CROWN CORONATION: COVID-19 Research Outcomes Worldwide Network for CORONAvirus prevenTION (CROWN CORONA)

• ClinicalTrials.gov Identifier: NCT04333732
• Recruitment Status: Completed
• First Posted: April 3, 2020
• Last Update Posted: January 27, 2022
• Sponsor: Washington University School of Medicine
• Collaborator: COVID -19 Therapeutics Accelerator
• Information provided by (Responsible Party): Michael Avidan, Washington University School of Medicine

Tracking Information

• First Submitted Date: March 31, 2020
• First Posted Date: April 3, 2020
• Last Update Posted Date: January 27, 2022
• Actual Study Start Date: September 4, 2020
• Actual Primary Completion Date: August 10, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 25, 2021)

Symptomatic COVID-19 [ Time Frame: 60 days after receiving trial intervention ]

Incidence of symptomatic (i.e. any of the following: cough, shortness of breath or difficulty breathing, fever, chills, muscle pain, sore throat, new loss of taste or smell, nausea, vomiting, or diarrhea), laboratory test-confirmed COVID-19 in the intervention and control groups in adults with repeated exposures to SARS-CoV-2 by day 60 after receiving trial intervention.

Original Primary Outcome Measures (submitted: April 2, 2020)

• Symptomatic COVID-19 [ Time Frame: 3 months ]
  Clinical diagnosis of COVID-19 with limitation of activities (WHO Severity Scale 2-8)
• Peak severity of COVID-19 over the study period [ Time Frame: 3 months ]
  i) Uninfected - no clinical or virological evidence of infection (Score = 0) ii) Ambulatory - no limitation of activities (score=1) or with limitation (Score=2) iii) Hospitalized - mild no oxygen (Score=3) or with oxygen (Score=4) iv) Hospitalized severe - Scores 5-7* v) Dead * Score 5 is non-invasive ventilation or high flow oxygen; Score 6 is intubation with mechanical ventilation; Score 7 is intubation with additional organ support (e.g. pressors, renal replacement therapy, extra corporeal membrane oxygenation [ECMO]) These outcome definitions are based on WHO R&D Blueprint consensus definitions for COVID-19.

Current Secondary Outcome Measures (submitted: October 25, 2021)

• Symptomatic COVID-19 [ Time Frame: 150 days after receiving trial intervention ]
  Incidence of symptomatic (i.e. any of the following: cough, shortness of breath or difficulty breathing, fever, chills, muscle pain, sore throat, new loss of taste or smell, nausea, vomiting, or diarrhea), laboratory test-confirmed COVID-19 in the intervention and control groups in adults with repeated exposures to SARS-CoV-2 by day 150 after receiving trial intervention.
• Severity of COVID-19 [ Time Frame: 60 days after receiving trial intervention ]
  Severity of COVID-19 in adults who become infected with SARS-CoV-2 by day 60 after receiving trial intervention. Severity will be graded on a simplified version of the ordinal WHO COVID-19 severity scale ((i) uninfected, (ii) infected but ambulatory [mild disease], (iii) infected and hospitalized [moderate or severe disease] or dead).
• Severity of COVID-19 [ Time Frame: 150 days ]
  Severity of COVID-19 in adults who become infected with SARS-CoV-2 by day 150 after receiving trial intervention. Severity will be graded on a simplified version of the ordinal WHO COVID-19 severity scale ((i) uninfected, (ii) infected but ambulatory [mild disease], (iii) infected and hospitalized [moderate or severe disease] or dead).
• SARS-CoV-2 infection [ Time Frame: 150 days ]
  Incidence of SARS-CoV-2 infection by serology (anti-nucleocapsid antibody) in the intervention and control groups in adults with repeated exposures to SARS-CoV-2 by day 150 after receiving trial intervention.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: CROWN CORONATION: COVID-19 Research Outcomes Worldwide Network for CORONAvirus prevenTION
• Official Title: An International, Multi-site, Bayesian Platform Adaptive, Randomized, Placebo-controlled Trial Assessing the Effectiveness of Candidate Agents in Mitigating COVID-19 Disease in Adults
• Brief Summary: The objective of CROWN CORONATION is the prevention of symptomatic COVID-19 by using combinations of approved and safe repurposed interventions, with complementary mechanisms of action.

Detailed Description

CROWN CORONATION is an international, Bayesian platform adaptive, randomized, placebo-controlled trial assessing the effectiveness of candidate interventions in preventing COVID-19 disease in adults.

Randomization will be stratified by age (<50 and ≥50) and site. Participants will be healthcare workers at risk of contracting SARS-CoV-2. Participants will be randomized into one of two arms:

• Education and surveillance plus MR or MMR vaccine
• Education and surveillance plus Placebo

While the initial intervention to be tested on the platform will be the MR or MMR vaccine, other interventions might be added or removed over the course of the trial. The trial will evaluate which of the intervention arms is most effective at decreasing the incidence of symptomatic COVID-19 disease, without unacceptable side effects or safety events.

All participants will require be required to have a mobile phone to participate. This is standard in all the countries in this study. Most, but not all, will also have a smartphone. Participants will complete weekly data logs via SMS texting. Follow-up information will be collected until approximately 5 months after the end of treatment or death. Participants who develop symptomatic COVID-19 during the last month of observation will at a minimum be followed-up until symptom resolution and at a maximum until 6 months after randomization (whichever comes first). Telemedicine approaches to collecting information on participants will be used where possible. The trial will provide adherence support interventions that have been shown in randomized controlled trials to improve adherence to Human Immunodeficiency Virus treatment and adapted for HIV Pre-Exposure Prophylaxis (HIV PrEP) (e.g. two-way SMS with check in for those that report symptoms or adverse events). The database will be hosted on UK-based servers which are expected to be managed by Sealed Envelope Ltd. Local investigators will have access to the part of the CRF to enable recording of outcome data and/or severity of COVID-19 symptoms. Participants will be given a secure login to enable them to complete an initial participant health questionnaire and the regular data logs. It is envisaged that these will be completed at least weekly.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

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

An international, multi-site, randomized, placebo-controlled, Bayesian platform clinical trial. Initially there will be 2 arms, but we anticipate adding intervention arms to the platform. Combining interventions, allowing assessment of potential interactions, will be considered when arms are added.

Masking: Double (Participant, Investigator)
Masking Description:

For the MR or MMR vaccine, there will be a placebo vaccine. Attempts will be made to maintain masking for other interventions (e.g. oral tablets) added to the platform by including suitable placebo options.

Primary Purpose: Prevention

• Condition: COVID 19

Intervention

• Drug: MR or M-M-R II ® vaccine
  Education and surveillance plus MR or M-M-R II ® vaccine
  Other Name: Merck
• Drug: Placebo
  Placebo injection

Study Arms

• Experimental: M-M-R II ®
  Education and surveillance plus M-M-R II ®
  Intervention: Drug: MR or M-M-R II ® vaccine
• Placebo Comparator: Placebo
  Education and surveillance plus placebo
  Intervention: Drug: Placebo

Publications *

• Hirsch C, Park YS, Piechotta V, Chai KL, Estcourt LJ, Monsef I, Salomon S, Wood EM, So-Osman C, McQuilten Z, Spinner CD, Malin JJ, Stegemann M, Skoetz N, Kreuzberger N. SARS-CoV-2-neutralising monoclonal antibodies to prevent COVID-19. Cochrane Database Syst Rev. 2022 Jun 17;6(6):CD014945. doi: 10.1002/14651858.CD014945.pub2.
• Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 19, 2021): 3545
• Original Estimated Enrollment (submitted: April 2, 2020): 55000
• Actual Study Completion Date: December 3, 2021
• Actual Primary Completion Date: August 10, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria

1. Volunteers without clinical evidence of COVID-19 infection aged 18 years and older.
2. Healthcare workers based in a primary, secondary or tertiary healthcare setting with a high risk of developing COVID-19 due to their potential exposure to patients with SARS-CoV-2 infection.
3. Must have a mobile phone and access to the Internet for data collection purposes.
4. Participants who are willing and able to provide informed consent via an electronic consent process.

Exclusion criteria

1. Prior enrollment into other COVID-19 interventional prevention or treatment trials (observational trials not excluded).
2. Self-reported or diagnosed current infection with SARS-CoV-2 or previous COVID-19 diagnosis.
3. Self-reported current acute respiratory infection.
4. Concurrent and/or recent involvement in other research or use of the investigational product, a product considered to be equivalent to the investigational product, or any other product that is likely to interfere with the investigational products in this trial used within three months of study enrolment.
5. Self-reported known allergies to any of the IMPs and excipients of the IMPs and placebo.
6. Self-reported presence or history of the conditions listed in the appendices.
7. Self-reported current use of medication known to interact with any of the medications listed in the appendices.
8. Inability or unwillingness to be followed up for the trial period.

For M-M-R II

• Pregnant women.
• Individuals receiving high dose corticosteroids, other immuno-suppressive drugs, alkylating agents or anti-metabolites.
• Individuals undergoing radiotherapy.
• Any malignant disease either untreated or currently undergoing therapy.
• History of administration of gammaglobulin or blood transfusions within the previous 3 months.
• Participants with an allergy to the MR (MMR) vaccine or its components, including neomycin.
• Idiopathic thrombocytopenic purpura (ITP)
• Untreated tuberculosis
• Prior receipt of any vaccines (licensed or investigational) ≤30 days before enrollment
• Planned receipt of any vaccine other than the study intervention within 30 days before and after the study vaccination (not including the flu vaccination via injection)
• Prior receipt of an investigational or licensed vaccine likely to impact on interpretation of the trial data (e.g. Adenovirus vectored vaccines, any coronavirus vaccines).
• Any confirmed or suspected immunosuppressive or immunodeficient state, including untreated HIV infection with a CD4T count <200 /mL
• Asplenia

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: Ghana, South Africa, United Kingdom, United States, Zambia
• Removed Location Countries: Australia, Canada, Ireland, Netherlands, Uganda, Zimbabwe

Administrative Information

• NCT Number: NCT04333732
• Other Study ID Numbers: 202004099; INV-017499 ( Other Grant/Funding Number: Bill and Melinda Gates Foundation )
• 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: Individual participant data that underlie the results reported in the main publication may be shared, after de-identification.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: From 3 months after the last patient last visit onward.
• Access Criteria: Investigators whose proposed use of the data has been approved by a review committee identified for this purpose.

• Current Responsible Party: Michael Avidan, Washington University School of Medicine
• Original Responsible Party: Same as current
• Current Study Sponsor: Washington University School of Medicine
• Original Study Sponsor: Same as current
• Collaborators: COVID -19 Therapeutics Accelerator

Investigators

• Principal Investigator: Michael S. Avidan, MBBCh; Washington Univeristy School of Medicine
• Principal Investigator: Ramani Moonesinghe, MD; University College, London
• Principal Investigator: Helen Rees, MD; Wits University

• PRS Account: Washington University School of Medicine
• Verification Date: October 2021