IcoSema for Type 2 Diabetes

(COMBINE 4 Trial)

No longer recruiting at 135 trial locations

Overseen By Novo Nordisk

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Novo Nordisk A/S

Must be taking: Oral antidiabetics

Must not be taking: Corticosteroids, Orlistat, others

Disqualifiers: Pregnancy, Pancreatitis, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 40 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new weekly injection called IcoSema for people with type 2 diabetes to determine if it controls blood sugar better than the daily insulin, insulin glargine. Participants will receive either IcoSema or insulin glargine, aiming to improve blood sugar levels in those whose current oral diabetes medications aren't effective enough. Ideal candidates for this trial have had type 2 diabetes for at least 6 months, struggle with blood sugar control despite taking oral diabetes medications, and have never used long-term insulin. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop your current medications. However, you must be on stable doses of 1-3 oral diabetes medications for at least 90 days before joining the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that IcoSema, a new treatment for type 2 diabetes, has been tested in studies involving over 2,600 patients. In these studies, 9% of patients experienced serious side effects, but no deaths were directly linked to the treatment. This indicates that while some serious side effects occurred, they were uncommon.

For insulin glargine, which is already widely used, studies indicate it is generally safe. The risk of major health issues like heart attacks or strokes is low, and most people tolerate it well, with a low chance of serious side effects.

Both treatments have undergone thorough study, and evidence suggests they are generally safe, with only a few serious side effects reported. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for type 2 diabetes?

Most treatments for type 2 diabetes, like standard insulin therapies, require daily injections and primarily focus on managing blood sugar levels. But IcoSema is different because it combines once-weekly dosing with a unique mechanism that integrates both insulin and a GLP-1 receptor agonist. This combination not only simplifies the treatment schedule but also helps improve blood sugar control while potentially offering weight management benefits. Researchers are excited about IcoSema because it could enhance convenience and efficacy for patients compared to the daily insulin injections currently available.

What evidence suggests that this trial's treatments could be effective for type 2 diabetes?

This trial will compare IcoSema with insulin glargine for treating type 2 diabetes. Studies have shown that IcoSema, a once-a-week combination of insulin icodec and semaglutide, better controls blood sugar levels and reduces the risk of low blood sugar compared to other treatments. It also aids in weight loss, a common challenge for people with type 2 diabetes. In contrast, insulin glargine, taken daily, effectively improves blood sugar control and is known for its low risk of causing low blood sugar. Both treatments are effective, but IcoSema offers the convenience of weekly dosing and additional support for weight management. ^{1 2 4 6 7}

Who Is on the Research Team?

Clinical Transparency (dept. 2834)

Principal Investigator

Novo Nordisk A/S

Are You a Good Fit for This Trial?

This trial is for people with type 2 diabetes whose blood sugar isn't well-controlled by oral medications. Participants will be randomly chosen to receive either the new weekly medicine IcoSema or daily insulin glargine. The study excludes specific details on eligibility criteria.

Inclusion Criteria

I've been taking 1-3 diabetes pills daily for at least 90 days.

HbA1c ≥ 8.0% (≥ 64.0 millimoles per mole [mmol/mol]) as assessed by central laboratory on the day of screening

Body mass index (BMI) less than or equal to 40.0 kilogram per square meter (kg/m^2)

Exclusion Criteria

I haven't had a heart attack, stroke, or severe heart chest pain in the last 6 months.

My heart failure is severe, limiting my ability to carry out any physical activity without discomfort.

I haven't had diabetic ketoacidosis or taken diabetes/obesity meds not listed in the criteria in the last 90 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either once weekly IcoSema or daily insulin glargine for 40 weeks

40 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

7 weeks

What Are the Treatments Tested in This Trial?

Interventions

• IcoSema
• Insulin glargine

Trial Overview

The effectiveness of a new once-weekly medication, IcoSema (a mix of insulin icodec and semaglutide), is being compared to the daily use of insulin glargine in controlling blood sugar levels over approximately 11 months.

How Is the Trial Designed?

Group I: Insulin glargine Experimental Treatment 1 Intervention

Participants will receive once daily insulin glargine subcutaneously with or without oral anti diabetic drugs for 40 weeks.

Group II: IcoSema Experimental Treatment 1 Intervention

Participants will receive once weekly IcoSema subcutaneously with or without oral anti diabetic drugs for 40 weeks.

Who Is Running the Clinical Trial?

