{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T19:36:19Z","timestamp":1779219379544,"version":"3.51.4"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.15565.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2020,8,25]],"date-time":"2020-08-25T00:00:00Z","timestamp":1598313600000}}],"reference-count":46,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2020,8,25]],"date-time":"2020-08-25T00:00:00Z","timestamp":1598313600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002992","name":"Department for International Development, UK Government","doi-asserted-by":"publisher","award":["MR\/S004963\/1"],"award-info":[{"award-number":["MR\/S004963\/1"]}],"id":[{"id":"10.13039\/501100002992","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/S004963\/1"],"award-info":[{"award-number":["MR\/S004963\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["MR\/S004963\/1"],"award-info":[{"award-number":["MR\/S004963\/1"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["210772"],"award-info":[{"award-number":["210772"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["MR\/S004963\/1"],"award-info":[{"award-number":["MR\/S004963\/1"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:<\/ns4:bold>\n                    Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in &gt;50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg\/kg) for 8 weeks will improve survival compared to standard of care (10 mg\/kg), without excess adverse events.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Protocol:<\/ns4:bold>\n                    We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg\/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg\/kg\/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Discussion:<\/ns4:bold>\n                    Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Trial registration:<\/ns4:bold>\n                    <ns4:ext-link xmlns:ns3=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" ns3:href=\"http:\/\/www.isrctn.com\/ISRCTN15668391\">ISRCTN15668391<\/ns4:ext-link>\n                    (17\/06\/2019)\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.15565.2","type":"journal-article","created":{"date-parts":[[2020,8,25]],"date-time":"2020-08-25T03:50:07Z","timestamp":1598327407000},"page":"190","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)"],"prefix":"10.12688","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8050-9610","authenticated-orcid":false,"given":"Suzaan","family":"Marais","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5070-532X","authenticated-orcid":false,"given":"Fiona V","family":"Cresswell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5007-7896","authenticated-orcid":false,"given":"Raph L.","family":"Hamers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsey H.M.","family":"te Brake","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmad 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.17819.r40134, Olivier Marcy, Centre INSERM U1219, Bordeaux Population Health, University of Bordeaux, Bordeaux, France, 07 Oct 2020, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-190\/v2#referee-response-40134","order":0,"name":"referee-response-40134","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.17046.r39145, Tihana Bicanic, Centre for Global Health, Institute for Infection and Immunity, St George's, University of London, London, UK, 02 Jul 2020, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-190\/v1#referee-response-39145","order":1,"name":"referee-response-39145","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Fiona Cresswell<\/b>; \n<i>Posted: 03 Aug 2020<\/i>; We thank Dr Bicanic for her expert comments on the protocol and address them in turn below.Comment 1. The rationale for the study is based on sound phase 2 data, however (as mentioned by Reviewer 1) I would urge the authors\/investigators to expand a little on the rationale for the choice of the 35mg\/kg rifampicin dose.&nbsp;\n<i>Response 1. We have added further detail explaining the rationale for this choice of dose in pulmonary TB treatment, as shown below. We have also added further detail to the description of the PK-PD model-based analysis using data from Indonesian patients with TBM. Together, we hope this makes the rationale for this choice of 35mg\/kg dose in the Harvest trial clear.