COVID 19
Conditions
Keywords
COVID 19, Health care workers, M-M-R II ®
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.
Interventions
DRUGMR or M-M-R II ® vaccine
Education and surveillance plus MR or M-M-R II ® vaccine
DRUGPlacebo
Placebo injection
Sponsors
COVID -19 Therapeutics Accelerator
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, 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.
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Symptomatic COVID-19 at 60 Days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Symptomatic COVID-19 at 150 Days | 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 Measured at 60 Days After Intervention | 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). 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. |
| Severity of COVID-19 at 150 Days After Intervention | 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). 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. |
| Risk of SARS-CoV-2 Infection up to 150 Days After Trial Intervention | 150 days | 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. |
Countries
Ghana, South Africa, United Kingdom, United States, Zambia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| M-M-R II ® Education and surveillance plus M-M-R II ®
MR or M-M-R II ® vaccine: Education and surveillance plus MR or M-M-R II ® vaccine | 1,722 |
| Placebo Education and surveillance plus placebo
Placebo: Placebo injection | 1,689 |
| Total | 3,411 |
Baseline characteristics
| Characteristic | M-M-R II ® | Placebo | Total |
|---|---|---|---|
| Age, Customized <50 years | 1566 Participants | 1539 Participants | 3105 Participants |
| Age, Customized >=50 years | 156 Participants | 150 Participants | 306 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Ghana | 76 participants | 75 participants | 151 participants |
| Region of Enrollment South Africa | 1252 participants | 1240 participants | 2492 participants |
| Region of Enrollment United Kingdom | 26 participants | 22 participants | 48 participants |
| Region of Enrollment United States | 85 participants | 68 participants | 153 participants |
| Region of Enrollment Zambia | 283 participants | 284 participants | 567 participants |
| Sex: Female, Male Female | 1033 Participants | 992 Participants | 2025 Participants |
| Sex: Female, Male Male | 689 Participants | 697 Participants | 1386 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1,722 | 0 / 1,689 |
| other Total, other adverse events | 0 / 1,722 | 0 / 1,689 |
| serious Total, serious adverse events | 11 / 1,722 | 5 / 1,689 |
Outcome results
Primary
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.
Time frame: 60 days after receiving trial intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| M-M-R II ® | Number of Participants With Symptomatic COVID-19 at 60 Days | 24 Participants |
| Placebo | Number of Participants With Symptomatic COVID-19 at 60 Days | 19 Participants |
Comparison: The primary endpoint was analysed using a Bayesian logistic regression, including as covariates the treatment arm, age (\<50 vs. ≥50), and a random effect for sitep-value: 0.5295% CI: [-0.5, 1.1]Regression, Logistic
Secondary
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.
Time frame: 150 days after receiving trial intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| M-M-R II ® | Number of Participants With Symptomatic COVID-19 at 150 Days | 65 Participants |
| Placebo | Number of Participants With Symptomatic COVID-19 at 150 Days | 64 Participants |
Comparison: The endpoint was analysed using a Bayesian logistic regression, including as covariates the treatment arm, age (\<50 vs. ≥50), and a random effect for sitep-value: 0.9595% CI: [-1.4, 1.3]Regression, Logistic
Secondary
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.
Time frame: 150 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| M-M-R II ® | Risk of SARS-CoV-2 Infection up to 150 Days After Trial Intervention | 100 Participants |
| Placebo | Risk of SARS-CoV-2 Infection up to 150 Days After Trial Intervention | 98 Participants |
Secondary
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.
Time frame: 150 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| M-M-R II ® | Severity of COVID-19 at 150 Days After Intervention | 3 Participants |
| Placebo | Severity of COVID-19 at 150 Days After Intervention | 1 Participants |
Secondary
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.
Time frame: 60 days after receiving trial intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| M-M-R II ® | Severity of COVID-19 Measured at 60 Days After Intervention | 3 Participants |
| Placebo | Severity of COVID-19 Measured at 60 Days After Intervention | 1 Participants |