Shock, Septic
Conditions
Keywords
Sepsis, LR12, TREM1, TREM-1
Brief summary
This is a randomised, double-blind, two-stage, placebo controlled study. It is designed to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of 3 doses of nangibotide versus placebo in adult patients with septic shock.
Detailed description
This was a randomised, double-blind, two-stage, placebo-controlled study. It was composed of 2 stages with a similar treatment regimen in which 0.3, 1.0 or 3.0 mg/kg/h of nangibotide was tested versus placebo. Stage 1 was performed to investigate ascending doses of nangibotide or placebo in a sequential design in cohorts of 4 patients (3:1 randomisation). After completion of a cohort (for up to 5 days of infusion), safety and available PK data were blindly reviewed by an independent data safety monitoring board (DSMB) before progressing to the next cohort. After completion of stage 1 DSMB evaluation, the study progressed to stage 2. Stage 2 investigated 3 doses of nangibotide in a randomised, balanced, parallel-group design involving up to 3 doses of nangibotide and a placebo arm. Only dose arms of nangibotide considered to be safe and well tolerated during Stage 1 were to be administered in Stage 2.
Interventions
DRUGNangibotide 0.3 mg/kg
Formulated LR12 peptide
DRUGPlacebo
placebo
DRUGNangibotide 1 mg/kg
Formulated LR12 peptide
DRUGNangibotide 3 mg/kg
Formulated LR12 peptide
Sponsors
Inotrem
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomised, Double-blind, Two-Stage, Placebo Controlled
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Provide written informed consent (proxy/legal representative) according to local regulations * Age 18 to 80 years * Documented or suspected infection: lung, abdominal or elderly UTI (≥65 years) * Organ dysfunction defined as acute change in SOFA score ≥ 2 points * Refractory hypotension requiring vasopressors to maintain MAP ≥65mm Hg despite adequate volume resuscitation of at least 20 ml/kg within 6 hours * Hyperlactatemia (blood lactate \>2 mmol/L or 18 mg/dL). This criterion must be met at least once for the purpose of diagnosis within the 24 hours before study drug administration
Exclusion criteria
- * Previous episode of septic shock (vasopressor administration) within current hospital stay * Underlying concurrent immunodepression (specified in appendix 2) * Solid organ transplant requiring immunosuppressive therapy * Known pregnancy (positive serum pregnancy test) * Prolonged QT syndrome (QTc ≥ 440 ms) * Shock of any other cause, e.g. hypotension related to gastrointestinal bleeding * Ongoing documented or suspected endocarditis, history of prosthetic heart valves * End-stage neurological disease * End-stage cirrhosis (Child Pugh Class C) * Acute Physiology And Chronic Health Evaluation (APACHE) II score ≥ 34 * End stage chronic renal disease requiring chronic dialysis * Home oxygen therapy on a regular basis for \> 6 h/day * Severe obesity (BMI ≥ 40) * Recent CPR (within current hospital stay) * Moribund patients * Decision to limit full care taken before obtaining informed consent * Participation in another interventional study in the 3 months prior to randomisation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Anti-Drug Antibodies (ADA Monomer) | Anti-Drug Antibodies test were measured at D0, D10 and D28. | Anti-Drug Antibodies test was performed for all patients. |
| Median Arterial Pressure (MAP) | Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5) and on final study day at day 28 (D28). | MAP at each visit is summarized by treatment group. |
| Heart Rate | Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5). | Median heart rate at each visit is summarized by treatment group. |
| Temperature | Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5). | Median temperature at each visit is summarized by treatment group. |
| Electrocardiogram | Electrocardiogram was performed each day from D0 (before IMP initiation) to D5 (EOI) and on D28 (EOS). | Abnormal and emergent clinically significant electrocardiogram were summarized for each group. |
| Anti-Drug Antibodies (ADA Dimer) | Anti-Drug Antibodies test were done at D0, D10 and D28 in all patients. | Anti-Drug Antibodies test was performed for all patients. |
| Number of Patients Experiencing Treatment Emergent Adverse Events From Screening Until Study Completion | Adverse events experienced until D28 (End of study visit) | Analyses were performed in the Safety Set composed of all randomized patients who received at least any dose of the study drug (nangibotide or placebo). Adverse events: Summary statistics of treatment emergent adverse events (TEAEs). Clinical events, including death, related to severe sepsis and sepsis complications were exempt from SAE reporting, unless the investigator deemed the event to be related to the administration of the study drug. |
| Systolic Blood Pressure (SBP) | Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5) and on final study day at day 28 (D28). | Systolic blood pressure measured by sphygmomanometer at study site. Median SBP at each visit is summarized by treatment group. |
| Diastolic Blood Pressure (DBP) | Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5) and on final study day at day 28 (D28). | Median DBP at each visit is summarized by treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Parameters From the Non-compartmental Analysis: Tmax | Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI | Time to reach the maximum observed nangibotide plasma concentration (h) was measured for all groups. |
| Pharmacokinetic Parameters From the Non-compartmental Analysis: AUC0-last | Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI | Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration Clast was calculated using the log-linear trapezoidal method. |
| Pharmacokinetic Parameters From the Non-compartmental Analysis: Cavg | Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI | Steady-state concentration during the maintenance infusion was calculated as the median of the observed pre-dose concentration from day2 onwards up to the last pre-dose concentration available in the study. |
| Pharmacokinetic Parameters From the Non-compartmental Analysis: CL | Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI | Systemic clearance was calculated as the ratio between the infusion rate during the maintenance infusion and Cavg. |
| Pharmacokinetic Parameters From the Non-compartmental Analysis: Cmax | Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI | As no pharmacokinetic sample was planned just after the loading dose, maximum observed nangibotide plasma concentration (Cmax) was in the same magnitude as steady-state concentration during the maintenance infusion, calculated as the median of the observed pre-dose concentration from day2 onwards up to the last pre-dose concentration available in the study (Cavg). |
Countries
Belgium, France, Netherlands, Spain
Participant flow
Recruitment details
Patients were enrolled from 03 July 2017 (first patient first visit) to 11 June 2018 (last patient last visit) in 11 centers in 4 countries (Belgium, France, Spain, The Netherlands). 50 patients were included and randomized. 49 (98.0%) patients received the IMP and one patient died before IMP administration.
