A Multiple Ascending Dose Trial Assessing Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ZP7570

Study Overview
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Brief Summary
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This is a randomised, double-blind, placebo-controlled, multiple ascending dose trial in healthy subjects, randomised to ZP7570 or placebo within each cohort

Detailed Description
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Forty subjects are planned to be studied in four cohorts in this multiple ascending dose trial. Ten subjects will be allocated to four dose levels. Intermediate dose levels may be applied. A sentinel dosing approach (sequential dosing) will be applied. The entire observation period comprises 51 days starting with a 96 hours in-house stay after the first dose injection, where discharge is planned for Day 5, followed by one outpatient visit. For the second and the third injection dose a 36 hours in-house stay is planned. After the fourth dose injection there is also a 96 hour in-house stay where discharge is planned for Day 26, followed by five outpatient visits and an End of Trial Visit on Day 51. A blinded evaluation of each cohort will be performed by a Trial Safety Group to determine whether the trial will progress to the next planned dose level based on the stopping rules specified in the protocol.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Multiple Ascending Dose Trial Assessing Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Subcutaneous Doses of ZP7570 in Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: ZP7570
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated informed consent obtained before any trial-related activities. Trial-related activities are any procedures that would not have been done during normal management of the subject. Healthy male or female subject (only women not of childbearing potential) aged between 18 and 55 years, both inclusive. Body Mass Index (BMI) between 18.5 and 28.0 kg/m2, both inclusive A body weight of at least 60 kg. Heart rate after 5 minutes rest in supine position inside the range of 50-90 beats/min at screening Exclusion Criteria: Any history of a disorder which in the investigator's opinion might jeopardize subjects safety, evaluation of results or compliance with the protocol. History of gallbladder disease or cholecystectomy. History of pancreatitis History of major depressive disorder or a Patient Health Questionnaire (PHQ-9) > 9 completed at screening, or a history of other severe psychiatric disorders (e.g. schizophrenia or bipolar disorder). Any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) within 6 months prior to screening. Family history of multiple endocrinological neoplasia type 2 (MEN2) or medullary thyroid carcinoma (MTC). Clinically significant abnormal standard 12-lead ECG after 5 min resting in supine position at screening, including a QTcF > 450 ms (males) or QTcF > 470 ms (females), PR ≥ 220 ms and QRS ≥ 110 ms. History of severe hypersensitivity to medicines or foods or history of severe medicinal/food induced anaphylactic reaction . Any clinically significant abnormal hematology, biochemistry, or urinalysis screening tests, as judged by the investigator. TSH values outside of normal reference ranges of safety laboratory Estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73 m2, as defined by - Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Known or suspected hypersensitivity to IMP(s) or related products. Systolic blood pressure < 90 mmHg or >139 mmHg and/or diastolic blood pressure < 50 mmHg or > 89 mmHg (one repeat test will be acceptable in case of suspected white-coat hypertension). Symptoms of arterial hypotension Women of childbearing potential Men with non-pregnant partner(s) of childbearing potential not willing to use male contraception (condom) in addition to a highly effective contraceptive method until 28 days after dosing Men with pregnant partner not willing to use male contraception (condom) until 28 days after dosing, in order to avoid exposure of the embryo/fetus to seminal fluid.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Parallel Assignment
Interventional Model Description: A randomized, double-blind, placebo-controlled, single ascending dose trial in healthy subjects, randomized to ZP7570 or placebo
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZP7570<br>Four ascending doses of ZP7570 | Drug: ZP7570<br>* Each subject will be randomly allocated to multiple doses of ZP7570 at one of four dose levels in each cohort.<br>* Other names: Dual GLP-1R/GLP-2R agonist;|
| Placebo Comparator: Placebo<br>Corresponding volume of placebo | Drug: Placebo<br>* Placebo; corresponding volume<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability - Incidence of treatment emergent adverse events as assessed by type and severity | The incidence, type and severity of treatment emergent adverse events | From time 0 to 51 days after first dosing (29 days after fourth dosing) ] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics - Area under the plasma concentration-time curve - through | AUCτ, Area under the plasma concentration-time curve from zero to through concentration. | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Pharmacokinetics - Area under the plasma concentration-time curve - infinity | AUCinf, Area under the plasma concentration-time curve from zero to infinity concentration. | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Pharmacokinetics - Area under the plasma concentration-time curve - last | AUClast, Area under the plasma concentration-time curve-from zero to last concentration. | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Pharmacokinetics - Maximum plasma concentration - Cmax | Cmax, Measured maximum plasma drug concentration after dosing | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Pharmacokinetics - Time to maximum plasma concentration - Tmax | Tmax, Sampling time until reaching Cmax after dosing | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Pharmacokinetics - Elimination rate constant - λz | λz, Elimination rate constant | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Pharmacokinetics - Half-life - t½ | t½, Half-life of ZP7570 | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Pharmacokinetics - Volume of distribution - Vz/f | Vz/f, Apparent volume of distribution of ZP7570 during terminal phase | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Pharmacokinetics - Body clearance - CL/f | CL/f, Apparent total body clearance | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Pharmacokinetics - Mean residence time - MRT | MRT, Mean residence time | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Pharmacodynamics - Acetaminophen concentration-time curves | Acetaminophen concentration-time curves following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the the forth dose | 
| Pharmacodynamics - Maximum acetaminophen concentration - Cmax | Cmax, maximum acetaminophen concentration following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the the forth dose | 
