| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| COVID-19 (SARS-CoV-2) infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| Coronavirus infection (a respiratory disease caused by a novel coronavirus) |
|
| E.1.1.2 | Therapeutic area | Health Care [N] - Environment and Public Health [N06] |
| 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 | 10051905 |
| E.1.2 | Term | Coronavirus infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 primary endpoint of this trial in hospitalized patients is an ordinal outcome based on the patient’s clinical status on Day 7. It includes 7 mutually exclusive categories capturing the range of organ dysfunction that may be associated with progression of COVID-19, such as respiratory dysfunction and coagulation-related complications:
7. Death
6. End-organ failure
5. Life-threatening end-organ dysfunction
4. Serious end-organ dysfunction
3. Moderate end-organ dysfunction
2. Limiting symptoms due to COVID-19
1. No limiting symptoms due to COVID-19
The rationale behind this approach is to estimate in a clinically meaningful way whether the study drug has had a favourable clinical impact on the patient. |
|
| E.2.2 | Secondary objectives of the trial |
1. All-cause mortality through Day 28.
2. The primary ordinal outcome on Days 3, 5, 14 and 28.
3. Change in National Early Warning Score (NEWS) from baseline at Day 3. This is a scoring system validated in the UK, which is able to score how sick people are, and their risk of dying, based on things like their blood pressure, pulse rate and body temperature.
4. Time to the 3 least favourable categories of the primary outcome measure
5. Time to the 2 most favourable categories of the primary outcome measure.
6. Hospitalization status (alive and discharged from the hospital to home or rehabilitation, versus dead or hospitalized) at Days 7, 14 and 28.
7. Time to discharge.
8. Days alive outside of a hospital through Day 28.
9. Pulmonary only components of the primary outcome measure at Days 3, 5, 7, 14 and 28
10. Thrombotic components of the primary outcome measure (stroke, myocardial infarction, venous and arterial thrombosis or embolism, plus disseminated intravascular |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
INSIGHT Genomics Study (INSIGHT Protocol No. 004 version 2.0, dated 27 August 2013).
The purpose of this study is to obtain a whole blood sample from which DNA will be extracted to study polymorphisms in immune response genes and other genetic variants that may be associated with an increased risk of disease progression among individuals with infectious diseases of public health importance who are enrolled in qualifying INSIGHT studies. |
|
| E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, a participant must meet all of the following criteria:
1. SARS-CoV-2 infection, documented by PCR or other nucleic acid test (NAT) within 3 days prior to randomization OR documented by NAT more than 3 days prior to randomization AND progressive disease suggestive of ongoing SARS-CoV-2 infection.
2. Symptomatic COVID-19 disease
3. Duration of symptoms attributable to COVID-19 ≤ 12 days
4. Requiring inpatient hospital medical care for clinical manifestations of COVID-19 (admission for public health or quarantine only is not included)
5. Age ≥ 18 years
6. Willingness to abstain from participation in other COVID-19 treatment trials until after study day 7
7. Provision of informed consent by participant or legally authorized representative
|
|
| E.4 | Principal exclusion criteria |
1. Prior receipt of SARS-CoV-2 hIVIG or convalescent plasma from a person who recovered from COVID-19 at any time
2. Prior receipt of standard IVIG (not hyperimmune to SARS-CoV-2) within 45 days
3. Prior receipt of any SARS-CoV-2 monoclonal antibody treatments at any time
4. Current or predicted imminent (within 24 hours) requirement for any of the following:
• Invasive ventilation
• Non-invasive ventilation
• Extracorporeal membrane oxygenation
• Mechanical circulatory support
• Continuous vasopressor therapy
5. History of allergy to IVIG or plasma products
6. History of selective IgA deficiency with documented presence of anti-IgA antibodies
7. Any medical conditions for which receipt of the required volume of intravenous fluid may be dangerous to the patient
• Includes New York Heart Association Class III or IV stage heart failure
8. Any of the following thrombotic or procoagulant disorders:
• Acute coronary syndromes, cerebrovascular syndromes and pulmonary or deep venous thrombosis within 28 days of randomization
• History of prothrombin gene mutation 20210, homozygous Factor V Leiden mutations, antithrombin III deficiency, protein C deficiency, protein S deficiency or antiphospholipid syndrome
9. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant or that could prevent, limit, or confound the protocol-specified assessments
10. Prior participation in a COVID-19 treatment trial within 6 months of enrolment
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of this trial in hospitalized patients is an ordinal outcome based on the patient’s clinical status on Day 7. It includes 7 mutually exclusive categories capturing the range of organ dysfunction that may be associated with progression of COVID-19, such as respiratory dysfunction and coagulation-related complications. Categories are:
7. Death
6. End-organ failure
5. Life-threatening end-organ dysfunction
4. Serious end-organ dysfunction
3. Moderate end-organ dysfunction
2. Limiting symptoms due to COVID-19
1. No limiting symptoms due to COVID-19
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. All-cause mortality through Day 28.
