Strategies and Treatments for Respiratory Infections &Amp; Viral Emergencies (STRIVE): Immune Modulation Strategy Trial

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
Strategies and Treatments for Respiratory Infections &Amp; Viral Emergencies (STRIVE): Immune Modulation Strategy Trial

Conditions
-----------------
COVID-19

Intervention / Treatment
-----------------
* Drug: abatacept infusion
* Drug: Placebo group


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmation of SARS-CoV2 infection by nucleic acid test (NAT) or equivalent non-NAT test [list of approved tests in the PIM] within 14 days of randomization. Requiring hospitalization for the management of COVID-19 Has evidence of COVID-19 pneumonia (PNA) defined as either receiving supplementary oxygen ≤2L of low flow oxygen with evidence of airspace disease on chest imaging (X ray, computer tomography or ultrasound) OR receiving supplementary oxygen &gt;2L and &lt;10 L of low flow oxygen. Currently receiving or planned to receive (ordered) one IM drug (for example, a corticosteroid or baricitinib) as part of treatment of COVID-19 prior to randomization. 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 baseline and other above criteria are met. Investigator agrees that the pneumonia is due to COVID-19. Exclusion Criteria: Oxygen requirement of ≥10L or more of low flow oxygen (or equivalent if using Venturi mask, etc), or requiring either HFNO, NIV, IMV, or ECMO. Participant has received more than one baseline IM for treatment of the current COVID-19 infection at time of trial enrollment. (Examples: corticosteroid, baricitinib, tocilizumab, anakinra, abatacept, or infliximab.) Participant anticipated to not meet all inclusion criteria within 24 hours of randomization in the opinion of the investigator. Allergy to investigational agent. Neutropenia (absolute neutrophil count <1000 cells/μL) (<1.0 x 10 3 /μL or <1.0 G/L) on most recent lab within 2 calendar days of randomization. Lymphopenia (absolute lymphocyte count <200 cells/μL) (<0.20 x 10 3 /μL or <0.20 G/L) on most recent lab within 2 calendar days of randomization. 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. 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). Have 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. Pre-existing immunomodulation or immunosuppression that meets any of the following: Participant has received abatacept for an indication other than COVID- 19 within 5 half-lives (65 days) of enrollment (Abatacept elimination half-life is 13.1 days.) Participant is receiving immune modulatory therapy for autoimmune, transplant management or another indication AND has one or more of the following: evidence of active infection (other than COVID-19) or 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 has required intensification in immunotherapy 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) Participant has recently received or is anticipated to require immune modulatory agents for their underlying disease including chemotherapeutic treatments likely to induce neutropenia (&lt;1.0 x 10 9 cells/µL) or lymphopenia (&lt;1.0 x 10 9 cells/µL) Participant has untreated advanced HIV (known CD4 &lt;200 in the past 6 months) AND is not established on antiretroviral therapy Pregnancy Breastfeeding Co-enrollment in other trials not predetermined to be compatible with this trial. In the investigator's judgment, the patient has any advanced organ dysfunction that would not make participation appropriate. The treating clinician expects inability to participate in trial procedures or participation would not be in the best interests of the patient.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: active treatment group<br>Active treatment group (IV abatacept infusion, 10 mg/kg up to 1750 mg) + baseline IM | Drug: abatacept infusion<br>* 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, so any participant with weight of >175 kg will receive a dose of 1750 mg. + baseline IM (immune modulator)<br>|
| Placebo Comparator: Control group<br>Placebo group (IV infusion of normal saline) + baseline IM | Drug: Placebo group<br>* Placebo group (IV infusion of normal saline) + baseline IM<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days to Recovery Scale | DRS-60 is a version of the STRIVE clinical recovery scale (CRS) which combines time to recovery with non-recovered clinical state and death to an ordinal outcome.0 indicates best results, 60 represents recovered on Day 60, with not recovered by Day 60 coded as 61 and death (worst outcome) as 62. | 60 days post-intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| time to sustained recovery though Day 60 | Time to sustained recovery is defined as being discharged from the index hospitalization, followed by being alive and home for 14 consecutive days prior to the end of follow-up | baseline to day 60 | 
| all-cause mortality though Day 60 | substantial attempts will be made to determine vital status through the end of follow-up by a combined approach of follow-up visits with the participant or proxy, chart review, and review of other available information sources. | baseline to day 60 | 
| time to progression | will be defined by the study day on which a participant experiences a definite progression. Definite progression is defined as a participant requiring HFNO, NIV, IMV, or ECMO therapy, OR, if HFNO is unavailable, a participant requiring ≥15 L/min conventional oxygen. Probable progression is defined as a participant not meeting criteria for definite progression but requiring ≥10 L/min conventional oxygen, OR, a participant with an oxygen requirement that has increased by ≥4 L/min in the preceding 24 hours. | baseline to 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 | categories defined as: Can independently undertake usual activities with minimal or no symptoms Symptomatic and currently unable to independently undertake usual activities but no need of supplemental oxygen (or not above premorbid requirements) Supplemental oxygen <4 liters/min (or <4 liters/min above premorbid requirements) Supplemental oxygen ≥4 liters/min (or ≥4 liters/min above premorbid requirements, but not high-flow oxygen) Non-invasive ventilation or high-flow oxygen Invasive ventilation, extracorporeal membrane oxygenation (ECMO), mechanical circulatory support, or new receipt of renal replacement therapy Death | Day 5, 14, and 28 |