- Research purpose: This is a strategy trial to test the hypothesis that early intensification of immune modulation will improve outcomes in patients hospitalized with COVID-19. Current  National Institutes of Health (NIH) guidelines recommend the standard of care (SOC) use of a single immune modulator (IM) (typically dexamethasone) in patients who are hospitalized and on low flow oxygen. Guidelines recommend intensification of immune modulation if a patient has a rapidly progressing need for oxygen support and/or if a patient progresses to require high flow nasal oxygen (HFNO) or more support . It is unclear if use of a second immune modulator early in the disease course for hospitalized patients is beneficial. 

- Background: The pathogenesis of SARS CoV-2 is thought to differ depending on the stage of disease with early disease driven by viral replication while later stage disease is driven by immune dysregulation. Many studies have shown that the addition of IMs in patients hospitalized with moderate to severe COVID-19 has resulted in decreased mortality. 
Early in the pandemic, data from the RECOVERY (dexamethasone) trial demonstrated reduced 28-day mortality in hospitalized participants who received dexamethasone, with the greatest benefit observed in those receiving mechanical ventilation at randomization. Consequently, corticosteroids quickly became SOC as the baseline IM drug.
Currently, NIH guidelines  recommend use of a second IM in those requiring HFNO, non-invasive ventilation (NIV), invasive mechanical ventilation (IMV), extracorporeal membrane oxygenation (ECMO), or in those who have a rapidly increasing oxygen requirement. These recommendations are because of several large, randomized trials that examined the use of interleukin (IL)-6 inhibitors or Janus kinase (JAK) inhibitors in the presence or absence of corticosteroids.
 Corticosteroid and additional targeted immune modulation decreases mortality and improves clinical outcomes in hospitalized patients with COVID-19, with agents targeting a variety of pathways all demonstrating similar findings. 

- Hypothesized and Clinical Trial Plan: COVID-19 can trigger a dysregulated immune response, and previous studies have shown that immune modulation can improve outcomes in hospitalized patients. This trial is designed to determine whether 
intensification of immune modulation early in the course of the disease (while patients are on low flow oxygen) with abatacept (active arm) combined with standard of care (SOC) improves recovery as compared with placebo + SOC (placebo arm). For both groups, intensification of immunomodulation will be provided as part of SOC in case of signs of disease progression (patient requires high flow nasal oxygen (HFNO) or more support) and/or if the patient has rapidly increasing oxygen requirement.

Treatment

Randomization will be 1:1 allocation to active (i.e., abatacept) plus SOC or matched placebo plus SOC. Blinding will be accomplished by use of matching 0.9% saline infusion, with an amber sleeve placed over the infusion bags of both active agent and placebo.  All participants and study personnel will be blinded, with the exception of the DSMB, the unblinded statisticians responsible for preparing the closed DSMB reports, and the site pharmacist(s) responsible for preparing the infusion bag.
Abatacept (Brand name - ORENCIA) for Injection is a lyophilized powder for IV infusion. The dose of abatacept will be 10 mg/kg given as a single infusion on Day 0, with a maximum dose of 1,750 mg.

Arm Label

Target Number of Participant

Arm Type

Arm Description

 (IV abatacept infusion, 10 mg/kg up to 1750 mg) + baseline IM (Immune modulator)

Arm Label

Target Number of Participant

Arm Type

Arm Description

(IV infusion of normal saline) +  baseline IM (Immune modulator)

Gender

Age

Description

1. Confirmation of SARS-CoV2 infection by nucleic acid test (NAT) or equivalent  non-NAT test [list of approved tests in the PIM] collected within 14 days of  randomization.
2. Requiring hospitalization for the management of COVID-19.
3. Has evidence of COVID-19 pneumonia (PNA) defined as either: 
a. Receiving supplemental low flow oxygen, >0 L/min and ≤2 L/min, with evidence of airspace disease on chest imaging (X-ray, computer tomography or ultrasound).OR
b. Receiving supplemental low flow oxygen, >2 L/min and <10 L/min.
4. Currently receiving or planned to receive (ordered) one IM drug (for example, a corticosteroid or baricitinib, but NOT abatacept) as part of treatment of COVID-19 prior to randomization.
5. Has started supplemental oxygen for the treatment of COVID-19 within the past  5 calendar days. Patients on home oxygen are eligible if current oxygen flow rate is increased from pre-COVID-19 level and all other study criteria are met.
6. Investigator agrees that the pneumonia is due to COVID-19.

