	responders			213 / 315	hypothetical; full analysis; R0019776:Table 2
26	A2 vs A4	or	4.1	2.9 to 5.8		hypothetical; full analysis; R0019776:Table 2
26	A2	responders			219 / 340	treatment policy; full analysis; R0019776:Table 2
26	A2 vs A4	or	3.3	2.3 to 4.6		treatment policy; full analysis; R0019776:Table 2
26	A3	responders			240 / 332	treatment policy; full analysis; R0019776:Table 2
26	A3 vs A4	or	6.5	4.5 to 9.3		hypothetical; full analysis; R0019776:Table 2
26	A3 vs A4	or	4.8	3.3 to 6.8		treatment policy; full analysis; R0019776:Table 2
26	A3	responders			226 / 298	hypothetical; full analysis; R0019776:Table 2
26	A4	responders			122 / 334	hypothetical; full analysis; R0019776:Table 2
26	A4	responders			125 / 350	treatment policy; full analysis; R0019776:Table 2

Level 2 or 3 hypoglycemia (participants) (12 lines; O04)

Arm	Statistic	Events / N	Detail
A1	events	5 / 361	while on treatment; safety; R0019776:Table 3
A1	events	2 / 361	while on treatment; safety; registry:outcomes
A1	events	0 / 361	while on treatment; safety; R0019776:Table 3
A2	events	0 / 358	while on treatment; safety; R0019776:Table 3
A2	events	2 / 358	while on treatment; safety; R0019776:Table 3
A2	events	2 / 358	while on treatment; safety; registry:outcomes
A3	events	0 / 361	while on treatment; safety; R0019776:Table 3
A3	events	2 / 361	while on treatment; safety; R0019776:Table 3
A3	events	2 / 361	while on treatment; safety; registry:outcomes
A4	events	1 / 358	while on treatment; safety; registry:outcomes
A4	events	0 / 358	while on treatment; safety; R0019776:Table 3
A4	events	0 / 358	while on treatment; safety; R0019776:Table 3

Systolic blood pressure change (14 lines; O05)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
26	A1	change	-2 mmHg		325	while on treatment; safety; R0019776:ESM Table 5
26	A1	change	-2 mmHg		342	treatment policy; safety; R0019776:ESM Table 5
26	A1 vs A4	md	1 mmHg	-1 to 2		treatment policy; safety; R0019776:ESM Table 5
26	A1 vs A4	md	0 mmHg	-1 to 2		while on treatment; safety; R0019776:ESM Table 5
26	A2 vs A4	md	-1 mmHg	-3 to 1		treatment policy; safety; R0019776:ESM Table 5
26	A2	change	-4 mmHg		325	while on treatment; safety; R0019776:ESM Table 5
26	A2 vs A4	md	-2 mmHg	-3 to -0		while on treatment; safety; R0019776:ESM Table 5
26	A2	change	-3 mmHg		343	treatment policy; safety; R0019776:ESM Table 5
26	A3 vs A4	md	-1 mmHg	-2 to 1		treatment policy; safety; R0019776:ESM Table 5
26	A3	change	-3 mmHg		305	while on treatment; safety; R0019776:ESM Table 5
26	A3	change	-3 mmHg		333	treatment policy; safety; R0019776:ESM Table 5
26	A3 vs A4	md	-1 mmHg	-3 to 0		while on treatment; safety; R0019776:ESM Table 5
26	A4	change	-2 mmHg		340	while on treatment; safety; R0019776:ESM Table 5
26	A4	change	-2 mmHg		350	treatment policy; safety; R0019776:ESM Table 5

