parallel randomized trial

COMBINE 2

A 52 Week Study Comparing the Efficacy and Safety of Once Weekly IcoSema and Once Weekly Semaglutide, Both Treatment Arms With or Without Oral Anti Diabetic Drugs, in Participants With Type 2 Diabetes Inadequately Controlled With a GLP 1 Receptor Agonist. COMBINE 2

Type 2 diabetes (adults)NCT05259033S000155

Design

Randomized: 683
Start year: 2022
Treatment: 52 weeks, follow-up 57 weeks
Countries: multinational (121 sites)
Sponsor: Novo Nordisk (industry)
Eligibility: adults T2D on GLP-1 RA with or without oral drugs; HbA1c 7.0 to 10.0 percent

Conduct and analysis

Blinding: open label
Sequence generation: not reported
Allocation concealment: central
Outcome adjudication: not reported
Primary estimand: treatment policy
Analysis population: full analysis
Missing data: multiple imputation

Arms

Arm	Treatment	Background	Randomized	Analyzed	Completed treatment
A1	Insulin icodec and semaglutide (IcoSema) subcutaneous once weekly titrated IcoSema	non-insulin glucose lowering drugs except sulfonylurea, glinide and DPP-4i; lifestyle: not reported	342	342	320
A2	Semaglutide 1.0 mg subcutaneous once weekly Semaglutide 1.0 mg	non-insulin glucose lowering drugs except sulfonylurea, glinide and DPP-4i; lifestyle: not reported	341	341	328

Baseline characteristics

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

Characteristic	Statistic	Insulin icodec and semaglutide (IcoSema) subcutaneous once weekly titrated A1	Semaglutide 1.0 mg subcutaneous once weekly A2
age	mean (years)	59.9	58.3
age	sd (years)	10.5	9.8
asian	percent	28.9	26.4
black	percent	3.5	2.6
bmi	mean (kg/m2)	30.58	31.65
bmi	sd (kg/m2)	4.69	4.66
diabetes duration	mean (years)	12.94	12.34
diabetes duration	sd (years)	6.82	6.97
egfr: 60 to less than 90	n	157	152
egfr: 90 or more	n	161	165
egfr: less than 60	n	24	24
female	n	141	145
hba1c	mean (percent)	8.07	7.93
hba1c	sd (percent)	0.76	0.73
hispanic	percent	10.8	10.9
metformin use	percent	87.1	89.4
other american indian alaska native	percent	0.3	0
other glp1ra use	percent	99.1	100.0
other male	n	201	196
other male	percent	58.8	57.5
other sulfonylurea use	percent	28.9	28.2
sglt2i use	percent	40.6	46.9
weight	mean (kg)	87.58	90.82
weight	sd (kg)	18.20	17.74
white	percent	61.4	65.7

Analyses this trial contributes to

Results

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

HbA1c change (5 lines; O01)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
52	A1	change	-1.40 percent	0.91		325	not stated; full analysis; registry:outcomes
52	A1	change	-1.35 percent	0.04		342	treatment policy; full analysis; R0005851:Results
52	A1 vs A2	md	-0.44 percent		-0.56 to -0.33		treatment policy; full analysis; R0005851:Table 2
52	A2	change	-0.86 percent	0.96		335	not stated; full analysis; registry:outcomes
52	A2	change	-0.90 percent	0.04		341	treatment policy; full analysis; R0005851:Results

Body weight change in kilograms (diabetes) (5 lines; O02)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
52	A1	change	0.89 kg	4.36		325	not stated; full analysis; registry:outcomes
52	A1	change	0.84 kg			342	treatment policy; full analysis; R0005851:Table 2
52	A1 vs A2	md	4.54 kg		3.84 to 5.23		treatment policy; full analysis; R0005851:Table 2
52	A2	change	-3.77 kg	4.60		336	not stated; full analysis; registry:outcomes
52	A2	change	-3.70 kg			341	treatment policy; full analysis; R0005851:Table 2

