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

April 26, 2017 updated by: Lone Graff Stensballe

Bacille Calmette Guérin Immunisation at Birth and Childhood Morbidity in Danish Children. A Prospective, Randomised, Clinical Trial.

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.

Study Overview

Status

Completed

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

4262

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Copenhagen, Denmark, 2650
        • Hvidovre Hospital
      • Kolding, Denmark, 6000
        • Kolding Sygehus
    • Copenhagen Ø
      • Copenhagen, Copenhagen Ø, Denmark, 2100
        • Rigshospitalet

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 1 week (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Single Group Assignment
  • Masking: Single

Arms and Interventions

Participant Group / 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.

No Intervention: No Intervention
Control children will be treated as usual, since no suitable placebo exists.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
All-cause Hospitalisations
Time Frame: 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.
0-15 months of age

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Antibiotics
Time Frame: 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).
0-15 months of age
Atopic Dermatitis
Time Frame: 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.
13 months of age
Specific IgE
Time Frame: 13 months of age
Number of participants with specific IgE (Phadiatop Infant) above the clinical cut-of level of 0.35.
13 months of age
Standardized Weight at 13 Months
Time Frame: 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.
13 months of age
Psychomotor Development in Premature Infants
Time Frame: 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.
13 months of age
DTaP-IPV-Hib Vaccination Coverage at 12 Months of Age
Time Frame: 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.
13 months of age
Standardized Weight, Length and Head Circumference of Premature Children at 13 Months
Time Frame: 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.
13 months of age
Episodic Viral Wheeze
Time Frame: 13 months
Number of participants diagnosed with episodic viral wheeze by a physician and treated with anti-asthmatic medicine according to the telephone interview.
13 months
Food Allergy
Time Frame: 13 months
Number of participants with food allergy diagnosed by a physician and mentioned in the telephone interview at 13 months of age
13 months
Length at 13 Months of Age
Time Frame: 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.
13months
Standardized Head Circumference at 13 Months of Age
Time Frame: 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.
13 months
Thymic Gland Size at 3 Months of Age
Time Frame: 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.
3 months of age
Leucocyte Count 4 Days After Randomisation/Vaccination
Time Frame: 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).
4 days after randomisation/vaccination within 7 days after birth
Monocyte Count 4 Days After Randomisation/Vaccination
Time Frame: 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).
4 days after randomisation/vaccination within 7 days after birth
Interferon Gamma Response
Time Frame: 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.
13 months of age
Number of Participants With Antibody Concentration (AC) Against Tetanus of > 0.1 IU/mL
Time Frame: 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.
13 months of age
Number of Events of Common Cold
Time Frame: 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.
13 months of age
Number of Events of Pneumonia
Time Frame: 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.
13 months of age
Number of Events of Febrile Episodes
Time Frame: 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.
13 months of age
Number of Events With Diarrhoea and Vomiting
Time Frame: 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.
13 months of age
Number of Events of Acute Otitis Media
Time Frame: 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.
13 months of age
Number of Events of Febrile Convulsions
Time Frame: 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.
13 months of age

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Decisional Conflict Scale Score
Time Frame: 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.
The decisional conflict score was measured before randomisation
Quality of Communication and Information
Time Frame: 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.
2 days after the information was given

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2012

Primary Completion (Actual)

January 1, 2015

Study Completion (Actual)

January 1, 2015

Study Registration Dates

First Submitted

September 22, 2012

First Submitted That Met QC Criteria

September 25, 2012

First Posted (Estimate)

September 26, 2012

Study Record Updates

Last Update Posted (Actual)

May 24, 2017

Last Update Submitted That Met QC Criteria

April 26, 2017

Last Verified

April 1, 2017

More Information

Terms related to this study

Other Study ID Numbers

  • EudraCT2010-021979-85

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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