parallel randomized trial

PIONEER 6

A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes

Type 2 diabetes (adults)NCT02692716S001381

Design

Randomized: 3,183
Start year: 2017
Treatment: , follow-up 87 weeks
Countries: multinational
Sponsor: Novo Nordisk A/S (industry)
Eligibility: T2D; age 50 or more with CVD or CKD, or 60 or more with CV risk factors

Conduct and analysis

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

Arms

Arm	Treatment	Background	Randomized	Analyzed	Completed treatment
A1	Semaglutide 14 mg oral once daily (original tablet) Oral semaglutide 14 mg	standard of care; lifestyle: not reported	1,591	1,591
A2	Placebo Placebo	standard of care; lifestyle: not reported	1,592	1,592

Baseline characteristics

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

Characteristic	Statistic	Semaglutide 14 mg oral once daily (original tablet) A1	Placebo A2	Whole trial ALL
age	mean (years)	66	66
age	sd (years)	7	7
asian	n	324	306
black	n	89	103
bmi	mean (kg/m2)			32.3
bmi	sd (kg/m2)			6.5
diabetes duration	mean (years)			14.9
diabetes duration	sd (years)			8.5
egfr	mean (mL/min/1.73 m2)	74.2	74.2
egfr	sd (mL/min/1.73 m2)	21.1	20.9
established cvd	n	1350	1345
female	n	507	500
hba1c	mean (percent)	8.2	8.2
hba1c	sd (percent)	1.6	1.6
hispanic	n	253	261
insulin use	percent	61.2	61.2
metformin use	n			2464
metformin use	percent			77.4
other american indian or alaska native	n	14	15
other cv risk factors age 60 plus	n	241	247
other cvd or ckd age 50 plus	n	1350	1345
other native hawaiian or pacific islander	n	5	1
other previous heart failure	percent	11.9	12.4
other previous mi	percent	35.3	36.9
other previous stroke or tia	percent	15.2	16.6
other race other	n	11	15
sbp	mean (mmHg)			135.6
sbp	sd (mmHg)			17.6
weight	mean (kg)			90.9
weight	sd (kg)			21.2
white	n	1148	1152

Analyses this trial contributes to

Results

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

HbA1c change (2 lines; O01)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
83	A1	change	-1.0 percent	1.4		1489	not stated; other; registry:outcomes
83	A2	change	-0.3 percent	1.3		1473	not stated; other; registry:outcomes

Body weight change in kilograms (diabetes) (2 lines; O02)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
83	A1	change	-4.2 kg	5.7		1510	not stated; other; registry:outcomes
83	A2	change	-0.8 kg	4.5		1493	not stated; other; registry:outcomes

Level 2 or 3 hypoglycemia (participants) (10 lines; O04)

Arm	Statistic	Events / N	Detail
A1	events	9 / 1591	while on treatment; safety; hypoglycaemic unconsciousness; registry:adverse_events
A1	events	13 / 434	not stated; full analysis; egfr:<60; R0006400:Table 4
A1	events	13 / 1150	not stated; full analysis; egfr:>=60; R0006400:Table 4
A1	events	5 / 1591	while on treatment; safety; hypoglycaemia; registry:adverse_events
A1	events	1 / 1591	while on treatment; safety; hypoglycaemic seizure; registry:adverse_events
A2	events	13 / 1158	not stated; full analysis; egfr:>=60; R0006400:Table 4
A2	events	3 / 422	not stated; full analysis; egfr:<60; R0006400:Table 4
A2	events	4 / 1591	while on treatment; safety; hypoglycaemia; registry:adverse_events
A2	events	0 / 1591	while on treatment; safety; hypoglycaemic seizure; registry:adverse_events
A2	events	6 / 1591	while on treatment; safety; hypoglycaemic unconsciousness; registry:adverse_events

Systolic blood pressure change (2 lines; O05)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
83	A1	change	-5 mmHg	18		1345	not stated; other; registry:outcomes
83	A2	change	-2 mmHg	18		1411	not stated; other; registry:outcomes

Acute kidney injury (8 lines; O121)

