CClinicalTrials.gg
Sign In
CompletedNCT02409290STREAMUpdated Sep 28, 2023Results posted

The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB

A Phase 3 interventional study of Regimen A locally-used WHO-approved MDR-TB regimen (2011 guideline) and Moxifloxacin in MDR-TB, sponsored by IUATLD, Inc. Completed at 13 sites in 7 countries. Open to participants aged 15 Years and older. Per ClinicalTrials.gov, last updated 2023-09-28.

Sponsored by IUATLD, Inc · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
588
Allocation
Randomized
Ages
15 Years and older
Sex
All
01

Study summary

Tuberculosis (TB) is a common, infectious, bacterial disease that is spread when an infected person transmits their saliva through the air by coughing or sneezing. Despite the availability and effectiveness of affordable six-month treatments for tuberculosis (TB), the worldwide control of this disease is currently being impacted by the emergence of multidrug resistant TB (MDR-TB). MDR-TB refers to TB that is resistant to at least isoniazid and rifampicin. These are the two most powerful first-line drugs used to treat pulmonary TB. MDR-TB usually develops while a person is taking TB treatment due to either inappropriate treatment or failure of patients to comply with their treatment. This strain of drug-resistant bacteria can also be spread to other people through the air. With the incident rate of MDR-TB on the rise, there is a need to investigate optimal treatment regimens using effective drugs.

Read the detailed description

The STREAM study is an international, multi-centre, parallel-group, open-label, randomised, controlled trial in patients with multi-drug resistant tuberculosis (MDR-TB) including patients with rifampicin-resistant and isoniazid-sensitive TB.

Background and Rationale:

In 2011, World Health Organisation (WHO) guidelines for the treatment for MDR-TB recommended an intensive phase of treatment based on at least four drugs known to be effective and given for a minimum of 20 months; this is referred to as the WHO 2011 long regimen. Outcomes with this approach are generally poor. In the most recent WHO TB surveillance report only 50% of MDR-TB patients were successfully treated and a recent meta-analysis reported on average 62% successful outcome and a mortality of 11%.

In 2010, Van Deun et al (2010) reported excellent long-term outcomes in a cohort of over 200 patients in Bangladesh with MDR-TB who were treated with a regimen given for only nine to 11 months. Such a regimen, if successful, would represent a considerable advance over current practice. Evaluation of this regimen is the objective of Stage 1 of STREAM.

In 2016, following review of the available data, the WHO MDR TB treatment guidelines were modified to recommend a 9-12 month shortened regimen under specific conditions similar to Regimen B used in STREAM Stage 1 (referred to as the WHO 2016 short regimen).

Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity. In a phase II trial of patients with MDR-TB time to culture conversion was significantly less in patients receiving bedaquiline compared to those receiving an optimised background regimen only (Diacon et al (2012). In December 2012 the US Food and Drug Administration (FDA) approved bedaquiline as part of the treatment regimen for MDR-TB when other agents are unavailable. Stage 2 of STREAM was designed to investigate ways in which Regimen B could be improved either by removing the second-line injectable, which is associated with severe drug toxicity, or by shortening the regimen to 6 months.

Treatments that are evaluated within the STREAM trial include:

Regimen A The locally-used MDR-TB regimen in accordance with 2011 WHO MDR-TB treatment guidelines.

Regimen B is based on the regimen described by Van Deun 2010. At the start of STREAM this consisted of clofazimine, ethambutol, moxifloxacin, and pyrazinamide given for 40 weeks, supplemented by isoniazid, kanamycin, and prothionamide in the first 16 weeks (intensive phase). ); this combination is referred to as Regimen Bmox. With Version 8.0 of the protocol Regimen B is modified by replacement of moxifloxacin with levofloxacin (referred to as Regimen Blev). Regimen B without specification of which fluoroquinolone is in the regimen refers to either (Bmox or Blev).

Regimen C is a 40-week all-oral regimen consisting of bedaquiline, clofazimine, ethambutol, levofloxacin, and pyrazinamide given for 40 weeks supplemented by isoniazid and prothionamide for the first 16 weeks (intensive phase).

Regimen D is a 28-week regimen consisting of bedaquiline, clofazimine, levofloxacin, and pyrazinamide given for 28 weeks supplemented by isoniazid and kanamycin for the first 8 weeks (intensive phase).

The primary objectives of the STREAM2 trial are:

To assess whether the proportion of participants with a favourable efficacy outcome at week 76 on Regimen C is non-inferior to that on Regimen B

Study Population: Stage 2 will aim to randomise at least 200 patients to each of Regimens B and C.

All patients will be followed up to Week 132. The primary analysis will be based on the data accrued to Week 76 and is based on the proportion of patients with a favourable outcome at that time point ; the data accrued to Week 132 will be used in secondary analyses.

Although the STREAM study is an open-label study, wherever possible it will be conducted masked to treatment allocation.

02

Conditions studied

  • MDR-TB
03

Who can participate

Ages eligible
15 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Consent: Is willing and able to give informed consent to participate in the trial treatment and follow-up (signed or witnessed consent if the patient is illiterate). If the patient is below the age of consent (according to local regulations), the parent/caregiver should be able and willing to give consent, and the patient be informed about the study and asked to give positive assent, if feasible
  2. Age: Is aged 18 years or older (Stage 1) or 15 years or older (Stage 2)
  3. AFB or GeneXpert results: Has a positive AFB sputum smear result at screening (at least scanty), or a positive GeneXpert result (with a cycle threshold (Ct) value of 25 or lower) from a test performed at screening or from a test performed within the four weeks prior to screening
  4. Has evidence of resistance to rifampicin either by line probe assay (Hain Genotype), GeneXpert or culture-based drug susceptibility testing (DST), from a test performed at screening or from a test performed within the four weeks prior to screening
  5. Is willing to have an HIV test and, if positive, is willing to be treated with ART in accordance with the national policies but excluding ART contraindicated for use with bedaquiline
  6. Is willing to use effective contraception: pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilised must agree to use a barrier method or an intrauterine device unless their partner has had a vasectomy; men who have not had a vasectomy must agree to use condoms. In Stage 2 pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilised must agree to use two methods of contraception, for example a hormonal method and a barrier method
  7. Resides in the area and expected to remain for the duration of the study.
  8. Has had a chest X-ray that is compatible with a diagnosis of pulmonary TB (if such a chest X-ray taken within 4 weeks of randomisation is available, a repeat X-ray is not required)
  9. Has normal K+, Mg2+ and corrected Ca2+ at screening.

Exclusion criteria

Exclusion Criteria:

  1. Is infected with a strain of M. tuberculosis resistant to second-line injectables by line probe assay (Hain Genotype) from a test performed at screening or from a test performed within the four weeks prior to screening
  2. Is infected with a strain of M. tuberculosis resistant to fluoroquinolones by line probe assay (Hain Genotype) from a test performed at screening or from a test performed within the four weeks prior to screening
  3. Has tuberculous meningitis or bone and joint tuberculosis
  4. Is critically ill, and in the judgment of the investigator, unlikely to survive more than 4 months
  5. Is known to be pregnant or breast-feeding
  6. Is unable or unwilling to comply with the treatment, assessment, or follow-up schedule
  7. Is unable to take oral medication
  8. Has AST or ALT more than 5 times the upper limit of normal for Stage 1, and AST or ALT more than 3 times the upper limit of normal for Stage 2
  9. Has any condition (social or medical) which in the opinion of the investigator would make study participation unsafe
  10. In the investigator's opinion the patient is likely to be eligible for treatment with bedaquiline according to local guidelines due to a pre-existing medical condition such as hearing loss or renal impairment
  11. Is taking any medications contraindicated with the medicines in any trial regimen
  12. Has a known allergy to any fluoroquinolone antibiotic
  13. Is currently taking part in another trial of a medicinal product

  14. Has a QT or QTcF interval at screening or immediately prior to randomisation of more than or equal to 500 ms for Stage 1, and more than or equal to 450 ms for Stage 2

    In addition to the criteria above, for Stage 2 only, a patient will not be eligible for randomisation to the study if he/she:

  15. Has experienced one or more of the following risk factors for QT prolongation:

    • A confirmed prolongation of the QT or QTcF more than or equal to 450 ms in the screening ECG (retesting to reassess eligibility will be allowed once using an unscheduled visit during the screening phase)
    • Pathological Q-waves (defined as Q-wave more than 40 ms or depth more than 0.4-0.5 mV)
    • Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome)
    • Electrocardiographic evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block
    • Evidence of second or third degree heart block
    • Intraventricular conduction delay with QRS duration more than 120 ms
    • Bradycardia as defined by sinus rate less than 50 bpm
    • Personal or family history of Long QT Syndrome
    • Personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, with the exception of sinus arrhythmia
    • Syncope (i.e. cardiac syncope not including syncope due to vasovagal or epileptic causes)
    • Risk factors for Torsades de Pointes (e.g., heart failure, hypokalaemia, or hypomagnesemia)
  16. Has received treatment for MDR-TB in the 12 weeks prior to screening, other than the maximum permitted treatment specified in Section 5.2.1
  17. Has a history of cirrhosis and classified as Child's B or C at screening or a bilirubin more than 1.5 times upper limit of normal.
  18. Has an estimated creatinine clearance (CrCl) less than 30 mL/min based on the Cockcroft-Gault equation
  19. Is HIV positive and has a CD4 count less than 50 cells/mm3
  20. Has pancreatic amylase elevation more than two times above the upper limit of normal
  21. Has a history of alcohol and/or drug abuse
  22. Has had previous treatment with bedaquiline
  23. Has taken rifampicin in the seven days prior to randomisation
  24. There has been a delay of more than four weeks between the screening consent and randomisation
  25. Is an employee or family member of the investigator or study site staff with direct involvement in the proposed study.
04

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
588 participants (actual)

Study arms

  • Active comparator
    Regimen A

    Regimen A locally-used WHO-approved MDR-TB regimen in accordance with 2011 WHO MDR-TB treatment guidelines.