Pre-assignment details
The duration of this study for each patient was a maximum of 13 weeks (including screening, up to 5 days of treatment and follow-up assessments 28 and 90 days after randomization). The purpose of the screening phase was to confirm patient eligibility for enrolment in the study based on the inclusion and exclusion criteria and to obtain written ICF.
Participants by arm
| Arm | Count |
|---|---|
| Nangibotide 0.3 mg/kg/h Nangibotide: 0.3 mg/kg Formulated LR12 peptide | 13 |
| Nangibotide 1.0 mg/kg/h Nangibotide: 1 mg/kg Formulated LR12 peptide | 12 |
| Nangibotide 3.0 mg/kg/h Nangibotide: 3 mg/kg Formulated LR12 peptide | 12 |
| Placebo Placebo: placebo | 12 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 3 | 2 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Nangibotide 0.3 mg/kg/h | Nangibotide 1.0 mg/kg/h | Nangibotide 3.0 mg/kg/h | Placebo | Total |
|---|---|---|---|---|---|
| Age, Customized Age≤65 | 8 Participants | 3 Participants | 7 Participants | 5 Participants | 23 Participants |
| Age, Customized Age>65 | 5 Participants | 9 Participants | 5 Participants | 7 Participants | 26 Participants |
| BMI | 24.8 kg/m^2 | 26.0 kg/m^2 | 25.1 kg/m^2 | 27.5 kg/m^2 | 26.1 kg/m^2 |
| Height | 168.0 cm | 168.5 cm | 165.0 cm | 167.5 cm | 167.0 cm |
| Race/Ethnicity, Customized Black | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Caucasian | 13 Participants | 9 Participants | 11 Participants | 8 Participants | 41 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 4 Participants | 4 Participants | 19 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 8 Participants | 8 Participants | 30 Participants |
| Weight | 75.0 kg | 76.5 kg | 68.0 kg | 77.0 kg | 74.0 kg |
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 | 3 / 12 | 4 / 13 | 2 / 12 | 4 / 12 |
| other Total, other adverse events | 10 / 12 | 12 / 13 | 12 / 12 | 11 / 12 |
| serious Total, serious adverse events | 7 / 12 | 4 / 13 | 2 / 12 | 4 / 12 |
Outcome results
Primary
Anti-Drug Antibodies (ADA Dimer)
Anti-Drug Antibodies test was performed for all patients.
Time frame: Anti-Drug Antibodies test were done at D0, D10 and D28 in all patients.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D28 | MISSING | 3 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D10 | POSITIVE | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D28 | POSITIVE | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D10 | MISSING | 11 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D0 | POSITIVE | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D0 | NEGATIVE | 12 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D28 | NEGATIVE | 9 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D10 | NEGATIVE | 1 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D0 | MISSING | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D10 | NEGATIVE | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D28 | MISSING | 4 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D10 | POSITIVE | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D0 | NEGATIVE | 13 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D0 | MISSING | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D0 | POSITIVE | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D28 | POSITIVE | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D28 | NEGATIVE | 9 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D10 | MISSING | 13 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D10 | NEGATIVE | 3 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D0 | MISSING | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D0 | NEGATIVE | 12 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D0 | POSITIVE | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D10 | MISSING | 9 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D10 | POSITIVE | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D28 | MISSING | 2 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D28 | NEGATIVE | 10 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Dimer) | D28 | POSITIVE | 0 Participants |
| Placebo | Anti-Drug Antibodies (ADA Dimer) | D28 | MISSING | 3 Participants |
| Placebo | Anti-Drug Antibodies (ADA Dimer) | D10 | MISSING | 7 Participants |
| Placebo | Anti-Drug Antibodies (ADA Dimer) | D0 | POSITIVE | 0 Participants |
| Placebo | Anti-Drug Antibodies (ADA Dimer) | D28 | POSITIVE | 0 Participants |
| Placebo | Anti-Drug Antibodies (ADA Dimer) | D28 | NEGATIVE | 9 Participants |
| Placebo | Anti-Drug Antibodies (ADA Dimer) | D0 | NEGATIVE | 12 Participants |
| Placebo | Anti-Drug Antibodies (ADA Dimer) | D10 | POSITIVE | 0 Participants |
| Placebo | Anti-Drug Antibodies (ADA Dimer) | D10 | NEGATIVE | 5 Participants |
| Placebo | Anti-Drug Antibodies (ADA Dimer) | D0 | MISSING | 0 Participants |
Primary
Anti-Drug Antibodies (ADA Monomer)
Anti-Drug Antibodies test was performed for all patients.
