COMBINE 4

CompletedPhase 3

A Research Study to See How Well New Weekly Medicine IcoSema, Which is a Combination of Insulin Icodec and Semaglutide, Controls Blood Sugar Levels in People With Type 2 Diabetes (T2D), Compared to Daily Insulin Glargine (COMBINE 4)

A 40-week Study Comparing the Efficacy and Safety of Once Weekly IcoSema and Daily Insulin Glargine 100 Units/mL in Participants With Type 2 Diabetes Inadequately Controlled on Oral Anti Diabetic Drugs COMBINE 4

Lead sponsor

Novo Nordisk A/S

Asset

Semaglutide

GLP-1 agonist

Listed sites

118

Recruiting sites

—

Enrollment

485

actual

Study population

Type 2 diabetes

Key I/E criterion

•HbA1c ≥8%

Primary endpoint

•HbA1c, change

Footprint

Where this trial recruits

Site locations as reported to ClinicalTrials.gov. Site count is not enrollment count; per-site enrollment is not available from source.

Identifiers

Registered as

NCT IDNCT06269107

Org study IDNN1535-4988

Secondary ID2022-502484-38-00European Medicines Agency (EMA)

Secondary IDU1111-1283-8648World Health Organization (WHO)

Timeline

Milestones

Study start2024-02-15actual

Study first posted2024-02-21actual

Primary completion2025-05-27actual

Study completion2025-07-08actual

Last update posted2026-05-28actual

Assets

Investigational agents

Semaglutide

Study populations

Who this study enrolls

Type 2 diabetes

Eligibility

Who can enroll

Minimum age18 Years

SexAll

Healthy volunteersNot accepted

Inclusion criteria

•Male or female and age above or equal to 18 years at the time of signing the informed consent.

•Diagnosed with T2D greater than or equal to (≥) 180 days before screening.

•HbA1c ≥ 8.0% (≥ 64.0 millimoles per mole [mmol/mol]) as assessed by central laboratory on the day of screening.

•Insulin naïve. Short term insulin treatment for a maximum of 14 consecutive days before screening is allowed, as is prior insulin treatment for gestational diabetes.

•Currently treated with 1-3 oral anti diabetic drug (OADs) with stable daily doses ≥ 90 days before screening comprising any of the following anti diabetic drug(s) at effective or maximum tolerated dose.

–Metformin

–Sulfonylureas

–Meglitinides (glinides)

–Dipeptidyl peptidase (DPP) 4 inhibitors

–Sodium glucose co transporter 2 inhibitors

–Alpha glucosidase inhibitors

–Thiazolidinediones

–Marketed oral combination products only including the products listed above.

•Body mass index (BMI) less than or equal to (≤) 40.0 kilogram per square meter (kg/m^2).

Exclusion criteria

•Female who is pregnant, breast-feeding or intends to become pregnant or is of childbaring potential and not using highly effective contraceptive method.

•Anticipated initiation or change in concomitant medication (for more than 14 consecutive days) known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid hormones, or systemic corticosteroids).

•Any episodes of diabetic ketoacidosis or treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria within 90 days before screening.

•Presence or history of pancreatitis (acute or chronic) within 180 days before screening.

•Any of the following: Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic attack within 180 days before screening.

•Chronic heart failure classified as being in New York Heart Association Class IV at screening.

•Recurrent severe hypoglycaemic episodes within the last year (12 months) as judged by the investigator.

•Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within the past 90 days before screening or in the period between screening and randomisation. Pharmacological pupil dilation is a requirement unless using a digital fundus photography camera specified for non dilated examination.

Endpoints (11)

What's being measured

Protocol endpoints and posted registry outcome measures, grouped into outcome categories. Composite endpoints show their component event types. Standard codes (LOINC, SNOMED CT) are shown where available.

Coverage by outcome category

Glycemic / diabetes

Safety / tolerability / PK

Weight & body composition

Patient-reported / QoL

Weight & body composition

1 endpoint

Secondary/protocol endpoint

Change in body weight

Time frame:From baseline (week 0) to week 40

Body weight, absolute change (kg)

change from baseline, improvement

Glycemic / diabetes

6 endpoints

Primary/protocol endpoint

Change in glycated haemoglobin (HbA1c)

Time frame:From baseline (week 0) to week 40

HbA1c, change

change from baseline, improvement

LOINC 4548-4

Secondary/protocol endpoint

Time in range 3.9-10.0 millimoles per liter (mmol/L) (70-180 milligram per deciliter [mg/dL])

Time frame:From week 36 to week 40

CGM time-in-range

descriptive, improvement

Secondary/protocol endpoint

Time spent less than (<) 3.0 mmol/L (54 mg/dL)

Time frame:From week 36 to week 40

CGM time-below-range

percent change from baseline, improvement

Secondary/protocol endpoint

Time spent greater than (>) 10.0 mmol/L (180 mg/dL)

Time frame:From week 36 to week 40

CGM time-above-range

percent change from baseline, improvement

Secondary/protocol endpoint

Weekly basal insulin dose

Time frame:From week 38 to week 40

descriptive

Secondary/protocol endpoint

Change in fasting plasma glucose (FPG)

Time frame:From baseline (week 0) to week 40

Fasting glucose, change

change from baseline, improvement

LOINC 1558-6

Patient-reported / QoL

1 endpoint

Secondary/protocol endpoint

Change in Diabetes Treatment Satisfaction Questionnaire (DTSQs) in total treatment satisfaction

Time frame:From baseline (week 0) to week 40

change from baseline, improvement

Safety / tolerability / PK

3 endpoints

Secondary/protocol endpoint

Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by blood glucose meter) or severe hypoglycaemic episodes (level 3)

Time frame:From baseline (week 0) to week 45

event count, event

componentsDocumented hypoglycemia, Severe hypoglycemia

Secondary/protocol endpoint

Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by BG meter)

Time frame:From baseline (week 0) to week 45

Documented hypoglycemia

event count, event

Secondary/protocol endpoint

Number of severe hypoglycaemic episodes (level 3)

Time frame:From baseline (week 0) to week 45

Severe hypoglycemia

event count, event

Provenance

Sources

Trial identity, design, statusClinicalTrials.gov API v2

Snapshot dateJuly 1, 2026

Endpoint classificationDelfa endpoint taxonomy v2 (May 13, 2026)

Results tableno registry results posted yet

Trial facts come from public ClinicalTrials.gov records. Endpoint categories are Delfa's classification of those records, not a ClinicalTrials.gov field. All figures reflect the July 1, 2026 snapshot.