Arm	Statistic	Events / N	Detail
A1	events	13 / 1591	while on treatment; safety; acute kidney injury; registry:adverse_events
A1	events	0 / 1591	while on treatment; safety; acute prerenal failure; registry:adverse_events
A1	events	10 / 1150	not stated; full analysis; egfr:>=60; acute kidney failure; R0006400:Table 4
A1	events	13 / 434	not stated; full analysis; egfr:<60; acute kidney failure; R0006400:Table 4
A2	events	14 / 1591	while on treatment; safety; acute kidney injury; registry:adverse_events
A2	events	1 / 1591	while on treatment; safety; acute prerenal failure; registry:adverse_events
A2	events	12 / 422	not stated; full analysis; egfr:<60; acute kidney failure; R0006400:Table 4
A2	events	10 / 1158	not stated; full analysis; egfr:>=60; acute kidney failure; R0006400:Table 4

All cause mortality (3 lines; O20)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1 vs A2	hr	0.51	0.31 to 0.84		not stated; full analysis; registry:outcomes
A1	events			23 / 1591	not stated; full analysis; registry:outcomes
A2	events			45 / 1592	not stated; full analysis; registry:outcomes

Three point MACE (3 lines; O21)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1	events			61 / 1591	not stated; full analysis; registry:outcomes
A1 vs A2	hr	0.79	0.57 to 1.11		not stated; full analysis; registry:outcomes
A2	events			76 / 1592	not stated; full analysis; registry:outcomes

Hospitalization for heart failure (3 lines; O23)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1	events			21 / 1591	not stated; full analysis; registry:outcomes
A1 vs A2	hr	0.86	0.48 to 1.55		not stated; full analysis; registry:outcomes
A2	events			24 / 1592	not stated; full analysis; registry:outcomes

Serious adverse events (6 lines; O25)

Arm	Statistic	Events / N	Detail
A1	events	117 / 434	not stated; full analysis; egfr:<60; R0006400:Table 4
A1	events	301 / 1591	while on treatment; safety; registry:adverse_events
A1	events	207 / 1150	not stated; full analysis; egfr:>=60; R0006400:Table 4
A2	events	120 / 422	not stated; full analysis; egfr:<60; R0006400:Table 4
A2	events	249 / 1158	not stated; full analysis; egfr:>=60; R0006400:Table 4
A2	events	358 / 1591	while on treatment; safety; registry:adverse_events

Discontinuation due to adverse events (7 lines; O26)

Arm	Statistic	Estimate	95% CI	Events / N	Detail
A1	events			139 / 434	not stated; full analysis; egfr:<60; R0006400:Table 4
A1 vs A2	hr	1.81	1.42 to 2.30		not stated; full analysis; registry:outcomes
A1	events			184 / 1591	not stated; full analysis; registry:outcomes
A1	events			285 / 1150	not stated; full analysis; egfr:>=60; R0006400:Table 4
A2	events			89 / 422	not stated; full analysis; egfr:<60; R0006400:Table 4
A2	events			104 / 1592	not stated; full analysis; registry:outcomes
A2	events			178 / 1158	not stated; full analysis; egfr:>=60; R0006400:Table 4

Nausea (2 lines; O27A)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				2 / 1591	while on treatment; safety; nausea; registry:adverse_events
	A2	events				1 / 1591	while on treatment; safety; nausea; registry:adverse_events

Vomiting (2 lines; O27B)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				4 / 1591	while on treatment; safety; vomiting; registry:adverse_events
	A2	events				0 / 1591	while on treatment; safety; vomiting; registry:adverse_events

Diarrhea (2 lines; O27C)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				4 / 1591	while on treatment; safety; diarrhoea; registry:adverse_events
	A2	events				0 / 1591	while on treatment; safety; diarrhoea; registry:adverse_events

Constipation (2 lines; O27D)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 1591	while on treatment; safety; constipation; registry:adverse_events
	A2	events				1 / 1591	while on treatment; safety; constipation; registry:adverse_events

Gallbladder and biliary disease (20 lines; O28)

