| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of symptomatic patients with moderate to severe coronavirus disease 2019 (COVID-19) |
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| E.1.1.1 | Medical condition in easily understood language |
| Treatment of patients with moderate to severe coronavirus disease 2019 (COVID-19) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10084268 |
| E.1.2 | Term | COVID-19 |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| 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 |
Part 1:
• To evaluate the safety and tolerability of a single dose of COR-101 at various dose levels compared to that of the placebo-control (both as add-on therapy to standard of care [SOC]) in hospitalized patients with moderate to severe COVID-19
Part 2:
• To evaluate the efficacy and safety of a single dose of COR-101 compared to that of the placebo-control (both as add-on therapy to SOC) in hospitalized patients with moderate to severe COVID-19 |
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| E.2.2 | Secondary objectives of the trial |
Part 1:
• To evaluate the preliminary efficacy of a single dose of COR-101 at various dose levels compared to that of the placebo-control (both as add-on therapy to SOC) in hospitalized patients with moderate to severe COVID-19
• To assess the pharmacokinetics (PK) and pharmacodynamics (PD) of a single dose of COR-101 at various dose levels compared to that of the placebo-control (both as add-on therapy to SOC) in hospitalized patients with moderate to severe COVID-19.
Part 2:
• To assess PK, PD, and immunogenicity of a single dose of COR-101 in hospitalized patients with moderate to severe COVID-19
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The patient must be willing and able to give informed consent to participate in the study and to adhere to the procedures stated in the protocol.
2. The patient is male or female adult ≥18 years (as per local laws) of age at the time of giving informed consent.
3. The patient is admitted to a hospital (<72 hours prior to randomization) due to COVID-19 and has a positive SARS-CoV-2 test by standard Reverse Transcription Polymerase Chain Reaction (RT-PCR) assay or equivalent test.
4. The patient has the presence of moderate to severe clinical signs indicative of moderate or severe illness with COVID-19 prior to study treatment on Day 1:
i. Radiologically or clinically confirmed COVID-19 disease
ii. Clinical signs suggestive of moderate/severe illness with COVID-19, such as:
a. respiratory rate ≥20 breaths per minute, or
b. SpO2 >93% (moderate) or ≤ 93% (severe) on room air at sea level or,
c. heart rate ≥90 (moderate) or ≥ 125 (severe) beats per minute for moderate or severe illness, respectively
d. No clinical signs indicative of critical COVID-19
Please note: To standardize the assessment of COVID-19 severity, respiratory rate, SpO2, and heart rate will be measured when the patient is on room air (ie, no supplemental oxygen) and at rest for at least 5 minutes.
5. The patient agrees to not participate in another clinical study of antibody therapy from screening until Day 80, and of any other investigational drug expected to interfere with the study endpoints from screening until Day 28.
6. Patients with preterminal or terminal renal failure requiring dialysis, as well as patients with compensated chronic heart failure, may be treated with COR-101 within the study. As the infusion of COR-101 imposes a potentially clinically relevant volume load, the treating physician shall monitor patients for any signs of decompensation.
7. Men whose sexual partners are women of childbearing potential (WOCBP) must agree to comply with one of the following contraception requirements from the time of first dose of screening until at least 80 days after the last dose of study medication:
a. Vasectomy with documentation of azoospermia.
b. Sexual abstinence (defined as refraining from heterosexual intercourse from the time of screening until at least 80 days after the last dose of study medication)
c. Male condom plus partner use of one of the contraceptive options below: contraceptive subdermal implant; intrauterine device or intrauterine system; oral contraceptive, either combined or progestogen alone; injectable progestogen; contraceptive vaginal ring; percutaneous contraceptive patches.
8. WOCBP must agree to comply with one of the following contraception requirements from the time of screening until at least 80 days after the last dose of study medication:
a. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
i. oral
ii. intravaginal
iii. transdermal
b. progestogen-only hormonal contraception associated with inhibition of ovulation :
i. oral
ii. injectable
iii. implantable
c. intrauterine device (IUD)
d. intrauterine hormone-releasing system ( IUS)
e. bilateral tubal occlusion
f. vasectomised partner with documentation of azoospermia
g. sexual abstinence (defined as refraining from heterosexual intercourse from the time of screening until at least 80 days after the last dose of study medication).
