دورية أكاديمية
Adjunctive dexamethasone for the treatment of HIV-uninfected adults with tuberculous meningitis stratified by Leukotriene A4 hydrolase genotype (LAST ACT): Study protocol for a randomised double blind placebo controlled non-inferiority trial.
| العنوان: | Adjunctive dexamethasone for the treatment of HIV-uninfected adults with tuberculous meningitis stratified by Leukotriene A4 hydrolase genotype (LAST ACT): Study protocol for a randomised double blind placebo controlled non-inferiority trial. |
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| المؤلفون: | Donovan J; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Phu NH; Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam., Thao LTP; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam., Lan NH; Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam., Mai NTH; Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam., Trang NTM; Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam., Hiep NTT; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam., Nhu TB; Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam., Hanh BTB; Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam., Mai VTP; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam., Bang ND; Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam., Giang DC; Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam., Ha DTM; Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam., Day J; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Thuong NT; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Vien NN; Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam., Geskus RB; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Hien TT; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam., Kestelyn E; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Wolbers M; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam., Chau NVV; Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam., Thwaites GE; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. |
| المصدر: | Wellcome open research [Wellcome Open Res] 2018 Mar 20; Vol. 3, pp. 32. Date of Electronic Publication: 2018 Mar 20 (Print Publication: 2018). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wellcome Trust Country of Publication: England NLM ID: 101696457 Publication Model: eCollection Cited Medium: Print ISSN: 2398-502X (Print) Linking ISSN: 2398502X NLM ISO Abbreviation: Wellcome Open Res Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: [London] : Wellcome Trust, [2016]- |
| مستخلص: | Background: Tuberculosis kills more people than any other bacterial infection worldwide. In tuberculous meningitis (TBM), a common functional promoter variant (C/T transition) in the gene encoding leukotriene A4 hydrolase (LTA4H), predicts pre-treatment inflammatory phenotype and response to dexamethasone in HIV-uninfected individuals. The primary aim of this study is to determine whether LTA4H genotype determines benefit or harm from adjunctive dexamethasone in HIV-uninfected Vietnamese adults with TBM. The secondary aim is to investigate alternative management strategies in individuals who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy. Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled, multi-centre Phase III non-inferiority trial, comparing dexamethasone versus placebo for 6-8 weeks in addition to standard anti-tuberculosis treatment in HIV-uninfected patients with TBM stratified by LTA4H genotype. The primary endpoint will be death or new neurological event. The trial will enrol approximately 720 HIV-uninfected adults with a clinical diagnosis of TBM, from two hospitals in Ho Chi Minh City, Vietnam. 640 participants with CC or CT- LTA4H genotype will be randomised to either dexamethasone or placebo, and the remaining TT- genotype participants will be treated with standard-of-care dexamethasone. We will also perform a randomised comparison of three management strategies for anti-tuberculosis DILI. An identical ancillary study will also be perfomed in the linked randomised controlled trial of dexamethasone in HIV-infected adults with TBM (ACT HIV). Discussion: Previous data have shown that LTA4H genotype may be a critical determinant of inflammation and consequently of adjunctive anti-inflammatory treatment response in TBM. We will stratify dexamethasone therapy according to LTA4H genotype in HIV-uninfected adults, which may indicate a role for targeted anti-inflammatory therapy according to variation in LTA4H C/T transition. A comparison of DILI management strategies may allow the safe continuation of rifampicin and isoniazid. Competing Interests: No competing interests were disclosed. |
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| معلومات مُعتمدة: | United Kingdom WT_ Wellcome Trust; 110179/Z/15/Z United Kingdom WT_ Wellcome Trust; 206724/Z/17/Z United Kingdom WT_ Wellcome Trust |
| فهرسة مساهمة: | Keywords: Adrenal suppression; Dexamethasone; Drug induced liver injury; HIV-uninfected; Hyponatraemia; LTA4H; Tuberculous meningitis |
| تواريخ الأحداث: | Date Created: 20181027 Latest Revision: 20240221 |
| رمز التحديث: | 20240221 |
| مُعرف محوري في PubMed: | PMC6182672 |
| DOI: | 10.12688/wellcomeopenres.14007.1 |
| PMID: | 30363837 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2398-502X |
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| DOI: | 10.12688/wellcomeopenres.14007.1 |