Clinical trial NCT03085758: Treatment of Patients With Early Septic Shock and Bio-Adrenomedullin(ADM) Concentration > 70 pg/ml With ADRECIZUMAB
Official title: A Double-Blind, Placebo-Controlled, Randomized, Multicenter, Proof of Concept and Dose-Finding Phase II Clinical Trial to Investigate the Safety, Tolerability and Efficacy of ADRECIZUMAB in Patients With Septic Shock and Elevated Adrenomedullin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Septic Shock
Keywords: Early Septic Shock
Lead sponsor: Adrenomed AG
Sponsor class: INDUSTRY
First posted: 2017-03-21
Enrollment: 301
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double Blind, Placebo-Controlled, Randomized, Multicenter Proof of Concept and Dose-Finding Phase II Clinical Trial
Primary purpose: TREATMENT

Brief summary: This is a double-blind, placebo-controlled, randomized, multicenter proof of concept and dose-finding phase II study using two doses of ADRECIZUMAB in patients with early septic shock and a bio-ADM plasma concentration at admission of \> 70 pg/ml.

Detailed description: This is a double-blind, placebo-controlled, randomized, multicenter proof of concept and dose-finding phase II study using two doses of ADRECIZUMAB in patients with early septic shock and a bio-ADM plasma concentration at admission of \> 70 pg/ml.

"Early" septic shock is defined as a life-threatening organ dysfunction due to dysregulated host response to a proven or suspected infection which leads to a decline of Mean Arterial Pressure (MAP) \< 65 mmHg, which is refractory to fluid resuscitation and requires vasopressors. Early is defined as a maximum of less than 12 hours between onset of the cardiovascular organ-dysfunction and administration of ADRECIZUMAB. Refractoriness to fluid resuscitation is defined as a lack of response to the administration of 30 mL of fluid per kilogram of body weight or is determined according to a clinician's assessment of inadequate hemodynamic results.

It is intended to enroll 300 patients from surgical, medical and mixed ICU at multiple centers in Europe.

All patients will be treated according to "International Guidelines for Management of Severe Sepsis and Septic Shock".

Eligible patients (confirmed by central verification) will be randomized (1:1:2) to ADRECIZUMAB treatment arm A (2 mg/kg) or to ADRECIZUMAB treatment arm B (4 mg/kg) or to placebo as control group. Patients assigned to the treatment arm A or B will be administered a single dose of ADRECIZUMAB as intravenous infusion over approximately 1 hour; patients assigned to the control group will be administered placebo as intravenous infusion over approximately 1 hour.

As long as the patients are on the ICU, daily measurements of clinical signs and laboratory data will be collected for safety reasons and for determination of Sequential Organ Failure Assessment Score (SOFA score). Additional blood samples for central laboratory analyses will be taken at inclusion on day 1, day 3, day 5, day 7 or day of discharge (whatever comes first) for measurement of biomarkers.

The SOFA score and its components will be determined daily for all patients over the entire stay on the ICU (28 days or until discharge whatever comes first). Safety monitoring for each patient will begin at the time of signing the Informed Consent Form and continue for 90 days after end of short-term infusion of study medication.

At selected study centers a pharmacokinetic (PK) substudy will be performed to determine the profile of ADRECIZUMAB in 80 randomized patients.

An interim analysis for efficacy is planned after 50% of patients have completed the study (n=150).

Eligibility criteria: Inclusion Criteria:

1. Written informed consent by patient or legal representative (according to country - specific regulations)
2. Male and female patient, age ≥ 18 years
3. Body weight 50 kg - 120 kg
4. Bio-ADM concentration \> 70 pg/ml
5. Patient with early septic shock (start of vasopressor therapy \< 12 hours)
6. Women of childbearing potential must have a negative serum or urine pregnancy test before randomization
7. Highly effective method of contraception must be maintained for 6 months after study start by women of childbearing potential and sexually active men.
8. No care limitation

Exclusion Criteria:

1. Moribund
2. Pre-existing unstable condition (e.g. a recent cerebral hemorrhage or infarct, a recent acute unstable myocardial infarction (all \< 3 months), congestive heart failure - New York Heart Association (NYHA) Class IV
3. Patients that required cardiopulmonary resuscitation in the last 4 weeks prior to evaluation for enrollment
4. Severe Chronic Obstructive Pulmonary Disease (COPD) with chronic oxygen need at home (GOLD IV)
5. Any organ or bone marrow transplant within the past 24 weeks
6. Uncontrolled serious hemorrhage (≥ 2 units of blood / platelets in the previous 24 hrs.). Patients may be considered for enrollment if bleeding has stopped and patient is otherwise qualified
7. Uncontrolled hematological / oncological malignancies
8. Absolute neutropenia \< 500 per µL
9. Severe chronic liver disease (Child-Pugh C)
10. Systemic fungal infection or active tuberculosis
11. Neuromuscular disorders that impact breathing / spontaneous ventilation
12. Burns \> 30% of body surface
13. Plasmapheresis
14. Breastfeeding women
15. Participation in a clinical trial involving another investigational drug within 4 weeks prior to inclusion
16. Unwilling or unable to be fully evaluated for all follow-up visits

