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 Insulin Glargine Taken Daily With Insulin Aspart (COMBINE 3)
A 52 Week Study Comparing the Efficacy and Safety of Once Weekly IcoSema and Daily Insulin Glargine 100 Units/mL Combined With Insulin Aspart, Both Treatment Arms With or Without Oral Anti Diabetic Drugs, in Participants With Type 2 Diabetes Inadequately Controlled With Daily Basal Insulin. COMBINE 3
4 other identifiers
interventional
679
14 countries
182
Brief Summary
This study will compare the new medicine IcoSema, which is a combination of insulin icodec and semaglutide, taken once a week, to insulin glargine taken daily with insulin aspart 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 glargine taken with insulin aspart. Participants will either get IcoSema or insulin glargine taken with insulin aspart. Which treatment participants get is decided by chance. IcoSema is a new medicine that doctors cannot prescribe. Doctors can already prescribe insulin glargine and insulin aspart in many countries. Participants will get IcoSema or insulin glargine together with insulin aspart. Participants must inject IcoSema once a week or inject insulin glargine once daily and insulin aspart 2-4 times a day. Participants will inject the medicines 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 be asked to wear a sensor that measures participants blood sugar level all the time during an 8 week period at the beginning of the study and a 4 week period at the end of the study. Women cannot take part if pregnant, breast-feeding or plan to get pregnant during the study period.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_3 diabetes-mellitus-type-2
Started Nov 2021
Typical duration for phase_3 diabetes-mellitus-type-2
182 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 13, 2021
CompletedFirst Posted
Study publicly available on registry
August 19, 2021
CompletedStudy Start
First participant enrolled
November 30, 2021
CompletedPrimary Completion
Last participant's last visit for primary outcome
November 14, 2023
CompletedStudy Completion
Last participant's last visit for all outcomes
November 14, 2023
CompletedDecember 2, 2025
November 1, 2025
2 years
August 13, 2021
November 27, 2025
Conditions
Outcome Measures
Primary Outcomes (1)
Change in HbA1c
Percent-points
From baseline week 0 (V2) to week 52 (V54)
Secondary Outcomes (10)
Change in body weight
From baseline week 0 (V2) to week 52 (V54)
Number of clinically significant hypoglycaemic episodes (level 2) (less than 3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3)
From week 0 (V52) to week 52 (V54)
Time in range 3.9 - 10.0 mmol/L (70 - 180 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6
From week 48 (V50) to week 52 (V54)
Time spent more than 10.0 mmol/L (180 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6
From week 48 (V50) to week 52 (V54)
Time spent less than 3.0 mmol/L (54 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6
From week 48 (V50) to week 52 (V54)
- +5 more secondary outcomes
Study Arms (2)
IcoSema
EXPERIMENTALParticipants will receive once weekly subcutaneous (s.c) injections of IcoSema during the 52-week treatment period.
Insuling glargine/insulin aspart
ACTIVE COMPARATORParticipants will receive subcutaneous (s.c) injections of insulin glargine once daily combined with 2-4 times daily injections of insulin aspart.
Interventions
Participants will receive a once weekly subcutanous (s.c.) injection of IcoSema, on the same day every week for 52 weeks.
Participants will receive a once daily subcutaneous (s.c.) injection of insulin glargine combined with Insulin aspart 2-4 times a day during mealtimes for 52 weeks.
Participants will receive a once daily subcutaneous (s.c.) injection of insulin glargine combined with Insulin aspart 2-4 times a day during mealtimes for 52 weeks.
Eligibility Criteria
You may qualify if:
- 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 percentage (53.- 85.8 mmol/mol) (both inclusive) as assessed by central laboratory on the day of screening.
- 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 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 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.
- Body mass index (BMI) less than or equal to 40.0 kg/m\^2.
- Sulfonylureas, meglitinides (glinides) and DPP-4 inhibitors must be discontinued at randomisation.
You may not qualify if:
- 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).
- Any episodes of diabetic ketoacidosis within 90 days before screening. As declared by the participant or in the medical records.
- 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.
- Recurrent severe hypoglycaemic episodes within the last year (12 months) as judged by the investigator.
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Novo Nordisk A/Slead
Study Sites (182)
Lakeview Clinical Research, LLC
Guntersville, Alabama, 35976, United States
Valley Research
Fresno, California, 93720, United States
Scripps Wht Diab Inst La Jolla
La Jolla, California, 92037, United States
Torrance Clin Res Inst, Inc.
