Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04351724
Recruitment Status : Recruiting
First Posted : April 17, 2020
Last Update Posted : April 24, 2020
Sponsor:
Collaborators:
Kaiser Franz Josef Hospital
SMZ-Ost Donauspital
Otto Wagner Hospital
Hospital Hietzing
Wilhelminenspital Vienna
Medical University Innsbruck
Information provided by (Responsible Party):
Bernd Jilma, Medical University of Vienna

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, lopinavir/ritonavir 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 (clazakizumab 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.


Condition or disease Intervention/treatment Phase
COVID-19 Drug: Chloroquine or Hydroxychloroquine Drug: Lopinavir/Ritonavir Other: Best standard of care Drug: Rivaroxaban Drug: Thromboprophylaxis Drug: Candesartan Drug: non-RAS blocking antihypertensives Drug: Clazakizumab Drug: placebo for clazakizumab Phase 2 Phase 3

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 500 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : April 16, 2020
Estimated Primary Completion Date : December 1, 2020
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: (Hydroxy)Chloroquine

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

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 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: Clazakizumab
patients with respiratory deterioration qualify for this treatment arm
Drug: Clazakizumab
25mg i.v. single dose, possibly a repeated dose

Placebo Comparator: Placebo
patients with respiratory deterioration qualify for this treatment arm
Drug: placebo for clazakizumab
sodium chloride bolus infusions as placebo for clazakizumab
Other Name: sodium chloride




Primary Outcome Measures :
  1. sustained improvement (>48h) of one point on the WHO Scale [ Time Frame: Inclusion to day 29, daily evaluation ]

    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).



Secondary Outcome Measures :
  1. Time to improvement on WHO Scale [ Time Frame: Inclusion to day 29, daily evaluation ]
    The scale described in the primary endpoint is used

  2. Mean change in the ranking on an ordinal scale from baseline [ Time Frame: Inclusion to day 29, daily evaluation ]
    The scale described in the primary endpoint is used

  3. time to discharge or a National Early Warning Score (NEWS) ≤2 (maintained for 24h), whichever occurs first [ Time Frame: Inclusion to day 29, daily evaluation ]
    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)

  4. change from baseline in National Early Warning Score (NEWS) [ Time Frame: Inclusion to day 29, daily evaluation ]
    The scale described in the primary endpoint is used

  5. Oxygenation free days [ Time Frame: Inclusion to day 29, daily evaluation ]
  6. Incidence of new oxygen use during the trial [ Time Frame: Inclusion to day 29, daily evaluation ]
    new oxygen may include insufflation or oxygen mask, high flow oxygen devices, non-invasive ventilation devices or mechanical ventilation

  7. duration of oxygen use during the trial [ Time Frame: Inclusion to day 29, daily evaluation ]
  8. Ventilator free days until day 29 [ Time Frame: Inclusion to day 29, daily evaluation ]
    number of days with requirement of mechanical ventilation

  9. Incidence of new mechanical ventilation use during the trial [ Time Frame: Inclusion to day 29, daily evaluation ]
  10. duration of mechanical ventilation use during the trial [ Time Frame: Inclusion to day 29, daily evaluation ]
  11. Viral load/viral clearance [ Time Frame: Inclusion to day 29, daily evaluation ]
    obtained by polymerase chain reaction in nasal/oropharyngeal swabs, performed at baseline and then three times a week, if possible

  12. Duration of Hospitalization [ Time Frame: Inclusion to day 29, daily evaluation ]
  13. Mortality [ Time Frame: 15-day, 29-day mortality ]
  14. Obesity - mortality [ Time Frame: BMI at admission, mortality until day 29 ]
    BMI (kg/m2), within all subjects the impact of obesity on overall mortality will be investigated

  15. Obesity - duration of hospitalization [ Time Frame: BMI at admission, duration of hospitalization until day 29 or discharge ]
    BMI (kg/m2) , within all subjects the impact of obesity on the duration of hospitalization will be investigated

  16. Obesity - ICU admission [ Time Frame: BMI at admission, ICU admission until day 29 or discharge ]
    BMI (kg/m2) , within all subjects the impact of obesity on ICU admission will be investigated

  17. Obesity - new oxygen use [ Time Frame: BMI at admission, new oxygen use until day 29 or discharge ]
    BMI (kg/m2) new oxygen may include insufflation or oxygen mask, high flow oxygen devices, non-invasive ventilation devices or mechanical ventilation

  18. Drug-drug interactions with lopinavir/ritonavir [ Time Frame: Inclusion to day 29, daily evaluation ]
    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.

