Clinical trial NCT04351724: Austrian CoronaVirus Adaptive Clinical Trial (COVID-19)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: COVID-19
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
Collaborators: name: Kaiser Franz Josef Hospital
name: SMZ-Ost Donauspital
name: Otto Wagner Hospital
name: Hospital Hietzing
name: Wilhelminenspital Vienna
name: Medical University Innsbruck
name: Medical University of Graz
name: Kepler University Hospital
First posted: 2020-04-17
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Three main study arms (antiviral treatments) and three substudies (A, B, C) are planned. The main study arms are exclusive, while patients from the main study arms may participate in one or more substudies.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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

Primary outcomes:
measure: sustained improvement (>48h) of one point on the WHO Scale
timeFrame: Inclusion to day 29, daily evaluation
Secondary outcomes:
measure: Time to improvement on WHO Scale
timeFrame: Inclusion to day 29, daily evaluation
measure: Mean change in the ranking on an ordinal scale from baseline
timeFrame: Inclusion to day 29, daily evaluation
measure: time to discharge or a National Early Warning Score (NEWS) ≤2 (maintained for 24h), whichever occurs first
timeFrame: Inclusion to day 29, daily evaluation
measure: change from baseline in National Early Warning Score (NEWS)
timeFrame: Inclusion to day 29, daily evaluation
measure: Oxygenation free days
timeFrame: Inclusion to day 29, daily evaluation
measure: Incidence of new oxygen use during the trial
timeFrame: Inclusion to day 29, daily evaluation
measure: duration of oxygen use during the trial
timeFrame: Inclusion to day 29, daily evaluation
measure: Ventilator free days until day 29
timeFrame: Inclusion to day 29, daily evaluation
measure: Incidence of new mechanical ventilation use during the trial
timeFrame: Inclusion to day 29, daily evaluation
measure: duration of mechanical ventilation use during the trial
timeFrame: Inclusion to day 29, daily evaluation
measure: Viral load/viral clearance
timeFrame: Inclusion to day 29, daily evaluation
measure: Duration of Hospitalization
timeFrame: Inclusion to day 29, daily evaluation
measure: Mortality
timeFrame: 15-day, 29-day, 60-day, 90-day mortality
measure: Obesity - mortality
timeFrame: BMI at admission, mortality until day 29
measure: Obesity - duration of hospitalization
timeFrame: BMI at admission, duration of hospitalization until day 29 or discharge
measure: Obesity - ICU admission
timeFrame: BMI at admission, ICU admission until day 29 or discharge
measure: Obesity - new oxygen use
timeFrame: BMI at admission, new oxygen use until day 29 or discharge
measure: Drug-drug interactions with lopinavir/ritonavir
timeFrame: Inclusion to day 29, daily evaluation
measure: Renin Angiotensin System (RAS) fingerprint
timeFrame: Inclusion to day 29, daily evaluation
measure: SpO2/FiO2 ratio
timeFrame: Inclusion to day 29, daily evaluation
measure: paO/FiO2 ratio
timeFrame: Inclusion to day 29, daily evaluation
measure: modified Sequential Organ Failure Assessment
timeFrame: Inclusion to day 29, daily evaluation
measure: C-reactive protein
timeFrame: baseline, day 2, 3, 4, 5, 7
measure: Interleukin-6
timeFrame: baseline, day 2, 3, 4, 5, 7
measure: procalcitonin
timeFrame: baseline, day 2, 3, 4, 5, 7
measure: IgM Concentrations
timeFrame: baseline, day 2, 3, 4, 5, 7
measure: IgA Concentrations
timeFrame: baseline, day 2, 3, 4, 5, 7
measure: differential blood counts
timeFrame: baseline, day 2, 3, 4, 5, 7
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Medical University of Innsbruck
state: Tirol
city: Graz
country: Austria
facility: Medical University of Graz
city: Linz
country: Austria
facility: Kepler University Hospital
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Vienna
country: Austria
facility: Wilhelminenspital
city: Vienna
country: Austria
facility: SMZ Süd Kaiser Franz Josef Spital
city: Vienna
country: Austria
facility: KH Hietzing
city: Vienna
country: Austria
facility: SMZ Baumgartner Höhe Otto Wagner Spital
city: Vienna
country: Austria
facility: SMZ Ost Donauspital
Study officials:
affiliation: Medical University of Vienna
name: Bernd Jilma, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.