    Drug: Regimen A locally-used WHO-approved MDR-TB regimen (2011 guideline)

  • Active comparator
    Regimen B

    Regimen B is based on the regimen described by Van Deun 2010. With Version 8.0 of the protocol Regimen B (Regimen Bmox) is modified by replacement of moxifloxacin with levofloxacin (Regimen Blev). Regimen B without specification of which fluoroquinolone is in the regimen refers to either (Bmox or Blev). Product and dose for \[\<33 kg, 33-50kg, \>50 kg\] respectively: Moxifloxacin \[400mg, 600mg, 800mg\] OR Levofloxacin \[750mg, 750mg,1000mg\]; Clofazimine \[50mg,100mg,100mg\]; Ethambutol \[800mg,800mg,1200mg\]; Pyrazinamide \[1000mg,1500mg, 2000mg\]; Isoniazid 300mg, 400mg, 600mg\]; Prothionamide \[250mg,500mg,750mg\]; Kanamycin \[15mg per kilogram body weight (maximum 1g)\].

    Drug: Moxifloxacin · Drug: Clofazimine · Drug: Ethambutol · Drug: Pyrazinamide · Drug: Isoniazid · Drug: Prothionamide · Drug: Kanamycin · Drug: Levofloxacin

  • Experimental
    Regimen C

    Regimen C is a 40-week all-oral regimen consisting of bedaquiline, clofazimine, ethambutol, levofloxacin, and pyrazinamide given for 40 weeks supplemented by isoniazid and prothionamide for the first 16 weeks (intensive phase). Product and dose for \[\<33kg, 33-50kg, \>50 kg\] respectively: Bedaquiline 400mg once daily for first 14 days/200 mg thrice weekly thereafter; Levofloxacin \[750mg, 750mg,1000mg\]; Clofazimine \[50mg, 100mg, 100mg\]; Ethambutol \[800mg, 800mg, 1200mg\]; Pyrazinamide \[1000mg,1500mg, 2000mg\]; Isoniazid \[300mg, 400mg, 600mg\]; Prothionamide \[250mg, 500mg,750mg\].

    Drug: Clofazimine · Drug: Ethambutol · Drug: Pyrazinamide · Drug: Isoniazid · Drug: Prothionamide · Drug: Levofloxacin · Drug: Bedaquiline

  • Experimental
    Regimen D

    Regimen D is a 28-week regimen consisting of bedaquiline, clofazimine, levofloxacin, and pyrazinamide given for 28 weeks supplemented by isoniazid and kanamycin for the first 8 weeks (intensive phase). Product and dose for \[\<33kg, 33 to\<40kg, 40-50kg, \>50-60 kg, \>60 kg\] respectively: Bedaquiline 400mg once daily for first 14 days/200mg thrice weekly thereafter; Levofloxacin \[750mg, 750mg, 750mg, 1000mg, 1000mg\]; Clofazimine \[50mg, 100mg, 100mg, 100mg, 100mg\]; Pyrazinamide \[1000mg,1500mg, 1500mg, 2000mg, 2000mg\]; Isoniazid \[400mg, 500mg, 600mg, 800mg, 900mg\]; Kanamycin \[15 mg per kilogram body weight (maximum 1g)\].

    Drug: Clofazimine · Drug: Pyrazinamide · Drug: Isoniazid · Drug: Kanamycin · Drug: Levofloxacin · Drug: Bedaquiline

Interventions

  • DrugRegimen A locally-used WHO-approved MDR-TB regimen (2011 guideline)

    Drug: Locally-used WHO-approved MDR-TB regimen

  • DrugMoxifloxacin

    Moxifloxacin is an 8-methoxy quinolone, and an anti-bacterial fluoroquinolone

    Also known as: Avelox

  • DrugClofazimine

    Clofazimine, is an antileprosy and anti-bacterial agent. Its chemical name is 3-(p-chloroanilino)-10-(p-chlorophenyl)-2, 10-dihydro-2-isopropyliminophenazine.

    Also known as: Lamprene

  • DrugEthambutol

    Ethambutol is a bacteriostatic that acts against virtually all strains of Mycobacterium tuberculosis and M. bovis and is also active against other mycobacteria such as M. Kansasii.

    Also known as: Myambutol

  • DrugPyrazinamide

    Pyrazinamide is bactericidal against intracellular mycobacterium tuberculosis. It is a prodrug that is converted into its active form, pyrazinoic acid, by a mycobacterial enzyme, pyrazinamidase, as well as through hepatic metabolism.

