Evaluation of a Novel Hypoglycemic Clamp Procedure to Determine Spontaneous Recovery Time from Hypoglycemia in Type 2 Diabetes Using Insulin Aspart

Trial ID: 2025-520996-16-00
Sponsor: Medical University Of Graz

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Diseases & Conditions

Type 2 diabetes mellitus

Objectives

The primary objective of this study is to describe the relationship in the **insulin** dose required to lower plasma glucose (PG) from 90–70 mg/dL versus lowering PG from 70–48 mg/dL. This is clinically relevant as it aims to enhance understanding of insulin dosing precision, which is crucial for optimizing glycemic control in individuals with **Type 2 Diabetes Mellitus**. Accurate insulin dosing is essential to prevent both hyperglycemia and hypoglycemia, thereby improving patient outcomes.

Secondary objectives include:

Describing the relationship in the insulin dose required to induce hypoglycemia in people with diabetes compared with people without diabetes.
Describing the amount of insulin needed for hypoglycemia induction.
Assessing the feasibility of the hypoglycemic clamp procedure.

Participants

The clinical trial involves participants diagnosed with **Type 2 Diabetes Mellitus** as well as healthy individuals. The study population includes both male and female subjects aged between 18 to 64 years. Participants with diabetes have been diagnosed for at least six months and are on a stable treatment regimen involving diet, exercise, and metformin, with or without other oral antidiabetic medications or GLP-1 receptor agonists. The trial also includes healthy participants who are considered to be in good health based on medical history and clinical assessments. All participants are required to have a body mass index (BMI) within specified ranges and must maintain a stable body weight, with less than a 5% change, for more than three months prior to screening. Lifestyle considerations include an agreement not to initiate intensive diet or exercise programs aimed at weight reduction during the study. Women of childbearing potential must use highly effective contraceptive methods. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy of a novel hypoglycemic clamp procedure in assessing the time to spontaneous recovery from hypoglycemia in individuals with and without **Type 2 Diabetes Mellitus**. The trial will utilize **insulin aspart** as the active substance, administered via **intravenous infusion**. The primary objective is to describe the relationship between the insulin dose required to lower plasma glucose from 90 to 70 mg/dL versus from 70 to 48 mg/dL. The trial is expected to commence on May 12, 2025, and conclude by January 15, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, health status, and body mass index. The inclusion criteria differ slightly for participants with and without diabetes, ensuring a comprehensive assessment of the procedure's efficacy across both groups. Following the screening, participants will attend multiple follow-up visits, where the hypoglycemic clamp procedure will be conducted to measure insulin rates and glucose levels. The end-of-study visit will involve a final assessment of the participants' health status and the collection of any remaining data.

The expected duration of participant involvement is approximately eight months, with conditions for early termination including significant deviations from the protocol, adverse events, or withdrawal of consent. The primary endpoint focuses on the ratio of insulin rates required to achieve specific plasma glucose reductions, while secondary endpoints include comparisons of insulin rates and amounts between participants with and without diabetes, as well as the number of participants achieving spontaneous recovery from hypoglycemia. The study aims to provide valuable insights into the management of hypoglycemia in diabetic and non-diabetic populations.

Treatment

The clinical trial involves the administration of **NovoRapid**, a **100 units/ml solution for injection** in a vial, which contains the active substance **insulin aspart**. This pharmaceutical form is specifically designed for **intravenous infusion**. The medication is produced by **NOVO NORDISK A/S** and is classified under the ATC code **A10AB05**. Insulin aspart is a rapid-acting insulin analog used to manage blood glucose levels. The solution is administered intravenously, allowing for precise control of insulin delivery during the trial. The frequency and dosage of administration are determined based on the study protocol, which aims to assess the insulin dose required to lower plasma glucose from 90–70 mg/dL versus 70–48 mg/dL.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of NovoRapid to evaluate its efficacy in achieving the desired plasma glucose levels. Participant compliance is monitored through regular assessments and adherence to the dosing schedule as outlined in the trial protocol. The trial does not involve any pediatric formulations, and the product is not classified as an orphan drug. The study is conducted under strict regulatory compliance to ensure the safety and efficacy of the treatment being investigated.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the insulin requirements and recovery from **hypoglycemia** in participants with and without diabetes. The primary endpoint focuses on the ratio of insulin rates (mU/kg/min) necessary to lower plasma glucose (PG) from 90 to 70 mg/dL within 90 minutes (±30 minutes) compared to the insulin rates required to lower PG from 70 to 48 mg/dL within the same timeframe.

