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)

Recruitment Status
COMPLETED - HAS RESULTS
(See Contacts and Locations)Verified June 2025 by Novo Nordisk A/S
Sponsor
Novo Nordisk A/S
Information Provided by (Responsible Party)
Novo Nordisk A/S
Clinicaltrials.gov Identifier
NCT05259033
Other Study ID Numbers:
NN1535-4592
First Submitted
February 9, 2022
First Posted
February 27, 2022
Results First Posted
December 10, 2024
Last Update Posted
July 8, 2025
Last Verified
June 2025

ClinicalTrials.gov processed this data on July 2025Link to the current ClinicalTrials.gov record .

History of Changes

Study Details

Study Description

Condition or DiseaseIntervention/Treatment
Diabetes Mellitus, Type 2
Drug: IcoSemaDrug: Semaglutide 1 mg

Study Design

Study TypeInterventional
Actual Enrollment683 participants
Design AllocationRandomized
Interventional ModelParallel Assignment
MaskingNone (Open Label)
Primary PurposeTreatment
Official TitleA 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
Study Start DateApril 10, 2022
Actual Primary Completion DateDecember 12, 2023
Actual Study Completion DateJanuary 15, 2024

Groups and Cohorts

Group/CohortIntervention/Treatment
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.
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.

Outcome Measures

Primary Outcome Measures
  1. 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.
Secondary Outcome Measures
  1. 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.
  2. 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.
  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)
    Hypoglycaemic episodes were classified according to the American Diabetes Association/ International Hypoglycaemia Study Group, where glycemic criteria for level 2 was less than (\&lt;) 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)
    Hypoglycaemic episodes were classified according to the American Diabetes Association/ International Hypoglycaemia Study Group, where glycemic criteria for level 2 was \&lt; 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)
    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.

Eligibility Criteria

Ages Eligible for Study(Adult, Older Adult)
Sexes Eligible for StudyAll
Accepts Healthy VolunteersNo
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

