Adrecizumab in Cardiogenic Shock

NCT ID: NCT03989531

Last Updated: 2021-10-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 150 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-04-04
• Study Completion Date: 2021-04-26

Brief Summary

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.

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.

Conditions

Cardiogenic Shock; Endothelial Dysfunction

Study Design

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

Study Groups

Adrecizumab on top of standard of care

8 mg/kg body weight Adrecizumab diluted in up to 100 mL saline as single dose infusion

Group Type: EXPERIMENTAL

Adrecizumab

Intervention Type: BIOLOGICAL

Drip infusion over 60 minutes

Placebo on top of standard of care

100 mL saline as single dose infusion

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Drip infusion over 60 minutes

Interventions

Adrecizumab

Drip infusion over 60 minutes

Intervention Type: BIOLOGICAL

Placebo

Drip infusion over 60 minutes

Intervention Type: DRUG

Other Intervention Names

Saline

Eligibility Criteria

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

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

Sponsors

Dr. med. Mahir Karakas

OTHER

Sponsor Role: lead

Responsible Party

Dr. med. Mahir Karakas

PD Dr Mahir Karakas, MBA

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Mahir Karakas, MD, MBA

Role: PRINCIPAL_INVESTIGATOR

University Heart Center Hamburg

Locations

University of Berlin, Campus Benjamin-Franklin

Berlin, , Germany

University Heart Center Hamburg

Hamburg, , Germany

University of Ulm

Ulm, , Germany

Countries

Germany

References

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.

Reference Type: DERIVED

PMID: 34895483 (View on PubMed)

Other Identifiers

Accost

Identifier Type: -

Identifier Source: org_study_id