Secondary endpoints include several comparative analyses: the ratio of insulin rates in participants with diabetes versus those without, the total insulin amount (mU/kg) needed to achieve a nadir of PG 48 mg/dL (2.7 mmol/L) at the first versus the second clamp visit, and the total insulin amount required in participants with versus without diabetes. Additional secondary endpoints will measure the number of participants achieving spontaneous recovery from hypoglycemia, those who did not reach the nadir, and those who did not recover spontaneously after reaching the nadir. The time to spontaneous recovery from hypoglycemia will also be recorded, along with the glucose administered intravenously (mg/kg) within the first 30 minutes and rescue glucose administered from 31 to 60 minutes after reaching the nadir.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Inclusion Criteria for Participants with Diabetes: 1. Participant must be 18 to 64 years of age, both inclusive, at the time of signing the informed consent. 2. Have been diagnosed with T2D for at least 6 months prior to screening. 3. Treated with diet and exercise and stable treatment with metformin with or without allowed OAM or GLP-1 receptor agonists, 3 months prior to screening (allowed OAMs include DPP-IV inhibitors, SGLT2 inhibitors, glinides, or sulfonylureas). 4. Have a HbA1c value of ≤9.5% at screening (Visit 1). 5. Have venous access sufficient to allow for blood sampling as per the protocol. 6. Have clinical laboratory test results within normal reference range for the population or results with acceptable deviations that are judged to be not clinically significant by the Investigator. 7. Have a body mass index (BMI) within the range 25.0 kg/m2 and 45.0 kg/m2 (both inclusive). 8. Have had a stable body weight that is less than 5% change in body weight for more than 3 months prior to screening (Visit 1). 9. Agree not to initiate an intensive diet or exercise program during the study with the intent of reducing body weight other than lifestyle and dietary measures for diabetes treatment. 10. Women of childbearing potential (WOCBP) must use highly effective contraceptive methods, stable at least 2 months prior to the screening. 11. Are capable of giving signed informed consent as described in Section 10.1.2 of the protocol, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 12. Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures.
Inclusion Criteria for Participants without Diabetes: 1. Participant must be 18 to 64 years of age, both inclusive, at the time of signing the informed consent. 2. Considered to be healthy based on medical history, physical examination, results of vital signs and ECG. 3. Have venous access sufficient to allow for blood sampling as per the protocol. 4. Have clinical laboratory test results within normal reference range for the population or results with acceptable deviations that are judged to be not clinically significant by the Investigator. 5. Have a body mass index (BMI) within the range 25.0 kg/m2 and 29.9 kg/m2 (both inclusive). 6. Have had a stable body weight that is less than 5% change in body weight for more than 3 months prior to screening (Visit 1). 7. Agree not to initiate an intensive diet or exercise program during the study with the intent of reducing body weight other than lifestyle and dietary measures for diabetes treatment. 8. WOCBP must use highly effective contraceptive methods, stable at least 2 months prior to the screening. Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. For the contraception requirements of this protocol. For methods of contraception see Section 10.4. 9. Are capable of giving signed informed consent as described in Section 10.1.2, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 10. Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures.

