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Trial · Interventional

CompletedPhase 3Results postedRegistry data

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

Short name COMBINE 1

NCTNCT05352815 (opens ClinicalTrials.gov in a new tab)Other idNN1535-4591Other idU1111-1260-8259Other id2020-005281-34
Open at ClinicalTrials.govAsk about this trial

This trial does not test a peptide that PepBank tracks.

  • Names Semaglutide, does not test it. It appears in the title.

Overview

Status
Completed
Phase
Phase 3
Enrollment
1,291 participants (actual)
Sponsor
Novo Nordisk A/S · Industry
Design
Randomized · Open label (no masking)
Countries
22 countries

United States, Australia, Belgium, Bulgaria, China, Croatia, Finland, India, Italy, Japan, Mexico, Norway, Poland, Portugal, Puerto Rico, Romania, Russia, Serbia, South Africa, South Korea, Taiwan, Turkey (Türkiye)

Start
1 Jun 2022
Primary completion
19 Mar 2024
Completion
23 Apr 2024
First posted
29 Apr 2022
Last update posted
4 Dec 2025
Conditions
Diabetes Mellitus, Type 2

Timeline

1 trial · 1 completed · 1 with posted results

  • Completed
  • Ongoing
  • Not yet recruiting
  • Stopped
  • Estimated dates (est.)
  • Results posted
2022202320242025
  1. Ph 3

    COMBINE 1

    NCT05352815

    1 Jun 2022 to 23 Apr 2024

Registry summary

Text and fields below are the sponsor's entries at ClinicalTrials.gov, shown as posted.

This study will compare the new medicine IcoSema, which is a combination of insulin icodec and semaglutide, taken once a week, to insulin icodec taken once a week in people with type 2 diabetes. The study will look at how well IcoSema controls blood sugar level in people with type 2 diabetes compared to insulin icodec. Participants will either get IcoSema or insulin icodec. Which treatment participants get is decided by chance. IcoSema and insulin icodec are both new medicines that doctors cannot prescribe. Participants will get IcoSema or insulin icodec, which participants must inject once a week with a pen, which has a small needle, in a skin fold in the thigh, upper arm, or stomach. The study will last for about 1 year and 1 month. Participants will have 21 clinic visits, 31 phone/video calls with the study doctor, and 4 contacts with the site that can either be clinic visits or phone/video calls At 11 clinic visits participants will have blood samples taken. At 7 clinic visits participants cannot eat or drink (except for water) for 8 hours before the visit. Women cannot take part if pregnant, breast-feeding or plan to get pregnant during the study period. Not applicable for China: Participants will be asked to wear a sensor that measures their blood sugar level all the time during a 5 week period at the end of the study.

Interventions

  • IcoSemaDrug
  • Insulin icodecDrug

Arms2

  • Experimental

    IcoSema

  • Active comparator

    Insulin icodec

Primary outcomes1

Outcomes the sponsor listed as primary.

  1. Change in Glycated Haemoglobin (HbA1c)

    Time frame · Baseline (Week 0), Week 52

    Registry description

    Change from baseline (week 0) to week 52 in HbA1c is presented. The outcome measure was evaluated based on the data from in study period, where all data from randomisation until last date of any of the following: 1) last direct participant-site contact; 2) participants who withdrew their informed consent; 3) last participant-investigator contact as defined by the investigator for participants who lost to follow-up (i.e. possibly an unscheduled phone visit); 4) death of participants who died before any of the above.

Secondary outcomes(9)

  1. Change in Body Weight

    Time frame · Baseline (Week 0), Week 52

    Registry description

    Change from baseline (week 0) to week 52 in body weight is presented. The outcome measure was evaluated based on the data from in study period, where all data from randomisation until last date of any of the following: 1) last direct participant-site contact; 2) participants who withdrew their informed consent; 3) last participant-investigator contact as defined by the investigator for participants who lost to follow-up (i.e. possibly an unscheduled phone visit); 4) death of participants who died before any of the above.