Lomita, California, 90717, United States
Downtown LA Res Ctr. Inc.
Los Angeles, California, 90017, United States
San Diego Family Care
San Diego, California, 92111, United States
NorCal Endocrinology and Internal Medicine
San Ramon, California, 94583, United States
Creekside Endocrine Associates
Denver, Colorado, 80209, United States
Clinical Res Of W Florida Inc
Clearwater, Florida, 33765, United States
Northeast Research Institute
Fleming Island, Florida, 32003, United States
Sweet Hope Research Specialty
Hialeah, Florida, 33016, United States
E Coast Inst for Rsrch LLC_Jacksonville
Jacksonville, Florida, 32204, United States
Northeast Res Inst. Inc.
Jacksonville, Florida, 32204, United States
East Coast Institute for Research, LLC
Jacksonville, Florida, 32216, United States
South Broward Research LLC
Miramar, Florida, 33027, United States
Adult Medicine of Lake County, Inc.
Mt. Dora, Florida, 32757, United States
Renstar Medical Research
Ocala, Florida, 34470, United States
Florida Inst For Clin Res
Orlando, Florida, 32825, United States
Metabolic Research Institute Inc
West Palm Beach, Florida, 33401, United States
Physicians Research Assoc. LLC
Lawrenceville, Georgia, 30046, United States
Endo Res Solutions Inc
Roswell, Georgia, 30076, United States
East West Med Res Inst
Honolulu, Hawaii, 96814, United States
Saltzer Medical Group Research
Nampa, Idaho, 83686-6011, United States
Endeavor Health
Skokie, Illinois, 60077, United States
Iowa Diab & Endo Res Center
West Des Moines, Iowa, 50266, United States
Cotton-O'Neil Diab & Endo Ctr
Topeka, Kansas, 66606, United States
The Research Group of Lexington LLC
Lexington, Kentucky, 40503, United States
New Orleans Center for Clinical Research
New Orleans, Louisiana, 70119, United States
MedStar Hlth Res Institute
Hyattsville, Maryland, 20782, United States
ActivMed Practice & Research LLC
Methuen, Massachusetts, 01844, United States
Northern Pines Hlth Ctr, PC
Buckley, Michigan, 49620, United States
StudyMetrix Research LLC
City of Saint Peters, Missouri, 63303, United States
Univ of Nebraska Medical CTR
Omaha, Nebraska, 68198-3020, United States
Palm Research Center Inc-Vegas
Las Vegas, Nevada, 89148, United States
Southern NH Diabetes and Endocrinology
Nashua, New Hampshire, 03060, United States
John J Shelmet, MD
Lawrenceville, New Jersey, 08648, United States
Mid Hudson Med Res-New Windsor
New Windsor, New York, 12553, United States
DiGiovanna Institute for Medical Education & Research
North Massapequa, New York, 11758-1802, United States
Southgate Medical Group, LLP
West Seneca, New York, 14224, United States
Physicians East Endocrinology
Greenville, North Carolina, 27834, United States
Piedmont Healthcare/Research
Statesville, North Carolina, 28625, United States
Accellacare
Wilmington, North Carolina, 28401, United States
Diab & Endo Assoc of Stark Co
Canton, Ohio, 44718, United States
Central Ohio Clinical Research LLC
Columbus, Ohio, 43213, United States
Prestige Clinical Research
Franklin, Ohio, 45005, United States
New Venture Medical Research
Wadsworth, Ohio, 44281, United States
Hillcrest Clinical Research
Simpsonville, South Carolina, 29681-1538, United States
AM Diabetes And Endocrinology Center
Bartlett, Tennessee, 38133, United States
Univ Diab & Endo Consultants
Chattanooga, Tennessee, 37411, United States
HealthStar Physicians PC
Morristown, Tennessee, 37813, United States
Amarillo Med Spec LLP
Amarillo, Texas, 79106, United States
Velocity Clinical Res-Dallas
Dallas, Texas, 75230, United States
PrimeCare Medical Group
Houston, Texas, 77024, United States
PlanIt Research, PLLC
Houston, Texas, 77079, United States
Protenium Clinical Research
Hurst, Texas, 76054, United States
Andres Garcia-Zuniga, MD, P.A
Laredo, Texas, 78041, United States
DCOL Ctr for Clin Res
Longview, Texas, 75605, United States
Clinical Investigations Of Texas
Plano, Texas, 75075, United States
Briggs Clinical Research, LLC
San Antonio, Texas, 78224, United States
NE Clin Res of San Antonio
San Antonio, Texas, 78233, United States
Simcare Medical Research, LLC
Sugar Land, Texas, 77478, United States
Chrysalis Clinical Research
St. George, Utah, 84790, United States
Amherst Family Practice P.C.
