Pharmacometrics to Advance Novel Regimens for Drug-resistant Tuberculosis-PandrTB Tuberculosis

NCT03827811 | Unknown

• 1 other identifier: PandrTB
• Study Type: observational
• Target: 625
• Locations: 6 countries
• Sites: 7

Brief Summary

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).

Conditions

Multi-drug Resistant Tuberculosis

Keywords

MDR

Outcome Measures

Primary Outcomes (3)

• Drug exposure (AUC)

  drug exposures derived using population PK models

  5 years

• 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

• 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

Study Arms (1)

PandrTB cohort

endTB and endTB-Q study participants on experimental regimen

Eligibility Criteria

• Age: 15 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Adults and adolescents (≥15 years) will be enrolled. There is increasing recognition that adolescents have been neglected in the development of treatments for diseases like HIV and TB, given that they comprise and important population. Minors are included in the endTB clinical trial and it would be wrong to exclude them from a PK study designed to optimize doses.

You may qualify if:

• All patients enrolled to the experimental arms of the endTB study and provide their written informed consent to participate in the PandrTB study.

Sponsors & Collaborators

• University of Cape Town: lead
• Partners in Health: collaborator
• Epicentre: collaborator
• Medecins Sans Frontieres, Netherlands: collaborator
• Institute of Tropical Medicine, Belgium: collaborator
• Interactive Research and Development: collaborator

Study Sites (7)

National Scientific Center of Phthisiopulmonology

Almaty, Kazakhstan

RECRUITING

Partners in Health Lesotho House 233 Corner Lancers and Caldwell Roads

Maseru, 100, Lesotho

COMPLETED

Indus Hospital

Karachi, Pakistan

RECRUITING

Peru-1

Lima, Peru

RECRUITING

Peru_2

Lima, Peru

RECRUITING

Khayelitsha Town 2 Clinic

Cape Town, Western Cape, 7764, South Africa

TERMINATED

Hanoi Lung Hospital

Hanoi, Vietnam

RECRUITING

Related Publications (45)

• Horsburgh CR, Rusen ID, Mitnick CD. Optimizing MDR-TB clinical trials: insights from the first global MDR-TB Clinical Trials Landscape Meeting. Int J Tuberc Lung Dis. 2016 Dec 1;20(12):1-3. doi: 10.5588/ijtld.16.0568. No abstract available.

  PMID: 28240564 BACKGROUND

• 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.

  PMID: 25140958 BACKGROUND

• Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, Becerra MC, Benedetti A, Burgos M, Centis R, Chan ED, Chiang CY, Cox H, D'Ambrosio L, DeRiemer K, Dung NH, Enarson D, Falzon D, Flanagan K, Flood J, Garcia-Garcia ML, Gandhi N, Granich RM, Hollm-Delgado MG, Holtz TH, Iseman MD, Jarlsberg LG, Keshavjee S, Kim HR, Koh WJ, Lancaster J, Lange C, de Lange WC, Leimane V, Leung CC, Li J, Menzies D, Migliori GB, Mishustin SP, Mitnick CD, Narita M, O'Riordan P, Pai M, Palmero D, Park SK, Pasvol G, Pena J, Perez-Guzman C, Quelapio MI, Ponce-de-Leon A, Riekstina V, Robert J, Royce S, Schaaf HS, Seung KJ, Shah L, Shim TS, Shin SS, Shiraishi Y, Sifuentes-Osornio J, Sotgiu G, Strand MJ, Tabarsi P, Tupasi TE, van Altena R, Van der Walt M, Van der Werf TS, Vargas MH, Viiklepp P, Westenhouse J, Yew WW, Yim JJ; Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Med. 2012;9(8):e1001300. doi: 10.1371/journal.pmed.1001300. Epub 2012 Aug 28.

  PMID: 22952439 BACKGROUND

• 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.

  PMID: 28240569 BACKGROUND

• 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.

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• 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.

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• 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.

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• 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.

  PMID: 22670901 BACKGROUND

• 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.

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• Lamprecht DA, Finin PM, Rahman MA, Cumming BM, Russell SL, Jonnala SR, Adamson JH, Steyn AJ. Turning the respiratory flexibility of Mycobacterium tuberculosis against itself. Nat Commun. 2016 Aug 10;7:12393. doi: 10.1038/ncomms12393.

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• 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.

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• Tang S, Yao L, Hao X, Liu Y, Zeng L, Liu G, Li M, Li F, Wu M, Zhu Y, Sun H, Gu J, Wang X, Zhang Z. Clofazimine for the treatment of multidrug-resistant tuberculosis: prospective, multicenter, randomized controlled study in China. Clin Infect Dis. 2015 May 1;60(9):1361-7. doi: 10.1093/cid/civ027. Epub 2015 Jan 20.

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• U.S. Food and Drug Administration. NDA 204-384 Sirturo™ (bedaquiline 100 mg tablets) for the treatment of adults (≥ 18 years) as part of combination therapy of pulmonary multi-drug resistant tuberculosis (MDRTB). 2012 Nov 28;1-69

  BACKGROUND

• 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.

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• 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.

  PMID: 28240573 BACKGROUND

• 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.

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• Cox HS, Sibilia K, Feuerriegel S, Kalon S, Polonsky J, Khamraev AK, Rusch-Gerdes S, Mills C, Niemann S. Emergence of extensive drug resistance during treatment for multidrug-resistant tuberculosis. N Engl J Med. 2008 Nov 27;359(22):2398-400. doi: 10.1056/NEJMc0805644. No abstract available.

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• 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

• 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.

  PMID: 26871879 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

• 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.

  PMID: 24821594 BACKGROUND

• 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.

  PMID: 25010492 BACKGROUND

• 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.

  PMID: 23901086 BACKGROUND

• Chigutsa E, Pasipanodya JG, Visser ME, van Helden PD, Smith PJ, Sirgel FA, Gumbo T, McIlleron H. Impact of nonlinear interactions of pharmacokinetics and MICs on sputum bacillary kill rates as a marker of sterilizing effect in tuberculosis. Antimicrob Agents Chemother. 2015 Jan;59(1):38-45. doi: 10.1128/AAC.03931-14. Epub 2014 Oct 13.

  PMID: 25313213 BACKGROUND

• 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.

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• Srivastava S, Pasipanodya JG, Meek C, Leff R, Gumbo T. Multidrug-resistant tuberculosis not due to noncompliance but to between-patient pharmacokinetic variability. J Infect Dis. 2011 Dec 15;204(12):1951-9. doi: 10.1093/infdis/jir658. Epub 2011 Oct 21.

  PMID: 22021624 BACKGROUND

• 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):e00139-10. doi: 10.1128/mBio.00139-10.

  PMID: 20802826 BACKGROUND

• 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.

  PMID: 26552972 BACKGROUND

• 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.

  PMID: 22411614 BACKGROUND

• 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.

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• 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.

  PMID: 26260983 BACKGROUND

• 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.

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• Irwin SM, Gruppo V, Brooks E, Gilliland J, Scherman M, Reichlen MJ, Leistikow R, Kramnik I, Nuermberger EL, Voskuil MI, Lenaerts AJ. Limited activity of clofazimine as a single drug in a mouse model of tuberculosis exhibiting caseous necrotic granulomas. Antimicrob Agents Chemother. 2014 Jul;58(7):4026-34. doi: 10.1128/AAC.02565-14. Epub 2014 May 5.

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• 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.

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• Te Brake LH, Russel FG, van den Heuvel JJ, de Knegt GJ, de Steenwinkel JE, Burger DM, Aarnoutse RE, Koenderink JB. Inhibitory potential of tuberculosis drugs on ATP-binding cassette drug transporters. Tuberculosis (Edinb). 2016 Jan;96:150-7. doi: 10.1016/j.tube.2015.08.004. Epub 2015 Oct 9.

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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.

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• Svensson EM, Aweeka F, Park JG, Marzan F, Dooley KE, Karlsson MO. Model-based estimates of the effects of efavirenz on bedaquiline pharmacokinetics and suggested dose adjustments for patients coinfected with HIV and tuberculosis. Antimicrob Agents Chemother. 2013 Jun;57(6):2780-7. doi: 10.1128/AAC.00191-13. Epub 2013 Apr 9.

  PMID: 23571542 BACKGROUND

• 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.

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• Mallikaarjun S, Wells C, Petersen C, Paccaly A, Shoaf SE, Patil S, Geiter L. Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects. Antimicrob Agents Chemother. 2016 Sep 23;60(10):5976-85. doi: 10.1128/AAC.00509-16. Print 2016 Oct.

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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.

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• Svensson E. A model-based analysis to describe bedaquiline's exposure-response relationship and predict the impact of drug-drug interactions. 9th Int workshop on Clinical Pharmacology of Tuberculosis Drugs 2016, Liverpool October 2016; Abstract O_01.

  BACKGROUND

• Taubel J, Naseem A, Harada T, Wang D, Arezina R, Lorch U, Camm AJ. Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers. Br J Clin Pharmacol. 2010 Apr;69(4):391-400. doi: 10.1111/j.1365-2125.2009.03595.x.

  PMID: 20406223 BACKGROUND

• 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.

  PMID: 28175315 BACKGROUND

Related Links

• World Health Organization. Global tuberculosis report 2016. Geneva: WHO; 2016

Biospecimen

Retention: SAMPLES WITH DNA

Whole blood will be stored for evaluation of genetic variants associated with drug concentrations and effects.

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant

Condition Hierarchy (Ancestors)

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

Study Officials

• Helen McIlleron, PhD

  University of Cape Town

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Helen McIlleron, PhD

CONTACT

27214066779; helen.mcilleron@uct.ac.za

Marilyn Solomons

CONTACT

0244066779; marilyn.solomons@uct.ac.za

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: August 7, 2018
• First Posted: February 1, 2019
• Study Start: January 30, 2020
• Primary Completion: April 30, 2023
• Study Completion: April 30, 2023
• Last Updated: November 4, 2022

Record last verified: 2022-11

Locations

VN (1); PA (1); LE (1); PE (2); KA (1); ZA (1)