    Also known as: Zinamide

  • DrugIsoniazid

    Isoniazid is a bactericidal in vitro and in vivo against actively dividing tubercle bacilli. Its primary action is to inhibit the synthesis of long-chain mycolic acids, which are unique constituents of mycobacterial cell wall.

    Also known as: Nydrazid, Isotamine

  • DrugProthionamide

    Prothionamide has a bacteriostatic action.

    Also known as: Peteha

  • DrugKanamycin

    Kanamycin is a bactericidal antibiotic from the group of aminoglycosides.

    Also known as: Kantrex

  • DrugLevofloxacin

    Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class that acts on the DNA-DNA-gyrase complex and topoisomerase IV. It is the S (-) enantiomer of the racemic active substance ofloxacin.

    Also known as: Levaquin

  • DrugBedaquiline

    Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity

    Also known as: SIRTURO

05

What researchers measure

Primary outcomes

  1. STREAM Stage 2 Primary Outcome Measure (the Proportion of Patients With a Favourable Outcome at Week 76)

    The primary efficacy outcome of the STREAM Stage 2 comparison is status at Week 76 i.e. the proportion of patients with a favourable outcome at Week 76

    Time frame: 76 weeks

Other outcomes

  1. Favourable Outcome After Long-term Follow-up (132 Weeks)

    The proportion of patients with a favourable outcome at their last efficacy visit

    Time frame: Last efficacy visit, between 96 and 132 weeks

  2. Proportion of Patients With Acquired Drug Resistance

    The proportion of patients with acquired drug resistance (any drug)

    Time frame: 132 weeks

  3. Failure or Recurrence (FoR)

    probable or definite failure or recurrence (FoR)

    Time frame: final efficacy week (between 96 and 132 weeks)

  4. Failure or Recurrence (FoR)

    The proportion of patients with failure or recurrence (FoR)

    Time frame: 132 weeks, control regimen (arm B) using concurrent controls only

06

Results

Posted Sep 28, 2023
Limitations and caveats
The main limitation of the trial is that the open-label design might have influenced decisions on regimen change, especially for non-bacteriological reasons.

Participant flow

Participants were assessed for eligibility from 13 hospital clinics in seven countries, and were randomised between March 2016 and January 2020

Participant flow — Overall Study
MilestoneRegimen A (Long Regimen)Regimen B (Control Regimen)Regimen C (Oral Regimen)Regimen D (6-month Regimen)
Started32202211143
Completed0187196134
Not completed3215159
Withdrew: Protocol violation3694
Withdrew: No positive culture/no baseline sample3965
Withdrew: Completed but not analysed as recruitment stopped to this arm26000

Outcome measures

PrimarySTREAM Stage 2 Primary Outcome Measure (the Proportion of Patients With a Favourable Outcome at Week 76)

The primary efficacy outcome of the STREAM Stage 2 comparison is status at Week 76 i.e. the proportion of patients with a favourable outcome at Week 76

Time frame:
76 weeks
Reported as:
Count of participants · Participants
STREAM Stage 2 Primary Outcome Measure (the Proportion of Patients With a Favourable Outcome at Week 76)
ParticipantsRegimen A (Long Regimen)Regimen B (Control Regimen)Regimen C (Oral Regimen)Regimen D (6-month Regimen)
STREAM Stage 2 Primary Outcome Measure (the Proportion of Patients With a Favourable Outcome at Week 76)0133162122
Other pre-specifiedFavourable Outcome After Long-term Follow-up (132 Weeks)

The proportion of patients with a favourable outcome at their last efficacy visit

Time frame:
Last efficacy visit, between 96 and 132 weeks
Reported as:
Count of participants · Participants
Favourable Outcome After Long-term Follow-up (132 Weeks)
ParticipantsRegimen A (Long Regimen)Regimen B (Control Regimen)Regimen C (Oral Regimen)Regimen D (6-month Regimen)
Favourable Outcome After Long-term Follow-up (132 Weeks)17126152115
Other pre-specifiedProportion of Patients With Acquired Drug Resistance

The proportion of patients with acquired drug resistance (any drug)

Time frame:
132 weeks
Reported as:
Count of participants · Participants
Proportion of Patients With Acquired Drug Resistance
ParticipantsRegimen A (Long Regimen)Regimen B (Control Regimen)Regimen C (Oral Regimen)Regimen D (6-month Regimen)
Proportion of Patients With Acquired Drug Resistance0553
Other pre-specifiedFailure or Recurrence (FoR)

probable or definite failure or recurrence (FoR)

Time frame:
final efficacy week (between 96 and 132 weeks)
Reported as:
Count of participants · Participants
Failure or Recurrence (FoR)
ParticipantsRegimen A (Long Regimen)Regimen B (Control Regimen)Regimen C (Oral Regimen)Regimen D (6-month Regimen)
Failure or Recurrence (FoR)01740
Statistical analysis
  • Regimen B (Control Regimen) vs Regimen C (Oral Regimen) · Log Rank · p = 0.0016 · Cox proportional hazard: 0.20 · 95% CI 0.07 to 0.61
Other pre-specifiedFailure or Recurrence (FoR)

The proportion of patients with failure or recurrence (FoR)

Time frame:
132 weeks, control regimen (arm B) using concurrent controls only
Reported as:
Count of participants · Participants
Failure or Recurrence (FoR)
ParticipantsRegimen A (Long Regimen)Regimen B (Control Regimen)Regimen C (Oral Regimen)Regimen D (6-month Regimen)
Failure or Recurrence (FoR)—14—2
Statistical analysis
  • Regimen B (Control Regimen) vs Regimen D (6-month Regimen) · Log Rank · p = 0.0005 · Cox proportional hazard: 0.11 · 95% CI 0.03 to 0.50

Adverse events

Collected over 132 weeks. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Regimen A (Long Regimen)0/32 (0%)8/32 (25%)21/32 (65.6%)
Regimen B (Control Regimen)8/202 (4%)44/202 (21.8%)114/202 (56.4%)
Regimen C (Oral Regimen)11/211 (5.2%)44/211 (20.9%)109/211 (51.7%)
Regimen D (6-month Regimen)2/143 (1.4%)33/143 (23.1%)82/143 (57.3%)
Most frequent serious events
Showing 10 of 23
Most frequent serious events
EventRegimen A (Long Regimen)Regimen B (Control Regimen)Regimen C (Oral Regimen)Regimen D (6-month Regimen)
Gastrointestinal disordersGastrointestinal disorders2/321/2025/2111/143
Psychiatric disordersPsychiatric disorders2/321/2020/2110/143
Infections and infestationsInfections and infestations0/3212/2029/2113/143
Hearing and vestibular disorders (SMQ)Ear and labyrinth disorders0/327/2027/2117/143
General disorders and administration site conditionsGeneral disorders1/326/2022/2116/143
InvestigationsInvestigations1/323/2024/2115/143
Respiratory, thoracic and mediastinal disordersRespiratory, thoracic and mediastinal disorders0/327/2025/2112/143
Hepatic disorders (SMQ)Hepatobiliary disorders1/325/2024/2111/143
Pregnancy, puerperium and perinatal conditionsPregnancy, puerperium and perinatal conditions1/321/2023/2113/143
Social circumstancesSocial circumstances1/321/2022/2111/143
Most frequent other events
Showing 10 of 23
Most frequent other events
EventRegimen A (Long Regimen)Regimen B (Control Regimen)Regimen C (Oral Regimen)Regimen D (6-month Regimen)
Metabolism and nutrition disordersMetabolism and nutrition disorders10/3222/20230/21120/143
InvestigationsInvestigations10/3225/20219/21114/143
Torsade de pointes/QT prolongation (SMQ)Cardiac disorders2/3247/20252/21138/143
Hepatic disorders (SMQ)Hepatobiliary disorders3/3231/20233/21115/143
Hearing and vestibular disorders (SMQ)Ear and labyrinth disorders2/3220/2029/2116/143
Gastrointestinal disordersGastrointestinal disorders3/322/2024/2113/143
Psychiatric disordersPsychiatric disorders3/321/2020/2110/143
Musculoskeletal and connective tissue disordersMusculoskeletal and connective tissue disorders2/322/2020/2111/143
General disorders and administration site conditionsGeneral disorders0/325/2024/2116/143
Blood and lymphatic system disordersBlood and lymphatic system disorders0/324/2023/2116/143

Baseline characteristics

Age, Continuous
Age, Continuous(years)Regimen A (Long Regimen)Regimen B (Control Regimen)Regimen C (Oral Regimen)Regimen D (6-month Regimen)Total
Median37.0 (26.0 to 42.0)32.8 (25.7 to 40.6)32.8 (26.9 to 42.8)30.8 (25.5 to 41.6)32.7 (26. to 42.1)
Sex: Female, Male
Sex: Female, Male(Participants)Regimen A (Long Regimen)Regimen B (Control Regimen)Regimen C (Oral Regimen)Regimen D (6-month Regimen)Total
Female17817959236
Male1512113284352
Race and Ethnicity Not Collected
Race and Ethnicity Not Collected(Participants)Regimen A (Long Regimen)Regimen B (Control Regimen)Regimen C (Oral Regimen)Regimen D (6-month Regimen)Total
Count of participants————0
Region of Enrollment
Region of Enrollment(participants)Regimen A (Long Regimen)Regimen B (Control Regimen)Regimen C (Oral Regimen)Regimen D (6-month Regimen)Total
Mongolia11464825130
South Africa628322692
Uganda02225956
Moldova42526863
Georgia01312732
Ethiopia621202067
India5474848148
07

