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) (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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: IcoSema; Drug: Semaglutide 1 mg

• Study Type: Interventional
• Enrollment (Actual): 683
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Ceara
    • Fortaleza, Ceara, Brazil, 60150-162
      • Centro De Diabetes Metabolismo E Endocrinologia
  • Goias
    • Aparecida de Goiania, Goias, Brazil, 74935-530
      • Instituto de Ciências Farmacêuticas de Estudos e Pesquisas
  • Parana
    • Curitiba, Parana, Brazil, 80810-040
      • Centro de Diabetes Curitiba
    • Curitiba, Parana, Brazil, 80045-110
      • Quanta Diagnóstico Nuclear / Medicina Nuclear Alto da XV
  • Sao Paulo
    • São José dos Campos, Sao Paulo, Brazil, 12243-280
      • Instituto São José dos Campos em Pesquisas Médicas
    • São Paulo, Sao Paulo, Brazil, 01236-030
      • BR Trials - Ensaios Clínicos e Consultoria Ltda.
• Canada
  • Quebec, Canada, G1G 3Y8
    • Recherche Clinique Sigma inc
  • Ontario
    • Concord, Ontario, Canada, L4K 4M2
      • LMC Clinical Res Thornhill
    • Courtice, Ontario, Canada, L1E2J5
      • Medical Trust Clinics, Inc.
    • Hamilton, Ontario, Canada, L8L 5G8
      • Wharton Med Clin Trials
    • London, Ontario, Canada, N6G 2M1
      • Western Univ. Cnt for Studies in Fam Med
    • Sarnia, Ontario, Canada, N7T 4X3
      • Bluewater Clin Res Group,Inc
    • Toronto, Ontario, Canada, M4G 3E8
      • LMC Endo Centres Ltd.(Bayview)
  • Quebec
    • Montreal, Quebec, Canada, H1M 1B1
      • Recherche GCP Research
    • Montreal, Quebec, Canada, H4T 1Z9
      • LMC Clin Rsrch Inc. (Montreal)
    • Montreal, Quebec, Canada, H1Y 3H5
      • Recherche GCP Research
    • Saint-Laurent, Quebec, Canada, H4T 1Z9
      • LMC Clin Rsrch Inc. (Montreal)
• China
  • Anhui
    • Hefei, Anhui, China, 230001
      • Anhui Provincial Hospital-Endocrinology
  • Beijing
    • Beijing, Beijing, China, 100044
      • Peking University People's Hospital-Endocrinology
  • Chongqing
    • Chongqing, Chongqing, China, 404000
      • Chongqing University Three Gorges Hospital
  • Guangdong
    • Huizhou, Guangdong, China, 516001
      • Huizhou Central People's Hospital-Endocrinology
  • Jiangsu
    • Changzhou, Jiangsu, China, 213003
      • Changzhou No.2 People's Hospital, Yanghu Branch
    • Nanjing, Jiangsu, China, 210011
      • The Second Affiliated Hospital of Nanjing Medical University-Endocrinology
  • Shandong
    • Ji'nan, Shandong, China, 250013
      • Jinan Central Hospital
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • Shanghai Huashan Hospital, Affiliated to Fudan University
    • Shanghai, Shanghai, China, 200240
      • Shanghai Fifth People's Hospital-Endocrinology
    • Shanghai, Shanghai, China, 200040
      • Huashan Hospital Fudan University-Endocrinology
  • Tianjin
    • Tianjin, Tianjin, China, 300052
      • General Hospital of Tianjin Medical University-Endocrinology
    • Tianjin, Tianjin, China, 300070
      • Tianjin Medical University Chu Hsien-I Memorial Hospital-Endocrinology
• France
  • Bois-Guillaume, France, 76230
    • Centre Hospitalier Universitaire de Rouen - Hopital de Bois Guillaume
  • Le Coudray, France, 28630
    • Les Hopitaux de Chartres-Hopital Louis Pasteur
  • Le Creusot, France, 71200
    • Groupe Sos Sante-Hopital Le Creusot-Hotel Dieu-1
  • Saint Herblain, France, 44800
    • Centre Hospitalier Universitaire de Nantes-Hopital Nord Laennec-1
  • Toulouse, France, 31054
    • Centre Hospitalier Universitaire de Toulouse-Hopital Rangueil-2
  • Venissieux, France, 69200
