Triple Therapy for Type 1 Diabetes

Overseen By Husam Ghanim, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: State University of New York at Buffalo

Must be taking: Insulin

Must not be taking: Weight loss drugs

Disqualifiers: Type 2 diabetes, Hepatic disease, Coronary event, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new three-part treatment for people with type 1 diabetes to determine if it manages blood sugar better than current treatments. It compares the effects of adding dapagliflozin (an oral medication) to a regimen that already includes semaglutide (a weekly injection) and insulin. Participants will receive either the new three-part therapy, a two-part therapy with semaglutide and insulin, or just insulin as usual. Those who have had type 1 diabetes for over a year, regularly check their blood sugar, and use insulin daily might be a good fit for this study. As a Phase 2, Phase 3 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering a chance to contribute to advancing diabetes care.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have used any diabetes treatment other than insulin in the last 3 months.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have used any diabetes treatment other than insulin in the last 3 months.

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

Research shows that semaglutide, one of the treatments in this trial, can lower the risk of major heart problems in people with diabetes. However, its safety and effectiveness for people with type 1 diabetes remain unknown, leaving uncertainty about how well they can tolerate this treatment.

In contrast, dapagliflozin, another treatment in this trial, has been studied more extensively in people with type 1 diabetes. Studies have found it helps control blood sugar and aids in weight loss. However, it also increases the risk of diabetic ketoacidosis (a serious diabetes complication) and other side effects compared to a placebo.

While promising evidence exists for these treatments, it is important to consider both potential benefits and risks. Prospective trial participants should weigh these factors and discuss them with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Type 1 Diabetes because they introduce new combinations and delivery methods that might improve blood sugar control. Unlike the standard of care, which typically involves insulin alone, this approach adds semaglutide, a GLP-1 receptor agonist, and dapagliflozin, an SGLT-2 inhibitor. Semaglutide is administered through a weekly injection and can enhance insulin sensitivity and promote weight loss. Dapagliflozin, taken as a daily pill, helps the body excrete excess glucose through urine. This triple therapy could offer more comprehensive blood sugar management and additional health benefits compared to insulin alone.

What evidence suggests that this trial's treatments could be effective for type 1 diabetes?

Research has shown that semaglutide, which participants in this trial may receive, can help people with type 1 diabetes better control their blood sugar levels. It also aids in weight loss and lowers the risk of heart problems. Dapagliflozin, another treatment option in this trial, has been proven to lower HbA1c levels, a key measure of blood sugar control, and assist with weight loss. However, it might increase the risk of diabetic ketoacidosis (DKA), a serious condition where the body produces too many blood acids. Overall, using semaglutide and dapagliflozin together with insulin, as tested in this trial, has shown promise in improving blood sugar control in type 1 diabetes. ^{2 5 6 7 8}

Who Is on the Research Team?

Husam Ghanim, PhD

Principal Investigator

State University of NY at Buffalo

Are You a Good Fit for This Trial?

Adults aged 18-70 with Type 1 Diabetes for at least a year, on stable insulin treatment, and regularly monitoring blood sugar can join. They must have a BMI ≥25 kg/m2 and not be on weight loss programs or intensive exercise. Excluded are those with recent severe hypoglycemia, heart issues, kidney failure, liver disease, certain infections or cancers, pregnant women or those not using contraception.

Inclusion Criteria

I take at least 0.5 U/kg of insulin for multiple daily injections or 0.4 U/kg for pump therapy.

I have had Type 1 Diabetes for over a year and use an insulin pump or take four or more insulin shots daily.

Your C-peptide level is lower than 0.23 nM.

Exclusion Criteria

I have been diagnosed with diabetes or chronic pancreatitis recently or have MODY.

I had weight loss surgery within the last year.

I haven't used diabetes medication other than insulin in the last 3 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive semaglutide and insulin for the first 6 months, with dapagliflozin added for the second 6 months in the triple therapy group

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dapagliflozin
• Insulin
• Placebo to Dapagliflozin
• Semaglutide

Trial Overview The trial is testing if adding dapagliflozin to semaglutide and insulin (triple therapy) better controls blood sugar in Type 1 Diabetes than just semaglutide and insulin (dual therapy) or insulin alone. Participants will receive one of these combinations to compare effectiveness.

How Is the Trial Designed?

