Leukotriene A4 Hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-uninfected Adults With Tuberculous Meningitis
NCT ID: NCT03100786
Last Updated: 2025-06-17
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE3
Total Enrollment
702 participants
Study Classification
INTERVENTIONAL
Study Start Date
2018-02-12
Study Completion Date
2024-03-09
Brief Summary
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The primary objective is to determine whether Leukotriene A4 hydrolase (LTA4H) genotype, defined at randomisation, determines dexamethasone's clinical effectiveness when added to the first 6-8 weeks of anti-tuberculosis treatment of TBM. The investigators will conduct a LTA4H genotype stratified, parallel group, randomised, double blind, placebo-controlled multi-centre Phase III non-inferiority trial evaluating dexamethasone versus placebo for 6-8 weeks in addition to standard anti-tuberculosis drugs.
The investigators will take a hybrid trial-design approach which assumes a modest harm of dexamethasone and aims to prove non-inferiority of placebo first but also allows claiming superiority of placebo in case dexamethasone causes substantial harm. Moreover, as it is possible that harm of dexamethasone only applies to the LTA4H CC genotype, the trial will allow dropping the CT group at an interim analysis but continue randomization of the CC group.
In making this assessment the investigators not only determine whether dexamethasone influences survival and the incidence of new neurological events (the primary endpoint), but also whether it influences disability assessed by the modified Rankin score 12 months after the start of treatment.
The secondary objective is to investigate alternative management strategies in a subset of patients who develop drug-induced liver injury that will enable the safe continuation of rifampicin and isoniazid therapy whenever possible.
The investigators will take a hybrid trial-design approach which assumes a modest harm of dexamethasone and aims to prove non-inferiority of placebo first but also allows claiming superiority of placebo in case dexamethasone causes substantial harm. Moreover, as it is possible that harm of dexamethasone only applies to the LTA4H CC genotype, the trial will allow dropping the CT group at an interim analysis but continue randomization of the CC group.
In making this assessment the investigators not only determine whether dexamethasone influences survival and the incidence of new neurological events (the primary endpoint), but also whether it influences disability assessed by the modified Rankin score 12 months after the start of treatment.
The secondary objective is to investigate alternative management strategies in a subset of patients who develop drug-induced liver injury that will enable the safe continuation of rifampicin and isoniazid therapy whenever possible.
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Detailed Description
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There is a longstanding hypothesis that death from TBM results from an excessive intracerebral inflammatory response. The corollary of this hypothesis has been that adjunctive anti-inflammatory treatment with corticosteroids (e.g. dexamethasone) improves survival, which has been demonstrated in predominantly HIV-uninfected individuals in a small number of trials. Yet how corticosteroids improve survival, and whether they do so in all patients, remain uncertain and is the focus of the LAST ACT trial.
Adjunctive dexamethasone might improve outcomes from TBM by controlling the early intracerebral inflammatory response, reducing cerebral oedema and intra-cranial pressure, and it may prevent the potentially life-threatening complications of hydrocephalus, infarction and tuberculoma formation. Despite the careful study of all participants enrolled into the last dexamethasone trial conducted in Vietnam, an anti-inflammatory effect linked to outcome was not found. An explanation for these puzzling findings was only forthcoming upon the subsequent discovery that a common functional promoter variant (C/T transition) in the gene encoding leukotriene A4 hydrolase (LTA4H), which determines the balance of pro- and anti-inflammatory eicosanoids, appeared to predict pre-treatment inflammatory phenotype and response to dexamethasone in HIV-uninfected participants.
In a retrospective study, analysing HIV-uninfected Vietnamese adults with TBM enrolled into the earlier randomized controlled trial of adjunctive dexamethasone, the investigators found that the survival benefit of dexamethasone was restricted to the hyper-inflammatory LTA4H TT-genotype patients, with possible harm suggested in the hypo-inflammatory CC-genotype patients. These preliminary findings suggested LTA4H genotype might be a critical determinant of inflammation and consequently of adjunctive anti-inflammatory treatment response.
