IcoSema for Type 2 Diabetes

(COMBINE 2 Trial)

Not currently recruiting at 298 trial locations

Overseen By Novo Nordisk

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Novo Nordisk A/S

Must be taking: GLP-1 receptor agonists

Must not be taking: Orlistat, thyroid hormones

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: 18

Duration: 52 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new weekly injectable treatment, IcoSema, for people with type 2 diabetes to evaluate its effectiveness in controlling blood sugar compared to semaglutide, another available weekly injection. Participants will randomly receive either IcoSema or semaglutide. It suits those diagnosed with type 2 diabetes for at least six months who currently use specific diabetes medications but have not been on insulin long-term. The study lasts just over a year and involves regular visits and check-ins with the study team. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking advancements in diabetes treatment.

Will I have to stop taking my current medications?

You may need to stop taking certain diabetes medications like sulfonylureas, meglitinides, and DPP 4 inhibitors when you start the trial. Other medications you are taking for diabetes should be stable for at least 90 days before joining the study.

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

Studies have shown that IcoSema, a new treatment for type 2 diabetes, is generally safe. In trials with over 2,600 patients, about 9% of those taking IcoSema experienced serious side effects, but researchers found no deaths linked to the treatment. This indicates that serious issues were uncommon.

For semaglutide, which has already received approval for use, most side effects are mild to moderate. The most common ones include stomach problems, such as nausea or diarrhea, which usually resolve on their own. Serious heart problems with semaglutide are rare.

Both treatments are administered once a week using a small needle. While researchers continue to study IcoSema, these findings suggest it is generally well-tolerated, similar to semaglutide. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about IcoSema because it combines two active ingredients—insulin Icodec and Semaglutide—into a single treatment, potentially offering a more comprehensive approach to managing type 2 diabetes. Unlike standard treatments that typically involve separate injections for insulin and GLP-1 receptor agonists like Semaglutide, IcoSema simplifies the regimen with a once-weekly injection. This dual-action could improve blood sugar control while also promoting weight loss, addressing two major concerns for people with type 2 diabetes in a more convenient way.

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

Research has shown that IcoSema, a combination of insulin icodec and semaglutide, greatly improves blood sugar control. In a study with 2,653 patients, IcoSema lowered HbA1c levels (a measure of long-term blood sugar control) and fasting blood sugar more effectively than semaglutide alone. It also aided in weight management and reduced concerns about low blood sugar. In this trial, participants will receive either IcoSema or Semaglutide as separate treatment options.

Semaglutide alone has already proven effective for managing type 2 diabetes. Studies in real-world settings have demonstrated that semaglutide improves overall health, aids in weight loss, and lowers the risk of heart issues. Both treatments are effective, but IcoSema might offer additional benefits by combining two medications. ^{1 2 4 5 6}

Who Is on the Research Team?

Clinical Transparency (dept. 1452)

Principal Investigator

Novo Nordisk A/S

Are You a Good Fit for This Trial?

Adults with type 2 diabetes, BMI ≤40.0 kg/m^2, stable on certain diabetes meds for 90+ days, and HbA1c between 7.0-10.0%. Excludes those with recent severe heart failure or pancreatitis, uncontrolled diabetic eye disease, recent major cardiovascular events, pregnant/breastfeeding women or those planning pregnancy without effective contraception.

Inclusion Criteria

You have been diagnosed with type 2 diabetes for at least 180 days before the screening.

Your HbA1c level is between 7.0% and 10.0% as tested by the central laboratory at the time of screening.

You have been taking a certain type of diabetes medicine called a GLP-1 receptor agonist at the same dose for at least 90 days before the study.

Exclusion Criteria

You have severe chronic heart failure.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either IcoSema or semaglutide once weekly for blood sugar control

52 weeks

18 clinic visits, 34 phone/video calls, 4 additional contacts

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 weeks

What Are the Treatments Tested in This Trial?

Interventions

• IcoSema
• Semaglutide 1 mg

Trial Overview The trial is testing IcoSema—a new weekly injectable combo of insulin icodec and semaglutide—against the existing diabetes medication semaglutide alone. Participants will be randomly assigned to one of these treatments for about a year and monitored through clinic visits and calls.

How Is the Trial Designed?

Group I: Semaglutide Experimental Treatment 1 Intervention

Participants will get once weekly dose

Group II: IcoSema Experimental Treatment 1 Intervention

Participants will get once weekly dose

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 12-week trial involving 75 adults with type 2 diabetes, semaglutide significantly improved both first- and second-phase insulin secretion, indicating enhanced beta cell function.

Semaglutide also led to better glycaemic control, with reduced fasting and postprandial glucose levels, and was well tolerated by participants, suggesting it is a safe and effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: a randomised, double-blind, placebo-controlled trial. Kapitza, C., Dahl, K., Jacobsen, JB., et al.[2022]

A total of 5,442 cases of gastrointestinal adverse events (AEs) associated with semaglutide were identified, with 45 signals detected, indicating a range of gastrointestinal issues, including 17 new and unexpected signals.

The study found that patient age and body weight were significant factors influencing the severity of gastrointestinal AEs, with a median time-to-onset of 23 days for strong signals, suggesting that while risks exist, they may decrease over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal adverse events associated with semaglutide: A pharmacovigilance study based on FDA adverse event reporting system. Shu, Y., He, X., Wu, P., et al.[2023]

In a post hoc analysis of the SUSTAIN 1-3 trials involving 2432 participants with type 2 diabetes, semaglutide significantly reduced body weight (BW) by 3.7 to 6.1 kg compared to comparators, which only saw reductions of 1.0 to 1.9 kg.