Group I: Triple therapy Experimental Treatment 3 Interventions

Once a day oral pill (green, plain, diamond shaped film coated 5 mg tablet) of Dapagliflozin (an SGLT-2 inhibitor) added to once a week injection of semaglutide and standard of care insulin in the second 6 months of 1/2 of the dual therapy arm (1/3 of total patients (38 patients)). Dapagliflozin will be started at 5 mg for one week, and then increased to 10 mg for the remainder of the study

Group II: Dual Therapy Experimental Treatment 2 Interventions

Once a week injection of Semaglutide (a GLP-1 receptor agonist) in addition to standard of care insulin for the first six months in 2/3 of patients (76 patients). Semaglutide is a clear, colorless solution that contains 2 mg of semaglutide in a 1.5 mL (1.34 mg/mL) pre-filled, disposable, single-patient-use pen injector. Semaglutide will be started at the 0.25 mg dose for the first two weeks, then increased to 0.5 mg at week 2, and then yet again increased to 1.0 mg at week 4.

Group III: Control Active Control 1 Intervention

Standard of care insulin will be used as an active comparator arm for 1/3 of patients (38 patients) for the entire duration of the study.

Group IV: Triple therapy control Placebo Group 3 Interventions

Once a day oral pill (green, plain, diamond shaped film coated 5 mg tablet) of the Placebo form of Dapagliflozin added to once a week injection of semaglutide and standard of care insulin in the second 6 months of 1/2 of the dual therapy arm (1/3 of total patients (38 patients)).

Insulin is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Insulin for:

• Diabetes mellitus

Approved in United States as Insulin for:

• Diabetes mellitus

Approved in Canada as Insulin for:

• Diabetes mellitus

Who Is Running the Clinical Trial?

State University of New York at Buffalo

Lead Sponsor

Trials

279

Recruited

52,600+

University of Glasgow

Collaborator

Trials

362

Recruited

24,980,000+

Juvenile Diabetes Research Foundation

Collaborator

Trials

237

Recruited

142,000+

Published Research Related to This Trial

Monotard HM and Actrapid HM insulin drugs significantly improved the management of type I diabetes by stabilizing the disease course and reducing the time needed to achieve metabolic compensation.

These insulin formulations also effectively treated post-injection lipodystrophies and body mass deficiency, while showing a trend towards lower daily insulin requirements and increased levels of free insulin in the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Use of human insulin preparations in the treatment of patients with insulin-dependent diabetes mellitus]. Perelygina, AA., Smirnova, OM., Lobanova, AM., et al.[2016]

In a meta-analysis of 22 randomized controlled trials involving 9691 patients with type 2 diabetes, basal analog (BA) insulin regimens showed similar efficacy to premix (PM) insulin regimens in reducing HbA1c and postprandial glucose levels, but with a significant reduction in fasting glucose levels.

BA regimens were associated with lower rates of total hypoglycemia and less weight gain compared to PM regimens, indicating a better safety profile for BA insulin in managing type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Basal Analog Regimens in Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis of Randomized Controlled Trials. Hong, T., Lu, J., Zhang, P., et al.[2020]

In a study involving 112 children and adolescents with type 1 diabetes, the combination of ultrashort acting insulin aspart with detemir or glargine showed a significant decrease in HbA1c levels, indicating improved blood sugar control over 12 and 24 weeks.

The use of detemir and glargine significantly reduced the risk of hypoglycemia compared to traditional NPH-insulin, while maintaining a stable body mass index in the detemir group, suggesting a safer and more effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Basal insulin analogue versus traditional NPH insulin in basal bolus therapy of children and adolescents with type 1 diabetes]. Prikhodina, OA., Surikova, SV., Girsh, YV.[2020]

Insulin glargine 300 U/mL (Gla-300) provides glycemic control similar to that of the standard Gla-100, with a mean reduction in glycated hemoglobin A1c of -1.02% in a meta-analysis of over 2400 patients with type 1 and type 2 diabetes.

Gla-300 is associated with a lower risk of nocturnal hypoglycemia (relative risk of 0.75) and potentially less weight gain compared to Gla-100, making it a promising alternative for long-acting insulin therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Insulin Glargine 300 U/mL for the Treatment of Type 1 and Type 2 Diabetes Mellitus. Goldman, J., White, JR.[2022]

Humalog, evaluated in 2834 patients across eight international studies, showed significant improvements in postprandial glycaemic control and a reduction in hypoglycaemic episodes, particularly at night, despite no significant decrease in overall HbA1C levels.

In a crossover study, patients using Humalog experienced five times fewer severe hypoglycaemic episodes compared to those on standard treatment, indicating its potential for safer diabetes management, although intensive treatment with multiple injections is recommended for optimal results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The insulin analog, Humalog, in discontinuous: from pharmacology to clinical use]. Tauber, JP.[2011]

In a study of 951 severely insulin-resistant type 2 diabetes patients, initiating Humulin R U-500 (U-500R) significantly improved treatment compliance and glycemic control, as evidenced by a reduction in HbA1c from 9.3% to 8.5%.

While U-500R improved overall insulin dosage and patient adherence, there was a modest increase in hypoglycemic events, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Patterns and Outcomes, Before and After Humulin R U-500 Initiation, Among High-Dose Type 2 Diabetes Mellitus Patients in the United States. Hood, RC., Borra, S., Fan, L., et al.[2022]

In a study involving 56 participants with type 1 diabetes, the experimental regular insulin produced by Bioton S.A. showed bioequivalence to Humulin® R, indicating similar pharmacokinetic and pharmacodynamic effects.

The findings suggest that introducing affordable biosimilar regular insulins could significantly enhance access to insulin for socioeconomically disadvantaged patients, improving diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized pharmacokinetic and pharmacodynamic trial of two regular human insulins demonstrates bioequivalence in type 1 diabetes and availability of biosimilar insulin may improve access to this medication. Vencio, S., Caiado-Vencio, R., Caixeta, LF., et al.[2023]

Insulin remains the primary treatment for type 1 diabetes, but recent advancements in insulin analogues have significantly improved glycemic control and allowed for more physiological basal/bolus insulin regimens.

New basal insulin analogues, such as degludec, pegylated lispro, and glargine U300, have shown improvements in duration of action and reduced risk of hypoglycemia, addressing key challenges in intensive diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New insulin types in type 1 diabetes mellitus]. Mesa, J.[2015]

A comprehensive review of 50 studies over the past 20 years revealed significant differences in bioactivity between human insulin and various insulin analogues, affecting metabolism, cell growth, and other cellular functions.

The clinical implications of these differences in bioactivity are still unclear and require further investigation to understand their impact on different patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differences in bioactivity between human insulin and insulin analogues approved for therapeutic use- compilation of reports from the past 20 years. Werner, H., Chantelau, EA.[2021]

In a study involving 1008 patients, short-acting insulin lispro and regular insulin Humulin R showed similar effectiveness in controlling blood sugar levels and had comparable safety profiles, with no significant differences in hypoglycemia incidents.

After a year of continued lispro therapy, glycosylated hemoglobin (HbA1C) levels returned to baseline, indicating that while lispro was well tolerated in the short term, long-term efficacy may need further evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lispro insulin as premeal therapy in type 1 diabetes: comparison with Humulin R. Daniels, AR., Bruce, R., McGregor, L.[2022]

Semaglutide (Ozempic®) is a new subcutaneous treatment for type 2 diabetes that effectively lowers blood glucose levels by stimulating insulin release and also helps reduce body weight.

The once-weekly injection has been approved in the US, Puerto Rico, and Canada, and is also under review in other countries, with ongoing clinical development for additional conditions like obesity and liver diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide: First Global Approval. Dhillon, S.[2019]

A comparison of insulin lispro and regular human insulin (Humulin R) in 3634 patients with type 1 and type 2 diabetes showed no significant differences in treatment-emergent adverse events, indicating similar safety profiles for both insulins.

Both insulin therapies did not differ in their effects on the progression of chronic diabetes complications, such as retinopathy, neuropathy, cardiovascular disease, or kidney disease, suggesting that insulin lispro is as safe as Humulin R.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of insulin lispro: pooled data from clinical trials. Glazer, NB., Zalani, S., Anderson, JH., et al.[2019]

Citations

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Efficacy and Safety of Dapagliflozin in Patients With ... Over 52 weeks, dapagliflozin led to improvements in glycemic control and weight loss in patients with type 1 diabetes, while increasing the risk of DKA.

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