Time frame: Anti-Drug Antibodies test were measured at D0, D10 and D28.
Population: The results are presented for the Day 28.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D10 | NEGATIVE | 1 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D0 | NEGATIVE | 12 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D10 | POSITIVE | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D28 | MISSING | 3 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D28 | POSITIVE | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D0 | POSITIVE | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D0 | MISSING | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D10 | MISSING | 11 Participants |
| Nangibotide 0.3 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D28 | NEGATIVE | 9 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D10 | MISSING | 13 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D0 | POSITIVE | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D28 | MISSING | 5 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D28 | POSITIVE | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D10 | POSITIVE | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D28 | NEGATIVE | 8 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D0 | NEGATIVE | 13 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D0 | MISSING | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D10 | NEGATIVE | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D10 | POSITIVE | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D0 | MISSING | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D0 | NEGATIVE | 12 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D0 | POSITIVE | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D10 | MISSING | 9 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D10 | NEGATIVE | 3 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D28 | MISSING | 2 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D28 | NEGATIVE | 10 Participants |
| Nangibotide 3.0 mg/kg/h | Anti-Drug Antibodies (ADA Monomer) | D28 | POSITIVE | 0 Participants |
| Placebo | Anti-Drug Antibodies (ADA Monomer) | D28 | MISSING | 3 Participants |
| Placebo | Anti-Drug Antibodies (ADA Monomer) | D10 | MISSING | 7 Participants |
| Placebo | Anti-Drug Antibodies (ADA Monomer) | D0 | POSITIVE | 0 Participants |
| Placebo | Anti-Drug Antibodies (ADA Monomer) | D28 | POSITIVE | 0 Participants |
| Placebo | Anti-Drug Antibodies (ADA Monomer) | D28 | NEGATIVE | 9 Participants |
| Placebo | Anti-Drug Antibodies (ADA Monomer) | D0 | NEGATIVE | 12 Participants |
| Placebo | Anti-Drug Antibodies (ADA Monomer) | D10 | POSITIVE | 0 Participants |
| Placebo | Anti-Drug Antibodies (ADA Monomer) | D10 | NEGATIVE | 5 Participants |
| Placebo | Anti-Drug Antibodies (ADA Monomer) | D0 | MISSING | 0 Participants |
Primary
Diastolic Blood Pressure (DBP)
Median DBP at each visit is summarized by treatment group.
Time frame: Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5) and on final study day at day 28 (D28).
Population: The data is not available for all subjects and the data in the tables below refers to only those participants who were measured and analyzed. Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Mean Arterial Pressure (mmHg), heart rate (bpm) and temperature in Celsius degrees were described at each time when it was available: D1, D2, D3, D4, D5 and EOS visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nangibotide 0.3 mg/kg/h | Diastolic Blood Pressure (DBP) | D0 | 53.5 mmHg |
| Nangibotide 0.3 mg/kg/h | Diastolic Blood Pressure (DBP) | D5/EOI | 55.5 mmHg |
| Nangibotide 0.3 mg/kg/h | Diastolic Blood Pressure (DBP) | D4 | 61.5 mmHg |
| Nangibotide 0.3 mg/kg/h | Diastolic Blood Pressure (DBP) | D1 | 59.0 mmHg |
| Nangibotide 0.3 mg/kg/h | Diastolic Blood Pressure (DBP) | D28/EOS | 70.0 mmHg |
| Nangibotide 0.3 mg/kg/h | Diastolic Blood Pressure (DBP) | D2 | 61.0 mmHg |
| Nangibotide 0.3 mg/kg/h | Diastolic Blood Pressure (DBP) | D3 | 58.5 mmHg |
| Nangibotide 1.0 mg/kg/h | Diastolic Blood Pressure (DBP) | D5/EOI | 58.0 mmHg |
| Nangibotide 1.0 mg/kg/h | Diastolic Blood Pressure (DBP) | D3 | 60.5 mmHg |
| Nangibotide 1.0 mg/kg/h | Diastolic Blood Pressure (DBP) | D2 | 63.5 mmHg |
| Nangibotide 1.0 mg/kg/h | Diastolic Blood Pressure (DBP) | D4 | 64.0 mmHg |
| Nangibotide 1.0 mg/kg/h | Diastolic Blood Pressure (DBP) | D28/EOS | 70.0 mmHg |
| Nangibotide 1.0 mg/kg/h | Diastolic Blood Pressure (DBP) | D1 | 55.0 mmHg |
| Nangibotide 1.0 mg/kg/h | Diastolic Blood Pressure (DBP) | D0 | 55.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Diastolic Blood Pressure (DBP) | D3 | 55.5 mmHg |
| Nangibotide 3.0 mg/kg/h | Diastolic Blood Pressure (DBP) | D0 | 59.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Diastolic Blood Pressure (DBP) | D1 | 59.5 mmHg |
| Nangibotide 3.0 mg/kg/h | Diastolic Blood Pressure (DBP) | D2 | 66.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Diastolic Blood Pressure (DBP) | D4 | 55.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Diastolic Blood Pressure (DBP) | D5/EOI | 57.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Diastolic Blood Pressure (DBP) | D28/EOS | 60.0 mmHg |
