COVID, COVID-19, SARS-CoV-2, SARS (Severe Acute Respiratory Syndrome)
Conditions
Brief summary
This protocol will serve as a platform for assessing treatments for adult patients hospitalized for medical management of COVID-19 without related serious end-organ failure. Trials will involve sites around the world strategically chosen to ensure rapid enrollment. This trial will compare hyperimmune intravenous immunoglobulin (hIVIG) with matched placebo, when added to standard of care (SOC), for preventing further disease progression and mortality related to COVID-19. SOC will include remdesivir unless it is contraindicated for an individual patient.
Detailed description
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. The ordinal endpoint is defined as follows: 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 Secondary endpoints include time to the 3 least favorable categories, time to the 2 most favorable categories, and the pulmonary only and thrombotic only components of the primary ordinal outcome. Mortality, adverse events (AEs), including infusion reactions, and biological correlates of therapeutic activity are also assessed. 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 (hIVIG + SOC versus placebo + SOC ) can be compared for multiple outcomes, and results can be compared or combined with other trials. Participants will be randomized (1:1) to a single infusion of hIVIG + SOC or placebo + SOC on the day of randomization (Day 0). Participants taking remdesivir prior to randomization may be enrolled if eligibility criteria are met. Randomized participants who were not taking remdesivir before randomization will start taking remdesivir immediately following the infusion of hIVIG or placebo unless remdesivir is contraindicated. Participants will be followed for 28 days and, if the trial goes to completion, the primary analysis will be completed after all participants are followed for 28 days.
Interventions
Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG) is derived from the plasma of individuals who recover and develop neutralizing antibodies. Participants will receive a single infusion.
OTHERPlacebo
Participants will receive a single infusion of the placebo (saline).
DRUGRemdesivir
Remdesivir will be given to participants in both groups as standard of care (SOC).
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
National Institutes of Health (NIH)
International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* SARS-CoV-2 infection documented by polymerase chain reaction (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 * Symptomatic COVID-19 disease * Duration of symptoms attributable to COVID-19 ≤ 12 days * Requiring inpatient hospital medical care for clinical manifestations of COVID-19 (admission for public health or quarantine only is not included) * Willingness to abstain from participation in other COVID-19 treatment trials until after study Day 7 * Provision of informed consent by participant or legally authorized representative
Exclusion criteria
* Prior receipt of SARS-CoV-2 hIVIG or convalescent plasma from a person who recovered from COVID-19 at any time * Prior receipt of standard IVIG (not hyperimmune to SARS-CoV-2) within 45 days * Current or predicted imminent (within 24 hours) requirement for any of the following: 1. Invasive ventilation 2. Non-invasive ventilation 3. Extracorporeal membrane oxygenation 4. Mechanical circulatory support 5. Continuous vasopressor therapy * History of allergy to IVIG or plasma products * History of selective IgA deficiency with documented presence of anti-IgA antibodies * Any medical conditions for which receipt of the required volume of intravenous fluid may be dangerous to the patient (includes New York Association Class III or IV stage heart failure) * Any of the following thrombotic or procoagulant disorders: 1. Acute coronary syndromes, cerebrovascular syndromes and pulmonary or deep venous thrombosis within 28 days of randomization 2. History of prothrombin gene mutation 20210, homozygous Factor V Leiden mutations, antithrombin III deficiency, protein C deficiency, protein S deficiency or antiphospholipid syndrome * Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject or that could prevent, limit, or confound the protocol-specified assessments
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ordinal Outcome Scale - Day 7 | 7 days | The primary objective is to compare the clinical status of patients in each group on day 7 of follow-up using the primary ordinal outcome with 7 mutually exclusive categories: 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 Outcome is reported as the percent of participants in each of 7 categories. Primary 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. Minimum value = 1, Maximum value = 7 Higher scores mean a worse outcome |
| Primary Safety Outcome - Death, SAE or Grade 3 or 4 Events Through Day 7 | Through Day 7 | Number of participants with death, SAE or Grade 3 or 4 event through Day 7 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| N Reaching 3 Least Favorable Categories | All of follow-up (through Day 28) | N Reaching 3 least favorable categories of ordinal outcome (Categories 5, 6, 7: life-threatening end organ dysfunction, end organ failure, or death) |
| N Reaching 2 Most Favorable Categories | All of follow-up (through Day 28) | N Reaching 2 most favorable categories of ordinal outcome (Categories 1 and 2: not requiring oxygen with or without limiting symptoms due to COVID-19) |
| N Discharged or in Most Favorable Category | All of follow-up (through Day 28) | N discharged from hospital or reaching most favorable ordinal category (category 1: not requiring oxygen and no limiting symptoms due to COVID-19) |
Countries
Denmark, Greece, Japan, Nigeria, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intervention Group Participants in this group will receive the investigational product and standard of care (SOC).
Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG): Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG) is derived from the plasma of individuals who recover and develop neutralizing antibodies. Participants will receive a single infusion.
Remdesivir: Remdesivir will be given to participants in both groups as standard of care (SOC). | 301 |
| Control Group Participants in this group will receive a placebo and standard of care (SOC).
Placebo: Participants will receive a single infusion of the placebo (saline).
