Bacille Calmette Guérin Immunisation at Birth and Childhood Morbidity in Danish Children.

• Sponsor: Lone Graff Stensballe (Other)
• Overall Status: Completed
• CT.gov ID: NCT01694108
• Collaborator: Hvidovre University Hospital (Other), Kolding Sygehus (Other), Danish National Research Foundation (Other), Research Center for Vitamins and Vaccines (CVIVA) (Other)
• Enrollment: 4,262
• Locations: 3
• Arms: 2
• Duration (Months): 28
• Patients Per Site: 1420.7
• Patients Per Site Per Month: 50.8

Study Details

Study Description

Brief Summary

In high-income societies the use of health care and medication is steadily increasing. Children have high morbidity, many visits at the general practitioner, an increasing number of hospitalisations, and an increasing use of medication. And, when children are ill, someone has to stay home to care for them. An un-explained global increase in the incidence of the allergic diseases eczema, wheezing, asthma and allergies means that 25% of high-income populations are affected. Cheap preventive measures are highly warranted. Recent studies have shown a positive, non-specific effect of early Bacille Calmette Guérin (BCG) immunisation on neonatal mortality in low-income countries and suggested a positive, non-specific effect on allergic disease in high-income countries. "Non-specific" means that the vaccine effect goes beyond prevention of the targeted disease, i.e. the BCG vaccine benefits the health status of the immunised individual in ways unrelated to protection against tuberculosis (TB). For instance, in a recent randomised trial in West Africa the investigators showed that the BCG vaccine at birth was safe in low birth weight (LBW) infants and significantly reduced neonatal mortality in these children, with a significant long-lasting effect on infant mortality in the smallest newborns with a birth weight <1.5 kg. There is an urgent need to explore the huge potential of the BCG's beneficial immune-stimulatory effects among children in high-income populations.

Therefore, the investigators will carry out a large prospective randomised clinical trial in Denmark primarily designed to test the hypothesis that infants who get the BCG vaccine at birth experience 20% fewer hospitalisations during early childhood.

Secondary outcomes

1. To test the hypothesis that infants who get the BCG vaccine at birth are prescribed less antibiotics during early childhood than non-BCG-immunised infants.

2. To test the hypothesis that Danish infants who get the BCG vaccine at birth develop less eczema, asthmatic bronchitis/wheeze and food allergy at 3 and 12 months of age: self-reported, diagnosed by a physician, or found at clinical examination; and are prescribed less anti-eczema/asthma/allergy medication during early childhood than non-BCG-immunised infants.

3. To test the hypothesis that infants who receive the BCG at birth respond in paraclinical measures: Specific IgE, thymic gland size, leucocyte count and differentiation, monocyte memory, cytokine profiles, and antibody titres following immunisation against diphtheria, tetanus, pertussis, pneumococcus, hemophilus.

4. To test the hypothesis that infants who get the BCG vaccine at birth respond in growth measures: weight, length and head circumference.

5. To test the hypothesis that infants who get the BCG vaccine at birth respond with decreased morbidity: common cold, pneumonia, febrile episodes, diarrhoea and vomiting, acute otitis media, febrile convulsions.

6. To test the hypothesis that premature infants with gestational age less than 37 weeks who get the BCG vaccine at birth have unaffected psychomotor development measures: Ages and Stages scores.

7. To test the hypothesis that infants who get the BCG vaccine at birth has unaffected coverage with the subsequent vaccinations in the Child Vaccination Programme.

8. To test the above mentioned hypotheses specifically in the strata of premature and low-birth-weight Danish infants.

Condition or Disease	Intervention/Treatment	Phase
Prospective; Single-blind; Clinical; Trial; Intervention	Biological: BCG-vaccine (SSI)	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 4262 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Bacille Calmette Guérin Immunisation at Birth and Childhood Morbidity in Danish Children. A Prospective, Randomised, Clinical Trial.
• Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Jan 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BCG-vaccine (SSI) Children born to mothers, who have accepted to participate, will be randomised to either intervention group or to the control group at birth. Block-randomisation stratified by hospital, gender and gestational age (≥37 weeks of gestation vs. < 37 weeks of gestation) will be performed electronically just before vaccination by the overall study electronic case report system (e-crf). Children randomised to the BCG vaccination group will receive an intradermal BCG vaccine (Statens Serum Institute "CG vaccine" in the standard dose 0.05 ml in the upper, lateral part of the arm of the child by a specially trained midwife or a study physician.	Biological: BCG-vaccine (SSI)
No Intervention: No Intervention Control children will be treated as usual, since no suitable placebo exists.