2. The primary ordinal outcome on Days 3, 5, 14 and 28.
3. Change in National Early Warning Score (NEWS) from baseline at Day 3. This is a scoring system validated in the UK, which is able to score how sick people are, and their risk of dying, based on things like their blood pressure, pulse rate and body temperature.
4. Time to the 3 least favourable categories of the primary outcome measure
5. Time to the 2 most favourable categories of the primary outcome measure.
6. Hospitalization status (alive and discharged from the hospital to home or rehabilitation, versus dead or hospitalized) at Days 7, 14 and 28.
7. Time to discharge.
8. Days alive outside of a hospital through Day 28.
9. Pulmonary only components of the primary outcome measure at Days 3, 5, 7, 14 and 28
10. Thrombotic components of the primary outcome measure (stroke, myocardial infarction, venous and arterial thrombosis or embolism, plus disseminated intravascular coagulation) at Days 3, 5, 7, 14, and 28.
11. Outcomes assessed in other treatment trials of COVID-19 for hospitalized participants in order to facilitate cross trial comparisons and overviews, e.g., 6-, 7- and 8- category ordinal scales at days 7, 14 and 28; and binary outcomes defined by improvement or worsening based on the primary ordinal outcome and ordinal outcomes used in other trials.
12. Clinical organ dysfunction defined by new onset of any one or more of the following conditions (or requirement for the following therapies) through Day 28:
a. Respiratory:
1. Extracorporeal membrane oxygenation (ECMO)
2. Invasive ventilation
3. Non-invasive ventilation or high flow oxygen
b. Cardiac and vascular:
1. Myocardial infarction
2. Myocarditis or pericarditis
3. NYHA Class III/IV congestive cardiac failure
4. Vasopressor therapy
c. Renal:
1. Renal replacement therapy (dialysis)
d. Hepatic:
1. Hepatic decompensation
e. Neurological
1. Cerebrovascular event (stroke)
2. Encephalitis, meningitis or myelitis
3. Acute delirium
f. Hematological:
1. Disseminated intravascular coagulation
2. New thrombotic events, including pulmonary embolism, deep venous thrombosis, or arterial thrombosis
g. Infective:
1. Microbiologically-proven severe infection (not including SARS-CoV-2)
13. Safety and tolerability will be assessed using outcomes described above and also assessed by the following outcomes:
a. A composite of incident grade 3 and 4 events (not limited to a laboratory abnormality), SAEs (see Section10.1.2), or death through Day 7 (primary safety endpoint)
b. Infusion reactions of any grade severity during the infusion and 2 hours post-infusion, and percentage of participants for whom the infusion was interrupted or stopped prior to completion
c. SAEs or deaths through Day 28
d. Prevalence of adverse events of any grade on Days 1, 3, 7 and 28.
14. Change in immunoglobulin levels (IgG, IgG subclasses, IgM, IgA) and neutralizing antibody titers from baseline to Days 1, 2, 3, 7, 28 and 90.
15. The primary endpoint by duration of symptoms at study entry.
16. The primary endpoint for other subgroups defined by the characteristics measured at baseline will also be assessed:
• Age
• Biological sex
• Race/ethnicity
• BMI
• Presence of selected chronic medical conditions (cardiovascular disease, diabetes, asthma, chronic obstructive pulmonary disease, hypertension, cancer)
• Geographic location
• hIVIG product administered
• hIVIG lot potency of administered product
• Upper respiratory SARS-CoV-2 viral load
• Neutralizing antibody level
• Oxygen saturation level
• Dyspnea severity
• Organ/respiratory dysfunction category based on ordinal primary outcome
• NEWS
• Disease progression risk score |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints for the measurements are described in connection with the individual secondary endpoints in section 23-2. |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Belgium |
| Denmark |
| France |
| Germany |
| Greece |
| Israel |
| Japan |
| Mexico |
| Nigeria |
| Peru |
| Poland |
| Portugal |
| Spain |
| Thailand |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| LVLS. However, the analysis of the stored samples for antibody levels will occur after the LVLS. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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