Title
Austrian CoronaVirus Adaptive Clinical Trial (COVID-19)
A Multicenter, Randomized, Active Controlled, Open Label, Platform Trial on the Efficacy and Safety of Experimental Therapeutics for Patients With COVID-19 (Caused by Infection With Severe Acute Respiratory Syndrome Coronavirus-2)
Phase
Phase 2/Phase 3Lead Sponsor
Medical University of ViennaStudy Type
InterventionalStatus
Unknown statusIndication/Condition
COVID-19Intervention/Treatment
Chloroquine or Hydroxychloroquine [chloroquine (102663), hydroxychloroquine (34770)] Lopinavir/Ritonavir [ritonavir (35332), lopinavir (65582)] Rivaroxaban Candesartan clazakizumab ...Study Participants
500The 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.
Hydroxychloroquine 200mg 2-0-2 on day 1 followed by 200mg 1-0-1, or Chloroquine 250mg 2-0-2, as available
Lopinavir/Ritonavir 200mg/50mg 2-0-2
best standard of care
2.5mg 2-0-2 or 10mg 1/2-0-1/2, as applicable
as local standard, most likely to be low molecular weight heparin
starting dose 4mg once daily, titrated to normotension
This excludes angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (AT-blockers, sartans) and includes alpha-receptor antagonists, calcium antagonists, amongst others
200mg on day 1, thereafter 100mg for a total of 5-10 treatment days, according to local standards
asunercept 400mg once per week, up to 4 doses in total
asunercept 100mg once per week, up to 4 doses in total
asunercept 25mg once per week, up to 4 doses in total
7ml/kg/day for 12h for 5 days
Due to limited availability of the experimental substances, this arm will include both chloroquine and hydroxychloroquine treatment. However, both substances are similar chemically and also with regards to the mechanism of action comparable. Dosage: Hydroxychloroquine 200mg 2-0-2 on day 1 followed by 200mg 1-0-1, or Chloroquine 250mg 2-0-2, as available
Dosage: 200mg/50mg 4-0-4 on day 1 and 3-0-3 thereafter
patients will be treated with "standard of care", which precludes treatment with lopinavir/ritonavir or (hydroxy-)chloroquine
Renin-Angiotensin-System-Blockade (RAS) by candesartan intake starting with 4mg once daily and titrated to normotension patients > 120/80 mmHG are eligible
non-RAS blocking antihypertensive agents titrated to normotension Those with normal blood pressure may only be controlled without further treatment
25mg 1x per week, maximum of four doses only patients with oxygen requirement
100mg 1x per week, maximum of four doses only patients with oxygen requirement
400mg 1x per week, maximum of four doses only patients with oxygen requirement
only patients with oxygen requirement
200mg loading dose on day 1, 100mg for a total treatment duration of 5-10 days
Patients treated at the intensive care unit only, continuous infusion of 7ml/kg/day over 12h for 5 days
Patients treated at the intensive care unit only
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