| Placebo | Diastolic Blood Pressure (DBP) | D2 | 67.0 mmHg |
| Placebo | Diastolic Blood Pressure (DBP) | D28/EOS | 65.0 mmHg |
| Placebo | Diastolic Blood Pressure (DBP) | D5/EOI | 57.0 mmHg |
| Placebo | Diastolic Blood Pressure (DBP) | D1 | 58.0 mmHg |
| Placebo | Diastolic Blood Pressure (DBP) | D0 | 55.5 mmHg |
| Placebo | Diastolic Blood Pressure (DBP) | D4 | 58.0 mmHg |
| Placebo | Diastolic Blood Pressure (DBP) | D3 | 62.0 mmHg |
Primary
Electrocardiogram
Abnormal and emergent clinically significant electrocardiogram were summarized for each group.
Time frame: Electrocardiogram was performed each day from D0 (before IMP initiation) to D5 (EOI) and on D28 (EOS).
Population: Some patients did not perform ECG at some visits
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D3 | ECGs - Missing | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D3 | ECGs - Abnormal CS | 1 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D3 | ECGs - Abnormal NCS | 1 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D2 | ECGs - Abnormal CS | 1 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D28/EOS | ECGs - Abnormal NCS | 5 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D3 | ECGs - Normal | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D2 | ECGs - Missing | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D1 | ECGs - Abnormal NCS | 3 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D28/EOS | ECGs - Normal | 3 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D5/EOI | ECGs - Missing | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D5/EOI | ECGs - Abnormal CS | 2 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D1 | ECGs - Abnormal CS | 5 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D1 | ECGs - Normal | 4 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D5/EOI | ECGs - Abnormal NCS | 4 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D5/EOI | ECGs - Normal | 3 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D1 | ECGs - Missing | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D28/EOS | ECGs - Missing | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D4 | ECGs - Missing | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D4 | ECGs - Abnormal CS | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D2 | ECGs - Normal | 1 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D28/EOS | ECGs - Abnormal CS | 1 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D4 | ECGs - Abnormal NCS | 1 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D4 | ECGs - Normal | 0 Participants |
| Nangibotide 0.3 mg/kg/h | Electrocardiogram | ECG - D2 | ECGs - Abnormal NCS | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D2 | ECGs - Abnormal NCS | 1 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D1 | ECGs - Normal | 1 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D1 | ECGs - Abnormal NCS | 4 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D1 | ECGs - Abnormal CS | 4 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D1 | ECGs - Missing | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D2 | ECGs - Normal | 2 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D2 | ECGs - Abnormal CS | 1 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D2 | ECGs - Missing | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D3 | ECGs - Normal | 1 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D3 | ECGs - Abnormal NCS | 1 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D3 | ECGs - Abnormal CS | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D3 | ECGs - Missing | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D4 | ECGs - Normal | 1 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D4 | ECGs - Abnormal NCS | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D4 | ECGs - Abnormal CS | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D4 | ECGs - Missing | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D5/EOI | ECGs - Normal | 3 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D5/EOI | ECGs - Abnormal NCS | 7 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D5/EOI | ECGs - Abnormal CS | 1 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D5/EOI | ECGs - Missing | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D28/EOS | ECGs - Normal | 5 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D28/EOS | ECGs - Abnormal NCS | 3 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D28/EOS | ECGs - Abnormal CS | 0 Participants |