  2. 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

    Registry description

    Hypoglycaemic episodes were classified according to the American Diabetes Association/ International Hypoglycaemia Study Group, where glycemic criteria for level 2 was less than (\<) 3.0 mmol/L (54 mg/dL) and level 3 had no specific glucose threshold. The outcome measure was evaluated based on data from on treatment period, where all data from date of first dose of randomised treatment as recorded on the electronic case report form (eCRF) until the first date of any of the following: 1) last follow-up visit ; 2) last date on randomised treatment +6 weeks (corresponding to 5 weeks after the end of the dosing interval for both treatment arms); 3) end-date for the in-study data points sets.

  3. 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

    Registry description

    Time in range was defined as 100 times the number of recorded measurements in glycemic range 3.9-10.0 mmol/L (70-180 mg/dL), both inclusive, divided by the total number of recorded measurements. The outcome measure was evaluated based on the data from in study period: Data from randomisation until last date of any of the following: 1) the last direct participant-site contact; 2) withdrawal for participants who withdraw their informed consent; 3) the last participant-investigator contact as defined by the investigator for participants who are lost to follow-up (i.e. possibly an unscheduled phone visit); 4) death for participants who die before any of the above.

  4. 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

    Registry description

    Time spent below threshold was defined as 100 times the number of recorded measurements below the threshold, divided by the total number of recorded measurements. The outcome measure was evaluated based on the data from in study period: Data from randomisation until last date of any of the following: 1) the last direct participant-site contact; 2) withdrawal for participants who withdraw their informed consent; 3) the last participant-investigator contact as defined by the investigator for participants who are lost to follow-up (i.e. possibly an unscheduled phone visit); 4) death for participants who die before any of the above.

  5. 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

    Registry description

    Time spent above threshold is defined as 100 times the number of recorded measurements above the threshold, divided by the total number of recorded measurements. The outcome measure was evaluated based on the data from in study period: Data from randomisation until last date of any of the following: 1) the last direct participant-site contact; 2) withdrawal for participants who withdraw their informed consent; 3) the last participant-investigator contact as defined by the investigator for participants who are lost to follow-up (i.e. possibly an unscheduled phone visit); 4) death for participants who die before any of the above.

  6. Change in Fasting Plasma Glucose (FPG)

    Time frame · Baseline (Week 0), Week 52

    Registry description

    Change in FPG from baseline (week 0) to week 52 is presented. The outcome measure was evaluated based on the data from in study period: Data from randomisation until last date of any of the following: 1) the last direct participant-site contact; 2) withdrawal for participants who withdraw their informed consent; 3) the last participant-investigator contact as defined by the investigator for participants who are lost to follow-up (i.e. possibly an unscheduled phone visit); 4) death for participants who die before any of the above.

  7. Weekly Basal Insulin Dose

    Time frame · From week 50 to week 52

    Registry description

    Estimated mean average weekly basal insulin dose from week 50 to week 52 of treatment is presented. The outcome measure was evaluated based on data from on treatment period, where all data from date of first dose of randomised treatment as recorded on the electronic case report form (eCRF) until the first date of any of the following: 1) last follow-up visit (V56); 2) last date on randomised treatment +6 weeks (corresponding to 5 weeks after the end of the dosing interval for both treatment arms); 3) end-date for the in-study data points sets.

  8. 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

    Registry description

    Hypoglycaemic episodes were classified according to the American Diabetes Association/ International Hypoglycaemia Study Group, where glycemic criteria for level 2 was less than (\<) 3.0 mmol/L (54 mg/dL). The outcome measure was evaluated based on data from on treatment period, where all data from date of first dose of randomised treatment as recorded on the electronic case report form (eCRF) until the first date of any of the following: 1) last follow-up visit ; 2) last date on randomised treatment +6 weeks (corresponding to 5 weeks after the end of the dosing interval for both treatment arms); 3) end-date for the in-study data points sets.

  9. Number of Severe Hypoglycaemic Episodes (Level 3)

    Time frame · From baseline week 0 to week 57

    Registry description

    Hypoglycaemic episodes were classified according to the American Diabetes Association/ International Hypoglycaemia Study Group, where glycemic criteria for level 3 had no specific glucose threshold. The outcome measure was evaluated based on data from on treatment period, where all data from date of first dose of randomised treatment as recorded on the electronic case report form (eCRF) until the first date of any of the following: 1) last follow-up visit; 2) last date on randomised treatment +6 weeks (corresponding to 5 weeks after the end of the dosing interval for both treatment arms); 3) end-date for the in-study data points sets.

