Dorzagliatin and 1st Phase Insulin and Beta-cell Glucose Sensitivity in IGT and NGT

Effects of Dorzagliatin on 1st Phase Insulin and Beta-cell Glucose Sensitivity in Individuals With Impaired and Normal Glucose Tolerance

Dorzagliatin, a novel dual allosteric activator of glucokinase. reduces blood glucose by increasing insulin secretion by enhancing sensitivity of beta cells to glucose. In this placebo controlled cross over study, we examined the effects of dorzagliatin in people with impaired glucose tolerance and normal glucose tolerance.

Study Overview

• Status: Not yet recruiting
• Conditions: Glucose Intolerance
• Intervention / Treatment: Drug: Placebo; Drug: Dorzagliatin

Detailed Description

Objective

To investigate the acute effects of a single dose dorzagliatin on first phase insulin secretion and beta cell glucose sensitivity (βCGS) in individuals with impaired and normal glucose tolerance

Methodology and rationale:

A total of 20 subjects will be recruited, 10 in impaired glucose tolerant (IGT) and 10 in normal glucose tolerant (NGT) groups, respectively. Eligible participants will have a two-hour hyperglycemic clamp following a single dose of dorzagliatin or placebo in a randomized crossover fashion on V2 or V3. Subjects will be randomized to dorzagliatin 50mg or placebo in the IGT and NGT groups. Arterialized blood glucose (venous blood drawn from back of the hand placed in a temperature regulated box), measured every 5 minutes at the bedside Yellow Spring Instrument (YSI) or EKF glucose analyser, will be maintained at 12 mmol/l using an infusion of dextrose. Blood will be sampled for insulin and C-peptide at regular intervals for evaluation of first and second phase insulin secretion. Glucagon-like peptide-1 (GLP-1) and glucagon will be evaluated at regular intervals during the clamp studies. After 14 ± 2 days washout out (Day 14), participants will receive a single dose of dorzagliatin or matched placebo followed by a repeat hyperglycemic clamp to evaluate differences in beta-cell function.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 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 IGT group

• Fasting plasma glucose <7.0 mmol/L and HbA1c < 6.5%
• 2 hour plasma glucose ≥7.8 and <11.1 mmol/L on 75g oral glucose tolerance test (OGTT)
• Never been treated with glucose lowering drugs (including traditional Chinese medicine for glycemic control)

Additional inclusion criteria for NGT group

• Fasting plasma glucose <5.6 mmol/L and HbA1c < 5.7%
• 2 hour plasma glucose <7.8 mmol/L on 75g oral glucose tolerance test (OGTT)
• Never been treated with glucose lowering drugs (including traditional Chinese medicine for glycemic control

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. History of diabetes mellitus.
10. Dehydration, diarrhoea or vomiting at the time of recruitment.
11. Subjects with severe infection, in perioperative period or with serious injury at the time of recruitment.
12. Subjects with anaemia (Haemoglobin <11.0mg/dL or haematocrit <0.35 ) at screening, known iron deficiency, haemoglobinopathies or anaemia due to chronic disease.
13. Pregnant or lactating or intending to become pregnant within 30 days after last dose of study drug.
14. Participation in a clinical trial with investigational product within 30 days before enrolment.
15. 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.
16. Subjects judged unsuitable for the study based on investigator judgment.
17. Use of strong or moderate CYP3A4 inhibitors or inducers and cannot be discontinued.
18. Unwilling or unable to follow protocol requirements

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo; matching placebo	Drug: Placebo; Matching placebo
Active Comparator: dorzagliatin; Dorzagliatin 50 mg single dose	Drug: Dorzagliatin; single oral dose of dorzagliatin 50 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
2-hour hyperglycemic clamp	first phase insulin secretion	2-hour

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Anticipated): August 1, 2022
• Primary Completion (Anticipated): April 1, 2023
• Study Completion (Anticipated): April 1, 2023

Study Registration Dates

• First Submitted: July 19, 2022
• First Submitted That Met QC Criteria: July 20, 2022
• First Posted (Actual): July 21, 2022

Study Record Updates

• Last Update Posted (Actual): July 25, 2022
• Last Update Submitted That Met QC Criteria: July 21, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperglycemia; Glucose Intolerance
• Other Study ID Numbers: 2021.516-T

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