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
Trial Snapshot
- Phase
- Phase 2
- Status
- Terminated
- Enrollment
- 16
- Locations
- 13
- Primary Endpoint
- Time to clinical improvement
Study Overview
Brief Summary
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 Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
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.
Intervention: Adrecizumab (HAM 8101) (Biological)
Placebo/ control substance (NaCl 0.9%)
100 mL saline as single dose infusion
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Time to clinical improvement
Time Frame: 90 days
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 1. Ambulatory No limitation of activities 2. Ambulatory Limitation of activities 3. Hospitalized, mild disease No oxygen therapy 4. Hospitalized, mild disease Oxygen by mask or nasal cannulae 5. Hospitalized, severe disease Non-invasive ventilation on high-flow oxygen 6. Hospitalized, severe disease Intubation and invasive mechanical ventilation 7. Hospitalized, severe disease Invasive mechanical ventilation and additional organ support 8. Death -
Secondary Outcomes
- Clinical status at day 28, as measured on the WHO 8-point ordinal scale(28 days)
- Rate of invasive mechanical ventilation until day 28 and day 90(28 and 90 days)
- Survival (time-to-event) until day 28 and end of follow-up (90 days)(90 days)
- Length of invasive mechanical ventilation until day 28 and day 90(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(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)