Adrecizumab (HAM8101) to Improve Prognosis and Outcomes in COVID-19 Trial (AGNES-19)

Multicenter, Randomized, Double-blind, Biomarker-guided, Phase II Trial With Adrecizumab (HAM 8101) to Improve proGNosis and outcomES in Patients With Moderate to Severe COVID-19

The clinical trial is designed as a prospective, multi-center, double-blind, randomised, placebo-controlled, interventional trial to assess safety, tolerability and efficacy of Adrecizumab (on top of SOC) in patients with COVID-19, and to evaluate if improvement of vascular integrity with Adrecizumab on top of SOC is superior to placebo/ control substance (NaCl 0.9%) on top of SOC in reduction of morbidity and mortality endpoints in patients with COVID-19.

The main reason for admission to ICU and need for mechanical ventilation of these patients is acute lung injury within a broad pneumonic spectrum, increased ventricular filling pressures and resulting congestion. It is hypothesized, that Adrenomedullin (ADM) is a key player in the (dys)-regulation of vascular integrity (Figure 2). 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. The mode of action for the anti-Adrenomedullin antibody Adrecizumab has been developed on the basis of published data, own experimental data and theoretical considerations.

Study Overview

• Status: Terminated
• Conditions: COVID-19
• Intervention / Treatment: Biological: Adrecizumab (HAM 8101); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany
    • Charité
  • Essen, Germany
    • Universitätsklinikum Essen
  • Frankfurt, Germany
    • Universitätsklinikum Frankfurt
  • Freiburg, Germany
    • Universitätsklinikum Freiburg
  • Göttingen, Germany
    • Universitätsmedizin Göttingen
  • Hamburg, Germany, 20246
    • University Medical Center Hamburg Eppendorf
  • Hanover, Germany, 30625
    • Medical School Hanover
  • Mannheim, Germany
    • Universitätsklinikum Mannheim
  • München, Germany
    • LMU München
  • München, Germany
    • Klinikum rechts der Isar TU München
  • Regensburg, Germany
    • Universitatsklinikum Regensburg
  • Tübingen, Germany
    • Universitätsklinikum Tübingen
  • Ulm, Germany
    • Universitätsklinikum Ulm

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Hospitalization with moderate to severe COVID-19, defined as fulfilling at a minimum the following clinical status category on the WHO 8-point ordinal scale: (i) "score 4" [oxygen via mask or nasal]
• Laboratory-confirmed SARS-CoV-2 infection at index hospitalisation as determined by PCR or other validated commercial or public health assay
• Bio-ADM ≥50 pg/mL or ≥30% increase until the end of the next day (with a minimum of 35 pg/mL at all)
• DPP3 ≤30 ng/mL
• Age ≥18 years at time of screening
• Body weight ≤ 150 kg at time of screening

Exclusion Criteria:

• Life expectancy less than 3 months before COVID-19 at the discretion of the Investigator
• Invasive mechanical ventilation ≥ 72 hours at time-point of randomization
• Resuscitation > 45 minutes
• Hypersensitivity to the active substance, to Adrecizumab or any of its excipients, or known serious hypersensitivity to other monoclonal antibodies
• Uncontrolled haematological/ oncological malignancies
• Pre-existing severe chronic liver disease (i.e. Child-Pugh C) before COVID-19 hospitalization
• Absolute neutropenia <500 per μL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adrecizumab (HAM 8101); Adrecizumab (HAM 8101) on top of standard of care. Adrecizumab (HAM8101) is a humanized IgG1 monoclonal antibody (mAb). 2 mg/kg body weight Adrecizumab diluted in up to 100 mL saline as single dose infusion.	Biological: Adrecizumab (HAM 8101); Drip infusion over 60 minutes.
Placebo Comparator: Placebo/ control substance (NaCl 0.9%); 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
Time to clinical improvement	Time to clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on the World Health Organisation 8-point ordinal scale or live discharge from the hospital, whichever came first. WHO 8-point ordinal scale; Ambulatory No limitation of activities; Ambulatory Limitation of activities; Hospitalized, mild disease No oxygen therapy; Hospitalized, mild disease Oxygen by mask or nasal cannulae; Hospitalized, severe disease Non-invasive ventilation on high-flow oxygen; Hospitalized, severe disease Intubation and invasive mechanical ventilation; Hospitalized, severe disease Invasive mechanical ventilation and additional organ support; Death -	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical status at day 28, as measured on the WHO 8-point ordinal scale	Please see Outcome 1 for details on WHO 8-point ordinal scale	28 days
Survival (time-to-event) until day 28 and end of follow-up (90 days)		90 days
Rate of invasive mechanical ventilation until day 28 and day 90	defined as use of endotracheal or tracheostomy tube assisted ventilation	28 and 90 days
Length of invasive mechanical ventilation until day 28 and day 90	defined as use of endotracheal or tracheostomy tube assisted ventilation	28 and 90 days
Rate of ECMO therapy until day 28 and day 90		28 and 90 days
Length of ECMO therapy until day 28 and day 90		28 and 90 days
Length of stay at ICU after application of IMP up to a total of 90 days		90 days
Length of hospital stay after application of IMP up to a total of 90 days		90 days
All-cause rehospitalisation within 90 days		90 days
Rate of renal replacement therapy until day 28 and day 90		28 and 90 days
Change in clinical status on the WHO 8-point ordinal scale for COVID-19 at days 7, 28, and 90	Please see Outcome 1 for Details in WHO 8-point ordinal scale	7, 28 and 90 days
Change in SOFA score sum (only during hospitalization on ICU) with-in 24 hours of IMP administration (start of infusion), 48 hours, day 7 post-infusion		24 hours, 48 hours and 7 days post-infusion
Between-group difference in life quality as assessed by EQ-5D-5L at discharge, day 28, day 90		28 and 90 days

Collaborators and Investigators

• Sponsor: Universitätsklinikum Hamburg-Eppendorf
• Investigators: Principal Investigator: Stefan Kluge, MD, University Medical Center Hamburg-Eppendorf - Department of Intensive Care Medicine

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2022
• Primary Completion (Actual): August 25, 2023
• Study Completion (Actual): November 15, 2023

Study Registration Dates

• First Submitted: December 2, 2021
• First Submitted That Met QC Criteria: December 9, 2021
• First Posted (Actual): December 14, 2021

Study Record Updates

• Last Update Posted (Estimated): January 3, 2024
• Last Update Submitted That Met QC Criteria: December 27, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Adrecizumab; acute lung injury; Vascular Integrity; Enibarcimab
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: AGNES-19

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