  19. Renin Angiotensin System (RAS) fingerprint [ Time Frame: Inclusion to day 29, daily evaluation ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Laboratory confirmed infection with SARS-CoV-2 ≤72 hours before randomization
  • Hospitalisation due to SARS-CoV-2 infection (for anti-viral treatment arms)
  • For "antiviral" therapy because of limited drug supplies: oxygen saturation <94% when breathing room 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 substudy C: obtaining informed consent may be impossible due to the severe condition of the patient and may be waived
  • ≥18 years of age
  • For female patients with childbearing potential: willingness to perform effective measures of contraception during the study.
  • Sub-study A: eGFR of >20 mL/min
  • Sub-study B: outpatients with COVID-19 may be included
  • Sub-study B: blood pressure ≥120/80mmHg in 2 consecutive measurements
  • 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: control group 2: healthy volunteers
  • Sub-study C: Signs of respiratory deterioration and progressing inflammation such as need for oxygen supplementation to achieve satisfactory blood oxygen saturation (sPO2>90% at room air) as well as the need for mechanical ventilation, novel onset of uni- or bilateral lung infiltrates in CXR/CT scan, CRP levels >5mg/dL

Exclusion Criteria:

  • Moribund or estimated life expectancy <1 month (e.g. terminal cancer, etc.)
  • Pregnancy or breastfeeding
  • Severe liver dysfunction (e.g. ALT/AST > 5 times upper limit of normal)
  • Stage 4 chronic kidney disease or requiring dialysis (except for ritonavir/lopinavir)
  • Allergy or intolerances to any of the experimental substances -> exclusion for the respective treatment arm
  • Anticipated discharge of hospital within 48 hours (for anti-viral treatment arms)
  • Contraindications treatment arm 1: chloroquine/ hydroxychloroquine: concomitant amiodarone treatment, retinopathy, psoriasis, glucose-6-phosphate deficiency, severe cardiomyopathy and known, clinically relevant arrhythmias, porphyria cutanea tarda
  • Clinically relevant QTc prolongation during screening
  • Contraindications treatment arm 2: severe hepatic impairment, CYP3A4/5 metabolized drugs as deemed relevant by treating physicians, HIV positive
  • Contraindications treatment arm 3: IgA deficiency
  • Sub-study A Contraindications: 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.
  • Sub-study A: ongoing therapeutic anticoagulation, which will continue, according to clinical practice
  • Sub-study B Contraindications chronic heart failure, allergies, hypersensitivities and intolerances, severe hepatic impairment and/or cholestasis, concomitant therapy with aliskiren-containing 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 B: Control group 1: with or without RAS blockers, Control group 2: Healthy volunteers: concomitant medication with RAS-blockers
  • Sub-study C: Contraindications Clazakizumab arm: history of gastrointestinal perforation, diverticulitis, or inflammatory bowel disease, treatment with an IL-6 or IL-6R blocking drug (e.g. tocilizumab, sarilumab, siltuximab) <30 days before study inclusion.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04351724


Contacts
Layout table for location contacts
Contact: Bernd Jilma, MD +4314040029810 klin-pharmakologie@meduniwien.ac.at
Contact: Christian Schörgenhofer, MD, PHD +4314040029810 klin-pharmakologie@meduniwien.ac.at

Locations
Layout table for location information
Austria
Medical University of Innsbruck Not yet recruiting
Innsbruck, Tirol, Austria, 6020
Contact: Günter Weiss, MD    +4351250423251    guenter.weiss@i-med.ac.at   
Medical University of Vienna Recruiting
Vienna, Austria, 1090
Contact: Bernd Jilma, MD    +4314040029810    klin-pharmakologie@meduniwien.ac.at   
Contact: Christian Schörgenhofer, MD, PHD    +4314040029810    klin-pharmakologie@meduniwien.ac.at   
Wilhelminenspital Not yet recruiting
Vienna, Austria, 1090
Contact: Georg-Christian Funk, MD    +431491502201    georg-christian.funk@wienkav.at   
SMZ Süd Kaiser Franz Josef Spital Recruiting
Vienna, Austria, 1100
Contact: Alexander Zoufaly, MD    431601912408    alexander.zoufaly@wienkav.at   
KH Hietzing Not yet recruiting
Vienna, Austria, 1130
Contact: Kurt Redlich, MD    +431801103173    kurt.redlich@wienkav.at   
SMZ Baumgartner Höhe Otto Wagner Spital Not yet recruiting
Vienna, Austria, 1140
Contact: Brigitte Schmied, MD    +4319106042713    brigitte.schmied@meduniwien.ac.at   
SMZ Ost Donauspital Not yet recruiting
Vienna, Austria, 1220
Contact: Thomas Stefenelli, MD    +431288023102    thomas.stefenelli@wienkav.at   
Sponsors and Collaborators
Medical University of Vienna
Kaiser Franz Josef Hospital
SMZ-Ost Donauspital
Otto Wagner Hospital
Hospital Hietzing
Wilhelminenspital Vienna
Medical University Innsbruck
Investigators
Layout table for investigator information
Principal Investigator: Bernd Jilma, MD Medical University of Vienna
Layout table for additonal information
Responsible Party: Bernd Jilma, Univ.Prof.Dr. Bernd Jilma, Medical University of Vienna
ClinicalTrials.gov Identifier: NCT04351724    
Other Study ID Numbers: ACOVACT
First Posted: April 17, 2020    Key Record Dates
Last Update Posted: April 24, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Anonymized and pseudonymized data will be published in peer reviewed journals and may be presented at congresses and conferences

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Ritonavir
Lopinavir
Hydroxychloroquine
Chloroquine
Candesartan
Rivaroxaban
Antihypertensive Agents
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Antirheumatic Agents
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Anticoagulants