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

Healthy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04612517
• Other study ID #: ZP7570-18145
• Secondary ID: 2019-001129-29
• Status: Completed
• Phase: Early Phase 1
• Start date: October 26, 2020
• Est. completion date: August 30, 2021

Study information

• Verified date: September 2021
• Source: Zealand Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: August 30, 2021
• Est. primary completion date: August 30, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• ZP7570
Each subject will be randomly allocated to multiple doses of ZP7570 at one of four dose levels in each cohort.
• Placebo
Placebo; corresponding volume

Locations

Country	Name	City	State
Germany	Profil Institut für Stoffwechselforschung GmbH	Neuss	North Rhine-Westphalia

Sponsors (1)

Lead Sponsor	Collaborator
Zealand Pharma

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Pharmacokinetics - Area under the plasma concentration-time curve - through	AUCt, 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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Pharmacokinetics - Elimination rate constant - ?z	?z, Elimination rate constant	From time 0 to 51 days after first dosing (29 days after fourth dosing)
Secondary	Pharmacokinetics - Half-life - t½	t½, Half-life of ZP7570	From time 0 to 51 days after first dosing (29 days after fourth dosing)
Secondary	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)
Secondary	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)
Secondary	Pharmacokinetics - Mean residence time - MRT	MRT, Mean residence time	From time 0 to 51 days after first dosing (29 days after fourth dosing)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Safety - Vital signs: pulse	Changes in pulse (beats per minute)	From time 0 to 51 days after first dosing (29 days after fourth dosing)
Secondary	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)
Secondary	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)
Secondary	Safety - Injection site reactions	Occurrence of injection site reactions	From time 0 to 51 days after first dosing (29 days after fourth dosing)