Download Standardised Treatment Regimen of Anti-TB Drugs for

Standardised Treatment Regimen of
Anti-TB Drugs for Patients with MDR-TB
Study Summary 2015
Background
Tuberculosis (TB) that is sensitive to the standard drugs is a
curable disease, and most patients can be treated effectively
and inexpensively in six months. However, multidrugresistant (MDR-TB), resistance to the drugs isoniazid and
rifampicin, is much more difficult to treat. MDR-TB
requires more drugs, given for a much longer time and has
much less satisfactory outcomes. MDR-TB patients who also
have HIV infection have particularly poor outcomes and a
greater risk of recurrence of their disease.
A study carried out in Bangladesh by Van Deun et al (2010)
reported very successful results in over 200 patients with
MDR-TB treated for only 9 months, a striking contrast to
the much less satisfactory results from standardised treatments
given for 18 months or more. A course of treatment given
for less than 12 months with a high success rate would
be a considerable advantage over standard practice. The
Standardised Treatment Regimen of Anti-TB Drugs for
Patients with MDR-TB (STREAM) study will be assessing
treatment very similar to that used in Bangladesh.
Trial Design – 1st Stage
Eligible patients will be randomly allocated to receive either
the 9-month study treatment or the locally used WHO
standardised treatment. A total of at least 400 participants
with MDR-TB will be enrolled from across sites in a number
of countries, including but not limited to South Africa,
Ethiopia, Mongolia and Vietnam.
The main aims are:
1. To compare the proportion of patients with a favourable
outcome at 27 months post enrolment.
2. To compare the proportion of patients who experience
severe side effects (grade 3 or more) on the two treatments.
Study regimen doses
Weight group
Product
Less than 33 kg
33 kg to 50 kg
More than 50 kg
Moxifloxacin
400 mg
600 mg
800 mg
Clofazimine
50 mg
100 mg
100 mg
Ethambutol
800 mg
800 mg
1200 mg
Pyrazinamide
1000 mg
1500 mg
2000 mg
Isoniazid
300 mg
400 mg
600 mg
Prothionamide
250 mg
500 mg
750 mg
Kanamycin
15 mg per kilogramme body weight (maximum 1g)
Treatments
The study treatment is based on the treatment used in the
Bangladesh study. Because gatifloxacin is no longer readily
available, it has been replaced by moxifloxacin. Treatment
will be based on the drugs moxifloxacin, clofazimine,
ethambutol and pyrazinamide given for nine months
(40 weeks) supplemented by kanamycin, isoniazid and
prothionamide given during the first four months (16 weeks);
see table on prior page for details. Each patient’s dose will
be based on their weight. Patients who are not responding
rapidly may have the initial 4-month intensive phase extended
by up to two additional months.
The control regimen will be the standard MDR-TB treatment
used at the site.
Selection of Patients
Patients who meet the eligibility criteria will be recruited
into the trial from tuberculosis clinics near the main site. The
criteria: aged 18 years or more, with smear positive MDRTB and willing to be tested for HIV and willing to attend
the hospital or clinic for follow-up visits and to follow study
procedures. Certain patients will be ineligible including those
infected with a strain of M. tuberculosis resistant to a secondline injectable drugs or a floroquinolone. Patients with
tuberculous meningitis or bone and joint tuberculosis and
those who are critically ill will also be ineligible. Full details
of eligibility criteria are given in the protocol.
Study Procedures
Patients must give their consent to take part in the trial before
any tests for the trial are carried out at the hospital. At the
screening and enrolment visits, the study, including potential
risks and benefits of taking part will be explained to a patient.
This will include information on the trial purpose and
procedures as well as the samples to be collected at these visits.
Patients will be asked to sign their consent form or provide a
thumb print in front of a witness, if they cannot read or write.
Patients have a right to refuse to take part in the trial without
giving reasons.