Recently, the investigators have extended these original observations in a new cohort of 786 prospectively characterized Vietnamese adults with TBM, all of whom received corticosteroids. In this new cohort the investigators found that LTA4H genotype influences the survival of HIV-uninfected patients, but not those infected with HIV in patients receiving dexamethasone. TT-genotype patients were significantly more likely to survive than CC-genotype patients by both univariable and multivariable analysis, which confirms the previous findings.
The investigators now have two independent studies that suggest LTA4H influences pre-treatment inflammatory phenotype in HIV-uninfected Vietnamese adults and dexamethasone-induced survival. The investigators now want to conduct a practice-defining RCT that addresses the hypothesis that in HIV-uninfected adults with TBM, LTA4H genotype can be used to select those most likely to benefit from dexamethasone.
The data strongly suggest 'hyperinflammatory' LTA4H TT genotype patients with TBM benefit from dexamethasone. Therefore, these patients will be enrolled to the trial and followed-up for 12 months but will receive open label dexamethasone for the first 6-8 weeks of anti-tuberculosis treatment.
The data supports the hypothesis that adjunctive dexamethasone does not benefit, and may cause harm, when given to LTA4H CT or CC-genotype Vietnamese adults with TBM. Therefore, participants with these two genotypes will be randomised to receive 6-8 weeks of placebo or dexamethasone in addition to anti-tuberculosis drugs.
The primary objective is to determine whether LTA4H genotype, defined at randomisation, determines dexamethasone's clinical effectiveness when added to the first 6-8 weeks of anti-tuberculosis treatment of TBM. In making this assessment the investigators not only determine whether dexamethasone increases survival and reduces the incidence of new neurological events (the primary endpoint), but also whether it reduces disability assessed by the modified Rankin score 12 months after the start of treatment. The primary endpoint is death or new neurological event (defined as a fall in Glasgow coma score by ≥2 points for ≥2 days from the highest previously recorded Glasgow coma score (including baseline) or the onset of any of the following clinical adverse events: cerebellar symptoms, focal neurological signs, or new onset of seizures) during 12 months from randomisation.
The secondary objective is to investigate alternative management strategies in a subset of patients who develop drug-induced liver injury that will enable the safe continuation of rifampicin and isoniazid therapy whenever possible. The investigators will perform an open, randomised comparison of three management strategies with the aim of demonstrating which strategy results in the least interruption in R and H treatment. All patients enrolled in the trial will be eligible to take part in this study, with the exception of those known to have TBM caused by isoniazid resistant or MDR M. tuberculosis. Consent will be sought at enrolment, with an option given to patients to enrol in the main study, but not the 'drug-induced liver injury strategy study'.
Eligible patients will be randomised to one of three strategies:
1. Observe: measure transaminases, bilirubin, and INR every 3 days; do not change/stop anti-tuberculosis drugs unless transaminases rise to ≥10x normal, or total bilirubin rises \>2.0mg/dl (\>34 µmol/L), or INR \>1.5 or symptoms of hepatitis worsen (nausea, vomiting, abdominal pain), in which case go to Strategy 3.
2. Stop Pyrazinamide (Z) alone. Observe, measuring transaminases, bilirubin, and INR every 3 days. If transaminases do not fall to \< 5x ULN by day 5, or total bilirubin rises \>2.0mg/dl (\>34 µmol/L), or INR \>1.5 or symptoms of hepatitis worsen at any time (nausea, vomiting, abdominal pain), go to Strategy 3.
3. Current standard of care (the current USA CDC guidelines): stop rifampicin (R), isoniazid (H) and Z immediately and add levofloxacin and an aminoglycoside to ethambutol. Restart R (at full dose) once transaminases are \<2X ULN and no hepatitis symptoms. If no increase in transaminases after 7 days add isoniazid (at full dose) and stop levofloxacin and aminoglycoside. If transaminases remain normal on full dose R and H, Z was the likely cause and it should not be re-started and treatment duration should be extended to ≥12 months. If transaminases rise ≥ 5x ULN, or ≥3x ULN with symptoms, at any time after re-introduction of R and/or H the physician should stop R and/or H (depending on which was associated with the transaminase rise). If neither R or H can be used, treat with levofloxacin, an aminoglycoside and ethambutol. If R can be used, but not H, treat with R, levofloxacin and ethambutol. If H can be used, but not R, treat with H, levofloxacin and ethambutol.
