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Eight Week Randomized Trial of Treatment with Pa-824, Moxifloxacin, and Pyrazinamide in Drug Sensitive and Multi-Drug Resistant Tuberculosis
July 21, 201420th International AIDS Conference
Daniel Everitt, MDFor the NC-002 Collaborators
12014 International AIDS Conference
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Participants with newly diagnosed smear positive DS and MDR Pulmonary TB
NC-002 Pa-M-Z Trial: First Novel Combination StudyIn patients with TB sensitive to Pa, M, and Z
Pa(200mg)-M-ZN=60
Pa(100mg)-M-ZN=60
H-R-Z-EN=60
Pa(200mg)-M-Z
N= up to 50
Pa = PA-824 M = moxifloxacin 400 mg Z = pyrazinamide at 1500mg
2 months of treatment
Randomize
Serial 16 hour pooled sputum samples for CFU Count
DS
DR
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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 Lab• NIMR- Mbeya Medical Research Programme Lab
Investigational Sites and Laboratories
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Treatment group
Total (N=207)
Age (years) 31
Males (%) 65
Weight (kg) 56
HIV-infected (%) 20
Ethnicity
Black (%) 71
Mixed ethnicity (%) 29
Enrolment Demographic Characteristics
2014 International AIDS Conference
Estimates of Mean Serial Log(CFU) Count Over Time Joint Bayesian NLME Regression
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Study Arm Log CFU Reduction per Day Over 56 Days
PA200-M-Z* (N=56) 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]
Daily Log CFU Reduction – 1o Endpoint
*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
Estimates of Mean Serial log(TTP) Over TimeJoint Bayesian NLME Regression
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Study Arm Median Time to Culture Conversion (Days)
Solid LiquidPA200-M-Z 28* 49*
PA100-M-Z 28 42
PA200-M-Z MDR
35 56
H-R-Z-E 35 56
Time to Culture Conversion – 2o Endpoint
*Statistically significant differences compared to HRZE for both solid and liquid culture
2014 International AIDS Conference
Culture Conversion is the Time when Culture is First Negative
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Study Arm Conversion to Negative Day 56 (%) Solid Liquid
PA200-M-Z 94.3 71.4*
PA100-M-Z 82.9 65.7*
PA200-M-Z-MDR
62.5 50.0
Rifafour 87.5 37.8
Eight Week Culture Conversion – 2o Endpoint
*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
Study / Arm Log CFU Daily (Days 7-14)
Log CFU Daily (Days 7-56)
Correlation Coefficient
H-R-Z-E (N=15) Pa100-M-Z (N=16) Pa200-M-Z (N= 13)
0.13
0.16
0.14
0.12
0.13
0.14
0.98
0.90
0.96
Data from Participants Enrolled in the EBA Substudy
Summary of Safety Findings
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Grade 1 to 4 Treatment-Emergent Adverse Events
Severity Statistic* PA100-M-Z
(N=60)
PA200-M-Z
(N=62)
H-R-Z-E(N=59)
PA200-M-Z MDR
(N=26)
Total(N=207)
Grade I % 72 77 78 69 75Grade II % 42 50 46 50 46Grade III % 30 32 25 23 29Grade IV % 5 15 10 8 10
* % = Percentage of patients with at least one AE in each category
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• 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
NC-002 Summary of Key Results and Next Steps
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Participants with newly diagnosed smear positive DS- and MDR-TB
The STAND Trial - Phase 3 Trial of Pa-M-Z“Shortening Treatment by Advancing Novel Drugs”
Pa(100mg)-M-ZN=300
Pa(200mg)-M-ZN=300
H-R-Z-EN=300
Pa(200mg)-M-Z
N= up to 300
Z = pyrazinamide at 1500mg Pa = PA-824 M = moxifloxacin 400 mg
4 months of treatment
Randomize
DS
DR
Pa(200mg)-M-Z
N= 300
6 months of treatment
12 & 24 mosf/u afterrandomization
2014 International AIDS Conference
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• Robert Schall– University of the Free State, and
Quintiles Biostatistics, Bloemfontein, SA
• Christo Van Niekerk– TB Alliance, Pretoria, SA
• Almari Conradie– TB Alliance, Pretoria, SA
• Carl Mendel– TB Alliance, New York, USA
• Rodney Dawson– University of Cape Town Lung
Institute, Cape Town, SA
• Andreas Diacon– Stellenbosch University, Tygerberg,
and TASK Applied Science, Bellville SA
• Divan Burger– University of the Free State, and
Quintiles Biostatistics, Bloemfontein, SA
To the Patients with Tuberculosis who Participated, volunteer Community Advisory Boards, and Lead Investigators and Colleagues:
Sincere Acknowledgments:
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2014 International AIDS Conference
TB Alliance Supporters
Bill & Melinda Gates Foundation
EuropeanCommission
United States Food and Drug Administration
Irish Aid
National Institute of Allergy and Infectious Diseases
UK aid
United States Agency for International Development
AIDS Clinical Trial Group
Global Health Innovative Technology Fund
UNITAIDAustralian AID
Thanks to all those who support our mission for better, fast TB drugs