Primary lateral sclerosis natural history study - planning, designing, and early enrollment.

Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results. In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion. We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.

Immune markers are associated with cognitive performance in a multiethnic cohort: The Northern Manhattan Study.

OBJECTIVE: To determine whether immune protein panels add significant information to correlates of cognition. BACKGROUND: Immune mechanisms in vascular cognitive aging are incompletely characterized. DESIGN/METHODS: A subsample of the prospective Northern Manhattan Study underwent detailed neuropsychological testing. Cognitive scores were converted into Z-scores and categorized into four domains (memory, language, processing speed, and executive function) based on factor analysis. Blood samples were analyzed using a 60-plex immunoassay. We used least absolute shrinkage and selection operator (LASSO) procedures to select markers and their interactions independently associated with cognitive scores. Linear regression models assessed cross-sectional associations of known correlates of cognition with cognitive scores, and assessed model fit before and after addition of LASSO-selected immune markers. RESULTS: Among 1179 participants (mean age 70 ± 8.9 years, 60% women, 68% Hispanic), inclusion of LASSO-selected immune markers improved model fit above age, education, and other risk factors (p for likelihood ratio test < 0.005 for all domains). C-C Motif Chemokine Ligand 11 (CCL 11, eotaxin), C-X-C Motif Chemokine Ligand 9 (CXCL9), hepatocyte growth factor (HGF), and serpin E1 (plasminogen activator inhibitor-1) were associated with each of the domains and with overall cognitive function. Immune marker effects were comparable to conventional risk factors: for executive function, each standard deviation (SD) increase in CCL11 was associated with an effect equivalent to aging three years; for memory, HGF had twice the effect of aging. CONCLUSIONS: Immune markers associate with cognitive function in a multi-ethnic cohort. Further work is needed to validate these findings and determine optimal treatment targets.

Correction to: Evaluating the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in severely ill adults with COVID-19: A structured summary of a study protocol for a randomized controlled trial.

An amendment to this paper has been published and can be accessed via the original article.

Evaluating the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in severely ill adults with COVID-19: A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: The aim of this study is to evaluate the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in hospitalized adults with severe SARS-CoV-2 infection. TRIAL DESIGN: This is a prospective, single-center, phase 2, randomized, controlled trial that is blinded to participants and clinical outcome assessor. PARTICIPANTS: Eligible participants include adults (≥ 18 years) with evidence of SARS-CoV-2 infection by PCR test of nasopharyngeal or oropharyngeal swab within 14 days of randomization, evidence of infiltrates on chest radiography, peripheral capillary oxygen saturation (SpO2) ≤ 94% on room air, and/or need for supplemental oxygen, non-invasive mechanical ventilation, or invasive mechanical ventilation, who are willing and able to provide written informed consent prior to performing study procedures or who have a legally authorized representative available to do so. Exclusion criteria include participation in another clinical trial of anti-viral agent(s)* for coronavirus disease-2019 (COVID-19), receipt of any anti-viral agent(s)* with possible activity against SARS-CoV-2 <24 hours prior to plasma infusion, mechanical ventilation (including extracorporeal membrane oxygenation [ECMO]) for ≥ 5 days, severe multi-organ failure, history of allergic reactions to transfused blood products per NHSN/CDC criteria, known IgA deficiency, and pregnancy. Included participants will be hospitalized at the time of randomization and plasma infusion. *Use of remdesivir as treatment for COVID-19 is permitted. The study will be undertaken at Columbia University Irving Medical Center in New York, USA. INTERVENTION AND COMPARATOR: The investigational treatment is anti-SARS-CoV-2 human convalescent plasma. To procure the investigational treatment, volunteers who recovered from COVID-19 will undergo testing to confirm the presence of anti-SARS-CoV-2 antibody to the spike trimer at a 1:400 dilution. Donors will also be screened for transfusion-transmitted infections (e.g. HIV, HBV, HCV, WNV, HTLV-I/II, T. cruzi, ZIKV). If donors have experienced COVID-19 symptoms within 28 days, they will be screened with a nasopharyngeal swab to confirm they are SARS-CoV-2 PCR-negative. Plasma will be collected using standard apheresis technology by the New York Blood Center. Study participants will be randomized in a 2:1 ratio to receive one unit (200 - 250 mL) of anti-SARS-CoV-2 plasma versus one unit (200 - 250 mL) of the earliest available control plasma. The control plasma cannot be tested for presence of anti-SARS-CoV-2 antibody prior to the transfusion, but will be tested for anti- SARS-CoV-2 antibody after the transfusion to allow for a retrospective per-protocol analysis. MAIN OUTCOMES: The primary endpoint is time to clinical improvement. This is defined as time from randomization to either discharge from the hospital or improvement by one point on the following seven-point ordinal scale, whichever occurs first. 1. Not hospitalized with resumption of normal activities 2. Not hospitalized, but unable to resume normal activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, requiring high-flow oxygen therapy or non-invasive mechanical ventilation 6. Hospitalized, requiring ECMO, invasive mechanical ventilation, or both 7. Death This scale, designed to assess clinical status over time, was based on that recommended by the World Health Organization for use in determining efficacy end-points in clinical trials in hospitalized patients with COVID-19. A recent clinical trial evaluating the efficacy and safety of lopinavir- ritonavir for patients hospitalized with severe COVID-19 used a similar ordinal scale, as have recent clinical trials of novel therapeutics for severe influenza, including a post-hoc analysis of a trial evaluating immune plasma. The primary safety endpoints are cumulative incidence of grade 3 and 4 adverse events and cumulative incidence of serious adverse events during the study period. RANDOMIZATION: Study participants will be randomized in a 2:1 ratio to receive anti-SARS-CoV-2 plasma versus control plasma using a web-based randomization platform. Treatment assignments will be generated using randomly permuted blocks of different sizes to minimize imbalance while also minimizing predictability. BLINDING (MASKING): The study participants and the clinicians who will evaluate post-treatment outcomes will be blinded to group assignment. The blood bank and the clinical research team will not be blinded to group assignment. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): We plan to enroll 129 participants, with 86 in the anti-SARS-CoV-2 arm, and 43 in the control arm. Among the participants, we expect ~70% or n = 72 will achieve clinical improvement. This will yield an 80% power for a one-sided Wald test at 0.15 level of significance under the proportional hazards model with a hazard ratio of 1.5. TRIAL STATUS: Protocol AAAS9924, Version 17APR2020, 4/17/2020 Start of recruitment: April 20, 2020 Recruitment is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04359810 Date of trial registration: April 24, 2020 Retrospectively registered FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of 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.

Correction to: Evaluating the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in severely ill adults with COVID-19: A structured summary of a study protocol for a randomized controlled trial.

An amendment to this paper has been published and can be accessed via the original article.