| Nangibotide 1.0 mg/kg/h | Electrocardiogram | ECG - D28/EOS | ECGs - Missing | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D28/EOS | ECGs - Missing | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D5/EOI | ECGs - Abnormal NCS | 3 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D4 | ECGs - Abnormal CS | 2 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D4 | ECGs - Normal | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D28/EOS | ECGs - Abnormal CS | 1 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D5/EOI | ECGs - Abnormal CS | 1 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D1 | ECGs - Missing | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D4 | ECGs - Abnormal NCS | 1 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D1 | ECGs - Abnormal NCS | 4 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D2 | ECGs - Missing | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D4 | ECGs - Missing | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D2 | ECGs - Abnormal CS | 2 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D3 | ECGs - Missing | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D3 | ECGs - Normal | 0 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D2 | ECGs - Normal | 1 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D1 | ECGs - Normal | 4 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D5/EOI | ECGs - Normal | 4 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D3 | ECGs - Abnormal NCS | 2 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D28/EOS | ECGs - Abnormal NCS | 6 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D2 | ECGs - Abnormal NCS | 2 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D28/EOS | ECGs - Normal | 4 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D3 | ECGs - Abnormal CS | 1 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D1 | ECGs - Abnormal CS | 1 Participants |
| Nangibotide 3.0 mg/kg/h | Electrocardiogram | ECG - D5/EOI | ECGs - Missing | 0 Participants |
| Placebo | Electrocardiogram | ECG - D5/EOI | ECGs - Abnormal CS | 4 Participants |
| Placebo | Electrocardiogram | ECG - D3 | ECGs - Missing | 0 Participants |
| Placebo | Electrocardiogram | ECG - D2 | ECGs - Normal | 4 Participants |
| Placebo | Electrocardiogram | ECG - D1 | ECGs - Normal | 5 Participants |
| Placebo | Electrocardiogram | ECG - D4 | ECGs - Normal | 2 Participants |
| Placebo | Electrocardiogram | ECG - D28/EOS | ECGs - Missing | 0 Participants |
| Placebo | Electrocardiogram | ECG - D4 | ECGs - Abnormal NCS | 1 Participants |
| Placebo | Electrocardiogram | ECG - D1 | ECGs - Missing | 0 Participants |
| Placebo | Electrocardiogram | ECG - D4 | ECGs - Abnormal CS | 1 Participants |
| Placebo | Electrocardiogram | ECG - D28/EOS | ECGs - Abnormal NCS | 4 Participants |
| Placebo | Electrocardiogram | ECG - D4 | ECGs - Missing | 0 Participants |
| Placebo | Electrocardiogram | ECG - D1 | ECGs - Abnormal CS | 2 Participants |
| Placebo | Electrocardiogram | ECG - D5/EOI | ECGs - Normal | 4 Participants |
| Placebo | Electrocardiogram | ECG - D5/EOI | ECGs - Abnormal NCS | 4 Participants |
| Placebo | Electrocardiogram | ECG - D1 | ECGs - Abnormal NCS | 5 Participants |
| Placebo | Electrocardiogram | ECG - D28/EOS | ECGs - Normal | 4 Participants |
| Placebo | Electrocardiogram | ECG - D2 | ECGs - Abnormal CS | 2 Participants |
| Placebo | Electrocardiogram | ECG - D2 | ECGs - Missing | 0 Participants |
| Placebo | Electrocardiogram | ECG - D28/EOS | ECGs - Abnormal CS | 1 Participants |
| Placebo | Electrocardiogram | ECG - D3 | ECGs - Normal | 2 Participants |
| Placebo | Electrocardiogram | ECG - D2 | ECGs - Abnormal NCS | 0 Participants |
| Placebo | Electrocardiogram | ECG - D5/EOI | ECGs - Missing | 0 Participants |
| Placebo | Electrocardiogram | ECG - D3 | ECGs - Abnormal NCS | 1 Participants |
| Placebo | Electrocardiogram | ECG - D3 | ECGs - Abnormal CS | 1 Participants |
Primary
Heart Rate
Median heart rate at each visit is summarized by treatment group.
Time frame: Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5).
Population: The data is not available for all subjects and the data in the tables below refers to only those participants who were measured and analyzed. systolic blood pressure (mmHg). Diastolic blood pressure (mmHg), mean arterial pressure (mmHg), heart rate (bpm) and temperature i celcius degrees were described at each time when it was available: D0, D1, D2, D3, D4 and D5/EOI visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nangibotide 0.3 mg/kg/h | Heart Rate | D0 | 83.5 bpm |
| Nangibotide 0.3 mg/kg/h | Heart Rate | D4 | 75.0 bpm |
| Nangibotide 0.3 mg/kg/h | Heart Rate | D2 | 74.0 bpm |
| Nangibotide 0.3 mg/kg/h | Heart Rate | D5/EOI | 86.0 bpm |
| Nangibotide 0.3 mg/kg/h | Heart Rate | D1 | 89.0 bpm |
| Nangibotide 0.3 mg/kg/h | Heart Rate | D3 | 95.0 bpm |
| Nangibotide 1.0 mg/kg/h | Heart Rate | D1 | 86.0 bpm |
| Nangibotide 1.0 mg/kg/h | Heart Rate | D4 | 61.0 bpm |
| Nangibotide 1.0 mg/kg/h | Heart Rate | D5/EOI | 91.0 bpm |
| Nangibotide 1.0 mg/kg/h | Heart Rate | D0 | 94.0 bpm |
| Nangibotide 1.0 mg/kg/h | Heart Rate | D2 | 85.0 bpm |
| Nangibotide 1.0 mg/kg/h | Heart Rate | D3 | 60.5 bpm |
| Nangibotide 3.0 mg/kg/h | Heart Rate | D1 | 91.0 bpm |
| Nangibotide 3.0 mg/kg/h | Heart Rate | D2 | 110.0 bpm |
| Nangibotide 3.0 mg/kg/h | Heart Rate | D0 | 104.5 bpm |
| Nangibotide 3.0 mg/kg/h | Heart Rate | D3 | 102.5 bpm |
| Nangibotide 3.0 mg/kg/h | Heart Rate | D4 | 121.0 bpm |
| Nangibotide 3.0 mg/kg/h | Heart Rate | D5/EOI | 93.5 bpm |
| Placebo | Heart Rate | D5/EOI | 91.0 bpm |
| Placebo | Heart Rate | D4 | 84.5 bpm |
| Placebo | Heart Rate | D0 | 97.5 bpm |
| Placebo | Heart Rate | D2 | 83.0 bpm |
| Placebo | Heart Rate | D3 | 88.5 bpm |
| Placebo | Heart Rate | D1 | 98.0 bpm |
Primary
Median Arterial Pressure (MAP)
MAP at each visit is summarized by treatment group.
