The Evaluation of a Standardised Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-

STREAM

The Evaluation of a Standardised Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB

Andrew Nunn MRC Clinical Trials Unit Thursday 23rd August 2013

Objectives of the session

•

Current status of MDR-TB world-wide

•

WHO guidance for treatment of MDR-TB

•

A short-course regimen for MDR-TB

•

STREAM trial

•

Future developments

Objectif Introduction

Conclusion

Status of MDR-TB world-wide Number of cases % of total % of newly diagnosed % of previously treated

~500,000 5% 4% (range <1%, 32%) 20% WHO 2013

Systematic reviews of the results of treating patients with MDR-TB report disappointing results Median success rates: individualised regimens ~ 65% standardised regimens ~ 55% Orenstein et al, Lancet 2009

WHO estimate only 1 in 5 MDR-TB patients are treated and in < 50% of those treated is the outcome favourable

Lack of evidence There is no good evidence, based on randomised clinical trials, to show that one treatment for MDR-TB is better than another.

Controversies outweigh solid evidence for the management of patients with MDR-TB. Current international recommendations are based only on the opinions of the experts.

Current Guidance â&#x20AC;˘ WHO guidance published in 2011 addressed drug sensitivity testing, monitoring of response, selection of regimens, duration of treatment, use of anti-retrovirals and models of care.

Introdion

Objectif

MĂŠthodes

Conclusion

9-month regimen used in Bangladesh • Between 1997 and 2007 six regimens for the treatment of MDR-TB were studied in sequentially recruited cohorts.

• Changes to the regimen included introduction of different quinolones and a reduction in duration from 15 or more months to 9 months • The most effective regimen required 9 months of treatment with gatifloxacin, clofazimine, ethambutol, and pyrazinamide supplemented by prothionamide, kanamycin, and high-dose isoniazid during the first 4 months

Introdion

Objectif

Méthodes

Conclusion

Am J Respir Crit Care Med Vol 182. pp 684â&#x20AC;&#x201C;692, 2010

Results of the regimen used in Bangladesh Published cohort (206 pts) Cure

Updated total (476 pts)

82.5%

83.8%

Completion

5.3%

2.3%

Default

5.8%

7.4%

Death

5.3%

5.5%

Failure

0.5%

1.1%

Relapse

0.5%

0.7%

Overall success rate:

Overall success rate:

87.9% (95% CI 82.7, 92.6)

86.1% (95% CI 82.7, 89.1)

Am J Respir Crit Care Med Vol 182. pp 684â&#x20AC;&#x201C;692, 2010

Abstract, 43rd World Lung Conference, 2012

Introdion

Objectif

MĂŠthodes

Conclusion

Use of a shortened regimen in Africa â&#x20AC;˘ Several African countries (mainly Francophone) are currently using a shortened regimen in patients with MDR-TB â&#x20AC;˘ Latest results of 12 month regimen in Cameroon Treatment initiated Results available Culture conversion 2m Cured Died Lost to follow-up

214 158 88% 89% 7% 4%

STREAM study partners Funder: USAID

Sponsor: International Union Against Tuberculosis and Lung Disease, New York

Design, Management, Analysis Impact Assessment: Liverpool School of Tropical Medicine

Microbiology: Institute of Tropical Medicine, Antwerp

ETHIOPIA Armaeur Hansen Research Institute (AHRI) St. Peterâ&#x20AC;&#x2122;s Tuberculosis Specialised Hospital/ Global Health Committee

SOUTH AFRICA King George V Hospital, Durban Sizwe Tropical Diseases Hospital

VIETNAM Ho Chi Minh City Hospital

INDIA National Institute for Research in Tuberculosis, Chennai B J Medical College, Ahmedabad

STREAM study design • STREAM is a randomised controlled trial of noninferiority design • The control regimen is the locally used WHO recommended regimen in the participating countries • The study regimen is closely similar to the regimen used

by Van Deun in Bangladesh with the exception that high dose moxifloxacin replaces high dose gatifloxacin

STREAM study regimen (40 weeks)

Months Moxifloxacin Clofazimine

Ethambutol

1-9

Pyrazinamide Isoniazid Prothionamide Kanamycin

1-4

<33kg

33 - 50kg

>50kg

400 mg

600 mg

800 mg

50 mg

100 mg

100 mg

800 mg

800 mg

1200 mg

1000 mg

1500 mg

2000 mg

300 mg

400 mg

600 mg

250 mg

500 mg

750 mg

15 mg/kg body weight (max 1g)

Kanamycin 3-weekly after 12 weeks

STREAM study regimen (40 weeks)

Months Moxifloxacin Clofazimine

Ethambutol

1-9

Pyrazinamide Isoniazid Prothionamide Kanamycin

1-4

<33kg

33 - 50kg

>50kg

400 mg

600 mg

800 mg

50 mg

100 mg

100 mg

800 mg

800 mg

1200 mg

1000 mg

1500 mg

2000 mg

300 mg

400 mg

600 mg

250 mg

500 mg

750 mg

15 mg/kg body weight (max 1g)

Kanamycin 3-weekly after 12 weeks

Inclusion criteria Adults with smear-positive pulmonary tuberculosis with resistance to rifampicin by line probe assay (LPA) or other DST, but sensitive on LPA to kanamycin, capreomycin and amikacin and to fluoroquinolones Willing to have an HIV test QTcF < 500ms

Agreement to use effective barrier contraception during treatment phase for pre-menopausal women Identifiable home address and expected to remain in the area for the duration of the study

Primary efficacy endpoint

â&#x20AC;˘ The primary efficacy endpoint is the status 27 months after enrolment â&#x20AC;˘ An unfavourable outcome is: o Need to change 2 or more drugs o Extension of chemotherapy beyond 11 months o Culture positive at 27 months o Death from any cause o Default any time before 15 months

Primary safety endpoint

â&#x20AC;˘ A grade 3 or 4 adverse event at any time during the 27 months of follow-up (whether on or off treatment)

ECG assessment schedule • All patients are monitored with a 12-lead ECG at the following visits: o Screening o 2 hours and 4 hours after the first dose o Weeks 1, 2, 3, 4 o Weeks 12, 24, 36 • A 24-hour ECG (Holter monitor) is undertaken in any participant whose QTc is ≥ 450msec.

Treatment modification in the event of a QTcF raised above 500ms

â&#x20AC;˘ In the event of a patientâ&#x20AC;&#x2122;s QTcF exceeding 500ms without an alternative explanation: o moxifloxacin is reduced to standard 400mg dose o if prolongation persists moxifloxacin replaced with 750mg levofloxacin

STREAM timelines

Actual

First patient randomised: Enrolled

Planned

27th July 2012 130

400

Completion of recruitment:

July 2014

Final patient follow-up visit:

October 2016

Database lock and final analysis:

Q1 2017

Future plans â&#x20AC;˘ Janssen pharmaceuticals are preparing to start a trial in which bedaquiline will be added to a regimen closely similar to the STREAM regimen â&#x20AC;˘ MRC Clinical Trials Unit are planning to add a third arm to STREAM simplifying the regimen by reducing the number of drugs and/or shortening the duration of treatment

Conclusion • The evidence base for current WHO recommendations for the treatment of MDR-TB is weak • The cohort studies in Bangladesh and Cameroon suggest that effective treatment can be given for much less than 24 months • The STREAM trial will provide strong evidence of the comparative effectiveness of a 9-month regimen and the WHO standard treatment • Prospects for short regimens for MDR-TB are good.