Percent body weight change (18 lines; O10)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
26	A1	percent change	-2 percent	4		322	hypothetical; full analysis; registry:outcomes
26	A1 vs A4	md	-1.2 percent		-1.8 to -0.6		treatment policy; full analysis; R0019776:Table 2
26	A1	percent change	-1.7 percent			343	treatment policy; full analysis; R0019776:Table 2
26	A1	percent change	-1.7 percent			322	hypothetical; full analysis; R0019776:Table 2
26	A1 vs A4	md	-1.2 percent		-1.8 to -0.6		hypothetical; full analysis; R0019776:Table 2
26	A2	percent change	-4 percent	4		319	hypothetical; full analysis; registry:outcomes
26	A2 vs A4	md	-3.1 percent		-3.6 to -2.5		hypothetical; full analysis; R0019776:Table 2
26	A2	percent change	-3.5 percent			319	hypothetical; full analysis; R0019776:Table 2
26	A2	percent change	-3.3 percent			342	treatment policy; full analysis; R0019776:Table 2
26	A2 vs A4	md	-2.8 percent		-3.4 to -2.2		treatment policy; full analysis; R0019776:Table 2
26	A3 vs A4	md	-3.8 percent		-4.4 to -3.2		treatment policy; full analysis; R0019776:Table 2
26	A3	percent change	-4.8 percent			300	hypothetical; full analysis; R0019776:Table 2
26	A3	percent change	-5 percent	5		300	hypothetical; full analysis; registry:outcomes
26	A3 vs A4	md	-4.3 percent		-4.9 to -3.7		hypothetical; full analysis; R0019776:Table 2
26	A3	percent change	-4.3 percent			333	treatment policy; full analysis; R0019776:Table 2
26	A4	percent change	-0.5 percent			335	hypothetical; full analysis; R0019776:Table 2
26	A4	percent change	-0.5 percent			351	treatment policy; full analysis; R0019776:Table 2
26	A4	percent change	-1 percent	3		335	hypothetical; full analysis; registry:outcomes

Weight loss of 5 percent or more (14 lines; O11A)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
26	A1 vs A4	or	2.3	1.4 to 3.7		hypothetical; full analysis; R0019776:Table 2
26	A1	responders			55 / 343	treatment policy; full analysis; R0019776:Table 2
26	A1 vs A4	or	2.3	1.4 to 3.7		treatment policy; full analysis; R0019776:Table 2
26	A1	responders			51 / 322	hypothetical; full analysis; R0019776:Table 2
26	A2 vs A4	or	6.0	3.8 to 9.5		hypothetical; full analysis; R0019776:Table 2
26	A2	responders			106 / 319	hypothetical; full analysis; R0019776:Table 2
26	A2	responders			107 / 342	treatment policy; full analysis; R0019776:Table 2
26	A2 vs A4	or	5.1	3.3 to 8.0		treatment policy; full analysis; R0019776:Table 2
26	A3 vs A4	or	8.9	5.7 to 13.8		treatment policy; full analysis; R0019776:Table 2
26	A3	responders			137 / 300	hypothetical; full analysis; R0019776:Table 2
26	A3 vs A4	or	10.0	6.4 to 15.6		hypothetical; full analysis; R0019776:Table 2
26	A3	responders			149 / 333	treatment policy; full analysis; R0019776:Table 2
26	A4	responders			28 / 351	treatment policy; full analysis; R0019776:Table 2
26	A4	responders			27 / 335	hypothetical; full analysis; R0019776:Table 2

Weight loss of 10 percent or more (14 lines; O11B)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
26	A1 vs A4	or	2.9	0.6 to 14.8		hypothetical; full analysis; R0019776:Table 2
26	A1	responders			5 / 322	hypothetical; full analysis; R0019776:Table 2
26	A1	responders			5 / 343	treatment policy; full analysis; R0019776:Table 2
26	A1 vs A4	or	2.6	0.5 to 13.3		treatment policy; full analysis; R0019776:Table 2
26	A2 vs A4	or	14.0	3.3 to 59.3		hypothetical; full analysis; R0019776:Table 2
26	A2	responders			24 / 342	treatment policy; full analysis; R0019776:Table 2
26	A2 vs A4	or	11.7	2.8 to 49.2		treatment policy; full analysis; R0019776:Table 2
26	A2	responders			23 / 319	hypothetical; full analysis; R0019776:Table 2
26	A3	responders			40 / 300	hypothetical; full analysis; R0019776:Table 2
26	A3 vs A4	or	28.2	6.8 to 117.0		hypothetical; full analysis; R0019776:Table 2
26	A3	responders			42 / 333	treatment policy; full analysis; R0019776:Table 2
26	A3 vs A4	or	22.4	5.5 to 91.7		treatment policy; full analysis; R0019776:Table 2
26	A4	responders			2 / 335	hypothetical; full analysis; R0019776:Table 2
26	A4	responders			2 / 351	treatment policy; full analysis; R0019776:Table 2