Primary outcomes:
measure: Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Mortality)
timeFrame: 90 days
measure: Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Interruption of Infusion)
timeFrame: 90 days
measure: Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Frequency of TEAEs)
timeFrame: 90 days
measure: Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Severity and Frequency of TEAEs) - Mild Severity
timeFrame: 90 days
measure: Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Severity and Frequency of TEAEs) - Moderate Severity
timeFrame: 90 days
measure: Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Severity and Frequency of TEAEs) - Severe Severity
timeFrame: 90 days
Secondary outcomes:
measure: Efficacy to be Determined by Sepsis Support Index (SSI)
timeFrame: 14 days
measure: Sepsis Support Index (SSI)
timeFrame: 28 days
measure: Penalized Sepsis Support Index (pSSI) at 14 Day Follow-up
timeFrame: day 14
measure: Persistent Organ Dysfunction or Death at 14 and 28 Day Follow-up
timeFrame: day 14 and day 28
measure: Mortality Rate
timeFrame: day 28
measure: SSI and pSSI Excluding the Renal Component
timeFrame: day 14 and day 28
measure: SSI Weighted for Mortality
timeFrame: day 14
measure: Individual Sepsis Support Index Components
timeFrame: day 14 and day 28
measure: Sequential Organ Failure Assessment (SOFA) Score : Composite Measure: SOFA Score and Its Changes Over Time
timeFrame: 28 days
measure: Change in Renal Function (Creatinine)
timeFrame: day 1, day 3 and day 7
measure: Duration of Stay at ICU/ Hospital
timeFrame: 90 days
measure: Changes of Functional Parameter Mean Arterial Pressure During Stay at ICU
timeFrame: 28 days
measure: Changes of Functional Parameter Creatinine During Stay at ICU
timeFrame: 28 days
measure: Changes of Functional Parameter Partial Pressure of Oxygen in Arterial Blood(PaO2) / Fraction of Inspired Oxygen (FiO2) During Stay at ICU
timeFrame: 28 days
measure: Changes of Functional Parameter Blood Lactate During Stay at ICU
timeFrame: 28 days
measure: Changes of Functional Parameter Fluid Balance During Stay at ICU
timeFrame: 28 days
measure: Changes of Functional Parameter Mid-Regional Pro-Adrenomedullin (MR-proADM) During Stay at ICU
timeFrame: 28 days
measure: Changes of Functional Parameter Inflammatory Marker Procalcitonine (PCT) During Stay at ICU
timeFrame: 28 days
measure: Changes of Functional Parameter Inflammatory Marker Interleukin-6 (IL-6) During Stay at ICU
timeFrame: 28 days
measure: Changes of Functional Parameter Dipeptidyl Peptidase 3 (DPP3) During Stay at ICU
timeFrame: 28 days
measure: Vasopressor Use (Drug, Highest Dose)
timeFrame: 28 days
measure: Patient Reported Outcomes : Quality of Life by Euro-QoL-5
timeFrame: day 28 and day 90
measure: Vital Signs
timeFrame: 7 days
measure: Penalized Sepsis Support Index (pSSI) at 28 Day Follow-up
timeFrame: day 28
measure: Vasopressor Use (Drug, Duration)
timeFrame: 28 days
measure: Change in Renal Function (penKid)
timeFrame: day 1, day 3 and day 7
measure: Vital Signs - Blood Pressure
timeFrame: 7 days
Other outcomes:
measure: In Sub-study Key Pharmacokinetic Parameters Peak Plasma Concentrations (Cmax) Are to be Determined in 80 Patients
timeFrame: 28 days
measure: In Sub-study Key Pharmacokinetic Parameters Time to Cmax (Tmax) Are to be Determined in 80 Patients
timeFrame: 28 days
measure: In Sub-study Key Pharmacokinetic Parameter AUC is to be Determined in 80 Patients
timeFrame: 28 days
measure: In Sub-study Key Pharmacokinetic Parameter Volume of Distribution is to be Determined in 80 Patients
timeFrame: 28 days
measure: In Sub-study Key Pharmacokinetic Parameter Systemic Clearance is to be Determined in 80 Patients
timeFrame: 28 days
measure: In Sub-study Key Pharmacokinetic Parameter Elimination Half-life is to be Determined in 80 Patients
timeFrame: 28 days
Locations:
city: Brussels
country: Belgium
facility: Clinique Universitaire Saint-Luc (UCL Bruxelles)
city: Edegem
country: Belgium
