E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040070 |
E.1.2 | Term | Septic shock |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety and tolerability of MOTREM in patients with septic shock |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the effects of MOTREM exposure over up to 5 days in patients with septic shock - To evaluate the PK/PD and dose/PD relationship to TREM-1 pathway related makers - To evaluate the effect of MOTREM on transcriptomics - To evaluate the effect of MOTREM on clinical parameters (e.g. vasopressor doses, vasopressor-free days, ventilator-free days, mortality) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provide written informed consent (proxy/legal representative) according to local regulations 2. Age 18* to 80 years * 16 to 80 years in the Netherlands
Sepsis 3. Documented or suspected infection: lung, abdominal or elderly UTI (≥ 65 years) 4. Organ dysfunction defined as acute change in SOFA score ≥ 2 points
Shock 5. Refractory hypotension requiring vasopressors to maintain MAP ≥65 mmHg despite adequate volume resuscitation of at least 20 ml/kg within 6 hours 6. Hyperlactatemia (blood lactate > 2mmol/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 |
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E.4 | Principal exclusion criteria |
1. Previous episode of septic shock (vasopressor administration) within current hospital stay 2. Underlying concurrent immunodepression 3. Solid organ transplant requiring immunosuppressive therapy 4. Known pregnancy (positive serum pregnancy test) 5. Prolonged QT syndrome (QTc ≥ 440 ms) 6. Shock of any other cause, e.g. hypotension related to gastrointestinal bleeding 7. Ongoing documented or suspected endocarditis, history of prosthetic heart valves 8. End-stage neurological disease 9. End-stage cirrhosis (Child Pugh Class C) 10. Acute Physiology And Chronic Health Evaluation (APACHE) II score ≥ 34 11. End stage chronic renal disease requiring chronic dialysis 12. Home oxygen therapy on a regular basis for > 6 h/day 13. Severe obesity (BMI ≥ 40) 14. Recent CPR (within current hospital stay) 15. Moribund patients 16. Decision to limit full care taken before obtaining informed consent 17. Participation in another interventional study in the 3 months prior to randomisation |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability parameters: 1. Vital signs: systolic (SBP) and diastolic (DBP) blood pressure, heart rate, and body temperature (tympanic) 2. ECG (12-lead ECG) 3. Safety laboratory tests: haematology, coagulation, plasma biochemistry 4. Presence of anti-LR12 antibodies 5. Adverse events : from screening until study completion |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Screening, Baseline, Day 1 to Day 5, End of Study 2. Screening, Baseline, Day 1 to Day 5, End of Study 3. Screening, Baseline, Day 1 to Day 5 4. Baseline (pre-dose), End of Infusion and FU day 28 5. From Screening until study completion |
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E.5.2 | Secondary end point(s) |
Pharmacokinetics Plasma concentrations of LR12 will be measured by a validated LC-MS/MS assay and analysed using non-compartmental methods to obtain estimates of the PK parameters.
Pharmacodynamics (exploratory) The concentration profiles of biomarkers (sTREM-1, immune and vascular related biomarkers) over time and biomarker mRNA levels will be analysed..
Clinical parameters (exploratory) 1. Resolution of organ dysfunction (SOFA score total and individual domains) 2. Vasopressor use 3. Invasive mechanical ventilation 4. Renal support 5. Time until shock reversal defined as cessation of vasopressor support for 24 hours 6. Mortality at day 28 and Day 90 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK: Baseline (pre-dose), Day 1 to Day 5 + End of infusion
PD: Baseline, Day 1 to Day 5, End of Study
Clinical parameters: 1. Screening, Baseline, Day 1 to Day 5, End of Study 2. Baseline, Day 1 to Day 5, End of Study 3. Baseline, Day 1 to Day 5, End of Study 4. Baseline, Day 1 to Day 5, End of Study 5. Cessation of vasopressor support for 24 hours 6. Day 28 and Day 90 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |