CONNECTS

NECTAR: Novel Experimental COVID Therapies Affecting Host Response

The ACTIV4 Host Tissue platform is testing treatments targeting the host-tissue response to SARS-CoV-2 infection. The initial agents on the platform will target the Renin-Angiotensin-Aldosterone System (RAAS). The goal of this platform is to determine if these host-tissue targeted agents hasten recovery and prevent illness progression in patients hospitalized with COVID-19.

Formal Name: CONNECTS Master Protocol for Clinical Trials targeting macro-, micro-immuno-thrombosis, vascular hyperinflammation, and hypercoagulability and renin-angiotensin-aldosterone system (RAAS) in hospitalized patients with COVID-19 (ACTIV4 Host Tissue)

Current or previously assessed agents: TXA127 (enrollment stopped on 4/20/2022, TRV027 (enrollment stopped on 4/20/2022), Fostamatinib

Agent(s) V. Placebo

Key Personnel

Sean P. Collins, MD, MSC Study Chairsean.collins@vumc.org

Wesley Self, MD, MPH CCC PIwesley.self@vumc.org

Matthew S. Shotwell, PhD DCC PImatt.shotwell@vumc.org

Primary Outcome(s)

Oxygen-free days (OFD) from randomization through day 28; mortality coded as -1

Population

Adult patients hospitalized for COVID-19 with laboratory confirmed SARS-CoV-2 infection and treated with oxygen for hypoxemia

Intervention

TXA127, TRV027, Fostamatinib, and Placebo arm

Planned Enrollment

1,600 total; 300 per arm + ~400 for common placebo

Power and Interim Assessments

For each arm, we will use pre-planned interim analyses at fixed recruitment intervals to consider ending enrollment early due to strong evidence of inferiority or futility regarding the primary efficacy analysis. Early stopping and final analysis thresholds will be selected to ensure a type-I error probability of 2.5%, separately for each study agent.

Two planned interim analyses will occur at 33% (100 participants in both the active and matching placebo group have completed 28-day follow-up) and 66% of maximum enrollment for each arm. Prior to the first interim analysis, sample size adequacy will be re-assessed based on the pooled (across all active and placebo arms) distribution of the primary outcome.

A maximum sample size of 300 participants per arm (and matching placebo) provides over 85% power to detect an odds ratio of 1.55, corresponding to a 2.3-day difference in mean OFDs.

Follow-up

Duration of hospitalization with post-discharge follow-up for up to 90 days after randomization. Participants may be contacted beyond 90 days for long-term follow-up.