ZT-01 for Type 1 Diabetes

(ZONE Trial)

Recruiting at 24 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Zucara Therapeutics Inc.

Disqualifiers: Type 2 diabetes, Kidney disease, others

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

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

Duration: 8 weeks

186 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how the new drug ZT-01 can assist people with type 1 diabetes who frequently experience low blood sugar (or "hypos") at night. ZT-01 boosts a hormone that helps control blood sugar levels, and the study aims to determine if it can reduce nighttime hypos. Participants will use both ZT-01 and a placebo (a non-active look-alike) to compare effects. This trial suits individuals who have had type 1 diabetes for at least 5 years and frequently experience low blood sugar at night. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you will continue using your usual methods of measuring blood sugar and giving insulin during the study.

Is there any evidence suggesting that ZT-01 is likely to be safe for humans?

Research has shown that ZT-01 was tested in earlier studies and found to be safe and well-tolerated. In trials involving both healthy individuals and those with type 1 diabetes, ZT-01 did not raise major safety concerns. Most participants experienced the treatment without serious side effects. Similar treatments sometimes reported mild and temporary stomach issues, but these were not serious. Overall, evidence from past studies suggests that ZT-01 is safe for humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for type 1 diabetes?

Most treatments for Type 1 Diabetes focus on insulin replacement or regulation. However, ZT-01 stands out because it's designed to improve glucose regulation by potentially enhancing the body's own insulin sensitivity through a novel mechanism. This treatment is administered via a simple subcutaneous injection, which is a familiar method for diabetes patients, making it convenient. Researchers are particularly excited about ZT-01 because it could offer a more efficient way to manage blood sugar levels with fewer fluctuations, which is a significant improvement over current therapies.

What evidence suggests that ZT-01 might be an effective treatment for type 1 diabetes?

Research has shown that ZT-01 might lower the risk of low blood sugar (hypoglycemia) in people with type 1 diabetes. Studies have found that ZT-01 boosts glucagon, a hormone that raises blood sugar when it drops too low. In animal studies, ZT-01 prevented blood sugar from dropping excessively, with over 60% of rats avoiding dangerous lows. It works by blocking a specific part of the pancreas, which may help the body release more glucagon during low blood sugar episodes. These findings suggest that ZT-01 could effectively reduce nighttime low blood sugar in people with type 1 diabetes. Participants in this trial will receive different dosages of ZT-01—7 mg, 15 mg, and 22 mg—to evaluate its effectiveness and safety. ^{1 2 5 6 7}

Are You a Good Fit for This Trial?

Adults with type 1 diabetes who have had the condition for at least 5 years and experience low blood sugar at night. They must have an HbA1c level of 10% or less, a BMI between 18.5 to <33 kg/m^2, and no severe hypoglycemia or hospitalizations for diabetic ketoacidosis recently. People with abnormal liver function, significant kidney disease, other specific health conditions, or using automated insulin delivery systems cannot participate.

Inclusion Criteria

I have had type 1 diabetes for 5 years or more.

You have experienced low blood sugar episodes at night in the recent past.

Your body mass index (BMI) at screening needs to be between 18.5 and 33 kg/m2.

Exclusion Criteria

I have a serious kidney condition.

I have been hospitalized for diabetic ketoacidosis more than once in the last 6 months.

You are currently using an automated insulin delivery system, like a closed loop or artificial pancreas.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive ZT-01 or placebo by subcutaneous injection daily for 28 days in two crossover periods

8 weeks

6 visits (in-person), 2 phone calls

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• ZT-01

Trial Overview The trial is testing ZT-01's ability to prevent nighttime low blood sugar in people with type 1 diabetes by increasing glucagon levels. Participants will self-inject either ZT-01 at varying doses or a placebo before bed while wearing a glucose monitor over two separate periods without knowing which they're receiving.

How Is the Trial Designed?

Group I: ZT-01 7 mg Experimental Treatment 2 Interventions

Participants receive placebo and ZT-01 7 mg each by subcutaneous injection daily for 28 days, randomized to order

Group II: ZT-01 22 mg Experimental Treatment 2 Interventions

Participants receive placebo and ZT-01 22 mg by subcutaneous injection daily for 28 days, randomized to order

Group III: ZT-01 15 mg Experimental Treatment 2 Interventions

Participants receive placebo and ZT-01 15 mg by subcutaneous injection daily for 28 days, randomized to order

ZT-01 is already approved in United States, Canada for the following indications:

Approved in United States as ZT-01 for:

• Prevention of nocturnal hypoglycemia in type 1 diabetes

Approved in Canada as ZT-01 for:

• Prevention of nocturnal hypoglycemia in type 1 diabetes

Who Is Running the Clinical Trial?

