Clinical trial NCT01694108: Bacille Calmette Guérin Immunisation at Birth and Childhood Morbidity in Danish Children.
Official title: Bacille Calmette Guérin Immunisation at Birth and Childhood Morbidity in Danish Children. A Prospective, Randomised, Clinical Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Prospective
Single-blind
Clinical
Trial
Intervention
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Hvidovre University Hospital
name: Kolding Sygehus
name: Danish National Research Foundation
name: Research Center for Vitamins and Vaccines (CVIVA)
First posted: 2012-09-26
Enrollment: 4262
Sex: ALL
Maximum age (years): 7
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

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.


Eligibility criteria: 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.

Primary outcomes:
measure: All-cause Hospitalisations
timeFrame: 0-15 months of age
Secondary outcomes:
measure: Antibiotics
timeFrame: 0-15 months of age
measure: Atopic Dermatitis
timeFrame: 13 months of age
measure: Specific IgE
timeFrame: 13 months of age
measure: Standardized Weight at 13 Months
timeFrame: 13 months of age
measure: Psychomotor Development in Premature Infants
timeFrame: 13 months of age
measure: DTaP-IPV-Hib Vaccination Coverage at 12 Months of Age
timeFrame: 13 months of age
measure: Standardized Weight, Length and Head Circumference of Premature Children at 13 Months
timeFrame: 13 months of age
measure: Episodic Viral Wheeze
timeFrame: 13 months
measure: Food Allergy
timeFrame: 13 months
measure: Length at 13 Months of Age
timeFrame: 13months
measure: Standardized Head Circumference at 13 Months of Age
timeFrame: 13 months
measure: Thymic Gland Size at 3 Months of Age
timeFrame: 3 months of age
measure: Leucocyte Count 4 Days After Randomisation/Vaccination
timeFrame: 4 days after randomisation/vaccination within 7 days after birth
measure: Monocyte Count 4 Days After Randomisation/Vaccination
timeFrame: 4 days after randomisation/vaccination within 7 days after birth
measure: Interferon Gamma Response
timeFrame: 13 months of age
measure: Number of Participants With Antibody Concentration (AC) Against Tetanus of > 0.1 IU/mL
timeFrame: 13 months of age
measure: Number of Events of Common Cold
timeFrame: 13 months of age
measure: Number of Events of Pneumonia
timeFrame: 13 months of age
measure: Number of Events of Febrile Episodes
timeFrame: 13 months of age
measure: Number of Events With Diarrhoea and Vomiting
timeFrame: 13 months of age
measure: Number of Events of Acute Otitis Media
timeFrame: 13 months of age
measure: Number of Events of Febrile Convulsions
timeFrame: 13 months of age
Other outcomes:
measure: Decisional Conflict Scale Score
timeFrame: The decisional conflict score was measured before randomisation
measure: Quality of Communication and Information
timeFrame: 2 days after the information was given
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet
state: Copenhagen Ø
city: Copenhagen
country: Denmark
facility: Hvidovre Hospital
city: Kolding
country: Denmark
facility: Kolding Sygehus
Study officials:
affiliation: Rigshospitalet. The Danish National Hospital in Denmark.
name: Lone G Stensballe, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Birk NM, Nissen TN, Ladekarl M, Zingmark V, Kjaergaard J, Jensen TM, Jensen SK, Thostesen LM, Kofoed PE, Stensballe LG, Andersen A, Pryds O, Nielsen SD, Benn CS, Jeppesen DL. The association between Bacillus Calmette-Guerin vaccination (1331 SSI) skin reaction and subsequent scar development in infants. BMC Infect Dis. 2017 Aug 3;17(1):540. doi: 10.1186/s12879-017-2641-0.
citation: Kjaergaard J, Birk NM, Nissen TN, Thostesen LM, Pihl GT, Benn CS, Jeppesen DL, Pryds O, Kofoed PE, Aaby P, Greisen G, Stensballe LG. Nonspecific effect of BCG vaccination at birth on early childhood infections: a randomized, clinical multicenter trial. Pediatr Res. 2016 Nov;80(5):681-685. doi: 10.1038/pr.2016.142. Epub 2016 Jul 18.
citation: Stensballe LG, Sorup S, Aaby P, Benn CS, Greisen G, Jeppesen DL, Birk NM, Kjaergaard J, Nissen TN, Pihl GT, Thostesen LM, Kofoed PE, Pryds O, Ravn H. BCG vaccination at birth and early childhood hospitalisation: a randomised clinical multicentre trial. Arch Dis Child. 2017 Mar;102(3):224-231. doi: 10.1136/archdischild-2016-310760. Epub 2016 Jul 21.
citation: Kjaergaard J, Stensballe LG, Birk NM, Nissen TN, Thostesen LM, Pihl GT, Nielsen AV, Kofoed PE, Aaby P, Pryds O, Greisen G. Bacillus Calmette-Guerin vaccination at birth: Effects on infant growth. A randomized clinical trial. Early Hum Dev. 2016 Sep;100:49-54. doi: 10.1016/j.earlhumdev.2016.05.015. Epub 2016 Jul 7.
citation: Kjaergaard J, Stensballe LG, Birk NM, Nissen TN, Foss KT, Thostesen LM, Pihl GT, Andersen A, Kofoed PE, Pryds O, Greisen G. Lack of a Negative Effect of BCG-Vaccination on Child Psychomotor Development: Results from the Danish Calmette Study - A Randomised Clinical Trial. PLoS One. 2016 Apr 28;11(4):e0154541. doi: 10.1371/journal.pone.0154541. eCollection 2016.
citation: Nissen TN, Birk NM, Kjaergaard J, Thostesen LM, Pihl GT, Hoffmann T, Jeppesen DL, Kofoed PE, Greisen G, Benn CS, Aaby P, Pryds O, Stensballe LG. Adverse reactions to the Bacillus Calmette-Guerin (BCG) vaccine in new-born infants-an evaluation of the Danish strain 1331 SSI in a randomized clinical trial. Vaccine. 2016 May 11;34(22):2477-82. doi: 10.1016/j.vaccine.2016.03.100. Epub 2016 Apr 7.