Evaluation of a - PowerPoint Presentation

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

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DR-TB case detection in

Zimbabwe 2010 – 2015

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DR-TB case detection in Zimbabwe

2015

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Why New drugs/ regimens for MDR TB?

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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

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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 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

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. 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

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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/ora 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 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

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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