Austrian CoronaVirus Adaptive Clinical Trial (COVID-19) (ACOVACT)

Medical University of Vienna

Status and phase: Unknown; Phase 3; Phase 2

Conditions: COVID-19

Treatments: Drug: Pentaglobin; Drug: non-RAS blocking antihypertensives; Drug: Remdesivir; Drug: Candesartan; Drug: Asunercept 400mg; Other: Best standard of care; Drug: Chloroquine or Hydroxychloroquine; Drug: Asunercept 25mg; Drug: Asunercept 100mg; Drug: Lopinavir/Ritonavir; Drug: Thromboprophylaxis; Drug: Rivaroxaban

Study type: Interventional

Funder types: Other

Identifiers

NCT04351724

ACOVACT

Details and patient eligibility

About

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.

Enrollment: 500 estimated patients

Sex: All

Ages: 18 to 99 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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500 participants in 14 patient groups

(Hydroxy)Chloroquine (STOPPED)

Experimental group

Description:

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

Treatment:

Drug: Chloroquine or Hydroxychloroquine

Lopinavir/Ritonavir

Experimental group

Description:

Dosage: 200mg/50mg 4-0-4 on day 1 and 3-0-3 thereafter

Treatment:

Drug: Lopinavir/Ritonavir

Standard of Care

Other group

Description:

patients will be treated with "standard of care", which precludes treatment with lopinavir/ritonavir or (hydroxy-)chloroquine

Treatment:

Other: Best standard of care

Rivaroxaban

Experimental group

Description:

5mg 1-0-1

Treatment:

Drug: Rivaroxaban

Thromboprophylaxis

Active Comparator group

Description:

according to local standard

Treatment:

Drug: Thromboprophylaxis

RAS Blockade

Experimental group

Description:

Renin-Angiotensin-System-Blockade (RAS) by candesartan intake starting with 4mg once daily and titrated to normotension patients \> 120/80 mmHG are eligible

Treatment:

Drug: Candesartan

non-RAS-Blockade

Active Comparator group

Description:

non-RAS blocking antihypertensive agents titrated to normotension Those with normal blood pressure may only be controlled without further treatment

Treatment:

Drug: non-RAS blocking antihypertensives

Asunercept 25mg

Experimental group

Description:

25mg 1x per week, maximum of four doses only patients with oxygen requirement

Treatment:

Drug: Asunercept 25mg

Asunercept 100mg

Experimental group

Description:

100mg 1x per week, maximum of four doses only patients with oxygen requirement

Treatment:

Drug: Asunercept 100mg

Asunercept 400mg

Experimental group

Description:

400mg 1x per week, maximum of four doses only patients with oxygen requirement

Treatment:

Drug: Asunercept 400mg

Best Standard of Care - Control Group for Asunercept

Other group

Description:

only patients with oxygen requirement

Treatment:

Other: Best standard of care

Remdesivir

Experimental group

Description:

200mg loading dose on day 1, 100mg for a total treatment duration of 5-10 days

Treatment:

Drug: Remdesivir

Pentaglobin

Experimental group

Description:

Patients treated at the intensive care unit only, continuous infusion of 7ml/kg/day over 12h for 5 days

Treatment:

Drug: Pentaglobin

best standard of care

Other group

Description:

Patients treated at the intensive care unit only

Treatment:

Other: Best standard of care