Convalescent Plasma to Limit SARS-CoV-2 Associated Complications (CSSC-004)

• ClinicalTrials.gov Identifier: NCT04373460
• Recruitment Status: Active, not recruiting
• First Posted: May 4, 2020
• Last Update Posted: June 7, 2022
• Sponsor: Johns Hopkins University
• Collaborators: State of Maryland; Bloomberg Foundation; United States Department of Defense; National Institute of Allergy and Infectious Diseases (NIAID); National Center for Advancing Translational Science (NCATS)
• Information provided by (Responsible Party): Johns Hopkins University

Tracking Information

• First Submitted Date: April 30, 2020
• First Posted Date: May 4, 2020
• Last Update Posted Date: June 7, 2022
• Actual Study Start Date: June 3, 2020
• Actual Primary Completion Date: January 14, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 17, 2020)

• Cumulative incidence of hospitalization or death prior to hospitalization [ Time Frame: Up to day 28 ]
  Cumulative incidence measured as the proportion of subjects who were hospitalized or who died prior to hospitalization
• Cumulative incidence of treatment-related serious adverse events [ Time Frame: Up to day 28 ]
  Cumulative incidence of treatment-related serious adverse events categorized separately as either severe infusion reactions or Acute Respiratory Distress Syndrome (ARDS) during the study period.
• Cumulative incidence of treatment-related grade 3 or higher adverse events [ Time Frame: Up to day 90 ]
  Cumulative incidence measured as the proportion of subjects experiencing a Grade 3 or higher.

Original Primary Outcome Measures (submitted: April 30, 2020)

• Cumulative incidence of hospitalization or death prior to hospitalization [ Time Frame: Up to day 28 ]
  Cumulative incidence measured as the proportion of subjects who were hospitalized or who died prior to hospitalization
• Cumulative incidence of treatment-related serious adverse events [ Time Frame: Up to day 28 ]
  Cumulative incidence measured as the proportion of subjects experiencing an Serious Adverse Event (SAE).
• Cumulative incidence of treatment-related grade 3 or higher adverse events [ Time Frame: Up to day 90 ]
  Cumulative incidence measured as the proportion of subjects experiencing a Grade 3 or higher.

Current Secondary Outcome Measures (submitted: June 2, 2022)

• Change in serum SARS-CoV-2 antibody titers [ Time Frame: Days 0, 14, 28 and 90 ]
  Analysis of serum SARS-CoV-2 antibody titers will also primarily be descriptive, comparing the geometric mean titers at day 0, 14, 28 and 90 between the randomized arms and calculating the shift or change in the titer distribution.
• Time to SARS-CoV-2 Polymerase Chain Reaction (PCR) negativity [ Time Frame: Day 0, 14 and 28 ]
  Compare the rates and duration of SARS-CoV-2 RNA positivity by Real-Time (RT)-PCR of nasopharyngeal or oropharyngeal fluid between active and control groups at days 0, 14 and 28. PCR results take up to 6 months to process and be available to the study team for data analysis.

Original Secondary Outcome Measures (submitted: April 30, 2020)

• Change in serum SARS-CoV-2 antibody titers [ Time Frame: Days 0, 14, 28 and 90 ]
  Analysis of serum SARS-CoV-2 antibody titers will also primarily be descriptive, comparing the geometric mean titers at day 0, 14, 28 and 90 between the randomized arms and calculating the shift or change in the titer distribution.
• Time to SARS-CoV-2 Polymerase Chain Reaction (PCR) negativity [ Time Frame: Up to day 28 ]
  Duration in days of SARS-CoV-2 PCR time to negativity will be analyzed by calculating the number of days taken for a positive participant to lose positivity from day 0 to day 28.

Current Other Pre-specified Outcome Measures (submitted: June 2, 2022)

• Change in level of SARS-CoV-2 RNA [ Time Frame: Day 0, 14 and 28 ]
  Compare the levels of SARS-CoV-2 RNA between active and control groups at days 0, 14 and 28. RNA results take up to 6 months to process and be available to the study team for data analysis.
• Change in oxygen saturation levels [ Time Frame: Day 0 to Day 28 (where available) ]
  Comparison of participant self-assessed blood oxygen saturation levels (in percentage oxygen) between treatment arms using pulse oximetry from Day 0 to Day 28.
• Rate of participant-reported secondary infection of housemates [ Time Frame: Up to day 90 ]
  Secondary infection will be assessed by measuring the number of individuals that live in the same house as the active arm who became sick by the end of follow-up period.
• Time to ICU admission, invasive mechanical ventilation or death in hospital [ Time Frame: Up to day 90 ]
  Disease severity measured by time (in days) to admission to the ICU or , invasive mechanical ventilation or time to death.
• Time to resolution of COVID-19 symptoms [ Time Frame: Up to day 90 ]
  Time (in days) to resolution of COVID-19 symptoms will be based on temperature logs and symptom score sheets.
• Impact of convalescent plasma on outcome as assessed by change in hospitalization rate [ Time Frame: Day 0 to Day 90 ]
  Assess change in hospitalization rate as measured by number of hospitalizations stratified by age groups <65 and >=65
• Impact of donor antibody titers on hospitalization rate of convalescent plasma recipients [ Time Frame: Day 0 to Day 90 ]
  Impact of donor antibody titers (high/low) will be assessed by hospitalization rate as measured by number of hospitalizations.
• Impact of donor antibody titers on antibody levels of convalescent plasma recipients [ Time Frame: Day 0 to Day 90 ]
  Impact of donor antibody titers (high/low) will be assessed by antibody levels
• Impact of donor antibody titers on viral positivity rates of convalescent plasma recipients [ Time Frame: Day 0 to Day 90 ]
  Impact of donor antibody titers (high/low) will be assessed by viral positivity rates (number of SARS-CoV-2 positive cases per total cases)