Zucara Therapeutics Inc.

Lead Sponsor

Trials

2

Recruited

210+

Published Research Related to This Trial

GLP-1 receptor agonists (like exenatide and liraglutide) can significantly lower hemoglobin A1C levels, plasma glucose, and body weight in patients with type 1 diabetes who are already on insulin, without increasing the risk of hypoglycemia.

The most common side effects of GLP-1 RAs are mild and transient gastrointestinal issues, making them a safe option for patients struggling with insulin side effects or those needing to lose weight.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive Role of Glucagon-Like Peptide-1 Receptor Agonists in the Management of Type 1 Diabetes Mellitus. Harris, KB., Boland, CL.[2022]

Complete loss of the zinc transporter ZnT8 accelerated the onset of type 1 diabetes (T1D) in NOD mice, indicating that ZnT8 plays a significant role in autoimmunity related to T1D.

Heterozygous mice with partial loss of ZnT8 showed increased mitochondrial fitness in beta cells, suggesting that maintaining zinc homeostasis could be a potential strategy for modulating T1D progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zinc transporter 8 haploinsufficiency protects against beta cell dysfunction in type 1 diabetes by increasing mitochondrial respiration. Kim, YK., Walters, JA., Moss, ND., et al.[2023]

The review highlights a growing need for effective therapies for type 1 diabetes (T1D), as currently, insulin is the only approved treatment, and many new drugs are in clinical development, including those with established and novel mechanisms of action.

New drug classes under investigation include SGLT inhibitors, GLP-1 agonists, and immunomodulatory drugs, with many compounds currently in Phase 1 and 2 trials, indicating a promising future for combination therapies that could enhance treatment options for T1D.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addressing Unmet Medical Needs in Type 1 Diabetes: A Review of Drugs Under Development. Mittermayer, F., Caveney, E., De Oliveira, C., et al.[2018]

Despite the discovery of insulin 100 years ago, managing type 1 diabetes (T1D) remains difficult due to the need for constant adjustments in insulin dosages and carbohydrate intake, highlighting the limitations of current treatments.

There is a pressing need for disease-modifying therapies (DMTs) that can preserve or restore insulin-producing β-cells, and the paper suggests that combination therapies and innovative trial designs could accelerate the development and evaluation of these potential treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes. Anderson, RL., DiMeglio, LA., Mander, AP., et al.[2023]

ZnT8 is a crucial biomarker for diagnosing and characterizing type 1 diabetes mellitus (T1DM), as it helps identify autoantibodies and specific T cells related to the disease.

Research indicates that ZnT8 could serve as a potential therapeutic target for T1DM, with studies suggesting that ZnT8-specific immunotherapy may offer a new treatment approach, although further research is needed before widespread clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current and Future Clinical Applications of Zinc Transporter-8 in Type 1 Diabetes Mellitus. Yi, B., Huang, G., Zhou, ZG.[2022]

In a study of 213 pediatric patients with Type 1 diabetes, anti-ZnT8 antibodies (ZnT8A) were found in 49.8% of patients, enhancing the diagnostic sensitivity for T1D from 85.9% to 90.6%.

ZnT8A demonstrated similar sensitivity to GADA at disease onset (61.1%) and identified 4.7% of patients who were previously classified as autoantibody negative, highlighting its potential as a crucial addition to current diagnostic methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-zinc transporter protein 8 autoantibodies significantly improve the diagnostic approach to type 1 diabetes: an Italian multicentre study on paediatric patients. Fabris, M., Zago, S., Liguori, M., et al.[2020]

Zinc transporter 8 (ZnT8) is linked to both type 1 and type 2 diabetes, with its expression and zinc content in beta cells decreasing in diabetic mice, suggesting it plays a role in insulin production and beta cell function.

The prevalence of ZnT8 autoantibodies (ZnT8A) increases with the severity of diabetes, indicating that ZnT8 may have different implications in the pathogenesis of type 1 and type 2 diabetes, as well as varying responses to ZnT8 treatment in these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Different role of zinc transporter 8 between type 1 diabetes mellitus and type 2 diabetes mellitus. Yi, B., Huang, G., Zhou, Z.[2022]

Insulin replacement therapy has made type 1 diabetes manageable, but it does not fully replicate the body's natural insulin response, leading to potential long-term complications.

