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

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)

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 Overview

• Status: Unknown
• Conditions: COVID-19
• Intervention / Treatment: Drug: Chloroquine or Hydroxychloroquine; Drug: Lopinavir/Ritonavir; Other: Best standard of care; Drug: Rivaroxaban; Drug: Thromboprophylaxis; Drug: Candesartan; Drug: non-RAS blocking antihypertensives; Drug: Asunercept 25mg; Drug: Asunercept 100mg; Drug: Asunercept 400mg; Drug: Remdesivir; Drug: Pentaglobin

• Study Type: Interventional
• Enrollment (Anticipated): 500
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Bernd Jilma, MD; Phone Number: +4314040029810; Email: klin-pharmakologie@meduniwien.ac.at
• Study Contact Backup: Name: Christian Schörgenhofer, MD, PHD; Phone Number: +4314040029810; Email: klin-pharmakologie@meduniwien.ac.at

Study Locations

• Austria
  • Graz, Austria
    • Recruiting
    • Medical University of Graz
    • Contact: Robert Krause, Prof.Dr.; Phone Number: +43 316 385 81796; Email: robert.krause@medunigraz.at
    • Principal Investigator: Robert Krause, Prof.Dr.
  • Linz, Austria
    • Recruiting
    • Kepler University Hospital
    • Contact: Bernd Lamprecht, MD; Phone Number: +43 (0)5 7680 83 - 6910; Email: Bernd.Lamprecht@kepleruniklinikum.at
  • Vienna, Austria, 1090
    • Recruiting
    • Medical University of Vienna
    • Contact: Bernd Jilma, MD; Phone Number: +4314040029810; Email: klin-pharmakologie@meduniwien.ac.at
    • Contact: Christian Schörgenhofer, MD, PHD; Phone Number: +4314040029810; Email: klin-pharmakologie@meduniwien.ac.at
  • Vienna, Austria, 1090
    • Not yet recruiting
    • Wilhelminenspital
    • Contact: Georg-Christian Funk, MD; Phone Number: +431491502201; Email: georg-christian.funk@wienkav.at
  • Vienna, Austria, 1100
    • Recruiting
    • SMZ Süd Kaiser Franz Josef Spital
    • Contact: Alexander Zoufaly, MD; Phone Number: 431601912408; Email: alexander.zoufaly@wienkav.at
  • Vienna, Austria, 1130
    • Not yet recruiting
    • KH Hietzing
    • Contact: Kurt Redlich, MD; Phone Number: +431801103173; Email: kurt.redlich@wienkav.at
  • Vienna, Austria, 1140
    • Not yet recruiting
    • SMZ Baumgartner Höhe Otto Wagner Spital
    • Contact: Brigitte Schmied, MD; Phone Number: +4319106042713; Email: brigitte.schmied@meduniwien.ac.at
  • Vienna, Austria, 1220
    • Not yet recruiting
    • SMZ Ost Donauspital
    • Contact: Thomas Stefenelli, MD; Phone Number: +431288023102; Email: thomas.stefenelli@wienkav.at
  • Tirol
    • Innsbruck, Tirol, Austria, 6020
      • Not yet recruiting
      • Medical University of Innsbruck
      • Contact: Günter Weiss, MD; Phone Number: +4351250423251; Email: guenter.weiss@i-med.ac.at

