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

Phase 2

Completed

Conditions: Shock, Septic

Interventions: Drug: Nangibotide 3 mg/kg
Drug: Nangibotide 0.3 mg/kg
Drug: Nangibotide 1 mg/kg
Drug: Placebo

Registration Number: NCT03158948

Lead Sponsor: Inotrem

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 50

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
nangibotide 3.0 mg/kg/h	Nangibotide 3 mg/kg	-
nangibotide 0.3 mg/kg/h	Nangibotide 0.3 mg/kg	-
nangibotide 1.0 mg/kg/h	Nangibotide 1 mg/kg	-
Placebo to nangibotide	Placebo	-

Primary Outcome Measures

Name	Time	Method
Number of Patients Experiencing Treatment Emergent Adverse Events From Screening Until Study Completion	Adverse events experienced until D28 (End of study visit)	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.
Systolic Blood Pressure (SBP)	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).	Systolic blood pressure measured by sphygmomanometer at study site. Median SBP at each visit is summarized by treatment group.
Diastolic Blood Pressure (DBP)	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 DBP at each visit is summarized by treatment group.
Median Arterial Pressure (MAP)	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).	MAP at each visit is summarized by treatment group.
Heart Rate	Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5).	Median heart rate at each visit is summarized by treatment group.
Temperature	Vital signs were assessed each day from day zero (D0 [before investigational medicinal product initiation]) to end of infusion at day 5 (D5).	Median temperature at each visit is summarized by treatment group.
Electrocardiogram	Electrocardiogram was performed each day from D0 (before IMP initiation) to D5 (EOI) and on D28 (EOS).	Abnormal and emergent clinically significant electrocardiogram were summarized for each group.
Anti-Drug Antibodies (ADA Dimer)	Anti-Drug Antibodies test were done at D0, D10 and D28 in all patients.	Anti-Drug Antibodies test was performed for all patients.
Anti-Drug Antibodies (ADA Monomer)	Anti-Drug Antibodies test were measured at D0, D10 and D28.	Anti-Drug Antibodies test was performed for all patients.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetic Parameters From the Non-compartmental Analysis: Cmax	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	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).
Pharmacokinetic Parameters From the Non-compartmental Analysis: Tmax	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	Time to reach the maximum observed nangibotide plasma concentration (h) was measured for all groups.
Pharmacokinetic Parameters From the Non-compartmental Analysis: AUC0-last	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	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	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	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	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	Systemic clearance was calculated as the ratio between the infusion rate during the maintenance infusion and Cavg.

Trial Locations

Locations (4): Inserm Clinical Investigational Center, CHU Dupuytren (there may be other sites in this country)
🇫🇷
Limoges Cedex, France
Radboudumc (there may be other sites in this country)
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Nijmegen, Netherlands
Hospital Clínico San Carlos, Medicina Intensiva (there may be other sites in this country)
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Madrid, Spain
Cliniques Universitaires Saint-Luc (there may be other sites in this country)
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Brussels, Belgium