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

NCT02409290 | Completed Phase 3 Results DMC

• 1 other identifier: 78372190/18148631 (Stage 1/2)
• Study Type: interventional
• Target: 588
• Locations: 6 countries
• Sites: 12

Brief 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.

Conditions

MDR-TB

Outcome Measures

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

  76 weeks

Other Outcomes (4)

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

  Last efficacy visit, between 96 and 132 weeks

• Proportion of Patients With Acquired Drug Resistance

  132 weeks

• Failure or Recurrence (FoR)

  final efficacy week (between 96 and 132 weeks)

Study Arms (4)

Regimen A

ACTIVE COMPARATOR

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)

Regimen B

ACTIVE COMPARATOR

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

Regimen C

EXPERIMENTAL

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

Regimen D

EXPERIMENTAL

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

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

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

Regimen A

Moxifloxacin DRUG

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

Also known as: Avelox

Regimen B

Clofazimine DRUG

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

Regimen B; Regimen C; Regimen D

Ethambutol DRUG

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

Regimen B; Regimen C

Pyrazinamide DRUG

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

Regimen B; Regimen C; Regimen D

Isoniazid DRUG

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

Regimen B; Regimen C; Regimen D

Prothionamide DRUG

Prothionamide has a bacteriostatic action.

Also known as: Peteha

Regimen B; Regimen C

Kanamycin DRUG

Kanamycin is a bactericidal antibiotic from the group of aminoglycosides.

Also known as: Kantrex

Regimen B; Regimen D

Levofloxacin DRUG

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

Regimen B; Regimen C; Regimen D

Bedaquiline DRUG

Bedaquiline is a novel diarylquinoline antibiotic with bactericidal activity

Also known as: SIRTURO

Regimen C; Regimen D

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Age: Is aged 18 years or older (Stage 1) or 15 years or older (Stage 2)
• 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
• 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
• 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
• 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
• Resides in the area and expected to remain for the duration of the study.
• 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)
• Has normal K+, Mg2+ and corrected Ca2+ at screening.

You may not qualify if:

• 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
• 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
• Has tuberculous meningitis or bone and joint tuberculosis
• Is critically ill, and in the judgment of the investigator, unlikely to survive more than 4 months
• Is known to be pregnant or breast-feeding
• Is unable or unwilling to comply with the treatment, assessment, or follow-up schedule
• Is unable to take oral medication
• 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
• Has any condition (social or medical) which in the opinion of the investigator would make study participation unsafe
• 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
• Is taking any medications contraindicated with the medicines in any trial regimen
• Has a known allergy to any fluoroquinolone antibiotic
• Is currently taking part in another trial of a medicinal product
• 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:

Sponsors & Collaborators

• IUATLD, Inc: lead
• Medical Research Council: collaborator
• Institute of Tropical Medicine, Belgium: collaborator
• Liverpool School of Tropical Medicine: collaborator
• Rede TB: collaborator

Study Sites (13)

Armauer Hanssen Research Institute

Addis Ababa, Ethiopia

Location

St. Peter's Tuberculosis Specializes Hospital

Addis Ababa, Ethiopia

Location

JSC National Center for Tuberculosis and Lung Diseases

Tbilisi, Georgia

Location

BJ Medical College Civil Hospital

Ahmedabad, India

Location

The National Institute for Research in Tuberculosis

Chennai, India

Location

Rajan Babu Institute for Pulmonary Medicine and Tuberculosis

New Delhi, India

Location

Institute of Phthisiopneumology 'Chiril Draganiuc'

Chisinau, Moldova

Location

National Centre for Communicable Diseases

Ulaanbaatar, Mongolia

Location

King Dinizulu Hospital

Durban, South Africa

Location

Helen Joseph Hospital

Johannesburg, South Africa

Location

Doris Goodwin Hospital

Pietermaritzburg, South Africa

Location

Empilweni TB Hospital

Port Elizabeth, South Africa

Location

Makerere University (Mulago Referral Hospital)

Kampala, Uganda

Location

Related Publications (38)

• 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.

