The Austrian Coronavirus Adaptive Clinical Trial (ACOVACT) is a randomized, controlled, multicenter, open-label basket trial that aims to compare various antiviral treatments for COVID-19. Moreover three substudies have been integrated. Currently, patients will be randomized to receive (hydroxy-)chloroquine (Treatment stopped after reports of safety issues), lopinavir/ritonavir, remdesivir or standard of care. Moreover, these patients are eligible for substudy A (randomized to rivaroxaban 5mg 1-0-1 vs. standard of care), substudy B (renin-angiotensin (RAS) blockade vs. no RAS blockade for patients with blood pressure >120/80mmHg), and substudy C (asunercept vs standard of care, pentglobin vs. standard of care for patients with respiratory deterioration and high inflammatory biomarkers). Endpoints were chosen based on the master protocol published by the World Health Organisation and include a 7-point scale of clinical performance, mortality, oxygen requirement (both dose and type), duration of hospitalization, viral load and safety.
Drug: Chloroquine or Hydroxychloroquine
Hydroxychloroquine 200mg 2-0-2 on day 1 followed by 200mg 1-0-1, or Chloroquine 250mg 2-0-2, as available
Drug: Lopinavir/Ritonavir
Lopinavir/Ritonavir 200mg/50mg 2-0-2
Other: Best standard of care
best standard of care
Drug: Rivaroxaban
2.5mg 2-0-2 or 10mg 1/2-0-1/2, as applicable
Drug: Thromboprophylaxis
as local standard, most likely to be low molecular weight heparin
Drug: Candesartan
starting dose 4mg once daily, titrated to normotension
Drug: non-RAS blocking antihypertensives
This excludes angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (AT-blockers, sartans) and includes alpha-receptor antagonists, calcium antagonists, amongst others
Drug: Remdesivir
200mg on day 1, thereafter 100mg for a total of 5-10 treatment days, according to local standards
Drug: Asunercept 400mg
asunercept 400mg once per week, up to 4 doses in total
Drug: Asunercept 100mg
asunercept 100mg once per week, up to 4 doses in total
Drug: Asunercept 25mg
asunercept 25mg once per week, up to 4 doses in total
Drug: Pentaglobin
7ml/kg/day for 12h for 5 days
Inclusion Criteria
Laboratory confirmed (i.e. PCR-based assay) infection with SARS-CoV-2 (ideally but not
necessarily
≤72 hours before randomization for "antiviral" treatments) OR radiological signs of
COVID-19 in chest X-ray or computed tomography
- Hospitalisation due to SARS-CoV-2 infection, except for sub-study B, which may also
include outpatients with COVID-19
- Requirement of oxygen support (due to oxygen saturation <94% on ambient air or >3%
drop in case of chronic obstructive lung disease)
- Informed Consent obtained, the patient understands and agrees to comply with the
planned study procedures, except for sub-study C: obtaining informed consent may be
impossible due to the severe condition of the patient and may be waived
- ≥18 years of age
- Sub-study A: not on chronic anticoagulation Sub-study B: Sub-study B: blood pressure
≥130/85mmHg in 2 consecutive measurements OR patients with established and treated
hypertension
- Sub-study B: Control group 1: Patients with suspicion of but negative tests for
COVID-19. This group may consist of hospitalized and non-hospitalized patients.
- Sub-study B: healthy volunteers
- Sub-study C: Signs of respiratory deterioration and progressing inflammation: need for
oxygen supplementation, non-invasive ventilation, high-flow oxygen devices or
mechanical ventilation AND CRP levels >5mg/dL (for Pentaglobin only) and ICU admission
(for Pentaglobin only)
- For female patients with childbearing potential: willingness to perform effective
measures of contraception during the study
Exclusion Criteria
- Moribund, or estimated life expectancy <1 month (e.g. terminal cancer, etc.)
- Patient does not qualify for intensive care, based on local triage criteria
- Pregnancy or breastfeeding
- Severe liver dysfunction (e.g. ALT/AST > 5 times upper limit of normal)
- Stage 4 chronic kidney disease or requiring dialysis for direct anticoagulant
treatment
- Allergy or intolerances to experimental substance (ineligibility for treatment arm),
for Asunercept known hereditary fructose intolerance
- Anticipated discharge from hospital within 48 hours (for any given reason)
- Contraindications for treatment arm 2 (lopinavir/ritonavir): severe hepatic
impairment, CYP3A4/5 metabolized drugs, as deemed relevant by treating physicians
- Contraindications for treatment arm 3 (remdesivir): <40kg bodyweight
- Known active HIV or viral hepatitis
- Substudy A contraindications for rivaroxaban: active bleeding or bleeding diathesis,
lesion or condition considered as major risk factor for bleeding, recent brain or
spinal injury, recent brain or spinal or ophthalmic surgery, recent intracranial
hemorrhage, known or suspected esophageal varices, arteriovenous malformations,
vascular aneurysms, major intraspinal or intracerebral vascular abnormalities, ongoing
therapeutic anticoagulation, which will be continued, according to clinical practice
- Sub-study B contraindications for nitrendipine: chronic heart failure, allergies,
hypersensitivities and intolerances, severe hepatic impairment and/or cholestasis,
concomitant therapy with aliskirencontaining medications (for patients with diabetes
mellitus or a GFR<60ml/min/1.73m2), known significant bilateral renal artery stenosis
or renal artery stenosis of a solitary kidney
- Sub-study C contraindications for IL-6 blockade: Contraindications: allergies and
intolerances, active untreated diverticulitis, inflammatory bowel disease, any
treatment with an IL-6 or IL-6R blocking drug (e.g. tocilizumab, sarilumab,
siltuximab) <30 days before study inclusion.
- Sub-study C: Known active tuberculosis.
- Asunercept: females of childbearing potential
- Sub-study C with Pentaglobin: Contraindications to Pentaglobin
Medical University of Innsbruck
Innsbruck, Tirol, Austria
Medical University of Graz
Graz, Austria
Kepler University Hospital
Linz, Austria
Medical University of Vienna
Vienna, Austria
Wilhelminenspital
Vienna, Austria
SMZ Süd Kaiser Franz Josef Spital
Vienna, Austria
KH Hietzing
Vienna, Austria
SMZ Baumgartner Höhe Otto Wagner Spital
Vienna, Austria
SMZ Ost Donauspital
Vienna, Austria
Bernd Jilma, MD
+4314040029810
klin-pharmakologie@meduniwien.ac.at
Christian Schörgenhofer, MD, PHD
+4314040029810
klin-pharmakologie@meduniwien.ac.at
Bernd Jilma, MD, Principal Investigator
Medical University of Vienna