S tandardized T reatment Re gimen of A ntiTuberculosis Drugs for Patients with M DRTB ST REAM Nehemiah Nhando UZUCSF ANNUAL RESEARCH DAY 08 April 2016 Harare 2 3 DRTB case detection in ID: 543348
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Slide1
Evaluation of a
S
tandardized
T
reatment
Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB (STREAM)Nehemiah NhandoUZ-UCSF ANNUAL RESEARCH DAY 08 April 2016HarareSlide2
2Slide3
3Slide4
DR-TB case detection in
Zimbabwe 2010 – 2015
4Slide5
DR-TB case detection in Zimbabwe
2015
5Slide6
Why New drugs/ regimens for MDR TB?
6
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 efficacySlide7
Previous Studies
Successful results from MDR-TB patients
treated with a 9-month regimen in Bangladesh suggest there are better options even without the introduction of new drugsThe 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, 82.7-91.6) among 206 patients. Major adverse drug reactions were infrequent and manageableVan 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.Slide8
The
9-month Bangladesh Regimen
Weeks Drug doses by weight group
Drug < 33 kg 33 - 50 kg > 50 kg
Kanamycin* 1 - 16 15 mg per kilogramme body weight
Isoniazid (H) 1 - 16 300 mg 400 mg 600 mgProthionamide 1 - 16 250 mg 500 mg 750 mg Clofazimine 1 - 40 50 mg 100 mg 100 mg Moxifloxacin 1 - 40 400 mg 600 mg 800 mg Ethambutol 1 - 40 800 mg 800 mg 1200 mg Pyrazinamide 1 - 40 1000 mg 1500 mg 2000 mg Kanamycin 3 times/week after week 12The intensive phase may be extended by 4 or 8 weeks if smear conversion has not occurred by 16 or 20 weeks 8Slide9
Results of the 9-month regimen in Bangladesh
Introdion
Objectif
Méthodes
Conclusion
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, 2010Slide10
STREAM
International, multi-centre, parallel-group, open-label, randomised, controlled trial ……
…….. To evaluate a Standardized Treatment Regimen of
Anti-Tuberculosis Drugs for Patients with MDR-TB (STREAM)……. ………. Including
patients with rifampicin resistant and isoniazid-sensitive TB. 10Slide11
W
hy 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-coinfectionTo develop a better evidence base for shorter MDR-TB treatmentIf 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 follow-up, on Regimen B as compared to Regimen A. 12Slide13
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 countriesThe study regimen
(B) is closely similar to the regimen used in Bangladesh with the exception that high dose moxifloxacin replaces high dose gatifloxacin
13Slide14
Stage 1 trial entry, randomisation, treatment and follow-up
14Slide15
15
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 treatmentSlide16
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 132The 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 132Secondary
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
16
. Slide17
Stage 1: current status
Enrolment to Stage 1 commenced: July 2012Sites: Ethiopia (2), South Africa (3), Vietnam and Mongolia
424 of initial target of 400 patients enrolledAccrual closed: June 30th 2015Primary endpoint at 30 months Last Patient Last Visit: Q4 2017Results from Stage 1 expected: Q1/2 2018
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Trial recruitment Stages
18Slide19
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/ora shorter and simpler regimen
To assess the shorter regimens in a variety of settings including sites with high levels of HIV-coinfection.
19Slide20
STREAM Stage 2 design
Because it is possible that Regimen B might not be found to be non-inferior 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
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All Stage 2 Sites
Regimen A - 165
Regimen B – 330
Regimen C – 330Regimen D – 330Total participants
1155Zimbabwe Sites100 participants Slide23
Regimens for Stage 2Slide24
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. 24Slide25
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 Antwerp2 sites have been assessed by the Union in late January 2016 - BRIDH Harare - Khami
Road Clinic in BulawayoApplications for ethical and clinical trial regulatory authorities will start mid-MarchApprovals by July 2016Training and implementation by August 2016 (start with Harare then activate Bulawayo site after 6 months)25Slide26
Acknowledgements
26
Funder: USAID
Design, Management, Analysis
Impact Assessment: Liverpool School
of Tropical
Medicine
Microbiology:
Institute of
Tropical Medicine,
Antwerp
Sponsor:
The Union
UZ-UCSF
Collaborative Research
Programme