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COMBINE 1

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 Insulin Icodec

A 52 Week Study Comparing the Efficacy and Safety of Once Weekly IcoSema and Once Weekly Insulin Icodec, Both Treatment Arms With or Without Oral Anti Diabetic Drugs, in Participants With Type 2 Diabetes Inadequately Controlled With Daily Basal Insulin.

Lead sponsor

Novo Nordisk A/S

Asset

Semaglutide

GLP-1 agonist

Listed sites

281

Recruiting sites

Enrollment

1,291

actual

Study population

Type 2 diabetes

Key I/E criterion

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 IDNCT05352815
Org study IDNN1535-4591
Secondary ID2020-005281-34
Secondary IDU1111-1260-8259World Health Organization (WHO)

Timeline

Milestones

Study first posted2022-04-29actual
Study start2022-06-01actual
Primary completion2024-03-19actual
Study completion2024-04-23actual
Results first posted2025-04-03actual
Last update posted2025-12-04actual

Assets

Investigational agents

Study populations

Who this study enrolls

Type 2 diabetes

Eligibility

Who can enroll

Minimum age18 Years
SexAll
Healthy volunteersNot accepted

Eligibility criteria

Key inclusion criteria

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

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

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

4. Treated with once daily or twice daily basal insulin (neutral protamine hagedorn insulin, insulin degludec, insulin detemir, insulin glargine 100 units/mL, or insulin glargine 300 units/mL) 20- 80 units/day for 90 days or more before screening. Short term bolus insulin treatment for a maximum of 14 days before screening is allowed, as is prior insulin treatment for gestational diabetes. 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 (a)
Meglitinides (glinides) (a)
DPP 4 inhibitors (a)
Sodium glucose co transporter 2 inhibitors
Alpha glucosidase inhibitors
Thiazolidinediones
Marketed oral combination products only including the products listed above.

5. Body mass index (BMI) below or equal to 40.0 kg/m^2. (a) Sulfonylureas, meglitinides (glinides) and DPP 4 inhibitors must be discontinued at randomisation.

Key exclusion criteria

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

2. 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).

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

4. Any episodes (as declared by the participant or in the medical records.) of diabetic ketoacidosis within 90 days before screening.

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

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

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

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

9. 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 (20)

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
12
Safety / tolerability / PK
6
Weight & body composition
2

Weight & body composition

2 endpoints
Secondary/registry result

Change in Body Weight

Time frame:Baseline (Week 0), Week 52

Body weight, absolute change (kg)

change from baseline, improvement

Posted result

GroupValue (mean), Kilogram (Kg)95% CI
IcoSema-3.71
Insulin Icodec1.96
Secondary/protocol endpoint

Change in Body Weight

Time frame:Baseline (Week 0), Week 52

Body weight, absolute change (kg)

change from baseline, improvement

Glycemic / diabetes

12 endpoints
Primary/registry result

Change in Glycated Haemoglobin (HbA1c)

Time frame:Baseline (Week 0), Week 52

HbA1c, change

change from baseline, improvement

LOINC 4548-4

Posted result

GroupValue (mean), Percentage point of HbA1c95% CI
IcoSema-1.60
Insulin Icodec-0.90
Treatment difference-0.6695% CI-0.76-0.57p<0.0001ANCOVA
Primary/protocol endpoint

Change in Glycated Haemoglobin (HbA1c)

Time frame:Baseline (Week 0), Week 52

HbA1c, change

change from baseline, improvement

LOINC 4548-4

Secondary/registry result

Percentage of Time in Range 3.9-10.0 mmol/L (70-180 mg/dL) Using Continuous Glucose Monitoring (CGM) System, Dexcom G6

Time frame:From week 48 to week 52

CGM time-in-range

descriptive, improvement

Posted result

GroupValue (mean), Percentage of time95% CI
IcoSema75.9
Insulin Icodec61.9
Secondary/registry result

Percentage of Time Spent < 3.0 mmol/L (54 mg/dL) Using Continuous Glucose Monitoring (CGM) System, Dexcom G6

Time frame:From week 48 to week 52

CGM time-below-range

descriptive, improvement

Posted result

GroupValue (mean), Percentage of time95% CI
IcoSema0.27
Insulin Icodec0.33
Secondary/registry result

Percentage of Time Spent > 10.0 mmol/L (180 mg/dL) Using Continuous Glucose Monitoring (CGM) System, Dexcom G6

Time frame:From week 48 to week 52

CGM time-above-range

descriptive, improvement

Posted result

GroupValue (mean), Percentage of time95% CI
IcoSema23.2
Insulin Icodec36.7
Secondary/registry result

Change in Fasting Plasma Glucose (FPG)

Time frame:Baseline (Week 0), Week 52

Fasting glucose, change

change from baseline, improvement

LOINC 1558-6

Posted result

GroupValue (mean), Millimoles per litre (mmol/L)95% CI
IcoSema-1.90
Insulin Icodec-1.65
Secondary/registry result

Weekly Basal Insulin Dose

Time frame:From week 50 to week 52

descriptive

Posted result

GroupValue (mean), Units of insulin95% CI
IcoSema170.6
Insulin Icodec366.5
Secondary/protocol endpoint

Percentage of Time in Range 3.9-10.0 mmol/L (70-180 mg/dL) Using Continuous Glucose Monitoring (CGM) System, Dexcom G6

Time frame:From week 48 to week 52

CGM time-in-range

descriptive, improvement

Secondary/protocol endpoint

Percentage of Time Spent < 3.0 mmol/L (54 mg/dL) Using Continuous Glucose Monitoring (CGM) System, Dexcom G6

Time frame:From week 48 to week 52

CGM time-below-range

percent change from baseline, improvement

Secondary/protocol endpoint

Percentage of Time Spent > 10.0 mmol/L (180 mg/dL) Using Continuous Glucose Monitoring (CGM) System, Dexcom G6

Time frame:From week 48 to week 52

CGM time-above-range

descriptive, improvement

Secondary/protocol endpoint

Change in Fasting Plasma Glucose (FPG)

Time frame:Baseline (Week 0), Week 52

Fasting glucose, change

change from baseline, improvement

LOINC 1558-6

Secondary/protocol endpoint

Weekly Basal Insulin Dose

Time frame:From week 50 to week 52

descriptive

Safety / tolerability / PK

6 endpoints
Secondary/registry result

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

Time frame:From baseline week 0 to week 57

Documented hypoglycemia

event count, event

componentsDocumented hypoglycemia, Severe hypoglycemia

Posted result

GroupValue (number), Episodes95% CI
IcoSema91
Insulin Icodec424
Secondary/registry result

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 57

Documented hypoglycemia

event count, event

Posted result

GroupValue (number), Episodes95% CI
IcoSema90
Insulin Icodec419
Secondary/registry result

Number of Severe Hypoglycaemic Episodes (Level 3)

Time frame:From baseline week 0 to week 57

Severe hypoglycemia

event count, event

Posted result

GroupValue (number), Episodes95% CI
IcoSema1
Insulin Icodec5
Secondary/protocol endpoint

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

Time frame:From baseline 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:From baseline week 0 to week 57

Documented hypoglycemia

event count, event

Secondary/protocol endpoint

Number of Severe Hypoglycaemic Episodes (Level 3)

Time frame:From baseline 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

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.