Winchester, Virginia, 22601, United States
Sound Medical Research
Port Orchard, Washington, 98366, United States
Rainier Clin Res Ctr Inc
Renton, Washington, 98057, United States
Ascension Medical Group- Germantown Clinic
Milwaukee, Wisconsin, 53211, United States
Fakultni nemocnice Plzen
Pilsen, Czech Republic, 304 60, Czechia
Fakultni nemocnice Plzen
Pilsen, Czech Republic, 323 00, Czechia
Ambulance Brno s.r.o.
Brno, 602 00, Czechia
Fakultní nemocnice U sv. Anny v Brně
Brno, 602 00, Czechia
University Hospital U sv. Anny
Brno, 656 91, Czechia
Dum zdravi
Hodonín, 695 01, Czechia
FN Hradec Kralove
Hradec Králové, 500 05, Czechia
Klinika Dr. Pírka s.r.o.
Mladá Boleslav, 29301, Czechia
Diabet2 s.r.o.
Prague, 110 00, Czechia
Diabetologická a interní ambulance Diabet2
Prague, 110 00, Czechia
III. interni klinika VFN a 1. LK UK v Praze
Prague, 12000, Czechia
Institut klinicke a experimentalni mediciny_Praha
Prague, 14021, Czechia
Fledip s.r.o.
Prague, 160 00, Czechia
ResTrial s.r.o.
Prague, 18100, Czechia
Centre Hospitalier Departemental Vendee- La Roche Sur Yon
La Roche-sur-Yon, 85295, France
Les Hopitaux de Chartres-Hopital Louis Pasteur
Le Coudray, 28630, France
Groupe Sos Sante-Hopital Le Creusot-Hotel Dieu-2
Le Creusot, 71200, France
Centre Hospitalier de Narbonne
Narbonne, 11108, France
Aphp-Hopital Lariboisiere-1
Paris, 75010, France
Centre Hospitalier Universitaire de Bordeaux-Hopital Haut Leveque-2
Pessac, 33600, France
Centre de Recherche Clinique Portes Du Sud
Vénissieux, 69200, France
InnoDiab Forschung GmbH
Essen, 45136, Germany
Plassmann
Essen, 45359, Germany
Wendisch/Dahl Hamburg (DZHW)
Hamburg, 22607, Germany
Uniklinik Schleswig-Holstein - Medizinischen Klinik I am Campus Lübeck
Lübeck, 23538, Germany
Institut für Diabetesforschung GmbH Münster - Dr. med. Rose
Münster, 48145, Germany
RED-Institut für medizinische Forschung und Fortbildung GmbH
Oldenburg in Holstein, 23758, Germany
Zentrum für klinische Studien Alexander Segner
Saint Ingbert-Oberwürzbach, 66386, Germany
Békés Megyei Központi Kórház - dr. Réthy Pál Tagkórház
Békéscsaba, 5600, Hungary
Clinexpert Egészségügyi Szolgáltató és Kereskedelmi Kft.
Budapest, 1036, Hungary
Szőcs Depot Egészségügyi Szolgáltató Kft.
Budapest, 1042, Hungary
Semmelweis Egyetem II. Belgyógyászati Klinika
Budapest, 1088, Hungary
ClinDiab Egészségügyi Szolgáltató és Kereskedelmi Kft.
Budapest, 1089, Hungary
Coromed SMO Kft.
