Clinical Trial Results:
Reducing health care workers absenteeism in SARS-CoV-2 pandemic by enhanced trained immune responses through Bacillus Calmette-Guérin vaccination, a randomized controlled trial (COVID-19).
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Summary
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EudraCT number |
2020-000919-69 |
Trial protocol |
NL |
Global end of trial date |
17 May 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
18 Jun 2022
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First version publication date |
18 Jun 2022
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Other versions |
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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 |
73249
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04328441 | ||
WHO universal trial number (UTN) |
U1111-1249-1107 | ||
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Sponsors
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Sponsor organisation name |
University Medical Center Utrecht
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Sponsor organisation address |
Heidelberglaan 100, Utrecht, Netherlands,
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Public contact |
Marc J. M. Bonten, University Medical Center Utrecht, 0031 8875 503 50 , M.J.M.Bonten@umcutrecht.nl
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Scientific contact |
Marc J. M. Bonten, University Medical Center Utrecht, 0031 8875 503 50 , M.J.M.Bonten@umcutrecht.nl
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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 |
17 May 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
17 May 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
17 May 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 HCW with direct patient contacts during the epidemic phase of SARS-CoV-2.
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Protection of trial subjects |
Participants were instructed throughout to contact the study team in case of (serious) adverse events, . Participants that reported a hospital admission in the mobile phone application were contacted by the research team. Known systemic and local injection site side effects of BCG vaccination were solicited during the first 7 days after injection, and local side effects again at the end of the trial.
Statistical analysis
The primary endpoint was analyzed as total counts (i.e. one total count per participant) using a Bayesian negative binomial regression and corrected for participant baseline characteristics. Secondary count endpoints (e.g. number of days reporting symptoms) were analyzed using maximum likelihood estimation (frequentist model) and are reported as RR with 95% confidence interval (CI), and secondary time-to-event endpoints (e.g. incidence of COVID-19) using Cox-proportional hazard models reporting hazard rations (HR) and 95% CIs, with adjustment for the same baseline participant characteristics as the primary analysis. COVID-19 related absenteeism was analyzed using the same method as the primary endpoint.
Interim analyses were performed as described for the primary outcome and were performed biweekly from weeks 4 to 26 and monthly from week 26 to study end (March 2021). Unblinded results of the interim analysis and incidence of (serious) adverse events were reported to the data safety monitoring board, once per month from week 4 to 26 and once per two months from week 26 to study end.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 May 2020
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy, Scientific research | ||
Long term follow-up duration |
1 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Netherlands: 1511
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Worldwide total number of subjects |
1511
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EEA total number of subjects |
1511
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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) |
1511
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants were adult (≥18 years) healthcare workers (HCWs) working in the participating hospitals or their affiliated ambulance services, with expected exposure to COVID-19 patients as part of their clinical duties. Primary exclusion criteria were known allergy to BCG, active or latent Mycobacterium tuberculosis infection, any other active infec | |||||||||||||||
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Pre-assignment
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Screening details |
Participants were recruited with advertisements on the hospital website or bij email. All participants provided written informed consent. | |||||||||||||||
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Period 1
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Period 1 title |
Inclusion period (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Data analyst, Carer | |||||||||||||||
Blinding implementation details |
Participants and study personnel conducting participant follow-up were blinded to treatment allocation. Study personnel preparing and administering the study vaccines were not blinded but could not influence treatment allocations or data collection. The trial statistician that conducted the interim and final analyses was not blinded throughout the trial but was not otherwise involved in trial conduct.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||
Arm description |
Placebo, normal saline solution as an intradermal injection in the left upper arm | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Not Applicable
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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 |
Normal saline solution 0.1 mL as an intradermal injection in the left upper arm.
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Arm title
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Bacillus Calmette-Guérin | |||||||||||||||
Arm description |
0.1 mL of the Danish strain 1331, SSI, Denmark, equivalent to 0.075 mg attenuated Mycobacterium bovis | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Bacillus Calmette-Guérin
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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 |
0.1 mL of the Danish strain 1331, SSI, Denmark, equivalent to 0.075 mg attenuated Mycobacterium bovis
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo, normal saline solution as an intradermal injection in the left upper arm | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Bacillus Calmette-Guérin
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Reporting group description |
0.1 mL of the Danish strain 1331, SSI, Denmark, equivalent to 0.075 mg attenuated Mycobacterium bovis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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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 were included for analysis. If participants did not complete the follow-up period, the available data untill that time were included.
