A Phase 1 Study of HEC88473 Injection in Healthy Subjects, Obese Subjects and T2DM Subjects

Study Overview
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Brief Summary
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This is a single-center, randomized, double-blind, placebo-controlled, escalating single-dose and multiple-dose study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of HEC88473 injection in healthy subjects, obese subjects and subjects with type 2 diabetes mellitus (T2DM).

Detailed Description
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This study is divided into two parts, Part A is an escalating single-dose study in healthy subjects and obese subjects, and Part B is an escalating multiple-dose study in subjects with T2DM.

Official Title
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A Phase 1, Randomised, Double-blind, Placebo-controlled, Single and Multiple Dose Study to Investigate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of HEC88473 Injection in Healthy Subjects, Obese Subjects and T2DM Subjects

Conditions
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Obesity, Healthy Subjects, T2DM (Type 2 Diabetes Mellitus)

Intervention / Treatment
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* Drug: HEC88473 injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A Males or females, between 18 and 45 years of age, inclusive, at screening. Body weight ≥ 50 kg for males and body weight ≥ 45 kg for females. 18≤body mass index (BMI)<28 kg/m2 for nonobese subjects and 28≤BMI≤45 kg/m2 for obese subjects. Part B Males or females, between 18 and 65 years of age, inclusive, at screening. 24 kg/m2≤BMI≤35 kg/m2. Subjects diagnosed with T2DM, newly diagnosed subjects at screening, or treated with diet and exercise alone within 3 months before screening and still have poor blood glucose control, or treated with a stable dose of metformin for ≥ 3 months before screening. 7.0%≤ HbA1c ≤10.5% at screening. Exclusion Criteria: Part A Smoked more than 5 cigarettes per day within 3 months before the study. Immunization with a live attenuated vaccine or coronavirus vaccination within 1 month prior to screening or planned vaccination during the course of the study. Positive alcohol breath test result or positive urine drug screen. Blood donation (> 300 mL) or massive blood loss (> 400 mL) within 3 months before screening. Part B Have type 1 diabetes mellitus. Have had ≥1 episode of severe hypoglycemia within 6 months before screening, or history of recurrent hypoglycemia (history of hypoglycemia more than 3 times in 3 months). Have acute or chronic hepatitis, signs and symptoms of any other liver disease other than nonalcoholic fatty liver disease (NAFLD), or alanine aminotransferase (ALT) level >5 times the upper limit of the reference range at screening. Have serum calcitonin ≥20 ng/L at screening. Have a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2; or have hereditary diseases that can easily induce MTC. Fasted triglycerides > 5.7 mmol/L at screening. If the patient is on lipid-lowering therapies, doses must be stable for 30 days prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single dose of 0.5 mg HEC88473<br>Healthy subjects, receiving a single dose of 0.5 mg HEC88473 (N=8) or placebo(N=2) after meal. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|
| Experimental: Single dose of 1.7 mg HEC88473<br>Healthy subjects, receiving a single dose of 1.7 mg HEC88473 (N=8) or placebo(N=2) after meal. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|
| Experimental: Single dose of 5.1 mg HEC88473<br>Healthy subjects, receiving a single dose of 5.1 mg HEC88473 (N=8) or placebo(N=2) after meal. Obese subjects, receiving a single dose of 5.1 mg HEC88473 (N=8) or placebo(N=2) after meal. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|
| Experimental: Single dose of 10.2 mg HEC88473<br>Healthy subjects, receiving a single dose of 10.2 mg HEC88473 (N=8) or placebo(N=2) after meal. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|
| Experimental: Single dose of 17.0 mg HEC88473<br>Healthy subjects, receiving a single dose of 17.0 mg HEC88473 (N=8) or placebo(N=2) after meal. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|
| Experimental: Single dose of 25.5 mg HEC88473<br>Healthy subjects, receiving a single dose of 25.5 mg HEC88473 (N=8) or placebo(N=2) after meal. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|
| Experimental: Single dose of 35.7 mg HEC88473<br>Healthy subjects, receiving a single dose of 35.7 mg HEC88473 (N=8) or placebo(N=2) after meal. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|
| Experimental: Single dose of 47.6 mg HEC88473<br>Healthy subjects, receiving a single dose of 47.6 mg HEC88473 (N=8) or placebo(N=2) after meal. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|
| Experimental: Single dose of 62.9 mg HEC88473<br>Healthy subjects, receiving a single dose of 62.9 mg HEC88473 (N=8) or placebo(N=2) after meal. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|
| Experimental: Single dose of 81.6 mg HEC88473<br>Healthy subjects, receiving a single dose of 81.6 mg HEC88473 (N=8) or placebo(N=2) after meal. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|
| Experimental: Multiple doses of 5.1 mg HEC88473<br>T2DM subjects, receiving a weekly dose of 5.1 mg HEC88473 (N=10) or placebo (N=2) for 5 consecutive weeks after meal. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|
| Experimental: Multiple doses of 15.3 mg HEC88473<br>T2DM subjects, receiving a weekly dose of 15.3 mg HEC88473 (N=10) or placebo (N=2) for 5 consecutive weeks after meal. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|
| Experimental: Multiple doses of 30.6 mg HEC88473<br>T2DM subjects, receiving a weekly dose of HEC88473 (N=10) or placebo (N=2) for 5 consecutive weeks after meal. The 30.6 mg cohort was administered by titration. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|
| Experimental: Multiple doses of 45.9 mg HEC88473<br>T2DM subjects, receiving a weekly dose of HEC88473 (N=10) or placebo (N=2) for 5 consecutive weeks after meal. The 45.9 mg cohort was administered by titration. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|
| Experimental: Multiple doses of 68.0 mg HEC88473<br>T2DM subjects, receiving a weekly dose of HEC88473 (N=10) or placebo (N=2) for 5 consecutive weeks after meal. The 68.0 mg cohort was administered by titration. | Drug: HEC88473 injection<br>* HEC88473 will be provided as a 17 mg/mL solution and will be administered by subcutaneous injection in the abdomen.<br>Drug: Placebo<br>* Placebo will be administered by subcutaneous injection in the abdomen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) after a single dose of HEC88473 | Adverse Events (AEs) | Baseline to day 15 | 
| Frequency and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) after multiple dose of HEC88473 | Adverse Events (AEs) | Baseline to day 43 | 
| Cmax | Maximum observed serum concentration of HEC88473 | Predose and postdose 4、8、10、12、14、24、48、72、96、168、216、336 hours | 
| AUC | Area under the serum concentration-time curve (AUC) | Predose and postdose 4、8、10、12、14、24、48、72、96、168、216、336 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OGTT | Oral glucose tolerance test | Day-1, Day3 and Day 7 | 
| Change from baseline of Adiponectin at day 38 | Adiponectin | Baseline to day 38 | 
| Fasting lipid concentration | Fasting lipid concentration | Baseline to day 43 | 
| Change from baseline of HbA1c at day 38 | HbA1c | Baseline to day 38 | 
| Assessment of the incidence of anti drug antibodies (ADA) developed against HEC88473 after dosing | anti drug antibodies (ADA) | Baseline to day 43 |