COVID-19 and Therapeutic Strategies Launching CONNECTS: A - PowerPoint PPT Presentation

Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies Launching CONNECTS: A Partnership Between Research Triangle Institute, Vanderbilt University Medical Center, and NHLBI Sonia Thomas, DrPH RTI and Gordon Bernard, MD VUMC September 11, 2020

Collaboration of 34+ Networks and 1,000+ Sites 2

Website nhlbi-connects.org 3

Why a CONNECTS collaborative? Current unprecedented and urgent public health crisis • Assemble expertise and resources in a nimble fashion • Ensure appropriate geographic reach and expertise • Enable resource deployment when and where needed This collaborative transcends what any individual network may do alone “The whole is greater than the sum of its parts” 4

CONNECTS Vision • Overarching Purpose: • Test host-directed therapies for COVID-19 via rapid, efficient, collaborative adaptive platform trials aimed at helping to prevent infection, slow or halt disease progression, and speed recovery • Strategic approach : • Fully integrate major NHLBI networks under one organizational umbrella to ensure efficiencies; standardization; collaboration; and sharing of control groups (as appropriate), resources, and data • Nimbly shift studies as needed, based on new knowledge and changing pandemic clinical landscape • Expectation: • Innovative model of seamless collaboration; all set aside their own “team jerseys” to join an All -Star Team 5

CONNECTS Is Is Part of f a Larger Ecosystem Strategic direction, oversight, and key partnerships: OWS • NHLBI-directed • In collaboration with BARDA; Operation Warp Speed; and as appropriate, other ICs (e.g., NIAID, NINDS) • Engage clinical trials/networks, other NIH ICs, Clinical Data Interchange Standards Consortium • Trials are aligned with, or formally part of, NIH ACTIV (e.g., ACTIV-4) 6

NHLBI COVID-19 Clinical Studies Framework COVID-19+ Progression Hospital Outpatient Emergency Hospital Conva- Outpatient Recovered Prevention Vent/CPAP- Asymptomatic Symptomatic Department ICU lescence free Point of Care Diagnostics Host-Directed Therapeutics Clinical Trials Database Patient Registry and Long-term Follow up Biorepository Cohort of Cohorts and Analytics REDS-IV-P Sero-surveillance Community-Based Research Consortium 7

CONNECTS In Infrastructure Institute Director Executive Committee Steering Committee Administrative Coordinating Sub-Committees and Center (ACC) - RTI Study Teams Working Groups 8 ACC Science Unit - VUMC

CONNECTS Is Is a Research Collaborative A community promoting collaboration, harmonization, and sharing of scientific expertise and resources. 9

Steering & Executive Committee Chairs Steering Committee Executive Committee Clyde Yancy , Chair (Northwestern University) Robert Harrington , Co-Chair (Stanford University) Serpil Erzurum , Vice-Chair Amy Patterson , Co-Chair (Cleveland Clinic) (NHLBI) Diane Nugent , Vice-Chair 10 (CHOC Children’s Hospital)

CONNECTS and ACT CTIV Cli linical Trials NCATS NIAID NHLBI CONNECTS Clinical Trials Clinical Trials Clinical Trials C3PO ACTIV 4A ACTIV 2 ACTIV 1a Convalescent Plasma Anticoagulant Inpatient Outpatient mAbs Immunomodulators: TNFa v. SOC ACTIV 3 Other Host Directed ACTIV1b Therapeutics Inpatient mAbs TBD Immunomodulators: CTLA-4 + SOC ACTIV 4B ACTIV 5 Inpatient POC mAbs ACTIV 1c Anticoagulant Outpatient Immunomodulators: CCR2/5 Inhibition + SOC ACTIV 4C Anticoagulant Conval 11

Designing New Studies Gordon Bernard, MD CONNECTS ACC Science Unit PI Vanderbilt University Medical Center 12

Our Im Immediate Goal: : Desig ign and Im Implement Master Protocol Dri riven Adaptive Cli linical Tri rials Inpatient Master Recovering Outpatient Master Protocols Master Protocols Protocols 13

Le Leveraging Network Expertise for Master Protocol and Agent Pri rioritization le leadership groups Nominated Expert Areas of Expertise Progress to Date • All network-nominated experts are Biostatistics 15 currently engaged by the ACC. 34 Adaptive Trial Design Master Protocols 17 • Experts are serving as members in Clinical Science 18 Master Protocols and Agent COVID-19 Characteristics & Risk Assessment 16 Prioritization committees. Passive Immunization/Neutralizing Antibodies 8 Anticoagulation 1 16 Immunomodulation • Additional nominations are always 13 Host tissue response-directed welcome 11 Deep phenotyping Precision medicine 5 Use of biospecimens 6 Drug prioritization 2 Other 14 Number of Experts 0 10 20 30 40

Master Protocol Committee Structure: Draft fting and harmonization of f master protocols acr cross patie ient stages Master Protocol Development Committee Develop master Outpatient Inpatient Recovering protocols with a Master Protocol Master Protocol Master Protocol Subcommittee Subcommittee Subcommittee standard of care arm Outpatient Inpatient Recovering ACTIV I Immunomodulatory Immunomodulatory Immunomodulatory Appendix Working Group Appendix Working Group Appendix Working Group Outpatient Host Tissue Inpatient Host Tissue Recovering Host Tissue Response Appendix Response Appendix Response Appendix Develop Working Group Working Group Working Group appendices to master protocols Outpatient Passive Inpatient Passive Recovering Passive with therapeutic ACTIV I, III Immunity Appendix Immunity Appendix Immunity Appendix Working Group Working Group Working Group domain-specific content/arms (Recovering (Outpatient Anticoagulant (Inpatient Anticoagulation ACTIV IV Anticoagulation Appendix Working Group) Appendix Working Group) 15 Working Group)

Statistical Design Concepts for COVID-19 19 • What are the most informative/statistically powerful outcomes? • Proposal: An ordered scale that includes clinically relevant and patient-centered features, that combines both safety and efficacy information, and that encompasses information pertinent across all settings and disease severities. • What types and levels of evidence are needed to stop a trial? • Proposal: • Sequential design with frequent looks based on calendar time and a range of expected accrual rates rather than enrollment so that decisions can be made in a timely way. • Bayesian interim analysis methods incorporating a skeptical prior for efficacy, an uninformative prior for inefficacy/harm, and setting the acceptable level of evidence posterior probability such as ≥ 0.95.

Agent Pri rioritization Committee Structure: Revie iew and prio ioritiz ization of potential l nomin inated therapeutics Agent Prioritization Committee Immunomodulatory Host Tissue Response Passive Immunity Anticoagulation Agent Working Group Agent Working Group Agent Working Group Agent Working Group

Overarching Agent Pri rioritization Committee (u (under constr truction) Workstreams Groups Additional Members Immunomodulatory Passive Immunity Host-tissue Response Anticoagulation Neil Aggarwal – NIH/NHLBI Gordon Bernard – CONNECTS ACC VUMC Science Unit PI Ann Farrell – FDA, DNH, CDER/FDA Michael Matthay 1 Judith Hochman Mary J. Homer – Chief, RNC, BARDA Marie-Carmelle Elie 2 Thomas R. Martin Zorina Galis – NIH/NHLBI Clark Files 3 Chad Miller David Goff – Committee Co-Chair, NHLBI Dir, DCVS Macky Neal 4 Duane Mitchell James Kiley – Committee Co-Chair , NHLBI Dir, DLD Richard Becker Thomas Ortel Andrei Kindzelski - NIH/NHLBI Jeffrey Berger Liise-Anne Pirofski Tony Punturieri – NIH/NHLBI Javed Butler Todd Rice Lora Reineck – NIH/NHLBI Ivor Douglas Paul Ridker Yves Rosenberg – NIH/NHLBI Serpil Erzurum Wes Self Sonia Thomas – CONNECTS ACC PI Michael Felker Chris Seymour Workstreams Chairs: 1 Immunomodulatory; 2 Proposed Passive Immunity; 3 Host-tissue Response; 4 Proposed Anticoagulation.

Nominations can and should come fr from multiple pla laces New ideas from members! Ideas from NIH/ Early ACTIV nominations from members Standardized evidence summary Expert voting

Science Unit Support of f Agent Pri rioritization: Su Summary Packages Mechanism of action : Informs hypotheses related to drug efficacy and potential side effects Safety considerations : Informs exclusion criteria and trial surveillance needs Explanation of the drug’s protein target in the context of COVID -19 disease: Informs hypothesis related to drug efficacy and potential side effects Timing of intervention: Informs where along the COVID-19 disease progression spectrum the drug is likely to have efficacy and be feasible to administer Elements of a Summary Package Pharmacology assessments: Informs dosing regimen and potential drug interactions Preclinical data : Animal or human models establish disease mechanism, define patient population, and inform clinical trial endpoints Prior studies in other coronavirus outbreaks : Informs trial design, including feasibility Pharmacogenomic considerations : Genetic variants that may alter an individual’s response to drug therapy 20