Trial Outcomes & Findings for Bacille Calmette Guérin Immunisation at Birth and Childhood Morbidity in Danish Children. (NCT NCT01694108)

NCT ID: NCT01694108

Last Updated: 2017-05-24

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 4262 participants
• Primary outcome timeframe: 0-15 months of age
• Results posted on: 2017-05-24

Participant Flow

Participant milestones

Measure	BCG-vaccine	Control Children (no Intervention)
Overall Study STARTED	2129	2133
Overall Study COMPLETED	2129	2133
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	BCG-vaccine n=2095 Participants SSI strain 1331 standard dose	Control Children n=2089 Participants No intervention	Total n=4184 Participants Total of all reporting groups
Age, Continuous	32.0 years STANDARD_DEVIATION 4.6 • n=5 Participants	31.9 years STANDARD_DEVIATION 4.4 • n=7 Participants	31.95 years STANDARD_DEVIATION 4.5 • n=5 Participants
Sex: Female, Male Female	1003 Participants n=5 Participants	985 Participants n=7 Participants	1988 Participants n=5 Participants
Sex: Female, Male Male	1092 Participants n=5 Participants	1104 Participants n=7 Participants	2196 Participants n=5 Participants
Region of Enrollment Denmark	2095 participants n=5 Participants	2089 participants n=7 Participants	4184 participants n=5 Participants
Premature birth	61 participants n=5 Participants	60 participants n=7 Participants	121 participants n=5 Participants

PRIMARY outcome

Timeframe: 0-15 months of age

Population: Intention-to-treat

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

Outcome measures

Measure	BCG-vaccine n=2129 Participants	Control Children (no Intervention) n=2133 Participants
All-cause Hospitalisations	637 Events	633 Events

SECONDARY outcome

Timeframe: 0-15 months of age

Population: Intention-to-treat

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).

Outcome measures

Measure	BCG-vaccine n=2129 Participants	Control Children (no Intervention) n=2133 Participants
Antibiotics	934 participants	931 participants

SECONDARY outcome

Timeframe: 13 months of age

Population: 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%.

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.

Outcome measures

Measure	BCG-vaccine n=2052 Participants	Control Children (no Intervention) n=1952 Participants
Atopic Dermatitis	466 participants	495 participants

SECONDARY outcome

Timeframe: 13 months of age

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

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

Outcome measures

Measure	BCG-vaccine n=743 Participants	Control Children (no Intervention) n=627 Participants
Specific IgE	55 participants	50 participants

SECONDARY outcome

Timeframe: 13 months of age

Population: 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%.

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.

Outcome measures

Measure	BCG-vaccine n=2052 Participants	Control Children (no Intervention) n=1950 Participants
Standardized Weight at 13 Months	0.58 Weight z-score at 13 months Standard Deviation 0.90	0.61 Weight z-score at 13 months Standard Deviation 0.94

SECONDARY outcome

Timeframe: 13 months of age

Population: 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%.

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.

Outcome measures

Measure	BCG-vaccine n=56 Participants	Control Children (no Intervention) n=59 Participants
Psychomotor Development in Premature Infants	141.8 Score on ASQ scale Standard Deviation 53	153.5 Score on ASQ scale Standard Deviation 53.5

SECONDARY outcome

Timeframe: 13 months of age

Population: 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.

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.

Outcome measures

Measure	BCG-vaccine n=2018 Participants	Control Children (no Intervention) n=2097 Participants
DTaP-IPV-Hib Vaccination Coverage at 12 Months of Age	1175 participants	1207 participants

SECONDARY outcome

Timeframe: 13 months of age

Population: 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%.

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.

Outcome measures

Measure	BCG-vaccine n=63 Participants	Control Children (no Intervention) n=61 Participants
Standardized Weight, Length and Head Circumference of Premature Children at 13 Months Weight	0.33 z-score Standard Deviation 0.95	0.34 z-score Standard Deviation 1.03
Standardized Weight, Length and Head Circumference of Premature Children at 13 Months Length	0.10 z-score Standard Deviation 0.97	0.02 z-score Standard Deviation 1.00
Standardized Weight, Length and Head Circumference of Premature Children at 13 Months Head circumference	0.51 z-score Standard Deviation 0.97	0.57 z-score Standard Deviation 0.99

SECONDARY outcome

Timeframe: 13 months

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

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

Outcome measures

Measure	BCG-vaccine n=2108 Participants	Control Children (no Intervention) n=2081 Participants
Episodic Viral Wheeze	211 participants	195 participants

SECONDARY outcome

Timeframe: 13 months

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

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

Outcome measures

Measure	BCG-vaccine n=2107 Participants	Control Children (no Intervention) n=2076 Participants
Food Allergy	15 participants	10 participants

SECONDARY outcome

Timeframe: 13months

Population: 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%.

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.

Outcome measures

Measure	BCG-vaccine n=2050 Participants	Control Children (no Intervention) n=1947 Participants
Length at 13 Months of Age	0.54 Length z-score Standard Deviation 0.99	0.55 Length z-score Standard Deviation 1.00

SECONDARY outcome

Timeframe: 13 months

Population: 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%.

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.

Outcome measures

Measure	BCG-vaccine n=2052 Participants	Control Children (no Intervention) n=1952 Participants
Standardized Head Circumference at 13 Months of Age	0.78 Head circumference z-score Standard Deviation 0.93	0.76 Head circumference z-score Standard Deviation 0.95

SECONDARY outcome

Timeframe: 3 months of age

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

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.