Arm	Statistic	Events / N	Detail
A1	events	0 / 1591	while on treatment; safety; biliary sepsis; registry:adverse_events
A1	events	1 / 1591	while on treatment; safety; cholangitis acute; registry:adverse_events
A1	events	1 / 1591	while on treatment; safety; gallbladder empyema; registry:adverse_events
A1	events	2 / 1591	while on treatment; safety; cholelithiasis; registry:adverse_events
A1	events	1 / 1591	while on treatment; safety; cholecystitis chronic; registry:adverse_events
A1	events	0 / 1591	while on treatment; safety; cholecystitis infective; registry:adverse_events
A1	events	1 / 1591	while on treatment; safety; cholecystitis; registry:adverse_events
A1	events	1 / 1591	while on treatment; safety; bile duct stone; registry:adverse_events
A1	events	0 / 1591	while on treatment; safety; biliary fistula; registry:adverse_events
A1	events	3 / 1591	while on treatment; safety; cholecystitis acute; registry:adverse_events
A2	events	0 / 1591	while on treatment; safety; cholecystitis chronic; registry:adverse_events
A2	events	0 / 1591	while on treatment; safety; bile duct stone; registry:adverse_events
A2	events	1 / 1591	while on treatment; safety; biliary fistula; registry:adverse_events
A2	events	1 / 1591	while on treatment; safety; biliary sepsis; registry:adverse_events
A2	events	0 / 1591	while on treatment; safety; cholangitis acute; registry:adverse_events
A2	events	0 / 1591	while on treatment; safety; gallbladder empyema; registry:adverse_events
A2	events	2 / 1591	while on treatment; safety; cholecystitis acute; registry:adverse_events
A2	events	1 / 1591	while on treatment; safety; cholecystitis infective; registry:adverse_events
A2	events	2 / 1591	while on treatment; safety; cholecystitis; registry:adverse_events
A2	events	4 / 1591	while on treatment; safety; cholelithiasis; registry:adverse_events

Acute pancreatitis (4 lines; O29)

Arm	Statistic	Events / N	Detail
A1	events	0 / 1591	while on treatment; safety; pancreatitis acute; registry:adverse_events
A1	events	1 / 1591	while on treatment; safety; pancreatitis; registry:adverse_events
A2	events	1 / 1591	while on treatment; safety; pancreatitis acute; registry:adverse_events
A2	events	1 / 1591	while on treatment; safety; pancreatitis; registry:adverse_events

Medullary thyroid carcinoma (2 lines; O32A)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				1 / 1591	while on treatment; safety; medullary thyroid cancer; registry:adverse_events
	A2	events				0 / 1591	while on treatment; safety; medullary thyroid cancer; registry:adverse_events

Thyroid cancer (any) (2 lines; O32B)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				2 / 1591	not stated; full analysis; R0000453:Table 1
	A2	events				0 / 1592	not stated; full analysis; R0000453:Table 1

Diabetic retinopathy complications (2 lines; O33)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 1591	while on treatment; safety; retinopathy proliferative; registry:adverse_events
	A2	events				1 / 1591	while on treatment; safety; retinopathy proliferative; registry:adverse_events

Pancreatic cancer (8 lines; O38)

Arm	Statistic	Events / N	Detail
A1	events	0 / 1591	while on treatment; safety; adenocarcinoma pancreas; registry:adverse_events
A1	events	2 / 1591	while on treatment; safety; pancreatic carcinoma metastatic; registry:adverse_events
A1	events	0 / 1591	while on treatment; safety; pancreatic carcinoma; registry:adverse_events
A1	events	1 / 1591	while on treatment; safety; pancreatic neuroendocrine tumour metastatic; registry:adverse_events
A2	events	2 / 1591	while on treatment; safety; adenocarcinoma pancreas; registry:adverse_events
A2	events	1 / 1591	while on treatment; safety; pancreatic carcinoma metastatic; registry:adverse_events
A2	events	1 / 1591	while on treatment; safety; pancreatic carcinoma; registry:adverse_events
A2	events	0 / 1591	while on treatment; safety; pancreatic neuroendocrine tumour metastatic; registry:adverse_events