Patients eligible to take part after screening will be assessed
further at enrolment, after being given more information about
the trial as well as having a chance to ask any questions they
may have before they consent to taking part in the trial. Once
they consent, they will be given a copy of the signed consent
form together with the Patient Information Sheet. Patients
who are ineligible or do not wish to take part will be referred
to the National Tuberculosis Programme (NTP) for further
management.
Eligible patients will have their information entered into a
computer which will select randomly whether they receive
the study or the control course of treatment. All patient
information will be kept securely and only the treatment staff
will have access to it.
During treatment, patients will have their treatment supervised
closely - on a daily basis in most sites (Directly Observed
Treatment -DOT). All patients in the study will be closely
monitored by frequent clinic visits, blood tests and other
investigations. Patients will be assessed weekly for the first
four weeks then every four weeks throughout the trial, both
during and after treatment. They will be required to provide
sputum samples for assessment; they will also have a clinical
examination and will be asked if they have had any side
effects from the drugs. They will have a monthly blood test to
monitor liver and kidney function during the intensive phase.
In some patients, particularly those taking moxifloxacin as part
of the study treatment, there may be an effect on the electrical
activity of the heart such that the QT interval is prolonged.
If extreme, this may put patients at an increased risk of a
change to the rhythm of the heart which although rare, may
be serious. Following their first dose of treatment patients will
be monitored using an ECG to assess whether the treatment
prolongs the QT measurement. This will be repeated every
week for the first four weeks on treatment and then at months,
3, 6 and 9. The effects of drugs on the electrical activity of the
heart is reversible and if doctors find a problem the drug that is
causing it will be stopped.
After completion of their treatment patients will be expected to
continue to attend the study clinic every four weeks where they
will be asked to provide sputum samples and they will be asked
about any adverse events that may have occurred after their last
visit. These visits will continue until 27 months from the time
they started their treatment.
Continued on the next page
Treatment Supervision & Management
Patients will be counselled about the importance of taking
their treatment as advised. Other medications being taken in
addition to the trial course of treatment have to be recorded.
DOT will be carried out by Treatment Supervisors, who will
record whether the treatment was taken on a treatment card.
Treatment supervisors may be clinic staff or family members
or other members of the community. Treatment Cards must
be returned to the study clinic at each monthly visit where a
new card will be provided.
Information on contact details for each patient will be
collected at enrolment and checked at each subsequent visit.
Patients who fail to attend will be contacted by phone call,
text message or home visit. If a patient no longer wants to
take part in the study, information on their reasons should be
requested and the patient encouraged to attend the clinic for
final assessments.
For some patients it may be necessary to stop or change their
treatment on account of adverse effects or failure to respond.
Modifications of the allocated treatment should only be
made by study clinic staff after discussion with the STREAM
central clinical team. All of these patients should continue to
be followed up.
Women who become pregnant will have their treatment
stopped and will be referred to the NTP for further
management because some of the drugs may be harmful
during pregnancy.
Trial Design – 2nd Stage
By 2016, it is expected that randomisation will commence to
two additional regimens, both of which will be compared to
the 9-month regimen studied in stage 1 i.e. the modified
Bangladesh regimen. In both of these regimens a recently
licensed drug, bedaquiline, will be included.
In the first of the new regimens, total treatment duration
will be reduced to 6 months, and kanamycin will be given
for only 2 months. The second of the new regimens will
be completely oral; the kanamycin in the original 9-month
regimen will be replaced by bedaquiline.
Reference
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
Partners
Sponsor: The International Union Against Tuberculosis and Lung Disease (IUATLD, Inc.)
Funders: The United States Agency for International Development (USAID) & Medical Research Council (UK)
Management and Coordination: MRC Clinical Trials Unit (MRC CTU)
Microbiology: Institute of Tropical Medicine, Antwerp
Impact Assessment: Liverpool School of Tropical Medicine
TREAT TB is supported through USAID Cooperative Agreement GHN-A-00-08-00004-00