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Background: Camostat, an oral protease inhibitor, blocks entry and replication of SARS-CoV-1 and SARS-CoV-2 in vitro. It is approved for therapy of recurrent pancreatitis in several countries. Camostat has an excellent safety profile and repurposing for COVID-19 treatment was proposed. Methods: We conducted a Phase II randomized, placebo-controlled trial of camostat in adult outpatients with confirmed COVID-19 and one or more risk factors for severe disease (including age ≥65 years, severe obesity, hypertension, diabetes, chronic lung, heart or liver disease). Participants were randomized 2:1 to oral camostat 200 mg or matching placebo four times a day for 14 days. Exclusion criteria were end-stage liver disease, severe renal impairment, oxygen saturation ≤94% on room air, and experimental treatment for COVID-19. The primary efficacy endpoint was hospitalization or death within 28 days. Secondary efficacy included positivity for SARS-CoV-2 by PCR on mid-nasal turbinate swabs on days 7 and 15 compared to baseline. Results: We enrolled 295 participants, 57.3% were female, 15.6% Black and 60% Latinx. Mean age was 51 years (18-93 years). Most (75.3%) were randomized ≤5 days after symptom onset. Common risk factors were hypertension (63.4%), chronic lung disease (33.2%) and diabetes (25.4%), with 46.8% having >1 risk factor. With a lower than anticipated event rate, the primary endpoint of hospitalization or death was not significantly different in the camostat (5.3%, 10/194) and placebo groups (6.1%, 6/99;p=0.78). In the intention-to-treat population, there was a trend towards a lower proportion of PCR positivity in the camostat compared to the placebo group at day 7 (65.2% vs. 75.7%, p=0.12) and day 15 (22.0% vs. 34.3%, p=0.06). Similarly, in a post hoc as treated population, fewer participants in the camostat than in the placebo group remained PCR positive at day 7 (64.7%, 88/136 vs. 76.8%, 53/96;p=0.077) and day 15 (21.8%, 29/133, vs. 34.8%, 23/66;p=0.05). Adverse events occurred in 13% of participants in the placebo and 9% in the camostat group. All severe adverse events (5% in both groups) were related to COVID-19. Conclusion: With a low overall event rate, we did not observe a decrease in risk of hospitalization or death in camostat treated outpatients with COVID-19 at risk for severe disease. SARS-CoV-2 PCR turned negative faster on camostat treatment. Camostat was well tolerated.
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Background: Camostat, a serine protease inhibitor, prevents activation of the SARS-CoV-2 spike protein and blocks SARS-CoV-2 infection in vitro. We studied the safety and antiviral and clinical efficacy of orally administered camostat in non-hospitalized adults with mild-moderate COVID-19. Methods: ACTIV-2/A5401 is a platform trial to evaluate therapies for non-hospitalized adults with mild-moderate COVID-19. In a Phase II portion of the study, participants were enrolled within 10 days of COVID-19 related symptom onset and randomized to camostat 200 mg orally every 6 hours for 7 days or the pooled placebo group. Objectives were to evaluate the safety and efficacy of camostat to reduce the duration of COVID-19 symptoms and increase the proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) from nasopharyngeal (NP) swabs on days 3, 7, and 14. Participants completed a study diary from day 0 to day 28 scoring COVID-19 symptoms as absent, mild, moderate, or severe. Results: Of the 224 participants enrolled from 54 US sites, 215 participants (108 camostat, 107 placebo) initiated study intervention and formed the modified intent-to-treat population. Fifty-four percent were female, >99% cis-gender, 85% White, 9% Black, and 51% Latinx. Median age was 37 years;47% reported ≤5 days of symptoms at study entry and 26% met the protocol definition of higher risk of progression to severe COVID-19. Most frequent symptoms on day 0 were cough (86%), fatigue (85%), nasal obstruction/congestion (71%) and body/muscle aches (71%). There was no significant difference between camostat and placebo arms in grade 3 or higher adverse events (7.4% vs. 6.5%, respectively). Median (Q1, Q3) time to symptom improvement was 9 days for both camostat (5, 20) and placebo (6, 19). There were no significant differences in the proportion of participants with NP SARS-CoV-2 RNA<="" div=""> Conclusion: Camostat was well-tolerated. Despite compelling in vitro data, camostat did not show evidence of antiviral or clinical efficacy in ACTIV-2/A5401. This highlights the critical importance of randomized controlled trials in the evaluation of therapies for COVID-19.
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BACKGROUND: Branch duct (BD)-IPMNs with increased risk for malignant transformation are typically treated with surgical resection, and alternate therapies are needed for patients with prohibitive risks for perioperative complications. Injection of cysts with paclitaxel may prevent or reverse transformation, but current formulations are not retained in cysts to provide durable benefit. A Submicron Particle formulation of Paclitaxel (SPP) has been designed to avoid clearance into the systemic circulation and effectively provides a depot effect releasing the drug at constant saturation levels. In this initial study of EUS-guided fine needle injection (FNI) with SPP we evaluated safety, tolerability, pharmacokinetics, and cyst response in BD-IPMNs. METHODS: A diagnosis of BD-IPMNs was confirmed by EUSguided confocal laser endomicroscopy and cyst fluid next generation sequencing. Subjects received EUS-FNI of SPP (15mg/mL concentration) at volumes equal to the aspirated cyst fluid as part of an ongoing clinical trial [NCT03188991] (Study was interrupted due to COVID-19 pandemic). This report covers 5 of the study subjects enrolled at one site. SPP was administered on two occasions 12 weeks apart in 4/5 subjects and once in 1 subject. CT Scans were performed at 0, 12, and 24 weeks to assess changes in cyst size. RESULTS: The mean6standard deviation duration of follow-up from 1st EUS-FNI was 37.3±19.8 weeks. The mean size on CT-Scan of BD-IPMNs at time 0 weeks (1st EUS-FNI) was 3.360.8 cm, 12 weeks (2nd EUS-FNI) was 3.02±1.2 cm, and 24 weeks was 3.15±1.8 cm (Table 1). The mean dosage of SPP injected by EUS-FNI was 75±39 mg for 1st dose and 40.6±15.1 mg for 2nd dose. No dose limiting toxicities, study-related serious adverse events, or clinically significant changes in blood work were observed. The paclitaxel levels (PK) in plasma and cyst fluid is shown in Figure 1. Systemic paclitaxel concentration did not exceed 1 ng/mL at any point post-administration, falling below lower limit of quantitation (25 pg/mL) within, at most, 4 weeks. Cyst fluid analysis confirmed sustained presence of SPP for at least 12 weeks. At baseline evaluation, 4 of 5 subjects had GNAS mutations in cyst fluid (Table 1). In total, DNA mutations (KRAS or GNAS) were not detectable in two of 4 (50%) subjects after EUS-FNI with SPP (Table 1);both subjects (Figure 1) had a dose-dependent high intracystic concentration (> 1000 ng/mL) of SPP immediately prior to 2nd EUS-FNI (week 12). CONCLUSION: EUS-FNI of intracystic SPP appears to be safe and tolerable in patients with BD-IPMNs. SPP is likely retained in these cysts up to 12 weeks in a dose-dependent manner and higher doses are associated with regression of mutations that are specific for BD-IPMNs. Future studies with additional injections and longer-term follow-up are needed to understand the durability of the benefits observed.(Table presented)(figure presented)