Healthy Volunteers, Safety and Tolerability
Conditions
Brief summary
Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of several cardiovascular mediators. During cardiogenic shock, upregulation of the vasoconstrictive molecule angiotensin II is a physiologic and potentially life-saving response aimed at maintaining adequate tissue perfusion. As circulating (c)DPP3 is able to effectively cleave angiotensin II, it may represent a novel factor contributing to hemodynamic instability during cardiogenic shock. Recently, a cDPP3-antagonizing antibody called AK1967 (commonly referred to as Procizumab) has been developed. In animal models of cardiogenic- and septic shock, inhibition of cDPP3 by AK1967 resulted in improved cardiac function and survival. Furthermore, AK1967 has shown an excellent safety record in different preclinical studies. In the current study the safety, tolerability and pharmacokinetics/-dynamics of AK1967 will be investigated in healthy male subjects.
Interventions
DRUGAK1967 (Procizumab)
DPP3 inhibition using the humanized monoclonal antibody AK1967 (Procizumab)
DRUGPlacebo
Application of placebo
Sponsors
4TEEN4 Pharmaceuticals GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
* Written informed consent to participate in this trial prior to any study-mandated procedure. * Male subjects aged 18 to 35 years inclusive. * Subjects have to agree to use a reliable way of contraception with their partners from study entry until one month after study drug administration. * BMI between 18 and 30 kg/m², with a lower limit of body weight of 50 kg and an upper limit of 100 kg. * Healthy as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram, and clinical laboratory parameters.
Exclusion criteria
* Unwillingness to abstain from any medication, including recreational drugs or vitamin supplements during the course of the study and within two days prior to the treatment day. * Unwillingness to abstain from alcohol within one day prior to the treatment day until one day after the treatment day. * Surgery or trauma with significant blood loss or blood donation within one month prior to the treatment day. * History, signs or symptoms of cardiovascular disease, in particular: * History of frequent vasovagal collapse or of orthostatic hypotension * Resting pulse rate ≤45 or ≥100 beats/min * Hypertension (RR systolic \>160 or RR diastolic \>90 mmHg) * Hypotension (RR systolic \<100 or RR diastolic \<50 mmHg) * Conduction abnormalities on the ECG consisting of a 1st degree atrioventricular block or a complex bundle branch block * Any chronic cardiac arrhythmias (except PAC's, PVC's) * Renal impairment: plasma creatinine \>120 μmol/L * Liver function tests (alkaline phosphatase, AST, ALT and/or γ-GT) above 2x the upper limit of normal. * History of asthma * Atopic constitution * CRP above 2x the upper limit of normal, or clinically significant acute illness, including infections, within two weeks prior to the treatment day. * Treatment with investigational drugs or participation in any other clinical trial within 30 days prior to the treatment day. * Known or suspected of not being able to comply with the trial protocol. * Known hypersensitivity or allergic reactions to drug compounds, (i.e. previous adverse drug reactions). * Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability | 28 days | Number of adverse events (AEs) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of AK1967 - t1/2 | 28-days | Pharmacokinetics of AK1967 - t1/2 (Half life) |
| Pharmacokinetics of AK1967 - AUC | 28 days | Pharmacokinetics of AK1967 - Area Under the Curve |
Countries
Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Single intravenous infusion of placebo (vehicle solution matching AK1967) over a 2-hour period | 6 |
| AK1967 3 mg/kg/Body Weight Single intravenous infusion of AK1967 (Procizumab) at a dose of 3 mg/kg over a 2-hour period | 6 |
| AK1967 6 mg/kg/Body Weight Single intravenous infusion of AK1967 (Procizumab) at a dose of 6 mg/kg over a 2-hour period | 6 |
| AK1967 12 mg/kg/Body Weight Single intravenous infusion of AK1967 (Procizumab) at a dose of 12 mg/kg over a 2-hour period | 6 |
| Total | 24 |
Baseline characteristics
| Characteristic | Placebo | AK1967 3 mg/kg/Body Weight | AK1967 6 mg/kg/Body Weight | AK1967 12 mg/kg/Body Weight | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 24 Participants |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 5 / 6 | 6 / 6 | 5 / 6 | 2 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Safety and Tolerability
Number of adverse events (AEs)
Time frame: 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Safety and Tolerability | 7 AEs |
| AK1967 3 mg/kg/Body Weight | Safety and Tolerability | 8 AEs |
| AK1967 6 mg/kg/Body Weight | Safety and Tolerability | 12 AEs |
| AK1967 12 mg/kg/Body Weight | Safety and Tolerability | 3 AEs |
Secondary
Pharmacokinetics of AK1967 - AUC
Pharmacokinetics of AK1967 - Area Under the Curve
Time frame: 28 days
Population: PK measurements were done in all arms, however for the participants from the placebo group, the measurement results was below the Lower Limit of Quantification.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pharmacokinetics of AK1967 - AUC | NA µg*h/ml | — |
| AK1967 3 mg/kg/Body Weight | Pharmacokinetics of AK1967 - AUC | 345 µg*h/ml | Standard Deviation 67.9 |
| AK1967 6 mg/kg/Body Weight | Pharmacokinetics of AK1967 - AUC | 845 µg*h/ml | Standard Deviation 336 |
| AK1967 12 mg/kg/Body Weight | Pharmacokinetics of AK1967 - AUC | 2076 µg*h/ml | Standard Deviation 584 |
Secondary
Pharmacokinetics of AK1967 - t1/2
Pharmacokinetics of AK1967 - t1/2 (Half life)
Time frame: 28-days
Population: PK measurements were done in all arms, however for the participants from the placebo group, the measurement results was below the Lower Limit of Quantification.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pharmacokinetics of AK1967 - t1/2 | NA h | — |
| AK1967 3 mg/kg/Body Weight | Pharmacokinetics of AK1967 - t1/2 | 24.3 h | Standard Deviation 2.81 |
| AK1967 6 mg/kg/Body Weight | Pharmacokinetics of AK1967 - t1/2 | 34.3 h | Standard Deviation 16.6 |
| AK1967 12 mg/kg/Body Weight | Pharmacokinetics of AK1967 - t1/2 | 53.1 h | Standard Deviation 21.5 |