<\/i>&nbsp;\n<i>&quot;The PanACEA multi-arm multistage trial showed that time to stable culture conversion in liquid media was faster in the 35 mg\/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1&middot;78; 95% confidence interval (CI) 1&middot;22\u20132&middot;58, p=0&middot;003), but not in other experimental arms. In an additional analysis, increasing rifampicin exposure was also associated with shortened time to stable culture conversion. The effect did not plateau, indicating that doses &gt;35 mg\/kg could be yet more effective.<\/i>\n<i>High-doses rifampicin was also associated with a greater estimated fall in M. tuberculosis bacillary load in sputum of patients with pulmonary TB at 2 weeks follow up, i.e. high-dose rifampicin showed increased \u2018early bactericidal activity\u2019. Recent analyses of one of these latter trials (the PanACEA HIGHRIF1 trial) included doses up to 40 mg\/kg, demonstrating a further effect of rifampicin exposure on early bactericidal activity and clinical trial simulations showed greater early bactericidal activity for 50 mg\/kg rifampicin. Recent evaluations of administration of this 50 mg\/kg rifampicin dose show that this dose is not well-tolerated. The maximum tolerable dose for rifampicin in PTB is therefore set at 40 mg\/kg daily (R. Aarnoutse and L. te Brake, personal communication, data from the PanACEA HIGHRIF1 trial).<\/i>\n<i>In summary, data from pulmonary TB have shown that higher rifampicin doses, starting with at least 20 mg\/kg daily but certainly at 35 mg\/kg orally, result in strongly increased systemic exposures to rifampicin, were safe, tolerated, and resulted in increased response, as reflected in improved early bactericidal activity and shorter time to culture conversion. These lessons learnt in pulmonary TB are relevant to TBM treatment, considering the key role of rifampicin in TBM treatment and the limited CSF penetration seen at standard dose.<\/i>\n<i>Further, model-based meta-analysis of data from TB meningitis patients in Indonesia predicted an increase in 6-month survival from approximately 50% to approximately 70% upon increasing the oral rifampicin dose from 10 to 30 mg\/kg, and predicted that even higher doses would further improve survival\u201d<\/i>Comment 2.&nbsp;The study design, study endpoints and sample size calculation are sound.I have a few minor suggestions for improvement of the manuscript\/protocol:&nbsp;Comment 3.&nbsp;Introduction - limitations of standard dose rifampicin - are there any data (animal or human) on brain (in addition to CSF) penetration of rifampicin? If so, include.\n<i>Response 3. Thank you for raising this point. There is some interesting recent data on brain (intralesional) rifampicin pharmacokinetics derived from rabbit models of experimentally induced TBM using serial noninvasive dynamic 11C-rifampin positron emission tomography (PET) over 6 weeks. Rifampin penetration into infected brain lesions is limited, spatially heterogeneous, and decreases rapidly as early as 2 weeks into treatment. Moreover, rifampin concentrations in the cerebrospinal fluid did not correlate well with those in the brain lesions. First-in-human 11C-rifampin PET performed in a patient with TBM confirmed these findings. PK modeling using this data predicted that rifampin doses (\u226530 mg\/kg) were required to achieve adequate intralesional concentrations in TBM (Tucker EW, Sci Transl Med, 2018). This information and citation have been added to the protocol.<\/i>Comment 4.&nbsp;Introduction - fig 1- this figure seems quite generic and out of context and could be omitted.\n<i>Response 4. We have decided to retain the figure as we are keen to visually highlight that fact that the CSF compartment, blood and brain compartment are distinct (yet related). &nbsp;<\/i>Comment 5. High dose rifampicin justification: these are key background data to the dosing chosen in the trial - which is not sufficiently justified here - suggest expand and\/or perhaps include diagram summarising any preliminary data from animal\/human phase II studies - could replace fig 1.&nbsp;Specifically need to expand any known data on relationship between dose and mycobacterial clearance - is there a threshold?&nbsp;I realise no CFU data in TBM specifically - but from animal pulmonary TB models\/human EBA data is there a correlation between higher doses rif and CFU counts\/faster clearance. You mention time to culture conversion - important to cite the actual data for all experimental arms in PanACEA.In the absence of clearance data from CSF (animal nor human), we have added further detail relating to PK-PD targets from murine PTB and findings relating to clearance in human PTB from the PanACEA studies.