Patients will receive two cycles of Placebo (NaCl solution) at an interval of three months.
Each cycle will consist of intravenously administered (within 3-5 seconds) Placebo twice weekly on days 1, 4, 8 and 11.

Patients will receive two cycles of Bortezomib (Velcade®) at an interval of three months.
Each cycle will consist of intravenously administered (within 3-5 seconds) Bortezomib 1.3 mg/m2 twice weekly on days 1, 4, 8 and 11.

Late Rejection of Renal Transplant

Antibody-mediated Rejection

Bortezomib

Placebo

Medical University of Vienna, Department of Nephrology and Dialysis

Bortezomib in Late Antibody-mediated Kidney Transplant Rejection

Bortezomib in Late Antibody-mediated Kidney Transplant Rejection (BORTEJECT Study)

Peripheric venous blood samples (4ml) will be obtained after 0, 6, 12, 18 an 24 months to assess the change of eGFR slopes over time.
In case of loss of follow-up the GFR is assumed to be 0ml/min.

Peripheric venous blood samples (10mL) will be obtained after 0, 6, 12, 18 and 24 months to assess DSA levels by Luminex® technology.
Maximum and sum of MFI of DSA
Number of DSA
Broadness of sensitization (virtual PRA)

Survival will be assessed after 12 and 24 months after randomization

Graft loss will be assessed after 12 and 24 months after randomization with or without re-transplantation

Cr-EDTA GFR will be assessed by measuring the clearance of a defined peripheric administered dose of Chromium-51 EDTA according to a standard protocol.

Protein excretion (protein/creatinine ratio) will be measured in 24h urine at 0, 6, 12, 18 and 24 months after randomization.

Diagnosed at protocol biopsy after month 24 after randomization or whenever clinically indicated

Acute AMR score (0-9)
Sum of:
Glomerulitis 0, 1, 2, 3
Peritubular capillaritis 0, 1, 2, 3
C4d in peritubular capillaries 0, 1, 2, 3

Chronic AMR score (0-9)
Sum of:
Transplant glomerulopathy 0, 1, 2, 3
Peritubular capillary basement membrane lamellation 0, 1, 2, 3
Chronic vasculopathy 0, 1, 2, 3

Farsad Eskandary

Farsad Eskandary, MD

Medical University of Vienna

Medical University Innsbruck

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.

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

BCG-vaccine

Control Children

Total

Gender of the child. In multiple births: gender of the first born child.

Sex: Female, Male

All three study sites are situated in Denmark.

Region of Enrollment

Premature birth

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

Control Children (no Intervention)

All-cause Hospitalisations

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).

Antibiotics

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.

Atopic Dermatitis

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

Specific IgE

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.

Standardized Weight at 13 Months

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.

Psychomotor Development in Premature Infants

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.

DTaP-IPV-Hib Vaccination Coverage at 12 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.

Standardized Weight, Length and Head Circumference of Premature Children at 13 Months

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

Episodic Viral Wheeze

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

Food Allergy

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.

Length at 13 Months of Age

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.

Standardized Head Circumference at 13 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.

Thymic Gland Size at 3 Months of Age

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).

Leucocyte Count 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).

Monocyte Count 4 Days After Randomisation/Vaccination

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.

Interferon Gamma Response

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 Participants With Antibody Concentration (AC) Against Tetanus of > 0.1 IU/mL

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 Common Cold

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 Pneumonia

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 of Febrile Episodes

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 With Diarrhoea and Vomiting

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 Acute Otitis Media

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.

Number of Events of Febrile Convulsions

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.

Mothers who decided to let their child participate in the study

Participating Mothers

Mothers who decided not to let their child participate in the study

Declining Mothers

Decisional Conflict Scale Score

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.

Randomized to receive information about the study by telephone

Telephone

Randomized to receive information about the study by standard face-to-face consultation.

common cold/vemšana

Bortezomib in Late Antibody-mediated Kidney Transplant Rejection

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

Efficacy of Systemic Glucocorticoid in the Treatment of Wheezing in Children

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