E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 23.1 |
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 |
|
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 efficacy of two doses of nangibotide on organ dysfunction (Sequential Organ Failure Assessment (SOFA) score) in patients with septic shock in relation to their soluble TREM-1 (sTREM-1) plasma levels (patients with high sTREM-1 levels at baseline or all patients) |
|
E.2.2 | Secondary objectives of the trial |
Secondary objectives of the study are to investigate the safety and efficacy of two doses of nangibotide in patients with septic shock in relation to their sTREM-1 levels. This includes: •To evaluate the effect of nangibotide on mortality for up to 12 months •To evaluate the effect of nangibotide on other clinical parameters (e.g. duration of shock, vasopressor use, ventilator and renal replacement use, secondary infections) •To evaluate the safety and tolerability of nangibotide •To evaluate the effect of nangibotide on quality of life, resource utilisation and post shock morbidity •To evaluate the predictive value of the SOFA score reduction as surrogate marker for 28-day
|
To evaluate the predictive value of the SOFA score reduction as surrogate marker for 28-day |
|
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 85 years (inclusive) Sepsis 3.Documented or suspected infection: lung, abdominal or urinary tract infection (UTI) in the elderly UTI (≥65 years) 4.Organ dysfunction defined as acute change in total SOFA score ≥ 2 points Shock 5. Refractory hypotension requiring vasopressors to maintain MAP ≥65mm Hg despite adequate volume resuscitation (as per recommendations of the Surviving Sepsis Campaign) 6. 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
|
|
E.4 | Principal exclusion criteria |
1. Previous episode of septic shock requiring vasopressor administration within current hospital stay 2. Underlying concurrent immunodepression with anti-CD52 alemtuzumab (Campath) or glucocorticoids >75 mg prednisone daily or equivalent for more than 7 days 3. Immunosuppressive therapy related to recent (<6 months) transplantation 4. Cancer chemotherapy (<3 months) implying an immunodepression 5. Known HIV infection with chronic low CD4 cell count (<200) for at least 6 months 6. Known pregnancy (positive urine or serum pregnancy test) 7. Shock of any other cause, e.g. hypotension related to gastrointestinal bleeding 8. Ongoing documented or suspected endocarditis , history of prosthetic heart valves 9. Prolonged QT syndrome 10. End-stage neurological disease 11. End-stage cirrhosis (Child Pugh Class C) 12. Acute Physiology and Chronic Health Evaluation (APACHE II) score <15 or ≥ 34 13. Home oxygen therapy on a regular basis for > 6 h/day 14. Recent cardiopulmonary resuscitation (CPR) (within current hospital stay) 15. Body mass index (BMI) ≥ 40 kg/m2 or weight ≥ 130 kg 16. Moribund patients 17. Decision to limit full care taken before obtaining informed consent 18. Participation in another interventional study in the 3 months prior to randomization
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Change of total SOFA score (improvement of organ dysfunction) from baseline to day 5 (in the subgroup defined by patients with elevated sTREM-1 baseline levels and in the overall population), which will be primarily analyzed on the modified ITT Set. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Key secondary endpoint : • Survival and all-cause mortality on D28; Efficacy Parameters • Duration of ICU stay, hospitalization • Organ support free survival • Sepsis support index (SSI) • Daily change of total SOFA score and individual subscores • Vasopressor use • Invasive mechanical ventilation • Renal support • All-cause mortality up to 12 months • Septic shock related mortality up to 12 months • Incidence of secondary infections and post shock antibiotic use Safety Parameters • Vital signs: systolic (SBP) and diastolic (DBP) blood pressure, heart rate, and body temperature • Electrocardiogram (12-lead ECG) • Safety laboratory tests: hematology, coagulation, plasma biochemistry • Presence of anti-nangibotide antibodies • Adverse events (AEs), serious adverse events (SAEs)and deaths Pharmacokinetics • Nangibotide plasma levels Pharmacodynamics (exploratory) • sTREM-1, immune and vascular related biomarkers Pharmacoeconomic Endpoints up to 12 months) • Health related quality of life (EQ 5D) •Post shock morbidity • Health care resource utilization |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | Yes |
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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
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 | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Denmark |
Finland |
France |
Ireland |
Spain |
United States |
|
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
|
The end of study is defined as the last patient, last visit (LPLV) at day 28. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |