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BackgroundEnsovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection.ObjectiveTo investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone.DesignDouble-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978).SettingMultinational, multicenter trial.ParticipantsAdults hospitalized with COVID-19.InterventionIntravenous ensovibep, 600 mg, or placebo.MeasurementsEnsovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90.ResultsAn independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n=247) or placebo (n=238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P=0.68; OR>1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR>1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR&nbsp

Supplemental material, sj-pdf-1-ctj-10.1177_17407745211049829 for Design and implementation of an international, multi-arm, multi-stage platform master protocol for trials of novel SARS-CoV-2 antiviral agents: Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) by Daniel D Murray, Abdel G Babiker, Jason V Baker, Christina E Barkauskas, Samuel M Brown, Christina C Chang, Victoria J Davey, Annetine C Gelijns, Adit A Ginde, Birgit Grund, Elizabeth Higgs, Fleur Hudson, Virginia L Kan, H Clifford Lane, Thomas A Murray, Roger Paredes, Mahesh KB Parmar, Sarah Pett, Andrew N Phillips, Mark N Polizzotto, Cavan Reilly, Uriel Sandkovsky, Shweta Sharma, Marc Teitelbaum, B Taylor Thompson, Barnaby E Young, James D Neaton and Jens D Lundgren in Clinical Trials

Supplemental material, sj-docx-3-ctj-10.1177_17407745211049829 for Design and implementation of an international, multi-arm, multi-stage platform master protocol for trials of novel SARS-CoV-2 antiviral agents: Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) by Daniel D Murray, Abdel G Babiker, Jason V Baker, Christina E Barkauskas, Samuel M Brown, Christina C Chang, Victoria J Davey, Annetine C Gelijns, Adit A Ginde, Birgit Grund, Elizabeth Higgs, Fleur Hudson, Virginia L Kan, H Clifford Lane, Thomas A Murray, Roger Paredes, Mahesh KB Parmar, Sarah Pett, Andrew N Phillips, Mark N Polizzotto, Cavan Reilly, Uriel Sandkovsky, Shweta Sharma, Marc Teitelbaum, B Taylor Thompson, Barnaby E Young, James D Neaton and Jens D Lundgren in Clinical Trials

Supplemental material, sj-docx-3-ctj-10.1177_17407745211049829 for Design and implementation of an international, multi-arm, multi-stage platform master protocol for trials of novel SARS-CoV-2 antiviral agents: Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) by Daniel D Murray, Abdel G Babiker, Jason V Baker, Christina E Barkauskas, Samuel M Brown, Christina C Chang, Victoria J Davey, Annetine C Gelijns, Adit A Ginde, Birgit Grund, Elizabeth Higgs, Fleur Hudson, Virginia L Kan, H Clifford Lane, Thomas A Murray, Roger Paredes, Mahesh KB Parmar, Sarah Pett, Andrew N Phillips, Mark N Polizzotto, Cavan Reilly, Uriel Sandkovsky, Shweta Sharma, Marc Teitelbaum, B Taylor Thompson, Barnaby E Young, James D Neaton and Jens D Lundgren in Clinical Trials

Supplemental material, sj-pdf-2-ctj-10.1177_17407745211049829 for Design and implementation of an international, multi-arm, multi-stage platform master protocol for trials of novel SARS-CoV-2 antiviral agents: Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) by Daniel D Murray, Abdel G Babiker, Jason V Baker, Christina E Barkauskas, Samuel M Brown, Christina C Chang, Victoria J Davey, Annetine C Gelijns, Adit A Ginde, Birgit Grund, Elizabeth Higgs, Fleur Hudson, Virginia L Kan, H Clifford Lane, Thomas A Murray, Roger Paredes, Mahesh KB Parmar, Sarah Pett, Andrew N Phillips, Mark N Polizzotto, Cavan Reilly, Uriel Sandkovsky, Shweta Sharma, Marc Teitelbaum, B Taylor Thompson, Barnaby E Young, James D Neaton and Jens D Lundgren in Clinical Trials

Supplemental material, sj-pdf-2-ctj-10.1177_17407745211049829 for Design and implementation of an international, multi-arm, multi-stage platform master protocol for trials of novel SARS-CoV-2 antiviral agents: Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) by Daniel D Murray, Abdel G Babiker, Jason V Baker, Christina E Barkauskas, Samuel M Brown, Christina C Chang, Victoria J Davey, Annetine C Gelijns, Adit A Ginde, Birgit Grund, Elizabeth Higgs, Fleur Hudson, Virginia L Kan, H Clifford Lane, Thomas A Murray, Roger Paredes, Mahesh KB Parmar, Sarah Pett, Andrew N Phillips, Mark N Polizzotto, Cavan Reilly, Uriel Sandkovsky, Shweta Sharma, Marc Teitelbaum, B Taylor Thompson, Barnaby E Young, James D Neaton and Jens D Lundgren in Clinical Trials