Outcome measures

Measure	BCG-vaccine n=153 Participants	Control Children (no Intervention) n=148 Participants
Thymic Gland Size at 3 Months of Age	33.10 Thymic index Interval 31.22 to 34.81	34.24 Thymic index Interval 32.42 to 36.16

SECONDARY outcome

Timeframe: 4 days after randomisation/vaccination within 7 days after birth

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

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).

Outcome measures

Measure	BCG-vaccine n=75 Participants	Control Children (no Intervention) n=78 Participants
Leucocyte Count 4 Days After Randomisation/Vaccination	10.59 cell concentrations (GM*10^9 cells/L) Interval 10.06 to 11.15	10.70 cell concentrations (GM*10^9 cells/L) Interval 10.24 to 11.17

SECONDARY outcome

Timeframe: 4 days after randomisation/vaccination within 7 days after birth

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

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).

Outcome measures

Measure	BCG-vaccine n=75 Participants	Control Children (no Intervention) n=78 Participants
Monocyte Count 4 Days After Randomisation/Vaccination	1.58 Cell concentrations (GM*10^9 cells/L) Interval 1.47 to 1.7	1.71 Cell concentrations (GM*10^9 cells/L) Interval 1.6 to 1.82

SECONDARY outcome

Timeframe: 13 months of age

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

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.

Outcome measures

Measure	BCG-vaccine n=75 Participants	Control Children (no Intervention) n=68 Participants
Interferon Gamma Response	41 participants	3 participants

SECONDARY outcome

Timeframe: 13 months of age

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

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.

Outcome measures

Measure	BCG-vaccine n=80 Participants	Control Children (no Intervention) n=78 Participants
Number of Participants With Antibody Concentration (AC) Against Tetanus of > 0.1 IU/mL	80 participants	78 participants

SECONDARY outcome

Timeframe: 13 months of age

Population: 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%.

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.

Outcome measures

Measure	BCG-vaccine n=2096 Participants	Control Children (no Intervention) n=2071 Participants
Number of Events of Common Cold	3990 Events	3928 Events

SECONDARY outcome

Timeframe: 13 months of age

Population: 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%.

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.

Outcome measures

Measure	BCG-vaccine n=2100 Participants	Control Children (no Intervention) n=2070 Participants
Number of Events of Pneumonia	207 Events	162 Events

SECONDARY outcome

Timeframe: 13 months of age

Population: 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%.

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.

Outcome measures

Measure	BCG-vaccine n=2098 Participants	Control Children (no Intervention) n=2069 Participants
Number of Events of Febrile Episodes	1385 Events	1302 Events

SECONDARY outcome

Timeframe: 13 months of age

Population: 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%.

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.

Outcome measures

Measure	BCG-vaccine n=2103 Participants	Control Children (no Intervention) n=2071 Participants
Number of Events With Diarrhoea and Vomiting	870 Events	845 Events

SECONDARY outcome

Timeframe: 13 months of age

Population: 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%.

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.

Outcome measures

Measure	BCG-vaccine n=2098 Participants	Control Children (no Intervention) n=2072 Participants
Number of Events of Acute Otitis Media	595 Events	591 Events

SECONDARY outcome

Timeframe: 13 months of age

Population: 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%.

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.

Outcome measures

Measure	BCG-vaccine n=2103 Participants	Control Children (no Intervention) n=2070 Participants
Number of Events of Febrile Convulsions	44 Events	25 Events

OTHER_PRE_SPECIFIED outcome

Timeframe: The decisional conflict score was measured before randomisation

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

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.

Outcome measures

Measure	BCG-vaccine n=667 Participants	Control Children (no Intervention) n=320 Participants
Decisional Conflict Scale Score	18.8 decisional conflict score Interval 0.0 to 53.1	17.2 decisional conflict score Interval 0.0 to 67.2

OTHER_PRE_SPECIFIED outcome

Timeframe: 2 days after the information was given

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

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.

Outcome measures

Measure	BCG-vaccine n=59 Participants	Control Children (no Intervention) n=59 Participants
Quality of Communication and Information	61.40 Score on QuIC scale Interval 58.0 to 65.0	64.42 Score on QuIC scale Interval 63.0 to 67.0

Adverse Events

BCG-vaccine

Serious events: 65 serious events

Other events: 233 other events

Deaths: 0 deaths

Control Children (no Intervention)

Serious events: 45 serious events

Other events: 123 other events

Deaths: 0 deaths

Serious adverse events

Measure	BCG-vaccine n=2129 participants at risk	Control Children (no Intervention) n=2133 participants at risk
General disorders Dead	0.14% 3/2129 • Number of events 3	0.05% 1/2133 • Number of events 1
General disorders Other than dead	2.9% 62/2129 • Number of events 62	2.1% 44/2133 • Number of events 44

Other adverse events

Measure	BCG-vaccine n=2129 participants at risk	Control Children (no Intervention) n=2133 participants at risk
Infections and infestations BCG-vaccine related event	10.0% 212/2129 • Number of events 212	0.00% 0/2133
General disorders Other than BCG-vaccine related	0.99% 21/2129 • Number of events 2129	5.8% 123/2133 • Number of events 2133

Additional Information

Lone Graff Stensballe, Research leader, Pediatrician, PhD

Rigshospitalet

Phone: +0045 35459727

Email: lone.graff.stensballe@regionh.dk

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place