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).

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).