Efficacy, Safety and Tolerability of Nangibotide in Patients With Septic Shock

Study Overview
=================
Brief Summary
-----------------
This is a randomized, double-blind, placebo-controlled dose-selection study in which two doses of nangibotide are tested versus placebo.

Detailed Description
-----------------
All patients with a diagnosis of septic shock will be considered for study participation. All potential study patients will receive standard of care for the treatment of septic shock. After screening for eligibility, patients meeting all inclusion and no exclusion criterion will be randomized. Patients will be randomized to one of three treatment arms. Treatment with study drug must be initiated as early as possible, but no later than 24 hours after the onset of septic shock, defined by the start of vasopressor therapy. Patients will be treated for at least 3 days with study drug. After the first 3 days of treatment, patients still requiring vasopressor will be treated until 24 hours after vasopressor withdrawal with a maximum treatment duration of 5 days. Patients will be assessed at the End of Study (EoS) visit at day 28. After the last patient's day 28 visit, the study will be analyzed. Additional follow up (FU) visits will be conducted after 90 days, 6 and 12 months. The objective of the study ist to compare the safety, tolerability and efficacy of two doses of nangibotide versus placebo, when given in addition to standard of care.

Official Title
-----------------
Efficacy, Safety and Tolerability of Nangibotide in Patients With Septic Shock. A Randomized, Double-blind, Placebo Controlled Dose Selection Study

Conditions
-----------------
Shock, Septic

Intervention / Treatment
-----------------
* Drug: nangibotide low dose
* Drug: nangibotide high dose
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provide written informed consent Age 18 to 85 years (inclusive) Documented or suspected infection: lung, abdominal or urinary tract infection (UTI) in the elderly (≥65 years) Organ dysfunction defined as acute change in total SOFA score ≥ 2 points Refractory hypotension requiring vasopressors to maintain MAP ≥65mm Hg despite adequate volume resuscitation Hyperlactatemia (blood lactate >2 mmol/L or 18 mg/dL). Exclusion Criteria: Previous episode of septic shock requiring vasopressor administration within current hospital stay Underlying concurrent immunodepression with anti-CD52 alemtuzumab (Campath) or glucocorticoids >75 mg prednisone daily or equivalent for more than 7 days Immunosuppressive therapy related to recent (<6 months) transplantation Cancer chemotherapy (<3 months) implying an immunodepression Known HIV infection with low CD4 cell count (<200) for at least 6 months Known pregnancy (positive urine or serum pregnancy test) Shock of any other cause, e.g. hypotension related to gastrointestinal bleeding Ongoing documented or suspected endocarditis, history of prosthetic heart valves Prolonged QT syndrome End-stage neurological disease End-stage cirrhosis (Child Pugh Class C) Acute Physiology and Chronic Health Evaluation (APACHE II) score <15 or ≥ 34 Home oxygen therapy on a regular basis for > 6 h/day Recent cardiopulmonary resuscitation (CPR) (within current hospital stay) Body mass index (BMI) ≥ 40 kg/m2or weight ≥ 130 kg Moribund patients Decision to limit full care taken before obtaining informed consent Participation in another interventional study in the 3 months prior to randomization

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nangibotide 1<br>Treatment with study drug at at dose of 0.3mg/kg/hr | Drug: nangibotide low dose<br>* nangibotide 0.3 mg/kg/h<br>* Other names: LR12;|
| Experimental: nangibotide 2<br>Treatment with study drug at at dose of 1.0mg/kg/hr | Drug: nangibotide high dose<br>* nangibotide 1.0 mg/kg/h<br>* Other names: LR12;|
| Placebo Comparator: Placebo<br>Treatment with a matched placebo infusion | Drug: placebo<br>* matching placebo<br>* Other names: matched placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sequential organ failure assessment (SOFA) score | Change of total SOFA score from baseline to day 5 (in the subgroup defined by patients with elevated sTREM-1 baseline levels and in the overall population) | day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality | all-cause mortality on D5 and D28 | day 5 and day 28 | 
| Duration of ICU stay | hospitalization | day 28 | 
| Organe support free survival | time to organe support free | day 28 | 
| Sepsis support index (SSI) | Sepsis support index | day 28 | 
| Daily change of total Sequential organ failure assessment (SOFA) score and individual subscores | Daily change of total SOFA score and individual subscores | day 1, day 2, day 3, day 4, day 5, day 6 and day 7 | 
| Duration of Vasopressor use | Change in the Duration of Vasopressor use | day 28 | 
| Duration of Invasive mechanical ventilation (IMV) | Change in the Duration of Invasive mechanical ventilation (IMV) | day 28 | 
| Duration of Renal support | Change in the Duration of renal replacement therapy, RRT | day 28 | 
| All-cause mortality | all-cause mortality up to 12 months | 12 months | 
| Septic shock related mortality at day 28 | mortality caused by septic shock | day 28 | 
| Incidence of secondary infections and post shock antibiotic use | Incidence of secondary infections and post shock antibiotic use | day 28 | 
| Alive and organ support free at day 28 | Proportion of patients alive and free of organ support at day 28 | day 28 | 
| Overall survival on day 28 | time from the date of study drug start to date of death from any cause | day 28 | 
| Overall survival up to 12 months | Overall survival up to 12 months | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Septic Shock