Monoclonal antibodies (mAbs) are promising tools for treating type 1 diabetes due to their high specificity, and engineering these antibodies can enhance their effectiveness in immunomodulatory therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered antibodies for type 1 diabetes. Hampe, CS.[2021]

The study reveals that the ZnT8 protein, found on the surface of pancreatic β-cells, can trigger a strong immune response, indicating its role as a self-antigen in type 1 diabetes.

In patients with type 1 diabetes, antibodies against ZnT8 were shown to bind to live insulin-producing cells, suggesting that these antibodies may contribute to β-cell dysfunction and damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A subclass of serum anti-ZnT8 antibodies directed to the surface of live pancreatic β-cells. Merriman, C., Huang, Q., Gu, W., et al.[2021]

A Phase I/II study involving pediatric patients with recent-onset Type 1 diabetes showed that multiple infusions of α-1 antitrypsin (AAT) are safe and well-tolerated, with no serious adverse events reported over a long-term follow-up of up to 5 years.

Participants demonstrated normal growth and pubertal development, suggesting that AAT could be a promising immunotherapy for preserving β-cell function in Type 1 diabetes without compromising overall health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety of α-1 antitrypsin therapy in children and adolescents with Type 1 diabetes. Brener, A., Lebenthal, Y., Interator, H., et al.[2019]

A small phase 1 trial has shown that a peptide-based antigen-specific immunotherapy is safe for recently diagnosed adults with type 1 diabetes.

This treatment approach is considered promising for potentially preventing or reversing type 1 diabetes, highlighting its role as a disease-modifying strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antigen-Specific Peptide Immunotherapy for Type 1 Diabetes: Proof of Safety, Hope for Efficacy. Coppieters, K., von Herrath, M.[2018]

Current treatments for Type 1 diabetes (T1D), like cyclosporin, show that it is possible to prevent the disease, but they come with significant long-term safety risks.

The concept of antigen-specific tolerization is proposed as a safer strategy to achieve long-term protection against T1D, emphasizing the need for careful trial design to balance safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trials in type 1 diabetes: Antigen-specific therapies. Coppieters, KT., Harrison, LC., von Herrath, MG.[2021]

Research indicates that using pancreatic islet auto-antigens, like the ZnT8 protein, for immune regulation may provide a safe and specific treatment for Type 1 diabetes (T1DM) by identifying high-risk individuals and potentially preventing the disease.

ZnT8-specific CD8+ T cells are prevalent in T1DM patients and targeting them through antigen-based immunotherapy could help restore beta cell function and slow the progression of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antigen-specific immunotherapies in type 1 diabetes. Zhang, X., Dong, Y., Liu, D., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10951717/

Evaluating the effectiveness of a novel somatostatin receptor 2 ... ZT-01 treatment in the T2D rats increased glucagon levels above the control response within 60 min of dosing, and values remained elevated ...

2. breakthrought1d.org breakthrought1d.org/grants/canada/ontario/phase-2-clinical-study-evaluating-zt-01-for-the-prevention-of-nocturnal-hypoglycemia-in-type-1-diabetes/

Phase 2 clinical study evaluating ZT-01 for the prevention ... The trial will test a novel mechanism of action by which ZT-01 reduces hypoglycemia in T1D, namely that blocking somatostatin receptor 2 in the pancreas will ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05762107

A Study of the Effect of ZT-01 on Night-time Hypoglycemia ... The goal of this clinical trial is to learn about the effect of the study drug (ZT-01) on low blood sugar (hypoglycemia) in adults with type 1 diabetes (T1D)

4. zucara.ca zucara.ca/news/zucara-therapeutics-announces-publication-of-preclinical-study-demonstrating-zt-01s-ability-to-restore-glucagon-release-in-type-1-diabetes/

ZT-01 restored glucagon secretion, and reduced ... Average blood glucose levels following ZT-01 treatment reached a nadir of 3.8 mM, with more than 60% of rats completely avoiding significant ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05007977

Effect of ZT-01 on Glucagon During Hypoglycemia in Type ... The purpose of this study is to determine whether ZT-01 increases the glucagon response to hypoglycemia in type 1 diabetes (T1D). ZT-01 is a ...

6. zucara.ca zucara.ca/product/

Product Completed Phase 1 single and multiple ascending dose trial in healthy volunteers and Type 1 diabetics where ZT-01 was shown to be safe and well tolerated.

7. withpower.com withpower.com/trial/phase-2-diabetes-mellitus-2-2023-1f728

ZT-01 for Type 1 Diabetes (ZONE Trial) The safety data for ZT-01 is not directly available, but similar treatments like GLP-1 receptor agonists have shown mild and temporary gastrointestinal side ...