Transcript stream - UZ-UCSF

Evaluation of a Standardized Treatment Regimen
of Anti-Tuberculosis Drugs for Patients with
MDR-TB (STREAM)
Nehemiah Nhando
UZ-UCSF ANNUAL RESEARCH DAY
08 April 2016
Harare
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DR-TB case detection in Zimbabwe
2010 – 2015
Estimated DR-TB cases
450
950
400
412 421
393 381 405
351
350
DR-TB cases detected
412 (43%)
DR - TB cases initiated
on treatment
300
200
149
150
118
100
50
381 (92%)
DR-TB
cases
detected
250
4028
105
64
Cases
initiated
on
treatment
0
201020112012201320142015
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DR-TB case detection in Zimbabwe
2015
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Why New drugs/ regimens for MDR TB?
• Current WHO recommended
standard of treatment for MDR
TB lasts for two years or more Shorten therapy
• Isoniazid and pyrazinamide
remain are toxic - Decrease
toxicity
• Multidrug-resistant TB, or
intolerance to first-line drugs Improve efficacy
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Previous Studies
• Successful results from MDR-TB patients treated with a 9month regimen in Bangladesh suggest there are better
options even without the introduction of new drugs
• The most effective regimen required a minimum of 9 months
of treatment with gatifloxacin, clofazimine, ethambutol, and
pyrazinamide throughout the treatment period supplemented
by prothionamide, kanamycin, and high-dose isoniazid during
an intensive phase of a minimum of 4 months, giving a
relapse-free cure of 87.9% (95% confidence interval, 82.791.6) among 206 patients. Major adverse drug reactions were
infrequent and manageable
– Van Deun A, Maug AKJ, Salim MAH, Das PK, Sarker MR, Daru P, et al. Short, Highly
Effective, and Inexpensive Standardized Treatment of Multidrug-resistant
Tuberculosis. Am J Respir Crit Care Med. 2010; 182(5): 684-92.
The 9-month Bangladesh Regimen
Weeks
Drug
Kanamycin*
Isoniazid (H)
Prothionamide
Clofazimine
Moxifloxacin
Ethambutol
Pyrazinamide
Drug doses by weight group
< 33 kg
1 - 16
1 - 16
1 - 16
1 - 40
1 - 40
1 - 40
1 - 40
33 - 50 kg
> 50 kg
15 mg per kilogramme body weight
300 mg
400 mg
600 mg
250 mg
500 mg
750 mg
50 mg
100 mg
100 mg
400 mg
600 mg
800 mg
800 mg
800 mg
1200 mg
1000 mg
1500 mg
2000 mg
• Kanamycin 3 times/week after week 12
The intensive phase may be extended by 4 or 8 weeks if smear conversion has
not occurred by 16 or 20 weeks
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Results of the 9-month regimen in Bangladesh
Published cohort (206 pts)
Cure
82.5%
Completion
5.3%
Default
5.8%
Death
5.3%
Failure
0.5%
Relapse
0.5%
Overall success rate:
87.9% (95% CI 82.7, 92.6)
Am J Respir Crit Care Med Vol 182. 684–692, 2010
Introdion
Objectif
Méthodes
Conclusion
STREAM
• International, multi-centre, parallel-group, open-label,
randomised, controlled trial ……
…….. To evaluate a Standardized Treatment Regimen of AntiTuberculosis Drugs for Patients with MDR-TB (STREAM)…….
………. Including patients with rifampicin resistant and
isoniazid-sensitive TB.
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Why a randomised controlled trial?
• To eliminate risk that patient selection biased results
obtained from cohort studies
• To assess the 9-month regimen in a variety of
settings including high levels of HIV-coinfection
• To develop a better evidence base for shorter MDRTB treatment
• If successful, to provide a new standard of care for
comparison with potentially better regimens
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STREAM Stage 1
• Primary Objectives
1. To assess whether the proportion of patients with a
favourable efficacy outcome at Week 132 on Regimen B is not
inferior to that on Regimen A (WHO approved MDR-TB
regimen)
2. To compare the proportion of patients who experience
grade 3 or greater adverse events, during treatment or followup, on Regimen B as compared to Regimen A.
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STREAM Stage 1 study design
• STREAM is a randomised
controlled trial of non-inferiority
design currently being conducted
in Ethiopia, South Africa, Vietnam
and Mongolia
• The control regimen (A) is the
locally used WHO recommended
regimen in the participating
countries
• The study regimen (B) is closely
similar to the regimen used in
Bangladesh with the exception
that high dose moxifloxacin
replaces high dose gatifloxacin
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Stage 1 trial entry, randomisation, treatment
and follow-up
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Study Population
• Adults (18 years or older) who has given consent for
treatment and follow-up
• Smear-positive pulmonary tuberculosis, or if HIV positive may
be smear negative
• Evidence of initial resistance to rifampicin on line-probe assay,
GeneXpert or other DST
• No evidence of initial resistance to fluoroquinolone or 2nd-line
injectables on line-probe assay
• No pre-existent QT prolongation >500msec
• If pre-menopausal woman, not pregnant or breast feeding
and agrees to use effective barrier contraception/IUCD during
treatment
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.