The primary endpoint is the proportion of time in the 60 days following randomisation during which neither rifampicin nor isoniazid are given (or the subject is dead). For example, if RH is interrupted for 18 days and the participant dies 48 days after randomization, the endpoint will be 50% \[(18+(60-48))/60\]. Rifampicin and isoniazid are considered critical drugs in early TBM treatment; inability to use these agents (either through bacterial resistance or patient intolerance) is associated with poor outcome. The vast majority of interruptions are expected to be shorter than one month for strategy 3 (standard of care) but as management strategies 1 and 2 delay the time point of the interruption, a longer cut-off of 60 days was chosen.
Adjunctive dexamethasone might improve outcomes from TBM by controlling the early intracerebral inflammatory response, reducing cerebral oedema and intra-cranial pressure, and it may prevent the potentially life-threatening complications of hydrocephalus, infarction and tuberculoma formation. Despite the careful study of all participants enrolled into the last dexamethasone trial conducted in Vietnam, an anti-inflammatory effect linked to outcome was not found. An explanation for these puzzling findings was only forthcoming upon the subsequent discovery that a common functional promoter variant (C/T transition) in the gene encoding leukotriene A4 hydrolase (LTA4H), which determines the balance of pro- and anti-inflammatory eicosanoids, appeared to predict pre-treatment inflammatory phenotype and response to dexamethasone in HIV-uninfected participants.
In a retrospective study, analysing HIV-uninfected Vietnamese adults with TBM enrolled into the earlier randomized controlled trial of adjunctive dexamethasone, the investigators found that the survival benefit of dexamethasone was restricted to the hyper-inflammatory LTA4H TT-genotype patients, with possible harm suggested in the hypo-inflammatory CC-genotype patients. These preliminary findings suggested LTA4H genotype might be a critical determinant of inflammation and consequently of adjunctive anti-inflammatory treatment response.
Recently, the investigators have extended these original observations in a new cohort of 786 prospectively characterized Vietnamese adults with TBM, all of whom received corticosteroids. In this new cohort the investigators found that LTA4H genotype influences the survival of HIV-uninfected patients, but not those infected with HIV in patients receiving dexamethasone. TT-genotype patients were significantly more likely to survive than CC-genotype patients by both univariable and multivariable analysis, which confirms the previous findings.
The investigators now have two independent studies that suggest LTA4H influences pre-treatment inflammatory phenotype in HIV-uninfected Vietnamese adults and dexamethasone-induced survival. The investigators now want to conduct a practice-defining RCT that addresses the hypothesis that in HIV-uninfected adults with TBM, LTA4H genotype can be used to select those most likely to benefit from dexamethasone.
The data strongly suggest 'hyperinflammatory' LTA4H TT genotype patients with TBM benefit from dexamethasone. Therefore, these patients will be enrolled to the trial and followed-up for 12 months but will receive open label dexamethasone for the first 6-8 weeks of anti-tuberculosis treatment.
The data supports the hypothesis that adjunctive dexamethasone does not benefit, and may cause harm, when given to LTA4H CT or CC-genotype Vietnamese adults with TBM. Therefore, participants with these two genotypes will be randomised to receive 6-8 weeks of placebo or dexamethasone in addition to anti-tuberculosis drugs.
The primary objective is to determine whether LTA4H genotype, defined at randomisation, determines dexamethasone's clinical effectiveness when added to the first 6-8 weeks of anti-tuberculosis treatment of TBM. In making this assessment the investigators not only determine whether dexamethasone increases survival and reduces the incidence of new neurological events (the primary endpoint), but also whether it reduces disability assessed by the modified Rankin score 12 months after the start of treatment. The primary endpoint is death or new neurological event (defined as a fall in Glasgow coma score by ≥2 points for ≥2 days from the highest previously recorded Glasgow coma score (including baseline) or the onset of any of the following clinical adverse events: cerebellar symptoms, focal neurological signs, or new onset of seizures) during 12 months from randomisation.