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Exclusion Criteria

Exclusion Criteria for Participants with Diabetes - Medical Conditions: 1. Have type 1 diabetes mellitus. 2. Have known allergies to insulin aspart. 3. Have had an episode of severe hypoglycemia, as defined by the American Diabetes Association criteria, within 6 months before screening or has a history of hypoglycemia unawareness or poor recognition of hypoglycemic symptoms. 4. Do not have enough ability to communicate an understanding of hypoglycemic symptoms and the appropriate treatment of hypoglycemia in the opinion of the Investigator. 5. Have had an episode of ketoacidosis or hyperosmolar state/coma requiring hospitalization within the 6 months prior to screening (Visit 1). 6. Proliferative retinopathy or maculopathy and/or severe neuropathy, in particular autonomic neuropathy, as judged by the Investigator. 7. Have impaired renal estimated glomerular filtration rate <60 mL/min/1.73 m2 calculated by Chronic Kidney Disease-Epidemiology. 8. Show evidence of possible chronic or active hepatitis B, including hepatitis B core antibody and/or hepatitis B surface antigen positivity. 9. Have a positive HCV antibody test. Participants with a positive HCV antibody test at screening can be included only if a confirmatory HCV RNA test is negative. 10. Have evidence of HIV infection and/or positive HIV antibodies. 11. Have a history of • acute myocardial infarction, • peripheral artery disease, • ischemic heart disease, • congestive heart failure, New York Heart Association class III or IV, • cerebrovascular accident (stroke [including transient ischemic attack]), • coronary artery revascularization, • hospitalization for unstable angina, and/or • hospitalization due to congestive heart failure. 12. Have a history of additional risk factors for Torsades de Pointes (for example, heart failure, hypokalemia, family history of Long QT Syndrome). 13. Have a 12-lead ECG abnormality at screening that, in the opinion of the Investigator, increases the risks associated with participating in the study or may confound ECG data analysis. 14. Have the following sustained measurements at screening for at least 3 months: systolic blood pressure of greater than 160 mm Hg, diastolic blood pressure of greater than 100 mm Hg, or sitting pulse rate of less than 50 bpm or greater than 100 bpm. This exclusion criterion also pertains to participants being on antihypertensives. 15. Have an active or untreated malignancy or have been in remission from a clinically significant malignancy for <5 years prior to screening (Visit 1). Exceptions: • Basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years; • Cervical carcinoma in situ, with no evidence of recurrence within the 5 years prior to baseline; or • In situ prostate cancer. 16. Have a history or current cardiovascular, respiratory, hepatic, renal, gastrointenstinal, endocrine, hematological, neurological, or mental health disorders constituting a risk when undergoing hypoglycemic clamp; or of interfering with the interpretation of data, as judged by the Investigator. 17. Have had a blood donation of 500 mL or more in the last 3 months or any blood donation within the last month prior to screening (Visit 1). 18. Have a history of significant atopy (severe or multiple allergic manifestations), or anaphylactic reaction.
Exclusion Criteria for Participants with Diabetes - Prior or Concomitant Therapy: 19. Have taken any glucose-lowering medications other than metformin, DPP-IV inhibitors, sulfonylureas, glinides, or SGLT2 inhibitors or GLP-1 receptor agonists any time within the 3 months prior to screening. • Short term use of insulin (<14 days) for treatment of acute conditions is allowed in the 3-month period prior to screening. 20. Treated with any medication known to interfere with glucose metabolism, i.e. non-selective beta-blockers, systemic glucocorticoid therapy (excluding topical, intraarticular or inhaled preparations not reaching circulation), monoamine oxidase (MAO) inhibitors within 30 days or 5 half-lifes (whichever is longer) before screening. Stable therapy with hormonal contraceptives (2 months) is allowed.
Exclusion Criteria for Participants with Diabetes - Substance Abuse: 21. Having a history of alcohol abuse within 1 year prior to screening, or positive alcohol breath test at screening. 22. Smoke more than 10 cigarettes, or cigarette equivalent (as determined by Investigator), per day or are unable to abide by the study site’s tobacco and nicotine containing product restrictions. 23. History of drug abuse or positive result on urine drug test for drugs of abuse at screening. Have evidence of current or history of any substance use disorder(s) of any severity as defined by the DSM-V in the opinion of the Investigator, excepting disorders of nicotine or caffeine use. 24. Are unwilling to comply with the lifestyle and dietary restrictions required for this study.