  PMID: 20442432 BACKGROUND

• 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.

  PMID: 17639223 BACKGROUND

• 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.

  PMID: 16845631 BACKGROUND

• 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.

  PMID: 17624830 BACKGROUND

• 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/

  PMID: 23844450 BACKGROUND

• 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.

  PMID: 19779624 BACKGROUND

• 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.

  PMID: 16837502 BACKGROUND

• 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.

  PMID: 12519922 BACKGROUND

• 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.

  PMID: 15664227 BACKGROUND

• 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.

  PMID: 19246019 BACKGROUND

• 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.

  PMID: 22391540 BACKGROUND

• 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.

  PMID: 21144235 BACKGROUND

• 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.

  PMID: 16776446 BACKGROUND

• 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.

  PMID: 2521683 BACKGROUND

• 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.

  PMID: 25057101 BACKGROUND

• 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.

  PMID: 25134476 BACKGROUND

• 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.

  PMID: 2223692 BACKGROUND

• 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.

  PMID: 19386845 BACKGROUND

• 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.

  PMID: 21956950 BACKGROUND

• 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.

  PMID: 15478070 BACKGROUND

• 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.

  PMID: 17241772 BACKGROUND

• 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.

  PMID: 17876386 BACKGROUND

• 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.

  PMID: 12109926 BACKGROUND

• 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.

  PMID: 21228407 BACKGROUND

• 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.

  PMID: 16472283 BACKGROUND

• Sherazi S, DiSalle M, Daubert JP, Shah AH. Moxifloxacin-induced torsades de pointes. Cardiol J. 2008;15(1):71-3.

  PMID: 18651388 BACKGROUND

• 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.

  PMID: 17284508 BACKGROUND

• 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.

  PMID: 11909831 BACKGROUND

• 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.

  PMID: 16304291 BACKGROUND

• 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.

  PMID: 11180026 BACKGROUND

• 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.

  PMID: 12709719 BACKGROUND

• 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.

  PMID: 19846355 BACKGROUND

• 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.

  PMID: 9687407 BACKGROUND

• 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.

  PMID: 18362186 BACKGROUND

• 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.

  PMID: 21150558 BACKGROUND

• Hughes G, Young WJ, Bern H, Crook A, Lambiase PD, Goodall RL, Nunn AJ, Meredith SK. T-wave morphology abnormalities in the STREAM stage 1 trial. Expert Opin Drug Saf. 2024 Apr;23(4):469-476. doi: 10.1080/14740338.2024.2322116. Epub 2024 Mar 10.

  PMID: 38462751 DERIVED

• 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.

  PMID: 30865791 DERIVED

• 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.

  PMID: 26929418 DERIVED

Related Links

• Medical Research Council at UCL's web page containing information on the trial
• The International Union Against Tuberculosis and Lung Disease web page containing information on the trial

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant

Interventions

Moxifloxacin; Clofazimine; Ethambutol; Pyrazinamide; Isoniazid; Prothionamide; Kanamycin; Levofloxacin; bedaquiline

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Phenazines; Heterocyclic Compounds, 3-Ring; Ethylenediamines; Diamines; Polyamines; Amines; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Aminoglycosides; Glycosides; Carbohydrates; Ofloxacin

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.

Results Point of Contact

• Title: Dr Ruth Goodall
• Organization: MRC CTU at UCL, University College London, London UK

r.goodall@ucl.ac.uk

+44 2076704728

Study Officials

• Sarah Meredith, MD

  Medical Research Council

  PRINCIPAL INVESTIGATOR

• Andrew Nunn, PhD

  Medical Research Council

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 31, 2015
• First Posted: April 6, 2015
• Study Start: March 1, 2016
• Primary Completion: May 13, 2022
• Study Completion: May 2, 2023
• Last Updated: September 28, 2023
• Results First Posted: September 28, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: From May 2024 at the latest.
• Access Criteria: Application to CPATH as described on the website.

Locations

IN (3); MO (1); GE (1); ZA (4); ET (2); UG (1)