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Type 2 DiabetesPhase 3COMBINE 4NCT06269107

A Research Study to See How Well New Weekly Medicine IcoSema, Which is a Combination of Insulin Icodec and Semaglutide, Controls Blood Sugar Levels in People With Type 2 Diabetes (T2D), Compared to Daily Insulin Glargine (COMBINE 4)

A Phase 3 study testing IcoSema and Insulin glargine in people with Type 2 Diabetes, run by Novo Nordisk A/S at 118 sites in 10 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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 (mentioned as insulin glargine in this form) taken daily in people with type 2 diabetes. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Type 2 Diabetes
What is being tested?
IcoSema and Insulin glargine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
485 participants
Where
118 sitesin 10 countries
Study dates
15 Feb 2024to 8 Jul 2025
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or female and age above or equal to 18 years at the time of signing the informed consent.
  • Diagnosed with T2D greater than or equal to (≥) 180 days before screening.
  • HbA1c ≥ 8.0% (≥ 64.0 millimoles per mole [mmol/mol]) as assessed by central laboratory on the day of screening.
  • Insulin naïve. Short term insulin treatment for a maximum of 14 consecutive days before screening is allowed, as is prior insulin treatment for gestational diabetes.
  • Currently treated with 1-3 oral anti diabetic drug (OADs) with stable daily doses ≥ 90 days before screening comprising any of the following anti diabetic drug(s) at effective or maximum tolerated dose.
  • Metformin
Show all 14Show fewer
  • Sulfonylureas
  • Meglitinides (glinides)
  • Dipeptidyl peptidase (DPP) 4 inhibitors
  • 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 kilogram per square meter (kg/m^2).

Who cannot join

  • Female who is pregnant, breast-feeding or intends to become pregnant or is of childbaring potential and not using 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 or treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria 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.
  • 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.

Trial locations and contacts

118 sites in 10 countries.

118 sites in 10 countries

United States43 sites

  • AMC Community Endocrinology

    Albany, New York, 12203

  • Albuquerque Clin Trials, Inc.

