E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe COVID-19 POSITIVE hospitalized male or female, between 18 and ≤ 80 years of age |
Stationäre, positiv getestete weibliche oder männliche COVID-19 Patienten mit schwerem Verlauf; Alter zwischen 18 und 80 Jahren |
|
E.1.1.1 | Medical condition in easily understood language |
Hospitalised Severe Covid-19 positive tested patients between 18 and 80 years old |
Stationäre, positiv getestete weibliche oder männliche COVID-19 Patienten mit schwerem Verlauf; Alter zwischen 18 und 80 Jahren |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
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 |
To assess clinical efficacy of APN01 using a composite outcome of all cause-death or need of invasive mechanical ventilation up to 28 days |
|
E.2.2 | Secondary objectives of the trial |
To assess efficacy of APN01 using log transformed levels of Lactate dehydrogenase (LDH) as a surrogate marker for organ damage.
To evaluate the safety of APN01 in patients with severe COVID-19
To monitor other biomarker changes (e.g. IL-6, AngII) in patient with severe COVID-19 treated with APN01
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Hospitalised male or female, ≥ 18 to ≤ 80 years of age at the time of consent. The date of signing informed consent is defined as the beginning of the screening period. This inclusion criterion will only be assessed at the first screening visit.
2. Diagnosed to be COVID-19 POSITIVE (SARS-CoV-2 nucleic acid – qPCR)
3. Oxygenation criterion
• Oxygen saturation ≤93 % (either on Room Air or while the patient is on supplement oxygen)
4. ALT < 5xULN; bilirubin ≤ 1.5xULN
5. Signed informed consent form |
|
E.4 | Principal exclusion criteria |
1. Patients whose clinical condition is deteriorating rapidly or any patient for whom the investigator does not consider there is a reasonable expectation that they will be able to complete the study.
2. Known positive Hepatitis B surface antigen, Hepatitis C antibody or HIV antibody
3. Current or chronic history of liver disease (Child Pugh score ≥ 10), or known hepatic or biliary abnormalities (with the excep-tion of Gilbert's syndrome or asymptomatic gallstones).
4. The patient has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
5. Patients requiring high doses of loop diuretics (i.e. > 240 mg fu-rosemide daily) with significant intravascular volume depletion, as assessed clinically.
6. History of sensitivity to any of the study medications, or compo-nents thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
7. Pregnant females as determined by positive serum or urine hCG test prior to dosing.
8. Lactating females.
9. Unwillingness or inability to follow the procedures outlined in the protocol.
10. Unstable Hemoglobin (Hb < 7) at time of drug infusion (i.e. Hb must be > 7 mg/dL at the time of drug infusion. Transfusion is permitted to increase Hb levels to allow entry into the study.
11. Malignancy or other irreversible condition for which 6 month mortality is estimated to be >50%.
12. Arterial blood pH less than 7.2 or serum HCO3- <15 (if ABG not available) before infusion is started.
13. Known severe chronic pulmonary disease:
- known FEV1/FVC less than 45% predicted, or
- known chronic hypercapnia (PaCO2 > 45 mmHg) or chronic hypoxemia [(PaO2<55 mmHg) on FiO2 =0.21, or supplemental oxygen therapy prior to this admission], or
- known FEV1 <15 ml/kg (e.g. 1L for 70 kg person), or
- known radiographic evidence of chronic interstitial infil-tration, or
- known hospitalization within the past six months for respiratory failure (PaCO2 > 50 mmHg or PaO2 < 55 mmHg, or oxygen saturation <88% on FiO2 = 0.21)
- known chronic restrictive, obstructive, neuromuscular, chest wall, or pulmonary vascular disease resulting in severe exercise restriction (i.e. unable to climb stairs or perform household duties), known secondary polycythemia,
severe pulmonary hypertension, or ventilator dependency
14. Known vasculitis with diffuse alveolar hemorrhage
15. Lung transplantation
16. Pre-existing renal failure, i.e. requiring renal replacement ther-apy with hemodialysis or peritoneal dialysis
17. There are other uncontrolled co-morbidities that increase the risks associated with the study drug administration, that are as-sessed by the medical expert team as unsuitable
18. Patient in clinical trials with an IMP for COVID-19 within 30 days before signing informed consent form (ICF)
19. Unstable hemodynamics in the preceding 4 hours (MAP ≤ 65 mmHg, or SAP < 90 mmHg, DAP < 60 mmHg, and vaso-active agents required)
20. Immunocompromised patients (chemotherapy, HIV, organ transplants, stem cell transplants),
21. Receive any Angiotensin-Converting-Enzyme inhibitor (ACEi) or renin inhibitor treatment within 7 days before ICF |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is a composite endpoint of all cause-death or invasive mechanical ventilation up to 28 days or hospital discharge. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Continioulsy over the duration of the trial |
|
E.5.2 | Secondary end point(s) |
1. Log transformed levels of Lactate dehydrogenase (LDH) at day 5 as a surrogate marker for organ damage (powered secondary endpoint)
2. 28-day mortality (all cause-death)
3. Ventilator-free days (VFD) up to 28 days or hospital discharge
4. Proportion of responders, defined as ≥2 improvement in WHO’s 11-Point Score system at day 7, 10, 14 and 28
5. Time to death (all cause)
6. Proportion of patients with any use of invasive mechanical ven-tilation up to 28 days or hospital discharge
7. Time to first use of invasive mechanical ventilation up to 28 days or hospital discharge
8. Absolute values and absolute change in P/F ratio over time
9. Absolute values and absolute change in the modified Sequential organ failure assessment score (mSOFA score) over time
10. Time to a 2-point decrease in WHO scoring scheme
11. Absolute values and absolute change in lymphocyte counts over time
12. Absolute values and absolute change in C-reactive protein lev-els over time
13. Absolute values and absolute change in D-dimer over time
14. Absolute values and absolute change in log transformed levels of LDH over time
15. Time to hospital discharge
16. Change in viral RNA over time
Biomarker endpoints: Absolute values and absolute changes in relevant biomarkers over time:
1. Angiotensin II (Ang II), Angiotensin 1-7 (Ang 1-7), Angiotensin 1-5 (Ang 1-5), renin and aldosterone, Angiotensin-converting enzyme (ACE), Angiotensin-converting enzyme 2 (ACE2), Angiotensin I (Ang I), Angiotensin 1-9 (Ang 1-9)
2. Cytokines: Interleukin 6 (IL-6), Interleukin 8 (IL-8), soluble Tumor Necrosis Factor receptor type II (sTNFrII), Plasminogen Activator Inhibitor type-1 (PAI-1), von Willebrand Factor (vWF), Tumor necrosis factor-α (TNF-α)
3. Alveolar epithelial markers: soluble Receptor for Advanced Glycation End products (sRAGE), Surfactant protein-D(SP-D)
4. Endothelial markers: Angiopoietin-2
5. Change in clinical laboratory markers associated with poor outcome over time (e.g., lymphocyte counts, hsTnI (high sensitivity troponin))
6. NT-proBNP
Safety endpoints:
Frequency of adverse events (AEs) and serious adverse events (SAEs) in vital signs, clinical laboratory assessments and in ECG parameters |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Continioulsy over the duration of the trial |
|
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Denmark |
Germany |
Russian Federation |
United Kingdom |
United States |
|
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
|
Overall End of Study is defined as the date of last patient last visit (LPO) |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 8 |