The improvement in insulin resistance (IR) was primarily linked to weight loss, with 70% to 80% of the IR reduction from semaglutide 0.5 mg and 34% to 94% from semaglutide 1.0 mg being mediated by the decrease in BW.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reductions in Insulin Resistance are Mediated Primarily via Weight Loss in Subjects With Type 2 Diabetes on Semaglutide. Fonseca, VA., Capehorn, MS., Garg, SK., et al.[2023]

In a study of 20 patients with type 2 diabetes in Slovenia, oral semaglutide significantly reduced HbA1c levels and fasting plasma glucose, indicating its efficacy in improving glycaemic control.

Patients reported high satisfaction with the treatment, and while some experienced mild gastrointestinal side effects, the overall safety profile was considered good, suggesting that oral semaglutide is a promising option for diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, safety, and patient satisfaction with oral semaglutide: first single-centre clinical experience. Janić, M., Jovanović, M., Janež, A., et al.[2023]

In a 56-week study involving 1231 participants with type 2 diabetes, semaglutide significantly reduced HbA1c levels by 1.3% and 1.6% for the 0.5 mg and 1.0 mg doses, respectively, compared to a 0.5% reduction with sitagliptin, demonstrating superior efficacy in glycaemic control.

Semaglutide also led to greater weight loss, with reductions of 4.3 kg and 6.1 kg for the two doses, compared to 1.9 kg with sitagliptin, while maintaining a similar safety profile, primarily with gastrointestinal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. Ahrén, B., Masmiquel, L., Kumar, H., et al.[2022]

In a meta-analysis of 23 randomized trials involving 22,096 patients with type 2 diabetes, semaglutide was not found to significantly increase the overall risk of diabetic retinopathy (DR) compared to control groups.

However, the analysis indicated that semaglutide was associated with a higher risk of DR in specific subgroups, particularly in patients aged 60 years or older and those with a diabetes duration of 10 years or more, suggesting that caution is warranted in these populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide and Diabetic Retinopathy Risk in Patients with Type 2 Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trials. Wang, F., Mao, Y., Wang, H., et al.[2022]

In a study involving 2117 participants treated with semaglutide 2.4 mg for 68 weeks, gastrointestinal adverse events (AEs) like nausea and diarrhea were more common than in the placebo group, but these AEs were mostly mild and transient, with only 4.3% of participants discontinuing treatment due to them.

Weight loss with semaglutide was significant and similar in participants with and without GI AEs, indicating that the weight loss effects of semaglutide are largely independent of these gastrointestinal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss. Wharton, S., Calanna, S., Davies, M., et al.[2022]

Semaglutide, a GLP-1 receptor agonist, has been shown to effectively improve blood sugar control and promote weight loss, with a favorable safety profile similar to other GLP-1RAs, based on extensive phase 3 trials including cardiovascular outcome studies.

The most common side effects of semaglutide are mild-to-moderate gastrointestinal disturbances, and while there are concerns about pancreatic and thyroid cancer, no unexpected safety issues have been identified, making it a beneficial option for patients with type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Semaglutide. Smits, MM., Van Raalte, DH.[2023]

In the SUSTAIN 1 to 5 trials involving 3918 participants with type 2 diabetes, semaglutide significantly helped more individuals achieve their HbA1c targets (47% to 74%) compared to placebo (7% to 19%) and other active comparators (16% to 29%).

Semaglutide was effective in achieving these results while minimizing unwanted outcomes, such as weight gain, severe hypoglycaemia, and gastrointestinal side effects, making it a safer option for managing type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Achieving glycaemic control without weight gain, hypoglycaemia, or gastrointestinal adverse events in type 2 diabetes in the SUSTAIN clinical trial programme. DeVries, JH., Desouza, C., Bellary, S., et al.[2022]

Semaglutide, a GLP-1 receptor agonist for type 2 diabetes, has a good safety profile but is associated with a high prevalence of gastrointestinal disorders, reported in over 3500 cases (53.2%).

Compared to other diabetes medications like sitagliptin and empagliflozin, semaglutide has a significantly higher number of reported gastrointestinal adverse events, indicating the need for careful monitoring in certain patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal disorders potentially associated with Semaglutide: an analysis from the Eudravigilance Database. Cabral Lopes, A., Roque, F., Lourenço, O., et al.[2023]

A study analyzing over 9 million adverse event reports found that glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with a significantly lower frequency of retinal adverse events compared to other glucose-lowering medications, with a rate of 2.53 per 1000 reports for GLP-1RAs versus 6.62 per 1000 for other medications.

Despite patients on GLP-1RAs having more comorbid conditions and concomitant medications, there was no evidence linking GLP-1RAs to an increased risk of retinopathy progression, suggesting they are a safer option in this regard for treating type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide-1 receptor agonists are not associated with retinal adverse events in the FDA Adverse Event Reporting System. Fadini, GP., Sarangdhar, M., Avogaro, A.[2022]

Oral semaglutide, particularly at doses of 14 mg or flexibly dosed, significantly reduced HbA1c levels and body weight in patients with type 2 diabetes compared to other treatments, especially in those with higher baseline HbA1c levels.

The safety profile of oral semaglutide was comparable to that of other treatments, although it was associated with a higher incidence of gastrointestinal adverse events, which were consistent across different patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. Aroda, VR., Bauer, R., Christiansen, E., et al.[2022]

Citations

1. 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 ...

2. 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 ...

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

Efficacy and Safety of Once-Weekly IcoSema in Adults With ... IcoSema, evaluated in 3 low-bias randomized controlled trials (RCTs) with 2653 patients with type 2 diabetes, significantly improved HbA1c ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39820580/

the COMBINE 2 randomised clinical trial The estimated mean change in fasting plasma glucose from baseline to week 52 was statistically significantly reduced with IcoSema vs semaglutide (-2.48 mmol/l ...

5. 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 ...

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 ...