Outcome Measures

Primary Outcome Measures

1. All-cause Hospitalisations [0-15 months of age]

   To test that infants who get the BCG vaccine at birth experience 20% fewer hospitalisations in early childhood than non-BCG-immunised infants.

Secondary Outcome Measures

1. Antibiotics [0-15 months of age]

   To test that infants who get the BCG vaccine at birth are prescribed less antibiotics during early childhood than non-BCG-immunised infants. Use of antibiotics was defined as one or more precriptions of systemic antibiotics (ATC groups J01, J02, J05, all subgroups inclusive).

2. Atopic Dermatitis [13 months of age]

   To test if BCG vaccination within 7 days after birth influence the risk of atopic dermatitis defined by clinical examination at 13 months of age using "scoring atopic dermatitis (SCORAD)" or by parental report of physician diagnosed atopic dermatitis in the telephone interview at 13 months of age.

3. Specific IgE [13 months of age]

   Number of participants with specific IgE (Phadiatop Infant) above the clinical cut-of level of 0.35.

4. Standardized Weight at 13 Months [13 months of age]

   To test that infants who get the BCG vaccine at birth respond in weight.The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.

5. Psychomotor Development in Premature Infants [13 months of age]

   To test that premature infants with gestational age less than 37 weeks who get the BCG vaccine at birth have unaffected psychomotor development measures: ASQ: Ages and stages questionnaire - a parent reported questionnaire that measures child psychomotor development. Total range of ASQ score: 0 to 300 points. Higher scores indicate higher level of psychomotor development.

6. DTaP-IPV-Hib Vaccination Coverage at 12 Months of Age [13 months of age]

   To test that infants who get the BCG vaccine at birth has unaffected coverage with the subsequent 3rd diphtheria, tetanus, acellular pertussis, polio, Haemophilus influenzae type b (DTaP-IPV-Hib) vaccination scheduled to 12 months of age according to the Danish child vaccination programme. Since we did not expect all children to get their immunizations exactly at 12 months of age, the children were followed up until 13-months of age.

7. Standardized Weight, Length and Head Circumference of Premature Children at 13 Months [13 months of age]

   The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.

8. Episodic Viral Wheeze [13 months]

   Number of participants diagnosed with episodic viral wheeze by a physician and treated with anti-asthmatic medicine according to the telephone interview.

9. Food Allergy [13 months]

   Number of participants with food allergy diagnosed by a physician and mentioned in the telephone interview at 13 months of age

10. Length at 13 Months of Age [13months]

    To test if infants who get the BCG vaccine at birth respond in length. The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.

11. Standardized Head Circumference at 13 Months of Age [13 months]

    To test if infants who get the BCG vaccine at birth respond in head circumference. The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.

12. Thymic Gland Size at 3 Months of Age [3 months of age]

    To test that infants who receive the BCG at birth respond in thymic gland size defined by ultra sound examination. First, the thymus gland was identified in a horizontal scanning plane and the largest transverse diameter of the thymus was obtained. Second, in a sagittal scanning plane, the area of the largest lobe was assessed. Both measurements were obtained twice, and in case of more than 15% difference, both measurements were repeated. The mean of the two measurements were multiplied and defined as the thymic index.

13. Leucocyte Count 4 Days After Randomisation/Vaccination [4 days after randomisation/vaccination within 7 days after birth]

    To test if infants who receive the BCG at birth respond in leucocyte count (white blood cell count) measured as geometric mean (GM) cell concentrations (GM*10^9 cells/L).

14. Monocyte Count 4 Days After Randomisation/Vaccination [4 days after randomisation/vaccination within 7 days after birth]

    To test if infants who receive the BCG at birth respond in monocyte count measured as geometric mean (GM) cell concentrations (GM*10^9 cells/L).

15. Interferon Gamma Response [13 months of age]

    To test that infants who receive the BCG at birth respond in interferon-gamma response upon stimulation with BCG. The interferon gamma response was defined as a value above the cut-off value of 107 pg/ml.

