E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects infected with SARS-CoV-2, admitted to hospital due to COVID-19 |
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E.1.1.1 | Medical condition in easily understood language |
Infection with Coronavirus SARS-CoV-2/COVID-19 that leads to hospitalisation |
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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 | 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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10084460 |
E.1.2 | Term | COVID-19 treatment |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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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 |
The primary objective is to compare the clinical status of participants in the hIVIG + SOC and placebo + SOC groups on Day 7 using an ordinal outcome with 7 mutually exclusive categories. On Day 7, the worst of the 7 categories the participant was in that day will constitute the primary outcome. The 7 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 Appendix F in the protocol provides clinical definitions of each category. In addition to the overall summary odds ratio (OR) that will be estimated as described in Section 11.1, ORs will be estimated for the 6 dichotomized definitions of improvement that can be formulated from the categories of the ordinal outcome. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives will be assessed by comparing hIVIG + SOC with placebo + SOC over the 28 day follow-up period for outcomes listed below. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion 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
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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. Current or predicted imminent (within 24 hours) requirement for any of the following: following: Invasive ventilation Non-invasive ventilation Extracorporeal membrane oxygenation Mechanical circulatory support Continuous vasopressor therapy 4. History of allergy to IVIG or plasma products 5. History of selective IgA deficiency with documented presence of anti-IgA antibodies 6. 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 7. 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 8. 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
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E.5 End points |
E.5.1 | Primary end point(s) |
The goals of this study are to assess the safety, tolerability and efficacy of a single infusion of hIVIG in preventing further progression and mortality related to COVID-19 when administered at the onset of clinical progression, with the aim of improving the long term outcome of the disease process. There is as yet no consensus on the optimal endpoint for determining clinical benefit from COVID-19 therapies, including the constituent elements of the endpoint and the timing of its assessment after randomization. Both may differ depending on the target population and the nature of the treatment studied. The primary ordinal outcome captures the range of severity experienced by hospitalized patients with COVID 19, recognizing that end-organ manifestations in addition to pneumonia and ARDS are increasingly emerging as significant contributors to morbidity. The ordinal outcome includes 7 well-defined mutually exclusive categories that assess further progression of disease as well as recovery from COVID-19. The ordinal outcome includes both pulmonary manifestations as assessed in prior COVID-19 trials and additional components representing key non-pulmonary outcomes; the latter are highlighted as “extra-pulmonary” in the guidance table (Appendix F). The primary endpoint will include both pulmonary and extra-pulmonary components, while the pulmonary manifestation scale only will be reported as a secondary endpoint. Day 7 was chosen for the timing of the primary endpoint for several reasons based on the following assumptions. The impact of hIVIG on disease progression may not be immediate; a few days may be needed to see the effects on clinical outcomes as measured by the ordinal outcome. Also, transient treatment effects that are no longer present at Day 7 may be clinically less relevant. Assessment of the ordinal outcome at a later time point may result in a diminished treatment difference because spontaneous recovery from COVID-19 may have begun in many participants. Also, antibody differences between the treatment groups, an important biologic mechanism for observing a clinical benefit, are assumed to be greatest during the first week after infusion. Lastly, use of Day 7 to characterize the clinical severity of participants in 7 categories as studied here, results in a distribution of participants in the placebo group for the ordinal outcome that is sufficiently granular and not overly skewed to the most severe or least severe categories and, therefore, provides good power for comparing the two treatment groups with a feasible sample size given the difficulty in producing large quantities of hIVIG (see Section 5.5). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 7 was chosen for the timing of the primary endpoint for several reasons based on the following assumptions. The impact of hIVIG on disease progression may not be immediate; a few days may be needed to see the effects on clinical outcomes as measured by the ordinal outcome. Also, transient treatment effects that are no longer present at Day 7 may be clinically less relevant.
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E.5.2 | Secondary end point(s) |
Secondary objectives will be assessed by comparing hIVIG + SOC with placebo + SOC over the 28 day follow-up period for outcomes listed in the protocol page 25. Because there is no established endpoint for evaluating the clinical efficacy of treatments for COVID-19, other clinically relevant outcomes, including outcomes used in other COVID-19 treatment trials, will be recorded. Thus, the randomized groups can be compared for multiple outcomes, and results can be compared or combined with other trials. Many of the endpoints used in other trials are ordinal outcomes or are defined based on a dichotomy of an ordinal outcome and assessed at a single follow-up time point or as a time-to-event outcome. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During the 28 day follow-up period. |
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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 | 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 |
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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 | 10 |
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 |
Denmark |
France |
Germany |
Greece |
Israel |
Japan |
Mexico |
Nigeria |
Peru |
Spain |
Thailand |
United Kingdom |
United States |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |