Clinical trial NCT04055909: Efficacy, Safety and Tolerability of Nangibotide in Patients With Septic Shock
Official title: Efficacy, Safety and Tolerability of Nangibotide in Patients With Septic Shock. A Randomized, Double-blind, Placebo Controlled Dose Selection Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Shock, Septic
Keywords: Septic Shock
Lead sponsor: Inotrem
Sponsor class: INDUSTRY
First posted: 2019-08-14
Enrollment: 355
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Provide written informed consent
2. Age 18 to 85 years (inclusive)
3. Documented or suspected infection: lung, abdominal or urinary tract infection (UTI) in the elderly (≥65 years)
4. Organ dysfunction defined as acute change in total SOFA score ≥ 2 points
5. Refractory hypotension requiring vasopressors to maintain MAP ≥65mm Hg despite adequate volume resuscitation
6. Hyperlactatemia (blood lactate \>2 mmol/L or 18 mg/dL).

Exclusion Criteria:

1. Previous episode of septic shock requiring vasopressor administration within current hospital stay
2. Underlying concurrent immunodepression with anti-CD52 alemtuzumab (Campath) or glucocorticoids \>75 mg prednisone daily or equivalent for more than 7 days
3. Immunosuppressive therapy related to recent (\<6 months) transplantation
4. Cancer chemotherapy (\<3 months) implying an immunodepression
5. Known HIV infection with low CD4 cell count (\<200) for at least 6 months
6. Known pregnancy (positive urine or serum pregnancy test)
7. Shock of any other cause, e.g. hypotension related to gastrointestinal bleeding
8. Ongoing documented or suspected endocarditis, history of prosthetic heart valves
9. Prolonged QT syndrome
10. End-stage neurological disease
11. End-stage cirrhosis (Child Pugh Class C)
12. Acute Physiology and Chronic Health Evaluation (APACHE II) score \<15 or ≥ 34
13. Home oxygen therapy on a regular basis for \> 6 h/day
14. Recent cardiopulmonary resuscitation (CPR) (within current hospital stay)
15. Body mass index (BMI) ≥ 40 kg/m2or weight ≥ 130 kg
16. Moribund patients
17. Decision to limit full care taken before obtaining informed consent
18. Participation in another interventional study in the 3 months prior to randomization

Primary outcomes:
measure: Sequential organ failure assessment (SOFA) score
timeFrame: day 5
Secondary outcomes:
measure: All-cause mortality
timeFrame: day 5 and day 28
measure: Duration of ICU stay
timeFrame: day 28
measure: Organe support free survival
timeFrame: day 28
measure: Sepsis support index (SSI)
timeFrame: day 28
measure: Daily change of total Sequential organ failure assessment (SOFA) score and individual subscores
timeFrame: day 1, day 2, day 3, day 4, day 5, day 6 and day 7
measure: Duration of Vasopressor use
timeFrame: day 28
measure: Duration of Invasive mechanical ventilation (IMV)
timeFrame: day 28
measure: Duration of Renal support
timeFrame: day 28
measure: All-cause mortality
timeFrame: 12 months
measure: Septic shock related mortality at day 28
timeFrame: day 28
measure: Incidence of secondary infections and post shock antibiotic use
timeFrame: day 28
measure: Alive and organ support free at day 28
timeFrame: day 28
measure: Overall survival on day 28
timeFrame: day 28
measure: Overall survival up to 12 months
timeFrame: 12 months
Other outcomes:
Locations:
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg
city: Gent
country: Belgium
facility: UZ Gent
city: La Louvière
country: Belgium
facility: Centre hospitalier Jolimont-Lobbes
city: Lodelinsart
country: Belgium
facility: CHU Marie Curie
city: Ottignies
country: Belgium
facility: Clinique Saint-Pierre
city: Yvoir
country: Belgium
facility: CHU UCL Namur asbl
city: Hillerod
country: Denmark
facility: Nordsjællandshospital Hillerød
city: Helsinki
country: Finland
facility: Helsinki University Hospital Adult ICU PPDS
city: Kuopio
country: Finland
facility: Kuopion Yliopistollinen sairaala
city: Tampere
country: Finland
facility: Tampereen yliopistollinen sairaala
city: Angers
country: France
facility: CHU Angers
city: Argenteuil
country: France
facility: Centre hospitalier Victor Dupouy
city: Bourg-en-Bresse
country: France
facility: Hôpital Fleyriat
city: Béthune
country: France
facility: Centre hospitalier de Béthune
city: Dijon
country: France
facility: CHU Dijon - Hôpital François Mitterrand
city: La Roche sur Yon
country: France
facility: CHD les Oudairies
city: Le Kremlin Bicêtre
country: France
facility: Hôpital de Bicêtre
city: Le Mans
country: France
facility: CHU LE Mans
city: Lille
country: France
facility: CHRU Lille - Hôpital Roger Salengro
city: Limoges
country: France
facility: Hôpital Universitaire Dupuytren
city: Lyon
country: France
facility: Centre Hospitalier Lyon Sud
city: Marseille
country: France
facility: Hôpital Nord
city: Melun
country: France
facility: Centre hospitalier de Melun
city: Nancy
country: France
facility: CHRU Nancy - Hôpital Central
city: Nantes
country: France
facility: Hôtel Dieu - Nanates
city: Nîmes
country: France
facility: CHU de Nîmes
city: Orléans
country: France
facility: Hôpital de la source
city: Paris
country: France
facility: Hôpital Lariboisière
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Groupe hospitalier Pitié-Salpêtrière
city: Paris
country: France
facility: Hôpital Cochin
city: Tours
country: France
facility: CHRU Hôpital Bretonneau
city: Villenave d'Ornon
country: France
facility: Hôpital d'instruction des Armées Robert Picqué
city: Dublin
country: Ireland
facility: St Jame's Hospital
city: Galway
country: Ireland
facility: Galway University Hospital
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón
city: Barcelone
country: Spain
facility: Hospital del mar
city: Madrid
country: Spain
facility: Hospital Clinical San Carlos
city: Oviedo
country: Spain
facility: Hospital Universitario Dentral de Asturias
city: Terrassa
country: Spain
facility: Hospital Universitari Mutua de Terrassa
city: Valencia
country: Spain
facility: Hospital universitario DR. Peset Aleixandre
city: Valencia
country: Spain
facility: Hospital Universitario y Politecnico la Fe
Study officials:
affiliation: CEO and Medical Officer
name: Jean-Jacques Garaud, MD
role: STUDY_DIRECTOR
References:
citation: Francois B, Lambden S, Gibot S, Derive M, Olivier A, Cuvier V, Witte S, Grouin JM, Garaud JJ, Salcedo-Magguilli M, Levy M, Laterre PF. Rationale and protocol for the efficacy, safety and tolerability of nangibotide in patients with septic shock (ASTONISH) phase IIb randomised controlled trial. BMJ Open. 2021 Jul 7;11(7):e042921. doi: 10.1136/bmjopen-2020-042921.