The 10,000 Families Study (10KFS) is a Minnesota-based cohort study designed to study longitudinal changes in health. Here we report our efforts from a pilot study of 10KFS. During health fairs hosted by the study, we measured anthropometrics, blood pressure, and grip strength; collected biospecimens; performed vision and hearing assessments; and measured lung function and cognitive function. We describe the field deployment of digital applications for measurement of cognitive function, lung function, and hearing assessment in 10KFS. We measure cognitive function using the Digital Clock Drawing (dDCT) test (Cognition Technologies Inc.), a multidimensional task that evaluates spatial skills, semantic knowledge, planning, and motor functioning. We perform spirometry to assess lung function using an Air Smart Spirometer (Pond Healthcare Innovation) that uses a spirometry app (NuvoAir) to estimate forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF). We measure hearing using an iPad-enabled audiometry device (Shoebox, Inc.) that allows us to estimate air conduction and bone conduction over a range of tones from 500-8000 Hertz. These digital devices are low cost and the measurements are readily implemented with minimal training of study staff (training time 2-3 hours). To date, we have performed these measurements on 139 10KFS participants (age range: 5 years–100 years) during an in-person clinic visit. A vast majority (88%; n=123) of eligible 10KFS participants successfully completed all these measurements; participants across the age spectrum were comfortable using these digital technologies during their clinic visit. The Digital Clock Drawing test was administered only to adults >40 years old and completion rates were 92% (n=34) for participants between 41-64 years old and 95% (n=35) for those over 65 years old. The Air Smart Spirometer was administered to participants over 4 years old without a contraindication and completion rates were 96% (n=22) for children 5-17 years old, 98% (n=64) for adults 18-64 years old, and 100% (n=36) for adults over the age of 65 years. The audiometry test was administered to participants >3 years old and completion rates were 87% (n=20) for children 4-17 years old, 100% (n=67) for adults 18-64 years old, and 100% (n=37) for adults over the age of 65 years. As compared to traditional methods for collecting information on cognitive function, lung function, and hearing, these devices allow for real-time monitoring of quality-control measures and allow deployment of standardized methods of data collection in a variety of settings that do not require specialized equipment or have space constraints. In the future we anticipate deploying these methods to a broader range of data collection venues that may include in-home visits, remote assessments, and clinic visits. This abstract is also being presented as Poster A28. Citation Format: Bharat Thyagarajan, Lazovich DeAnn, Nelson H. Heather, Poynter Jen, Prizment Anna, Roesler Michelle, Cassidy Erin, Putnam Sara, Reilly Cavan, Spector Logan. Field application of digital technologies for health assessment in the 10,000 Families Study [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr PR09.

Cumulative data for targeted biomarkers in healthy control and CF infants. (PDF 49 kb)

Figure S3. Dinucleotide contexts of G-to-A mutations not occurring within G-to-A hypermutants. The dinucleotide contexts of all G-to-A mutations from HIV-1 and HIV-2 single mutants (i.e. non-hypermutants) were determined, demonstrating the lack of a bias toward GA and/or GG dinucleotides.

Heat map of HOMINGS data. The color key is on a logarithmic scale. The Bray-Curtis distance metric was used to generate the dendrograms. Each column represents a plaque, NS, or WS microcosm sample; labels provided for the columns are colored blue for plaque, green for NS, or red for WS. Each row represents one of the 453 HOMINGS probes that were positive for at least one sample (probes that were not detected in any sample are excluded). Row labels are not shown, since they would not be legible. Additional files 3, 4, and 5 list all positive probes.

Figure S1. Bias of transversion spectra toward C-to-A and G-to-T mutations. The transversion spectra for HIV-1 and HIV-2 biological samples and plasmid controls are illustrated, revealing a clear bias toward C-to-A and G-to-T transversion types, particularly for the plasmid controls.

Heat map of MEGAN5 SEED assignments. The color key is on a logarithmic scale. The Bray-Curtis distance metric was used to generate the dendrograms. Each column represents a NS, or WS microcosm sample; labels provided for the columns are colored green for NS or red for WS. Each row represents one of the 1969 SEED-assigned proteins. Row labels are not shown, since they would not be legible. Additional file 9 lists all protein assignments.

Heat map of species-level MEGAN5 LCA assignments. The color key is on a logarithmic scale. The Bray-Curtis distance metric was used to generate the dendrograms. Each column represents a NS, or WS microcosm sample; labels provided for the columns are colored green for NS or red for WS. Each row represents one of the 303 LCA-assigned species. Row labels are not shown, since they would not be legible. Additional file 6 lists all species assignments.

Figure S2. Transition frequencies are similar across amplicons in the absence of G-to-A hypermutants. The frequencies of transitions were determined in all five amplicons after exclusion of all G-to-A hypermutants (individual read pairs containing two or more G-to-A mutations).

Figure S2. Transition frequencies are similar across amplicons in the absence of G-to-A hypermutants. The frequencies of transitions were determined in all five amplicons after exclusion of all G-to-A hypermutants (individual read pairs containing two or more G-to-A mutations).

Table summarizing the culture results for all CF infants. (PDF 34 kb)

Supplementary information. (DOCX 2881 kb)

Table summarizing the culture results for all CF infants. (PDF 34 kb)

Supplementary information. (DOCX 2881 kb)