Posted results

Values are shown as posted at ClinicalTrials.gov, with their units. PepBank has not converted, pooled or compared them.

Primary outcome results

Primary outcomeMean· Baseline (Week 0), Week 52

Change in Glycated Haemoglobin (HbA1c)

GroupValue (Percentage point of HbA1c)Spread
IcoSema-1.600.99
Insulin Icodec-0.901.01
Secondary and other outcome results(7)
Secondary outcomeMean· Baseline (Week 0), Week 52

Change in Body Weight

GroupValue (Kilogram (Kg))Spread
IcoSema-3.714.87
Insulin Icodec1.964.76
Secondary outcomeNumber· From baseline week 0 to week 57

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)

GroupValue (Episodes)
IcoSema91
Insulin Icodec424
Secondary outcomeMean· From week 48 to week 52

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

GroupValue (Percentage of time)Spread
IcoSema75.916.1
Insulin Icodec61.918.1
Secondary outcomeMean· From week 48 to week 52

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

GroupValue (Percentage of time)Spread
IcoSema0.270.55
Insulin Icodec0.330.82
Secondary outcomeMean· From week 48 to week 52

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

GroupValue (Percentage of time)Spread
IcoSema23.216.3
Insulin Icodec36.718.7
Secondary outcomeMean· Baseline (Week 0), Week 52

Change in Fasting Plasma Glucose (FPG)

GroupValue (Millimoles per litre (mmol/L))Spread
IcoSema-1.903.01
Insulin Icodec-1.652.96
Secondary outcomeMean· From week 50 to week 52

Weekly Basal Insulin Dose

GroupValue (Units of insulin)Spread
IcoSema170.683.3
Insulin Icodec366.5225.5

Adverse events, as posted

Adverse events as posted: participants affected out of participants at risk, by group
GroupDeathsSerious eventsOther events
IcodecParticipants received once-weekly subcutaneous injections of 700 U/mL of insulin icodec for 52 weeks.3 / 64569 / 644258 / 644
IcoSemaParticipants received once-weekly subcutaneous injections of 700 units per milliliter (U/mL) of insulin icodec and 2 milligrams per milliliter (mg/mL) of semaglutide for 52 weeks.2 / 64659 / 644354 / 644

Each cell reads participants affected / participants at risk, as the registry posted them.

Registry data comes from ClinicalTrials.gov. Study results come from studies, not from the registry. How PepBank works

Studies3

Studies that cite this trial.

Studies with results

2 studies on this page

Indexing hint: Randomized controlled trial · 2026

7 results

Efficacy and Hypoglycaemia Outcomes With Once-Weekly IcoSema Versus Comparators in Individuals With Type 2 Diabetes by Kidney and Liver Function: A Post Hoc Analysis of the COMBINE 1-3 Trials.

Ji et al. 2026Diabetes, obesity & metabolismcited by 1

PMID 42557064PMC13538793DOI 10.1111/dom.70895PUB-42557064

Free to read · publisher termsCC BY-NC7 results
Read at sourceSee results (7)

Indexing hint: Randomized controlled trial · 2025

5 results

Once‑weekly IcoSema versus once‑weekly insulin icodec in type 2 diabetes management (COMBINE 1): an open‑label, multicentre, treat‑to‑target, randomised, phase 3a trial.

Mathieu et al. 2025The lancet. Diabetes & endocrinologycited by 20

PMID 40482671DOI 10.1016/s2213-8587(25)00096-8PUB-40482671

Full text at the publisher5 results
Publisher pageSee results (5)

More studies

1 study on this page

PubMed tag: none · 2026

CGM-derived postprandial glucose with IcoSema versus other insulin regimens: a post hoc analysis of COMBINE 1 and 3.

De Block et al. 2026EClinicalMedicine

PMID 42306490PMC13266221DOI 10.1016/j.eclinm.2026.103985PUB-42306490

Free to read · publisher termsCC BY-NC-ND
Read at source

Eligibility

Who could join, as posted.

Sex
All
Age
from 18 Years
Healthy volunteers
Not accepted
Inclusion and exclusion criteria, as posted
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.

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