Exclusion Criteria for Participants with Diabetes - Others: 25. Women who are lactating, pregnant or intend to become pregnant or to breastfeed during the study. 26. Are currently enrolled in any other clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study. 27. Are study site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
Exclusion Criteria for Participants without Diabetes - Medical Conditions: 1. Have impaired renal estimated glomerular filtration rate <60 mL/min/1.73 m2 calculated by Chronic Kidney Disease-Epidemiology. 2. Show evidence of possible chronic or active hepatitis B, including hepatitis B core antibody and/or hepatitis B surface antigen positivity. 3. Have a positive HCV antibody test. Participants with a positive HCV antibody test at screening can be included only if a confirmatory HCV RNA test is negative. 4. Have evidence of HIV infection and/or positive HIV antibodies. 5. Have a history of • acute myocardial infarction, • peripheral artery disease, • ischemic heart disease, • congestive heart failure, New York Heart Association class III or IV, • cerebrovascular accident (stroke [including transient ischemic attack]), • coronary artery revascularization, • hospitalization for unstable angina, and/or • hospitalization due to congestive heart failure. 6. Have a history of additional risk factors for Torsades de Pointes (for example, heart failure, hypokalemia, family history of Long QT Syndrome). 7. Have a 12-lead ECG abnormality at screening that, in the opinion of the Investigator, increases the risks associated with participating in the study or may confound ECG data analysis. 8. Supine blood pressure at screening outside the range of 90 – 140 mmHg for systolic or 50 – 90 mmHg for diastolic (excluding white-coat hypertension; therefore, if a repeated measurement shows values within the range, the participant can be included in the study). 9. Have an active or untreated malignancy or have been in remission from a clinically significant malignancy for <5 years prior to screening (Visit 1). Exceptions: • Basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years; • Cervical carcinoma in situ, with no evidence of recurrence within the 5 years prior to baseline; or • In situ prostate cancer. 10. Have a history or current cardiovascular, respiratory, hepatic, renal, gastrointenstinal, endocrine, hematological, neurological, or mental health disorders constituting a risk when undergoing hypoglycemic clamp; or of interfering with the interpretation of data, as judged by the Investigator. 11. Have had a blood donation of 500 mL or more in the last 3 months or any blood donation within the last month prior to screening (Visit 1). 12. Have a history of significant atopy (severe or multiple allergic manifestations), or anaphylactic reaction.
Exclusion Criteria for Participants without Diabetes - Prior or Concomitant Therapy: 13. Treated with any medication known to interfere with glucose metabolism, i.e. non-selective beta-blockers, systemic glucocorticoid therapy (excluding topical, intraarticular or inhaled preparations not reaching circulation), monoamine oxidase (MAO) inhibitors within 30 days or 5 half-lifes (whichever is longer) before screening. Stable therapy with hormonal contraceptives (2 months) is allowed.
Exclusion Criteria for Participants without Diabetes - Substance Abuse: 14. Having a history of alcohol abuse within 1 year prior to screening, or positive alcohol breath test at screening. 15. Smoke more than 10 cigarettes, or cigarette equivalent (as determined by Investigator), per day or are unable to abide by the study site’s tobacco and nicotine containing product restrictions. 16. History of drug abuse or positive result on urine drug test for drugs of abuse at screening. Have evidence of current or history of any substance use disorder(s) of any severity as defined by the DSM-V in the opinion of the Investigator, excepting disorders of nicotine or caffeine use. 17. Are unwilling to comply with the lifestyle and dietary restrictions required for this study.
Exclusion Criteria for Participants without Diabetes - Others: 18. Women who are lactating, pregnant or intend to become pregnant or to breastfeed during the study. 19. Are currently enrolled in any other clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study. 20. Are study site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.