The above is an all-inclusive list of those methods that meet the following definition of highly effective: having a failure rate of less than 1% per year when used consistently and correctly and, when applicable, in accordance with the product label. For non-product methods (eg, male sterility), the investigator will determine what is consistent and correct use. The investigator is responsible for ensuring that patients understand how to properly use these methods of contraception.
Women of non-reproductive potential are defined as: a) Premenopausal females with one of the following: documented tubal ligation; documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; hysterectomy; documented bilateral oophorectomy. b) Postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample will be required with simultaneous follicle stimulating hormone and estradiol levels tested locally and consistent with menopause [refer to local laboratory reference ranges for confirmatory levels]). Women on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods listed above if they wish to continue their HRT during the study. |
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| E.4 | Principal exclusion criteria |
1. The patient has a diagnosis of asymptomatic COVID-19, mild COVID-19, or critical COVID-19 on Day 1.
a. Asymptomatic COVID-19 is defined as a patient with a positive SARS-CoV-2 test by standard RT-PCR assay or equivalent test but not experiencing symptoms.
b. Mild COVID-19 is defined as a patient with a positive SARS-CoV-2 test by standard RT-PCR assay or equivalent test and experiencing symptoms of mild illness (especially no dyspnea) but no clinical signs indicative of moderate, severe, or critical COVID-19.
c. Critical COVID-19 is defined as a patient with a positive SARS-CoV-2 test by standard RT-PCR assay or equivalent test and experiencing at least one of the following: shock defined by systolic blood pressure <90 mm Hg or diastolic blood pressure <60 mm Hg, or requiring vasopressors; respiratory failure requiring endotracheal intubation and invasive mechanical ventilation, oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5), non-invasive positive pressure ventilation, extracorporeal membrane oxygenation (ECMO), or clinical diagnosis of respiratory failure (ie, clinical need for one of the preceding therapies, but preceding therapies not able to be administered in setting of resource limitation), and/or multi-organ dysfunction/failure.
2. The patient has clinically significant ECG abnormalities at the day of screening.
3. The patient has experienced new onset stroke or seizure disorder during hospitalization and prior to Day 1 of the study.
4. The patient has a history of relevant CNS pathology or current relevant CNS pathology.
5. The patient has acute left ventricular failure or myocardial infarction.
6. Body weight at screening and/or Day 1 >120 kg (for part 1) or >135 kg for part 2.
7. A female patient who is pregnant or planning to become pregnant during the study, breastfeeding, or has a positive pregnancy test at screening (by serum) or prior to dosing on Day 1 (by urine) as determined by human chorionic gonadotrophin tests.
8. The patient is planning to donate or bank ova or sperm from Day 1 until 80 days after the last dose of study drug.
9. The patient has a known history of drug or alcohol abuse within 6 months of study start that would interfere with the patient’s participation in the study.
10. The patient has a history of sensitivity to any of the study drugs or components thereof or a history of drug or other allergy (including systemic anaphylaxis) that, in the opinion of the investigator or medical monitor, would contraindicate their participation.
11. The patient has participated in and/or plan to participate in another clinical study using an investigational product within the following period prior to the first dosing day in the current study: 30 days, 5 half-lives, or twice the duration of the biological effect of the investigational product (whichever is longer).
12. The patient has received immunoglobulins (or other antibodies), convalescent plasma, or other monoclonal antibodies to SARS-CoV-2 within 30 days prior to randomization.
13. The patient will be transferred to another hospital which is not a study site within 72 hours. Note: if the investigator has admitting privileges to the transfer hospital, the patient may be considered for randomization.
14. The patient is employed by CORAT Therapeutics, the contract research organization (CRO), or clinical site personnel directly involved in the clinical study.
15. The investigator makes a decision that study involvement is not in patient’s best interest, or the patient has any condition, in the opinion of the investigator, that will not allow the protocol to be followed safely.
16. For Part 1 only: The patient has received a COVID-19 vaccination within 30 days prior to start of the treatment in study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1:
- Incidence of adverse events (AEs): Serious adverse events (SAE), treatment-emergent adverse events (TEAEs), mortality, and AEs requiring medical intervention until Day 28.
