ADRENOSS-2

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.

 

The AdrenOSS-2 Study (ClinicalTrials.gov: NCT03085758) investigates whether the administration of ADRECIZUMAB is safe and well tolerated in patients with septic shock, as demonstrated in healthy volunteers (ClinicalTrials.gov: NCT02991508), and whether ADRECIZUMAB is able to improve organ function (heart, kidney, lung) and survival in these patients.

Indication: Septic Shock

Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to an infection.

 

Adrenoss-2 is conducted in patients with septic shock, a subset of sepsis in which the underlying circulatory and cellular/metabolic abnormalities are substantially increasing mortality. The overwhelming inflammatory immune response leads to acute vascular dysfunctions, such as systemic vasodilation and vascular leakage, resulting in a massive drop in blood pressure.

 

Patients with septic shock can be identified as patients with sepsis that show a persisting hypotension requiring vasopressors, despite adequate volume resuscitation in order to maintain a mean arterial pressure (MAP) > 65 mm Hg.

Target: Adrenomedullin

The vasoactive hormone Adrenomedullin (ADM) is a key factor in the pathogenesis of septic shock.

 

ADM is a small peptide hormone. Due to its size of 52 amino acids it can freely diffuse between blood stream and interstitium. In the interstitium it acts on the vascular smooth muscle cells, leading to muscle relaxation and vasodilation. In the blood stream it positively regulates vascular integrity, by acting on endothelial cells.

 

Plasma concentrations of biologically active ADM (bio-ADM) are significantly elevated in septic patients that suffer a fatal outcome. In contrast, septic patients that recover from sepsis, display decreasing bio-ADM concentrations.

 

In several observational clinical studies in patients with sepsis and septic shock it could be demonstrated that patients with high plasma bio-ADM concentrations had a significantly higher mortality, compared to those with a low bio-ADM concentrations.

ADRECIZUMAB: Mode of Action

ADRECIZUMAB is a humanized non-neutralizing monoclonal antibody that is highly specific for Adrenomedullin (ADM), but does not completely block its biological activity. In contrast to ADM, ADRECIZUMAB cannot pass the endothelial barrier to enter the interstitium and is hence restricted to the blood stream.


Based on preclinical and clinical data, is can be assumed that ADRECIZUMAB has several beneficial effects: Firstly, binding to ADM does not only prevent ADM from leaving the blood stream, where it positively affects vascular integrity, it also results in an influx of ADM from the interstitium. This in turn reduces ADM concentration in the interstitium, reducing vasodilation. Secondly, ADRECIZUMAB stabilizes ADM and prolongs its half-life.


Taken together, ADRECIZUMAB application is intended to improve vascular integrity and reduce vasodilation in patients with septic shock, thereby improving organ function and survival.

Patients and treatments

Eligible patients have to have an early septic shock, meaning that the vasopressor therapy must have started max.12 hours before the start of the ADRECIZUMAB infusion, and ADM plasma level of ≥ 70 pg/mL at the time of ICU admission.


Adrenoss-2 is a double-blind, placebo-controlled study. There will be two treatments arms receiving ADRECIZUMAB and a control arm receiving placebo.


Treatment arm A: 2 mg ADRECIZUMAB per kilogram body weight
Treatment arm B: 4 mg ADRECIZUMAB per kilogram body weight

Control arm: placebo.


ADRECIZUMAB/placebo will be administered as single intravenous infusion of 50 mL over one hour.

Study outline

Each patient that enters the ICU with septic shock or developed septic shock during ICU stay will be screened and tested for elevated plasma ADM levels. After confirmation of eligibility the patient will receive ADRECIZUMAB or placebo via an intravenous infusion over one hour.

After infusion, the patient will be monitored during his stay until he/she is released from the ICU (max until day 28). If the patient is released earlier than day 28 he/she has to return to the ICU for a safety visit. A final safety assessment will be done on day 90 via phone.

  • Mortality and vasopressor need
  • Length of ICU stay
  • Vital signs and physical examination
  • Safety and immunological laboratory
  • Evaluation of sepsis and shock symptoms (SOFA score, SSI)
  • Quality of life

     

Further information

Adrenoss-2 is an international, multi-center clinical phase II trial with up to 30 participating sites in Germany, France, Belgium, and the Netherlands. A complete list can be found here:


https://clinicaltrials.gov/show/NCT03085758



Further information on Adrenomedullin, ADRECIZUMAB and the sponsor Adrenomed AG can be found here:

http://www.adrenomed.com/