OUTCOME MEASURES FOR STAGE 1
Primary Outcome Measures
The primary efficacy outcome measure comparison is the proportion of patients
with a favourable outcome at Week 132
The primary safety outcome measure is the proportion of patients experiencing a grade 3 or
greater adverse event, as defined by the DAIDS criteria, during treatment and follow-up.
Favourable Outcome defined as negative last two culture results taken on separate visits; the
latest of which being no more than six weeks earlier than Week 132
Secondary outcome measures
Time to sputum smear conversion
Time to sputum culture conversion
Time to unfavourable efficacy outcome
Time to cessation of clinical symptoms based on PI assessment
All-cause mortality during treatment or follow-up
Change of regimen for adverse drug reactions
Number of serious adverse reactions occurring on treatment and during the follow-up
period
Adherence to treatment.
In selected sites, costs and acceptability of Regimens A and B to stakeholders will be analysed
in terms of:
Costs to the health system
Household costs
Patient treatment and support experiences
Health worker experiences
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Stage 1: current status
•
•
•
•
•
•
•
Enrolment to Stage 1 commenced: July 2012
Sites: Ethiopia (2), South Africa (3), Vietnam and Mongolia
424 of initial target of 400 patients enrolled
Accrual closed: June 30th 2015
Primary endpoint at 30 months
Last Patient Last Visit: Q4 2017
Results from Stage 1 expected: Q1/2 2018
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Trial recruitment Stages
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STREAM Stage 2 …
• After the provisional licensing of bedaquiline consideration
was made to determine:
– Possibility of including additional regimens to the
STREAM trial in its present form?
– if so, what would be the appropriate regimen(s) to
evaluate?
• After extensive discussions between the study partners and
other experts it was agreed that the primary interest to
patients and programmes would be:
– a fully oral regimen (no kanamycin) and/or
– a shorter and simpler regimen
– To assess the shorter regimens in a variety of settings
including sites with high levels of HIV-coinfection.
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STREAM Stage 2 design
• Because it is possible that Regimen B might not be found to be noninferior to Regimen A it was decided to continue to enrol patients to
Regimen A
• Secondary objectives include the comparisons of Regimen C and
Regimen D to Regimen A; these will be particularly important if
Regimen B is found to be inferior to Regimen A
• A total of at least 1155 participants from sites in a number of
countries will be randomised to either Regimen A, Regimen B,
Regimen C, or Regimen D in a ratio 1:2:2:2 (i.e. 165 allocated
to Regimen A, 330 allocated to Regimen B, 330 allocated to Regimen
C, and 330 allocated to Regimen D).
• Sample size for Stage 2 = 1155
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STREAM STAGE 2 OBJECTIVES
Primary objectives:
• To assess whether the proportion of patients with a
favourable efficacy outcome on Regimen C, the fully oral
regimen, is as effective as Regimen B at 76 weeks (18 months)
• To assess whether the proportion of patients with a
favourable efficacy outcome on Regimen D, the 6-month
regimen, is as effective as Regimen B at 76 weeks (18 months)
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Stage 2 trial entry, randomisation, treatment
and follow-up
All Stage 2 Sites
Regimen A - 165
Regimen B – 330
Regimen C – 330
Regimen D – 330
Total participants 1155
Zimbabwe Sites
100 participants
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Regimens for Stage 2
OUTCOME MEASURES STAGE 2
Primary Outcome Measures
The primary efficacy outcome measure of the Stage 2 comparisons is the proportion of patients
with a favourable outcome at Week 76.
Favourable outcome defined as negative last two culture results taken on separate visits; the
latest of which being no more than six weeks earlier than Week 76.
Secondary Outcome Measures
 Time to sputum culture conversion
 Time to sputum smear conversion
 Efficacy status at end of follow-up
 Time to unfavourable efficacy outcome
 Time to cessation of clinical symptoms based on PI assessment
All-cause mortality during treatment or follow-up
 Proportion of patients experiencing a grade 3 or greater adverse event, as defined by
the DAIDS criteria, during treatment and follow-up
 Change of regimen for adverse drug reactions
 Number of adverse events occurring on treatment and during the follow-up period
Pharmacokinetic outcomes
 Adherence to treatment.
In selected sites, costs and acceptability of the four regimens to stakeholders will be analysed in
terms of:
 Costs to the health system
 Household costs
 Patient treatment and support experiences
 Health worker experiences.
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STREAM STAGE 2 TRIAL TIMELINES in
ZIMBABWE
• Partnership between The MoHCC, City of Harare, the Union
MRC Clinical Trials Unit (UCL)and UZ-UCSF Research Program
and Institute of Tropical Medicine Antwerp
• 2 sites have been assessed by the Union in late January 2016
- BRIDH Harare
- Khami Road Clinic in Bulawayo
• Applications for ethical and clinical trial regulatory authorities
will start mid-March
• Approvals by July 2016
• Training and implementation by August 2016 (start with
Harare then activate Bulawayo site after 6 months)
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Acknowledgements
Funder: USAID
Sponsor:
The Union
Design, Management, Analysis
Impact Assessment:
Liverpool School
of Tropical
Medicine
Microbiology:
Institute of
Tropical Medicine,
Antwerp
UZ-UCSF
Collaborative
Research Programme
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