Contacts and Locations

Sponsors and CollaboratorsNovo Nordisk A/S
Locations
Univ of AL at Birmingham_BRM | Birmingham Alabama, United States, 35294Pri Med Grp dba/Gil Ctr Fam | Gilbert Arizona, United States, 85296Clinical Research Institute of Arizona | Sun City West Arizona, United States, 85375John Muir Physicians Network | Concord California, United States, 94520Velocity Clin Res Los Angeles | Los Angeles California, United States, 90017Velocity Clin Res Wstlke | Los Angeles California, United States, 90057Valley Clinical Trials, Inc. | Northridge California, United States, 91325Premier Medical Center, Inc. | Toluca Lake California, United States, 91602Northeast Research Institute | Fleming Island Florida, United States, 32003Northeast Res Inst. Inc. | Jacksonville Florida, United States, 32204Est Cst Inst for Rsrch,Jksnvil | Jacksonville Florida, United States, 32216South Broward Research LLC | Miramar Florida, United States, 33027Adult Medicine of Lake County, Inc. | Mt. Dora Florida, United States, 32757Florida Inst For Clin Res | Orlando Florida, United States, 32825Florida Institute For Clinical Research | Orlando Florida, United States, 32825Oviedo Medical Research, LLC | Oviedo Florida, United States, 32765Metabolic Research Institute Inc | West Palm Beach Florida, United States, 33401Javara/Privia Med Grp GA,LLC | Albany Georgia, United States, 31707East West Med Res Inst | Honolulu Hawaii, United States, 96814Saltzer Medical Group Research | Nampa Idaho, United States, 83686-6011Endeavor Health | Skokie Illinois, United States, 60077Ileana J Tandron APMC | Slidell Louisiana, United States, 70461-4231MedStar Hlth Res Institute | Hyattsville Maryland, United States, 20782Northern Pines Hlth Ctr, PC | Buckley Michigan, United States, 49620Palm Research Center Inc-Vegas | Las Vegas Nevada, United States, 89148John J Shelmet, MD | Lawrenceville New Jersey, United States, 08648Albuquerque Clin Trials, Inc. | Albuquerque New Mexico, United States, 87102Southgate Medical Group, LLP | West Seneca New York, United States, 14224PharmQuest Life Sciences LLC | Greensboro North Carolina, United States, 27408Diab & Endo Assoc of Stark Co | Canton Ohio, United States, 44718New Venture Medical Research | Wadsworth Ohio, United States, 44281Thomas Jefferson Univ Di Rsrch Ctr | Philadelphia Pennsylvania, United States, 19107Palmetto Clinical Research | Summerville South Carolina, United States, 29485AM Diabetes And Endocrinology Center | Bartlett Tennessee, United States, 38133Chattanooga Medical Research, LLC | Chattanooga Tennessee, United States, 37404Amarillo Med Spec LLP | Amarillo Texas, United States, 79106Texas Diab & Endo, P.A. | Austin Texas, United States, 78731Texas Diabetes & Endocrinology | Austin Texas, United States, 78749Osvaldo A. Brusco MD PA | Corpus Christi Texas, United States, 78414North Texas Endocrine Center | Dallas Texas, United States, 75231UT Southwestern Med Cntr | Dallas Texas, United States, 75390-9302Diabetes and Thyroid Ctr of FW | Fort Worth Texas, United States, 76132DCOL Ctr for Clin Res | Longview Texas, United States, 75605Texas Diabetes & Endocrinology_Round Rock | Round Rock Texas, United States, 78681NE Clin Res of San Antonio | San Antonio Texas, United States, 78233Sugar Lakes Family Practice PA | Sugar Land Texas, United States, 77479Chrysalis Clinical Research | St. George Utah, United States, 84790Javara Inc. / Privia Medical Group LLC_Forest | Forest Virginia, United States, 24551Javara Inc/Privia Md GpLLC Fst | Forest Virginia, United States, 24551TPMG Clinical Research | Newport News Virginia, United States, 23606Centro de Diabetes Metabolismo e Endocrinologia | Fortaleza Ceará, Brazil, 60150-162Instituto de Ciências Farmacêuticas de Estudos e Pesquisas | Aparecida de Goiânia Goiás, Brazil, 74935-530Quanta Diagnóstico Nuclear / Medicina Nuclear Alto da XV | Curitiba Paraná, Brazil, 80045-110Centro de Diabetes Curitiba | Curitiba Paraná, Brazil, 80810-040Instituto São José dos Campos em Pesquisas Médicas | São José dos Campos São Paulo, Brazil, 12243-280BR Trials - Ensaios Clínicos e Consultoria Ltda. | São Paulo São Paulo, Brazil, 01236-030LMC Clinical Res Thornhill | Concord Ontario, Canada, L4K 4M2Medical Trust Clinics, Inc. | Courtice Ontario, Canada, L1E2J5Wharton Med Clin Trials | Hamilton Ontario, Canada, L8L 5G8Western Univ. Cnt for Studies in Fam Med | London Ontario, Canada, N6G 2M1Bluewater Clin Res Group,Inc | Sarnia Ontario, Canada, N7T 4X3LMC Endo Centres Ltd.