16. Number of Participants With Antibody Concentration (AC) Against Tetanus of > 0.1 IU/mL [13 months of age]

    To test the tetenus antibody response in BCG-vaccinated vs. non-BCG vaccinated children following routine immunisation against tetanus at 3, 5 and 12 months of age in blood samples obtained 13 months of age.

17. Number of Events of Common Cold [13 months of age]

    To test that Danish infants who get the BCG vaccine at birth experience less events of common cold until 13 months of age than non-BCG-immunised infants.

18. Number of Events of Pneumonia [13 months of age]

    To test that Danish infants who get the BCG vaccine at birth get less pneumonia at 13 months of age than non-BCG-immunised infants.

19. Number of Events of Febrile Episodes [13 months of age]

    To test that Danish infants who get the BCG vaccine at birth get less febrile episodes at 13 months of age than non-BCG-immunised infants.

20. Number of Events With Diarrhoea and Vomiting [13 months of age]

    To test that Danish infants who get the BCG vaccine at birth develop less episodes with diarrhoea and vomiting at 13 months of age than non-BCG-immunised infants.

21. Number of Events of Acute Otitis Media [13 months of age]

    To test that Danish infants who get the BCG vaccine at birth develop less acute otitis media at 13 months of age than non-BCG-immunised infants.

22. Number of Events of Febrile Convulsions [13 months of age]

    To test that Danish infants who get the BCG vaccine at birth develop less febrile convulsions at 13 months of age than non-BCG-immunised infants.

Other Outcome Measures

1. Decisional Conflict Scale Score [The decisional conflict score was measured before randomisation]

   After parents having made the decision about whether to accept vaccination of their newborn through participation in The Danish Calmette Study, O'Connor's Decisional Conflict Scale was used to identify decisional conflicts. The score ranges from 0 (no decisional conflict) til 100 (maximum decisional conflict). Scores lower than 25 are associated with implementing decisions; scores exceeding 37.5 are associated with decision delay or feeling unsure about implementation; so a low score reflects a low level of doubt about the decision about participation/decline participation in the trial, and a high score reflects a high level of doubt.

2. Quality of Communication and Information [2 days after the information was given]

   To test that the use of telephone and internet was acceptable in the study population using the Quality of Informed Consent (QuIC) questionnaire. The questionnaire was divided into six categories; five on study comprehension and one on satisfaction with the information process. The items in the first five categories could be answered with "yes", "no" or "do not know". The last category was rated on a 7-point Likert scale, with 1 being "very dissatisfied" and 7 being "very satisfied". The primary outcome was the sum of the score for comprehension items and satisfaction items. Comprehension items were scored 1 point for each correct answer and 0 points for each incorrect answer. Satisfaction items were scored as rated on the 7-point Likert scale. Total score ranged from 7 to 69 points, comprehension score from 0 to 20 points and satisfaction score from 7 to 49 points. The higher score, the better comprehension and satisfaction.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 7 Days
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• All parents planning to give birth at Rigshospitalet, Hvidovre Hospital and Kolding Hospital will receive at letter during 2nd/3rd trimester of pregnancy with information on the study and be offered inclusion in the study.

Exclusion Criteria:

• Infants born before gestational age 32 weeks and/or birth weight < 1000g, infants with known congenital disease, anomaly or malformation, immune deficiency and HIV, will be excluded. Non-Danish speaking parents will be excluded.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rigshospitalet	Copenhagen	Copenhagen Ø	Denmark	2100
2	Hvidovre Hospital	Copenhagen		Denmark	2650
3	Kolding Sygehus	Kolding		Denmark	6000

Sponsors and Collaborators

• Lone Graff Stensballe
• Hvidovre University Hospital
• Kolding Sygehus
• Danish National Research Foundation
• Research Center for Vitamins and Vaccines (CVIVA)

Investigators

• Principal Investigator: Lone G Stensballe, MD, PhD, Rigshospitalet. The Danish National Hospital in Denmark.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Study home page

Publications

None provided.