The secondary objective is to investigate alternative management strategies in a subset of patients who develop drug-induced liver injury that will enable the safe continuation of rifampicin and isoniazid therapy whenever possible. The investigators will perform an open, randomised comparison of three management strategies with the aim of demonstrating which strategy results in the least interruption in R and H treatment. All patients enrolled in the trial will be eligible to take part in this study, with the exception of those known to have TBM caused by isoniazid resistant or MDR M. tuberculosis. Consent will be sought at enrolment, with an option given to patients to enrol in the main study, but not the 'drug-induced liver injury strategy study'.
Eligible patients will be randomised to one of three strategies:
1. Observe: measure transaminases, bilirubin, and INR every 3 days; do not change/stop anti-tuberculosis drugs unless transaminases rise to ≥10x normal, or total bilirubin rises \>2.0mg/dl (\>34 µmol/L), or INR \>1.5 or symptoms of hepatitis worsen (nausea, vomiting, abdominal pain), in which case go to Strategy 3.
2. Stop Pyrazinamide (Z) alone. Observe, measuring transaminases, bilirubin, and INR every 3 days. If transaminases do not fall to \< 5x ULN by day 5, or total bilirubin rises \>2.0mg/dl (\>34 µmol/L), or INR \>1.5 or symptoms of hepatitis worsen at any time (nausea, vomiting, abdominal pain), go to Strategy 3.
3. Current standard of care (the current USA CDC guidelines): stop rifampicin (R), isoniazid (H) and Z immediately and add levofloxacin and an aminoglycoside to ethambutol. Restart R (at full dose) once transaminases are \<2X ULN and no hepatitis symptoms. If no increase in transaminases after 7 days add isoniazid (at full dose) and stop levofloxacin and aminoglycoside. If transaminases remain normal on full dose R and H, Z was the likely cause and it should not be re-started and treatment duration should be extended to ≥12 months. If transaminases rise ≥ 5x ULN, or ≥3x ULN with symptoms, at any time after re-introduction of R and/or H the physician should stop R and/or H (depending on which was associated with the transaminase rise). If neither R or H can be used, treat with levofloxacin, an aminoglycoside and ethambutol. If R can be used, but not H, treat with R, levofloxacin and ethambutol. If H can be used, but not R, treat with H, levofloxacin and ethambutol.
The primary endpoint is the proportion of time in the 60 days following randomisation during which neither rifampicin nor isoniazid are given (or the subject is dead). For example, if RH is interrupted for 18 days and the participant dies 48 days after randomization, the endpoint will be 50% \[(18+(60-48))/60\]. Rifampicin and isoniazid are considered critical drugs in early TBM treatment; inability to use these agents (either through bacterial resistance or patient intolerance) is associated with poor outcome. The vast majority of interruptions are expected to be shorter than one month for strategy 3 (standard of care) but as management strategies 1 and 2 delay the time point of the interruption, a longer cut-off of 60 days was chosen.