| Pharmacodynamics - Time to maximum acetaminophen concentration - Tmax | Tmax, Time to maximum acetaminophen concentration following ingestion of mixed meal test and acetaminophene | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Area under the concentration-time curve - AUCacetaminohen,0-60min | AUCacetaminohen,0-60min, area under the acetaminophen concentration-time curve from 0 to 60 min post-ingestion | From time 0 to 60 minutes at baseline, 24 hours after a single dose and 24 hours after the the forth dose | 
| Pharmacodynamics - Area under the concentration-time curve - AUCacetaminohen,0-240min | AUCacetaminohen,0-240min, area under the acetaminophen concentration -time curve from 0 to 240 min post-ingestion | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Plasma glucose concentration-time curves | Plasma glucose concentration-time curves following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the the forth dose | 
| Pharmacodynamics - Maximum plasma glucose concentration - Cmax | Cmax, Maximum plasma glucose concentration following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the the forth dose | 
| Pharmacodynamics - Time to maximum plasma glucose concentration - Tmax | Tmax, Time to maximum plasma glucose concentration following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Area under the concentration-time curve - AUCplasma glucose,0-60min | AUCplasma glucose,0-60min, area under the plasma glucose concentration-time curve from 0 to 60 min post-ingestion | From time 0 to 60 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Area under the concentration-time curve - AUCplasma glucose,0-240min | AUCplasma glucose,0-240min, area under the acetaminophen concentration -time curve from 0 to 240 min post-ingestion | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Insulin concentration-time curves | Insulin concentration-time curves following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Maximum insulin concentration - Cmax | Cmax, Maximum insulin concentration following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Time to maximum insulin concentration - Tmax | Tmax, Time to maximum insulin concentration following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Area under the concentration-time curve - AUCinsulin,0-60min | AUCinsulin,0-60min, area under the insulin concentration-time curve from 0 to 60 min post-ingestion | From time 0 to 60 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Area under the concentration-time curve - AUCinsulin, 0-240min | AUCinsulin,0-240min, area under the insulin concentration-time curve from 0 to 240 min post-ingestion | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Glucagon concentration-time curves (optional) | Glucagon concentration-time curves following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Maximum glucagon concentration - Cmax (optional) | Cmax, Maximum glucagon concentration following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Time to maximum glucagon concentration - Tmax (optional) | Tmax, Time to maximum glucagon concentration following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Area under the concentration-time curve - AUCglucagon,0-60min (optional) | AUCglucagon,0-60min, area under the glucagon concentration-time curve from 0 to 60 min post-ingestion | From time 0 to 60 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Area under the concentration-time curve - AUCglucagon, 0-240min (optional) | AUCglucagon,0-240min, area under the glucagon concentration-time curve from 0 to 240 min post-ingestion | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Free fatty acids concentration-time curves | Free fatty acids concentration-time curves following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Maximum free fatty acids concentration - Cmax | Cmax, Maximum free fatty acids concentration following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Time to maximum free fatty acids concentration - Tmax | Tmax, Time to maximum free fatty acids concentration following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Area under the concentration-time curve - AUCfree fatty acids, 0-60min | AUCfree fatty acids,0-60min, area under the free fatty acids concentration-time curve | From time 0 to 60 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Area under the concentration-time curve - AUCfree fatty acids, 0-240min | AUCfree fatty acids,0-240min, area under the free fatty acids concentration-time curve | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Triglycerides concentration-time curves | Triglycerides concentration-time curves following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Maximum triglycerides concentration - Cmax | Cmax, Maximum triglycerides concentration following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Time to maximum triglycerides concentration - Tmax | Tmax, Time to maximum triglycerides concentration following ingestion of mixed meal test and acetaminophen | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Area under the concentration-time curve - AUCtriglycerides, 0-60min | AUCtriglycerides,0-60min, area under the triglycerides concentration-time | From time 0 to 60 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Pharmacodynamics - Area under the concentration-time curve - AUCtriglycerides,0-240min | AUCtriglycerides,0-240min, area under the triglycerides concentration-time curve | From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose | 
| Anti-ZP7570 antibodies - Incidence and titres | Overall anti-ZP7570 antibody incidence and titers. Incidence of anti-ZP7570 antibodies cross-reacting with endogenous GLP-1 or GLP-2. | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Safety Lab - Haematological values vs. reference ranges and baseline | Abnormal values or changes in haematology. | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Safety Lab - Clinical chemistry values vs. reference ranges and baseline | Abnormal values or changes in chemical chemistry | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Safety Lab - Urinalysis values vs. reference ranges and baseline | Abnormal values or changes in urinalysis | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Safety - Vital signs: blood pressure | Changes in diastolic and systolic blood pressure (in mmHg) | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Safety - Vital signs: pulse | Changes in pulse (beats per minute) | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Safety - Physical Examination | Changes in physical examination of the body. Outcome will be measured as 'normal' or 'abnormal', if abnormal as 'not clinically significant' or 'clinically significant'. | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Safety - ECG | Changes or abnormalities in ECG parameters (in ms): Heart rate, PR, QRS, QT, QTcF | From time 0 to 51 days after first dosing (29 days after fourth dosing) | 
| Safety - Injection site reactions | Occurrence of injection site reactions | From time 0 to 51 days after first dosing (29 days after fourth dosing) |