    • Centre de Recherche Clinique Portes Du Sud
• Greece
  • Athens, Greece, 10676
    • Evangelismos Hospital
  • Athens, Greece, 115 25
    • Iatriko Psychicou Private Clinic
  • Athens, Greece, 115 27
    • 'G. Gennimatas' General Hospital of Athens
  • Larissa, Greece, 41110
    • Univ Gen Hospital Larisa
  • Thessaloniki, Greece, 57001
    • "Thermi" Private Hosital
  • Thessaloniki, Greece, 54642
    • "Ippokrateio" G.H. of Thessaloniki
  • Thessaloniki, Greece, 54635
    • General Hospital of Thessaloniki 'G. Gennimatas
  • Thessaloniki, Greece, 57010
    • General Hospital of Thessaloniki "G.Papanikolaou"
• Hungary
  • Budapest, Hungary, 1132
    • MED-TIMA Kft.
  • Baranya Vármegye
    • Pécs, Baranya Vármegye, Hungary, 7623
      • PTE-AOK II. Belgyogyaszati Klinika es Nephrologiai Centrum
  • Hajdu-Bihar
    • Debrecen, Hajdu-Bihar, Hungary, 4032
      • Debreceni Egyetem Belgyógyászati Klinika
    • Debrecen, Hajdu-Bihar, Hungary, H-4043
      • Debreceni Egyetem Klinikai Központ Belgyógyászati Klinika D épület
• Israel
  • Haifa, Israel, 35152
    • Linn clinic - Clalit Health Services
  • Herzeliya, Israel, 4630945
    • Clalit sick fund Herzeliya
  • Holon, Israel, 58100
    • Diabetes Clinic Wolfson MC
  • Jerusalem, Israel, 91120
    • Diabetes Unit Hadassah Ein Karem MC
  • Kfar Saba, Israel, 44281
    • Diabetes Clinic Meir MC
  • Tel Hashomer, Israel, 52621
    • Endrocrinolgy Clinic - Sheba Medical Center
• Japan
  • Chuo-ku, Tokyo, Japan, 103-0002
    • The Institute of Medical Science, Asahi Life Foundation
  • Fukuoka-shi, Fukuoka, Japan, 819-0006
    • Futata Tetsuhiro Clinic Meinohama
  • Gifu, Japan, 501-1194
    • Gifu University Hospital
  • Ibaraki, Japan, 311-0113
    • Naka Kinen Clinic
  • Osaka, Japan, 569-1045
    • Takatsuki Red Cross Hospital
  • Saitama, Japan, 336-0967
    • Shimizu Clinic Fusa
  • Saitama, Japan, 340-0015
    • Soka Sugiura Internal Medicine Clinic_Internal Medicine
  • Sendai-shi, Miyagi, Japan, 983-0039
    • Shinden Higashi Clinic
  • Miyazaki
    • Miyazaki-shi, Miyazaki, Japan, 880-0034
      • Heiwadai Hospital
• Russian Federation
  • Irkutsk, Russian Federation, 664049
    • Irkutsk State Medical Academy of Postgraduate Education
  • Moscow, Russian Federation, 117292
    • National Medical Research Center of Endocrinology
  • Novosibirsk, Russian Federation, 630099
    • Limited Law Company "Healthy Family" Medicine Center"
  • Omsk, Russian Federation, 644029
    • BHI of Omsk Region "City Hospital № 3"
  • Penza, Russian Federation, 440052
    • Penza Regional Clinical Hospital named after N.N. Burdenko
  • Rostov-on-Don, Russian Federation, 344022
    • Rostov State Medical University_Rostov-on-Don
  • Yoshkar-Ola, Russian Federation, 424004
    • Polyclinic #2 in Yoshkar-Ola
• Slovakia
  • Kosice, Slovakia, 040 01
    • Human-Care s.r.o.
  • Kosice, Slovakia, 040 01
    • DIOLI s.r.o.
  • Kosice, Slovakia, 04190
    • FNsP L. Pasteura
  • Kosice, Slovakia, 04011
    • DIADAN, s.r.o. Kosice
  • Levice, Slovakia, 93401
    • DIA - KONTROL s.r.o.
  • Turcianske Teplice, Slovakia, 039 01
    • MUDr. Alena Lomencikova, s.r.o
• Sweden
  • Göteborg, Sweden, 413 46
    • Primary Care Trial Center, PTC ,Gothia Forum
  • Stockholm, Sweden, 113 65
    • Centrum for Diabetes, Academical Specialist Centrum
  • Örebro, Sweden, 703 62
    • Enheten för Kliniska Studier (EKS), Örebro
• Switzerland
  • Luzern 16, Switzerland, 6000
    • Luzerner Kantonsspital
  • Olten, Switzerland, 4600
    • Kantonsspital Olten
  • Zollikerberg, Switzerland, 8125
    • Diabetes Adipositas Zentrum Zürich
• Taiwan
  • Taichung, Taiwan, 402