    Albuquerque, New Mexico, 87102

  • Amarillo Med Spec LLP

    Amarillo, Texas, 79106

  • Atlanta Diabetes Associates

    Atlanta, Georgia, 30318

  • Velocity Clinical Research- Cedar Park

    Austin, Texas, 78759

  • Univ of Alabama_Birmingham

    Birmingham, Alabama, 35233

  • Elite Clinical Trials

    Blackfoot, Idaho, 83221

  • Wade Family Medicine

    Bountiful, Utah, 84010

  • Diab & Endo Assoc of Stark Co

    Canton, Ohio, 44718

  • Cedar-Crosse Research Center

    Chicago, Illinois, 60607

  • John Muir Physicians Network

    Concord, California, 94520

  • Velocity Clinical Res-Dallas

    Dallas, Texas, 75230

  • North Texas Endocrine Center

    Dallas, Texas, 75231

  • Northeast Research Institute

    Fleming Island, Florida, 32003

  • Diabetes and Thyroid Ctr of FW

    Fort Worth, Texas, 76132

  • PharmQuest Life Sciences LLC

    Greensboro, North Carolina, 27408

  • Physician's East Endocrinology

    Greenville, North Carolina, 27834

  • East West Medical Research Institute_Honolulu

    Honolulu, Hawaii, 96814

  • East Coast Institute For Research

    Jacksonville, Florida, 32208

  • Holston Medical Group

    Kingsport, Tennessee, 37660

  • Scripps Whittier Diabetes Inst

    La Jolla, California, 92037

  • Fmc Science, Llc

    Lampasas, Texas, 76550

  • First Valley Med Grp Lancaster

    Lancaster, California, 93534

  • The Research Group of Lexington LLC

    Lexington, Kentucky, 40503

  • Clinical Trials Research_Sacramento

    Lincoln, California, 95821

  • Advanced Medical Research

    Maumee, Ohio, 43537

  • TPMG Clinical Research

    Newport News, Virginia, 23606

  • Methodist Phys. Clinic

    Omaha, Nebraska, 68114

  • Desert Oasis Hlthcr Med Group

    Palm Springs, California, 91355

  • Desert Oasis Hlthcr Med Group

    Palm Springs, California, 92262

  • Epic Medical Research

    Red Oak, Texas, 75154

  • Endo and Metab Consultants

    Rockville, Maryland, 20852

  • Endo Res Solutions Inc

    Roswell, Georgia, 30076

  • Quality Research Inc

    San Antonio, Texas, 78209

  • Flourish Research

    San Antonio, Texas, 78229

  • Consano Clinical Research, LLC

    Shavano Park, Texas, 78231

  • Endeavor Health

    Skokie, Illinois, 60077

  • Simcare Medical Research, LLC

    Sugar Land, Texas, 77478

  • Cotton-O'Neil Diab & Endo Ctr

    Topeka, Kansas, 66606

  • Essential Medical Research LLC

    Tulsa, Oklahoma, 74137

  • New Venture Medical Research

    Wadsworth, Ohio, 44281-9236

  • Southgate Medical Group, LLP

    West Seneca, New York, 14224

  • Clinical Research of Cent FL

    Winter Haven, Florida, 33880

Other trials in United States

India16 sites

  • Ramaiah Memorial Hospital

    Bangalore, Karnataka, 560054

  • Sai A Health Wellness LLP

    Bangalore, Karnataka, 560080

  • Post Graduate Institute of Medical Education & Research

    Chandigarh, 160012

  • Madras Diabetes Research Foundation

    Chennai, Tamil Nadu, 600086

  • Goa Medical College

    Goa, Maharashtra, 403 202

  • CHL Hospitals

    Indore, Madhya Pradesh, 452008

  • SMS Medical College & Hospital

    Jaipur, Rajasthan, 302004

  • Diabetes, Thyroid and Endocrine Centre

    Jaipur, Rajasthan, 302006

  • IPGME&R and SSKM Hospital

    Kolkata, 700020

  • METTA Clinic (a unit of Healious Global Pvt. Ltd.)

    Kolkata, 700039

  • Udyaan Health Care

    Lucknow, Uttar Pradesh, 226002

  • BYL Nair Hospital and T N Medical College Department of endo

    Mumbai, Maharashtra, 400008

  • Seth GS Medical College & KEM Hospital

    Mumbai, Maharashtra, 400012

  • BSES MG hospital

    Mumbai, Maharashtra, 400058

  • Mysore Medical College and Research Institute

    Mysore, Karnataka, 570001

  • Chellaram Diabetes Institute

    Pune, Maharashtra, 411021

Other trials in India

Poland14 sites

  • NZOZ Specjalistyczny Osrodek Internistyczno-Diabetologiczny Małgorzata Arciszewska

    Bialystok, Podlaskie Voivodeship, 15-435

  • SNZOZ Lege Artis

    Bialystok, 15-404

  • Uniwersyteckie Centrum Kliniczne Regionalne Centrum Diabetologii

    Gdansk, 80-214

  • Care Clinic Sp. z o. o.

    Katowice, 40-568

  • Grazyna Pulka Specjalistyczny Osrodek "All-Med"

    Krakow, 30-033

  • Gabinet Lekarski Malgorzata Saryusz-Wolska

    Lodz, 90-132

  • Centrum Terapii Wspolczesnej J.M. Jasnorzewska S.K.A.

    Lodz, 90-338

  • NZOZ Przychodnia Specjalistyczna Medica

    Lublin, Lubelski, 20-538

  • Velocity Nova Sp. z o.o.

    Lublin, 20-362

  • Velocity Nova Sp. z o.o.

    Staszów, Świętokrzyskie Voivodeship, 28-200

  • NBR Polska Tomasz Klodawski

    Warsaw, 00-710

  • PANSTWOWY INSTYTUT MEDYCZNY MSWiA

    Warsaw, 02-507

  • Medical Concierge Centrum Medyczne

    Warsaw, 02-798

  • Clinhouse Centrum Medyczne

    Zabrze, 41-807

Other trials in Poland

China9 sites

  • Peking University People's Hospital-Endocrinology

    Beijing, Beijing Municipality, 100044

  • Beijing Friendship Hospital, Capital Medical University-Endocrinology

    Beijing, Beijing Municipality, 100050

  • Chongqing University Three Gorges Hospital

    Chongqing, Chongqing Municipality, 404000

  • Hengshui People's Hospital (Harrison International Peace Hospital)-Endocrinology

