TB trials: new approaches and
surrogate markers
Patrick Phillips
patrick.phillips@ucl.ac.uk
MRC Clinical Trials Unit at UCL
23rd March 2016
Outline
• Why do we need better tools for regimen
development?
• The STEP Phase IIC trial design
• STEP in practice: The PanACEA consortium
1. Phillips PPJ, Mendel CM, Burger DA, et al: Limited role of culture conversion
for decision-making in individual patient care and for advancing novel
regimens to confirmatory clinical trials. BMC Medicine 2016, 14(1):19.
2. Phillips PPJ, Dooley KE, Gillespie SH, et al: A new trial design to accelerate
tuberculosis drug development: The Phase IIC Selection Trial with
Extended Post-treatment follow-up (STEP). BMC Medicine 2016
Why do we need better tools for regimen
development?
• 4594 patients
randomised
• $100m?
• 4 novel 4-month
regimens
• 0 regimens noninferior
Nimmo, Lipman M, Phillips PPJ, McHugh T, Nunn A, Abubakar I.
Shortening treatment of tuberculosis: lessons from fluoroquinolone
trials. The Lancet Infectious Diseases 2015; 15(2): 141-3. C
Where is the bottleneck?
Phase I:
Safety
Phase IIA:
Dose
selection
Phase IIB:
Exploratory
efficacy
Middle Development
• Small studies, often
healthy volunteers
• Primary objective is
to rule out gross
toxicities
• Identify optimal
dose or doses
• Select most
promising regimens
for Phase III
evaluation
Phase III:
Confirmatory
(non-inferiority)
• Large, expensive
• Yield robust evidence
to convince regulators
and change policy and
practice
Where is the bottleneck?
‘Culture
positive’
Time to
culture
conversion
‘Culture
negative’
Time to culture conversion is a poor
predictor of 18-month outcome
Phillips PPJ, Mendel CM, Burger DA, et al: Limited role of culture conversion for
decision-making in individual patient care and for advancing novel regimens
to confirmatory clinical trials. BMC Medicine 2016, 14(1):19.
Time to culture conversion is a poor
predictor of 18-month outcome
•
•
•
•
Strong association
Treatment effect independent of
time to culture conversion
Non-zero asymptotes
Time to culture conversion
doesn’t fully capture treatment
differences
Phillips PPJ, Mendel CM, Burger DA, et al: Limited role of culture conversion for
decision-making in individual patient care and for advancing novel regimens
to confirmatory clinical trials. BMC Medicine 2016, 14(1):19.
Optimising middle development:
Reducing the risk of expensive phase III failure
Phase I:
Safety
Phase IIA:
Dose
selection
Phase IIB:
Exploratory
efficacy
Middle Development
Phase III:
Confirmatory
(non-inferiority)
Optimising middle development:
Reducing the risk of expensive phase III failure
Phase I:
Safety
Phase IIA:
Dose
selection
Phase IIB:
STEP
Exploratory
Phase
IIC:
efficacy
Bridging
the gap
Middle Development
Phase III:
Confirmatory
(non-inferiority)
Traditional Phase IIB trial for novel TB
regimens (PanACEA MAMS-TB)
•
•
N=80-100 per arm
Primary endpoint
• Culture conversion
to 12 weeks
The Phase IIC Selection Trial with Extended Posttreatment follow-up (STEP)
End treatment on experimental
regimens after 4 (or 3) months
The Phase IIC Selection Trial with Extended Posttreatment follow-up (STEP)
End treatment on experimental
regimens after 4 (or 3) months
12 months postrandomisation follow-up
for relapse
•
•
•
N=80-100 per arm
Primary endpoint
• Culture conversion to 3-4
months
Secondary endpoint
• Long-term cure with
absence of relapse
STEP Phase IIC design
• Novel treatments given for their
intended duration in phase II
• Patients followed to 12 months
post-randomisation
Primary
endpoint:
Time to culture
conversion
Adequate power to
detect
differences between
regimens
Intermediate endpoint
that only partially reflects
long-term clinical
outcome
Secondary
endpoint:
Long-term
relapse-free cure
Trial underpowered to
detect differences in
relapse rates
Patient-relevant clinical
outcome
Decision-making for progression to phase III
• Critical question at phase II:
• Will this regimen succeed in phase III?
• What is the probability that this shorter
regimen will have efficacy at least as good as
the 6-month control in a future phase III trial?
• Naturally fits into a Bayesian framework
• Predictive probability that the unfavourable
proportion ≤ p1 in a hypothetical future phase III
trial
Bayesian predictive probabilities
Sceptical prior (solid lines), Flat prior (dashed lines)
Phillips PPJ, Dooley KE, Gillespie SH, et al: A new trial design to accelerate
tuberculosis drug development: The Phase IIC Selection Trial with Extended
Post-treatment follow-up (STEP). BMC Medicine 2016,
‘Traffic light system’ for Bayesian
predictive probabilities, for some p1
What would a STEP Phase IIC trial added
prior to the RIFAQUIN phase III trial?
• 10,000 random draws from RIFAQUIN trial
data with sample sizes 60,80, 100.
STEP in practice:
The PanACEA Consortium
Conclusions
• New tools are needed to more efficiently deliver new
regimens.
• Culture conversion during treatment has only a limited
role in decision-making for advancing regimens into
phase III trials.
• Collection of definitive clinical outcome data in a
relatively small number of participants over only 12
months provides valuable information about the
likelihood of success in a future phase III trial.
• The STEP Phase IIC trial design is an important tool that
allows for more informed decision-making and
accelerates regimen development.
Acknowledgements
•
Limited role of culture conversion for decision-making in individual
patient care and for advancing novel regimens to confirmatory clinical
trials. BMC Medicine 2016, 14(1):19.
• Carl Mendel, Divan Burger, Angela Crook, Andrew Nunn, Rod
Dawson, Andreas Diacon, Stephen Gillespie
•
A new trial design to accelerate tuberculosis drug development: The
Phase IIC Selection Trial with Extended Post-treatment follow-up
(STEP). BMC Medicine 2016
• Kelly Dooley, Stephen Gillespie, Norbert Heinrich, Jason Stout,
Payam Nahid, Andreas Diacon, Rob Aarnoutse, Gibson Kibiki,
Martin Boeree, Michael Hoelscher