Original Other Pre-specified Outcome Measures (submitted: April 30, 2020)

• Change in level of SARS-CoV-2 RNA [ Time Frame: Day 0 to Day 28 ]
  Change in levels of SARS-CoV-2 RNA between randomized arms from Day 0 to Day 28.
• Change in oxygen saturation levels [ Time Frame: Day 0 to Day 28 ]
  Comparison of participant self-assessed blood oxygen saturation levels (in percentage oxygen) between treatment arms using pulse oximetry from Day 0 to Day 28.
• Rate of participant-reported secondary infection of housemates [ Time Frame: Up to day 90 ]
  Secondary infection will be assessed by measuring the number of individuals that live in the same house as the active arm who became sick by the end of follow-up period.
• Time to ICU admission, invasive mechanical ventilation or death in hospital [ Time Frame: Up to day 90 ]
  Disease severity measured by time (in days) to admission to the ICU or , invasive mechanical ventilation or time to death.
• Time to resolution of COVID-19 symptoms [ Time Frame: Up to day 90 ]
  Time (in days) to resolution of COVID-19 symptoms will be based on temperature logs and symptom score sheets.
• Impact of convalescent plasma on outcome as assessed by change in hospitalization rate [ Time Frame: Day 0 to Day 90 ]
  Assess change in hospitalization rate as measured by number of hospitalizations stratified by age groups <65 and >=65
• Impact of donor antibody titers on hospitalizaton rate of convalescent plasma recipients [ Time Frame: Day 0 to Day 90 ]
  Impact of donor antibody titers (high/low) will be assessed by hospitalization rate as measured by number of hospitalizations.
• Impact of donor antibody titers on antibody levels of convalescent plasma recipients [ Time Frame: Day 0 to Day 90 ]
  Impact of donor antibody titers (high/low) will be assessed by antibody levels
• Impact of donor antibody titers on viral positivity rates of convalescent plasma recipients [ Time Frame: Day 0 to Day 90 ]
  Impact of donor antibody titers (high/low) will be assessed by viral positivity rates (number of SARS-CoV-2 positive cases per total cases)

Descriptive Information

• Brief Title: Convalescent Plasma to Limit SARS-CoV-2 Associated Complications
• Official Title: Comparison of the Efficacy and Safety of Human Coronavirus Immune Plasma (HCIP) vs. Control (SARS-CoV-2 Non-immune) Plasma Among Outpatients With Symptomatic COVID-19
• Brief Summary: To assess the efficacy and safety of Human coronavirus immune plasma (HCIP) to reduce the risk of hospitalization or death, the duration of symptoms and duration of nasopharyngeal or oropharyngeal viral shedding.
• Detailed Description: The purpose of this randomized, double-blind, controlled, phase 2 trial is to evaluate the efficacy of treatment with HCIP in reducing hospitalization and death prior to hospitalization among outpatient adults who have RNA detection test-confirmed COVID-19 AND have developed any symptoms of COVID-19 including but not limited to fever, cough, or other COVID associated symptoms like anosmia. Ambulatory/outpatient adults subjects 18 years of age or older, regardless of risk factors for severe illness may participate. A total of approximately 1344 eligible subjects stratified with a target goal (but not binding) of 50:50 in the <65 vs ≥ 65 age range will be randomized in a 1:1 ratio to receive either HCIP or control plasma.
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

A total of approximately 1344 eligible subjects stratified with a target goal (but not binding) of 50:50 in the <65 vs ≥ 65 age range will be randomized in a 1:1 ratio to receive either HCIP or control plasma.

Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment

• Condition: SARS-CoV 2

Intervention

• Biological: SARS-CoV-2 convalescent plasma
  SARS-CoV-2 convalescent plasma (1 cup; minimum of 175 mL collected by apheresis from a volunteer who recovered from COVID-19 disease and has SARS-CoV-2 antibody titers ≥ 1:320 and after July 2021 meets FDA criteria for high titer plasma.
  Other Name: Human coronavirus immune plasma (HCIP)
• Biological: Plasma from a volunteer donor
  Plasma collected from a volunteer donor prior to January 1, 2020 will not be tested for SARS-CoV-2 antibodies. Plasma collected after December 31, 2019 will be confirmed as SARS-CoV-2 seronegative.