&nbsp;\n<i>Response 5. In plasma, the historical recommended target peak concentrations of rifampicin are 8-24mg\/L. This historical target is based on rifampicin concentrations typically observed in healthy adults (i.e. the reference range after a dose of 10mg\/kg orally), and is not optimized based on pharmacokinetic-pharmacodynamic (PK-PD) data. It is now accepted that total exposure to TB drugs, or the area under the 24-h concentration\u2013time curve (AUC<sub>0\u201324<\/sub>), is more relevant to the efficacy of first-line TB drugs. Ideally, AUC<sub>0\u201324 <\/sub>is considered together with the minimum inhibitory concentration (MIC) of the mycobacteria to yield an AUC<sub>0\u201324<\/sub>\/MIC ratio that is supposed to best predict response in murine models (Magis-Escurra, Int J Antimicrob Agents, 2014).&nbsp;A large meta-analysis of rifampicin pharmacokinetic data from 70 studies with PTB patients found that the mean plasma rifampicin peak concentration at steady state is only 5.79mg\/L (below the historical target concentration) and doses of &gt;25mg\/kg are needed to achieve the PK-PD target derived from murine studies (AUC\/MIC &gt;271) (Stott, J Antimicrob Chemother, 2018).&nbsp;We have added more detail about the PanACEA studies. The PanACEA multi-arm multistage trial showed that time to stable culture conversion in liquid media was faster in the 35 mg\/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1&middot;78; 95% confidence interval (CI) 1&middot;22\u20132&middot;58, p=0&middot;003), but not in other experimental arms. In an additional analysis, increasing rifampicin exposure was also associated with shortened time to stable culture conversion. The effect did not plateau, indicating that doses &gt;35 mg\/kg could be yet more effective (though are unlikely to be well tolerated). The exposure-response relationship for high-dose rifampicin has been explored by using pharmacokinetic-pharmacodynamic modelling based on data from the HIGHRIF studies. Rifampicin exposure was a significant covariate on the bacterial kill rate in sputum resulting in increased early bactericidal activity (Svensson R. J Infect Dis. 2018; 218(6):991-999).&nbsp;<\/i>Comment 6.&nbsp;Safety of rifampicin:&nbsp;'It was found that a three-fold increase in oral rifampicin was safe, and resulted in a large increase is CSF and plasma exposure' - please be more specific - to what dose, and what was size of increase?You mention PK data from Vietnam trial awaited - the trial was published in 2016\/17- are these data now available to you?\n<i>Response 6.&nbsp;Since intravenous rifampicin is an expensive and inconvenient route of administration, especially in low- and middle-income countries, two further oral rifampicin dose-finding trials were undertaken. We have added further detail to the protocol paper reflecting the below results.&nbsp;In the first follow-up study in 30 Indonesian TBM patients, exposures to and safety of higher oral rifampicin doses (750 mg, ca. 17 mg\/kg orally; 900 mg, ca. 20 mg\/kg orally) were compared with the same 600 mg IV rifampicin dose (Yunivita et al. Int J Antimicrob Agents. 2016;48:415-418), as studied by Ruslami et al. Both higher oral rifampicin doses resulted in approximately similar plasma AUC<sub>0-24<\/sub> but lower plasma C<sub>max<\/sub> values compared with 600 mg IV. In a second follow-up study, 60 Indonesian TBM patients were assigned in a random double-blinded study to standard 450 mg, 900 mg or 1350 mg (10, 20 and 30 mg\/kg for Indonesian subjects) oral rifampicin combined with other TB drugs for 30 days [Dian S. Antimicrob Agents and Chemotherapy. 2018;62(12):e01004-12]. Double and triple dose of oral rifampicin led to three and five-fold higher geometric mean total exposures in plasma, with proportional increases in CSF concentrations, without an increase in incidence of grade 3\/4 adverse events. Overall, tripling the standard dose was considered to be safe.&nbsp;The PK-PD analysis from the 2016 Vietnamese intensified TB treatment trial were published earlier this year (Ding J, Clin Pharmacol Ther, 2020). The nested PK\/PD study in 237 trial participants was published earlier this year and aimed to define exposure-response relationships in study participants. Rifampin 15mg\/kg increased plasma and CSF exposures compared to 10mg\/kg: day 14 plasma AUC0-24 increased from 48.2h&middot;mg\/L (range 18.2-93.8) to 82.5h&middot;mg\/L (range 8.7-161.0) and CSF AUC0-24 from 3.5h&middot;mg\/L (range 1.2-9.6) to 6.0h&middot;mg\/L (range 0.7-15.1). However, within the exposure range achieved, no relationship between rifampin exposure and survival was seen within the trial. It is possible, as seen in PTB studies (Svennson R), and in TBM PK-PD models (Svensson E), a rifampicin dose of greater than 15mg\/kg is required to achieve exposures capable of reducing time to culture conversion and improving survival, which may explain the lack of exposure-response relationship seen in this study.<\/i>Comment 7.&nbsp;Ancillary studies - management of DILI - it is unclear how management of DILI will be assessed as an endpoint\/compared between groups (agree with Reviewer 1 comments).Thank you for seeking clarity on this.\n<i>Response 7.&nbsp;We hope the response given to reviewer 1, and copied here, makes the purpose of this sub-study a little clearer. The aim of the sub-study is to determine the safety of a pragmatic management strategy, and does not involve comparison between trial arms. Based on safety data from prior Indonesian high dose rifampicin studies it appears that the majority (8 of 9) of TBM patients who develop transaminitis (ALT of &lt;10x upper limit of normal, ULN), liver enzymes settle without interruption of anti-TB drugs. Where transaminitis occurs, we therefore plan to closely monitor liver function tests whilst continuing TB treatment unless ALT exceeds a threshold of 10x ULN, at which point we will follow an algorithm of stopping and reintroducing TB drugs sequentially. Under trial endpoint #6 we use \u201cmanagement of DILI\u201d as a summary term under which we aim to describe incidence of DILI, frequency and duration of drug interruptions, hepatic outcomes, neurological outcomes. We recognise that \u201cmanagement of DILI\u201d is a little non-specific so we have added \u201cincidence and outcome\u201d and will notify IRBs at the time of next regulatory amendments.&nbsp;&nbsp; &nbsp;<\/i>Comment 8.&nbsp;Inclusion criteria, under case definition -' CSF abnormalities' very non-specific? Suggestive of meningitis? We all realise a lot of treatment is empiric - if clinician judgement only then states so. Agree with reviewer 1 point about which diagnostics likely to be available to clinicians at each site upon which to base inclusion (and subsequent exclusion is alternative diagnosis found).&nbsp;This is challenging point and something we discussed at length when writing the protocol. All sites will provide a minimum set of CSF tests which includes Gram\u2019s stain, bacteriological culture, Xpert MTB\/RIF Ultra, TB culture, Cryptococcal antigen if HIV-positive. Availability of other tests varies by site (including viral PCR, syphilis serology, fungal culture, cytology) and can be performed at clinician discretion.&nbsp;\n<i>Response 8. As the CSF picture of TBM varies hugely depending on degree of immunosuppression and ART status we have specified that only one CSF parameter must be abnormal (cell count, protein or glucose). Interpretation of CSF findings, within the clinical picture of the patient, and eligibility for enrolment is at the discretion of the study physician.&nbsp;In light of the fact that only around 50% of TBM is microbiologically confirmed and in advanced HIV disease it may be necessary to cover a number of CNS infections empirically whilst waiting for the results of diagnostics tests and imaging, we have gone on to specify in the full protocol that:<\/i>  \n<i>Empiric toxoplasmosis therapy is acceptable<\/i> \n<i>Positive CSF or blood cryptococcal antigen relating to prior treated cryptococcal meningitis and receiving secondary prophylaxis is acceptable if microbiologically-confirmed TBM<\/i> \n<i>Study sponsored withdrawal from the trial can take place if there is a microbiological confirmation of another CNS infection other than TBM prior to day 15 of the study<\/i>","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-190\/v2#referee-comment-4304","order":2,"name":"referee-comment-4304","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by the Wellcome Trust through a Clinical PhD Fellowship to FVC [210772] and funding to the Joint Global Health Trials scheme [MR\/S004963\/1].\n\nThis trial is supported by a Medical Research Council (MRC) Joint Global Health Trials grant [MR\/S004963\/1]. The Joint Global Health Trials scheme is jointly funded by the UK Department for International Development, the MRC, the National Institutes for Health Research, and the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}