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

NCT01694108 | Completed Phase 4 Results DMC

• 1 other identifier: EudraCT2010-021979-85
• Study Type: interventional
• Target: 4,262
• Locations: 1 country
• Sites: 3

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. 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. 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. 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. 4.To test the hypothesis that infants who get the BCG vaccine at birth respond in growth measures: weight, length and head circumference.
5. 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. 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. 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. 8.To test the above mentioned hypotheses specifically in the strata of premature and low-birth-weight Danish infants.

Conditions

Prospective; Single-blind; Clinical; Trial; Intervention

Outcome Measures

Primary Outcomes (1)

• All-cause Hospitalisations

  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 Outcomes (22)

• Antibiotics

  0-15 months of age

• Atopic Dermatitis

  13 months of age

• Specific IgE

  13 months of age

• Standardized Weight at 13 Months

  13 months of age

• Psychomotor Development in Premature Infants

  13 months of age

Other Outcomes (2)

• Decisional Conflict Scale Score

  The decisional conflict score was measured before randomisation

• Quality of Communication and Information

  2 days after the information was given

Study Arms (2)

BCG-vaccine (SSI)

EXPERIMENTAL

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.

Interventions

BCG-vaccine (SSI) BIOLOGICAL

BCG-vaccine (SSI)

Eligibility Criteria

• Age: Up to 7 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (3)

Rigshospitalet

Copenhagen, Copenhagen Ø, 2100, Denmark

Location

Hvidovre Hospital

Copenhagen, 2650, Denmark

Location

Kolding Sygehus

Kolding, 6000, Denmark

Location

Related Publications (7)

• Dybdal D, Stensballe LG, Greisen G, Kjaergaard J. Validity of parent-reported weight and length of infants. Dan Med J. 2023 Aug 23;70(9):A11220712.

  PMID: 37622649 DERIVED

• 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.

  PMID: 28774269 DERIVED

• 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.

  PMID: 27443836 DERIVED

• 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.

  PMID: 27429204 DERIVED

• 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.

  PMID: 27394195 DERIVED

• 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.

  PMID: 27123570 DERIVED

• 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.

  PMID: 27060379 DERIVED

MeSH Terms

Interventions

BCG Vaccine

Intervention Hierarchy (Ancestors)

Tuberculosis Vaccines; Bacterial Vaccines; Vaccines; Biological Products; Complex Mixtures

Limitations and 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.

Results Point of Contact

• Title: Lone Graff Stensballe, Research leader, Pediatrician, PhD
• Organization: Rigshospitalet

lone.graff.stensballe@regionh.dk

+0045 35459727

Study Officials

• Lone G Stensballe, MD, PhD

  Rigshospitalet. The Danish National Hospital in Denmark.

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: September 22, 2012
• First Posted: September 26, 2012
• Study Start: September 1, 2012
• Primary Completion: January 1, 2015
• Study Completion: January 1, 2015
• Last Updated: May 24, 2017
• Results First Posted: January 8, 2016

Record last verified: 2017-04

Locations

DK (3)