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, compared to daily insulin glargine (COMBINE 4)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novo Nordisk A/S

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

7 Feb 2024 → 8 Jul 2025

Decision date (initial)

2023-10-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novo Nordisk A/S

External identifiers

EU CT number

2022-502484-38-00

WHO UTN

U1111-1283-8648

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To confirm superiority of once weekly IcoSema compared with daily insulin glargine, both treatment arms with or without OADs, in terms of glycaemic control measured by change in HbA1c from baseline after 40 weeks in participants with T2D inadequately controlled with OADs

Secondary objectives 2

1. To confirm superiority of once weekly IcoSema compared with daily insulin glargine, both treatment arms with or without OADs, in terms of change in body weight from baseline after 40 weeks in participants with T2D inadequately controlled with OADs.
2. To compare parameters of glycaemic control, patient reported outcomes and safety of once weekly IcoSema with daily insulin glargine, both treatment arms with or without OADs, in participants with T2D inadequately controlled with OADs

Conditions and MedDRA coding

Type 2 diabetes

Regulatory references

Scientific advice from competent authorities

National Medical Products Administration, European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002988-PIP01-21

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Informed consent obtained before any study-related activities. Study-related activities are any procedures that are carried out as part of the study, including activities to determine suitability for the study.
2. Male or female.
3. Age 18 years or above at the time of signing the informed consent.
4. Diagnosed with type 2 diabetes mellitus ≥ 180 days before screening.
5. HbA1c ≥ 8.0% (≥ 64.0 mmol/mol) as assessed by central laboratory on the day of screening.
6. 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.
7. Currently treated with 1-3 OADs with stable daily doses ≥ 90 days before screening comprising any of the following anti‑diabetic drug(s) at effective or maximum tolerated dose (a): Metformin, Sulfonylureasa (b), Meglitinides (glinides) (b), DPP 4 inhibitors (b), Sodium glucose co transporter 2 inhibitors, Alpha glucosidase inhibitors, Thiazolidinediones, Marketed oral combination products only including the products listed above. a) As per investigator judgement participant is suitable for intensification with injectables. b) Sulfonylureas, meglitinides (glinides) and DPP 4 inhibitors must be discontinued at randomisation."
8. Body mass index (BMI) ≤ 40.0 kg/m2.

Exclusion criteria 21

1. Known or suspected hypersensitivity to study intervention(s) or related products.
2. Previous participation in this study. Participation is defined as signed informed consent.
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using highly effective contraceptive method, as defined in Appendix 4 (Section ‎10.4).
4. Participation (defined as signed informed consent) in any interventional clinical study within 90 days before screening. Note: Simultaneous participation in a study with the primary objective of evaluating an approved or non-approved investigational medicinal product for prevention or treatment of COVID-19 disease or postinfectious conditions is allowed if the last dose of the investigational medicinal product has been received more than 30 days before screening in the current study and if simultaneous participation is allowed by local authorities.(a) a) not applicable for Japan and China
5. Any disorder, except for conditions associated with T2D, which in the investigator’s opinion might jeopardise participant’s safety or compliance with the protocol.
6. 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).
7. Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria within 90 days before screening.
8. Any episodes(b) of diabetic ketoacidosis within 90 days before screening. b) as declared by the participant or in the medical records.
9. Personal or first‑degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma.
10. Presence or history of pancreatitis (acute or chronic) within 180 days before screening.(c) c) For Turkey, stricter exclusion criteria applies “Presence or history of pancreatitis (acute or chronic)” , see Appendix 16 (Section ‎‎10.16)
11. Any of the following: Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic attack within 180 days before screening.
12. Chronic heart failure classified as being in New York Heart Association Class IV at screening.
13. Planned coronary, carotid or peripheral artery revascularisation.
14. Renal impairment measured as estimated glomerular filtration rate value of < 30 ml/min/1.73 m2 at screening as defined by KDIGO 2012.
15. Impaired liver function, defined as alanine aminotransferase ≥ 2.5 times or bilirubin > 1.5 times upper normal limit at screening.
16. Known hypoglycaemic unawareness as indicated by the investigator according to Clarke’s questionnaire question 8.
17. Recurrent severe hypoglycaemic episodes within the last year (12 months) as judged by the investigator.
18. Inadequately treated blood pressure defined as systolic ≥ 180 mmHg or diastolic ≥ 110 mmHg at screening.
19. 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, see Section ‎8.2.5.
20. Presence or history of malignant neoplasm (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) within 5 years before screening.
21. For Italy, an additional exclusion criteria “known severe diabetic autonomic neuropathy as judged by the investigator” is applicable, please see protocol Appendix 16 (Section ‎10.16)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in HbA1c. From baseline week 0 (V2) to week 40 (V42)

Secondary endpoints 10

1. Change in body weight. From baseline week 0 (V2) to week 40 (V42)
2. Time in range 3.9‑10.0 mmol/L (70‑180 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6. From week 36 (V38) to week 40 (V42)
3. Time spent < 3.0 mmol/L (54 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6. From week 36 (V38) to week 40 (V42)
4. Time spent > 10.0 mmol/L (180 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6. From week 36 (V38) to week 40 (V42)
5. Weekly basal insulin dose. From week 38 (V40) to week 40 (V42)
6. Change in Diabetes Treatment Satisfaction Questionnaire (DTSQs) in total treatment satisfaction. From baseline week 0 (V2) to week 40 (V42)
7. Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3). From baseline week 0 (V2) to week 45 (V44)
8. Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by BG meter). From baseline week 0 (V2) to week 45 (V44)
9. Number of severe hypoglycaemic episodes (level 3). From baseline week 0 (V2) to week 45 (V44)
10. Change in fasting plasma glucose (FPG). From baseline week 0 (V2) to week 40 (V42)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novo Nordisk A/S

Sponsor organisation

Novo Nordisk A/S

Address

Novo Alle 1

City

Bagsvaerd

Postcode

2880

Country

Denmark

Scientific contact point

Organisation

Novo Nordisk A/S

Contact name

EU Submission Hub

Public contact point

Organisation

Novo Nordisk A/S

Contact name

EU Submission Hub

Third parties 10

Locations

3 EU/EEA countries · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 38 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications