| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038700 |
| E.1.2 | Term | Respiratory infection |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The overall objective of the study is to evaluate the clinical efficacy and safety of different investigational therapeutics relative to the standard of care in patients hospitalized with COVID-19. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the clinical efficacy of different investigational therapeutics as compared to one another or the control arm as assessed by Clinical Severity, Oxygenation, Mechanical Ventilation, Hospitalisation, Host thrombo-inflammatory status, Mortality and
Evaluate the safety of the interventions through 28 days of follow-up as compared to the control arm as assessed by
o Cumulative incidence of serious adverse events (SAEs) and adverse events (AEs) graded as severe.
o Discontinuation or temporary suspension of drug administration (for any reason).
o Changes in white cell count, haemoglobin, platelets, creatinine, glucose, total bilirubin, ALT, and AST over time. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject (≥18 years old) or legally authorized representative provides informed consent prior to initiation of any study procedures. When signed informed consent is not possible (e.g. due to restrictions to prevent viral transmission), verbal informed consent in the presence of a witness will be obtained and documented in the medical files. Signed informed consent will be obtained as soon as the safety concerns are mitigated.
2. Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
3. Male or non-pregnant female adult ≥18 years of age at time of enrolment.
4. Has a confirmed diagnosis of SARS-CoV-2 infection, defined as either:
a. laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other commercial or public health assay in any specimen as diagnosed within 72 hours prior to randomization
or
b. The combination of upper or lower respiratory infection symptoms (fever, cough, dyspnea, desaturation) and typical findings on chest CT scan and absence of other plausible diagnoses
5. Illness of any duration, and at least one of the following:
a. Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), or
b. Clinical assessment (evidence of rales/crackles on lung auscultation) AND SpO2 ≤ 94% on room air, or
c. Requiring mechanical ventilation and/or supplemental oxygen.
|
|
| E.4 | Principal exclusion criteria |
1. ALT/AST > 8 times the upper limit of normal.
2. Pregnancy or breastfeeding.
3. Allergy to any study medication.
4. Any medical condition which would impose an unacceptable safety hazard by participation in the study.
5. Study drug-specific exclusion criteria:
• For Aprotinin:
o Known active thromboembolic disease, defined as a history of idiopathic (unprovoked) deep vein thrombosis or pulmonary embolism, recent (<3m) deep vein thrombosis or pulmonary embolism, recent (<6m) myocardial infarction or coronary stenting, recent (<6m) ischemic stroke
o Renal insufficiency with CrCl <30ml/min or continuous renal replacement therapy, hemodialysis, or peritoneal dialysis
o Recent (<6m) cardiac surgery with cardiopulmonary bypass and/or use of aprotinin
• For LMWH:
o Active bleeding, a history of intracranial bleeding, or a recent (<3m) GI bleeding requiring transfusion and/or intervention, recent surgery in the central nervous system
o Renal insufficiency with CrCl < 20ml/min or continuous renal replacement therapy, hemodialysis, or peritoneal dialysis
o Blood platelet count < 30 000/µL
o Other conditions that are judged to carry an increased risk of bleeding as judged by the investigator
o Need for therapeutic anticoagulation (known active thrombo-embolic diseases, atrial fibrillation, mechanical prosthetic heart valve,…)
• For Anakinra:
o Impairment of cardiac function defined as severe heart failure, unstable angina pectoris, myocardial infarction within 6 months before enrollment, ventricular arrhythmia requiring treatment or intervention.
o Severe renal dysfunction (creatinine clearance ≤ 20mL/min) or receive continuous renal replacement therapy, hemodialysis, or peritoneal dialysis.
o Uncontrolled hypertension (persistent systolic blood pressure >180mmHg, or diastolic blood pressure >110mmHg)
o Clinical suspicion of latent tuberculosis
o Clinical suspicion of severe bacterial surinfection (e.g. ventilator-associated pneumonia) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Pilot phase of DAWN-ANTICO:
D-dimer on day 6
Clinical status of subject at day 15 (on a 7-point ordinal scale):
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.