    • Chung Shan Medical University Hospital
  • Taichung City, Taiwan, 402
    • Chung Shan Medical University Hospital
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital
  • Tainan City, Taiwan, 710
    • Chi Mei Medical Center
  • Taipei, Taiwan, 112
    • Taipei Veterans General Hospital
  • Taoyuan, Taiwan, 333
    • Chang Gung Medical Foundation - Linkou Branch
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Univ of AL at Birmingham_BRM
  • Arizona
    • Gilbert, Arizona, United States, 85296
      • Pri Med Grp dba/Gil Ctr Fam
    • Sun City West, Arizona, United States, 85375
      • Clinical Research Institute of Arizona
  • California
    • Concord, California, United States, 94520
      • John Muir Physicians Network
    • Los Angeles, California, United States, 90057
      • Velocity Clin Res Wstlke
    • Los Angeles, California, United States, 90017
      • Velocity Clin Res Los Angeles
    • Northridge, California, United States, 91325
      • Valley Clinical Trials, Inc.
    • Toluca Lake, California, United States, 91602
      • Premier Medical Center, Inc.
  • Florida
    • Fleming Island, Florida, United States, 32003
      • Northeast Research Institute
    • Jacksonville, Florida, United States, 32216
      • Est Cst Inst for Rsrch,Jksnvil
    • Jacksonville, Florida, United States, 32204
      • Northeast Res Inst. Inc.
    • Miramar, Florida, United States, 33027
      • South Broward Research LLC
    • Mount Dora, Florida, United States, 32757
      • Adult Medicine of Lake County, Inc.
    • Orlando, Florida, United States, 32825
      • Florida Institute for Clinical Research
    • Orlando, Florida, United States, 32825
      • Florida Inst For Clin Res
    • Oviedo, Florida, United States, 32765
      • Oviedo Medical Research, LLC
    • West Palm Beach, Florida, United States, 33401
      • Metabolic Research Institute Inc
  • Georgia
    • Albany, Georgia, United States, 31707
      • Javara/Privia Med Grp GA,LLC
  • Hawaii
    • Honolulu, Hawaii, United States, 96814
      • East West Med Res Inst
  • Idaho
    • Nampa, Idaho, United States, 83686-6011
      • Saltzer Medical Group Research
  • Illinois
    • Skokie, Illinois, United States, 60077
      • Endeavor Health
  • Louisiana
    • Slidell, Louisiana, United States, 70461-4231
      • Ileana J Tandron APMC
  • Maryland
    • Hyattsville, Maryland, United States, 20782
      • MedStar Hlth Res Institute
  • Michigan
    • Buckley, Michigan, United States, 49620
      • Northern Pines Hlth Ctr, PC
  • Nevada
    • Las Vegas, Nevada, United States, 89148
      • Palm Research Center Inc-Vegas
  • New Jersey
    • Lawrenceville, New Jersey, United States, 08648
      • John J Shelmet, MD
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • Albuquerque Clin Trials, Inc.
  • New York
    • West Seneca, New York, United States, 14224
      • Southgate Medical Group, LLP
  • North Carolina
    • Greensboro, North Carolina, United States, 27408
      • PharmQuest Life Sciences LLC
  • Ohio
    • Canton, Ohio, United States, 44718
      • Diab & Endo Assoc of Stark Co
    • Wadsworth, Ohio, United States, 44281
      • New Venture Medical Research
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson Univ Di Rsrch Ctr
  • South Carolina
    • Summerville, South Carolina, United States, 29485
      • Palmetto Clinical Research
  • Tennessee
    • Bartlett, Tennessee, United States, 38133
      • AM Diabetes And Endocrinology Center
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Medical Research, Llc
  • Texas
    • Amarillo, Texas, United States, 79106
      • Amarillo Med Spec LLP