Time frame: Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5) and on final study day at day 28 (D28).
Population: The data is not available for all subjects and the data in the tables below refers to only those participants who were measured and analyzed. Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Mean Arterial Pressure (mmHg), heart rate (bpm) and temperature in Celsius degrees were described at each time when it was available: D1, D2, D3, D4, D5 and EOS visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nangibotide 0.3 mg/kg/h | Median Arterial Pressure (MAP) | D0 | 72.0 mmHg |
| Nangibotide 0.3 mg/kg/h | Median Arterial Pressure (MAP) | D5/EOI | 75.0 mmHg |
| Nangibotide 0.3 mg/kg/h | Median Arterial Pressure (MAP) | D4 | 76.5 mmHg |
| Nangibotide 0.3 mg/kg/h | Median Arterial Pressure (MAP) | D1 | 77.5 mmHg |
| Nangibotide 0.3 mg/kg/h | Median Arterial Pressure (MAP) | D28/EOS | 87.0 mmHg |
| Nangibotide 0.3 mg/kg/h | Median Arterial Pressure (MAP) | D2 | 76.0 mmHg |
| Nangibotide 0.3 mg/kg/h | Median Arterial Pressure (MAP) | D3 | 71.0 mmHg |
| Nangibotide 1.0 mg/kg/h | Median Arterial Pressure (MAP) | D5/EOI | 78.0 mmHg |
| Nangibotide 1.0 mg/kg/h | Median Arterial Pressure (MAP) | D3 | 84.5 mmHg |
| Nangibotide 1.0 mg/kg/h | Median Arterial Pressure (MAP) | D2 | 82.5 mmHg |
| Nangibotide 1.0 mg/kg/h | Median Arterial Pressure (MAP) | D4 | 92.0 mmHg |
| Nangibotide 1.0 mg/kg/h | Median Arterial Pressure (MAP) | D28/EOS | 86.5 mmHg |
| Nangibotide 1.0 mg/kg/h | Median Arterial Pressure (MAP) | D1 | 76.0 mmHg |
| Nangibotide 1.0 mg/kg/h | Median Arterial Pressure (MAP) | D0 | 71.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Median Arterial Pressure (MAP) | D3 | 72.5 mmHg |
| Nangibotide 3.0 mg/kg/h | Median Arterial Pressure (MAP) | D0 | 78.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Median Arterial Pressure (MAP) | D1 | 74.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Median Arterial Pressure (MAP) | D2 | 80.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Median Arterial Pressure (MAP) | D4 | 71.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Median Arterial Pressure (MAP) | D5/EOI | 76.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Median Arterial Pressure (MAP) | D28/EOS | 74.0 mmHg |
| Placebo | Median Arterial Pressure (MAP) | D2 | 80.0 mmHg |
| Placebo | Median Arterial Pressure (MAP) | D28/EOS | 79.0 mmHg |
| Placebo | Median Arterial Pressure (MAP) | D5/EOI | 72.5 mmHg |
| Placebo | Median Arterial Pressure (MAP) | D1 | 77.0 mmHg |
| Placebo | Median Arterial Pressure (MAP) | D0 | 73.0 mmHg |
| Placebo | Median Arterial Pressure (MAP) | D4 | 77.0 mmHg |
| Placebo | Median Arterial Pressure (MAP) | D3 | 79.0 mmHg |
Primary
Number of Patients Experiencing Treatment Emergent Adverse Events From Screening Until Study Completion
Analyses were performed in the Safety Set composed of all randomized patients who received at least any dose of the study drug (nangibotide or placebo). Adverse events: Summary statistics of treatment emergent adverse events (TEAEs). Clinical events, including death, related to severe sepsis and sepsis complications were exempt from SAE reporting, unless the investigator deemed the event to be related to the administration of the study drug.
