Eight Week Randomized Trial
of Treatment with Pa-824,
Moxifloxacin, and Pyrazinamide
in Drug Sensitive and Multi-Drug
Resistant Tuberculosis
Daniel Everitt, MD
For the NC-002 Collaborators
July 21, 2014
20th International AIDS Conference
2014 International AIDS Conference
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NC-002 Pa-M-Z Trial: First Novel Combination Study
In patients with TB sensitive to Pa, M, and Z
Participants with newly diagnosed smear positive DS and MDR Pulmonary TB
Pa(200mg)-M-Z
N=60
DS
Pa(100mg)-M-Z
N=60
2 months of treatment
H-R-Z-E
N=60
Randomize
DR
Pa(200mg)-M-Z
N= up to 50
Serial 16 hour pooled sputum samples for CFU Count
Pa = PA-824
M = moxifloxacin 400 mg
Z = pyrazinamide at 1500mg
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Investigational Sites and Laboratories
South Africa
•
•
•
•
•
•
TASK Applied Science, Cape Town
Lab
University of Cape Town Lung Institute
Helen Joseph Hospital
Tembisa Hospital, Tembisa
Klerksdorp Tshepong Hospital
KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH),
Durban
Lab
Tanzania
• Ifakara Health Institute, Bagamoyo
• NIMR- Mbeya Medical Research Programme
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Lab
Lab
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Enrolment Demographic Characteristics
Treatment group
Age (years)
Males (%)
Weight (kg)
HIV-infected (%)
Ethnicity
Black (%)
Mixed ethnicity (%)
2014 International AIDS Conference
Total (N=207)
31
65
56
20
71
29
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Estimates of Mean Serial Log(CFU) Count Over Time
Joint Bayesian NLME Regression
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Daily Log CFU Reduction – 1o Endpoint
Study Arm
PA200-M-Z*
(N=56)
Log CFU Reduction per
Day Over 56 Days
0.155 CI [0.133; 0.178]
PA100-M-Z
(N=54)
0.133 CI [0.109; 0.155]
PA200-M-Z-MDR
(N=9)
0.117 CI [0.070; 0.174]
H-R-Z-E
(N=54)
0.112 CI [0.093; 0.131]
*p < 0.05 vs H-R-Z-E
No differences from above when adjusted for site, HIV
status or baseline CFU as baseline covariates
2014 International AIDS Conference
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Estimates of Mean Serial log(TTP) Over Time
Joint Bayesian NLME Regression
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Time to Culture Conversion – 2o Endpoint
Culture Conversion is the Time when Culture is First Negative
Study Arm
PA200-M-Z
Median Time to Culture Conversion
(Days)
Solid
Liquid
28*
49*
PA100-M-Z
28
42
PA200-M-Z
MDR
H-R-Z-E
35
56
35
56
*Statistically significant differences compared to
HRZE for both solid and liquid culture
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Eight Week Culture Conversion – 2o Endpoint
Study Arm
PA200-M-Z
Conversion to Negative Day 56 (%)
Solid
Liquid
94.3
71.4*
PA100-M-Z
82.9
65.7*
PA200-M-ZMDR
Rifafour
62.5
50.0
87.5
37.8
*Statistically significant difference from HRZE for liquid culture only
2014 International AIDS Conference
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Log CFU Daily Decreases and Pearson Correlation
Coefficients
Data from Participants Enrolled in the EBA Substudy
Study / Arm
H-R-Z-E
Log CFU Daily
(Days 7-14)
Log CFU Daily
(Days 7-56)
Correlation
Coefficient
0.13
0.12
0.98
0.16
0.13
0.90
0.14
0.14
0.96
(N=15)
Pa100-M-Z
(N=16)
Pa200-M-Z
(N= 13)
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Summary of Safety Findings
Grade 1 to 4 Treatment-Emergent Adverse Events
Severity
Grade I
Grade II
Grade III
Grade IV
Statistic*
%
%
%
%
PA100M-Z
PA200M-Z
(N=60)
(N=62)
PA200M-Z
MDR
77
50
32
15
(N=26)
69
50
23
8
72
42
30
5
H-R-Z-E
(N=59)
78
46
25
10
Total
(N=207)
75
46
29
10
* % = Percentage of patients with at least one AE in each category
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NC-002 Summary of Key Results and Next Steps
• Pa-M-Z Regimen was statistically significantly better than the H-R-Z-E control for
the primary and 3/5 key secondary endpoints
– Greater reduction in colony counts over 56 days
– More rapid time to culture conversion
– Higher conversion to negative at 8 weeks – Nearly twice the number converted in liquid
culture
• No significant difference in response for HIV infected patients
• Similar effects for patients with MDR-TB, albeit with small numbers
• Safety comparable to control
• Next Step: The STAND Phase 3 Trial
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The STAND Trial - Phase 3 Trial of Pa-M-Z
“Shortening Treatment by Advancing Novel Drugs”
Participants with newly diagnosed smear positive DS- and MDR-TB
Pa(100mg)-M-Z
N=300
4 months of
treatment
Pa(200mg)-M-Z
N=300
DS
12 & 24 mos
f/u after
randomization
Pa(200mg)-M-Z
N= 300
Randomize
DR
H-R-Z-E
N=300
6 months of treatment
Pa(200mg)-M-Z
N= up to 300
Z = pyrazinamide at 1500mg
Pa = PA-824
2014 International AIDS Conference
M = moxifloxacin 400 mg
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Sincere Acknowledgments:
To the Patients with Tuberculosis who Participated, volunteer Community
Advisory Boards, and Lead Investigators and Colleagues:
• Robert Schall
• Rodney Dawson
– University of the Free State, and
Quintiles Biostatistics, Bloemfontein,
SA
– University of Cape Town Lung
Institute, Cape Town, SA
• Andreas Diacon
– Stellenbosch University, Tygerberg,
and TASK Applied Science, Bellville SA
• Christo Van Niekerk
– TB Alliance, Pretoria, SA
• Almari Conradie
• Divan Burger
– University of the Free State, and
Quintiles Biostatistics, Bloemfontein,
SA
– TB Alliance, Pretoria, SA
• Carl Mendel
– TB Alliance, New York, USA
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TB Alliance Supporters
Thanks to all those who support our mission for better, fast TB drugs
Australian AID
Bill & Melinda
Gates Foundation
National Institute of Allergy
and Infectious Diseases
United States Agency for
International Development
UNITAID
AIDS Clinical
Trial Group
European
Commission
United States
Food and Drug
Administration
Irish Aid
Global Health Innovative
Technology Fund
UK aid
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