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

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: placebo; Drug: Dorzagliatin

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • The Chinese University of Hong Kong

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Group 1; receive a single oral dose of dorzagliatin 75mg tablet on visit 2 and receive one placebo tablet on visit 3	Drug: placebo; placebo; Drug: Dorzagliatin; tablet
Other: Group 2; receive a single oral dose of one placebo tablet on visit 2 and receive dorzagliatin 75mg tablet on visit 3	Drug: placebo; placebo; Drug: Dorzagliatin; tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
first phase insulin response to glucose	measure insulin between 0 to 10 minutes	10 mins

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2020
• Primary Completion (Actual): February 15, 2022
• Study Completion (Actual): February 15, 2022

Study Registration Dates

• First Submitted: August 26, 2020
• First Submitted That Met QC Criteria: August 27, 2020
• First Posted (Actual): August 28, 2020

Study Record Updates

• Last Update Posted (Actual): July 22, 2022
• Last Update Submitted That Met QC Criteria: July 19, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: CRE-2020.196

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No