Part 2:
The primary efficacy endpoint of Part 2 is:
- Proportion of patients with disease improvement as evaluated at multiple timepoints (Days 5, 10, 14) defined as the proportion of patients who achieved a sustained (≥3 days) improvement in the 10-point WHO ordinal scale of ≥2 points or have been discharged alive from hospital and do not relapse within 60 days.
The primary safety endpoints of Part 2 are:
- Incidence of (AEs): (SAE), (TEAEs), mortality, and AEs requiring medical intervention until Day 28.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Incidence of AE (also AE requiring medical intervention), SAE, TEAEs, and mortality: until Day 28
Proportion of patients with disease improvement: until Days 5, 10 and 14 |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints of Part 1 are:
• Proportion of patients with disease progression on Days 6, 14, 21, and 28, defined as the proportion of patients who are not alive or have respiratory failure. Respiratory failure is defined as the need for invasive or non-invasive mechanical ventilation, high-flow oxygen, ECMO until Days 6, 14, 21, and 28.
• Proportion of patients with disease resolution, as evidenced by resolution of symptoms at Days 6, 14, 21, and 28.
• Proportion of patients with viral clearance at Days 6, 14, 21 and 28.
• Mortality at Day 28.
• Mortality at Day 80.
• Proportion of patients free of respiratory failure on Day 28.
• Percentage of patients reporting each severity rating on the National Institute of Allergy and Infectious Diseases (NIAID) 8-point ordinal scale on Days 6, 14, 21, and 28.
• Change in National Early Warning Score 2 (NEWS2) from baseline on Days 6, 14, 21, and 28.
• Time to negative RT-PCR for SARS-CoV-2.
The secondary PK endpoint of Part 1 is:
• COR-101 serum concentrations and PK parameters including Cmax, tmax, AUC0-t, AUC0-∞, t½, λz, %AUCextra, MRT, CL, Vz after a single dose.
The secondary PD endpoint of Part 1 is:
• Change of the viral load of SARS-CoV-2 from baseline, as measured from nasopharyngeal swab samples by qRT-PCR on Days 2, 4, 6, 14, 21, 28, and 80.
The secondary safety endpoint of Part 1 is:
• AEs including SAEs, and Grade 3 and 4 AEs during long-term follow-up period from Day 28 through Day 80.
The secondary efficacy endpoints of Part 2 are:
• Proportion of patients with disease worsening, as evidenced by worsening of ≥1 point in the 10-point WHO-10 point ordinal scale at Days 5, 10, and 14.
• Proportion of patients with disease worsening, as evidenced by viral clearance at Days 5, 10, 14, 21 and 28, and at day of discharge as measured from nasopharyngeal swab samples.
• Mortality at Day 28
• Mortality at Day 80
• Proportion of patients free of respiratory failure on Day 28 (respiratory failure is defined as the need for invasive or non-invasive mechanical ventilation, high-flow oxygen, or ECMO).
• Percentage of patients reporting each severity rating on the WHO 10-point ordinal scale on Days 5, 10, and 14.
• Change in NEWS2 from baseline on Days 5, 10, and 14.
• Time to negative RT-PCR for SARS-CoV-2 as measured from nasopharyngeal swab samples.
The secondary PK endpoint of Part 2 is:
• COR-101 serum concentrations and PK parameters including Cmax, tmax, AUC0-t, AUC0-∞, t½, λz, %AUCextra, MRT, CL, Vz after a single dose
The secondary PD endpoint of Part 2 is:
• Change of the viral load of SARS-CoV-2 from baseline, as measured from nasopharyngeal swab samples by qRT-PCR on Days 5, 10, 14, 21, 28, and at day of discharge.
The secondary immunogenicity endpoints of Part 2 are:
• Percentage of patients with detectable ADAs in blood to COR-101 (anti-COR-101 antibodies) on Days 5, 14, 21, 28 and 80
• Percentage of patients with detectable neutralizing antibodies to COR-101 (anti-COR-101 antibodies) in blood on Days 5, 14, 21, 28 and 80.
The secondary safety endpoint of Part 2 is:
• AEs including SAEs, and Grade 3 and 4 AEs occurring during the follow-up period from Day 2 throughout Day 80
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As stated in the list of endpoints |
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| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, Immunogenicity |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | Yes |
| 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 | 5 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Argentina |
| Philippines |
| Viet Nam |
| Bulgaria |
| Romania |
| Spain |
| Germany |
| Ukraine |
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| 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
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| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 3 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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