• Responsible Party: Lone Graff Stensballe, MD, PhD, Rigshospitalet, Denmark
• ClinicalTrials.gov Identifier: NCT01694108
• Other Study ID Numbers: EudraCT2010-021979-85
• First Posted: Sep 26, 2012
• Last Update Posted: May 24, 2017
• Last Verified: Apr 1, 2017

• Additional relevant MeSH terms: BCG Vaccine

Study Results

Participant Flow

Arm/Group Title	BCG-vaccine	Control Children (no Intervention)
Arm/Group Description
Period Title: Overall Study
STARTED	2129	2133
COMPLETED	2129	2133
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	BCG-vaccine	Control Children	Total
Arm/Group Description	SSI strain 1331 standard dose	No intervention	Total of all reporting groups
Overall Participants	2095	2089	4184
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.0 (4.6)	31.9 (4.4)	31.95 (4.5)
Sex: Female, Male (Count of Participants)
Female	1003 47.9%	985 47.2%	1988 47.5%
Male	1092 52.1%	1104 52.8%	2196 52.5%
Region of Enrollment (participants) [Number]
Denmark	2095 100%	2089 100%	4184 100%
Premature birth (participants) [Number]
Number [participants]	61 2.9%	60 2.9%	121 2.9%

Outcome Measures

1. Primary Outcome

Title	All-cause Hospitalisations
Description	To test that infants who get the BCG vaccine at birth experience 20% fewer hospitalisations in early childhood than non-BCG-immunised infants.
Time Frame	0-15 months of age

Outcome Measure Data

Analysis Population Description

Intention-to-treat

Arm/Group Title	BCG-vaccine	Control Children (no Intervention)
Arm/Group Description
Measure Participants	2129	2133
Number [Events]	637	633

2. Secondary Outcome

Title	Antibiotics
Description	To test that infants who get the BCG vaccine at birth are prescribed less antibiotics during early childhood than non-BCG-immunised infants. Use of antibiotics was defined as one or more precriptions of systemic antibiotics (ATC groups J01, J02, J05, all subgroups inclusive).
Time Frame	0-15 months of age

Outcome Measure Data

Analysis Population Description

Intention-to-treat

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SSI strain 1331 standard dose	No intervention
Measure Participants	2129	2133
Number [participants]	934 44.6%	931 44.6%

3. Secondary Outcome

Title	Atopic Dermatitis
Description	To test if BCG vaccination within 7 days after birth influence the risk of atopic dermatitis defined by clinical examination at 13 months of age using "scoring atopic dermatitis (SCORAD)" or by parental report of physician diagnosed atopic dermatitis in the telephone interview at 13 months of age.
Time Frame	13 months of age

Outcome Measure Data

Analysis Population Description

This analysis includes children with follow-up data from clinical examination or telephone interview. As opposed to the register-based primary outcome, adherence to telephone-interview and clinical examination was slightly lower than 100%.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SS! strain 1331 standard dose	No intervention
Measure Participants	2052	1952
Number [participants]	466 22.2%	495 23.7%

4. Secondary Outcome

Title	Specific IgE
Description	Number of participants with specific IgE (Phadiatop Infant) above the clinical cut-of level of 0.35.
Time Frame	13 months of age

Outcome Measure Data

Analysis Population Description

This analysis includes children who participated with blood samples for this sub-study regarding specific IgE.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SSI strain 1331 standard dose	No intervention
Measure Participants	743	627
Number [participants]	55 2.6%	50 2.4%

5. Secondary Outcome

Title	Standardized Weight at 13 Months
Description	To test that infants who get the BCG vaccine at birth respond in weight.The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.
Time Frame	13 months of age

Outcome Measure Data

Analysis Population Description

This analysis only includes children with available follow-up data from telephone interviews or clinical examinations. As opposed to the primary outcome, follow-up was lower than 100%.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SS! strain 1331 standard dose	No intervention
Measure Participants	2052	1950
Mean (Standard Deviation) [Weight z-score at 13 months]	0.58 (0.90)	0.61 (0.94)

6. Secondary Outcome

Title	Psychomotor Development in Premature Infants
Description	To test that premature infants with gestational age less than 37 weeks who get the BCG vaccine at birth have unaffected psychomotor development measures: ASQ: Ages and stages questionnaire - a parent reported questionnaire that measures child psychomotor development. Total range of ASQ score: 0 to 300 points. Higher scores indicate higher level of psychomotor development.
Time Frame	13 months of age

Outcome Measure Data

Analysis Population Description

This analysis only includes children from a particular subgroup (premature children, N = 144), who had with available follow-up data. As opposed to the primary outcome, follow-up was lower than 100%.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SS! strain 1331 standard dose	No intervention
Measure Participants	56	59
Mean (Standard Deviation) [Score on ASQ scale]	141.8 (53)	153.5 (53.5)

7. Secondary Outcome

Title	DTaP-IPV-Hib Vaccination Coverage at 12 Months of Age
Description	To test that infants who get the BCG vaccine at birth has unaffected coverage with the subsequent 3rd diphtheria, tetanus, acellular pertussis, polio, Haemophilus influenzae type b (DTaP-IPV-Hib) vaccination scheduled to 12 months of age according to the Danish child vaccination programme. Since we did not expect all children to get their immunizations exactly at 12 months of age, the children were followed up until 13-months of age.
Time Frame	13 months of age

Outcome Measure Data

Analysis Population Description

Per-protocol analysis excluding 11 children randomised to BCG who did not receive the vaccine, and 36 children randomised to control who received the BCG vaccine.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SSI strain 1331 standard dose	No intervention
Measure Participants	2018	2097
Number [participants]	1175 56.1%	1207 57.8%

8. Secondary Outcome

Title	Standardized Weight, Length and Head Circumference of Premature Children at 13 Months
Description	The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.
Time Frame	13 months of age

Outcome Measure Data

Analysis Population Description

Premature children born with gestational age 32-36 weeks. This analysis only includes children from a particular subgroup (premature children, N = 144), who had with available follow-up data. As opposed to the primary outcome, follow-up was lower than 100%.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SSI strain 1331 standard dose	No intervention
Measure Participants	63	61
Weight	0.33 (0.95)	0.34 (1.03)
Length	0.10 (0.97)	0.02 (1.00)
Head circumference	0.51 (0.97)	0.57 (0.99)

9. Secondary Outcome

Title	Episodic Viral Wheeze
Description	Number of participants diagnosed with episodic viral wheeze by a physician and treated with anti-asthmatic medicine according to the telephone interview.
Time Frame	13 months

Outcome Measure Data

Analysis Population Description

This analysis only includes children with available follow-up telephone interview data. As opposed to the primary outcome, follow-up was lower than 100%.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SS! strain 1331 standard dose	No intervention
Measure Participants	2108	2081
Number [participants]	211 10.1%	195 9.3%

10. Secondary Outcome

Title	Food Allergy
Description	Number of participants with food allergy diagnosed by a physician and mentioned in the telephone interview at 13 months of age
Time Frame	13 months

Outcome Measure Data

Analysis Population Description

This analysis only includes children with available follow-up telephone interview data. As opposed to the primary outcome, follow-up was lower than 100%.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SSI strain 1331 standard dose	No intervention
Measure Participants	2107	2076
Number [participants]	15 0.7%	10 0.5%

11. Secondary Outcome

Title	Length at 13 Months of Age
Description	To test if infants who get the BCG vaccine at birth respond in length. The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.
Time Frame	13months

Outcome Measure Data

Analysis Population Description

This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SS! strain 1331 standard dose	No intervention
Measure Participants	2050	1947
Mean (Standard Deviation) [Length z-score]	0.54 (0.99)	0.55 (1.00)

12. Secondary Outcome

Title	Standardized Head Circumference at 13 Months of Age
Description	To test if infants who get the BCG vaccine at birth respond in head circumference. The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.
Time Frame	13 months

Outcome Measure Data

Analysis Population Description

This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SS! strain 1331 standard dose	No intervention
Measure Participants	2052	1952
Mean (Standard Deviation) [Head circumference z-score]	0.78 (0.93)	0.76 (0.95)

13. Secondary Outcome

Title	Thymic Gland Size at 3 Months of Age
Description	To test that infants who receive the BCG at birth respond in thymic gland size defined by ultra sound examination. First, the thymus gland was identified in a horizontal scanning plane and the largest transverse diameter of the thymus was obtained. Second, in a sagittal scanning plane, the area of the largest lobe was assessed. Both measurements were obtained twice, and in case of more than 15% difference, both measurements were repeated. The mean of the two measurements were multiplied and defined as the thymic index.
Time Frame	3 months of age

Outcome Measure Data

Analysis Population Description

This outcome was a sub-study to The Danish Calmette Study with 301 (BCG 153, Control 148) participating children.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SSI strain 1331 standard dose	No intervention
Measure Participants	153	148
Mean (95% Confidence Interval) [Thymic index]	33.10	34.24

