Clinical trial NCT03158948: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 3 Doses of MOTREM (Nangibotide) in Patients With Septic Shock
Official title: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 3 Doses of MOTREM in Patients With Septic Shock. A Randomised, Double-blind, Two-Stage, Placebo Controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Shock, Septic
Keywords: Sepsis
LR12
TREM1
TREM-1
Lead sponsor: Inotrem
Sponsor class: INDUSTRY
First posted: 2017-05-18
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised, Double-blind, Two-Stage, Placebo Controlled
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Patients Experiencing Treatment Emergent Adverse Events From Screening Until Study Completion
timeFrame: Adverse events experienced until D28 (End of study visit)
measure: Systolic Blood Pressure (SBP)
timeFrame: 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).
measure: Diastolic Blood Pressure (DBP)
timeFrame: 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).
measure: Median Arterial Pressure (MAP)
timeFrame: 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).
measure: Heart Rate
timeFrame: Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5).
measure: Temperature
timeFrame: Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5).
measure: Electrocardiogram
timeFrame: Electrocardiogram was performed each day from D0 (before IMP initiation) to D5 (EOI) and on D28 (EOS).
measure: Anti-Drug Antibodies (ADA Dimer)
timeFrame: Anti-Drug Antibodies test were done at D0, D10 and D28 in all patients.
measure: Anti-Drug Antibodies (ADA Monomer)
timeFrame: Anti-Drug Antibodies test were measured at D0, D10 and D28.
Secondary outcomes:
measure: Pharmacokinetic Parameters From the Non-compartmental Analysis: Cmax
timeFrame: 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
measure: Pharmacokinetic Parameters From the Non-compartmental Analysis: Tmax
timeFrame: 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
measure: Pharmacokinetic Parameters From the Non-compartmental Analysis: AUC0-last
timeFrame: 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
measure: Pharmacokinetic Parameters From the Non-compartmental Analysis: Cavg
timeFrame: 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
measure: Pharmacokinetic Parameters From the Non-compartmental Analysis: CL
timeFrame: 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
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc (there may be other sites in this country)
city: Limoges Cedex
country: France
facility: Inserm Clinical Investigational Center, CHU Dupuytren (there may be other sites in this country)
city: Nijmegen
country: Netherlands
facility: Radboudumc (there may be other sites in this country)
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos, Medicina Intensiva (there may be other sites in this country)
Study officials:
affiliation: Inserm 1435 Clinical Investigational Center, Limoges, France
name: Bruno François, MD
role: PRINCIPAL_INVESTIGATOR
References: