COMBINE 2

CompletedPhase 3Results posted

A Research Study to See How Well the New Weekly Medicine IcoSema, Which is a Combination of Insulin Icodec and Semaglutide, Controls Blood Sugar Level in People With Type 2 Diabetes Compared to Weekly Semaglutide (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

Lead sponsor

Novo Nordisk A/S

Asset

Semaglutide

Subcutaneous · GLP-1 agonist

Listed sites

136

Recruiting sites

—

Enrollment

683

actual

Study population

Type 2 diabetes

Key I/E criterion

•HbA1c 7-10%

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 IDNCT05259033

Org study IDNN1535-4592

Secondary ID2020 005308 21

Secondary IDU1111 1260 8268World Health Organization (WHO)

Timeline

Milestones

Study first posted2022-02-28actual

Study start2022-04-11actual

Primary completion2023-12-13actual

Study completion2024-01-16actual

Results first posted2025-01-17actual

Last update posted2025-07-09actual

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 informed consent.

•Diagnosed with type 2 diabetes mellitus 180 days or more before screening.

•HbA1c of 7.0 - 10.0% (53.0 - 85.8 mmol/mol) (both inclusive) as assessed by central laboratory on the day of screening.

•Insulin naïve. The following exceptions are permitted: short term insulin treatment for a maximum of 14 days before screening and/or prior insulin treatment for gestational diabetes.

•Treated with stable doses of daily or weekly GLP-1 receptor agonist (excluding once weekly semaglutide with doses higher than 1.0 mg) according to local label for the treatment of diabetes for 90 days or more before screening. The treatment can be with or without any of the following anti diabetic drugs with stable doses for 90 days or more before screening: Metformin - Sulfonylureas (Sulfonylureas, meglitinides (glinides) and DPP 4 inhibitors must be discontinued at randomisation) - Meglitinides (glinides)(Sulfonylureas, meglitinides (glinides) and DPP 4 inhibitors must be discontinued at randomisation) - DPP 4 inhibitors (Sulfonylureas, meglitinides (glinides) and DPP 4 inhibitors must be discontinued at randomisation) - Sodium glucose co transporter 2 inhibitors - Alpha-glucosidase inhibitors - Thiazolidinediones - Marketed oral combination products only including the products listed above.

•Body mass index (BMI) below or equal to 40.0 kg/m^2.

Exclusion criteria

•Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using a 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).

•Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria within 90 days before screening.

•Any episodes (as declared by the participant or in the medical records) of diabetic ketoacidosis 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.

•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 (12)

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

Safety / tolerability / PK

Glycemic / diabetes

Weight & body composition

2 endpoints

Secondary/registry result

Change From Baseline in Body Weight

Time frame:Baseline (week 0), (week 52)

Body weight, absolute change (kg)

change from baseline, improvement

Posted result

Group	Value (mean), Kilogram (kg)	95% CI
IcoSema	0.89	—
Semaglutide	-3.77	—

Secondary/protocol endpoint

Change From Baseline in Body Weight

Time frame:Baseline (week 0), (week 52)

Body weight, absolute change (kg)

change from baseline, improvement

Glycemic / diabetes

4 endpoints

Primary/registry result

Change From Baseline in Glycosylated Haemoglobin (HbA1c)

Time frame:Baseline (week 0), (week 52)

HbA1c, change

change from baseline, improvement

LOINC 4548-4

Posted result

Group	Value (mean), Percentage point of HbA1c	95% CI
IcoSema	-1.40	—
Semaglutide	-0.86	—

Estimated treatment difference-0.4495% CI-0.56 – -0.33p<0.0001ANCOVA

Treatment policy strategy

Primary/protocol endpoint

Change From Baseline in Glycosylated Haemoglobin (HbA1c)

Time frame:Baseline (week 0), (week 52)

HbA1c, change

change from baseline, improvement

LOINC 4548-4

Secondary/registry result

Change From Baseline in Fasting Plasma Glucose (FPG)

Time frame:Baseline (week 0), (week 52)

Fasting glucose, change

change from baseline, improvement

LOINC 1558-6

Posted result

Group	Value (mean), Millimoles per litre (mmol/L)	95% CI
IcoSema	-2.74	—
Semaglutide	-1.41	—

Secondary/protocol endpoint

Change From Baseline in Fasting Plasma Glucose (FPG)

Time frame:Baseline (week 0), (week 52)

Fasting glucose, change

change from baseline, improvement

LOINC 1558-6

Safety / tolerability / PK

6 endpoints

Secondary/registry result

Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (<3.0 mmol/L (54 Milligram Per Decilitre [mg/dL]) , Confirmed by Blood Glucose [BG] Meter) or Severe Hypoglycaemic Episodes (Level 3)

Time frame:Week 0 to Week 57

Documented hypoglycemia

event count, event

componentsDocumented hypoglycemia, Severe hypoglycemia

Posted result

Group	Value (number), Episodes	95% CI
IcoSema	15	—
Semaglutide	13	—

Secondary/registry result

Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (<3.0 mmol/L (54 mg/dL), Confirmed by BG Meter)

Time frame:Week 0 to Week 57

Documented hypoglycemia

event count, event

Posted result

Group	Value (number), Episodes	95% CI
IcoSema	15	—
Semaglutide	13	—

Secondary/registry result

Number of Severe Hypoglycaemic Episodes (Level 3)

Time frame:Week 0 to Week 57

Severe hypoglycemia

event count, event

Posted result

Group	Value (number), Episodes	95% CI
IcoSema	0	—
Semaglutide	0	—

Secondary/protocol endpoint

Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (<3.0 mmol/L (54 Milligram Per Decilitre [mg/dL]) , Confirmed by Blood Glucose [BG] Meter) or Severe Hypoglycaemic Episodes (Level 3)

Time frame:Week 0 to Week 57

Documented hypoglycemia

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:Week 0 to Week 57

Documented hypoglycemia

event count, event

Secondary/protocol endpoint

Number of Severe Hypoglycaemic Episodes (Level 3)

Time frame:Week 0 to Week 57

Severe hypoglycemia

event count, event

Publications (1)

Bibliography

Records linked to this trial through ClinicalTrials.gov references, PubMed NCT search, and curated study seeds. 'Canonical' marks design/result papers; others are registry references or candidates.

Registry references + supporting bibliography

Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial.
Diabetologia2025 Apr (month)PMID39820580doi:10.1007/s00125-024-06348-5via clinicaltrials gov reference derived + pubmed nct search

Provenance

Sources

Trial identity, design, statusClinicalTrials.gov API v2

Snapshot dateJuly 1, 2026

Endpoint classificationDelfa endpoint taxonomy v2 (May 13, 2026)

Results tableClinicalTrials.gov results section

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.