Pécs, 7623, Hungary
Apollo Hospital, Ahmedabad
Ahmedabad, Gujarat, 382428, India
Swasthya Diabetes Care
Ahmedabad, Gujarat, 390013, India
Apollo Hospital International Ltd
Gandhinagar, Gujarat, 382428, India
Diacon Hospital Private Limited
Bangalore, Karnataka, 560010, India
Sree Gokulam Medical College & Research Foundation
Trivandrum, Kerala, 695 607, India
TOTALL Diabetes Hormone Institute
Indore, Madhya Pradesh, 452010, India
Sahyadri Speciality Hospital
Pune, Maharashtra, 411004, India
Sahyadri Super Speciality Hospital
Pune, Maharashtra, 411004, India
chelleram Diabetes Institute
Pune, Maharashtra, 411021, India
Post Graduate Institute of Medical Education & Research
Chandigarh, Punjab, 160012, India
Christian Medical College and Hospital
Ludhiana, Punjab, 141008, India
Fortis Heart Institute and Multispeciality Hospital
Mohali, Punjab, 160062, India
Diabetes, Thyroid and Endocrine Centre
Jaipur, Rajasthan, 302006, India
Madras Diabetes Research Foundation
Chennai, Tamil Nadu, 600086, India
Christian Medical College Hospital, Vellore
Vellore, Tamil Nadu, 632004, India
Nizams Institute of Medical Science
Hyderabad, Telangana, 500082, India
Yashoda hospital
Hyderabad, Telangana, 500082, India
Medanta Lucknow Hospital
Lucknow, Uttar Pradesh, 226030, India
Swasthya Diabetes Care
Ahmedabad, 390013, India
Azienda Ospedaliero-Universitaria Renato Dulbecco
Catanzaro, CZ, 88100, Italy
Pol. Uni. Campus Biomedico
Roma, RM, 00128, Italy
Presidio Ospedale di Cittadella Azienda ULSS 6 Euganea
Cittadella, 35013, Italy
Azienda Ospedaliera Luigi Sacco
Milan, 20157, Italy
Ospedale Civico Partinico di Palermo
Partinico, 90047, Italy
IRCCS Multimedica
Sesto San Giovanni (MI), 20099, Italy
Ospedale San Bassiano
Vicenza, 36061, Italy
Heiwadai Hospital_Internal Medicine
Miyazaki, Miyazaki, 880-0034, Japan
Asano Clinic
Kawagoe-shi, Saitama, Japan, 350-0851, Japan
Tokyo Medical Univ. Hospital_Diabetes, Metabolism and Endocrinology
Shinjuku-ku, Tokyo, 1600023, Japan
TOSAKI Clinic for Diabetes and Endocrinology_Diabetes and Endocrinology
Aichi, 468-0009, Japan
Akaicho Clinic
Chiba-shi, Chiba, 260-0804, Japan
The Institute of Medical Science, Asahi Life Foundation_Internal Medicine
Chuo-ku, Tokyo, 103-0002, Japan
The Institute of Medical Science, Asahi Life Foundation
Chuo-ku, Tokyo, 103-0002, Japan
Naka Kinen Clinic_Internal medicine
Ibaraki, 311-0113, Japan
Minami Akatsuka Clinic
Mito-shi, Ibaraki, 311-4153, Japan
Takatsuki Red Cross Hospital_Diabetes and Endocrine Div.
Osaka, 569-1045, Japan
Tokyo-Eki Center-building Clinic_Internal Medicine
Tokyo, 103-0027, Japan
Fukuwa Clinic_Internal Medicine
Tokyo, 104-0031, Japan
Fukuwa Clinic
Tokyo, 104-0031, Japan
Hospital Universiti Sains Malaysia_Kota Bharu, Kelantan
Kota Bharu, Kelantan, 16150, Malaysia
Hospital Canselor Tuanku Muhriz UKM
Cheras, Kuala Lumpur, 56000, Malaysia
Hospital Universiti Kebangsaan Malaysia
Cheras, Kuala Lumpur, 56000, Malaysia
University Malaya Medical Centre
Kuala Lumpur, Kuala Lumpur, 59100, Malaysia
University Malaya Medical Centre
Lembah Pantai, Kuala Lumpur, 59100, Malaysia
Hospital Seri Manjung
Seri Manjung, Perak, 32040, Malaysia
Hospital Ampang
Ampang, Selangor, 68000, Malaysia
University Technology MARA (UiTM) - Puncak Alam
Sungai Buloh, Selangor, 47000, Malaysia
University Technology MARA (UiTM) - Sg Buloh
Sungai Buloh, Selangor, 47000, Malaysia
Klinik Kesihatan Simpang Kuala
Alor Star, 05400, Malaysia
Miri Hospital
Miri, Sarawak, 98000, Malaysia
NZOZ Specjalistyczny Osrodek Internistyczno-Diabetologiczny Małgorzata Arciszewska
Bialystok, Podlaskie Voivodeship, 15-435, Poland
NZOZ Vita-Diabetica Malgorzata Buraczyk
Bialystok, Podlaskie Voivodeship, 15-879, Poland
Centrum Medyczne Pratia Gdynia
Gdynia, Pomeranian Voivodeship, 81-338, Poland
SNZOZ Lege Artis
Bialystok, 15-404, Poland
Centrum Medyczne Pratia Katowice
Katowice, 40-081, Poland
Gabinet Lekarski Malgorzata Saryusz-Wolska
Lodz, 90-132, Poland
Centrum Terapii Wspolczesnej J.M. Jasnorzewska S.K.A.
Lodz, 90-338, Poland
NBR Polska Tomasz Klodawski
Warsaw, 00-710, Poland
PANSTWOWY INSTYTUT MEDYCZNY MSWiA
Warsaw, 02-507, Poland
Healthcare centre Kocevje
Kočevje, 1330, Slovenia
Healthcare Centre Koper
Koper, SI-6000, Slovenia
UKC Ljubljana, Endocrinology and Diabetes
Ljubljana, SI-1000, Slovenia
General Hospital Murska Sobota
Murska Sobota, SI-9000, Slovenia
General Hospital Nova Gorica_Diabetes
Nova Gorica, SI-5290, Slovenia
Medi-Clinic Bloemfontein
Bloemfontein, Free State, 9301, South Africa
Lenasia Clinical Trial Centre
Lenasia, Gauteng, 1827, South Africa
Prof P. Joshi
Pretoria, Gauteng, 0181, South Africa
Spoke Research Inc
Cape Town, Western Cape, 7441, South Africa
Maharaj Nakorn Chiang Mai Hospital_Endocrilogy
Chiang Mai, Mueang Chiang Mai District, 50200, Thailand
King Chulalongkorn Memorial Hospital_Endocrinology
Bangkok, 10330, Thailand
Rajavithi Hospital_Diabetes and Endocrinology
Bangkok, 10400, Thailand
Siriraj Hospital_Dept Endocrinology
Bangkok, 10700, Thailand
Maharaj Nakorn Chiang Mai Hospital_Endocrilogy
Chiang Mai, 50200, Thailand
Srinagarind Hospital
Khon Kaen, 40002, Thailand
Maharat Nakhon Ratchasima Hospital
Nakhon Ratchasima, 30000, Thailand
Başkent Üniversitesi Adana Dr. Turgut Noyan Uygulama ve Araştırma Merkezi
Adana, 01250, Turkey (Türkiye)
Gulhane Egitim Arastirma Hastanesi
Ankara, 06010, Turkey (Türkiye)
Akdeniz Üniversitesi Hastanesi- Endokrinoloji
Antalya, 07058, Turkey (Türkiye)
Aydın Adnan Menderes Üniversitesi Hastanesi
Aydin, 09010, Turkey (Türkiye)
Pamukkale Universitesi Tip Fakultesi
Denizli, 20070, Turkey (Türkiye)
Prof. Dr. Cemil Taşcıoğlu Şehir Hastanesi- Endokrinoloji
Istanbul, 34400, Turkey (Türkiye)
Dokuz Eylül Üniversitesi Araştırma Uygulama Hastanesi-Endokrinoloji
Izmir, 35340, Turkey (Türkiye)
Related Publications (1)
Billings LK, Andreozzi F, Frederiksen M, Gourdy P, Gowda A, Ji L, Pletsch-Borba L, Suzuki R, Unnikrishnan AG, Vianna AGD. Once-weekly IcoSema versus multiple daily insulin injections in type 2 diabetes management (COMBINE 3): an open-label, multicentre, treat-to-target, non-inferiority, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2025 Jul;13(7):556-567. doi: 10.1016/S2213-8587(25)00052-X. Epub 2025 Jun 4.
PMID: 40482670DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- STUDY DIRECTOR
Clinical Transparency (dept. 1452)
Novo Nordisk A/S
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
August 13, 2021
First Posted
August 19, 2021
Study Start
November 30, 2021
Primary Completion
November 14, 2023
Study Completion
November 14, 2023
Last Updated
December 2, 2025
Record last verified: 2025-11