A randomized, double-blind, placebo-controlled trial of intravenous alpha-1 antitrypsin for ARDS secondary to COVID-19.

Background: Patients with severe coronavirus disease 2019 (COVID-19) develop a febrile pro-inflammatory cytokinemia with accelerated progression to acute respiratory distress syndrome (ARDS). Here we report the results of a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of intravenous (IV) plasma-purified alpha-1 antitrypsin (AAT) for moderate to severe ARDS secondary to COVID-19 (EudraCT 2020-001391-15). Methods: Patients (n = 36) were randomized to receive weekly placebo, weekly AAT (Prolastin, Grifols, S.A.; 120 mg/kg), or AAT once followed by weekly placebo. The primary endpoint was the change in plasma interleukin (IL)-6 concentration at 1 week. In addition to assessing safety and tolerability, changes in plasma levels of IL-1ß, IL-8, IL-10, and soluble tumor necrosis factor receptor 1 (sTNFR1) and clinical outcomes were assessed as secondary endpoints. Findings: Treatment with IV AAT resulted in decreased inflammation and was safe and well tolerated. The study met its primary endpoint, with decreased circulating IL-6 concentrations at 1 week in the treatment group. This was in contrast to the placebo group, where IL-6 was increased. Similarly, plasma sTNFR1 was substantially decreased in the treatment group while remaining unchanged in patients receiving placebo. IV AAT did not definitively reduce levels of IL-1ß, IL-8, and IL-10. No difference in mortality or ventilator-free days was observed between groups, although a trend toward decreased time on ventilator was observed in AAT-treated patients. Conclusions: In patients with COVID-19 and moderate to severe ARDS, treatment with IV AAT was safe, feasible, and biochemically efficacious. The data support progression to a phase 3 trial and prompt further investigation of AAT as an anti-inflammatory therapeutic. Funding: ECSA-2020-009; Elaine Galwey Research Bursary.

A randomised, double-blind, placebo-controlled, pilot trial of intravenous plasma purified alpha-1 antitrypsin for SARS-CoV-2-induced Acute Respiratory Distress Syndrome: a structured summary of a study protocol for a randomised, controlled trial.

OBJECTIVES: The primary objective is to demonstrate that, in patients with PCR-confirmed SARS-CoV-2 resulting in Acute Respiratory Distress Syndrome (ARDS), administration of 120mg/kg of body weight of intravenous Prolastin®(plasma-purified alpha-1 antitrypsin) reduces circulating plasma levels of interleukin-6 (IL-6). Secondary objectives are to determine the effects of intravenous Prolastin® on important clinical outcomes including the incidence of adverse events (AEs) and serious adverse events (SAEs). TRIAL DESIGN: Phase 2, randomised, double-blind, placebo-controlled, pilot trial. PARTICIPANTS: The study will be conducted in Intensive Care Units in hospitals across Ireland. Patients with a laboratory-confirmed diagnosis of SARS-CoV-2-infection, moderate to severe ARDS (meeting Berlin criteria for a diagnosis of ARDS with a PaO2/FiO2 ratio <200 mmHg), >18 years of age and requiring invasive or non-invasive mechanical ventilation. All individuals meeting any of the following exclusion criteria at baseline or during screening will be excluded from study participation: more than 96 hours has elapsed from onset of ARDS; age < 18 years; known to be pregnant or breastfeeding; participation in a clinical trial of an investigational medicinal product (other than antibiotics or antivirals) within 30 days; major trauma in the prior 5 days; presence of any active malignancy (other than nonmelanoma skin cancer) which required treatment within the last year; WHO Class III or IV pulmonary hypertension; pulmonary embolism prior to hospital admission within past 3 months; currently receiving extracorporeal life support (ECLS); chronic kidney disease receiving dialysis; severe chronic liver disease with Child-Pugh score > 12; DNAR (Do Not Attempt Resuscitation) order in place; treatment withdrawal imminent within 24 hours; Prisoners; non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available; IgA deficiency. INTERVENTION AND COMPARATOR: Intervention: Either a once weekly intravenous infusion of Prolastin® at 120mg/kg of body weight for 4 weeks or a single dose of Prolastin® at 120mg/kg of body weight intravenously followed by once weekly intravenous infusion of an equal volume of 0.9% sodium chloride for a further 3 weeks. Comparator (placebo): An equal volume of 0.9% sodium chloride intravenously once per week for four weeks. MAIN OUTCOMES: The primary effectiveness outcome measure is the change in plasma concentration of IL-6 at 7 days as measured by ELISA. Secondary outcomes include: safety and tolerability of Prolastin® in the respective groups (as defined by the number of SAEs and AEs); PaO2/FiO2 ratio; respiratory compliance; sequential organ failure assessment (SOFA) score; mortality; time on ventilator in days; plasma concentration of alpha-1 antitrypsin (AAT) as measured by nephelometry; plasma concentrations of interleukin-1ß (IL-1ß), interleukin-8 (IL-8), interleukin-10 (IL-10), soluble TNF receptor 1 (sTNFR1, a surrogate marker for TNF-α) as measured by ELISA; development of shock; acute kidney injury; need for renal replacement therapy; clinical relapse, as defined by the need for readmission to the ICU or a marked decline in PaO2/FiO2 or development of shock or mortality following a period of sustained clinical improvement; secondary bacterial pneumonia as defined by the combination of radiographic findings and sputum/airway secretion microscopy and culture. RANDOMISATION: Following informed consent/assent patients will be randomised. The randomisation lists will be prepared by the study statistician and given to the unblinded trial personnel. However, the statistician will not be exposed to how the planned treatment will be allocated to the treatment codes. Randomisation will be conducted in a 1:1:1 ratio, stratified by site and age. BLINDING (MASKING): The investigator, treating physician, other members of the site research team and patients will be blinded to treatment allocation. The clinical trial pharmacy personnel and research nurses will be unblinded to facilitate intervention and placebo preparation. The unblinded individuals will keep the treatment information confidential. The infusion bag will be masked at the time of preparation and will be administered via a masked infusion set to maintain blinding. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 36 patients will be recruited and randomised in a 1:1:1 ratio to each of the trial arms. TRIAL STATUS: In March 2020, version 1.0 of the trial protocol was submitted to the local research ethics committee (REC), Health Research Consent Declaration Committee (HRCDC) and the Health Products regulatory Authority (HPRA). REC approval was granted on April 1st 2020, HPRA approval was granted on April 24th 2020 and the HRCDC provided a conditional declaration on April 17th 2020. In July 2020 a substantial amendment (version 2.0) was submitted to the REC, HRCDC and HPRA. Protocol changes in this amendment included: the addition of trial sites; extending the duration of the trial to 12 months from 3 months; removal of inclusion criteria requiring the need for vasopressors; amendment of randomisation schedule to stratify by age only and not BMI and sex; correction of grammatical error in relation to infusion duration; to allow for inclusion of subjects who may have been enrolled in a clinical trial involving either antibiotics or anti-virals in the past 30 days; to allow for inclusion of subjects who may be currently enrolled in a clinical trial involving either antibiotics or anti-virals; to remove the need for exclusion based on alpha-1 antitrypsin phenotype; removal of mandatory isoelectric focusing of plasma to confirm Pi*MM status at screening; removal of need for mandatory echocardiogram at screening; amendment on procedures around plasma analysis to reflect that this will be conducted at the central site laboratory (as trial is multi-site and no longer single site); wording amended to reflect that interim analysis of cytokine levels taken at 7 days may be conducted. HRCDC approved version 2.0 on September 14th 2020, and HPRA approved on October 22nd 2020. REC approved the substantial amendment on November 23rd. In November 2020, version 3.0 of the trial protocol was submitted to the REC and HPRA. The rationale for this amendment was to allow for patients with moderate to severe ARDS from SARS-CoV-2 with non-invasive ventilation. HPRA approved this amendment on December 1st 2020 and the REC approved the amendment on December 8th 2020. Patient recruitment commenced in April 2020 and the last patient will be recruited to the trial in April 2021. The last visit of the last patient is anticipated to occur in April 2021. At time of writing, patient recruitment is now complete, however follow-up patient visits and data collection are ongoing. TRIAL REGISTRATION: EudraCT 2020-001391-15 (Registered 31 Mar 2020). FULL PROTOCOL: The full protocol (version 3.0 23.11.2020) is attached as an additional file accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

A Summer Nutrition Benefit Pilot Program and Low-income Children's Food Security.

BACKGROUND: Federal summer meals programs serve less than one-sixth of children that receive free or reduced-price meals during the school year. To address this gap in food assistance for school-aged children, the Summer Electronic Benefits Transfer for Children (SEBTC) Demonstrations provided summer food assistance in the form of electronic benefits transfer cards to households with school-aged children certified for free or reduced-price meals during the school year. METHODS: Over 2011-2013, the SEBTC demonstrations were evaluated by using a random assignment design. Households were randomly assigned a monthly $60-per-child benefit, a monthly $30-per-child benefit, or no benefit, depending on the study year. Key outcomes included children's food security and consumption of foods and food groups related to a healthful diet (diet quality). At baseline (in the spring) and again in the summer, the evaluation surveyed ∼52 000 households over the course of the 3 years of the impact study. RESULTS: SEBTC reduced the prevalence of very low food security among children by one-third. It also had positive impacts on 6 of the 8 child nutrition outcomes measured (amounts of fruits and vegetables; whole grains; dairy foods; and added sugars). CONCLUSIONS: SEBTC is a promising model to improve food security and the dietary quality of low-income school-aged children in the summer months.

Improving Nutrition by Limiting Choice in the Supplemental Nutrition Assistance Program.

In contrast to the Special Supplemental Nutrition Program for Women, Infants, and Children, the Supplemental Nutrition Assistance Program (SNAP) currently allows the purchase of almost any food. This paper reconsiders the role of two forms of limiting choice in SNAP. Using economic theory, descriptive analysis of survey data, and discussion of random assignment evaluation evidence from the Summer Electronic Benefit Transfer for Children Demonstration, the paper argues that because households can substitute cash for SNAP, banning the use of SNAP for less nutritionally desirable foods (e.g., soda, candy) is unlikely to have a large impact. By contrast, because many households currently consume so little of more nutritionally desirable foods (e.g., whole grains, fruits, and vegetables), requiring that some portion of SNAP benefits be spent on those foods is likely to improve dietary intake. Summer Electronic Benefit Transfer for Children Demonstration impact estimates are consistent with this conjecture. Furthermore, these data and evidence from the Healthy Incentives Pilot implementation suggest that such a policy can be feasibly integrated into existing operational processes.

Improving Nutrition by Increasing Supplemental Nutrition Assistance Program Benefits.

The diets of Americans fall far short of recommended dietary guidelines, and those who live in low-income households have even poorer diets than higher-income households. Many low-income Americans rely on the Supplemental Nutrition Assistance Program (SNAP). The program's dual goals are to improve food security and nutrition. Among the possible strategies to address dietary shortfalls among low-income Americans is to increase the SNAP benefit. This article uses data from the random assignment evaluation of the Summer Electronic Benefit Transfer for Children demonstration to add new insights on the impact of SNAP on diet quality for households receiving SNAP who also received SNAP-like benefits through Summer Electronic Benefit Transfer for Children. Households received $60 each month per eligible school-aged child. The objective of the evaluation was to see if Summer Electronic Benefit Transfer for Children improved children's food security and nutrition. The evaluation surveyed these households to collect information about food expenditures, food security, and children's diets. For households receiving SNAP in sites that used the SNAP Electronic Benefit Transfer delivery system, the analysis showed increases in food expenditures and decreases in levels of food insecurity. The analysis also indicates improvements in dietary quality among school-aged children, but the impacts were modest.

Delivering Summer Electronic Benefit Transfers for Children through the Supplemental Nutrition Assistance Program or the Special Supplemental Nutrition Program for Women, Infants, and Children: Benefit Use and Impacts on Food Security and Foods Consumed.

BACKGROUND: The Summer Electronic Benefit Transfers for Children (SEBTC) demonstration piloted summer food assistance through electronic benefit transfers (EBTs), providing benefits either through the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) or the Supplemental Nutrition Assistance Program (SNAP) EBT. OBJECTIVE: To inform food assistance policy and describe how demonstrations using WIC and SNAP models differed in benefit take-up and impacts on food security and children's food consumption. DESIGN: Sites chose to deliver SEBTC using the SNAP or WIC EBT system. Within each site, in 2012, households were randomly assigned to a benefit group or a no-benefit control group. PARTICIPANTS: Grantees (eight states and two Indian Tribal Organizations) selected school districts serving many low-income children. Schoolchildren were eligible in cases where they had been certified for free or reduced-price meals during the school year. Before the demonstration, households in the demonstration sample had lower incomes and lower food security, on average, than households with eligible children nationally. INTERVENTION: Grantees provided selected households with benefits worth $60 per child per summer month using SNAP or WIC EBT systems. SNAP-model benefits covered most foods. WIC-model benefits could only be used for a specific package of foods. OUTCOME MEASURES: Key outcomes were children's food security (assessed using the US Department of Agriculture food security scale) and food consumption (assessed using food frequency questions). STATISTICAL ANALYSES: Differences in mean outcomes between the benefit and control groups measured impact, after adjusting for household characteristics. RESULTS: In WIC sites, benefit-group households redeemed a lower percentage of SEBTC benefits than in SNAP sites. Nonetheless, the benefit groups in both sets of sites had similar large reductions in very low food security among children, relative to no-benefit controls. Children receiving benefits consumed more healthful foods, and these impacts were larger in WIC sites. CONCLUSIONS: Results suggest the WIC SEBTC model deserves strong consideration.

The reliability of patient-reported pregnancy outcome data.

Pregnancy and neonatal outcome information is frequently used in disease management to evaluate the cost-effectiveness of prenatal interventions and for other research and reporting activities. The purpose of this study was to determine if a telephone interview process is a reliable methodology for collecting pregnancy outcomes. High-risk patients from a large maternal-fetal medicine practice who received outpatient preterm labor management services from January 1996 to June 2001 were identified. Patient-reported pregnancy outcome data for 285 mothers and 478 infants were collected via a telephone interview by a perinatal nurse and compared to pregnancy outcome data abstracted from the maternal and infant hospital records. Overall, concordance and/or Kappa coefficients between maternal report and the medical record were high for delivery date (96.4%), birth weight within 100 grams (88.9%), Cesarean delivery (99.0%, Kappa = 0.98), and high-level nursery admission (91.2%, Kappa = 0.82). Both singleton and multiple gestation types accurately reported pregnancy outcome information. A telephone interview with a skilled nurse can be a reliable methodology for collection of valuable clinical and research data related to pregnancy outcome. Data collected in this manner and maintained in a database may be used with a high level of confidence by health care providers, payers, and researchers.