NCT05590455招募中2 期
ANRS 12404 TIMPANI: Tnf Inhibitors to Reduce Mortality in HIV-1 Infected PAtients With Tuberculosis meNIngitis: a Phase II, Multicenter, Randomized Clinical Trial
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 130
- 试验地点
- 3
- 主要终点
- 3-month all-cause mortality
研究概览
简要总结
Randomized phase II clinical trial which aims to assess the impact on 3-month mortality and safety of adding adalimumab to standard treatment (anti-tuberculosis drugs and corticosteroids) in HIV patients with tuberculosis meningitis in 3 countries (Brazil, Mozambique, and Zambia).
详细描述
Phase II multicenter, open-label, randomized, proof of concept, comparative trial with a large alpha (type 1 error rate) to evaluate the impact on 3-month mortality of adding the tumor necrosis factor inhibitor adalimumab to the standard treatment with antituberculosis drugs and high-dose steroids in HIV-infected adults diagnosed with tuberculosis meningitis (TBM) in 3 countries (Brazil, Mozambique, and Zambia).
All HIV1-infected patients diagnosed with TBM will be started on standard TB therapy for the duration recommended by national guidelines (2 months intensive phase and 7 months maintenance phase) and high-dose dexamethasone up to 4 weeks.
As soon as possible during the first 3 days of the standard TBM treatment that includes antituberculosis treatment and high-dose steroids, consenting patients will be randomized to standard treatment alone or standard treatment + adalimumab. Randomization will be stratified on country and initial severity using the British Medical Research Council (MRC) score.
Adalimumab arm:
- Standard TBM treatment as described above
- Adalimumab 40 mg: one sub-cutaneous injection, every 2 weeks for 10 weeks (total 6 injections), started as soon as possible during the first 3 days of antituberculosis treatment and high-dose steroids As World Health Organization and national guidelines for early antiretroviral therapy (ART) introduction in patients with TBM advise caution, ART will be started after 4 weeks of TB treatment in both arms if patients are clinically improved (but no later than 8 weeks of anti-TB treatment).
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
- None
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
- •Age ≥18 years
- •HIV-1 infection
- •Definite or probable tuberculosis meningitis
- •Standard tuberculosis meningitis treatment ≤3 days: anti TB drugs at standard doses and high-dose dexamethasone as per WHO guidelines
- •Signed informed consent form by patient or relative.
排除标准
- •Other concomitant neurological infection, i.e. toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, bacterial meningitis, neuro-syphilis
- •Asymptomatic positive cryptococcal antigen in serum
- •HBsAg positive or anti hepatitis C virus antibodies positive
- •Alanine transaminase (ALT)>5 ULN
- •Rifampicin-resistant TB detected by GeneXpert MTB/RIF Ultra
- •History of previous TB treatment in patients with GeneXpert MTB/RIF Ultra negative or unavailable
- •Current use of drugs contraindicated with study drugs and that cannot be safely stopped
- •Allergy to study drugs or any of their components
- •Uncontrolled opportunistic infection
- •Moderate to severe cardiac insufficiency (NYHA classes III / IV)
- •Any condition which might, in the investigator's opinion, compromise the safety of treatment and/or patient's adherence to study procedures
- •For women of childbearing age: 1) Pregnancy or breastfeeding; 2) Refusal to use effective contraception to be discussed with the investigator
- •Subjects participating in another clinical trial evaluating therapies and including an exclusion period that is still in force during the screening phase
- •Person under guardianship, or deprived of freedom by a judicial or administrative decision
研究组 & 干预措施
Adalimumab arm
Experimental
- Standard TBM treatment
- Adalimumab 40 mg: one sub-cutaneous injection, every 2 weeks for 10 weeks (total 6 injections), started as soon as possible during the first 3 days of antituberculosis treatment and high-dose steroids
干预措施: Adalimumab Injection (Drug)
结局指标
主要结局
3-month all-cause mortality
时间窗: 3 months
次要结局
- 3-month incidence of severe/life threatening bacterial infections and opportunistic infections(3 months)
- 3-month incidence of grade 3 and 4 adverse reactions and those leading to ART or anti tuberculosis treatment (ATT) interruption(3 months)
- 3-month incidence of all grade 3 and 4 adverse events(3 months)
- 9-month and 12-month all-cause mortality(9 months and 12 months)
- 9-month disability free survival (using Rankin score)(9 months)
- 3-month and 9-month incidence of all grade infectious diseases and opportunistic infections(3 months and 9 months)
- 9-month neurological disability score (Rankin score)(9 months)
- Time to and severity of TB-associated paradoxical immune reconstitution inflammatory syndrome (IRIS) between D0 and 9 months(up to 9 months)
- Time to discharge(up to 9 months)
- Cerebrospinal fluid (CSF) pleocytosis/protein/glucose levels at W0, W1 and W4(week 0, week1 and week4)
- CSF mycobacterial cultures negativation (culture conversion), time to culture positivity and cycle threshold (GeneXpert Mycobacterium tuberculosis/Rifampicin Ultra) at W1, W4,(week1 and week4)
- Proportion of patients with HIV-1 RNA<50 copies/mL at 9 months(9 months)
- CD4 counts at 9 months (and gain from baseline)(9 months)
- Inflammatory biomarkers and cytokines profiles in CSF at W0, W1, W4(week 0, week1 and week4)
- Inflammatory biomarkers in blood at W0, W4, W10, M6 and M9(week 0, week4, week10, 6 months and 9 months)
- Cytokines profiles in blood at W0, W4, W10, M6 and M9(week 0, week4, week10, 6 months and 9 months)
- Proportion of participants with possible, probable or definite TBM diagnosis at pre-inclusion according to Marais score(Pre-inclusion)
- Proportion of participants with other CNS disease (opportunistic infections or other neurological conditions)(Pre-inclusion)
研究者
研究点 (3)
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