14. Secondary Outcome

Title	Leucocyte Count 4 Days After Randomisation/Vaccination
Description	To test if infants who receive the BCG at birth respond in leucocyte count (white blood cell count) measured as geometric mean (GM) cell concentrations (GM*10^9 cells/L).
Time Frame	4 days after randomisation/vaccination within 7 days after birth

Outcome Measure Data

Analysis Population Description

This was a sub study among 153 children with blood-samples at 4 days after randomisation/vaccination.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SSI strain 1331 standard dose	No intervention
Measure Participants	75	78
Geometric Mean (95% Confidence Interval) [cell concentrations (GM*10^9 cells/L)]	10.59	10.70

15. Secondary Outcome

Title	Monocyte Count 4 Days After Randomisation/Vaccination
Description	To test if infants who receive the BCG at birth respond in monocyte count measured as geometric mean (GM) cell concentrations (GM*10^9 cells/L).
Time Frame	4 days after randomisation/vaccination within 7 days after birth

Outcome Measure Data

Analysis Population Description

This was a sub study among 153 children with blood-samples at 4 days after randomisation/vaccination.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SSI strain 1331 standard dose	No intervention
Measure Participants	75	78
Geometric Mean (95% Confidence Interval) [Cell concentrations (GM*10^9 cells/L)]	1.58	1.71

16. Secondary Outcome

Title	Interferon Gamma Response
Description	To test that infants who receive the BCG at birth respond in interferon-gamma response upon stimulation with BCG. The interferon gamma response was defined as a value above the cut-off value of 107 pg/ml.
Time Frame	13 months of age

Outcome Measure Data

Analysis Population Description

This is a sub study using bloodsamples. Only a small sub population from the overall trial participated.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SSI strain 1331 standard dose	No intervention
Measure Participants	75	68
Number [participants]	41 2%	3 0.1%

17. Secondary Outcome

Title	Number of Participants With Antibody Concentration (AC) Against Tetanus of > 0.1 IU/mL
Description	To test the tetenus antibody response in BCG-vaccinated vs. non-BCG vaccinated children following routine immunisation against tetanus at 3, 5 and 12 months of age in blood samples obtained 13 months of age.
Time Frame	13 months of age

Outcome Measure Data

Analysis Population Description

This outcome was a sub-study with 158 participants. Antibody concentration (AC) of > 0.1 IU/mL was considered protective

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SSI strain 1331 standard dose	No intervention
Measure Participants	80	78
Number [participants]	80 3.8%	78 3.7%

18. Secondary Outcome

Title	Number of Events of Common Cold
Description	To test that Danish infants who get the BCG vaccine at birth experience less events of common cold until 13 months of age than non-BCG-immunised infants.
Time Frame	13 months of age

Outcome Measure Data

Analysis Population Description

This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SS! strain 1331 standard dose	No intervention
Measure Participants	2096	2071
Number [Events]	3990	3928

19. Secondary Outcome

Title	Number of Events of Pneumonia
Description	To test that Danish infants who get the BCG vaccine at birth get less pneumonia at 13 months of age than non-BCG-immunised infants.
Time Frame	13 months of age

Outcome Measure Data

Analysis Population Description

This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SSI strain 1331 standard dose	No intervention
Measure Participants	2100	2070
Number [Events]	207	162

20. Secondary Outcome

Title	Number of Events of Febrile Episodes
Description	To test that Danish infants who get the BCG vaccine at birth get less febrile episodes at 13 months of age than non-BCG-immunised infants.
Time Frame	13 months of age

Outcome Measure Data

Analysis Population Description

This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SSI strain 1331 standard dose	No intervention
Measure Participants	2098	2069
Number [Events]	1385	1302

21. Secondary Outcome

Title	Number of Events With Diarrhoea and Vomiting
Description	To test that Danish infants who get the BCG vaccine at birth develop less episodes with diarrhoea and vomiting at 13 months of age than non-BCG-immunised infants.
Time Frame	13 months of age

Outcome Measure Data

Analysis Population Description

This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SS! strain 1331 standard dose	No intervention
Measure Participants	2103	2071
Number [Events]	870	845

22. Secondary Outcome

Title	Number of Events of Acute Otitis Media
Description	To test that Danish infants who get the BCG vaccine at birth develop less acute otitis media at 13 months of age than non-BCG-immunised infants.
Time Frame	13 months of age

Outcome Measure Data

Analysis Population Description

This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SSI strain 1331 standard dose	No intervention
Measure Participants	2098	2072
Number [Events]	595	591

23. Secondary Outcome

Title	Number of Events of Febrile Convulsions
Description	To test that Danish infants who get the BCG vaccine at birth develop less febrile convulsions at 13 months of age than non-BCG-immunised infants.
Time Frame	13 months of age

Outcome Measure Data

Analysis Population Description

This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.