    • Austin, Texas, United States, 78749
      • Texas Diabetes & Endocrinology
    • Austin, Texas, United States, 78731
      • Texas Diab & Endo, P.A.
    • Corpus Christi, Texas, United States, 78414
      • Osvaldo A. Brusco MD PA
    • Dallas, Texas, United States, 75231
      • North Texas Endocrine Center
    • Dallas, Texas, United States, 75390-9302
      • UT Southwestern Med Cntr
    • Fort Worth, Texas, United States, 76132
      • Diabetes and Thyroid Ctr of FW
    • Longview, Texas, United States, 75605
      • DCOL Ctr for Clin Res
    • Round Rock, Texas, United States, 78681
      • Texas Diabetes & Endocrinology_Round Rock
    • San Antonio, Texas, United States, 78233
      • NE Clin Res of San Antonio
    • Sugar Land, Texas, United States, 77479
      • Sugar Lakes Family Practice PA
  • Utah
    • Saint George, Utah, United States, 84790
      • Chrysalis Clinical Research
  • Virginia
    • Forest, Virginia, United States, 24551
      • Javara Inc/Privia Md GpLLC Fst
    • Forest, Virginia, United States, 24551
      • Javara Inc. / Privia Medical Group LLC_Forest
    • Newport News, Virginia, United States, 23606
      • TPMG Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IcoSema; Participants will get once weekly dose	Drug: IcoSema; IcoSema once weekly subcutaneously (s.c., under the skin) using a needle and a pen. For about 1 year and 1 month.
Experimental: Semaglutide; Participants will get once weekly dose	Drug: Semaglutide 1 mg; Semaglutide once weekly subcutaneously (s.c., under the skin). Dose titrated to 1mg over 8 weeks (0.25 mg for 4 weeks, 0.5 mg for 4 weeks). For about 1 year and 1 month.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Glycosylated Haemoglobin (HbA1c)	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.	Baseline (week 0), (week 52)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Fasting Plasma Glucose (FPG)	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.	Baseline (week 0), (week 52)
Change From Baseline in Body Weight	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.	Baseline (week 0), (week 52)
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)	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.	Week 0 to Week 57
Number of Clinically Significant Hypoglycaemic Episodes (Level 2) (<3.0 mmol/L (54 mg/dL), Confirmed by BG Meter)	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.	Week 0 to Week 57
Number of Severe Hypoglycaemic Episodes (Level 3)	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.	Week 0 to Week 57

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S
• Investigators: Study Director: Clinical Transparency (dept. 1452), Novo Nordisk A/S

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2022
• Primary Completion (Actual): December 13, 2023
• Study Completion (Actual): January 16, 2024

Study Registration Dates

• First Submitted: February 10, 2022
• First Submitted That Met QC Criteria: February 17, 2022
• First Posted (Actual): February 28, 2022

Study Record Updates

• Last Update Posted (Actual): July 9, 2025
• Last Update Submitted That Met QC Criteria: July 8, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus, Type 2; Diabetes Mellitus; Glucagon-Like Peptide-1 Receptor Agonists; Physiological Effects of Drugs; Hypoglycemic Agents; Semaglutide
• Other Study ID Numbers: NN1535-4592; U1111 1260 8268 (Other Identifier: World Health Organization (WHO)); 2020 005308 21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: "According to the Novo Nordisk disclosure commitment on novonordisk-trials.com"

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No