    Hengshui, Hebei, 053000

  • Huizhou Central People's Hospital-Endocrinology

    Huizhou, Guangdong, 516001

  • Jinan Central Hospital

    Jinan, Shandong, 250013

  • The Second Affiliated Hospital of Nanjing Medical University

    Nanjing, Jiangsu, 210011

  • Shanghai Pudong New Area People's Hospital-Endocrinology

    Shanghai, Shanghai Municipality, 201200

  • The Affiliated Hospital of Jiangsu University

    Zhenjiang, Jiangsu, 212001

Other trials in China

Italy8 sites

  • I.N.R.C.A. Istituto Nazionale di Riposo E Cura Per Gli Anziani

    Ancona, 60127

  • Casa della Salute di Ceccano - Ambulatori Campus Biomedico

    Ceccano (Frosinone), 03023

  • Polo Ospedaliero di Chiavari

    Chiavari (genova), 16043

  • ASL Avezzano Sulmona L'Aquila - Ospedale San Salvatore - UOC Diabetologia

    L’Aquila, Abbruzzo, 67100

  • Grande Ospedale Metropolitano Niguarda

    Milan, 20162

  • Azienda Ospedaliera di Perugia;Ospedale S. Maria della Misericordia

    Perugia, 06129

  • A.O.U. Policlinico Umberto I

    Rome, Lazio, 00161

  • Casa Sollievo della Sofferenza reparto endocrinologia

    San Giovanni Rotondo, FG, 71013

Other trials in Italy

Turkey (Türkiye)8 sites

  • Akdeniz University Tip Fakultesi Hastanesi

    Antalya, 07058

  • Akdeniz Üniversitesi Hastanesi- Endokrinoloji

    Antalya, 07058

  • Seyrantepe Hamidiye Etfal Egitim ve Arastirma Hastanesi

    Istanbul, 34371

  • Şişli Hamidiye Etfal Eğitim ve Araştırma Hastanesi- Seyrantepe Yerleşkesi- Endokrinoloji

    Istanbul, 34371

  • İstanbul Üniversitesi İstanbul Tıp Fakültesi Hastanesi- Endokrinoloji

    Istanbul, 34390

  • Başakşehir Çam ve Sakura Şehir Hastanesi

    Istanbul, 34480

  • T.C. Saglik Bakanligi Pendik Egitim ve Arastirma Hastanesi

    Istanbul, 34899

  • Tekirdağ Namık Kemal Üniversitesi Hastanesi- Dahiliye

    Tekirdağ, 59030

Other trials in Turkey (Türkiye)

Japan7 sites

  • Tokuyama clinic_Diabetic internal medicine

    Chiba, 261-0004

  • Oodouri Diabetes, Internal medicine Clinic_Internal Medicine, Diabetes Internal Medicine

    Hokkaido, 060-0001

  • Heiwadai Hospital_Internal Medicine

    Miyazaki, Miyazaki, 880-0034

  • Oyama East Clinic_Internal Medicine

    Tochigi, 323-0022

  • Tokyo-Eki Center-building Clinic_Internal Medicine

    Tokyo, 103-0027

  • Fukuwa Clinic_Internal Medicine

    Tokyo, 104-0031

  • Juntendo University Hospital_Diabetes, endocrinology and metabolism

    Tokyo, 113-8431

Other trials in Japan

Greece6 sites

  • Evangelismos Hospital

    Athens, 10676

  • 'G. Gennimatas' General Hospital of Athens

    Athens, 115 27

  • "Laiko" General Hospital of Athens

    Athens, 11527

  • General Hospital of Kalamata - B Internal Medicine Department

    Kalamata, 24100

  • Univ Gen Hospital Larisa

    Larissa, 41110

  • "Thermi" Private Hosital

    Thessaloniki, 57001

Other trials in Greece

South Africa6 sites

  • Langeberg Clinical Trials

    Cape Town, Western Cape, 7572

  • Dr Pillay's Rooms

    Durban, KwaZulu-Natal, 4450

  • Dr R Dulabh

    Johannesburg, Gauteng, 1812

  • Newtown Clinical Research

    Johannesburg, Gauteng, 2001

  • Clinical Research Institute of South Africa

    KwaDukuza, KwaZulu-Natal, 4449

  • Roodepoort Medicross Clinical Research Centre

    Roodepoort, Gauteng, 1724

Other trials in South Africa

Puerto Rico1 site

  • Advanced Clinical Research LLC

    Bayamón, 00959

Other trials in Puerto Rico

About this study

Official title: A 40-week Study Comparing the Efficacy and Safety of Once Weekly IcoSema and Daily Insulin Glargine 100 Units/mL in Participants With Type 2 Diabetes Inadequately Controlled on Oral Anti Diabetic Drugs COMBINE 4

