Browsing by Author "Silverstein, Adam"

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    ItemOpen Access
    Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.
    (JAMA, 2023-07) O'Halloran, Jane A; Ko, Emily R; Anstrom, Kevin J; Kedar, Eyal; McCarthy, Matthew W; Panettieri, Reynold A; Maillo, Martin; Nunez, Patricia Segura; Lachiewicz, Anne M; Gonzalez, Cynthia; Smith, P Brian; de Tai, Sabina Mendivil-Tuchia; Khan, Akram; Lora, Alfredo J Mena; Salathe, Matthias; Capo, Gerardo; Gonzalez, Daniel Rodríguez; Patterson, Thomas F; Palma, Christopher; Ariza, Horacio; Lima, Maria Patelli; Blamoun, John; Nannini, Esteban C; Sprinz, Eduardo; Mykietiuk, Analia; Alicic, Radica; Rauseo, Adriana M; Wolfe, Cameron R; Witting, Britta; Wang, Jennifer P; Parra-Rodriguez, Luis; Der, Tatyana; Willsey, Kate; Wen, Jun; Silverstein, Adam; O'Brien, Sean M; Al-Khalidi, Hussein R; Maldonado, Michael A; Melsheimer, Richard; Ferguson, William G; McNulty, Steven E; Zakroysky, Pearl; Halabi, Susan; Benjamin, Daniel K; Butler, Sandra; Atkinson, Jane C; Adam, Stacey J; Chang, Soju; LaVange, Lisa; Proschan, Michael; Bozzette, Samuel A; Powderly, William G; ACTIV-1 IM Study Group Members

    Importance

    Immune dysregulation contributes to poorer outcomes in COVID-19.

    Objective

    To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia.

    Design, setting, and participants

    Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021.

    Interventions

    Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day).

    Main outcomes and measures

    The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale.

    Results

    Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies.

    Conclusions and relevance

    Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo.

    Trial registration

    ClinicalTrials.gov Identifier: NCT04593940.
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    ItemOpen Access
    Characterization of cardiovascular clinical events and impact of event adjudication on the treatment effect of darapladib versus placebo in patients with stable coronary heart disease: Insights from the STABILITY trial.
    (American heart journal, 2019-02) Held, Claes; White, Harvey D; Stewart, Ralph AH; Davies, Richard; Sampson, Shani; Chiswell, Karen; Silverstein, Adam; Lopes, Renato D; Heldestad, Ulrika; Budaj, Andrzej; Mahaffey, Kenneth W; Wallentin, Lars; STABILITY Investigators

    Background

    Clinical Endpoint Classification (CEC) in clinical trials allows FOR standardized, systematic, blinded, and unbiased adjudication of investigator-reported events. We quantified the agreement rates in the STABILITY trial on 15,828 patients with stable coronary heart disease.

    Methods

    Investigators were instructed to report all potential events. Each reported event was reviewed independently by 2 reviewers according to prespecified processes and prespecified end point definitions. Concordance between reported and adjudicated cardiovascular (CV) events was evaluated, as well as event classification influence on final study results.

    Results

    In total, CEC reviewed 7,096 events: 1,064 deaths (696 CV deaths), 958 myocardial infarctions (MI), 433 strokes, 182 transient ischemic attacks, 2,052 coronary revascularizations, 1,407 hospitalizations for unstable angina, and 967 hospitalizations for heart failure. In total, 71.8% events were confirmed by CEC. Concordance was high (>80%) for cause of death and nonfatal MI and lower for hospitalization for unstable angina (25%) and heart failure (50%). For the primary outcome (composite of CV death, MI, and stroke), investigators reported 2,086 events with 82.5% confirmed by CEC. The STABILITY trial treatment effect of darapladib versus placebo on the primary outcome was consistent using investigator-reported events (hazard ratio 0.96 [95% CI 0.87-1.06]) or adjudicated events (hazard ratio 0.94 [95% CI 0.85-1.03]).

    Conclusions

    The primary outcome results of the STABILITY trial were consistent whether using investigator-reported or CEC-adjudicated events. The proportion of investigator-reported events confirmed by CEC varied by type of event. These results should help improve event identification in clinical trials to optimize ascertainment and adjudication.
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    RECOVER-NEURO: study protocol for a multi-center, multi-arm, phase 2, randomized, active comparator trial evaluating three interventions for cognitive dysfunction in post-acute sequelae of SARS-CoV-2 infection (PASC).
    (Trials, 2024-05) Knopman, David S; Laskowitz, Daniel T; Koltai, Deborah C; Charvet, Leigh E; Becker, Jacqueline H; Federman, Alex D; Wisnivesky, Juan; Mahncke, Henry; Van Vleet, Thomas M; Bateman, Lucinda; Kim, Dong-Yun; O'Steen, Ashley; James, Melissa; Silverstein, Adam; Lokhnygina, Yuliya; Rich, Jennifer; Feger, Bryan J; Zimmerman, Kanecia O