1. Oxygen requirement of 10 L/min or more of low flow oxygen (or equivalent if using Venturi mask, etc.), or requiring high-flow oxygen (HFNO), non-invasive ventilation (NIV), invasive mechanical ventilation (IMV) or ECMO.
2. Received more than one baseline IM for treatment of the current COVID-19 
infection at the time of trial enrollment (examples: corticosteroid, baricitinib, 
tocilizumab, anakinra, abatacept, or infliximab).
3. Participant anticipated to not meet all inclusion criteria within 24 hours of randomization in the opinion of the investigator.
4. Allergy to investigational agent.
5. Neutropenia: absolute neutrophil count <1000 cells/μL (<1.0 x 103/μL or <1.0 x 109/L) on most recent lab within 2 calendar days of randomization.
6. Lymphopenia: absolute lymphocyte count <200 cells/μL (<0.20 x 103/μL or <0.20 x 109/L) on most recent lab within 2 calendar days of randomization.
7. Known or suspected active or recent serious infection (bacterial, fungal, viral, or parasitic infection, excepting SARS-CoV-2) that in the opinion of the investigator could constitute a risk when taking investigational agent. Note: 
Broad spectrum empiric antibiotic usage does not exclude participation.
8. Known or suspected history of untreated tuberculosis (TB). TB diagnosis may be suspected based on medical history and concomitant therapies that would suggest TB infection. Participants are also excluded if they have known, latent 
TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history only, no screening required).
9. Received any live vaccine (or live attenuated) within 3 months before screening or intend to receive a live vaccine (or live attenuated) during the trial. Use of prior non-live (inactivated) vaccinations is allowed for all participants, including any vaccine for COVID-19.
10.Pre-existing immunomodulation or immunosuppression that meets any of the following:
a. Participant has received abatacept for an indication other than COVID19 within 5 half-lives (65 days) of enrollment (Abatacept elimination halflife is 13.1 days.)
b. Participant is receiving immune modulatory therapy for autoimmune, transplant management or another indication AND has one or more of the following: 
i. evidence of active infection (other than COVID-19) or
ii. has required reduction in their immune modulatory therapy in the 
preceding 6 months due to infectious complication (routine reduction as SOC is not an exclusion) or 
iii. has required intensification in immune modulatory therapy within the preceding 6 months due to organ rejection/worsening underlying disease status (e.g., intensification with an additional agent on top of usual immunosuppressive regimen).
c. Participant has recently received or is anticipated to require immune modulatory agents for their underlying disease including chemotherapeutic treatments likely to induce neutropenia or lymphopenia.
d. Participant has untreated advanced HIV (known CD4 <200 cells/mm3 in the past 6 months) AND is not established on antiretroviral therapy.
11.Pregnancy or intention to become pregnant within 60 days of randomization.
12.Currently breastfeeding.
13.Co-enrollment in other trials not predetermined to be compatible with this trial. 
14.In the investigator’s judgment, the participant has any advanced organ dysfunction that would not make participation appropriate. 
15.The treating clinician expects inability to participate in trial procedures or participation would not be in the best interests of the patient.

The primary objective of this trial is to determine whether early administration of a second  IM (in addition to SOC baseline IM) in hospitalized patients with COVID-19 improves  clinical recovery through Day 60 compared with early administration of placebo.‘Days to Recovery Scale’ assessed over  60 days (DRS-60)

Day 60

The primary safety  endpoint for this trial will be a composite of grade 3/4 AEs, protocol-defined adverse  clinical events (PDACEs), SAEs, and death through Day 28.

Day 28,

 time to sustained recovery though Day 60

Day 60

all-cause mortality though Day 60

Day 60

time to progression (as defined elsewhere in this  document) through Day 60

Day 60

) three-category ordinal outcome, assessed at Day 60, with  categories “recovered (alive and at home at Day 60)”, “alive and not recovered”, and dead

Day 60

the pulmonary ordinal outcome on Days 5, 14, and 28

Days 5, 14, and 28

 clinically relevant infections (CRIs) through Day 120.

Day 120

Other important safety  outcomes are the composite of grade 3/4 AEs, SAEs, PDACEs, or death through Day 5;  death and the composite of SAEs, PDACEs, or death through Day 60; and the composite  of CRIs and death through Day 60 and Day 120.

Days 5, 60, and 120