Time frame: Adverse events experienced until D28 (End of study visit)
Population: Out of 49 patients included in all 4 groups, TEAEs were observed for 45 patients (12 patients experienced TEAEs in MOTREM 1 group, 12 patients experienced TEAEs in MOTREM 2 group, 11 patients experienced TEAEs in MOTREM 3 group and 10 patients experienced TEAEs in placebo group)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nangibotide 0.3 mg/kg/h | Number of Patients Experiencing Treatment Emergent Adverse Events From Screening Until Study Completion | 12 Participants |
| Nangibotide 1.0 mg/kg/h | Number of Patients Experiencing Treatment Emergent Adverse Events From Screening Until Study Completion | 12 Participants |
| Nangibotide 3.0 mg/kg/h | Number of Patients Experiencing Treatment Emergent Adverse Events From Screening Until Study Completion | 11 Participants |
| Placebo | Number of Patients Experiencing Treatment Emergent Adverse Events From Screening Until Study Completion | 10 Participants |
Primary
Systolic Blood Pressure (SBP)
Systolic blood pressure measured by sphygmomanometer at study site. Median SBP at each visit is summarized by treatment group.
Time frame: Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5) and on final study day at day 28 (D28).
Population: The data is not available for all subjects and the data in the tables below refers to only those participants who were measured and analyzed. Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Mean Arterial Pressure (mmHg), heart rate (bpm) and temperature in Celsius degrees were described at each time when it was available: D1, D2, D3, D4, D5 and EOS visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nangibotide 0.3 mg/kg/h | Systolic Blood Pressure (SBP) | D1 | 114.5 mmHg |
| Nangibotide 0.3 mg/kg/h | Systolic Blood Pressure (SBP) | D2 | 107.0 mmHg |
| Nangibotide 0.3 mg/kg/h | Systolic Blood Pressure (SBP) | D28/EOS | 135.0 mmHg |
| Nangibotide 0.3 mg/kg/h | Systolic Blood Pressure (SBP) | D3 | 94.0 mmHg |
| Nangibotide 0.3 mg/kg/h | Systolic Blood Pressure (SBP) | D5/EOI | 117.0 mmHg |
| Nangibotide 0.3 mg/kg/h | Systolic Blood Pressure (SBP) | D0 | 121.5 mmHg |
| Nangibotide 0.3 mg/kg/h | Systolic Blood Pressure (SBP) | D4 | 108.0 mmHg |
| Nangibotide 1.0 mg/kg/h | Systolic Blood Pressure (SBP) | D5/EOI | 118.0 mmHg |
| Nangibotide 1.0 mg/kg/h | Systolic Blood Pressure (SBP) | D0 | 110.0 mmHg |
| Nangibotide 1.0 mg/kg/h | Systolic Blood Pressure (SBP) | D28/EOS | 120.0 mmHg |
| Nangibotide 1.0 mg/kg/h | Systolic Blood Pressure (SBP) | D2 | 116.0 mmHg |
| Nangibotide 1.0 mg/kg/h | Systolic Blood Pressure (SBP) | D1 | 117.0 mmHg |
| Nangibotide 1.0 mg/kg/h | Systolic Blood Pressure (SBP) | D3 | 126.5 mmHg |
| Nangibotide 1.0 mg/kg/h | Systolic Blood Pressure (SBP) | D4 | 133.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Systolic Blood Pressure (SBP) | D3 | 108.5 mmHg |
| Nangibotide 3.0 mg/kg/h | Systolic Blood Pressure (SBP) | D0 | 121.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Systolic Blood Pressure (SBP) | D1 | 112.5 mmHg |
| Nangibotide 3.0 mg/kg/h | Systolic Blood Pressure (SBP) | D5/EOI | 114.5 mmHg |
| Nangibotide 3.0 mg/kg/h | Systolic Blood Pressure (SBP) | D4 | 105.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Systolic Blood Pressure (SBP) | D2 | 121.0 mmHg |
| Nangibotide 3.0 mg/kg/h | Systolic Blood Pressure (SBP) | D28/EOS | 111.0 mmHg |
| Placebo | Systolic Blood Pressure (SBP) | D28/EOS | 113.0 mmHg |
| Placebo | Systolic Blood Pressure (SBP) | D1 | 113.0 mmHg |
| Placebo | Systolic Blood Pressure (SBP) | D2 | 112.0 mmHg |
| Placebo | Systolic Blood Pressure (SBP) | D3 | 112.5 mmHg |
| Placebo | Systolic Blood Pressure (SBP) | D4 | 107.0 mmHg |
| Placebo | Systolic Blood Pressure (SBP) | D5/EOI | 109.0 mmHg |
| Placebo | Systolic Blood Pressure (SBP) | D0 | 111.0 mmHg |
Primary
Temperature
Median temperature at each visit is summarized by treatment group.
Time frame: Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5).
