Clinical Trial Results:
Using BCG vaccine to enhance non-specific protection of health care workers during the COVID-19 pandemic. A randomised controlled multi-center trial.
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Summary
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EudraCT number |
2020-001888-90 |
Trial protocol |
DK |
Global end of trial date |
31 Jul 2021
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Results information
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Results version number |
v2(current) |
This version publication date |
15 Nov 2023
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First version publication date |
16 Aug 2022
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Other versions |
v1 |
Version creation reason |
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Summary report(s) |
Published article |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
20201504
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04373291 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University of Southern Denmark
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Sponsor organisation address |
Studiestraede 6, Copenhagen K, Denmark, 1455
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Public contact |
Clinical Institute, OPEN, University of Southern Denmark, open.adm@rsyd.dk
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Scientific contact |
Clinical Institute, OPEN, University of Southern Denmark, open.adm@rsyd.dk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Jul 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Jul 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Jul 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To reduce absenteeism among health care workers during the COVID-19 pandemic.
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Protection of trial subjects |
Participants were instructed to report (serious) adverse events in the weekly questionnaire but were also encouraged to contact study personnel these cases.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
18 May 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Denmark: 1221
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Worldwide total number of subjects |
1221
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EEA total number of subjects |
1221
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
1181
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From 65 to 84 years |
40
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85 years and over |
0
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Recruitment
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Recruitment details |
Healthcare workers (HCWs) recruited at nine Danish hospitals from 18-05-2020 to 21-01-2021. Participants were adults (>18 years) and working at the hospital at least 22 hours/week. Exclusion criteria were the known contraindications for BCG and previous confirmed SARS-CoV-2 infection. | |||||||||
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Pre-assignment
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Screening details |
1293 HCWs were screened for inclusion and 1233 were randomised. Three persons were randomised by mistake (1 BCG/2 placebo) as they did not fulfil inclusion criteria. They were not included and never received treatment. Nine participants never responded after enrolment (3 BCG/6 placebo). The final study population included 1221 participants. | |||||||||
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Pre-assignment period milestones
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Number of subjects started |
1233 [1] | |||||||||
Number of subjects completed |
1221 | |||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Lost to follow up: 9 | |||||||||
Reason: Number of subjects |
Mistakenly randomised: 3 | |||||||||
| Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: In total 1233 persons were randomised. But three of these were randomised by mistake and were not included in the trial. Nine participants never responded after enrolment hence have no follow up data. All were alive at end of trial though. The true study population therefore consists of 1221 participants. |
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Single blind | |||||||||
Roles blinded |
Subject | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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BCG group | |||||||||
Arm description |
Standard dose intradermal BCG vaccination (Bacillus Calmette-Guérin), 0.1 ml (BCG strain 1331, AJ Vaccines, Denmark). | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
BCG vaccine, AJ Vaccines, Denmark
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
BCG was administered in the right upper arm, intradermally, 0.1 ml of the suspended vaccine.
After reconstitution one dose (0,1 ml) contains: Mycobacterium bovis BCG (Bacillus Calmette-Guerin), Danish strain 1331, live attenuated, 2-8 x 10_5 cfu.
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Arm title
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Placebo group | |||||||||
Arm description |
0.1 ml of sterile 0.9 % NaCl solution (saline). | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Sterile 0.9 % NaCl solution
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Investigational medicinal product code |
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Other name |
Saline
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
Placebo was administered in the right upper arm, intradermally, 0.1 ml of sterile 0.9 % NaCl solution.
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Baseline characteristics reporting groups
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Reporting group title |
BCG group
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Reporting group description |
Standard dose intradermal BCG vaccination (Bacillus Calmette-Guérin), 0.1 ml (BCG strain 1331, AJ Vaccines, Denmark). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo group
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Reporting group description |
0.1 ml of sterile 0.9 % NaCl solution (saline). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
BCG group
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Reporting group description |
Standard dose intradermal BCG vaccination (Bacillus Calmette-Guérin), 0.1 ml (BCG strain 1331, AJ Vaccines, Denmark). | ||
Reporting group title |
Placebo group
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Reporting group description |
0.1 ml of sterile 0.9 % NaCl solution (saline). | ||
Subject analysis set title |
Intention to treat
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Data from all enrolled participants. If participants did not complete the follow up period, the available data were included.
