Tuberculosis Trials from the AIDS Clinical
Trials Group
Susan Swindells MBBS
University of Nebraska Medical Center,
USA
AIDS Clinical Trials Group:
International Sites
The TB Transformative Science
Group (TSG) Scientific Agenda
1.0
TB TREATMENT SHORTENING
To identify regimens to shorten Drug-Susceptible TB
treatment to ≤3 months in patients with and without HIV
2.0
MDR-TB TREATMENT
To identify regimens for MDR TB treatment in <6 months in
patients with and without HIV
3.0
PREVENTIVE THERAPY
To treat latent TB in 1 month and MDR-TB infection in 3-6
months
The TB TSG Scientific Agenda
4.0
TB/HIV CO-TREATMENT
To optimize the treatment of TB/HIV co-infection
To evaluate and minimize drug-drug interactions
5.0
TRANSFORMATIVE SCIENCES
• Pharmacology
• Biomarkers
• Laboratory monitoring and diagnostics
• Host-directed therapies
TB Treatment Shortening Study Portfolio
Study
Description
Status
A5289
Phase 2 trial of Sutezolid for improving
sputum conversion at 8 weeks
In development
pending drug
availability
A5344/
STAND
Phase 3 trial of Pa824/Moxi/PZA to
shorten TB therapy to 4 months (with TB
Alliance)
On hold
A5349/
TBTC 31
Phase 3 trial of rifapentine + moxi to
shorten TB therapy to 4 months (with
TBTC)
Pending site
regulatory
approvals
PR698
Phase 2c trial of clofazimine in drug
susceptible TB
In development
Decline of lung CFU counts in mice treated with the first-line
regimen with or without clofazimine
Treatment
group
2RHZE/4RH
% of mice culture-positive after follow-up of 6 months
after treatment for
2 mo.
3 mo.
4 mo.
5 mo.
6 mo.
ND
ND
5/15
(33%)
3/15
(20%)
1/10*(10%)
0/15
0/15
ND
ND
2RHZCLO/RH 8/15
CLO
(53%)
Grosset et al., submitted
3-Pronged Strategy for MDR TB

Safety and activity studies in MDR patients
– A5343: BDQ and DLM cardiac safety trial in ZA
– Oxazolidinone trial to monitor mitochondrial toxicity (plts,
Hgb, neuropathy) and antimicrobial activity

Phase 2 study to eliminate injectables
– Nitroimidazole + oxazolidinone vs. ami/kana/capreo

Phase 3 study to achieve 6-month regimen
– BDQ/Nitroimidazole/Oxazolidinone + CLO and PZA (6 mos)
vs. Bangladesh regimen (9 mos)
MDR TB Studies in Progress or Development
Study
Description
Status
A5312
Early bactericidal activity of high-dose INH
in patients with MDR TB and inha
mutations
Enrolling (131/198)
A5356
A Phase 2a, Prospective, Randomized,
Multicenter Trial to Evaluate the Safety,
Tolerability, and Initial Efficacy of Linezolid
Dosing Strategies Combined with
Delamanid and Optimized Background
Therapy for the Treatment of Multidrug
Resistant Tuberculosis
In development
Novel drugs for MDR TB treatment
Class
Agent(s)
Comments
Availability to ACTG
Fluoroquinolones
Moxifloxacin
Levofloxacin
QT issues
Available
Nitroimidazoles
Delamanid
Pa824
QT issues
Available now
2 month use only
ATP Synthase
Inhibitor
Bedaquiline
Drug-drug interactions, ART agents restricted
QT, deaths
by Janssen
Oxazolidinones
Linezolid
Sutezolid
AZD
Tedizolid
Licensed, toxicity
Toxicity/efficacy
Toxicity/efficacy
Licensed
Available now
Sequella ?
AZ ?
Cubist ?
Phenazine dyes
Clofazimine
Skin toxicity, QT
Access on global
market limited
TB preventive therapy Studies
Study
Description
Status
A5279
Daily Rifapentine/INH for 1 month vs INH
for 9 months to prevent TB in HIV+
patients
Fully enrolled in Nov
2014 (3000/3000).
Follow up for 156
wks
A5300/
Phoenix
Phase 3 trial of delamanid vs INH for
high-risk contacts of MDR TB patients
In development
TB/HIV Coinfection Strategy Studies
Study
Description
Status
A5221/
STRIDE
Immediate Versus Deferred Initiation of
Antiretroviral Therapy for AIDS DiseaseFree Survival
Early ART
decreased
AIDS/death with
CD4 <50, not
above
(Havlir et al, NEJM
2011)
A5274/
REMEMBER
Reducing Early Mortality and Early
Morbidity by Empiric Tuberculosis
Treatment Regimens
Empiric tx does
not decrease early
mortality
(Presented at IAS
2015)
A5290
Phase 2 Rifampin-based vs Rifabutinbased TB treatment with HIV protease
inhibitors
Enrolling (69/471)
PK Study Portfolio

A5306: LPV/r had minimal effect on PaA824 but
EFV and RIF decreased exposure
– (Dooley et al, AAC 2014)

A5311: High dose RPT poorly tolerated by
healthy volunteers
– (Dooley et al, AAC 2015)

A5279: EFV safe with RPT
– (Podany et al, CID 2015)


A5338: DMPA with RIF and EFV (enrolling)
A5343: BDQ + DLM (pending)
Other Ongoing Initiatives

Innovation in trial design and execution
– Seamless and adaptive designs
– Nesting PK/PD studies into Phase 2 or 3



TB Laboratory Strengthening
Host directed therapies
Biomarker Research
– A5302 (with Alliance, TBTC): B-SMART



Policy & Advocacy
Mentoring
Collaboration
– IMPAACT, TBTC, TB Alliance, Pharma, Gates
TB TSG Membership and Leadership
Richard Chaisson, Johns Hopkins University, Chair
Gavin Churchyard, Aurum Institute, Co-Vice Chair
Diane Havlir, UCSF, Co-Vice Chair
Janet Andersen, SDAC
Susan Swindells, Univ Nebraska Medical Center
Sachiko Miyahara, SDAC
Parita Rathod, Network Coordinating Center
David Alland, Rutgers Medical School
Jorge Alave, Lima, Peru
Constance Benson, UCSD
Henry Blumberg, Emory University
Francesca Conradie, University of the Witwatersrand
Andreas Diacon, Stellenbosch University
Kelly Dooley, Johns Hopkins University
Jennifer Furin, Case Western Reserve University
Devasena Gnanashanmugam, DAIDS
Amita Gupta, Johns Hopkins University
Richard Hafner, DAIDS
Mark Harrington, Treatment Action Group
Bold = Steering Committee
Elizabeth Hawkins, Network Coordinating Center
Robert Horsburgh, Boston University
Lynne Jones, Data Management Center
Serena Koenig, Harvard University
Annie Luetkemeyer, UCSF
Gary Maartens, University of Cape Town
Neil Martinson, University of the Witwatersrand
Martha Mensah-King, UZ-Parirenyatwa CRS
John Metcalfe, UCSF
Bernard Mpairwe, Kampala, Uganda
Eric Nuermberger, Johns Hopkins University
Susan Rosenkranz, SDAC
Ian Sanne, Wits HIV CRS
Kim Scarsi, University of Nebraska Medical Center
Sarita Shah, Center for Disease Control
Tim Sterling, Vanderbilt University
Robert Wallis, Aurum Institute
Members In Training:
Munira Khan, Durban
Mey Leon, Lima, Peru
Christopher Vinnard, U Penn