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

Inotrem50 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Shock, Septic

Interventions

Nangibotide 0.3 mg/kgDRUG

Formulated LR12 peptide

PlaceboDRUG

placebo

Nangibotide 1 mg/kgDRUG

Formulated LR12 peptide

Nangibotide 3 mg/kg

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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

Locations (4)

Cliniques Universitaires Saint-Luc (there may be other sites in this country)

Brussels, Belgium

Inserm Clinical Investigational Center, CHU Dupuytren (there may be other sites in this country)

Limoges, France

Radboudumc (there may be other sites in this country)

Nijmegen, Netherlands

Hospital Clínico San Carlos, Medicina Intensiva (there may be other sites in this country)

Madrid, Spain

Outcomes

Primary Outcomes

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)

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).

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).

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).

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).

Temperature

Data from ClinicalTrials.gov

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Secondary Outcomes

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

Pharmacokinetic Parameters From the Non-compartmental Analysis: Tmax

Time to reach the maximum observed nangibotide plasma concentration (h) was measured for all groups.

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.

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.

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.