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo, normal saline solution as an intradermal injection in the left upper arm | ||
Reporting group title |
Bacillus Calmette-Guérin
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Reporting group description |
0.1 mL of the Danish strain 1331, SSI, Denmark, equivalent to 0.075 mg attenuated Mycobacterium bovis | ||
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 were included for analysis. If participants did not complete the follow-up period, the available data untill that time were included.
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End point title |
Unplanned absenteeism for any reason | ||||||||||||||||
End point description |
The primary endpoint was the number of days of unplanned absenteeism for any reason, reported as the average proportion of sick-days out of planned work days.
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End point type |
Primary
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End point timeframe |
Within 12 months
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Statistical analysis title |
Primary endpoint analysis | ||||||||||||||||
Statistical analysis description |
The primary endpoint was analyzed as total counts (i.e. one total count per participant) using a Bayesian negative binomial regression and corrected for participant baseline characteristics.
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Comparison groups |
Bacillus Calmette-Guérin v Placebo v Intention to treat
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Number of subjects included in analysis |
3022
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.05 [1] | ||||||||||||||||
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 primary endpoint was analyzed as total counts (i.e. one total count per participant) using a Bayesian negative binomial regression and corrected for participant baseline characteristics. These were defined on a 95% Credible interval. |
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End point title |
Documented COVID19 | ||||||||||||
End point description |
Documented COVID-19 required self-reporting of any respiratory tract symptom (cough, dyspnea, nasal cold, sore throat or loss of smell or taste of any reported severity) or fever (body temperature >= 38.0 degrees Celsius) within 7 days before or up to 14 days after a positive SARS-CoV-2 PCR or rapid antigen test.
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End point type |
Secondary
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End point timeframe |
Within 12 months
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Statistical analysis title |
Secondary endpoint | ||||||||||||
Statistical analysis description |
Secondary count endpoints (e.g. number of days reporting symptoms) were analyzed using maximum likelihood estimation (frequentist model) and are reported as RR with 95% confidence interval (CI), and secondary time-to-event endpoints (e.g. incidence of COVID-19) using Cox-proportional hazard models reporting hazard rations (HR) and 95% CIs, with adjustment for the same baseline participant characteristics as the primary analysis.
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Comparison groups |
Placebo v Bacillus Calmette-Guérin v Intention to treat
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Number of subjects included in analysis |
3022
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.05 | ||||||||||||
Method |
maximum likelihood estimation | ||||||||||||
Parameter type |
Risk ratio (RR) | ||||||||||||
Confidence interval |
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95% | ||||||||||||
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End point title |
COVID19 related hospitalization | ||||||||||||
End point description |
Participants that reported a hospital admission in the mobile phone application were contacted by the research team.
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End point type |
Secondary
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End point timeframe |
Within 12 months
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Acute respiratory symptoms and/or fever | ||||||||||||
End point description |
Presence of fever required a self-measured body temperature of ≥ 38.0℃ and respiratory symptoms required the presence of cough or dyspnea with a severity score of ≥ 2 (mild symptoms), or the presence of nasal congestion or sore throat with a severity score of ≥ 3 (moderate symptoms).
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End point type |
Secondary
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End point timeframe |
Within 12 months
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| No statistical analyses for this end point | |||||||||||||
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End point title |
COVID19 related absenteeism | ||||||||||||||||
End point description |
COVID-19 related absenteeism was analyzed using the same method as the primary endpoint.
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End point type |
Secondary
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End point timeframe |
Within 12 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 12 months
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Adverse event reporting additional description |
Participants were instructed throughout to contact the study team in case of (serious) adverse events. Participants that reported a hospital admission in the mobile phone application were contacted by the research team. Known systemic and local injection site side effects of BCG vaccination were solicited during the first 7 days after injection, an
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
List linings | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
NA
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo, normal saline solution as an intradermal injection in the left upper arm | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Bacillus Calmette-Guérin
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Reporting group description |
0.1 mL of the Danish strain 1331, SSI, Denmark, equivalent to 0.075 mg attenuated Mycobacterium bovis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 | |||