Acute kidney injury (4 lines; O121)

Arm	Statistic	Events / N	Detail
A1	events	1 / 361	treatment policy; safety; R0019776:ESM Table 4
A2	events	0 / 358	treatment policy; safety; R0019776:ESM Table 4
A3	events	2 / 361	treatment policy; safety; R0019776:ESM Table 4
A4	events	1 / 358	treatment policy; safety; R0019776:ESM Table 4

All cause mortality (4 lines; O20)

Arm	Statistic	Events / N	Detail
A1	events	2 / 361	treatment policy; safety; R0019776:ESM Table 4
A2	events	2 / 358	treatment policy; safety; R0019776:ESM Table 4
A3	events	1 / 361	treatment policy; safety; R0019776:ESM Table 4
A4	events	0 / 358	treatment policy; safety; R0019776:ESM Table 4

Hospitalization for heart failure (4 lines; O23)

Arm	Statistic	Events / N	Detail
A1	events	0 / 361	treatment policy; safety; R0019776:ESM Table 4
A2	events	0 / 358	treatment policy; safety; R0019776:ESM Table 4
A3	events	1 / 361	treatment policy; safety; R0019776:ESM Table 4
A4	events	0 / 358	treatment policy; safety; R0019776:ESM Table 4

SF-36 physical component summary change (4 lines; O24A)

Week	Arm	Statistic	Estimate	SE or SD	Events / N	Detail
26	A1	change	0.15 points	5.32	322	hypothetical; full analysis; registry:outcomes
26	A2	change	0.29 points	4.74	320	hypothetical; full analysis; registry:outcomes
26	A3	change	0.98 points	5.00	299	hypothetical; full analysis; registry:outcomes
26	A4	change	0.69 points	5.62	334	hypothetical; full analysis; registry:outcomes

Physical functioning (any instrument) (4 lines; O24B)

Week	Arm	Statistic	Estimate	SE or SD	Events / N	Detail
26	A1	change	0.20 points	5.63	322	hypothetical; full analysis; registry:outcomes
26	A2	change	0.48 points	3.95	320	hypothetical; full analysis; registry:outcomes
26	A3	change	0.93 points	4.51	299	hypothetical; full analysis; registry:outcomes
26	A4	change	0.31 points	5.25	334	hypothetical; full analysis; registry:outcomes

Serious adverse events (4 lines; O25)

Arm	Statistic	Events / N	Detail
A1	events	16 / 361	while on treatment; safety; R0019776:Table 3
A2	events	11 / 358	while on treatment; safety; R0019776:Table 3
A3	events	11 / 361	while on treatment; safety; R0019776:Table 3
A4	events	15 / 358	while on treatment; safety; R0019776:Table 3

Discontinuation due to adverse events (4 lines; O26)

Arm	Statistic	Events / N	Detail
A1	events	17 / 361	while on treatment; safety; R0019776:Table 3
A2	events	16 / 358	while on treatment; safety; R0019776:Table 3
A3	events	35 / 361	while on treatment; safety; R0019776:Table 3
A4	events	6 / 358	while on treatment; safety; R0019776:Table 3

Nausea (4 lines; O27A)