Conditions
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Tuberculosis
Tuberculous Meningitis
Drug-Induced Liver Injury
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Primary Study Purpose
TREATMENT
Blinding Strategy
DOUBLE
Participants
Caregivers
Study Groups
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Dexamethasone
standard anti-tuberculosis drugs plus dexamethasone for 6-8 weeks
Group Type
ACTIVE_COMPARATOR
Dexamethasone
Intervention Type
DRUG
Active treatment with dexamethasone from randomisation (IV followed by oral according to disease severity at the start of treatment): Dexamethasone for intravenous injection and dexamethasone for oral ingestion
Identical placebo
standard anti-tuberculosis drugs plus placebo for 6-8 weeks
Group Type
PLACEBO_COMPARATOR
Placebo
Intervention Type
OTHER
Treatment with matched placebo: Standard saline for intravenous injection and placebo oral tablets containing cellulose
Interventions
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Dexamethasone
Active treatment with dexamethasone from randomisation (IV followed by oral according to disease severity at the start of treatment): Dexamethasone for intravenous injection and dexamethasone for oral ingestion
Intervention Type
DRUG
Placebo
Treatment with matched placebo: Standard saline for intravenous injection and placebo oral tablets containing cellulose
Intervention Type
OTHER
Eligibility Criteria
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Inclusion Criteria
* Adult (18 years or older)
* HIV-uninfected
* Clinical diagnosis of TBM (≥5 days of meningitis symptoms, and CSF abnormalities) and anti-tuberculosis chemotherapy either planned or started by the attending physician
Note: Published diagnostic criteria will be applied to all enrolled participants at the end of the study when all mycobacterial culture results are available. The criteria will sub-divide all cases into definite, probable and possible TBM, and those with an alternative diagnosis.
* HIV-uninfected
* Clinical diagnosis of TBM (≥5 days of meningitis symptoms, and CSF abnormalities) and anti-tuberculosis chemotherapy either planned or started by the attending physician
Note: Published diagnostic criteria will be applied to all enrolled participants at the end of the study when all mycobacterial culture results are available. The criteria will sub-divide all cases into definite, probable and possible TBM, and those with an alternative diagnosis.
Exclusion Criteria
* An additional brain infection (other than TBM) confirmed or suspected: positive CSF Gram or India Ink stain; positive blood or CSF Cryptococcal antigen test
* More than 6 consecutive days of two or more drugs active against M. tuberculosis immediately before screening
* More than 3 consecutive days of any type of orally or intravenously administered corticosteroid immediately before randomisation
* Dexamethasone considered mandatory for any reason by the attending physician
* Dexamethasone considered to be contraindicated for any reason by the attending physician
* Previously been randomised into the trial for a prior episode of TBM
* Lack of consent from the participant or family member (if the participant is incapacitated by the disease)
* More than 6 consecutive days of two or more drugs active against M. tuberculosis immediately before screening
* More than 3 consecutive days of any type of orally or intravenously administered corticosteroid immediately before randomisation
* Dexamethasone considered mandatory for any reason by the attending physician
* Dexamethasone considered to be contraindicated for any reason by the attending physician
* Previously been randomised into the trial for a prior episode of TBM
* Lack of consent from the participant or family member (if the participant is incapacitated by the disease)
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam
OTHER
Sponsor Role
collaborator
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
OTHER
Sponsor Role
collaborator
Oxford University Clinical Research Unit, Vietnam
OTHER
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Guy Thwaites, MD
Role: PRINCIPAL_INVESTIGATOR
University of Oxford, UK
Locations
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Hospital for Tropical Diseases
Ho Chi Minh City, , Vietnam
Site Status
Oxford University Clinical Research Unit
Ho Chi Minh City, , Vietnam
Site Status
Pham Ngoc Thach Hospital
Ho Chi Minh City, , Vietnam
Site Status
Countries
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Vietnam
References
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Thwaites GE, van Toorn R, Schoeman J. Tuberculous meningitis: more questions, still too few answers. Lancet Neurol. 2013 Oct;12(10):999-1010. doi: 10.1016/S1474-4422(13)70168-6. Epub 2013 Aug 23.
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Thwaites GE, Duc Bang N, Huy Dung N, Thi Quy H, Thi Tuong Oanh D, Thi Cam Thoa N, Quang Hien N, Tri Thuc N, Ngoc Hai N, Thi Ngoc Lan N, Ngoc Lan N, Hong Duc N, Ngoc Tuan V, Huu Hiep C, Thi Hong Chau T, Phuong Mai P, Thi Dung N, Stepniewska K, Simmons CP, White NJ, Tinh Hien T, Farrar JJ. The influence of HIV infection on clinical presentation, response to treatment, and outcome in adults with Tuberculous meningitis. J Infect Dis. 2005 Dec 15;192(12):2134-41. doi: 10.1086/498220. Epub 2005 Nov 15.
