ABSTRACT
Background: SARS-CoV-2 related acute respiratory distress syndrome (ARDS) is associated with endothelial dysfunction and profound dysregulation of the thrombotic/fibrinolytic pathway, with thrombotic complications common in affected patients (pts). Fibrin deposition may be a key feature of the pathobiology, with markedly elevated levels of PAI-1 reported. Defibrotide (DF), a polyanionic naturally-derived polydeoxyribonucelotide with endothelial stabilizing activity, has fibrinolytic, antithrombotic and anti-inflammatory properties, with known activity in reducing PAI-1 levels and inhibiting heparanase. We now report a prospective, open label, safety and tolerability trial of defibrotide for the management of patients with advanced SARS-CoV-2 related ARDS. Patients and Methods: Eligible patients (pts) were ≥18 years in age, with clinical and radiographic signs of ARDS, no signs of active bleeding, a serum D-Dimer > 2X ULN, and a positive PCR-based assay for SARS-CoV-2. Concomitant use of systemic anticoagulants or fibrinolytics was initially precluded, with the study amended to allow prophylactic doses of systemic heparin in its latter stages. Defibrotide (6.25 mg/kg/dose IV q. 6 hours) was administered for a planned 7-day course, with day 1 defined as the first day of study therapy. Therapy was able to be discontinued prior to day 7 in pts who met the pulmonary response parameter at that earlier timepoint. Patients with a partial response to therapy (> 20% reduction in FiO2) by day 7 were allowed to receive an additional 7 days of therapy (14 days total). Response was defined as complete cessation of supplemental O2 support, or ≥ 2 point reduction in WHO ordinal score for 48 consecutive hours by day 7. Patients were recruited from a single center between October 2020 and March 2021. Results: Twelve pts (median 63 years, range 35-73 years) were treated, with 10 of 12 pts on mechanical ventilation (median FiO2 55%, PEEP 18 mmHg), and six on vasopressor support at the time of study entry. Baseline PaO2/FiO2 ratios ranged from 82 - 200 mmHg. The median D-Dimer was 3.25 mcg/ml (range 1.33-12.3 mcg/ml), and fibrinogen 637 mg/dl (range 250-1208 mg/dl) at study entry. Dexamethasone and remdesivir had been administered prior to DF in all pts, with no other SARS-CoV-2 targeted treatment given during DF therapy. Eleven pts received ≤7 days of therapy, with one pt receiving 14 days. The first 9 pts received DF without other concomitant anticoagulants, with the last 3 pts concurrently receiving prophylactic heparin plus DF. No hemorrhagic or bleeding complications occurred during DF therapy, including the 3 pts receiving concurrent heparin prophylaxis. Likewise, no thrombotic complications developed during study therapy, including the 9 patients in which DF was their sole anti-coagulant. All 12 patients were evaluable for response. Four pts met the day 7 pulmonary response parameter, with 2 pts having a complete cessation of O2 support within this period. Three pts died from progressive pulmonary disease, at 11, 17 and 34 days from study entry. The 3 pts (who died) had the lowest baseline PaO2/FiO2 ratios (82-115 mmHg) of all study subjects. Nine pts (75%) remain alive, 64 to 174 days from study entry, all 9 discharged from their primary hospitalization. Day 30 all-cause mortality was 17% (95%CI: 0-35%). Serial coagulation and fibrinolytic assays were available in 7 patients. Total PAI-1 levels decreased from a median 167 ng/ml (range 105-264 ng/ml) to a median 104 ng/ml (range 55-166 ng/ml) by day 4 of therapy, with all 7 subjects showing a decline in PAI-1 levels at that time point. Total tPA levels increased from a median 3.02 ng/ml (range 0.72 - 36.1 ng/ml) at baseline to 4.5 ng/ml (range 1.1-8.2 ng/ml) by day 4 in study subjects. Allowing for the small sample size, baseline PAI-1, tPA or D-Dimer levels did not impact response. One of two patients with a baseline D-Dimer > 10 mcg/ml responded, while both patients with a baseline D-Dimer <2.0 mcg/ml failed to meet the response parameter. Conclusion: The use of DF for t e management of SARS-CoV-2-related ARDS proved safe and tolerable in a prospective, open label trial. No hemorrhagic or thrombotic complications were reported during therapy. Outcomes were promising, including an overall survival of 75% in a patient population with a historically high mortality rate. (The study was supported by a research grant from Jazz Pharmaceuticals) Disclosures: Yanik: Jazz Pharmaceutical: Research Funding. Pipe: Sangamo Therapeutics: Other: Scientific Advisory Board;ASC Therapeutics: Other: Scientific Advisory Board;Apcintex: Consultancy;Bayer: Consultancy;Biomarin: Consultancy;Catalyst Biosciences: Consultancy;CSL Behring: Consultancy;Freeline: Consultancy;Grifols: Consultancy;HEMA Biologics: Consultancy;Novo Nordisk: Consultancy;Octapharma: Consultancy;Pfizer: Consultancy;Roche: Consultancy;Sanofi: Consultancy;Takeda: Consultancy;Spark Therapeutics: Consultancy;uniQure: Consultancy. Sisson: Translatebio: Other: Data Safety Committee member. Richardson: Celgene/BMS: Consultancy, Research Funding;Karyopharm: Consultancy, Research Funding;Oncopeptides: Consultancy, Research Funding;Janssen: Consultancy;Secura Bio: Consultancy;AstraZeneca: Consultancy;Takeda: Consultancy, Research Funding;Regeneron: Consultancy;AbbVie: Consultancy;Protocol Intelligence: Consultancy;GlaxoSmithKline: Consultancy;Sanofi: Consultancy;Jazz Pharmaceuticals: Consultancy, Research Funding. Lawrence: MDI Therapeutics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Defibrotide: Off label use for ARDS
ABSTRACT
Background : Adeno-associated virus (AAV)-mediated gene therapy is being investigated as a treatment for people with hemophilia A (PwHA). Commonly studied AAV serotypes include AAV5, AAV6, and AAV8. Pre-existing immunity against these AAVs restricts patient eligibility yet, published data on AAV seroprevalence and seroconversion rate in PwHA are limited. Aims : To describe design and recruitment methods used for the SAVVY study. This study is designed to characterize AAV antibody prevalence and titers, evaluate changes in antibody titer over time, and examine factors that may influence antibody positivity, titer, and seroconversion. Study design and recruitment methods seek to minimize the need for in-person study interactions during the COVID-19 pandemic. Methods : SAVVY is a patient-centered, decentralized, prospective, observational study involving blood draws at 2 time points. The target sample size of 1,000 PwHA represents approximately 5% of PwHA in the US. SAVVY employs a user-friendly mobile application, provides remote recruitment through e-consent, and uses a network of 1,800+ laboratories throughout the US for biospecimen sample collection. This approach minimizes patient travel, reduces potential exposure to COVID-19, and removes burden from HTC staff to perform study assessments. Recruitment has leveraged various forms of virtual outreach to physicians, HTC staff, and patient advocacy groups;direct-to-patients are being used to create awareness of the study and its scientific aims. See Table 1. Results : First patient enrollment occurred within four months of final protocol;41 patients were enrolled within 2 weeks of activation. At the time of abstract submission, 105 patients had consented to participate. Conclusions : The COVID-19 pandemic disrupted the progress of clinical studies necessary for the advancement of treatments. Adaptability to existing conditions is critical. Careful study design and multi-modal engagement with the hemophilia community can facilitate the conduct of studies, minimize risks associated with COVID-19, and may enhance patient experience and clinical trial recruitment.