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

14

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: (Hydroxy)Chloroquine (STOPPED); 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	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
EXPERIMENTAL: Lopinavir/Ritonavir; Dosage: 200mg/50mg 4-0-4 on day 1 and 3-0-3 thereafter	Drug: Lopinavir/Ritonavir; Lopinavir/Ritonavir 200mg/50mg 2-0-2
OTHER: Standard of Care; patients will be treated with "standard of care", which precludes treatment with lopinavir/ritonavir or (hydroxy-)chloroquine	Other: Best standard of care; best standard of care
EXPERIMENTAL: Rivaroxaban; 5mg 1-0-1	Drug: Rivaroxaban; 2.5mg 2-0-2 or 10mg 1/2-0-1/2, as applicable
ACTIVE_COMPARATOR: Thromboprophylaxis; according to local standard	Drug: Thromboprophylaxis; as local standard, most likely to be low molecular weight heparin
EXPERIMENTAL: RAS Blockade; Renin-Angiotensin-System-Blockade (RAS) by candesartan intake starting with 4mg once daily and titrated to normotension patients > 120/80 mmHG are eligible	Drug: Candesartan; starting dose 4mg once daily, titrated to normotension
ACTIVE_COMPARATOR: non-RAS-Blockade; non-RAS blocking antihypertensive agents titrated to normotension Those with normal blood pressure may only be controlled without further treatment	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
EXPERIMENTAL: Asunercept 25mg; 25mg 1x per week, maximum of four doses only patients with oxygen requirement	Drug: Asunercept 25mg; asunercept 25mg once per week, up to 4 doses in total
EXPERIMENTAL: Asunercept 100mg; 100mg 1x per week, maximum of four doses only patients with oxygen requirement	Drug: Asunercept 100mg; asunercept 100mg once per week, up to 4 doses in total
EXPERIMENTAL: Asunercept 400mg; 400mg 1x per week, maximum of four doses only patients with oxygen requirement	Drug: Asunercept 400mg; asunercept 400mg once per week, up to 4 doses in total
OTHER: Best Standard of Care - Control Group for Asunercept; only patients with oxygen requirement	Other: Best standard of care; best standard of care
EXPERIMENTAL: Remdesivir; 200mg loading dose on day 1, 100mg for a total treatment duration of 5-10 days	Drug: Remdesivir; 200mg on day 1, thereafter 100mg for a total of 5-10 treatment days, according to local standards
EXPERIMENTAL: Pentaglobin; Patients treated at the intensive care unit only, continuous infusion of 7ml/kg/day over 12h for 5 days	Drug: Pentaglobin; 7ml/kg/day for 12h for 5 days
OTHER: best standard of care; Patients treated at the intensive care unit only	Other: Best standard of care; best standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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: Not hospitalized, no limitations on activities; Not hospitalized, limitation on activities;; Hospitalized, not requiring supplemental oxygen;; Hospitalized, requiring supplemental oxygen;; Hospitalized, on non-invasive ventilation or high flow oxygen devices;; Hospitalized, on invasive mechanical ventilation or ECMO;; 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).	Inclusion to day 29, daily evaluation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to improvement on WHO Scale	The scale described in the primary endpoint is used	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	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)	Inclusion to day 29, daily evaluation
change from baseline in National Early Warning Score (NEWS)	The scale described in the primary endpoint is used	Inclusion to day 29, daily evaluation
Oxygenation free days		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	Inclusion to day 29, daily evaluation
duration of oxygen use during the trial		Inclusion to day 29, daily evaluation
Ventilator free days until day 29	number of days with requirement of mechanical ventilation	Inclusion to day 29, daily evaluation
Incidence of new mechanical ventilation use during the trial		Inclusion to day 29, daily evaluation
duration of mechanical ventilation use during the trial		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	Inclusion to day 29, daily evaluation
Duration of Hospitalization		Inclusion to day 29, daily evaluation
Mortality		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	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	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	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	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.	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	Inclusion to day 29, daily evaluation
SpO2/FiO2 ratio	for sub-study C only	Inclusion to day 29, daily evaluation
paO/FiO2 ratio	for sub-study C only, for ICU patients only	Inclusion to day 29, daily evaluation
modified Sequential Organ Failure Assessment	for sub-study C only	Inclusion to day 29, daily evaluation
C-reactive protein	unit mg/dL	baseline, day 2, 3, 4, 5, 7
Interleukin-6	unit pg/mL	baseline, day 2, 3, 4, 5, 7
procalcitonin	unit ng/mL	baseline, day 2, 3, 4, 5, 7
IgM Concentrations	unit mg/dL	baseline, day 2, 3, 4, 5, 7
IgA Concentrations	unit mg/dL	baseline, day 2, 3, 4, 5, 7
differential blood counts		baseline, day 2, 3, 4, 5, 7

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Collaborators: Medical University of Graz; Medical University Innsbruck; SMZ-Ost Donauspital; Hospital Hietzing; Kepler University Hospital; Otto Wagner Hospital; Kaiser Franz Josef Hospital; Wilhelminenspital Vienna

Publications and helpful links

General Publications

• Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
• Hofstetter L, Tinhof V, Mayfurth H, Kurnikowski A, Rathkolb V, Reindl-Schwaighofer R, Traugott M, Omid S, Zoufaly A, Tong A, Kropiunigg U, Hecking M. Experiences and challenges faced by patients with COVID-19 who were hospitalised and participated in a randomised controlled trial: a qualitative study. BMJ Open. 2022 Oct 11;12(10):e062176. doi: 10.1136/bmjopen-2022-062176.
• Karolyi M, Pawelka E, Omid S, Koenig F, Kauer V, Rumpf B, Hoepler W, Kuran A, Laferl H, Seitz T, Traugott M, Rathkolb V, Mueller M, Abrahamowicz A, Schoergenhofer C, Hecking M, Assinger A, Wenisch C, Zeitlinger M, Jilma B, Zoufaly A. Camostat Mesylate Versus Lopinavir/Ritonavir in Hospitalized Patients With COVID-19-Results From a Randomized, Controlled, Open Label, Platform Trial (ACOVACT). Front Pharmacol. 2022 Jul 22;13:870493. doi: 10.3389/fphar.2022.870493. eCollection 2022.
• Heber S, Pereyra D, Schrottmaier WC, Kammerer K, Santol J, Rumpf B, Pawelka E, Hanna M, Scholz A, Liu M, Hell A, Heiplik K, Lickefett B, Havervall S, Traugott MT, Neubock MJ, Schorgenhofer C, Seitz T, Firbas C, Karolyi M, Weiss G, Jilma B, Thalin C, Bellmann-Weiler R, Salzer HJF, Szepannek G, Fischer MJM, Zoufaly A, Gleiss A, Assinger A. A Model Predicting Mortality of Hospitalized Covid-19 Patients Four Days After Admission: Development, Internal and Temporal-External Validation. Front Cell Infect Microbiol. 2022 Jan 24;11:795026. doi: 10.3389/fcimb.2021.795026. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 16, 2020
• Primary Completion (ANTICIPATED): December 1, 2021
• Study Completion (ANTICIPATED): March 31, 2022

Study Registration Dates

• First Submitted: April 10, 2020
• First Submitted That Met QC Criteria: April 16, 2020
• First Posted (ACTUAL): April 17, 2020

Study Record Updates

• Last Update Posted (ACTUAL): March 2, 2021
• Last Update Submitted That Met QC Criteria: February 25, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antirheumatic Agents; Antimetabolites; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Antiprotozoal Agents; Antiparasitic Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; HIV Protease Inhibitors; Viral Protease Inhibitors; Antimalarials; Amebicides; Rivaroxaban; Ritonavir; Lopinavir; Antihypertensive Agents; Chloroquine; Candesartan; Hydroxychloroquine; Remdesivir; Candesartan cilexetil
• Other Study ID Numbers: ACOVACT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Anonymized and pseudonymized data will be published in peer reviewed journals and may be presented at congresses and conferences

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No