Treatment of Patients With Early Septic Shock and Bio-Adrenomedullin(ADM) Concentration > 70 pg/ml With ADRECIZUMAB

NCT ID: NCT03085758

Last Updated: 2024-02-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 301 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-12-12
• Study Completion Date: 2019-12-20

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).

Conditions

Septic Shock

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Treatment Arm A

Intravenous infusion over approximately 1 hour of single i.v. dose of 2 mg/kg Adrecizumab (treatment arm A)

Group Type: EXPERIMENTAL

Adrecizumab

Intervention Type: BIOLOGICAL

Single i.v. dose of 2 mg/kg (treatment arm A) or 4 mg/kg (treatment arm B)

Treatment Arm B

Intravenous infusion over approximately 1 hour of single i.v. dose of 4 mg/kg Adrecizumab (treatment arm B)

Group Type: EXPERIMENTAL

Adrecizumab

Intervention Type: BIOLOGICAL

Single i.v. dose of 2 mg/kg (treatment arm A) or 4 mg/kg (treatment arm B)

Control group

Intravenous infusion over approximately 1 hour of single i.v. dose of Placebo of Adrecizumab (control group)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: BIOLOGICAL

Single i.v. dose of placebo (control group)

Interventions

Adrecizumab

Single i.v. dose of 2 mg/kg (treatment arm A) or 4 mg/kg (treatment arm B)

Intervention Type: BIOLOGICAL

Placebo

Single i.v. dose of placebo (control group)

Intervention Type: BIOLOGICAL

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Adrenomed AG

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jens Zimmermann, Dr.

Role: STUDY_DIRECTOR

Adrenomed AG

Locations

Clinique Universitaire Saint-Luc (UCL Bruxelles)

Brussels, , Belgium

Antwerp University Hospital (UZA), Critical Care Medicine

Edegem, , Belgium

Groupe Jolimont, Hospitalier de Jolimont

Haine-Saint-Paul, , Belgium

Clinique St. Pierre, Intensive Care

Ottignies, , Belgium

Medical Intensive Care Medicine, Centre hospital - universitaire

Angers, Cedex, France

CH Victor Dupouy

Argenteuil, Cedex, France

Hopital Beaujon; Anesthesie Reanimation

Clichy, Cedex, France

CHU de Limoges

Limoges, Cedex, France

CHU de Nantes; Medicine Intensive Reanimation

Nantes, Cedex, France

CHRU Bretonneau, Medecine Intensive Réanimation

Tours, Cedex, France

University Hospital of Clermont-Ferrand, Dept. of Perioperative Medicine

Clermont-Ferrand, , France

AP-HP, Hopital Louis Mourier, Réanimation Médicale

Colombes, , France

CHD-Vendée

La Roche-sur-Yon, , France

Hôpital de Bicêtre, Service d'anesthésie-réanimation chirurgicale

Le Kremlin-Bicêtre, , France

Hôpital Lariboisière, Dept. d'Anesthesie

Paris, , France

Hôpital Lariboisière, Réanimation Médicale et Traumatologique

Paris, , France

Hôpital Saint-Louis, Service d'Anesthésie-Réanimation

Paris, , France

Hôpital Européen Georges Pompidou, Service d'Anesthésie-Réanimation Chirurgicale, Université Paris Descartes

Paris, , France

Nouvel Hopital Civil

Strasbourg, , France

Hôpital de Hautepierre , Hôpitaux Universitaires de Strasbourg, Unité de Réanimation Chirurgicale, Service d'Anesthésie-Réanimation Chirurgicale

Strasbourg, , France

Universitätsklinikum Aachen, Klinik für Operative Intensivmedizin

Aachen, , Germany

Universitätsklinikum Hamburg-Eppendorf Klinik für Intensivmedizin

Hamburg, , Germany

Universitätsklinikum Jena Klinik für Anästhesiologie und Intensivmedizin

Jena, , Germany

Universitätsklinikum Münster Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie

Münster, , Germany

Universitätsmedizin Rostock Klinik und Poliklinik für Anästhesiologie und Intensivtherapie

Rostock, , Germany

Gelderse Vallei Hospital, Department of Intensive Care

Ede, , Netherlands

Medisch Spectrum Twente, Department of Intensive Care

Enschede, , Netherlands

Zuyderland Medical Center, Department of Intensive Care

Heerlen, , Netherlands

Radboud UMC Intensive Care

Nijmegen, , Netherlands

Canisius-Wilhelmina-Ziekenhuis (CWZ), Intensive Care

Nijmegen, , Netherlands

Countries

Belgium; France; Germany; Netherlands

References

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.

Reference Type: DERIVED

PMID: 34605947 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30782906 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

ADR-02

Identifier Type: -

Identifier Source: org_study_id