Population: The data is not available for all subjects and the data in the tables below refers to only those participants who were measured and analyzed. Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Mean Arterial Pressure (mmHg), heart rate (bpm) and temperature in Celsius degrees were described at each time when it was available: D0, D1, D2, D3, D4, D5/EOI visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nangibotide 0.3 mg/kg/h | Temperature | D0 | 37.3 °C |
| Nangibotide 0.3 mg/kg/h | Temperature | D1 | 36.3 °C |
| Nangibotide 0.3 mg/kg/h | Temperature | D2 | 36.1 °C |
| Nangibotide 0.3 mg/kg/h | Temperature | D3 | 36.6 °C |
| Nangibotide 0.3 mg/kg/h | Temperature | D4 | 36.1 °C |
| Nangibotide 0.3 mg/kg/h | Temperature | D5/EOI | 36.9 °C |
| Nangibotide 1.0 mg/kg/h | Temperature | D5/EOI | 36.2 °C |
| Nangibotide 1.0 mg/kg/h | Temperature | D3 | 36.3 °C |
| Nangibotide 1.0 mg/kg/h | Temperature | D0 | 36.8 °C |
| Nangibotide 1.0 mg/kg/h | Temperature | D2 | 36.3 °C |
| Nangibotide 1.0 mg/kg/h | Temperature | D1 | 36.2 °C |
| Nangibotide 1.0 mg/kg/h | Temperature | D4 | 36.1 °C |
| Nangibotide 3.0 mg/kg/h | Temperature | D1 | 36.8 °C |
| Nangibotide 3.0 mg/kg/h | Temperature | D2 | 36.5 °C |
| Nangibotide 3.0 mg/kg/h | Temperature | D3 | 36.7 °C |
| Nangibotide 3.0 mg/kg/h | Temperature | D5/EOI | 36.5 °C |
| Nangibotide 3.0 mg/kg/h | Temperature | D4 | 36.9 °C |
| Nangibotide 3.0 mg/kg/h | Temperature | D0 | 37.0 °C |
| Placebo | Temperature | D4 | 36.6 °C |
| Placebo | Temperature | D5/EOI | 36.4 °C |
| Placebo | Temperature | D1 | 37.1 °C |
| Placebo | Temperature | D3 | 37.4 °C |
| Placebo | Temperature | D0 | 37.0 °C |
| Placebo | Temperature | D2 | 37.4 °C |
Secondary
Pharmacokinetic Parameters From the Non-compartmental Analysis: AUC0-last
Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration Clast was calculated using the log-linear trapezoidal method.
Time frame: Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nangibotide 0.3 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: AUC0-last | 1722 ng*h/mL |
| Nangibotide 1.0 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: AUC0-last | 7579 ng*h/mL |
| Nangibotide 3.0 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: AUC0-last | 47320 ng*h/mL |
Secondary
Pharmacokinetic Parameters From the Non-compartmental Analysis: Cavg
Steady-state concentration during the maintenance infusion was calculated as the median of the observed pre-dose concentration from day2 onwards up to the last pre-dose concentration available in the study.
Time frame: Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nangibotide 0.3 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: Cavg | 67.6 ng/mL |
| Nangibotide 1.0 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: Cavg | 223 ng/mL |
| Nangibotide 3.0 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: Cavg | 729 ng/mL |
Secondary
Pharmacokinetic Parameters From the Non-compartmental Analysis: CL
Systemic clearance was calculated as the ratio between the infusion rate during the maintenance infusion and Cavg.
Time frame: Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nangibotide 0.3 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: CL | 4.52 L/h/kg |
| Nangibotide 1.0 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: CL | 4.50 L/h/kg |
| Nangibotide 3.0 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: CL | 4.12 L/h/kg |
Secondary
Pharmacokinetic Parameters From the Non-compartmental Analysis: Cmax
As no pharmacokinetic sample was planned just after the loading dose, maximum observed nangibotide plasma concentration (Cmax) was in the same magnitude as steady-state concentration during the maintenance infusion, calculated as the median of the observed pre-dose concentration from day2 onwards up to the last pre-dose concentration available in the study (Cavg).
Time frame: Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nangibotide 0.3 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: Cmax | 71.2 ng/mL |
| Nangibotide 1.0 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: Cmax | 234 ng/mL |
| Nangibotide 3.0 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: Cmax | 914 ng/mL |
Secondary
Pharmacokinetic Parameters From the Non-compartmental Analysis: Tmax
Time to reach the maximum observed nangibotide plasma concentration (h) was measured for all groups.
Time frame: Baseline: pre-dose sample at Day 0 (D0) Daily up to Day 5 (D5) (or the last day in the study/EOI) If possible, at D5/EOI: - 15 min before end of infusion (EOI) - 10 min after EOI - 30 min after EOI - 2h after EOI
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nangibotide 0.3 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: Tmax | 22.7 h |
| Nangibotide 1.0 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: Tmax | 25.4 h |
| Nangibotide 3.0 mg/kg/h | Pharmacokinetic Parameters From the Non-compartmental Analysis: Tmax | 36.0 h |