A First-in-human Study Looking at the Safety of ZP8396 and How it Works in the Body of Healthy Trial Participants

Study Overview
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Brief Summary
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The research study will investigate the safety and tolerability of ZP8396 in healthy study participants. In addition, the study will investigate how ZP8396 works in the body (pharmacokinetics and pharmacodynamics). Participants will receive 1 single dose either as an injection under the skin (subcutaneous, s.c.) or an injection into a vein of one arm (intravenous, i.v.). Participants will have 9 visits with the study team. One of these visits consists of 8 overnight stays at the study site. For each participant, the study will last up to 66 days.

Official Title
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A First-in-human, Randomised, Single Ascending Dose Trial Assessing Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ZP8396 Administered to Healthy Subjects

Conditions
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Overweight, Healthy Volunteers

Intervention / Treatment
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* Drug: ZP8396
* Drug: Placebo (ZP8396)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male subject Body Mass Index (BMI) between 21.0 and 29.9 kg/m^2, both inclusive Body weight of at least 70.0 kg Glycosylated hemoglobin A1c (HbA1c) less than 5.7 percent Further inclusion criteria apply Exclusion Criteria: History of metabolic diseases more frequently associated with obesity, e.g. type-2-diabetes mellitus, hypertension, dyslipidemia, heart disease or stroke Systolic blood pressure < 90 mmHg or >139 mmHg and/or diastolic blood pressure less than 50 mmHg or greater than 89 mmHg Symptoms of arterial hypotension Further exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

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
Interventional Model Description: First human dose trial. A single-centre, placebo-controlled, double-blind (within cohorts), randomised single dose trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZP8396<br>Up to 10 single dose cohorts are planned with 8 subjects in each; 6 participants in each cohort will receive active treatment. | Drug: ZP8396<br>* Participants will receive 1 single dose of ZP8396 given subcutaneously (s.c., under the skin) or intravenously (i.v., in a vein of the arm). Dose level will depend on the cohort.<br>|
| Placebo Comparator: Placebo (ZP8396)<br>In each of the 10 single dose cohorts, 2 subjects will receive placebo. | Drug: Placebo (ZP8396)<br>* Participants will receive 1 single dose of placebo given subcutaneously (s.c., under the skin) or intravenously (i.v., in a vein of the arm).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment emergent adverse events (TEAEs) |  | From dosing (Day 1) to end of trial (Day 50) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of ZP8396 (AUCτ) | Area under the plasma concentration-time curve over a dosing interval | Day 1 (pre-dose) to Day 50 (1176 hours post-dose) | 
| Pharmacokinetics (PK) of ZP8396 (AUCinf) | Area under the plasma concentration-time curve from time zero to infinity | Day 1 (pre-dose) to Day 50 (1176 hours post-dose) | 
| Pharmacokinetics (PK) of ZP8396 (AUClast) | Area under the plasma concentration-time curve from time zero to the time of the last measurable concentration | Day 1 (pre-dose) to Day 50 (1176 hours post-dose) | 
| Pharmacokinetics (PK) of ZP8396 (Cmax) | Maximum (peak) plasma drug concentration | Day 1 (pre-dose) to Day 50 (1176 hours post-dose) | 
| Pharmacokinetics (PK) of ZP8396 (tmax) | Time to reach maximum (peak) plasma concentration | Day 1 (pre-dose) to Day 50 (1176 hours post-dose) | 
| Pharmacokinetics (PK) of ZP8396 (λz) | Elimination rate constant | Day 1 (pre-dose) to Day 50 (1176 hours post-dose) | 
| Pharmacokinetics (PK) of ZP8396 (t½) | Elimination half-life | Day 1 (pre-dose) to Day 50 (1176 hours post-dose) | 
| Pharmacokinetics (PK) of ZP8396 (Vz/f) | Apparent volume of distribution during terminal phase | Day 1 (pre-dose) to Day 50 (1176 hours post-dose) | 
| Pharmacokinetics (PK) of ZP8396 (Vz) | Volume of distribution during the terminal phase (i.v. only) | Day 1 (pre-dose) to Day 50 (1176 hours post-dose) | 
| Pharmacokinetics (PK) of ZP8396 (CL/f) | Apparent total clearance of the drug from plasma | Day 1 (pre-dose) to Day 50 (1176 hours post-dose) | 
| Pharmacokinetics (PK) of ZP8396 (CL) | Total body clearance of the drug (i.v. only) | Day 1 (pre-dose) to Day 50 (1176 hours post-dose) | 
| Pharmacokinetics (PK) of ZP8396 (MRT) | Mean residence time | Day 1 (pre-dose) to Day 50 (1176 hours post-dose) | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (Cmax acetaminophen) | Maximum acetaminophen concentration after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (Tmax acetaminophen) | Time to maximum acetaminophen concentration after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (AUCacetaminophen, 0-60 min) | Area under the acetaminophen concentration-time curve from 0 to 60 minutes after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (AUCacetaminophen, 0-240 min) | Area under the acetaminophen concentration-time curve from 0 to 240 minutes after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (Cmax, Plasma Glucose [PG]) | Maximum PG concentration from 0 to 240 minutes after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (Tmax, Plasma Glucose [PG]) | Time to maximum PG concentration from 0 to 240 minutes after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (AUCPG,0-60 min) | Area under the Plasma Glucose (PG) concentration-time curve from 0 to 60 minutes after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (AUCPG,0-240 min) | Area under the Plasma Glucose (PG) concentration-time curve from 0 to 240 minutes after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (Cmax, insulin) | Maximum insulin concentration from 0 to 240 minutes after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (Tmax, insulin) | Time to maximum insulin concentration from 0 to 240 minutes after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (AUCinsulin,0-60 min) | Area under the insulin concentration-time curve from 0 to 60 minutes after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (AUCinsulin,0-240 min) | Area under the insulin concentration-time curve from 0 to 240 minutes after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (Cmax, glucagon) | Maximum glucagon concentration from 0 to 240 minutes after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (Tmax, glucagon) | Time to maximum glucagon concentration from 0 to 240 minutes after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (AUCglucagon,0-60 min) | Area under the glucagon concentration-time curve from 0 to 60 minutes after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 | 
| Pharmacodynamics (PD) of ZP8396, for dose cohorts greater than or equal to 0.7 mg (AUCglucagon,0-240 min) | Area under the glucagon concentration-time curve from 0 to 240 minutes after ingestion of a standardised Mixed Test Meal (MTM) and 1000 mg acetaminophen | 0-240 minutes, relative to ingestion of MTM/acetaminophen on Day -1 and Day 5 |