Adrecizumab in Cardiogenic Shock (ACCOST-HH)

Investigator-initiated, Placebo-controlled, Double-blind, Multi-center, Randomized Trial to Assess the Efficacy and Safety of Adrecizumab in Subjects With Cardiogenic Shock

Cardiogenic shock is a serious medical condition with high mortality and morbidity. This trial assesses safety, tolerability and efficacy of Adrecizumab on top of standard of care in patients with cardiogenic shock.

Study Overview

• Status: Completed
• Conditions: Endothelial Dysfunction; Cardiogenic Shock
• Intervention / Treatment: Drug: Placebo; Biological: Adrecizumab

Detailed Description

Despite optimal treatment the mortality in patients with cardiogenic shock still exceeds 50% and surviving patients mostly suffer from severe heart failure due to an impaired cardiac function.It is hypothesized, that Adrenomedullin is a key player in the (dys)-regulation of vascular integrity. Adrecizumab is the first-in-class humanized monoclonal anti-Adrenomedullin antibody, and acts as a long-lasting plasma Adrenomedullin enhancer stabilizing barrier function at a reasonable safety profile.When the anti-Adrenomedullin antibody Adrecizumab is administered in the blood circulation at high concentrations by far exceeding those of plasma Adrenomedullin, the compartmental distribution of Adrenomedullin is altered. Adrecizumab, an IgG with a molecular weight of more than 150 kDa, is too large to freely diffuse from the blood circulation to the interstitium. With its fast association kinetics Adrecizumab quickly binds to Adrenomedullin in the blood circulation and "pulls" Adrenomedullin, which has been initially located in the interstitium, from this compartment to the blood circulation. The more Adrecizumab is applied, the stronger is the "pulling" effect and the higher the resulting concentrations of Adrecizumab-bound Adrenomedullin in the blood circulation. The increase of Adrecizumab-bound Adrenomedullin in the blood circulation occurs within 5-15 minutes after administration of Adrecizumab, since it induces a translocation of preformed Adrenomedullin. As a consequence of this redistribution, the Adrenomedullin concentration in the interstitium decreases, and less Adrenomedullin is able to act on smooth muscle cells to exert its vasodilatative activity. In the progression to cardiogenic shock, when it comes to excessive vasodilation and hypotension, administration of Adrecizumab thus can reduce vasodilation by substracting excessive levels of interstitially located Adrenomedullin.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 12203
    • University of Berlin, Campus Benjamin-Franklin
  • Hamburg, Germany, 20246
    • University Heart Center Hamburg
  • Ulm, Germany, 89081
    • University of Ulm

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

-Hospitalization for Cardiogenic shock (at the discretion of the local investigator)

Cardiogenic shock is usually defined as:

• Systolic blood pressure < 90 mmHg > 30 min or inotropes required to maintain pressure > 90 mmHg during systole
• Signs of left heart insufficiency and/ or pulmonary congestion
• Signs of impaired organ perfusion with at least one of the following:
• Altered mental status
• Cold, clammy skin
• Urine output <30 ml/h

• Serum lactate >2mmol/l

  • Age above 18 years at time of screening
  • Body weight below 150 kg at time of screening
  • Females/Males who agree to comply with the applicable contraceptive requirements of the protocol

Exclusion Criteria:

• Cardiogenic shock due to significant arrhythmias, which include any of the following: sustained ventricular tachycardia, bradycardia with sustained ventricular rate <35 beats per minute, or atrial fibrillation/ flutter with sustained ventricular response of >160 beats per minute
• Cardiogenic shock due to left ventricular outflow obstruction, obstructive hypertrophic cardiomyopathy or severe aortic stenosis (i.e., aortic valve area <0.8 cm2 or mean gradient >50 mmHg on prior or current echocardiogram), and severe mitral stenosis
• Cardiogenic shock due to mechanical cause or severe bleeding
• Cardiogenic shock due to untreated clinically significant CAD requiring revascularization
• Resuscitation > 60 minutes
• Severe pre-existing hepatic disease unrelated to cardiogenic shock
• Severe pre-existing renal disease (dialysis) unrelated to cardiogenic shock etiology

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Adrecizumab on top of standard of care; 8 mg/kg body weight Adrecizumab diluted in up to 100 mL saline as single dose infusion	Biological: Adrecizumab; Drip infusion over 60 minutes
PLACEBO_COMPARATOR: Placebo on top of standard of care; 100 mL saline as single dose infusion	Drug: Placebo; Drip infusion over 60 minutes; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Need of cardiovascular organ support within the first 30 days	Number of days through day 30 without need for cardiovascular organ support, including vasopressors, or mechanical support (VA-ECMO, Impella)	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
30-day-Mortality	All-cause mortality	30 days

Collaborators and Investigators

• Sponsor: Dr. med. Mahir Karakas

Publications and helpful links

General Publications

• Karakas M, Akin I, Burdelski C, Clemmensen P, Grahn H, Jarczak D, Kessler M, Kirchhof P, Landmesser U, Lezius S, Lindner D, Mebazaa A, Nierhaus A, Ocak A, Rottbauer W, Sinning C, Skurk C, Soffker G, Westermann D, Zapf A, Zengin E, Zeller T, Kluge S. Single-dose of adrecizumab versus placebo in acute cardiogenic shock (ACCOST-HH): an investigator-initiated, randomised, double-blinded, placebo-controlled, multicentre trial. Lancet Respir Med. 2022 Mar;10(3):247-254. doi: 10.1016/S2213-2600(21)00439-2. Epub 2021 Dec 8.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 4, 2019
• Primary Completion (ACTUAL): April 26, 2021
• Study Completion (ACTUAL): April 26, 2021

Study Registration Dates

• First Submitted: June 17, 2019
• First Submitted That Met QC Criteria: June 17, 2019
• First Posted (ACTUAL): June 18, 2019

Study Record Updates

• Last Update Posted (ACTUAL): October 8, 2021
• Last Update Submitted That Met QC Criteria: October 7, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Endothelial dysfunction; Adrecizumab; Cardiogenic Shock; Vascular integrity
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; Shock; Shock, Cardiogenic
• Other Study ID Numbers: Accost

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No