A Randomized Double Blind Placebo Controlled Non-inferiority Trial of Adjunctive Dexamethasone for the Treatment of HIV-uninfected Adults With Tuberculous Meningitis Stratified by Leukotriene A4 Hydrolase Genotype
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 702
- 试验地点
- 3
- 主要终点
- All-cause mortality or new neurological event
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Care Provider)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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)
研究组 & 干预措施
Dexamethasone
standard anti-tuberculosis drugs plus dexamethasone for 6-8 weeks
干预措施: Dexamethasone (Drug)
Identical placebo
standard anti-tuberculosis drugs plus placebo for 6-8 weeks
干预措施: Placebo (Other)
结局指标
主要结局
All-cause mortality or new neurological event
时间窗: 12 months from randomisation
The primary endpoint is all cause mortality 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. Survivors without a new neurological event known to be alive at 12 months will be censored at that time-point and subjects who withdrew or were lost to follow-up before 12 months will be censored at the date they were last known to be alive.
次要结局
- Overall survival until 12 months after randomization(12 months after randomization)
- Severe (grade 3 and 4) and serious adverse events by 12 months(by 12 months)
- Requirement for 'rescue' corticosteroids(during the 12 month follow-up)
- Neurological disability at 12 months (modified Rankin score)(at 12 months)