(Bayview) | Toronto Ontario, Canada, M4G 3E8Recherche GCP Research | Montreal Quebec, Canada, H1M 1B1Recherche GCP Research | Montreal Quebec, Canada, H1Y 3H5LMC Clin Rsrch Inc. (Montreal) | Montreal Quebec, Canada, H4T 1Z9LMC Clin Rsrch Inc. (Montreal) | Saint-Laurent Quebec, Canada, H4T 1Z9Recherche Clinique Sigma inc | Québec , Canada, G1G 3Y8Anhui Provincial Hospital-Endocrinology | Hefei Anhui, China, 230001Peking University People's Hospital-Endocrinology | Beijing Beijing Municipality, China, 100044Chongqing University Three Gorges Hospital | Chongqing Chongqing Municipality, China, 404000Huizhou Central People's Hospital-Endocrinology | Huizhou Guangdong, China, 516001Changzhou No.2 People's Hospital, Yanghu Branch | Changzhou Jiangsu, China, 213003The Second Affiliated Hospital of Nanjing Medical University-Endocrinology | Nanjing Jiangsu, China, 210011Jinan Central Hospital | Ji'nan Shandong, China, 250013Huashan Hospital Fudan University-Endocrinology | Shanghai Shanghai Municipality, China, 200040Shanghai Huashan Hospital, Affiliated to Fudan University | Shanghai Shanghai Municipality, China, 200040Shanghai Fifth People's Hospital-Endocrinology | Shanghai Shanghai Municipality, China, 200240General Hospital of Tianjin Medical University-Endocrinology | Tianjin Tianjin Municipality, China, 300052Tianjin Medical University Chu Hsien-I Memorial Hospital-Endocrinology | Tianjin Tianjin Municipality, China, 300070Centre Hospitalier Universitaire de Rouen - Hopital de Bois Guillaume | Bois-Guillaume , France, 76230Les Hopitaux de Chartres-Hopital Louis Pasteur | Le Coudray , France, 28630Groupe Sos Sante-Hopital Le Creusot-Hotel Dieu-1 | Le Creusot , France, 71200Centre Hospitalier Universitaire de Nantes-Hopital Nord Laennec-1 | Saint-Herblain , France, 44800Centre Hospitalier Universitaire de Toulouse-Hopital Rangueil-2 | Toulouse , France, 31054Centre de Recherche Clinique Portes Du Sud | Vénissieux , France, 69200Evangelismos Hospital | Athens , Greece, 10676Iatriko Psychicou Private Clinic | Athens , Greece, 115 25'G. Gennimatas' General Hospital of Athens | Athens , Greece, 115 27Univ Gen Hospital Larisa | Larissa , Greece, 41110General Hospital of Thessaloniki 'G. Gennimatas | Thessaloniki , Greece, 54635"Ippokrateio" G.H. of Thessaloniki | Thessaloniki , Greece, 54642"Thermi" Private Hosital | Thessaloniki , Greece, 57001General Hospital of Thessaloniki "G.Papanikolaou" | Thessaloniki , Greece, 57010PTE-AOK II. Belgyogyaszati Klinika es Nephrologiai Centrum | Pécs Baranya Vármegye, Hungary, 7623Debreceni Egyetem Belgyógyászati Klinika | Debrecen Hajdú-Bihar, Hungary, 4032Debreceni Egyetem Klinikai Központ Belgyógyászati Klinika D épület | Debrecen Hajdú-Bihar, Hungary, H-4043MED-TIMA Kft. | Budapest , Hungary, 1132Clalit sick fund Herzeliya | Herzeliya Israel, Israel, 4630945Linn clinic - Clalit Health Services | Haifa , Israel, 35152Diabetes Clinic Wolfson MC | Holon , Israel, 58100Diabetes Unit Hadassah Ein Karem MC | Jerusalem , Israel, 91120Diabetes Clinic Meir MC | Kfar Saba , Israel, 44281Endrocrinolgy Clinic - Sheba Medical Center | Tel Litwinsky , Israel, 52621Heiwadai Hospital | Miyazaki Miyazaki, Japan, 880-0034The Institute of Medical Science, Asahi Life Foundation | Chuo-ku, Tokyo , Japan, 103-0002Futata Tetsuhiro Clinic Meinohama | Fukuoka-shi, Fukuoka , Japan, 819-0006Gifu University Hospital | Gifu , Japan, 501-1194Naka Kinen Clinic | Ibaraki , Japan, 311-0113Takatsuki Red Cross Hospital | Osaka , Japan, 569-1045Shimizu Clinic Fusa | Saitama , Japan, 336-0967Soka Sugiura Internal Medicine Clinic_Internal Medicine | Saitama , Japan, 340-0015Shinden Higashi Clinic | Sendai-shi, Miyagi , Japan, 983-0039Irkutsk State Medical Academy of Postgraduate Education | Irkutsk , Russia, 664049National Medical Research Center of Endocrinology | Moscow , Russia, 117292Limited Law Company "Healthy Family" Medicine Center" | Novosibirsk , Russia, 630099BHI of Omsk Region "City Hospital № 3" | Omsk , Russia, 644029Penza Regional Clinical Hospital named after N.N. Burdenko | Penza , Russia, 440052Rostov State Medical University_Rostov-on-Don | Rostov-on-Don , Russia, 344022Polyclinic #2 in Yoshkar-Ola | Yoshkar-Ola , Russia, 424004DIOLI s.r.o. | Košice , Slovakia, 040 01HUMAN-CARE s.r.o. | Košice , Slovakia, 040 01DIADAN, s.r.o. Kosice | Košice , Slovakia, 04011FNsP L. Pasteura | Košice , Slovakia, 04190DIA - KONTROL s.r.o. | Levice , Slovakia, 93401MUDr. Alena Lomencikova, s.r.o | Turčianske Teplice , Slovakia, 039 01Primary Care Trial Center, PTC ,Gothia Forum | Gothenburg , Sweden, 413 46Enheten för Kliniska Studier (EKS), Örebro | Örebro , Sweden, 703 62Centrum for Diabetes, Academical Specialist Centrum | Stockholm , Sweden, 113 65Luzerner Kantonsspital | Lucerne , Switzerland, 6000Kantonsspital Olten | Olten , Switzerland, 4600Diabetes Adipositas Zentrum Zürich | Zollikerberg , Switzerland, 8125Chung Shan Medical University Hospital | Taichung , Taiwan, 402National Cheng Kung University Hospital | Tainan , Taiwan, 704Chi Mei Medical Center | Tainan , Taiwan, 710Taipei Veterans General Hospital | Taipei , Taiwan, 112Chang Gung Medical Foundation - Linkou Branch | Taoyuan , Taiwan, 333
Investigators
Study Director: Clinical Transparency (dept. 1452), Novo Nordisk A/S
Study Documents (Full Text)
Documents provided by Novo Nordisk A/SStudy Protocol  March 22, 2023Documents provided by Novo Nordisk A/SStatistical Analysis Plan  June 22, 2022