Remdesivir: Remdesivir will be given to participants in both groups as standard of care (SOC). | 292 |
| Total | 593 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 3 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 7 |
Baseline characteristics
| Characteristic | Control Group | Total | Intervention Group |
|---|---|---|---|
| Age, Continuous | 59.7 years | 59.0 years | 58.4 years |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 31 Participants | 70 Participants | 39 Participants |
| Race (NIH/OMB) Black or African American | 47 Participants | 87 Participants | 40 Participants |
| Race (NIH/OMB) More than one race | 13 Participants | 22 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 39 Participants | 75 Participants | 36 Participants |
| Race (NIH/OMB) White | 160 Participants | 334 Participants | 174 Participants |
| Sex: Female, Male Female | 108 Participants | 257 Participants | 149 Participants |
| Sex: Female, Male Male | 184 Participants | 336 Participants | 152 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 18 / 301 | 22 / 292 |
| other Total, other adverse events | 79 / 301 | 53 / 292 |
| serious Total, serious adverse events | 18 / 301 | 20 / 292 |
Outcome results
Primary
Ordinal Outcome Scale - Day 7
The primary objective is to compare the clinical status of patients in each group on day 7 of follow-up using the primary ordinal outcome with 7 mutually exclusive categories: 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 Outcome is reported as the percent of participants in each of 7 categories. Primary 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. Minimum value = 1, Maximum value = 7 Higher scores mean a worse outcome
Time frame: 7 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Intervention Group | Ordinal Outcome Scale - Day 7 | Category 7 - Died | 5 Participants |
| Intervention Group | Ordinal Outcome Scale - Day 7 | Category 3 - Moderate end organ dysfunction | 32 Participants |
| Intervention Group | Ordinal Outcome Scale - Day 7 | Category 2 - Limiting symptoms due to COVID-19 | 67 Participants |
| Intervention Group | Ordinal Outcome Scale - Day 7 | Category 5 - Life threatening end organ dysfunction | 26 Participants |
| Intervention Group | Ordinal Outcome Scale - Day 7 | Category 1 - No limiting symptoms due to COVID-19 | 129 Participants |
| Intervention Group | Ordinal Outcome Scale - Day 7 | Category 6 - End organ failure | 9 Participants |
| Intervention Group | Ordinal Outcome Scale - Day 7 | Missing | 2 Participants |
| Intervention Group | Ordinal Outcome Scale - Day 7 | Category 4 - Serious end organ dysfunction | 25 Participants |
| Control Group | Ordinal Outcome Scale - Day 7 | Missing | 5 Participants |
| Control Group | Ordinal Outcome Scale - Day 7 | Category 7 - Died | 5 Participants |
| Control Group | Ordinal Outcome Scale - Day 7 | Category 6 - End organ failure | 13 Participants |
| Control Group | Ordinal Outcome Scale - Day 7 | Category 5 - Life threatening end organ dysfunction | 26 Participants |
| Control Group | Ordinal Outcome Scale - Day 7 | Category 4 - Serious end organ dysfunction | 30 Participants |
| Control Group | Ordinal Outcome Scale - Day 7 | Category 2 - Limiting symptoms due to COVID-19 | 61 Participants |
| Control Group | Ordinal Outcome Scale - Day 7 | Category 1 - No limiting symptoms due to COVID-19 | 116 Participants |
| Control Group | Ordinal Outcome Scale - Day 7 | Category 3 - Moderate end organ dysfunction | 28 Participants |
Primary
Primary Safety Outcome - Death, SAE or Grade 3 or 4 Events Through Day 7
Number of participants with death, SAE or Grade 3 or 4 event through Day 7
Time frame: Through Day 7
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Group | Primary Safety Outcome - Death, SAE or Grade 3 or 4 Events Through Day 7 | 71 Participants |
| Control Group | Primary Safety Outcome - Death, SAE or Grade 3 or 4 Events Through Day 7 | 70 Participants |
Secondary
N Discharged or in Most Favorable Category
N discharged from hospital or reaching most favorable ordinal category (category 1: not requiring oxygen and no limiting symptoms due to COVID-19)
Time frame: All of follow-up (through Day 28)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Group | N Discharged or in Most Favorable Category | 268 Participants |
| Control Group | N Discharged or in Most Favorable Category | 252 Participants |
Secondary
N Reaching 2 Most Favorable Categories
N Reaching 2 most favorable categories of ordinal outcome (Categories 1 and 2: not requiring oxygen with or without limiting symptoms due to COVID-19)
Time frame: All of follow-up (through Day 28)
Population: Those in Category 2 at baseline are excluded from this analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Group | N Reaching 2 Most Favorable Categories | 178 Participants |
| Control Group | N Reaching 2 Most Favorable Categories | 160 Participants |
Secondary
N Reaching 3 Least Favorable Categories
N Reaching 3 least favorable categories of ordinal outcome (Categories 5, 6, 7: life-threatening end organ dysfunction, end organ failure, or death)
Time frame: All of follow-up (through Day 28)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Group | N Reaching 3 Least Favorable Categories | 45 Participants |
| Control Group | N Reaching 3 Least Favorable Categories | 48 Participants |