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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 Semaglutide (COMBINE 2)

Short name COMBINE 2

NCTNCT05259033 (opens ClinicalTrials.gov in a new tab)Other idNN1535-4592Other idU1111 1260 8268Other id2020 005308 21
Open at ClinicalTrials.govAsk about this trial

Overview

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

United States, Brazil, Canada, China, France, Greece, Hungary, Israel, Japan, Russia, Slovakia, Sweden, Switzerland, Taiwan, Ukraine

Start
11 Apr 2022
Primary completion
13 Dec 2023
Completion
16 Jan 2024
First posted
28 Feb 2022
Last update posted
12 Jun 2026
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 2

    NCT05259033

    11 Apr 2022 to 16 Jan 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 semaglutide 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 semaglutide. Participants will either get IcoSema or semaglutide. Which treatment participants get is decided by chance. IcoSema is a new medicine that doctors cannot prescribe. Doctors can already prescribe semaglutide in many countries. Participants will get IcoSema or semaglutide, which they 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 18 clinic visits, 34 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.

Interventions

  • IcoSemaDrug
  • Semaglutide 1 mgDrug

Arms2

  • Experimental

    IcoSema

    Participants will get once weekly dose

  • Experimental

    Semaglutide

    Participants will get once weekly dose

Primary outcomes1

Outcomes the sponsor listed as primary.

  1. Change From Baseline in Glycosylated 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(5)

  1. Change From Baseline in Fasting Plasma Glucose (FPG)

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

    Registry description

    Change from baseline (week 0) to week 52 in FPG 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. Change From Baseline 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.

  3. 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

    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 (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.

  4. 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

    Registry description

    Hypoglycaemic episodes were classified according to the American Diabetes Association/ International Hypoglycaemia Study Group, where glycemic criteria for level 2 was \< 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 (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.

  5. Number of Severe Hypoglycaemic Episodes (Level 3)

    Time frame · 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 (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.

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 From Baseline in Glycosylated Haemoglobin (HbA1c)

GroupValue (Percentage point of HbA1c)Spread
IcoSema-1.400.91
Semaglutide-0.860.96
Secondary and other outcome results(5)
Secondary outcomeMean· Baseline (week 0), (week 52)

Change From Baseline in Fasting Plasma Glucose (FPG)

GroupValue (Millimoles per litre (mmol/L))Spread
IcoSema-2.742.85
Semaglutide-1.412.89
Secondary outcomeMean· Baseline (week 0), (week 52)

Change From Baseline in Body Weight

GroupValue (Kilogram (kg))Spread
IcoSema0.894.36
Semaglutide-3.774.60
Secondary outcomeNumber· Week 0 to Week 57

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)

GroupValue (Episodes)
IcoSema15
Semaglutide13
Secondary outcomeNumber· Week 0 to Week 57

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

GroupValue (Episodes)
IcoSema15
Semaglutide13
Secondary outcomeNumber· Week 0 to Week 57

Number of Severe Hypoglycaemic Episodes (Level 3)

GroupValue (Episodes)
IcoSema0
Semaglutide0

Adverse events, as posted

Adverse events as posted: participants affected out of participants at risk, by group
GroupDeathsSerious eventsOther events
IcoSemaParticipants received once weekly 700 units per millilitre (U/mL) of insulin icodec and 2 milligram per millilitre (mg/mL) of semaglutide subcutaneously for 52 weeks. Participants were to perform once daily pre-breakfast self-monitoring plasma glucose (SMPG). The dose was adjusted based on 3 pre-breakfast SMPG values measured on the 2 previous days and the day of the contact. If at least one pre-breakfast SMPG value was: \< 4.4 mmol/L: dose re-duced by 10 U; 4.4-7.2 mmol/L: no adjustment; \> 7.2 mmol/L: dose increased by 10 U. Dose titration of IcoSema was based on the respective premeal(s) and bedtime self-measured plasma glucose (SMPG) measured weekly.2 / 34238 / 341163 / 341
SemaglutideParticipants received once weekly semaglutide subcutaneously in a dose escalation manner, with dose increases every 4 weeks for up to week 8 (0.25 milligrams \[mg\], 0.5 mg) followed by dose of 1.0 mg once weekly up to the end of treatment period.0 / 34121 / 340159 / 340

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

Studies2

Studies that cite this trial.

Studies with results

1 study 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)

More studies

1 study on this page

Indexing hint: Randomized controlled trial · 2025

Corrected

Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial.

Lingvay et al. 2025Diabetologiacited by 24

PMID 39820580PMC11950020DOI 10.1007/s00125-024-06348-5PUB-39820580

CC BY
Download PDFRead the notice

Eligibility

Who could join, as posted.

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

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