Clinical trial NCT04612517: A Multiple Ascending Dose Trial Assessing Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ZP7570
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Healthy
Lead sponsor: Zealand Pharma
Sponsor class: INDUSTRY
First posted: 2020-11-03
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomized, double-blind, placebo-controlled, single ascending dose trial in healthy subjects, randomized to ZP7570 or placebo
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety and Tolerability - Incidence of treatment emergent adverse events as assessed by type and severity
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing) ]
Secondary outcomes:
measure: Pharmacokinetics - Area under the plasma concentration-time curve - through
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Pharmacokinetics - Area under the plasma concentration-time curve - infinity
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Pharmacokinetics - Area under the plasma concentration-time curve - last
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Pharmacokinetics - Maximum plasma concentration - Cmax
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Pharmacokinetics - Time to maximum plasma concentration - Tmax
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Pharmacokinetics - Elimination rate constant - λz
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Pharmacokinetics - Half-life - t½
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Pharmacokinetics - Volume of distribution - Vz/f
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Pharmacokinetics - Body clearance - CL/f
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Pharmacokinetics - Mean residence time - MRT
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Pharmacodynamics - Acetaminophen concentration-time curves
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the the forth dose
measure: Pharmacodynamics - Maximum acetaminophen concentration - Cmax
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the the forth dose
measure: Pharmacodynamics - Time to maximum acetaminophen concentration - Tmax
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Area under the concentration-time curve - AUCacetaminohen,0-60min
timeFrame: From time 0 to 60 minutes at baseline, 24 hours after a single dose and 24 hours after the the forth dose
measure: Pharmacodynamics - Area under the concentration-time curve - AUCacetaminohen,0-240min
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Plasma glucose concentration-time curves
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the the forth dose
measure: Pharmacodynamics - Maximum plasma glucose concentration - Cmax
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the the forth dose
measure: Pharmacodynamics - Time to maximum plasma glucose concentration - Tmax
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Area under the concentration-time curve - AUCplasma glucose,0-60min
timeFrame: From time 0 to 60 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Area under the concentration-time curve - AUCplasma glucose,0-240min
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Insulin concentration-time curves
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Maximum insulin concentration - Cmax
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Time to maximum insulin concentration - Tmax
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Area under the concentration-time curve - AUCinsulin,0-60min
timeFrame: From time 0 to 60 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Area under the concentration-time curve - AUCinsulin, 0-240min
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Glucagon concentration-time curves (optional)
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Maximum glucagon concentration - Cmax (optional)
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Time to maximum glucagon concentration - Tmax (optional)
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Area under the concentration-time curve - AUCglucagon,0-60min (optional)
timeFrame: From time 0 to 60 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Area under the concentration-time curve - AUCglucagon, 0-240min (optional)
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Free fatty acids concentration-time curves
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Maximum free fatty acids concentration - Cmax
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Time to maximum free fatty acids concentration - Tmax
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Area under the concentration-time curve - AUCfree fatty acids, 0-60min
timeFrame: From time 0 to 60 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Area under the concentration-time curve - AUCfree fatty acids, 0-240min
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Triglycerides concentration-time curves
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Maximum triglycerides concentration - Cmax
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Time to maximum triglycerides concentration - Tmax
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Area under the concentration-time curve - AUCtriglycerides, 0-60min
timeFrame: From time 0 to 60 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Pharmacodynamics - Area under the concentration-time curve - AUCtriglycerides,0-240min
timeFrame: From time 0 to 240 minutes at baseline, 24 hours after a single dose and 24 hours after the forth dose
measure: Anti-ZP7570 antibodies - Incidence and titres
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Safety Lab - Haematological values vs. reference ranges and baseline
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Safety Lab - Clinical chemistry values vs. reference ranges and baseline
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Safety Lab - Urinalysis values vs. reference ranges and baseline
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Safety - Vital signs: blood pressure
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Safety - Vital signs: pulse
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Safety - Physical Examination
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Safety - ECG
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
measure: Safety - Injection site reactions
timeFrame: From time 0 to 51 days after first dosing (29 days after fourth dosing)
Other outcomes:
Locations:
city: Neuss
country: Germany
facility: Profil Institut für Stoffwechselforschung GmbH
state: North Rhine-Westphalia
Study officials:
affiliation: Profil Institut für Stoffwechselforschung GmbH
name: Ulrike Hövelmann
role: PRINCIPAL_INVESTIGATOR
References: