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A double-blinded randomised placebo-controlled phase II trial to evaluate high dose rifampicin for tuberculous meningitis: a dose finding study

View ORCID ProfileS Dian, V Yunivita, AR Ganiem, T Pramaesya, L Chaidir, K Wahyudi, TH Achmad, A Colbers, L te Brake, R van Crevel, R Ruslami, R Aarnoutse
doi: https://doi.org/10.1101/326587
S Dian
1Department of Internal Medicine, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, the Netherlands. Address: Geert Grooteplein Zuid 10, Nijmegen, the Netherlands. Postal code: 6525 GA (Route 456). Telephone: +31243616980
3Department of Neurology, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin Hospital, Bandung, Indonesia. Address: Pasteur 38, Sukajadi, Bandung, Indonesia. Postal code: 40161. Telephone: +6222 2036984; Fax: +6222 2036984
7TB/HIV Research Centre, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. Address: Eijkman 38, Bandung, Indonesia, Postal code: 40161 Telephone: +6222 2033915; Fax: +6222 2033915
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  • For correspondence: sofiatidian@gmail.com sofiati.dian@radboudumc.nl
V Yunivita
4Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. Address: Eijkman 38, Sukajadi, Bandung, Indonesia. Postal code: 40161
7TB/HIV Research Centre, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. Address: Eijkman 38, Bandung, Indonesia, Postal code: 40161 Telephone: +6222 2033915; Fax: +6222 2033915
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AR Ganiem
3Department of Neurology, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin Hospital, Bandung, Indonesia. Address: Pasteur 38, Sukajadi, Bandung, Indonesia. Postal code: 40161. Telephone: +6222 2036984; Fax: +6222 2036984
7TB/HIV Research Centre, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. Address: Eijkman 38, Bandung, Indonesia, Postal code: 40161 Telephone: +6222 2033915; Fax: +6222 2033915
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T Pramaesya
7TB/HIV Research Centre, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. Address: Eijkman 38, Bandung, Indonesia, Postal code: 40161 Telephone: +6222 2033915; Fax: +6222 2033915
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L Chaidir
5Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. Address: Eijkman 38, Bandung, Indonesia, Postal code: 40161 Telephone: +6222 2037823; Fax: +6222 2037823
7TB/HIV Research Centre, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. Address: Eijkman 38, Bandung, Indonesia, Postal code: 40161 Telephone: +6222 2033915; Fax: +6222 2033915
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K Wahyudi
6Division of Epidemiology and Biostatistics, Department of Public Health, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. Address: Eijkman 38, Bandung, Indonesia, Postal code: 40161 Telephone: +6222 2038138; Fax: +6222 2038138
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TH Achmad
5Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. Address: Eijkman 38, Bandung, Indonesia, Postal code: 40161 Telephone: +6222 2037823; Fax: +6222 2037823
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A Colbers
2Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, the Netherlands. Address: Geert Grooteplein Zuid 10, Nijmegen, the Netherlands. Postal code: 6525 GA (Route 864). Telephone: +31243617744
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L te Brake
2Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, the Netherlands. Address: Geert Grooteplein Zuid 10, Nijmegen, the Netherlands. Postal code: 6525 GA (Route 864). Telephone: +31243617744
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R van Crevel
1Department of Internal Medicine, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, the Netherlands. Address: Geert Grooteplein Zuid 10, Nijmegen, the Netherlands. Postal code: 6525 GA (Route 456). Telephone: +31243616980
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R Ruslami
4Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. Address: Eijkman 38, Sukajadi, Bandung, Indonesia. Postal code: 40161
7TB/HIV Research Centre, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. Address: Eijkman 38, Bandung, Indonesia, Postal code: 40161 Telephone: +6222 2033915; Fax: +6222 2033915
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R Aarnoutse
2Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, the Netherlands. Address: Geert Grooteplein Zuid 10, Nijmegen, the Netherlands. Postal code: 6525 GA (Route 864). Telephone: +31243617744
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ABSTRACT

Background High doses of rifampicin may help tuberculous meningitis (TBM) patients to survive. Pharmacokinetic-pharmacodynamic evaluations suggested that rifampicin doses higher than 13 mg/kg intravenously or 20 mg/kg orally (as previously studied) are warranted to maximize treatment response.

Methods In a double-blinded, randomised, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg or 1350 mg (10, 20 and 30 mg/kg) oral rifampicin combined with other TB drugs for 30 days. Endpoints included pharmacokinetic measures, adverse events and survival.

Results A double and triple dose of oral rifampicin led to three and five-fold higher geometric mean total exposures in plasma in the critical early days (2±1) of treatment (AUC0-24h: 53·5 mg.h/L vs 170·6 mg.h/L vs. 293·5 mg.h/L, p<0·001), with proportional increases in CSF concentrations and without an increase in the incidence of grade 3/4 adverse events. Six-month mortality was 7/20 (35%, 9/20 (45%) and 3/20 (15%) in the 10, 20 and 30 mg/kg groups, respectively (p=0·12).

Conclusions Tripling the standard dose caused a large increase in rifampicin exposure in plasma and CSF and was safe. Survival benefit with this dose should now be evaluated in a larger phase III clinical trial.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 21, 2018.
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A double-blinded randomised placebo-controlled phase II trial to evaluate high dose rifampicin for tuberculous meningitis: a dose finding study
S Dian, V Yunivita, AR Ganiem, T Pramaesya, L Chaidir, K Wahyudi, TH Achmad, A Colbers, L te Brake, R van Crevel, R Ruslami, R Aarnoutse
bioRxiv 326587; doi: https://doi.org/10.1101/326587
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A double-blinded randomised placebo-controlled phase II trial to evaluate high dose rifampicin for tuberculous meningitis: a dose finding study
S Dian, V Yunivita, AR Ganiem, T Pramaesya, L Chaidir, K Wahyudi, TH Achmad, A Colbers, L te Brake, R van Crevel, R Ruslami, R Aarnoutse
bioRxiv 326587; doi: https://doi.org/10.1101/326587

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