facility: Antwerp University Hospital (UZA), Critical Care Medicine
city: Haine Saint Paul
country: Belgium
facility: Groupe Jolimont, Hospitalier de Jolimont
city: Ottignies
country: Belgium
facility: Clinique St. Pierre, Intensive Care
city: Angers
country: France
facility: Medical Intensive Care Medicine, Centre hospital - universitaire
state: Cedex
city: Argenteuil
country: France
facility: CH Victor Dupouy
state: Cedex
city: Clichy
country: France
facility: Hopital Beaujon; Anesthesie Reanimation
state: Cedex
city: Limoges
country: France
facility: CHU de Limoges
state: Cedex
city: Nantes
country: France
facility: CHU de Nantes; Medicine Intensive Reanimation
state: Cedex
city: Tours
country: France
facility: CHRU Bretonneau, Medecine Intensive Réanimation
state: Cedex
city: Clermont-Ferrand
country: France
facility: University Hospital of Clermont-Ferrand, Dept. of Perioperative Medicine
city: Colombes
country: France
facility: AP-HP, Hopital Louis Mourier, Réanimation Médicale
city: La Roche Sur Yon
country: France
facility: CHD-Vendée
city: Le Kremlin-Bicêtre
country: France
facility: Hôpital de Bicêtre, Service d'anesthésie-réanimation chirurgicale
city: Paris
country: France
facility: Hôpital Lariboisière, Dept. d'Anesthesie
city: Paris
country: France
facility: Hôpital Lariboisière, Réanimation Médicale et Traumatologique
city: Paris
country: France
facility: Hôpital Saint-Louis, Service d'Anesthésie-Réanimation
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou, Service d'Anesthésie-Réanimation Chirurgicale, Université Paris Descartes
city: Strasbourg
country: France
facility: Nouvel Hopital Civil
city: Strasbourg
country: France
facility: Hôpital de Hautepierre , Hôpitaux Universitaires de Strasbourg, Unité de Réanimation Chirurgicale, Service d'Anesthésie-Réanimation Chirurgicale
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen, Klinik für Operative Intensivmedizin
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf Klinik für Intensivmedizin
city: Jena
country: Germany
facility: Universitätsklinikum Jena Klinik für Anästhesiologie und Intensivmedizin
city: Muenster
country: Germany
facility: Universitätsklinikum Münster Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie
city: Rostock
country: Germany
facility: Universitätsmedizin Rostock Klinik und Poliklinik für Anästhesiologie und Intensivtherapie
city: Ede
country: Netherlands
facility: Gelderse Vallei Hospital, Department of Intensive Care
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente, Department of Intensive Care
city: Heerlen
country: Netherlands
facility: Zuyderland Medical Center, Department of Intensive Care
city: Nijmegen
country: Netherlands
facility: Radboud UMC Intensive Care
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina-Ziekenhuis (CWZ), Intensive Care
Study officials:
affiliation: Adrenomed AG
name: Jens Zimmermann, Dr.
role: STUDY_DIRECTOR
References:
citation: Laterre PF, Pickkers P, Marx G, Wittebole X, Meziani F, Dugernier T, Huberlant V, Schuerholz T, Francois B, Lascarrou JB, Beishuizen A, Oueslati H, Contou D, Hoiting O, Lacherade JC, Chousterman B, Pottecher J, Bauer M, Godet T, Karakas M, Helms J, Bergmann A, Zimmermann J, Richter K, Hartmann O, Pars M, Mebazaa A; AdrenOSS-2 study participants. Safety and tolerability of non-neutralizing adrenomedullin antibody adrecizumab (HAM8101) in septic shock patients: the AdrenOSS-2 phase 2a biomarker-guided trial. Intensive Care Med. 2021 Nov;47(11):1284-1294. doi: 10.1007/s00134-021-06537-5. Epub 2021 Oct 4.
citation: Geven C, Blet A, Kox M, Hartmann O, Scigalla P, Zimmermann J, Marx G, Laterre PF, Mebazaa A, Pickkers P. A double-blind, placebo-controlled, randomised, multicentre, proof-of-concept and dose-finding phase II clinical trial to investigate the safety, tolerability and efficacy of adrecizumab in patients with septic shock and elevated adrenomedullin concentration (AdrenOSS-2). BMJ Open. 2019 Feb 19;9(2):e024475. doi: 10.1136/bmjopen-2018-024475.