E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects infected with SARS-CoV-2, admitted to the 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 hospitalization |
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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 | 23.1 |
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.1.2 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 |
The primary objective of this protocol is to determine whether investigational agents, initially focusing on those that are aimed at enhancing the host immune response to SARS-CoV-2 infection are safe and superior to control (e.g., placebo) when given with SOC for the primary endpoint of time to sustained recovery evaluated up to 90 days after randomization. SOC may be modified (updated based on data from this or other trials) during the course of evaluating different investigational agents with this master protocol.
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E.2.2 | Secondary objectives of the trial |
Two key secondary objectives are to compare each investigational agent with control for all-cause mortality and a composite outcome which considers both time to sustained recovery and mortality. Other secondary objectives are to compare each investigational agent with control for the secondary outcomes stated in section 4 in the protocol |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥ 18 years
2. Informed consent by the patient or the patient’s legally-authorized representative (LAR)*
3. SARS-CoV-2 infection, documented by a nucleic acid test (NAT) or equivalent testing within 3 days prior to randomization OR documented by NAT or equivalent testing more than 3 days prior to randomization AND progressive disease suggestive of ongoing SARS-CoV-2 infection per the responsible investigator. (For non-NAT tests only those deemed with equivalent specificity to NAT by the protocol team will be allowed. A central list of allowed non-NAT tests will be maintained.)
4. Duration of symptoms attributable to COVID-19 ≤ 12 days per the responsible investigator
5. Requiring admission for inpatient hospital acute medical care for clinical manifestations of COVID-19, per the responsible investigator, and NOT for purely public health or quarantine purposes
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E.4 | Principal exclusion criteria |
1. Prior receipt of • Any SARS-CoV-2 hIVIG, convalescent plasma from a person who recovered from COVID-19 or • SARS-CoV-2 nMAb at any time prior to hospitalization
2. Not willing to abstain from participation in other COVID-19 treatment trials until after Day 5 (with thie approval of study leadership enrollment before or on Day 5 is permitted for trials comparing different approaches for implementing SOC interventions that are recommended in a)i))(1)(a)(i)Appendix I
3. In the opinion of the responsible investigator, any condition for which, participation would not be in the best interest of the participant or that could limit protocol specified assessments
4. Expected inability to participate in study procedures
5. Women of child-bearing potential who are not already pregnant at study entry and who are unwilling acknowledge the strong advice to abstain from sexual intercourse with men or practice appropriate contraception through 18 month of the study
6. Men who are unwilling acknowledge the strong advice to to abstain from sexual intercourse with women of child-bearing potential or to use barrier contraception through 18 month of the study
Prior to the initial futility assessment for an investigational agent, the follwoing two additional exclusions (7 and 8) which define disease severity stratum 2 apply: 7. Presence at enrollment of any of the following: a. stroke b. meningitis c. encephalitis d. myelitis e. myocardial infarction f. myocarditis g. pericarditis h. symptomatic CHF (NYHA class III-IV) i. arterial or deep venous thrombosis or pulmonary embolism
8. Current requirement for any of the following: a. invasive mechanical ventilation b. ECMO c. mechanical circulatory support d. vasopressor therapy e. commencement of renal replacement therapy at this admission (i.e. not patients on chronic renal replacement therapy).
Additional exclusion citeria according to "Protocol amendment for Sweden, No. 2"
9. Pregnant and nursing women must be excluded.
10. AZD7442 are contraindicated in participants who have shown hypersensitivity to the active substance or any of the excipients or to other humanised mAbs.
11. For MP0420 there is currently no clinical experience, consequently no specific contraindications have been identified.