Study Arms

• Experimental: SARS-CoV-2 convalescent plasma
  SARS-CoV-2 convalescent plasma (1 cup; minimum of 175 mL collected by apheresis from a volunteer who recovered from COVID-19 disease and has SARS-CoV-2 antibody titers ≥ 1:320 and after July 2021 meets FDA criteria for high titer plasma.
  Intervention: Biological: SARS-CoV-2 convalescent plasma
• Active Comparator: Standard Control plasma
  Plasma collected from a volunteer donor prior to January 1, 2020 will not be tested for SARS-CoV-2 antibodies. Plasma collected after December 31, 2019 will be confirmed as SARS-CoV-2 seronegative.
  Intervention: Biological: Plasma from a volunteer donor

Publications *

• Sullivan DJ, Gebo KA, Shoham S, Bloch EM, Lau B, Shenoy AG, Mosnaim GS, Gniadek TJ, Fukuta Y, Patel B, Heath SL, Levine AC, Meisenberg BR, Spivak ES, Anjan S, Huaman MA, Blair JE, Currier JS, Paxton JH, Gerber JM, Petrini JR, Broderick PB, Rausch W, Cordisco ME, Hammel J, Greenblatt B, Cluzet VC, Cruser D, Oei K, Abinante M, Hammitt LL, Sutcliffe CG, Forthal DN, Zand MS, Cachay ER, Raval JS, Kassaye SG, Foster EC, Roth M, Marshall CE, Yarava A, Lane K, McBee NA, Gawad AL, Karlen N, Singh A, Ford DE, Jabs DA, Appel LJ, Shade DM, Ehrhardt S, Baksh SN, Laeyendecker O, Pekosz A, Klein SL, Casadevall A, Tobian AAR, Hanley DF. Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma. medRxiv. 2021 Dec 21. pii: 2021.12.10.21267485. doi: 10.1101/2021.12.10.21267485.
• Sullivan DJ, Gebo KA, Shoham S, Bloch EM, Lau B, Shenoy AG, Mosnaim GS, Gniadek TJ, Fukuta Y, Patel B, Heath SL, Levine AC, Meisenberg BR, Spivak ES, Anjan S, Huaman MA, Blair JE, Currier JS, Paxton JH, Gerber JM, Petrini JR, Broderick PB, Rausch W, Cordisco ME, Hammel J, Greenblatt B, Cluzet VC, Cruser D, Oei K, Abinante M, Hammitt LL, Sutcliffe CG, Forthal DN, Zand MS, Cachay ER, Raval JS, Kassaye SG, Foster EC, Roth M, Marshall CE, Yarava A, Lane K, McBee NA, Gawad AL, Karlen N, Singh A, Ford DE, Jabs DA, Appel LJ, Shade DM, Ehrhardt S, Baksh SN, Laeyendecker O, Pekosz A, Klein SL, Casadevall A, Tobian AAR, Hanley DF. Early Outpatient Treatment for Covid-19 with Convalescent Plasma. N Engl J Med. 2022 May 5;386(18):1700-1711. doi: 10.1056/NEJMoa2119657. Epub 2022 Mar 30.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: June 2, 2022): 1225
• Original Estimated Enrollment (submitted: April 30, 2020): 1344
• Estimated Study Completion Date: September 14, 2022
• Actual Primary Completion Date: January 14, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• ≥ 18 years of age
• Competent and capable to provide informed consent
• • Positive molecular test for presence of SARS-CoV-2 in fluid collected by saliva for antigen, oropharyngeal or nasopharyngeal swab
• Experiencing any symptoms of COVID-19 including but not limited to fever(T> 100.5º F), cough, or other COVID associated symptoms like anosmia
• ≤ 8 days since the first symptoms of COVID-19
• ≤ 8 days since first positive SARS-CoV-2 RNA test
• Able and willing to comply with protocol requirements listed in the informed consent

Exclusion Criteria:

• Hospitalized or expected to be hospitalized within 24 hours of enrollment
• Psychiatric or cognitive illness or recreational drug/alcohol use that in the opinion of the principal investigator, would affect subject safety and/or compliance
• History of prior reactions to transfusion blood products
• Inability to complete therapy with the study product within 24 hours after enrollment
• Receiving any treatment drug for COVID-19 within 14 days prior to screening evaluation (monoclonal antibodies, compassionate use or study trial related). Steroid treatment at any time does not affect study eligibility

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04373460
• Other Study ID Numbers: IRB00247590; R01AI152078 ( U.S. NIH Grant/Contract ); W911QY2090012 ( Other Grant/Funding Number: Department of Defense )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Anonymized individual participant data (IPD) collected in this study, including data dictionaries, will be made available to other researchers after the end of the study.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: After publication of initial study manuscript
• Access Criteria: Public

• Current Responsible Party: Johns Hopkins University
• Original Responsible Party: Same as current
• Current Study Sponsor: Johns Hopkins University
• Original Study Sponsor: Same as current

Collaborators

• State of Maryland
• Bloomberg Foundation
• United States Department of Defense
• National Institute of Allergy and Infectious Diseases (NIAID)
• National Center for Advancing Translational Science (NCATS)

Investigators

• Principal Investigator: David J Sullivan, MD; The Johns Hopkins University

• PRS Account: Johns Hopkins University
• Verification Date: June 2022