Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tuberculosis infection, compared with an interferon γ release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial.
Targeted screening and treatment of Mycobacterium tuberculosis infection substantially reduces the risk of developing active tuberculosis. C-Tb (Statens Serum Institute, Copenhagen, Denmark) is a novel specific skin test based on ESAT-6 and CFP10 antigens. We investigated the safety and diagnostic potential of C-Tb compared with established tests in the contact-tracing setting.



Negative controls, close contacts, occasional contacts, and patients with active pulmonary tuberculosis were enrolled at 13 centres in Spain. We compared C-Tb with the QuantiFERON-TB Gold In-Tube ([QFT] Qiagen, Hilden, Germany) interferon γ release assay (IGRA) and the purified protein derivative (PPD) RT 23 tuberculin skin test ([TST] Statens Serum Institute). All participants older than 5 years were tested with QFT. Some participants in the negative control group received C-Tb without the TST to test for potential interactions between C-Tb and PPD RT 23. The rest were randomly assigned in blocks of ten and tested with both C-Tb and TST, with five in each block receiving injection of C-Tb in the right arm and the TST in the left arm and five vice versa. The primary and safety analyses were done in all participants randomly assigned to a group who received any test. This trial is registered with ClinicalTrials.gov, number NCT01631266, and with EudraCT, number 2011-005617-36.



From July 24, 2012, to Oct 2, 2014, 979 participants were enrolled, of whom 263 were negative controls, 299 were occasional contacts, 316 were close contacts, and 101 were patients with tuberculosis. 970 (99%) participants completed the trial. Induration sizes were similar for C-Tb and TST, but TST positivity was affected by BCG vaccination status. We found a strong positive trend towards C-Tb test positivity with increasing risk of infection, from 3% in negative controls to 16% in occasional contacts, to 43% in close contacts. C-Tb and QFT results were concordant in 785 (94%) of 834 participants aged 5 years and older, and results did not differ significantly between exposure groups. The safety profile of C-Tb was similar to that for the TST.



C-Tb delivered IGRA-like results in a field-friendly format. Being unaffected by BCG vaccination status, the C-Tb skin test might provide more accurate treatment guidance in settings where the TST is commonly used.



Statens Serum Institut.
Department of Infectious Diseases Immunology, Statens Serum Institut, Copenhagen, Denmark. Electronic address: moru@ssi.dk.
Morten
M
Ruhwald
Department of Vaccine Development, Statens Serum Institut, Copenhagen, Denmark.
Henrik
H
Aggerbeck
Unidad de Tuberculosis, Servicio de Neumología, Complejo Hospitalario Universitario de Vigo, Vigo, Spain.
Rafael Vázquez
RV
Gallardo
Department of Infectious Diseases Immunology, Statens Serum Institut, Copenhagen, Denmark.
Søren T
ST
Hoff
Servicio de Medicina Preventiva Hospital Universitario Cruces, Bizkaia, Spain.
José I
JI
Villate
Department of Vaccine Development, Statens Serum Institut, Copenhagen, Denmark.
Bettine
B
Borregaard
Infectious Diseases Service, Hospital Clinic-IDIBAPS. University of Barcelona, Barcelona, Spain.
José A
JA
Martinez
Department of Vaccine Development, Statens Serum Institut, Copenhagen, Denmark.
Ingrid
I
Kromann
Unidad de Tuberculosis, Hospital Universitario Lucus Augusti, Lugo, Spain.
Antón
A
Penas
Unidad de Tuberculosis, Servicio Medicina Interna, Complexo Hospitalario Universitario de Pontevedra, Pontevedra, Spain.
Luis L
LL
Anibarro
Unitat de Tuberculosi Vall d'Hebron-Drassanes, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Maria Luiza
ML
de Souza-Galvão
Servicio de Enfermedades Infecciosas, Hospital del Mar, Barcelona, Spain.
Francisca
F
Sánchez
Servicio de Medicina Preventiva, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Jose Ángel
JÁ
Rodrigo-Pendás
CIBER de Epidemiologia y Salud Pública (CIBERESP), Madrid, Spain; Unitat d'Infeccions, Servei de Pediatria, Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Barcelona, Spain.
Antoni
A
Noguera-Julian
Hospital Universitari Mútua de Terrassa, Barcelona, Spain.
Xavier
X
Martínez-Lacasa
Unidad de Tuberculosis, Servicio de Medicina Preventiva, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain.
Maria Victoria
MV
Tuñez
Unidad de Tuberculosis, Servicio de Neumología, Complejo Hospitalario Universitario de Vigo, Vigo, Spain.
Virginia Leiro
VL
Fernández
Epidemiology Service, Public Health Agency of Barcelona, Barcelona, Spain; CIBER de Epidemiologia y Salud Pública (CIBERESP), Madrid, Spain.
Joan P
JP
Millet
Epidemiology Service, Public Health Agency of Barcelona, Barcelona, Spain; CIBER de Epidemiologia y Salud Pública (CIBERESP), Madrid, Spain.
Antonio
A
Moreno
Infectious Diseases Service, Hospital Clinic-IDIBAPS. University of Barcelona, Barcelona, Spain.
Nazaret
N
Cobos
Infectious Diseases Service, Hospital Clinic-IDIBAPS. University of Barcelona, Barcelona, Spain.
José M
JM
Miró
Epidemiology Service, Public Health Agency of Barcelona, Barcelona, Spain.
Llanos
L
Roldan
Epidemiology Service, Public Health Agency of Barcelona, Barcelona, Spain; CIBER de Epidemiologia y Salud Pública (CIBERESP), Madrid, Spain.
Angels
A
Orcau
Department of Infectious Diseases Immunology, Statens Serum Institut, Copenhagen, Denmark.
Peter
P
Andersen
Epidemiology Service, Public Health Agency of Barcelona, Barcelona, Spain; CIBER de Epidemiologia y Salud Pública (CIBERESP), Madrid, Spain.
Joan A
JA
Caylá
D000293:Adolescent; D000328:Adult; D001500:BCG Vaccine / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D059425:Interferon-gamma Release Tests / Q000379:methods*; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology; D013030:Spain; D014374:Tuberculin Test / Q000379:methods*; D014376:Tuberculosis / Q000175:diagnosis* / Q000517:prevention & control; D055815:Young Adult
D001500:BCG Vaccine