HbA1c below 7 percent (3 lines; O03)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
52	A1 vs A2	or	3.01	2.14 to 4.24		treatment policy; full analysis; R0005851:Table 3
52	A1	responders	73.5 percent		342	treatment policy; full analysis; R0005851:Table 3
52	A2	responders	48.0 percent		341	treatment policy; full analysis; R0005851:Table 3

Level 2 or 3 hypoglycemia (participants) (4 lines; O04)

Arm	Statistic	Events / N	Detail
A1	events	12 / 341	while on treatment; safety; R0005851:Table 4
A1	events	0 / 341	while on treatment; safety; R0005851:Table 4
A2	events	13 / 340	while on treatment; safety; R0005851:Table 4
A2	events	0 / 340	while on treatment; safety; R0005851:Table 4

Level 2 or 3 hypoglycemia (episode rate) (1 lines; O04B)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1 vs A2	rate ratio	1.20		0.53 to 2.69		hypothetical; full analysis; R0005851:Table 4

Systolic blood pressure change (3 lines; O05)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
52	A1	change	-0.42 mmHg		342	treatment policy; full analysis; R0005851:Supplement Table 6
52	A1 vs A2	md	2.64 mmHg	0.72 to 4.55		treatment policy; full analysis; R0005851:Supplement Table 6
52	A2	change	-3.06 mmHg		341	treatment policy; full analysis; R0005851:Supplement Table 6

Acute kidney injury (2 lines; O121)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				1 / 341	not stated; safety; acute kidney injury; registry:adverse_events
	A2	events				1 / 340	not stated; safety; acute kidney injury; registry:adverse_events

All cause mortality (4 lines; O20)

Arm	Statistic	Events / N	Detail
A1	events	2 / 342	not stated; randomized; registry:adverse_events
A1	events	2 / 341	not stated; safety; R0005851:Results
A2	events	0 / 340	not stated; safety; R0005851:Results
A2	events	0 / 341	not stated; randomized; registry:adverse_events

Serious adverse events (2 lines; O25)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				38 / 341	while on treatment; safety; R0005851:Table 4
	A2	events				21 / 340	while on treatment; safety; R0005851:Table 4

Discontinuation due to adverse events (2 lines; O26)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events	2.3			341	while on treatment; safety; R0005851:Results
	A2	events	2.6			340	while on treatment; safety; R0005851:Results

Nausea (2 lines; O27A)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				40 / 341	while on treatment; safety; R0005851:Table 4
	A2	events				39 / 340	while on treatment; safety; R0005851:Table 4

Vomiting (2 lines; O27B)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				18 / 341	while on treatment; safety; R0005851:Table 4
	A2	events				22 / 340	while on treatment; safety; R0005851:Table 4

Diarrhea (2 lines; O27C)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				38 / 341	while on treatment; safety; R0005851:Table 4
	A2	events				42 / 340	while on treatment; safety; R0005851:Table 4

Constipation (2 lines; O27D)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				11 / 341	while on treatment; safety; R0005851:Table 4
	A2	events				17 / 340	while on treatment; safety; R0005851:Table 4

Discontinuation due to gastrointestinal adverse events (2 lines; O27E)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				3 / 341	while on treatment; safety; R0005851:Results
	A2	events				2 / 340	while on treatment; safety; R0005851:Results

Gallbladder and biliary disease (2 lines; O28)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				2 / 341	not stated; safety; cholecystitis acute; registry:adverse_events
	A2	events				1 / 340	not stated; safety; cholecystitis acute; registry:adverse_events

Acute pancreatitis (2 lines; O29)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				1 / 341	not stated; safety; Pancreatitis acute; registry:adverse_events
	A2	events				0 / 340	not stated; safety; Pancreatitis acute; registry:adverse_events

Diabetic retinopathy complications (2 lines; O33)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				19 / 341	while on treatment; safety; Diabetic retinopathy; R0005851:Table 4
	A2	events				10 / 340	while on treatment; safety; Diabetic retinopathy; R0005851:Table 4

Nonarteritic anterior ischemic optic neuropathy (2 lines; O34)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Events / N	Detail
	A1	events				0 / 341	not stated; safety; optic ischaemic neuropathy; registry:adverse_events
	A2	events				1 / 340	not stated; safety; optic ischaemic neuropathy; registry:adverse_events