Novo Nordisk A/S

Lead Sponsor

Trials

1,578

Recruited

3,813,000+

Lars Fruergaard Jørgensen

Novo Nordisk A/S

Chief Executive Officer since 2017

MSc in Finance and Business Administration, Aarhus School of Business, Aarhus University, Denmark

Martin Holst Lange

Novo Nordisk A/S

Chief Medical Officer since 2021

MD from University of Copenhagen

Published Research Related to This Trial

In a pilot study of 52 patients with Type 2 diabetes, switching from premixed insulin to insulin glargine combined with oral antidiabetic drugs (OADs) led to significant reductions in HbA1c levels, indicating improved glycaemic control.

The study found no significant differences in hypoglycaemia rates between the treatment groups, suggesting that insulin glargine plus OADs is a safe alternative to premixed insulin for patients with inadequate glycaemic control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and treatment satisfaction of once-daily insulin glargine plus one or two oral antidiabetic agents versus continuing premixed human insulin in patients with Type 2 diabetes previously on long-term conventional insulin therapy: the SWITCH Pilot Study. Schiel, R., Müller, UA.[2022]

In a pilot study involving 52 patients with Type 2 diabetes poorly controlled on premixed insulin, switching to insulin glargine combined with oral antidiabetic drugs (OADs) significantly improved glycaemic control, as evidenced by a notable decrease in HbA1c levels in both treatment groups (A and B).

The study found no significant differences in hypoglycaemia rates between the treatment groups, indicating that insulin glargine plus OADs is a safe alternative to premixed insulin therapy, with high patient satisfaction leading to a majority opting to continue their assigned treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and treatment satisfaction of once-daily insulin glargine plus one or two oral antidiabetic agents versus continuing premixed human insulin in patients with type 2 diabetes previously on long-term conventional insulin therapy: the Switch pilot study. Schiel, R., Müller, UA.[2022]

In a study involving 1,291 patients with type 1 and type 2 diabetes, LY2963016 insulin glargine (LY IGlar) showed similar immunogenicity profiles to Lantus® insulin glargine (IGlar), with low levels of anti-insulin glargine antibodies observed in both groups.

There were no significant differences in clinical outcomes or safety between LY IGlar and IGlar, indicating that both treatments are equally effective and safe for managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus® insulin glargine in patients with type 1 or type 2 diabetes mellitus. Ilag, LL., Deeg, MA., Costigan, T., et al.[2018]

Citations

1.

endocrinologydiabetes.org

endocrinologydiabetes.org/article/S3050-9157(25)00070-0/fulltext

Efficacy and Safety of Once-Weekly IcoSema in Adults With ...

IcoSema lowered the risk of clinically significant hypoglycemia, but not severe hypoglycemia. It was well-tolerated without increasing ...

2.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/41048697/

Efficacy and Safety of Once-Weekly IcoSema in Adults With ...

Conclusions: IcoSema offers better glycemic control and less hypoglycemia risk than controls, with comparable safety for serious AEs. More RCTs ...

3.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S2213858725000968

Once‑weekly IcoSema versus once‑weekly insulin icodec ...

Overall, IcoSema might provide an option for insulin therapy intensification in adults with type 2 diabetes, reducing concerns around hypoglycaemia and weight ...

4.

sciencehub.novonordisk.com

sciencehub.novonordisk.com/content/dam/sciencehub/global/en/congresses-and-scientific-publications/congresses/easd2025/ji/documents/EASD25_Pre-trial_SGLT2i_ShortOral_12Sep25_Final.pdf

Efficacy and hypoglycaemia outcomes with

once-weekly IcoSema vs comparators in type 2 diabetes according to pre-trial sodium-glucose cotransporter-2 inhibitor use: a post hoc ...

5.

thelancet.com

thelancet.com/journals/landia/article/PIIS2213-8587(25)00052-X/abstract

Once-weekly IcoSema versus multiple daily insulin ...

Once-weekly IcoSema achieved non-inferior HbA1c reduction and superiority in change in bodyweight, weekly total insulin dose, and hypoglycaemia ...

6.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/40482670/

Once-weekly IcoSema versus multiple daily insulin ...

Once-weekly IcoSema achieved non-inferior HbA 1c reduction and superiority in change in bodyweight, weekly total insulin dose, and hypoglycaemia rates versus ...

7.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05259033

NCT05259033 | A Research Study to See How Well the ...

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 ...