Multi-drug Resistant Tuberculosis Clinical Trial
— PandrTBOfficial title:
Pharmacometrics to Advance Novel Regimens for Drug-resistant Tuberculosis
NCT number | NCT03827811 |
Other study ID # | PandrTB |
Secondary ID | |
Status | Recruiting |
Phase | |
First received | |
Last updated | |
Start date | January 30, 2020 |
Est. completion date | April 30, 2023 |
PandrTB is a study of the pharmacokinetics(PK) and pharmacodynamics(PD) of bedaquiline, delamanid, clofazimine, linezolid, moxifloxacin, levofloxacin and pyrazinamide used in novel combinations to treat multidrug-resistant tuberculosis(MDR-TB).
Status | Recruiting |
Enrollment | 625 |
Est. completion date | April 30, 2023 |
Est. primary completion date | April 30, 2023 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 15 Years to 99 Years |
Eligibility | Inclusion Criteria: All patients enrolled to the experimental arms of the endTB study and provide their written informed consent to participate in the PandrTB study. Exclusion Criteria: - |
Country | Name | City | State |
---|---|---|---|
Kazakhstan | National Scientific Center of Phthisiopulmonology | Almaty | |
Lesotho | Partners in Health Lesotho House 233 Corner Lancers and Caldwell Roads | Maseru | |
Pakistan | Indus Hospital | Karachi | |
Peru | Peru-1 | Lima | |
Peru | Peru_2 | Lima | |
South Africa | Khayelitsha Town 2 Clinic | Cape Town | Western Cape |
Vietnam | Hanoi Lung Hospital | Hanoi |
Lead Sponsor | Collaborator |
---|---|
University of Cape Town | Epicentre, Institute of Tropical Medicine, Belgium, Interactive Research and Development, Medecins Sans Frontieres, Netherlands, Partners in Health |
Kazakhstan, Lesotho, Pakistan, Peru, South Africa, Vietnam,
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Andries K, Villellas C, Coeck N, Thys K, Gevers T, Vranckx L, Lounis N, de Jong BC, Koul A. Acquired resistance of Mycobacterium tuberculosis to bedaquiline. PLoS One. 2014 Jul 10;9(7):e102135. doi: 10.1371/journal.pone.0102135. eCollection 2014. — View Citation
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Chigutsa E, Patel K, Denti P, Visser M, Maartens G, Kirkpatrick CM, McIlleron H, Karlsson MO. A time-to-event pharmacodynamic model describing treatment response in patients with pulmonary tuberculosis using days to positivity in automated liquid mycobacterial culture. Antimicrob Agents Chemother. 2013 Feb;57(2):789-95. doi: 10.1128/AAC.01876-12. Epub 2012 Nov 26. — View Citation
Chigutsa E, Visser ME, Swart EC, Denti P, Pushpakom S, Egan D, Holford NH, Smith PJ, Maartens G, Owen A, McIlleron H. The SLCO1B1 rs4149032 polymorphism is highly prevalent in South Africans and is associated with reduced rifampin concentrations: dosing implications. Antimicrob Agents Chemother. 2011 Sep;55(9):4122-7. doi: 10.1128/AAC.01833-10. Epub 2011 Jun 27. — View Citation
Chirehwa MT, Rustomjee R, Mthiyane T, Onyebujoh P, Smith P, McIlleron H, Denti P. Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction. Antimicrob Agents Chemother. 2015 Nov 9;60(1):487-94. doi: 10.1128/AAC.01830-15. Print 2016 Jan. Erratum in: Antimicrob Agents Chemother. 2016 May;60(5):3262. — View Citation
Cox H, Ford N. Linezolid for the treatment of complicated drug-resistant tuberculosis: a systematic review and meta-analysis. Int J Tuberc Lung Dis. 2012 Apr;16(4):447-54. doi: 10.5588/ijtld.11.0451. Review. — View Citation
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Dheda K, Esmail A, Limberis J, Maartens G. Selected questions and controversies about bedaquiline: a view from the field. Int J Tuberc Lung Dis. 2016 Dec 1;20(12):24-32. doi: 10.5588/ijtld.16.0065. Review. — View Citation
Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, Leimane V, Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, De Paepe E, van Heeswijk RP, Dannemann B; TMC207-C208 Study Group. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014 Aug 21;371(8):723-32. doi: 10.1056/NEJMoa1313865. — View Citation
Drusano GL, Sgambati N, Eichas A, Brown DL, Kulawy R, Louie A. The combination of rifampin plus moxifloxacin is synergistic for suppression of resistance but antagonistic for cell kill of Mycobacterium tuberculosis as determined in a hollow-fiber infection model. mBio. 2010 Aug 10;1(3). pii: e00139-10. doi: 10.1128/mBio.00139-10. — View Citation
Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, Gao M, Awad M, Park SK, Shim TS, Suh GY, Danilovits M, Ogata H, Kurve A, Chang J, Suzuki K, Tupasi T, Koh WJ, Seaworth B, Geiter LJ, Wells CD. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med. 2012 Jun 7;366(23):2151-60. doi: 10.1056/NEJMoa1112433. — View Citation
Gumbo T, Chigutsa E, Pasipanodya J, Visser M, van Helden PD, Sirgel FA, McIlleron H. The pyrazinamide susceptibility breakpoint above which combination therapy fails. J Antimicrob Chemother. 2014 Sep;69(9):2420-5. doi: 10.1093/jac/dku136. Epub 2014 May 12. — View Citation
Gupta R, Wells CD, Hittel N, Hafkin J, Geiter LJ. Delamanid in the treatment of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2016 Dec 1;20(12):33-37. doi: 10.5588/ijtld.16.0125. Review. — View Citation
Horita Y, Doi N. Comparative study of the effects of antituberculosis drugs and antiretroviral drugs on cytochrome P450 3A4 and P-glycoprotein. Antimicrob Agents Chemother. 2014 Jun;58(6):3168-76. doi: 10.1128/AAC.02278-13. Epub 2014 Mar 24. — View Citation
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Kang YA, Shim TS, Koh WJ, Lee SH, Lee CH, Choi JC, Lee JH, Jang SH, Yoo KH, Jung KH, Kim KU, Choi SB, Ryu YJ, Kim KC, Um S, Kwon YS, Kim YH, Choi WI, Jeon K, Hwang YI, Kim SJ, Lee HK, Heo E, Yim JJ. Choice between Levofloxacin and Moxifloxacin and Multidrug-Resistant Tuberculosis Treatment Outcomes. Ann Am Thorac Soc. 2016 Mar;13(3):364-70. doi: 10.1513/AnnalsATS.201510-690BC. — View Citation
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Lenaerts A, Barry CE 3rd, Dartois V. Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses. Immunol Rev. 2015 Mar;264(1):288-307. doi: 10.1111/imr.12252. Review. — View Citation
Lewis JM, Sloan DJ. The role of delamanid in the treatment of drug-resistant tuberculosis. Ther Clin Risk Manag. 2015 May 13;11:779-91. doi: 10.2147/TCRM.S71076. eCollection 2015. Review. — View Citation
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McIlleron H, Rustomjee R, Vahedi M, Mthiyane T, Denti P, Connolly C, Rida W, Pym A, Smith PJ, Onyebujoh PC. Reduced antituberculosis drug concentrations in HIV-infected patients who are men or have low weight: implications for international dosing guidelines. Antimicrob Agents Chemother. 2012 Jun;56(6):3232-8. doi: 10.1128/AAC.05526-11. Epub 2012 Mar 12. — View Citation
Modongo C, Pasipanodya JG, Magazi BT, Srivastava S, Zetola NM, Williams SM, Sirugo G, Gumbo T. Artificial Intelligence and Amikacin Exposures Predictive of Outcomes in Multidrug-Resistant Tuberculosis Patients. Antimicrob Agents Chemother. 2016 Sep 23;60(10):5928-32. doi: 10.1128/AAC.00962-16. Print 2016 Oct. — View Citation
Naidoo A, Chirehwa M, McIlleron H, Naidoo K, Essack S, Yende-Zuma N, Kimba-Phongi E, Adamson J, Govender K, Padayatchi N, Denti P. Effect of rifampicin and efavirenz on moxifloxacin concentrations when co-administered in patients with drug-susceptible TB. J Antimicrob Chemother. 2017 May 1;72(5):1441-1449. doi: 10.1093/jac/dkx004. — View Citation
Nuermberger E. Evolving strategies for dose optimization of linezolid for treatment of tuberculosis. Int J Tuberc Lung Dis. 2016 Dec 1;20(12):48-51. doi: 10.5588/ijtld.16.0113. Review. — View Citation
O'Donnell MR, Padayatchi N, Metcalfe JZ. Elucidating the role of clofazimine for the treatment of tuberculosis. Int J Tuberc Lung Dis. 2016 Dec 1;20(12):52-57. doi: 10.5588/ijtld.16.0073. Review. — View Citation
Pandie M, Wiesner L, McIlleron H, Hughes J, Siwendu S, Conradie F, Variava E, Maartens G. Drug-drug interactions between bedaquiline and the antiretrovirals lopinavir/ritonavir and nevirapine in HIV-infected patients with drug-resistant TB. J Antimicrob Chemother. 2016 Apr;71(4):1037-40. doi: 10.1093/jac/dkv447. Epub 2016 Jan 7. — View Citation
Pasipanodya JG, McIlleron H, Burger A, Wash PA, Smith P, Gumbo T. Serum drug concentrations predictive of pulmonary tuberculosis outcomes. J Infect Dis. 2013 Nov 1;208(9):1464-73. doi: 10.1093/infdis/jit352. Epub 2013 Jul 29. — View Citation
Savic RM, Ruslami R, Hibma JE, Hesseling A, Ramachandran G, Ganiem AR, Swaminathan S, McIlleron H, Gupta A, Thakur K, van Crevel R, Aarnoutse R, Dooley KE. Pediatric tuberculous meningitis: Model-based approach to determining optimal doses of the anti-tuberculosis drugs rifampin and levofloxacin for children. Clin Pharmacol Ther. 2015 Dec;98(6):622-9. doi: 10.1002/cpt.202. Epub 2015 Oct 22. — View Citation
Shenje J, Ifeoma Adimora-Nweke F, Ross IL, Ntsekhe M, Wiesner L, Deffur A, McIlleron HM, Pasipanodya J, Gumbo T, Mayosi BM. Poor Penetration of Antibiotics Into Pericardium in Pericardial Tuberculosis. EBioMedicine. 2015 Sep 16;2(11):1640-9. doi: 10.1016/j.ebiom.2015.09.025. eCollection 2015 Nov. — View Citation
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Svensson EM, Dooley KE, Karlsson MO. Impact of lopinavir-ritonavir or nevirapine on bedaquiline exposures and potential implications for patients with tuberculosis-HIV coinfection. Antimicrob Agents Chemother. 2014 Nov;58(11):6406-12. doi: 10.1128/AAC.03246-14. Epub 2014 Aug 11. — View Citation
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van Heeswijk RP, Dannemann B, Hoetelmans RM. Bedaquiline: a review of human pharmacokinetics and drug-drug interactions. J Antimicrob Chemother. 2014 Sep;69(9):2310-8. doi: 10.1093/jac/dku171. Epub 2014 May 23. Review. — View Citation
Zvada SP, Denti P, Sirgel FA, Chigutsa E, Hatherill M, Charalambous S, Mungofa S, Wiesner L, Simonsson US, Jindani A, Harrison T, McIlleron HM. Moxifloxacin population pharmacokinetics and model-based comparison of efficacy between moxifloxacin and ofloxacin in African patients. Antimicrob Agents Chemother. 2014;58(1):503-10. doi: 10.1128/AAC.01478-13. Epub 2013 Nov 4. — View Citation
* Note: There are 45 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Drug exposure (AUC) | drug exposures derived using population PK models | 5 years | |
Primary | Rate of decline of viable M.tubercolosis in sputum | A pharmacodynamic biomarker model of response to treatment will be used to derive the rate of decline of Mtb in MIGT cultures. The effect of PK on this measure will be evaluated. | 5 years | |
Primary | Collecting adverse events as a measure of safety | The effect of pharmacokinetics on drug and regimen saftey will be evaluated using recursive partitioning methods. | 5 years |
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