Austrian CoronaVirus Adaptive Clinical Trial (COVID-19)

COVID-19 Clinical Trial

— ACOVACT  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04351724
• Other study ID #: ACOVACT
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: April 16, 2020
• Est. completion date: March 31, 2022

Study information

• Verified date: February 2021
• Source: Medical University of Vienna
• Contact: Bernd Jilma, MD
• Phone: +4314040029810
• Email: klin-pharmakologie[@]meduniwien.ac.at
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: March 31, 2022
• Est. primary completion date: December 1, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• Coronavirus Infections
• COVID-19

Intervention

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

Other:
• Best standard of care
best standard of care

Drug:
• Rivaroxaban
2.5mg 2-0-2 or 10mg 1/2-0-1/2, as applicable
• Thromboprophylaxis
as local standard, most likely to be low molecular weight heparin
• Candesartan
starting dose 4mg once daily, titrated to normotension
• 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
• Remdesivir
200mg on day 1, thereafter 100mg for a total of 5-10 treatment days, according to local standards
• Asunercept 400mg
asunercept 400mg once per week, up to 4 doses in total
• Asunercept 100mg
asunercept 100mg once per week, up to 4 doses in total
• Asunercept 25mg
asunercept 25mg once per week, up to 4 doses in total
• Pentaglobin
7ml/kg/day for 12h for 5 days

Locations

Country	Name	City	State
Austria	Medical University of Graz	Graz
Austria	Medical University of Innsbruck	Innsbruck	Tirol
Austria	Kepler University Hospital	Linz
Austria	KH Hietzing	Vienna
Austria	Medical University of Vienna	Vienna
Austria	SMZ Baumgartner Höhe Otto Wagner Spital	Vienna
Austria	SMZ Ost Donauspital	Vienna
Austria	SMZ Süd Kaiser Franz Josef Spital	Vienna
Austria	Wilhelminenspital	Vienna

Sponsors (9)

Lead Sponsor	Collaborator
Medical University of Vienna	Hospital Hietzing, Kaiser Franz Josef Hospital, Kepler University Hospital, Medical University Innsbruck, Medical University of Graz, Otto Wagner Hospital, SMZ-Ost Donauspital, Wilhelminenspital Vienna

Country where clinical trial is conducted

Austria, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Time to improvement on WHO Scale	The scale described in the primary endpoint is used	Inclusion to day 29, daily evaluation
Secondary	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
Secondary	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
Secondary	change from baseline in National Early Warning Score (NEWS)	The scale described in the primary endpoint is used	Inclusion to day 29, daily evaluation
Secondary	Oxygenation free days		Inclusion to day 29, daily evaluation
Secondary	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
Secondary	duration of oxygen use during the trial		Inclusion to day 29, daily evaluation
Secondary	Ventilator free days until day 29	number of days with requirement of mechanical ventilation	Inclusion to day 29, daily evaluation
Secondary	Incidence of new mechanical ventilation use during the trial		Inclusion to day 29, daily evaluation
Secondary	duration of mechanical ventilation use during the trial		Inclusion to day 29, daily evaluation
Secondary	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
Secondary	Duration of Hospitalization		Inclusion to day 29, daily evaluation
Secondary	Mortality		15-day, 29-day, 60-day, 90-day mortality
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	SpO2/FiO2 ratio	for sub-study C only	Inclusion to day 29, daily evaluation
Secondary	paO/FiO2 ratio	for sub-study C only, for ICU patients only	Inclusion to day 29, daily evaluation
Secondary	modified Sequential Organ Failure Assessment	for sub-study C only	Inclusion to day 29, daily evaluation
Secondary	C-reactive protein	unit mg/dL	baseline, day 2, 3, 4, 5, 7
Secondary	Interleukin-6	unit pg/mL	baseline, day 2, 3, 4, 5, 7
Secondary	procalcitonin	unit ng/mL	baseline, day 2, 3, 4, 5, 7
Secondary	IgM Concentrations	unit mg/dL	baseline, day 2, 3, 4, 5, 7
Secondary	IgA Concentrations	unit mg/dL	baseline, day 2, 3, 4, 5, 7
Secondary	differential blood counts		baseline, day 2, 3, 4, 5, 7