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End point title |
Unplanned absenteeism | ||||||||||||
End point description |
Reported by randomisation group as mean number of days absent per 1000 workdays.
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End point type |
Primary
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End point timeframe |
Within 6 months
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Statistical analysis title |
Primary endpoint analysis | ||||||||||||
Statistical analysis description |
The primary endpoint was analysed as counts per week (multiple observations per subject) using Bayesian negative binomial regression and adjusted for hospital, gender and age.
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Comparison groups |
Placebo group v BCG group
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Number of subjects included in analysis |
1221
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
< 0.05 | ||||||||||||
Method |
Bayesian negative binomial regression | ||||||||||||
Parameter type |
95% Credible interval | ||||||||||||
Confidence interval |
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level |
95% | ||||||||||||
sides |
1-sided
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lower limit |
- | ||||||||||||
upper limit |
- | ||||||||||||
| Notes [1] - The effect was calculated as relative risk with 95% Credible interval. |
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End point title |
Verified COVID-19 | |||||||||
End point description |
Verified COVID-19 was defined as having a positive SARS-CoV-2 PCR (polymerase chain reaction) test, rapid antigen test or antibody test and was based on information from participants.
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End point type |
Secondary
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End point timeframe |
Within 6 months
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Statistical analysis title |
Secondary endpoints | |||||||||
Statistical analysis description |
Secondary time-to-event outcomes (incidence outcomes) were analysed using Cox proportional hazards regression models. The effect was reported as a relative risk (RR) with 95% confidence interval. Incidence of death and hospitalisation were reported per 1000 follow-up days, using total days of follow-up since inclusion. Disease episodes and respiratory symptoms were reported per 1000 follow-up days counted among the completed questionnaires.
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Comparison groups |
BCG group v Placebo group
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Number of subjects included in analysis |
1221
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Confidence interval |
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level |
95% | |||||||||
sides |
1-sided
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lower limit |
- | |||||||||
upper limit |
- | |||||||||
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End point title |
All-cause hospitalisation | |||||||||
End point description |
All hospitalisations were explored by study personnel. Only acute admissions were taken into account. Planned operations and visits to outpatient clinics were not included in the analysis.
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End point type |
Secondary
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End point timeframe |
Within 6 months
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| No statistical analyses for this end point | ||||||||||
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End point title |
Self-reported infection episodes | |||||||||
End point description |
Infectious disease episodes were defined by self-reported disease and symptoms of infection and were reported as total number of episodes per randomisation group. A new episode had to be separated from previous symptoms by 7 days or more. Each subject could contribute multible episodes.
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End point type |
Secondary
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End point timeframe |
Within 6 months
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| No statistical analyses for this end point | ||||||||||
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End point title |
Absenteeism due to infections | ||||||||||||
End point description |
Reported by randomisation group as mean number of days absent due to infectious disease per 1000 workdays.
Secondary absenteeism endpoints were analysed using the same method as the primary endpoint.
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End point type |
Secondary
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End point timeframe |
Within 6 months
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Absenteeism due to respiratory infection | ||||||||||||
End point description |
Reported by randomisation group as mean number of days absent due to respiratory infection per 1000 workdays.
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End point type |
Secondary
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End point timeframe |
Within 6 months
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Absenteeism due to verified COVID-19 | ||||||||||||
End point description |
Reported by randomisation group as mean number of days absent due to verified COVID-19 per 1000 workdays.
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End point type |
Secondary
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End point timeframe |
Within 6 months
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Days of self-reported respiratory symptoms | |||||||||
End point description |
Number of days with symptoms per 1000 follow-up days. Respiratory symptoms were defined as one or more of the following symptoms: cough, sore throat, runny nose, loss of smell/taste or dyspnoea with or without general symptoms such as fever, muscle ache, headache, and fatigue (dyspnoea only if in combination with fever).
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End point type |
Secondary
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End point timeframe |
Within 6 months
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Within 6 months.
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Adverse event reporting additional description |
Adverse events were registered within 7 days of randomisation. Serious adverse events until end of trial. Participants could report adverse events via the weekly electronic questionnaires or directly to the investigators at all times during the trial.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
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Reporting groups
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Reporting group title |
Placebo group
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Reporting group description |
Participants randomised to placebo. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BCG group
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Reporting group description |
Participants randomised to BCG vaccination. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