Arm/Group Title	BCG-vaccine	Control Children
Arm/Group Description	SSI strain 1331 standard dose	No intervention
Measure Participants	2103	2070
Number [Events]	44	25

24. Other Pre-specified Outcome

Title	Decisional Conflict Scale Score
Description	After parents having made the decision about whether to accept vaccination of their newborn through participation in The Danish Calmette Study, O'Connor's Decisional Conflict Scale was used to identify decisional conflicts. The score ranges from 0 (no decisional conflict) til 100 (maximum decisional conflict). Scores lower than 25 are associated with implementing decisions; scores exceeding 37.5 are associated with decision delay or feeling unsure about implementation; so a low score reflects a low level of doubt about the decision about participation/decline participation in the trial, and a high score reflects a high level of doubt.
Time Frame	The decisional conflict score was measured before randomisation

Outcome Measure Data

Analysis Population Description

This outcome was a sub-study to The Danish Calmette Study with 667 participating mothers and 320 declining mothers.

Arm/Group Title	Participating Mothers	Declining Mothers
Arm/Group Description	Mothers who decided to let their child participate in the study	Mothers who decided not to let their child participate in the study
Measure Participants	667	320
Mean (Inter-Quartile Range) [decisional conflict score]	18.8	17.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BCG-vaccine, Control Children (no Intervention)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Mann-Whitney-test comparing the decisional conflict scores of participating mothers vs. declining mothers.

25. Other Pre-specified Outcome

Title	Quality of Communication and Information
Description	To test that the use of telephone and internet was acceptable in the study population using the Quality of Informed Consent (QuIC) questionnaire. The questionnaire was divided into six categories; five on study comprehension and one on satisfaction with the information process. The items in the first five categories could be answered with "yes", "no" or "do not know". The last category was rated on a 7-point Likert scale, with 1 being "very dissatisfied" and 7 being "very satisfied". The primary outcome was the sum of the score for comprehension items and satisfaction items. Comprehension items were scored 1 point for each correct answer and 0 points for each incorrect answer. Satisfaction items were scored as rated on the 7-point Likert scale. Total score ranged from 7 to 69 points, comprehension score from 0 to 20 points and satisfaction score from 7 to 49 points. The higher score, the better comprehension and satisfaction.
Time Frame	2 days after the information was given

Outcome Measure Data

Analysis Population Description

This is a small, separate sub-study. 59 + 59 participants had sufficient follow-up data to participate in the analysis.

Arm/Group Title	Telephone	Face-to-face
Arm/Group Description	Randomized to receive information about the study by telephone	Randomized to receive information about the study by standard face-to-face consultation.
Measure Participants	59	59
Mean (Inter-Quartile Range) [Score on QuIC scale]	61.40	64.42

Adverse Events

Arm/Group Title	BCG-vaccine		Control Children (no Intervention)
Arm/Group Description
All Cause Mortality
	BCG-vaccine		Control Children (no Intervention)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	BCG-vaccine		Control Children (no Intervention)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	65/2129 (3.1%)		45/2133 (2.1%)
General disorders
Dead	3/2129 (0.1%)	3	1/2133 (0%)	1
Other than dead	62/2129 (2.9%)	62	44/2133 (2.1%)	44
Other (Not Including Serious) Adverse Events
	BCG-vaccine		Control Children (no Intervention)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	233/2129 (10.9%)		123/2133 (5.8%)
General disorders
Other than BCG-vaccine related	21/2129 (1%)	2129	123/2133 (5.8%)	2133
Infections and infestations
BCG-vaccine related event	212/2129 (10%)	212	0/2133 (0%)	0

Limitations/Caveats

The allocation was planned to be stratified by sex, study site, and prematurity, however, due to a programming error the allocation was stratified only by prematurity.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.