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

This study has been completed.
Sponsor:
Collaborators:
Hvidovre University Hospital
Kolding Sygehus
Danish National Research Foundation
Research Center for Vitamins and Vaccines (CVIVA)
Information provided by (Responsible Party):
Lone Graff Stensballe, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier:
NCT01694108
First received: September 22, 2012
Last updated: October 3, 2016
Last verified: October 2016
  Purpose

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 Intervention Phase
Prospective
Single-blind
Clinical
Trial
Intervention
Biological: BCG-vaccine (SSI)
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Bacille Calmette Guérin Immunisation at Birth and Childhood Morbidity in Danish Children. A Prospective, Randomised, Clinical Trial.

Resource links provided by NLM:


Further study details as provided by Rigshospitalet, Denmark:

Primary Outcome Measures:
  • All-cause Hospitalisations [ Time Frame: 0-15 months of age ] [ Designated as safety issue: No ]
    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:
  • Antibiotics [ Time Frame: 0-15 months of age ] [ Designated as safety issue: No ]
    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).

  • Atopic Dermatitis [ Time Frame: 13 months of age ] [ Designated as safety issue: No ]
    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.

  • Specific IgE [ Time Frame: 13 months of age ] [ Designated as safety issue: No ]
    Number of participants with specific IgE (Phadiatop Infant) above the clinical cut-of level of 0.35.

  • Standardized Weight at 13 Months [ Time Frame: 13 months of age ] [ Designated as safety issue: No ]
    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.

  • Psychomotor Development in Premature Infants [ Time Frame: 13 months of age ] [ Designated as safety issue: Yes ]
    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.

  • DTaP-IPV-Hib Vaccination Coverage at 12 Months of Age [ Time Frame: 13 months of age ] [ Designated as safety issue: No ]
    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.

  • Standardized Weight, Length and Head Circumference of Premature Children at 13 Months [ Time Frame: 13 months of age ] [ Designated as safety issue: No ]
    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.

  • Episodic Viral Wheeze [ Time Frame: 13 months ] [ Designated as safety issue: No ]
    Number of participants diagnosed with episodic viral wheeze by a physician and treated with anti-asthmatic medicine according to the telephone interview.

  • Food Allergy [ Time Frame: 13 months ] [ Designated as safety issue: No ]
    Number of participants with food allergy diagnosed by a physician and mentioned in the telephone interview at 13 months of age

  • Length at 13 Months of Age [ Time Frame: 13months ] [ Designated as safety issue: No ]
    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.

  • Standardized Head Circumference at 13 Months of Age [ Time Frame: 13 months ] [ Designated as safety issue: No ]
    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.

  • Thymic Gland Size at 3 Months of Age [ Time Frame: 3 months of age ] [ Designated as safety issue: No ]
    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.

  • Leucocyte Count 4 Days After Randomisation/Vaccination [ Time Frame: 4 days after randomisation/vaccination within 7 days after birth ] [ Designated as safety issue: No ]
    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).

  • Monocyte Count 4 Days After Randomisation/Vaccination [ Time Frame: 4 days after randomisation/vaccination within 7 days after birth ] [ Designated as safety issue: No ]
    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).

  • Interferon Gamma Response [ Time Frame: 13 months of age ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Antibody Concentration (AC) Against Tetanus of > 0.1 IU/mL [ Time Frame: 13 months of age ] [ Designated as safety issue: No ]
    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.

  • Number of Events of Common Cold [ Time Frame: 13 months of age ] [ Designated as safety issue: No ]
    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.

  • Number of Events of Pneumonia [ Time Frame: 13 months of age ] [ Designated as safety issue: No ]
    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.

  • Number of Events of Febrile Episodes [ Time Frame: 13 months of age ] [ Designated as safety issue: No ]
    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.

  • Number of Events With Diarrhoea and Vomiting [ Time Frame: 13 months of age ] [ Designated as safety issue: No ]
    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.

  • Number of Events of Acute Otitis Media [ Time Frame: 13 months of age ] [ Designated as safety issue: No ]
    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.

  • Number of Events of Febrile Convulsions [ Time Frame: 13 months of age ] [ Designated as safety issue: No ]
    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:
  • Decisional Conflict Scale Score [ Time Frame: The decisional conflict score was measured before randomisation ] [ Designated as safety issue: No ]
    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.

  • Quality of Communication and Information [ Time Frame: 2 days after the information was given ] [ Designated as safety issue: No ]
    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.


Enrollment: 4262
Study Start Date: September 2012
Study Completion Date: January 2015
Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

  Eligibility

Ages Eligible for Study:   up to 7 Days   (Child)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01694108

Locations
Denmark
Rigshospitalet
Copenhagen, Copenhagen Ø, Denmark, 2100
Hvidovre Hospital
Copenhagen, Denmark, 2650
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.
  More Information

Additional Information:
Responsible Party: Lone Graff Stensballe, MD, PhD, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT01694108     History of Changes
Other Study ID Numbers: EudraCT2010-021979-85 
Study First Received: September 22, 2012
Results First Received: December 3, 2015
Last Updated: October 3, 2016
Health Authority: The Committee on Health Research Ethics, Copenhagen, Denmark:
The Danish Data Protection Agency, Copenhagen, Denmark:
The Good Clinical Practise Unit in Copenhagen, Denmark:
The Good Clinical Practise Unit in South Denmark, Denmark:
The Danish Health and Medicines Authority, Copenhagen, Denmark:
EuDraCT, European Union, Europe:

Additional relevant MeSH terms:
Vaccines
BCG Vaccine
Immunologic Factors
Physiological Effects of Drugs
Adjuvants, Immunologic

ClinicalTrials.gov processed this record on December 02, 2016