Austrian CoronaVirus Adaptive Clinical Trial (COVID-19)

Medical University of Vienna500 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

500

Conditions

COVID-19

Interventions

Hydroxychloroquine 200mg 2-0-2 on day 1 followed by 200mg 1-0-1, or Chloroquine 250mg 2-0-2, as available

Lopinavir/RitonavirDRUG

Lopinavir/Ritonavir 200mg/50mg 2-0-2

Best standard of careOTHER

best standard of care

RivaroxabanDRUG

2.5mg 2-0-2 or 10mg 1/2-0-1/2, as applicable

ThromboprophylaxisDRUG

as local standard, most likely to be low molecular weight heparin

CandesartanDRUG

starting dose 4mg once daily, titrated to normotension

non-RAS blocking antihypertensivesDRUG

This excludes angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (AT-blockers, sartans) and includes alpha-receptor antagonists, calcium antagonists, amongst others

RemdesivirDRUG

200mg on day 1, thereafter 100mg for a total of 5-10 treatment days, according to local standards

Asunercept 400mgDRUG

asunercept 400mg once per week, up to 4 doses in total

Asunercept 100mgDRUG

asunercept 100mg once per week, up to 4 doses in total

Asunercept 25mgDRUG

asunercept 25mg once per week, up to 4 doses in total

PentaglobinDRUG

7ml/kg/day for 12h for 5 days

Eligibility

Sex: ALLMin age: 18 YearsMax age: 99 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (9)

Medical University of Innsbruck

Innsbruck, Tyrol, Austria

NOT_YET_RECRUITING

Medical University of Graz

Graz, Austria

RECRUITING

Kepler University Hospital

Linz, Austria

RECRUITING

Medical University of Vienna

Vienna, Austria

RECRUITING

Wilhelminenspital

Vienna, Austria

NOT_YET_RECRUITING

SMZ Süd Kaiser Franz Josef Spital

Vienna, Austria

RECRUITING

KH Hietzing

Vienna, Austria

NOT_YET_RECRUITING

SMZ Baumgartner Höhe Otto Wagner Spital

Vienna, Austria

NOT_YET_RECRUITING

SMZ Ost Donauspital

Vienna, Austria

NOT_YET_RECRUITING

Outcomes

Primary Outcomes

sustained improvement (>48h) of one point on the WHO Scale

The primary endpoint is time to clinical improvement which is defined as time from randomization to an (sustained) improvement of at least one category on two consecutive days compared to the status at randomization measured on a seven-category ordinal scale (proposed by WHO). The 7-categories of the World Health Organization proposed scale, as follows: 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities; 3. Hospitalized, not requiring supplemental oxygen; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 6. Hospitalized, on invasive mechanical ventilation or ECMO; 7. Death. During hospitalization this score will be determined daily (till day 29). If a patient is released from the hospital before day 29, the score will be determined at day 11 and 29 after randomization (depending when the patient was released or by telephone call).

Time frame: Inclusion to day 29, daily evaluation

Secondary Outcomes

Time to improvement on WHO Scale

The scale described in the primary endpoint is used

Time frame: Inclusion to day 29, daily evaluation

Mean change in the ranking on an ordinal scale from baseline

The scale described in the primary endpoint is used

Time frame: Inclusion to day 29, daily evaluation

time to discharge or a National Early Warning Score (NEWS) ≤2 (maintained for 24h), whichever occurs first

the National Early Warning Score includes respiratory rate, oxygen saturation, use of supplemental oxygen, temperature, systolic blood pressure, heart rate and levels of consciousness (AVPU Scale)

Time frame: Inclusion to day 29, daily evaluation

change from baseline in National Early Warning Score (NEWS)

The scale described in the primary endpoint is used

Time frame: Inclusion to day 29, daily evaluation

Oxygenation free days

Time frame: Inclusion to day 29, daily evaluation

Incidence of new oxygen use during the trial

new oxygen may include insufflation or oxygen mask, high flow oxygen devices, non-invasive ventilation devices or mechanical ventilation

Time frame: Inclusion to day 29, daily evaluation

duration of oxygen use during the trial

Time frame: Inclusion to day 29, daily evaluation

Ventilator free days until day 29

number of days with requirement of mechanical ventilation

Time frame: Inclusion to day 29, daily evaluation

Incidence of new mechanical ventilation use during the trial

Time frame: Inclusion to day 29, daily evaluation

duration of mechanical ventilation use during the trial

Time frame: Inclusion to day 29, daily evaluation

Viral load/viral clearance

obtained by polymerase chain reaction in nasal/oropharyngeal swabs, performed at baseline and then three times a week, if possible

Time frame: Inclusion to day 29, daily evaluation

Duration of Hospitalization

Time frame: Inclusion to day 29, daily evaluation

Mortality

Time frame: 15-day, 29-day, 60-day, 90-day mortality

Obesity - mortality

BMI (kg/m2), within all subjects the impact of obesity on overall mortality will be investigated

Time frame: BMI at admission, mortality until day 29

Obesity - duration of hospitalization

BMI (kg/m2) , within all subjects the impact of obesity on the duration of hospitalization will be investigated

Time frame: BMI at admission, duration of hospitalization until day 29 or discharge

Obesity - ICU admission

BMI (kg/m2) , within all subjects the impact of obesity on ICU admission will be investigated

Time frame: BMI at admission, ICU admission until day 29 or discharge

Obesity - new oxygen use

BMI (kg/m2) new oxygen may include insufflation or oxygen mask, high flow oxygen devices, non-invasive ventilation devices or mechanical ventilation

Time frame: BMI at admission, new oxygen use until day 29 or discharge

Drug-drug interactions with lopinavir/ritonavir

lopinavir and ritonavir both interact with numerous other drugs by inhibiting the cytochrome enzymes 3A4. Using commercially available drug-interaction programs, the number and severity grading of drug-drug-interactions will be documented (for instance uptodate interaction tool, medscape). This is an exploratory analysis of drug-drug interactions with the above mentioned substances. severity grading usually encompass "contraindicated", "serious", "monitor closely", "minor" interaction.

Time frame: Inclusion to day 29, daily evaluation

Renin Angiotensin System (RAS) fingerprint

for sub-study B only: RAS fingerprint measures metabolites involved in the renin-angiotensin-system. The influence of randomized treatment with candesartan (RAS blockade) will be analyzed

Time frame: Inclusion to day 29, daily evaluation

SpO2/FiO2 ratio

for sub-study C only

Time frame: Inclusion to day 29, daily evaluation

paO/FiO2 ratio

for sub-study C only, for ICU patients only

Time frame: Inclusion to day 29, daily evaluation

modified Sequential Organ Failure Assessment

for sub-study C only

Time frame: Inclusion to day 29, daily evaluation

C-reactive protein

unit mg/dL

Time frame: baseline, day 2, 3, 4, 5, 7

Interleukin-6

unit pg/mL

Time frame: baseline, day 2, 3, 4, 5, 7

procalcitonin

unit ng/mL

Time frame: baseline, day 2, 3, 4, 5, 7

IgM Concentrations

unit mg/dL

Time frame: baseline, day 2, 3, 4, 5, 7

IgA Concentrations

unit mg/dL

Time frame: baseline, day 2, 3, 4, 5, 7

differential blood counts

Time frame: baseline, day 2, 3, 4, 5, 7

Central Contacts

Bernd Jilma, MD

CONTACT

+4314040029810 klin-pharmakologie@meduniwien.ac.at

Christian Schörgenhofer, MD, PHD

CONTACT

+4314040029810 klin-pharmakologie@meduniwien.ac.at

Data from ClinicalTrials.gov

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