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

• ClinicalTrials.gov Identifier: NCT04531631
• Recruitment Status: Recruiting
• First Posted: August 28, 2020
• Last Update Posted: February 3, 2021
• Sponsor: Chinese University of Hong Kong
• Information provided by (Responsible Party): Juliana Chan, Chinese University of Hong Kong

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 2	Drug: Dorzagliatin; Drug: placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Other
• 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
• Actual Study Start Date: September 30, 2020
• Estimated Primary Completion Date: September 2021
• Estimated Study Completion Date: December 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. first phase insulin response to glucose [ Time Frame: 10 mins ]
   measure insulin between 0 to 10 minutes

Secondary Outcome Measures :

1. First phase C-peptide responses to glucose [ Time Frame: 10 mins ]
   measure C peptide between 0 to 10 minutes
2. Maximum concentration (Cmax) 1st phase insulin between 0 to 10 minutes [ Time Frame: 10 mins ]
   measure insulin between 0 to 10 minutes
3. Time to maximum (Tmax) of acute phase insulin response between 0 to 10 minutes [ Time Frame: 10 mins ]
   measure insulin between 0 to 10 minutes
4. Second phase insulin response [ Time Frame: 40 mins ]
   measure insulin at last 40 mins of hyperglycemic clamp
5. Beta cell glucose sensitivity [ Time Frame: 40 mins ]
   insulin secretion in last 40 minutes of hyperglycemic clamp
6. Insulin sensitivity index [ Time Frame: 40 mins ]
   glucose infusion rate in last 40 minutes of hyperglycemic clamp
7. Area under curve of glucagon levels [ Time Frame: 120 mins ]
   measure glucagon from 0-120 mins
8. Area under curve of GLP-1 levels [ Time Frame: 120 mins ]
   measure GLP-1 from 0-120 mins

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Hong Kong

The Chinese University of Hong Kong; Recruiting

Hong Kong, Hong Kong

Contact: Juliana Chan 35053138 jchan@cuhk.edu.hk

Sponsors and Collaborators

Chinese University of Hong Kong

More Information

• Responsible Party: Juliana Chan, Professor, Chinese University of Hong Kong
• ClinicalTrials.gov Identifier: NCT04531631
• Other Study ID Numbers: CRE-2020.196
• First Posted: August 28, 2020
• Last Update Posted: February 3, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases