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

An International, Multi-site, Bayesian Platform Adaptive, Randomized, Placebo-controlled Trial Assessing the Effectiveness of Candidate Agents in Mitigating COVID-19 Disease in Adults

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.

Study Overview

• Status: Completed
• Conditions: COVID 19
• Intervention / Treatment: Drug: Placebo; Drug: MR or M-M-R II ® vaccine

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
• Enrollment (Actual): 3411
• Phase: Phase 3

Contacts and Locations

Study Locations

• Ghana
  • Greater Accra Region
    • Accra, Greater Accra Region, Ghana, 00233
      • University of Ghana Medical Centre
• South Africa
  • Cape Town, South Africa, 7505
    • FAMCRU (Family Clinical Research with Ubuntu)
  • Chatsworth, South Africa, 4030
    • Chatsworth, HIV Prevention Research Unit, South African Medical Research Council
  • Durban, South Africa, 4133
    • Isipingo, HIV Prevention Research Unit, South African Medical Research Council
  • Tembisa, South Africa, 1632
    • Aurum Institute Tembisa
  • Cape Town
    • Mowbray, Cape Town, South Africa, 7925
      • Groote Schuur/J52, Desmond Tutu Health Foundation
    • Sunnydale, Cape Town, South Africa, 7975
      • Masiphumelele, Desmond Tutu Health Foundation
  • Free State
    • Bloemfontein, Free State, South Africa, 9301
      • Josha Research
  • Johannesburg
    • Auckland Park, Johannesburg, South Africa, 2092
      • Clinical HIV Research Unit (CHRU)
    • Diepkloof, Johannesburg, South Africa, 1864
      • Perinatal HIV Research Unit (PHRU)
  • Johannesburg,Gauteng
    • Hillbrow, Johannesburg,Gauteng, South Africa, 2001
      • Wits RHI, University of the Witwatersrand
  • Tshwane
    • Soshanguve, Tshwane, South Africa, 0152
      • Setshaba Research Centre
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7925
      • Groote Schuur Hospital
• United Kingdom
  • London, United Kingdom, W1W 7TY
    • University College London
• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
• Zambia
  • Lusaka, Zambia, 10101
    • Levy Mwanawasa University Teaching Hospital
  • Lusaka, Zambia, H8R9+9V
    • Centre for Infectious Disease Research in Zambia [CIDRZ]

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: M-M-R II ®; Education and surveillance plus M-M-R II ® Single dose, 0.5 mL subcutaneous injection of M-M-R II ®	Drug: MR or M-M-R II ® vaccine; Education and surveillance plus MR or M-M-R II ® vaccine; Other Names: Merck
Placebo Comparator: Placebo; Education and surveillance plus placebo Single dose, 0.5 mL subcutaneous injection of 0.9% saline	Drug: Placebo; Placebo injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Symptomatic COVID-19 at 60 Days	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.	60 days after receiving trial intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Symptomatic COVID-19 at 150 Days	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.	150 days after receiving trial intervention
Severity of COVID-19 Measured at 60 Days After 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). Practically, this outcome measure was treated as a binary outcome - participants were classified and counted as having severe COVID-19 if they met the definition for the primary outcome of symptomatic COVID-19 AND were hospitalized during the course of their COVID-19 illness.	60 days after receiving trial intervention
Severity of COVID-19 at 150 Days After Intervention	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). Practically, this outcome measure was treated as a binary outcome - participants were classified and counted as having severe COVID-19 if they met the definition for the primary outcome of symptomatic COVID-19 AND were hospitalized during the course of their COVID-19 illness.	150 days
Risk of SARS-CoV-2 Infection up to 150 Days After Trial Intervention	Risk 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. Infection with SARS CoV-2 during the course of the trial was diagnosed when IgG antibodies to the viral nucleocapsid protein were present from the 150 day specimen, but not the baseline specimen.	150 days

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• 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

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2020
• Primary Completion (Actual): August 10, 2021
• Study Completion (Actual): December 3, 2021

Study Registration Dates

• First Submitted: March 31, 2020
• First Submitted That Met QC Criteria: April 2, 2020
• First Posted (Actual): April 3, 2020

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: February 27, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: COVID 19; Health care workers; M-M-R II ®
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: 202004099; INV-017499 (Other Grant/Funding Number: Bill and Melinda Gates Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in the main publication may be shared, after de-identification.
• IPD Sharing Time Frame: From 3 months after the last patient last visit onward.
• IPD Sharing Access Criteria: Investigators whose proposed use of the data has been approved by a review committee identified for this purpose.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No