Arm	Statistic	Events / N	Detail
A1	events	36 / 361	while on treatment; safety; R0019776:Table 3
A2	events	39 / 358	while on treatment; safety; R0019776:Table 3
A3	events	44 / 361	while on treatment; safety; R0019776:Table 3
A4	events	14 / 358	while on treatment; safety; R0019776:Table 3

Vomiting (4 lines; O27B)

Arm	Statistic	Events / N	Detail
A1	events	16 / 361	while on treatment; safety; R0019776:Table 3
A2	events	18 / 358	while on treatment; safety; R0019776:Table 3
A3	events	29 / 361	while on treatment; safety; R0019776:Table 3
A4	events	1 / 358	while on treatment; safety; R0019776:Table 3

Diarrhea (4 lines; O27C)

Arm	Statistic	Events / N	Detail
A1	events	30 / 361	while on treatment; safety; R0019776:Table 3
A2	events	32 / 358	while on treatment; safety; R0019776:Table 3
A3	events	48 / 361	while on treatment; safety; R0019776:Table 3
A4	events	16 / 358	while on treatment; safety; R0019776:Table 3

Gallbladder and biliary disease (8 lines; O28)

Arm	Statistic	Events / N	Detail
A1	events	0 / 361	not stated; safety; cholecystitis acute; registry:adverse_events
A1	events	0 / 361	not stated; safety; cholelithiasis; registry:adverse_events
A2	events	0 / 358	not stated; safety; cholecystitis acute; registry:adverse_events
A2	events	0 / 358	not stated; safety; cholelithiasis; registry:adverse_events
A3	events	1 / 361	not stated; safety; cholelithiasis; registry:adverse_events
A3	events	1 / 361	not stated; safety; cholecystitis acute; registry:adverse_events
A4	events	0 / 358	not stated; safety; cholecystitis acute; registry:adverse_events
A4	events	0 / 358	not stated; safety; cholelithiasis; registry:adverse_events

Acute pancreatitis (4 lines; O29)

Arm	Statistic	Detail
A1	events	not stated; other; R0019776:Results
A2	events	not stated; other; R0019776:Results
A3	events	not stated; other; R0019776:Results
A4	events	not stated; other; R0019776:Results

Medullary thyroid carcinoma (4 lines; O32A)

Arm	Statistic	Detail
A1	events	not stated; other; R0019776:Results
A2	events	not stated; other; R0019776:Results
A3	events	not stated; other; R0019776:Results
A4	events	not stated; other; R0019776:Results

Diabetic retinopathy complications (12 lines; O33)

Arm	Statistic	Events / N	Detail
A1	events	17 / 361	not stated; other; R0019776:Results
A1	events	0 / 361	not stated; safety; diabetic retinopathy; registry:adverse_events
A1	events	13 / 361	while on treatment; safety; diabetic retinopathy; R0019776:Table 3
A2	events	0 / 358	not stated; safety; diabetic retinopathy; registry:adverse_events
A2	events	13 / 358	not stated; other; R0019776:Results
A2	events	11 / 358	while on treatment; safety; diabetic retinopathy; R0019776:Table 3
A3	events	0 / 361	not stated; safety; diabetic retinopathy; registry:adverse_events
A3	events	12 / 361	while on treatment; safety; diabetic retinopathy; R0019776:Table 3
A3	events	12 / 361	not stated; other; R0019776:Results
A4	events	18 / 358	while on treatment; safety; diabetic retinopathy; R0019776:Table 3
A4	events	1 / 358	not stated; safety; diabetic retinopathy; registry:adverse_events
A4	events	20 / 358	not stated; other; R0019776:Results

Any cancer (4 lines; O39)

Arm	Statistic	Events / N	Detail
A1	events	0 / 361	treatment policy; safety; R0019776:ESM Table 4
A2	events	0 / 358	treatment policy; safety; R0019776:ESM Table 4
A3	events	1 / 361	treatment policy; safety; R0019776:ESM Table 4
A4	events	0 / 358	treatment policy; safety; R0019776:ESM Table 4