Exclusions that may be appropriate for an investigational agent studied are referenced in the relevant appendix (H) for the investigational agent. The contraindications for use of components of SOC are outlined in Appendix I and in the PIM
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E.5 End points |
E.5.1 | Primary end point(s) |
Ordinal Outcomes for Early Futility Assessments: Two ordinal outcomes will be used to assess futility after approximately 300 patientes have been enrolled. Both outcomes are assessed 5 days after randomization (Day 5); the participant’s highest (i.e. most severe) observed score on Day 5 is used. The first ordinal outcome, referred to as the “pulmonary” ordinal outcome, is primarily defined based on oxygen requirements. The second ordinal outcome, referred to as “pulmonary+,” also assessed at Day 5, captures extra-pulmonary complications as well as respiratory dysfunction.
Primary and Secondary Outcomes to Evaluate Efficacy and Safety: The primary endpoint is time from randomization to sustained recovery, defined as being discharged from the index hospitalization, followed by being alive and home for 14 consecutive days prior to Day 90. Home is defined as the level of residence or facility where the participant was residing prior to hospital admission leading to enrollment in this protocol. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary outcome is assessed during 90 days of follow-up, which is longer than for other trials for COVID-19, which are typically 28 days. The longer follow-up will allow better ascertainment of recovery from the longer-term consequences of the underlying disease, and hence the efficacy of the investigational agent. This is likely to be particularly true for patients who experience extra-pulmonary disease in conjunction with their COVID-19, and for patients enrolled while receiving care for life-threatening organ failure.
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E.5.2 | Secondary end point(s) |
Several secondary efficacy endpoints will be assessed. These endpoints will be assessed for all participants enrolled: 1. All-cause mortality through 90 days of follow-up 2. Composite of time to sustained recovery and mortality through 90 days of follow-up 3. Time to discharge for the initial hospitalization 4. Days alive outside of a short-term acute care hospital up to day 90 5. Ordinal outcomes, pulmonary+ and pulmonary, on Days 1-7, and pulmonary ordinal outcome on Days 14 and 28 6. Clinical organ failure or serious infection defined by development of any one or more of the following clinical events through Day 28: a. Respiratory dysfunction b. Cardiac and vascular dysfunction c. Renal dysfunction d. Hepatic dysfunction e. Neurological dysfunction f. Haematological dysfunction g. Serious infection 7. A composite of death, clinical organ failure or serious infection (see above) 8. 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 assessed at Days 1-7, 14 and 28; time to improvement in 1 or 2 categories of ordinal scale; time to best 3 categories of ordinal scale, and binary outcomes defined by improvement or worsening based on other ordinal outcomes) 9. A composite of cardiovascular events (outcomes listed above in items 6) and thormboembolic events 10. Safety and tolerability as measured by: a. A composite of grade 3 and 4 clinical adverse events, SAEs, clinical organ failure or serious infections (see item 6) or death through Day 5 (primary safety endpoint) and through Day 28 b. Infusion-related reactions of any severity and percentage of participants for whom the infusion was interrupted or stopped prior to completion c. A composite of SAEs, clinical organ failure or serious infections (see item 6) or death through Day 90 d. Adverse events of any grade through Day 7 e. Prevalence of adverse events of any grade at day 14 and day 28 f. A composite of hospitalisations or death through 12 month 11. Change in antibody profile, overall titers of antibodies and neutralizing antibody levels from baseline to Days 1, 3, 5 and 28 and 90 12. Outcomse that consider home use of supplemental oxygen above pre-morbid oxygen use for sensitivity analyses fo rthe primary outcome: a. Alive at home and no use of continuous supplemental oxygen for an uninterrupted 14 day period b. Alive at home for an uninterrupted 14 day period and no use of continuous supplemental oxygen at the end of the 14 day time period
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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.
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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) | Yes |
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 | 3 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 |
Australia |
Brazil |
Georgia |
Mexico |
Peru |
Singapore |
Uganda |
United States |
Belgium |
Denmark |
France |
Germany |
Greece |
Poland |
Portugal |
Spain |
Sweden |
Switzerland |
United Kingdom |
Argentina |
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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 | 2 |
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 | 2 |