    Background

    Post-acute sequelae of SARS-CoV-2 infection (PASC) symptoms have broad impact, and may affect individuals regardless of COVID-19 severity, socioeconomic status, race, ethnicity, or age. A prominent PASC symptom is cognitive dysfunction, colloquially referred to as "brain fog" and characterized by declines in short-term memory, attention, and concentration. Cognitive dysfunction can severely impair quality of life by impairing daily functional skills and preventing timely return to work.

    Methods

    RECOVER-NEURO is a prospective, multi-center, multi-arm, phase 2, randomized, active-comparator design investigating 3 interventions: (1) BrainHQ is an interactive, online cognitive training program; (2) PASC-Cognitive Recovery is a cognitive rehabilitation program specifically designed to target frequently reported challenges among individuals with brain fog; (3) transcranial direct current stimulation (tDCS) is a noninvasive form of mild electrical brain stimulation. The interventions will be combined to establish 5 arms: (1) BrainHQ; (2) BrainHQ + PASC-Cognitive Recovery; (3) BrainHQ + tDCS-active; (4) BrainHQ + tDCS-sham; and (5) Active Comparator. The interventions will occur for 10 weeks. Assessments will be completed at baseline and at the end of intervention and will include cognitive testing and patient-reported surveys. All study activities can be delivered in Spanish and English.

    Discussion

    This study is designed to test whether cognitive dysfunction symptoms can be alleviated by the use of pragmatic and established interventions with different mechanisms of action and with prior evidence of improving cognitive function in patients with neurocognitive disorder. If successful, results will provide beneficial treatments for PASC-related cognitive dysfunction.

    Trial registration

    ClinicalTrials.gov NCT05965739. Registered on July 25, 2023.
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    ItemOpen Access
    Solithromycin in Children and Adolescents With Community-acquired Bacterial Pneumonia.
    (The Pediatric infectious disease journal, 2022-07) Lang, Jason E; Hornik, Christoph P; Elliott, Carrie; Silverstein, Adam; Hornik, Chi; Al-Uzri, Amira; Bosheva, Miroslava; Bradley, John S; Borja-Tabora, Charissa Fay Corazon; Di John, David; Mendez Echevarria, Ana; Ericson, Jessica E; Friedel, David; Gonczi, Ferenc; Isidro, Marie Grace Dawn; James, Laura P; Kalocsai, Krisztina; Koutroulis, Ioannis; Laki, Istvan; Ong-Lim, Anna Lisa T; Nad, Marta; Simon, Gabor; Syed, Salma; Szabo, Eva; Benjamin, Daniel K; Cohen-Wolkowiez, Michael; SOLI-PEDS Program

    Background

    Solithromycin is a new macrolide-ketolide antibiotic with potential effectiveness in pediatric community-acquired bacterial pneumonia (CABP). Our objective was to evaluate its safety and effectiveness in children with CABP.

    Methods

    This phase 2/3, randomized, open-label, active-control, multicenter study randomly assigned solithromycin (capsules, suspension or intravenous) or an appropriate comparator antibiotic in a 3:1 ratio (planned n = 400) to children 2 months to 17 years of age with CABP. Primary safety endpoints included treatment-emergent adverse events (AEs) and AE-related drug discontinuations. Secondary effectiveness endpoints included clinical improvement following treatment without additional antimicrobial therapy.

    Results

    Unrelated to safety, the sponsor stopped the trial prior to completion. Before discontinuation, 97 participants were randomly assigned to solithromycin (n = 73) or comparator (n = 24). There were 24 participants (34%, 95% CI, 23%-47%) with a treatment-emergent AE in the solithromycin group and 7 (29%, 95% CI, 13%-51%) in the comparator group. Infusion site pain and elevated liver enzymes were the most common related AEs with solithromycin. Study drug was discontinued due to AEs in 3 subjects (4.3%) in the solithromycin group and 1 (4.2%) in the comparator group. Forty participants (65%, 95% CI, 51%-76%) in the solithromycin group achieved clinical improvement on the last day of treatment versus 17 (81%, 95% CI, 58%-95%) in the comparator group. The proportion achieving clinical cure was 60% (95% CI, 47%-72%) and 68% (95% CI, 43%-87%) for the solithromycin and comparator groups, respectively.

    Conclusions

    Intravenous and oral solithromycin were generally well-tolerated and associated with clinical improvement in the majority of participants treated for CABP.