Randomized, Multi-Center, Double-Blinded, Placebo Controlled Safety and Early Efficacy Trial of Cryopreserved Cord Blood Derived T-Regulatory Cell Infusions (CK0802) in the Treatment of COVID-19 Induced ARDS. (RESOLVE Trial)
Authors: Gladstone Douglas E , Howard Christopher , Lyu Mi-Ae , Mock Jason , Adams Darryl , Gibbs Kevin , Li Li , Huang Meixian , Zeng Ke , D'Alessio Franco , Herlihy James , Trevino Sergio , Hari Parameswaran , Sadeghi Tara , Parmar Simrit , Slutsky Arthur , Mukherjee Siddhartha 
Published: November 2021

Abstract
Background. COVID19 associated moderate to severe acute respiratory distress syndrome (ARDS) is associated with high rates of morbidity and mortality. Immune dysfunction and hyper-inflammatory responses result in a vicious cycle of tissue inflammation and end organ damage. Based on the suggestion of early efficacy of adoptive therapy with allogeneic T regulatory cells in COVID19 ARDS (Gladstone et al., Ann Int Med 2020), Cellenkos ® initiated a randomized, placebo controlled, multi-center trial of multiple doses of CK0802 (allogeneic, off-the-shelf, cryopreserved, cord blood derived T regulatory cells) for treatment of moderate-to-severe COVID19-related ARDS patients.
Study design. Multi-center, randomized, blinded, placebo controlled trial of CK0802 at two different doses (100 million cells and 300 million cells ) were compared to placebo. Each patient was randomized to receive the assigned product on days 0, 3 and 7 (Figure 1), without HLA matching. Enrollment was staggered for the first 6 active treatment patients with 7 days between each patient while monitoring for any safety signals. Subsequent patients were enrolled on a continuous basis. DSMB monitoring occurred after every cohort of 15 patients (5 controls; 5 of each active treatment). Results are presented as median (with range) unless otherwise indicated.
Primary Outcomes . The two co-primary outcomes were: Dose Limiting Toxicity (DLT) = Regimen related grade 3, 4, or 5 toxicity within 48 hours of first infusionS28 = [Alive and not intubated 28 days after the date of first infusion] = 28-day treatment success
Secondary Outcomes . Secondary outcomes, recorded from first day of infusion up to 28 days later, included: i) time to extubation, ii) ventilator-free days; iii) organ failure-free days; iii) ICU free days; iv) PaO 2/FiO 2 between days 0 and 11; and v) 28-day all-cause mortality
Covariates. Patient covariates recorded at enrollment included: i) age, ii) gender iii) on vasopressors; iii) on hemodialysis; iv) duration of intubation prior to enrollment.
Study Conduct. The multicenter study (n=5 centers) was activated in October 2020 and enrollment completed in March 2021.
Results. Forty-five patients were enrolled (60% male, median age 60 [range 21-85], 46.7% Caucasian race). At baseline 13% were on hemodialysis; 62% on vasopressors; SOFA score=8 (6-13); PaO 2=85 mmHg (45-133); FiO 2=60% (40-100); PEEP=10 cmH 2O (5-18) with a median duration of intubation of 48 hrs (0-120) prior to enrollment. Patient were intubated a median of 72 [0-144] hours prior to infusion. Sixty percent of patients were alive and extubated at day 28. Median time to extubation from first infusion was 10.5 [2-46] days and median ventilator free days at day 28 was 12 [0-26]days. No treatment related SAEs were reported. Time to extubation from first infusion was 10.5 days (2-46) and at day 28 the ventilator free days were 12 (0-26). The estimated day 28 overall survival was 78.6% with the following breakdown according to the co-variates: i) age&gt;60 yrs =77.5% vs. age&lt;60yrs=79.9%; ii) female=85.7% vs male=73.7%; iii) on vasopressor=65.8% vs. 77.8%; iv) on hemodialysis=75% vs. 79%. Duration of intubation to enrollment had no impact on 28d survival. At baseline, 14 pts were positive for both HLA I and HLA II antibodies (Abs); 3 pts positive for HLA I Ab only, and 9 positive for HLA II Ab only. In 20 paired samples collected on day 0 and day 28, HLA I Ab and HLA II Ab seroconversion was observed in 4 and 1 pt, respectively.
Discussion
This is the first clinical trial to examine safety and early efficacy of multiple doses of allogenic, off-the-shelf, cryopreserved, T regulatory cells for the treatment of COVID-19-related ARDS. Full data analysis of treatment groups (placebo; CK0802-100 million; CK0802-300 million) is ongoing and will be presented at the conference. Additional data to be presented will include: 3- and 6- month QOL, mental health, and cognitive index analyses, and paired Biomarker analysis.
Figure 1 Figure 1.

Disclosures
Hari: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sadeghi: Cellenkos Inc.: Current Employment. Parmar: Cellenkos Inc.: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Mukherjee: Vor Biopharma: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: coinventor on issued and pending patent applications licensed to Vor Biopharma. S.M. has equity ownership and is on the Scientific Advisory Board of Vor Biopharma., Research Funding.