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The C-Tb skin test for LTBI- Key results from phase III studies
Morten Ruhwald, MD, PhD
Head of Human Immunologi
Statens Serum Institut
Copenhagen, Denmark
1
C-TBTHE C-Tb CONCEPT
2
ESAT-6
CFP-10
ESAT-6
CFP-10
PPD
C-Tb clinical development
TESAT trials(rdESAT-6)
T-01
T-07
T-05
T-02 T-03
T-04
T-06
Phase II Phase IIIPhase I Phase I
Toxicology incl. repeated toxicity
2007 20172008 2009 2010 2011 2012 2013 2014 2015 2016
Proprietary and Confidential
Embryo-fetal
toxicity
3
SEVEN CLINICAL TRIALS
3,109 participants
723 children
867 HIV-infected
Phase III results
Reporting/publications
4
C-TB CUT-OFF
Optimal cut-off: ≥ 5mm
ROC curve analysis
BC
G c
on
tro
ls
TB
pat i
en
ts
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
P P D
Ind
ura
tio
n
(mm
)
5
BC
G c
on
tro
ls
TB
pat i
en
ts
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
C -T b
Ind
ura
tio
n
(mm
)
5
Aggerbeck et al, PlosOne 2013; Hoff et al, ERJ 2016
BCG controls N=153 (all HIV-)
TB patients N=241 (146 HIV- and 95 HIV+)
CONTACT TRACING – TESEC06
5
13 sites in Catalonia, Galicia and Basque Country (N=979)
• Unexposed controls (n=263)• Occasional contacts (circle 2-3, n=299)• Close contacts (circle 1, n=318)• TB patients (n=101)
Ruhwald, Lancet RM 2017
C-Tb IS SPECIFIC IN BCG VACCINATED
BCG vaccinated (N=322)
BCG unvaccinated (N=505)
Unexposed (n=263)C-Tb PPD
Induration (mm)
Occasional contacts (n=299)
Close contacts (n=316)
01-
45-
9
10-1
4
15-1
9
20-2
4
25-2
9
30-3
4
35-3
9
40-4
4
45-4
9
0
10
20
30
40
60
100
01-
45-
9
10-1
4
15-1
9
20-2
4
25-2
9
30-3
4
35-3
9
40-4
4
45-4
9
0
10
20
30
40
60
100
01-
45-
9
10-1
4
15-1
9
20-2
4
25-2
9
30-3
4
35-3
9
40-4
4
45-4
9
0
10
20
30
40
60
100
01-
45-
9
10-1
4
15-1
9
20-2
4
25-2
9
30-3
4
35-3
9
40-4
4
45-4
9
0
10
20
30
40
60
100
01-
45-
9
10-1
4
15-1
9
20-2
4
25-2
9
30-3
4
35-3
9
40-4
4
45-4
9
0
10
20
30
40
60
100
01-
45-
9
10-1
4
15-1
9
20-2
4
25-2
9
30-3
4
35-3
9
40-4
4
45-4
9
0
10
20
30
40
60
100
% o
f to
tal
Unex
posed
Occ
asio
nal
Clo
se
0
10
20
30
40
50
60
70
80
90
100
Te
st
po
sit
ive
(%
)
0
10
20
30
40
50
60
70
80
90
100
Te
st
po
sit
ive
(%
)
Ruhwald, Lancet RM 2017
C-Tb COMPARED TO QuantiFERON®
7
Un
exp
osed
Occasio
nal
Clo
se
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
Te
st
po
sit
ive
(%
)
C-Tb QFT
All participants (N=834)
QFT+ - S
C-T
b + 162 22 184
- 27 623 650
S 189 645 834
P= 0.5682
Un
exp
osed
Occasio
nal
Clo
se
Ruhwald, Lancet RM 2017
POSITIVITY RATES IN CHILDREN AND PLHIV, TB SUSPECTS
Proprietary and Confidential 8
9 sites in South Africa (N=1190)
• TB suspects (n=905)317 children588 adults
296 HIV-infected
• Close contacts (n=185)185 children
• Endemic negative control children (age 5-11y) (n=100)
Aggerbaek, Dheda et al, in prep 2017
Cape Town Prof. K. Dheda, Langa Clinic
Cape Town Prof. A. Diacon and Dr. M. Lourens, TASK
Cape Town Dr. M. Siebert, Tiervlei Trial Centre
Paarl Dr. E. Hellstrom, Be Part Yoluntu Centre
Pretoria Dr. M. Malahleha, Setshaba Research Centre
Pretoria Dr. V. Seopela, Synexus Stanza Bopape Clinic
Port Elizabeth Dr. M. Gani, Primecure Medicentre
Benoni Dr. I. Mitha, Lakeview Hospital
TRIAL PARTICIPANTS & METHODS
9
TEST-POSITIVITY RATE INCREASES WITH AGE
10n=699 TB symptomatic participants (excluding HIV-infected)
C-Tb ROBUSTNESS SEEMS SUPERIOR IN HIV INFECTED
11
C-Tb
CD4 count
500+
400-
499
300-
399
200-
299
100-
199
0-99
C-T
b p
ositiv
es (
%)
0
10
20
30
40
50
60
70QFT
CD4 count
500+
400-
499
300-
399
200-
299
100-
199
0-99
QF
T p
ositiv
es (
%)
0
10
20
30
40
50
60
70
• C-Tb has comparable positivity rate in HIV uninfected TB suspects, but
significantly higher positivity rate in HIV infected
• C-Tb performance seems robust in HIV infected with CD4 >100
cells/uL
(n=534) (n=277)
*p<0.05, McNemar’s test
Aggerbaek, Dheda et al, submitted 2017
Excluding 15% QFT indeterminates
0-1
2-4
5-1
1
12-1
7
18-3
940+
0
1 0
1 5
2 0
2 5
3 0
3 5
4 0P P D
Ind
ura
tio
n
(mm
)
5
0-1
2-4
5-1
1
12-1
7
18-3
940+
0
1 0
1 5
2 0
2 5
3 0
3 5
4 0C -T b
Ind
ura
tio
n
(mm
)
5
INFLUENCE OF AGE ON INDURATION SIZE
12
Median +/- IQR
Age (years) Age (years)
Aggerbaek, Dheda et al, submitted 2017
CONCLUSION
13
• C-Tb test results correlate with exposure to M. tuberculosis
• C-Tb and QFT have similar positivity rates
• Safety profile of C-Tb is comparable to PPD, local ISRs
• C-Tb is impacted by HIV-infection with low CD4 counts (<100
cells/uL)
• C-Tb induration size is impacted by young age on a level with
PPD
• C-Tb deliver IGRA like performance in the field friendly skin test
format using a universal 5mm cut off
STATENS SERUM INSTITUT
Center for vaccine research• Peter L Andersen• Ingrid Kromann• Henrik Aggerbeck• Morten Ruhwald• Søren Tetens Hoff• Bettine Borregaard• Lina Saem Støy• Pernille Tingskov• Birgit Thierry-Carstensen & many others
Regulatory Affairs/BD• Katarina Berg• Camilla Pretzmann• Michael Stevner• Lars Nørgaard• Ole Wiiborg• Mai-Britt Kaltorf
ACKNOWLEDGEMENTS
National Investigators and PIs• Prof. Joan A. Cayla (Spain)• Prof. Keertan Dheda (South Africa)• Prof. Diacon (South Africa)• Prof. David Lewis (UK)• Prof. Åse Bengaard Andersen (DK)
Contact: [email protected]
