Tuberculosis

Tuberculous Meningitis

Drug-Induced Liver Injury

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

Dexamethasone

Treatment with matched placebo: Standard saline for intravenous injection and placebo oral tablets containing cellulose

Placebo

Hospital for Tropical Diseases

Oxford University Clinical Research Unit

Pham Ngoc Thach Hospital

Leukotriene A4 Hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-uninfected Adults With Tuberculous Meningitis

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

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.

Overall survival is defined as the time from randomization to death, during a follow-up period of 12 months. Survivors 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.

Neurological disability will be assessed by the modified Rankin score on months 3, 6, 9, and 12 from randomisation. The main endpoint is the 12 month assessment and subjects who died before 12 months will be treated as having a score of 6 ('Dead')

Comparison of the frequency of severe (grade 3&4) and serious adverse events, respectively, between treatment groups will form an important part of the study analysis.

Neurological complications occurring after the start of anti-tuberculosis chemotherapy for TBM are common. The cause varies, but includes hydrocephalus, infarcts, tuberculoma formation and hyponatraemia. If the symptoms are thought to be caused by tuberculomas, many doctors will re-start or increase the dose of corticosteroids. In this trial, any re-start or dose increase of corticosteroids during the 12 month follow-up will be defined as 'rescue' corticosteroids.

The Oxford University Clinical Research Unit recognizes the ethical obligation to ensure that optimal use is made of the data and specimens that the investigators collect for the research and the value of sharing individual level data. The investigators aim to ensure that data generated from all the research are collected, curated, managed and shared in a way that maximizes their benefit. When sharing data the investigators have an obligation to ensure that the interests of research participants, researchers and other stakeholders are appropriately protected. The Oxford University Clinical Research Unit data sharing policy and the data request form outline the default procedures for data sharing.

Oxford University Clinical Research Unit, Vietnam

Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam

Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

IRIS

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

Treatment with matched placebo:
Standard saline for intravenous injection and placebo oral tablets containing cellulose

Cipto Mangunkusumo Hospital

Eijkman-Oxford Clinical Research Unit

RSUP Persahabatan Hospital

Adjunctive Corticosteroids for Tuberculous Meningitis in HIV-infected Adults (The ACT HIV Trial)

A Randomized Double Blind Placebo Controlled Trial of Adjunctive Dexamethasone for the Treatment of HIV-infected Adults With Tuberculous Meningitis

The primary endpoint is overall survival, i.e. the time from randomization to death, during a follow-up period of 12 months. Survivors 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.

Neurological disability will be assessed by the modified Rankin score (see below) on months 3, 6, 9, 12, 18 and 24 from randomisation. The main endpoint is the 12 month assessment and subjects who died before 12 months will be treated as having a score of 6 ('Dead').
The Modified Rankin Scale Score Description 0 No symptoms
Minor symptoms not interfering with lifestyle
Symptoms that lead to some restriction in lifestyle, but do not interfere with the patients ability to look after themselves
Symptoms that restrict lifestyle and prevent totally independent living
Symptoms that clearly prevent independent living, although the patient does not need constant care and attention.
Totally dependent, requiring constant help day and night.
Death

A neurological event is 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 onset of seizures.

The rate is defined as the number of IRIS events divided by the observed person-time of follow-up in each treatment group.

AIDS-defining illnesses will be defined as per the WHO classification.

Comparison of the frequency of serious adverse events between treatment groups will form an important part of the study analysis.

The three major HIV-associated malignancies are Kaposi sarcoma, high grade B-cell non-Hodgkin lymphoma and invasive cervical cancer.

The main analysis of this trial will be performed at the time point where all randomized subjects have completed 12 months of follow-up. However, all participants will continue to be followed up for 24 months and overall survival will be reported once 24 month follow-up has been completed for all participants.

The main analysis of this trial will be performed at the time point where all randomized subjects have completed 12 months of follow-up. However, all participants will continue to be followed up for 24 months and neurological disability will be reported once 24 month follow-up has been completed for all participants.

The main analysis of this trial will be performed at the time point where all randomized subjects have completed 12 months of follow-up. However, all participants will continue to be followed up for 24 months and this outcome will be reported once 24 month follow-up has been completed for all participants.

The Oxford University Clinical Research Unit recognizes the ethical obligation to ensure that optimal use is made of the data and specimens that the investigators collect for our research and the value of sharing individual level data. The investigators aim to ensure that data generated from all our research are collected, curated, managed and shared in a way that maximizes their benefit. When sharing data the investigators have an obligation to ensure that the interests of research participants, researchers and other stakeholders are appropriately protected. The Oxford University Clinical Research Unit data sharing policy and the data request form outline the default procedures for data sharing.

tuberculoma/nàusea

Leukotriene A4 Hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-uninfected Adults With Tuberculous Meningitis

Adjunctive Corticosteroids for Tuberculous Meningitis in HIV-infected Adults (The ACT HIV Trial)

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