Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 3 Doses of MOTREM (Nangibotide) in Patients With Septic Shock

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 3 Doses of MOTREM in Patients With Septic Shock. A Randomised, Double-blind, Two-Stage, Placebo Controlled Study

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.

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.

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