This study will compare the new medicine IcoSema, which is a combination of insulin icodec and semaglutide, taken once a week, to insulin glargine (mentioned as insulin glargine in this form) taken daily in people with type 2 diabetes. The study will look at how well IcoSema controls blood sugar levels as compared to insulin glargine in people with type 2 diabetes who do not have their blood sugar properly controlled with other oral diabetes medicines. Participant will either get IcoSema or insulin glargine. Which treatment participants get is decided by chance. IcoSema is a new medicine that doctors cannot prescribe. Doctors can already prescribe insulin glargine in many countries. The study will last for about 11 months (47 weeks).

Conditions
Type 2 Diabetes
Being tested
IcoSema, Insulin glargine
Medical subject headings
Diabetes Mellitus, Type 2

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IcoSemaDrug

    IcoSema will be administered subcutaneously.

  • Insulin glargineDrug

    Insulin glargine will be administered subcutaneously.

Study groups in NCT06269107
Study groupRoleWhat they receive
IcoSemaExperimentalParticipants will receive once weekly IcoSema subcutaneously with or without oral anti diabetic drugs for 40 weeks.
Receives: Drug: IcoSema
Insulin glargineExperimentalParticipants will receive once daily insulin glargine subcutaneously with or without oral anti diabetic drugs for 40 weeks.
Receives: Drug: Insulin glargine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in glycated haemoglobin (HbA1c)

    Measured in percentage (%)-point.

    Measured: From baseline (week 0) to week 40

Secondary outcomes (10)

  1. Change in body weight

    Measured in kilogram (kg).

    Measured: From baseline (week 0) to week 40

  2. Time in range 3.9-10.0 millimoles per liter (mmol/L) (70-180 milligram per deciliter [mg/dL])

    Measured in % of readings.

    Measured: From week 36 to week 40

  3. Time spent less than (<) 3.0 mmol/L (54 mg/dL)

    Measured in % of readings.

    Measured: From week 36 to week 40

  4. Time spent greater than (>) 10.0 mmol/L (180 mg/dL)

    Measured in % of readings.

    Measured: From week 36 to week 40

  5. Weekly basal insulin dose

    Measured in units of insulin.

    Measured: From week 38 to week 40

  6. Change in fasting plasma glucose (FPG)

    Measured in mmol/l.

    Measured: From baseline (week 0) to week 40

  7. Change in Diabetes Treatment Satisfaction Questionnaire (DTSQs) in total treatment satisfaction

    The DTSQs items are scored on a 7-point graded response scale ranging from 0 to 6. Score ranges from 0 to 36. Higher scores indicate greater the satisfaction with medication.

    Measured: From baseline (week 0) to week 40

  8. Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by blood glucose meter) or severe hypoglycaemic episodes (level 3)

    Measured in number of episodes.

    Measured: From baseline (week 0) to week 45

  9. Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by BG meter)

    Measured in number of episodes.

    Measured: From baseline (week 0) to week 45

  10. Number of severe hypoglycaemic episodes (level 3)

    Measured in number of episodes.

    Measured: From baseline (week 0) to week 45

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Feb 2024
  2. Study start15 Feb 2024
  3. Primary completion27 May 2025
  4. Study completion8 Jul 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
485 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06269107
Sponsor's protocol ID
NN1535-4988
Other IDs
U1111-1283-8648, 2022-502484-38-00
Acronym
COMBINE 4
Status last verified
Jun 2026
First submitted
13 Feb 2024
Last updated
5 Jun 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com

Publications

  • Ji L, Benamar M, Mohan V, Pletsch-Borba L, Porcellati F, Wang N, Watada H, Rea RR. Once-weekly IcoSema versus once-daily insulin glargine U100 in type 2 diabetes management (COMBINE 4): an open-label, multicentre, treat-to-target, randomised, phase 3b trial. Lancet Diabetes Endocrinol. 2026 Aug 13:S2213-8587(26)00136-1. doi: 10.1016/S2213-8587(26)00136-1. Online ahead of print.

    PubMed 42594928

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing IcoSema and Insulin glargine in people with Type 2 Diabetes, run by Novo Nordisk A/S at 118 sites in 10 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 118 sites in United States, India, Poland, China, Italy and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in glycated haemoglobin (HbA1c) (time frame: From baseline (week 0) to week 40). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06269107, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jun 2026.

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