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

Subjects who do not carry the CES1 variant G143E (rs71647871) will receive 10 mg Enalapril orally once daily for 7 consecutive days.

Subjects who carry the CES1 variant G143E (rs71647871) will receive 10 mg Enalapril orally once daily for 7 consecutive days.

Healthy Volunteers

Study participants in both arms will be treated with 10 mg enalapril orally once daily for seven consecutive days

Enalapril

University of Michigan

Genetic Determinants of ACEI Prodrug Activation

To compare the mean AUC of enalaprilat plasma concentrations between the non-carrier control and the G143E carriers groups

To compare the maximum enalaprilat plasma concentrations between the non-carrier control and the G143E carriers groupsG143E carriers groups

To compare the plasma ACE activity between the non-carrier control and the G143E carriers groupsG143E carriers groups following enalapril treatment

To compare the changes of BPs between the non-carrier control and the G143E carriers groupsG143E carriers groups following enalapril treatment

Haojie Zhu

Associate Professor

Acute Coronary Syndrome

veliflapon (DG-031)

Veliflapon (DG-031)to Prevent Heart Attacks or Stroke in Patients With a History of Heart Attack or Unstable Angina

A Randomized, Double-Blind, Placebo-Controlled Study to Examine the Safety and Efficacy of Veliflapon (DG-031) in Reducing the Risk of Acute Cardiovascular Events in African American Patients With Coronary Artery Disease(The LTCAD Study).

hydrolase/infarkt

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

Genetic Determinants of ACEI Prodrug Activation

Veliflapon (DG-031)to Prevent Heart Attacks or Stroke in Patients With a History of Heart Attack or Unstable Angina

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