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Thwaites GE, Chau TT, Farrar JJ. Improving the bacteriological diagnosis of tuberculous meningitis. J Clin Microbiol. 2004 Jan;42(1):378-9. doi: 10.1128/JCM.42.1.378-379.2004.
Reference Type
BACKGROUND
Nhu NT, Heemskerk D, Thu do DA, Chau TT, Mai NT, Nghia HD, Loc PP, Ha DT, Merson L, Thinh TT, Day J, Chau Nv, Wolbers M, Farrar J, Caws M. Evaluation of GeneXpert MTB/RIF for diagnosis of tuberculous meningitis. J Clin Microbiol. 2014 Jan;52(1):226-33. doi: 10.1128/JCM.01834-13. Epub 2013 Nov 6.
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BACKGROUND
Patel VB, Connolly C, Singh R, Lenders L, Matinyenya B, Theron G, Ndung'u T, Dheda K. Comparison of amplicor and GeneXpert MTB/RIF tests for diagnosis of tuberculous meningitis. J Clin Microbiol. 2014 Oct;52(10):3777-80. doi: 10.1128/JCM.01235-14. Epub 2014 Jul 23.
Reference Type
BACKGROUND
Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes J; British Infection Society. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J Infect. 2009 Sep;59(3):167-87. doi: 10.1016/j.jinf.2009.06.011. Epub 2009 Jul 4.
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BACKGROUND
Masur H, Brooks JT, Benson CA, Holmes KK, Pau AK, Kaplan JE; National Institutes of Health; Centers for Disease Control and Prevention; HIV Medicine Association of the Infectious Diseases Society of America. Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Updated Guidelines from the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014 May;58(9):1308-11. doi: 10.1093/cid/ciu094. Epub 2014 Feb 27.
Reference Type
BACKGROUND
Thwaites GE. Advances in the diagnosis and treatment of tuberculous meningitis. Curr Opin Neurol. 2013 Jun;26(3):295-300. doi: 10.1097/WCO.0b013e3283602814.
Reference Type
BACKGROUND
Ellard GA, Humphries MJ, Allen BW. Cerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis. Am Rev Respir Dis. 1993 Sep;148(3):650-5. doi: 10.1164/ajrccm/148.3.650.
Reference Type
BACKGROUND
Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, Borm G, Aarnoutse RE, van Crevel R. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis. 2013 Jan;13(1):27-35. doi: 10.1016/S1473-3099(12)70264-5. Epub 2012 Oct 25.
Reference Type
BACKGROUND
Heemskerk AD, Bang ND, Mai NT, Chau TT, Phu NH, Loc PP, Chau NV, Hien TT, Dung NH, Lan NT, Lan NH, Lan NN, Phong le T, Vien NN, Hien NQ, Yen NT, Ha DT, Day JN, Caws M, Merson L, Thinh TT, Wolbers M, Thwaites GE, Farrar JJ. Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis. N Engl J Med. 2016 Jan 14;374(2):124-34. doi: 10.1056/NEJMoa1507062.
Reference Type
BACKGROUND
Tho DQ, Torok ME, Yen NT, Bang ND, Lan NT, Kiet VS, van Vinh Chau N, Dung NH, Day J, Farrar J, Wolbers M, Caws M. Influence of antituberculosis drug resistance and Mycobacterium tuberculosis lineage on outcome in HIV-associated tuberculous meningitis. Antimicrob Agents Chemother. 2012 Jun;56(6):3074-9. doi: 10.1128/AAC.00319-12. Epub 2012 Apr 2.
Reference Type
BACKGROUND
Thwaites GE, Lan NT, Dung NH, Quy HT, Oanh DT, Thoa NT, Hien NQ, Thuc NT, Hai NN, Bang ND, Lan NN, Duc NH, Tuan VN, Hiep CH, Chau TT, Mai PP, Dung NT, Stepniewska K, White NJ, Hien TT, Farrar JJ. Effect of antituberculosis drug resistance on response to treatment and outcome in adults with tuberculous meningitis. J Infect Dis. 2005 Jul 1;192(1):79-88. doi: 10.1086/430616. Epub 2005 May 20.
Reference Type
BACKGROUND
Seddon JA, Visser DH, Bartens M, Jordaan AM, Victor TC, van Furth AM, Schoeman JF, Schaaf HS. Impact of drug resistance on clinical outcome in children with tuberculous meningitis. Pediatr Infect Dis J. 2012 Jul;31(7):711-6. doi: 10.1097/INF.0b013e318253acf8.
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BACKGROUND
Dass R, Nagaraj R, Murlidharan J, Singhi S. Hyponatraemia and hypovolemic shock with tuberculous meningitis. Indian J Pediatr. 2003 Dec;70(12):995-7. doi: 10.1007/BF02723828.
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BACKGROUND
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BACKGROUND
Celik U, Celik T, Tolunay O, Baspinar H, Komur M, Levent F. Cerebral salt wasting in tuberculous meningitis: Two cases and review of the literature. Case Report. Neuro Endocrinol Lett. 2015;36(4):306-10.
Reference Type
BACKGROUND
Schoeman J, Donald P, van Zyl L, Keet M, Wait J. Tuberculous hydrocephalus: comparison of different treatments with regard to ICP, ventricular size and clinical outcome. Dev Med Child Neurol. 1991 May;33(5):396-405. doi: 10.1111/j.1469-8749.1991.tb14899.x.
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BACKGROUND
Chugh A, Husain M, Gupta RK, Ojha BK, Chandra A, Rastogi M. Surgical outcome of tuberculous meningitis hydrocephalus treated by endoscopic third ventriculostomy: prognostic factors and postoperative neuroimaging for functional assessment of ventriculostomy. J Neurosurg Pediatr. 2009 May;3(5):371-7. doi: 10.3171/2009.1.PEDS0947.
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BACKGROUND
Thwaites GE, Macmullen-Price J, Tran TH, Pham PM, Nguyen TD, Simmons CP, White NJ, Tran TH, Summers D, Farrar JJ. Serial MRI to determine the effect of dexamethasone on the cerebral pathology of tuberculous meningitis: an observational study. Lancet Neurol. 2007 Mar;6(3):230-6. doi: 10.1016/S1474-4422(07)70034-0.
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BACKGROUND
Sheu JJ, Hsu CY, Yuan RY, Yang CC. Clinical characteristics and treatment delay of cerebral infarction in tuberculous meningitis. Intern Med J. 2012 Mar;42(3):294-300. doi: 10.1111/j.1445-5994.2010.02256.x. Epub 2010 May 11.
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Shukla R, Abbas A, Kumar P, Gupta RK, Jha S, Prasad KN. Evaluation of cerebral infarction in tuberculous meningitis by diffusion weighted imaging. J Infect. 2008 Oct;57(4):298-306. doi: 10.1016/j.jinf.2008.07.012. Epub 2008 Aug 28.
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Springer P, Swanevelder S, van Toorn R, van Rensburg AJ, Schoeman J. Cerebral infarction and neurodevelopmental outcome in childhood tuberculous meningitis. Eur J Paediatr Neurol. 2009 Jul;13(4):343-9. doi: 10.1016/j.ejpn.2008.07.004. Epub 2008 Aug 30.
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Koh SB, Kim BJ, Park MH, Yu SW, Park KW, Lee DH. Clinical and laboratory characteristics of cerebral infarction in tuberculous meningitis: a comparative study. J Clin Neurosci. 2007 Nov;14(11):1073-7. doi: 10.1016/j.jocn.2006.07.014.
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BACKGROUND
Schoeman JF, Janse van Rensburg A, Laubscher JA, Springer P. The role of aspirin in childhood tuberculous meningitis. J Child Neurol. 2011 Aug;26(8):956-62. doi: 10.1177/0883073811398132. Epub 2011 May 31.
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DERIVED
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
110179/Z/15/Z
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
27TB
Identifier Type: -
Identifier Source: org_study_id
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