Primary outcome will be time from Day 0 to sustained clinical improvement or life discharge, whichever comes first, whereby a sustained clinical improvement is defined as an improvement of > 2 points vs the highest value of Day 0 and 1 and sustained for at least 3 days. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Status on an ordinal scale assessed daily while hospitalized and on days 15 and 28.
• Mortality on day 15 and day 28, time to death
• Time to clinical improvement (n° days from hospitalization to first 2-point improvement from highest previously recorded clinical state on the 7-point ordinal scale)
• Duration of supplemental oxygen.
• Duration of mechanical ventilation, time to live weaning from ventilation.
• Duration of hospitalization, time to live hospital discharge
• Duration of intensive care stay, time to live discharge from ICU
• Date and cause of death (if applicable).
• Use and cumulative dosesdose of corticosteroidsrescue anti-inflammatory therapy
• Adverse events graded as severe or SAEs, SARS, SUSARs.
• Lab values: including but not limited to CRP, white cell count, absolute neutrophil count, absolute lymphocyte count, absolute eosinophil count, hemoglobin, platelets, serum creatinine, eGFR (CKD-EPI) and CrCl (Cockroft-Gault), hsTroponin T, glucose, potassium, total bilirubin, ALT, and AST on days 1; 3, 5, 8, 11, 15 and 28 (If measured according to clinical indication).
• Markers of hyper-inflammation: (CRP, ferritin, LDH, interleukin profile) at baseline and on day 3, 6 and 15
• Markers of thrombotic activation and kallikrein-bradykinin activation: (D-dimers, fibrinogen, PT, aPTT, C1-inhibitor, factor XII) at baseline and on 3, 6 and 15
• Markers of adrenal function (Cortisol, ACTH, albumin/transcortin) at baseline and on day 3, 6 and 15
• Combined cardiac endpoint during hospitalization (any of the following: high sensitive troponin T levels >0.5ng/mL, ventricular arrhythmia requiring intervention, reanimation, sudden cardiac death)
• Incidence of thrombotic events during hospitalization
• Incidence of major bleeding complications during hospitalization as per ISTH criteria. ISTH major bleeding is defined as having a symptomatic presentation and
o Fatal bleeding, and/or
o Bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra‐articular or pericardial, or intramuscular with compartment syndrome, and/or
o Bleeding causing a fall in hemoglobin level of 20 g L−1 (1.24 mmol L−1) or more, or leading to transfusion of two or more units of whole blood or red cells.
• Incidence of and time to hyperinflammation during hospitalization in both arms (i.e., meeting the criteria to receive anakinra if patient would be randomized in the intervention arm)
• Assess the effect of anakinra on CXCL9, IL-1, IL-6, IL18, TNF and selected biomarkers relevant for hyperinflammation, at day 6 and 15
• Assess the effect of thromboinflammatory modulation on D-dimer levels on day 6 and the highest D-dimer level during follow-up.
• Qualitative and quantitative PCR for SARS-CoV-2 in (nasopharyngeal) swab on day 6 (when feasible in clinical care)
• Assess the effect of anakinra on CXCL9, IL-1, IL-6, IL18, TNF and selected biomarkers relevant for hyperinflammation, at day 6 and 15
• Assess the effect of thromboinflammatory modulation on D-dimer levels on day 6 and the highest D-dimer level during follow-up.
Long-term exploratory outcome
• In patients who are invited for follow-up clinical evaluation can be invited 5-7 weeks post-discharge as per routine clinicnal indication: at the respiratory clinic for lung functional, functional and radiological evaluation if possible
o Spirometry with reversibility
o Lung volumes and diffusing capacity
o Low dose CT scan
o Laboratory
o 6 minutes walk (at physicians discretion)
o Transthoracic Echocardiography (TTE)
• A telephone call on D90±2 weeks post-admission for survival status |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 1, 3, 5, 6, 8, 11, 15, 28 and 90 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
Print
