COVID-19
Conditions
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.
Interventions
Hydroxychloroquine 200mg 2-0-2 on day 1 followed by 200mg 1-0-1, or Chloroquine 250mg 2-0-2, as available
DRUGLopinavir/Ritonavir
Lopinavir/Ritonavir 200mg/50mg 2-0-2
best standard of care
DRUGRivaroxaban
2.5mg 2-0-2 or 10mg 1/2-0-1/2, as applicable
DRUGThromboprophylaxis
as local standard, most likely to be low molecular weight heparin
DRUGCandesartan
starting dose 4mg once daily, titrated to normotension
DRUGnon-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
DRUGRemdesivir
200mg on day 1, thereafter 100mg for a total of 5-10 treatment days, according to local standards
DRUGAsunercept 400mg
asunercept 400mg once per week, up to 4 doses in total
DRUGAsunercept 100mg
asunercept 100mg once per week, up to 4 doses in total
DRUGAsunercept 25mg
asunercept 25mg once per week, up to 4 doses in total
DRUGPentaglobin
7ml/kg/day for 12h for 5 days
Sponsors
Kaiser Franz Josef Hospital
SMZ-Ost Donauspital
Otto Wagner Hospital
Hospital Hietzing
Wilhelminenspital Vienna
Medical University Innsbruck
Medical University of Graz
Kepler University Hospital
Medical University of Vienna
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| sustained improvement (>48h) of one point on the WHO Scale | 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
| Measure | Time frame | Description |
|---|---|---|
| Mean change in the ranking on an ordinal scale from baseline | Inclusion to day 29, daily evaluation | The scale described in the primary endpoint is used |
| time to discharge or a National Early Warning Score (NEWS) ≤2 (maintained for 24h), whichever occurs first | 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) |
| change from baseline in National Early Warning Score (NEWS) | Inclusion to day 29, daily evaluation | The scale described in the primary endpoint is used |
| Oxygenation free days | Inclusion to day 29, daily evaluation | — |
| Incidence of new oxygen use during the trial | 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 |
| duration of oxygen use during the trial | Inclusion to day 29, daily evaluation | — |
| Ventilator free days until day 29 | Inclusion to day 29, daily evaluation | number of days with requirement of mechanical ventilation |
| 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 | 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 |
| Duration of Hospitalization | Inclusion to day 29, daily evaluation | — |
| Mortality | 15-day, 29-day, 60-day, 90-day mortality | — |
| Obesity - mortality | BMI at admission, mortality until day 29 | BMI (kg/m2), within all subjects the impact of obesity on overall mortality will be investigated |
| Time to improvement on WHO Scale | Inclusion to day 29, daily evaluation | The scale described in the primary endpoint is used |
| Obesity - ICU admission | 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 |
| Obesity - new oxygen use | 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 |
| Drug-drug interactions with lopinavir/ritonavir | 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. |
| Renin Angiotensin System (RAS) fingerprint | 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 |
| SpO2/FiO2 ratio | Inclusion to day 29, daily evaluation | for sub-study C only |
| paO/FiO2 ratio | Inclusion to day 29, daily evaluation | for sub-study C only, for ICU patients only |
| modified Sequential Organ Failure Assessment | Inclusion to day 29, daily evaluation | for sub-study C only |
| C-reactive protein | baseline, day 2, 3, 4, 5, 7 | unit mg/dL |
| Interleukin-6 | baseline, day 2, 3, 4, 5, 7 | unit pg/mL |
| procalcitonin | baseline, day 2, 3, 4, 5, 7 | unit ng/mL |
| IgM Concentrations | baseline, day 2, 3, 4, 5, 7 | unit mg/dL |
| IgA Concentrations | baseline, day 2, 3, 4, 5, 7 | unit mg/dL |
| differential blood counts | baseline, day 2, 3, 4, 5, 7 | — |
| Obesity - duration of hospitalization | 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 |
Countries
Austria
Contacts
Primary ContactBernd Jilma, MD
Backup ContactChristian Schörgenhofer, MD, PHD
Outcome results
None listed