Study locations

13 sites
  • Armauer Hanssen Research Institute
    Addis Ababa, Ethiopia
  • St. Peter's Tuberculosis Specializes Hospital
    Addis Ababa, Ethiopia
  • JSC National Center for Tuberculosis and Lung Diseases
    Tbilisi, Georgia
  • BJ Medical College Civil Hospital
    Ahmedabad, India
  • The National Institute for Research in Tuberculosis
    Chennai, India
  • Rajan Babu Institute for Pulmonary Medicine and Tuberculosis
    New Delhi, India
  • Institute of Phthisiopneumology 'Chiril Draganiuc'
    Chisinau, Moldova, Republic of
  • National Centre for Communicable Diseases
    Ulaanbaatar, Mongolia
  • King Dinizulu Hospital
    Durban, South Africa
  • Helen Joseph Hospital
    Johannesburg, South Africa
  • Doris Goodwin Hospital
    Pietermaritzburg, South Africa
  • Empilweni TB Hospital
    Port Elizabeth, South Africa
  • Makerere University (Mulago Referral Hospital)
    Kampala, Uganda
08

References and documents

Publications

  • Van Deun A, Maug AK, Salim MA, Das PK, Sarker MR, Daru P, Rieder HL. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2010 Sep 1;182(5):684-92. doi: 10.1164/rccm.201001-0077OC. Epub 2010 May 4. PubMed 20442432 ↗
  • Laserson KF, Wells CD. Reaching the targets for tuberculosis control: the impact of HIV. Bull World Health Organ. 2007 May;85(5):377-81; discussion 382-6. doi: 10.2471/blt.06.035329. PubMed 17639223 ↗
  • Zignol M, Hosseini MS, Wright A, Weezenbeek CL, Nunn P, Watt CJ, Williams BG, Dye C. Global incidence of multidrug-resistant tuberculosis. J Infect Dis. 2006 Aug 15;194(4):479-85. doi: 10.1086/505877. Epub 2006 Jul 12. PubMed 16845631 ↗
  • Wells CD, Cegielski JP, Nelson LJ, Laserson KF, Holtz TH, Finlay A, Castro KG, Weyer K. HIV infection and multidrug-resistant tuberculosis: the perfect storm. J Infect Dis. 2007 Aug 15;196 Suppl 1:S86-107. doi: 10.1086/518665. PubMed 17624830 ↗
  • Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis: 2011 Update. Geneva: World Health Organization; 2011. Available from http://www.ncbi.nlm.nih.gov/books/NBK148644/ PubMed 23844450 ↗
  • Seung KJ, Omatayo DB, Keshavjee S, Furin JJ, Farmer PE, Satti H. Early outcomes of MDR-TB treatment in a high HIV-prevalence setting in Southern Africa. PLoS One. 2009 Sep 25;4(9):e7186. doi: 10.1371/journal.pone.0007186. PubMed 19779624 ↗
  • Chiang CY, Enarson DA, Yu MC, Bai KJ, Huang RM, Hsu CJ, Suo J, Lin TP. Outcome of pulmonary multidrug-resistant tuberculosis: a 6-yr follow-up study. Eur Respir J. 2006 Nov;28(5):980-5. doi: 10.1183/09031936.06.00125705. Epub 2006 Jul 12. PubMed 16837502 ↗
  • Mitnick C, Bayona J, Palacios E, Shin S, Furin J, Alcantara F, Sanchez E, Sarria M, Becerra M, Fawzi MC, Kapiga S, Neuberg D, Maguire JH, Kim JY, Farmer P. Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med. 2003 Jan 9;348(2):119-28. doi: 10.1056/NEJMoa022928. PubMed 12519922 ↗
  • Leimane V, Riekstina V, Holtz TH, Zarovska E, Skripconoka V, Thorpe LE, Laserson KF, Wells CD. Clinical outcome of individualised treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort study. Lancet. 2005 Jan 22-28;365(9456):318-26. doi: 10.1016/S0140-6736(05)17786-1. PubMed 15664227 ↗
  • Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH, Moll AP, Gandhi NR, Galvani AP. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis. 2009 Mar;9(3):153-61. doi: 10.1016/S1473-3099(09)70041-6. PubMed 19246019 ↗
  • Diacon AH, Donald PR, Pym A, Grobusch M, Patientia RF, Mahanyele R, Bantubani N, Narasimooloo R, De Marez T, van Heeswijk R, Lounis N, Meyvisch P, Andries K, McNeeley DF. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob Agents Chemother. 2012 Jun;56(6):3271-6. doi: 10.1128/AAC.06126-11. Epub 2012 Mar 5. PubMed 22391540 ↗
  • Mann G, Squire SB, Bissell K, Eliseev P, Du Toit E, Hesseling A, Nicol M, Detjen A, Kritski A. Beyond accuracy: creating a comprehensive evidence base for TB diagnostic tools. Int J Tuberc Lung Dis. 2010 Dec;14(12):1518-24. PubMed 21144235 ↗
  • Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, Jankus DD, Debanne SM, Charlebois ED, Maciel E, Palaci M, Dietze R. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006 Jun;10(6):605-12. PubMed 16776446 ↗
  • Lancioni GE, Coninx F, Smeets PM. A classical conditioning procedure for the hearing assessment of multiply handicapped persons. J Speech Hear Disord. 1989 Feb;54(1):88-93. doi: 10.1044/jshd.5401.88. PubMed 2521683 ↗
  • Cegielski JP, Dalton T, Yagui M, Wattanaamornkiet W, Volchenkov GV, Via LE, Van Der Walt M, Tupasi T, Smith SE, Odendaal R, Leimane V, Kvasnovsky C, Kuznetsova T, Kurbatova E, Kummik T, Kuksa L, Kliiman K, Kiryanova EV, Kim H, Kim CK, Kazennyy BY, Jou R, Huang WL, Ershova J, Erokhin VV, Diem L, Contreras C, Cho SN, Chernousova LN, Chen MP, Caoili JC, Bayona J, Akksilp S; Global Preserving Effective TB Treatment Study (PETTS) Investigators. Extensive drug resistance acquired during treatment of multidrug-resistant tuberculosis. Clin Infect Dis. 2014 Oct 15;59(8):1049-63. doi: 10.1093/cid/ciu572. Epub 2014 Jul 23. PubMed 25057101 ↗
  • Fox GJ, Menzies D. A Review of the Evidence for Using Bedaquiline (TMC207) to Treat Multi-Drug Resistant Tuberculosis. Infect Dis Ther. 2013 Dec;2(2):123-44. doi: 10.1007/s40121-013-0009-3. Epub 2013 Aug 2. PubMed 25134476 ↗
  • McClure N, Dornal JC. Early identification of placenta praevia. Br J Obstet Gynaecol. 1990 Oct;97(10):959-61. doi: 10.1111/j.1471-0528.1990.tb02457.x. No abstract available. PubMed 2223692 ↗
  • Hillemann D, Rusch-Gerdes S, Richter E. Feasibility of the GenoType MTBDRsl assay for fluoroquinolone, amikacin-capreomycin, and ethambutol resistance testing of Mycobacterium tuberculosis strains and clinical specimens. J Clin Microbiol. 2009 Jun;47(6):1767-72. doi: 10.1128/JCM.00081-09. Epub 2009 Apr 22. PubMed 19386845 ↗
  • Mohamed K, Embleton A, Cuffe RL. Adjusting for covariates in non-inferiority studies with margins defined as risk differences. Pharm Stat. 2011 Sep-Oct;10(5):461-6. doi: 10.1002/pst.520. PubMed 21956950 ↗
  • Gumbo T, Louie A, Deziel MR, Parsons LM, Salfinger M, Drusano GL. Selection of a moxifloxacin dose that suppresses drug resistance in Mycobacterium tuberculosis, by use of an in vitro pharmacodynamic infection model and mathematical modeling. J Infect Dis. 2004 Nov 1;190(9):1642-51. doi: 10.1086/424849. Epub 2004 Sep 24. Erratum In: J Infect Dis. 2004 Dec 1;190(11):2059. PubMed 15478070 ↗
  • Falagas ME, Rafailidis PI, Rosmarakis ES. Arrhythmias associated with fluoroquinolone therapy. Int J Antimicrob Agents. 2007 Apr;29(4):374-9. doi: 10.1016/j.ijantimicag.2006.11.011. Epub 2007 Jan 22. PubMed 17241772 ↗
  • Altin T, Ozcan O, Turhan S, Ongun Ozdemir A, Akyurek O, Karaoguz R, Guldal M. Torsade de pointes associated with moxifloxacin: a rare but potentially fatal adverse event. Can J Cardiol. 2007 Sep;23(11):907-8. doi: 10.1016/s0828-282x(07)70850-4. PubMed 17876386 ↗
  • Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs. 2002;62(11):1649-71. doi: 10.2165/00003495-200262110-00006. PubMed 12109926 ↗
  • Florian JA, Tornoe CW, Brundage R, Parekh A, Garnett CE. Population pharmacokinetic and concentration--QTc models for moxifloxacin: pooled analysis of 20 thorough QT studies. J Clin Pharmacol. 2011 Aug;51(8):1152-62. doi: 10.1177/0091270010381498. Epub 2011 Jan 12. PubMed 21228407 ↗
  • Tsikouris JP, Peeters MJ, Cox CD, Meyerrose GE, Seifert CF. Effects of three fluoroquinolones on QT analysis after standard treatment courses. Ann Noninvasive Electrocardiol. 2006 Jan;11(1):52-6. doi: 10.1111/j.1542-474X.2006.00082.x. PubMed 16472283 ↗
  • Sherazi S, DiSalle M, Daubert JP, Shah AH. Moxifloxacin-induced torsades de pointes. Cardiol J. 2008;15(1):71-3. PubMed 18651388 ↗
  • Dale KM, Lertsburapa K, Kluger J, White CM. Moxifloxacin and torsade de pointes. Ann Pharmacother. 2007 Feb;41(2):336-40. doi: 10.1345/aph.1H474. Epub 2007 Feb 6. PubMed 17284508 ↗
  • Rubinstein E, Camm J. Cardiotoxicity of fluoroquinolones. J Antimicrob Chemother. 2002 Apr;49(4):593-6. doi: 10.1093/jac/49.4.593. No abstract available. PubMed 11909831 ↗
  • Morganroth J, Dimarco JP, Anzueto A, Niederman MS, Choudhri S; CAPRIE Study Group. A randomized trial comparing the cardiac rhythm safety of moxifloxacin vs levofloxacin in elderly patients hospitalized with community-acquired pneumonia. Chest. 2005 Nov;128(5):3398-406. doi: 10.1378/chest.128.5.3398. PubMed 16304291 ↗
  • Demolis JL, Kubitza D, Tenneze L, Funck-Brentano C. Effect of a single oral dose of moxifloxacin (400 mg and 800 mg) on ventricular repolarization in healthy subjects. Clin Pharmacol Ther. 2000 Dec;68(6):658-66. doi: 10.1067/mcp.2000.111482. PubMed 11180026 ↗
  • Noel GJ, Natarajan J, Chien S, Hunt TL, Goodman DB, Abels R. Effects of three fluoroquinolones on QT interval in healthy adults after single doses. Clin Pharmacol Ther. 2003 Apr;73(4):292-303. doi: 10.1016/s0009-9236(03)00009-2. PubMed 12709719 ↗
  • Sacco F, Spezzaferro M, Amitrano M, Grossi L, Manzoli L, Marzio L. Efficacy of four different moxifloxacin-based triple therapies for first-line H. pylori treatment. Dig Liver Dis. 2010 Feb;42(2):110-4. doi: 10.1016/j.dld.2009.05.013. Epub 2009 Oct 28. PubMed 19846355 ↗
  • Stass H, Dalhoff A, Kubitza D, Schuhly U. Pharmacokinetics, safety, and tolerability of ascending single doses of moxifloxacin, a new 8-methoxy quinolone, administered to healthy subjects. Antimicrob Agents Chemother. 1998 Aug;42(8):2060-5. doi: 10.1128/AAC.42.8.2060. PubMed 9687407 ↗
  • Alffenaar JW, de Vries PM, Luijckx GJ, van Soolingen D, van der Werf TS, van Altena R. Plasma and cerebrospinal fluid pharmacokinetics of moxifloxacin in a patient with tuberculous meningitis. Antimicrob Agents Chemother. 2008 Jun;52(6):2293-5. doi: 10.1128/AAC.01637-07. Epub 2008 Mar 24. No abstract available. PubMed 18362186 ↗
  • Soliman EZ, Lundgren JD, Roediger MP, Duprez DA, Temesgen Z, Bickel M, Shlay JC, Somboonwit C, Reiss P, Stein JH, Neaton JD; INSIGHT SMART Study Group. Boosted protease inhibitors and the electrocardiographic measures of QT and PR durations. AIDS. 2011 Jan 28;25(3):367-77. doi: 10.1097/QAD.0b013e328341dcc0. PubMed 21150558 ↗
  • Nunn AJ, Phillips PPJ, Meredith SK, Chiang CY, Conradie F, Dalai D, van Deun A, Dat PT, Lan N, Master I, Mebrahtu T, Meressa D, Moodliar R, Ngubane N, Sanders K, Squire SB, Torrea G, Tsogt B, Rusen ID; STREAM Study Collaborators. A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis. N Engl J Med. 2019 Mar 28;380(13):1201-1213. doi: 10.1056/NEJMoa1811867. Epub 2019 Mar 13. PubMed 30865791 ↗
  • Moodley R, Godec TR; STREAM Trial Team. Short-course treatment for multidrug-resistant tuberculosis: the STREAM trials. Eur Respir Rev. 2016 Mar;25(139):29-35. doi: 10.1183/16000617.0080-2015. PubMed 26929418 ↗

Study documents

  • Study protocol · Dec 15, 2020
  • Statistical analysis plan · Sep 9, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Data collected for the study, including individual participant data and a data dictionary defining each field in the set, will be made available no later than 12 months after the end of the trial through the TBPACT data repository.

Supporting information: Study protocol, Sap, Icf

09

Registry details

Key details

Study ID
NCT02409290
Lead sponsor
IUATLD, Inc
Collaborators
Medical Research Council, Institute of Tropical Medicine, Belgium, Liverpool School of Tropical Medicine, Rede TB
Responsible party
Sponsor
First posted
Apr 6, 2015
Start date
Mar 2016
Primary completion
May 13, 2022
Completion
May 2, 2023
Results posted
Sep 28, 2023
Last update
Sep 28, 2023

Study contacts

Sarah Meredith, MD
principal investigator · Medical Research Council
Andrew Nunn, PhD
principal investigator · Medical Research Council

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Sep 2023. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

Tuberculosis→

Start the discussion