Effects of Dorzagliatin on 1st Phase Insulin and Beta-cell Glucose Sensitivity in T2D and Monogenic Diabetes

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Effects of Dorzagliatin on 1st Phase Insulin and Beta-cell Glucose Sensitivity in Individuals With Recent-onset Type 2 Diabetes and Monogenic Diabetes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04531631
• Other study ID #: CRE-2020.196
• Status: Completed
• Phase: Phase 2
• Start date: September 30, 2020
• Est. completion date: February 15, 2022

Study information

• Verified date: July 2022
• Source: Chinese University of Hong Kong
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Diabetes is a disorder of energy energy metabolism. Glucose is the main energy substrate for generation of ATP to maintain cellular metabolism, structure and function. Glucokinase (GK) serves as a glucose sensor for the initiation of the energy generation.for energy metabolism. Dorzagliatin is a novel, first-in-class, dual-acting allosteric GK activator (GKA). It increases the affinity of GK for glucose by directly binding a pocket distal to its active site, thus lowering the set point for glucose-stimulated insulin secretion in the beta-cell.

Dorzagliatin is a new drug which acts as GK sensor activator (GKA). It can restore the sensitivity of the pancreas cells to glucose and improve glucose control. The drug has been trialled in healthy volunteers and in individuals with type 2 diabetes.

The aim of this study is to understand the way in which dorzagliatin works to improve blood sugar control in people with diabetes. The study will look at how dorzagliatin affects insulin secretion and the sensitivity of the pancreas to changes in blood sugar levels. We will examine whether dorzagliatin can restore the function of this GK sensor in patients with known mutations. In a cross-over study, we will evaluate the effects of dorzagliatin, a specific GKA versus placebo in terms of insulin secretion and beta-cell glucose sensitivity in patients with newly-diagnosed T2D and patients who are known heterozygous carriers of GK mutations.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: February 15, 2022
• Est. primary completion date: February 15, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Individuals aged = 18 years but < 65years

2. Male or female

3. Body mass index of over 18 kg/m2 and < 30 kg/m2 Additional Inclusion criteria for recent-onset T2D group

• Diagnosis of T2D for at least 3 months and less than 2 years

• On diet control only

• HbA1c>6.5 % and <8% Additional Inclusion criteria for GK MODY-2 group

• Abnormal fasting plasma glucose >5.6 mmol/l and known heterozygous carrier of pathogenic GK mutation

Exclusion Criteria:

1. Subjects who do not agree to participate in this study.

2. Country of birth is unknown

3. Body weight less than 45kg

4. Acute phase of cerebrovascular and cardiovascular diseases (within 6 months of recruitment).

5. Subjects with severe renal dysfunction as defined by eGFR <30 ml/min/1.73m2 or patients receiving renal dialysis (such as haemodialysis or continuous ambulatory peritoneal dialysis).

6. Severe hepatic dysfunction as defined by AST and/or ALT > 3 times upper limit of normal

7. Severe cardiovascular disease, history of stroke, heart failure (NYHA III or IV) or history of myocardial infarction within last 12 months

8. History of drug abuse or excessive alcohol intake based on investigator judgment

9. Severe hypoglycaemia resulting in seizure/unconsciousness/coma/hospitalization in the last 3 months before screening

10. Diagnosis with Type 1 Diabetes Mellitus (T1DM) or any previous episodes of diabetic ketoacidosis.

11. Dehydration, diarrhoea or vomiting at the time of recruitment

12. Subjects with severe infection, in perioperative period or with serious injury at the time of recruitment

13. Subjects with anaemia (Haemoglobin <9.0mg/dL)

14. Pregnant or lactating or intending to become pregnant within 30 days after last dose of study drug.

15. Participation in a clinical trial within 30 days before enrolment

16. Donation or loss of blood (excluding the volume of blood that will be drawn during screening procedures) as follows: >=300 mL of blood within 30 days prior to study drug administration.

17. Subjects judged unsuitable for the study based on investigator judgment

18. Use of metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 [GLP-1] agonists, sodium glucose transporter 2 inhibitors, insulin, thiazolidinediones, acarbose in the 3 months prior to study enrolment will not be permitted.

19. Use of strong or moderate CYP3A4 inhibitors or inducers and cannot be discontinued

20. Unwilling or unable to follow protocol requirements.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• Dorzagliatin
tablet
• placebo
placebo

Locations

Country	Name	City	State
Hong Kong	The Chinese University of Hong Kong	Hong Kong

Sponsors (1)

Lead Sponsor	Collaborator
Chinese University of Hong Kong

Country where clinical trial is conducted

Hong Kong, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	first phase insulin response to glucose	measure insulin between 0 to 10 minutes	10 mins
Secondary	First phase C-peptide responses to glucose	measure C peptide between 0 to 10 minutes	10 mins
Secondary	Maximum concentration (Cmax) 1st phase insulin between 0 to 10 minutes	measure insulin between 0 to 10 minutes	10 mins
Secondary	Time to maximum (Tmax) of acute phase insulin response between 0 to 10 minutes	measure insulin between 0 to 10 minutes	10 mins
Secondary	Second phase insulin response	measure insulin at last 40 mins of hyperglycemic clamp	40 mins
Secondary	Beta cell glucose sensitivity	insulin secretion in last 40 minutes of hyperglycemic clamp	40 mins
Secondary	Insulin sensitivity index	glucose infusion rate in last 40 minutes of hyperglycemic clamp	40 mins
Secondary	Area under curve of glucagon levels	measure glucagon from 0-120 mins	120 mins
Secondary	Area under curve of GLP-1 levels	measure GLP-1 from 0-120 mins	120 mins