A Randomized Trial to Compare Effectiveness of 4 Months Rifampin (4 RIF) With 9 Months Isoniazid (9 INH) in the Prevention of Active TB in Children: The P4v9 Trial
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 844
- 试验地点
- 9
- 主要终点
- Adverse events of all grades
研究概览
简要总结
Tuberculosis (TB) is spread by airborne transmission from adults with active contiguous TB to children, especially those living in the same household. Once children are exposed and infected they are at very high risk to develop active TB - which can be lethal if not detected and treated promptly. This makes it very important to detect TB infection as soon as possible, and treat this while it is still latent or dormant. Current therapy for latent TB infection is 9 months of Isoniazid; this is very effective if taken properly but because treatment is so long many children do not finish this. Four months of Rifampin is a recommended alternative. In adults this has been shown to be safer with much higher completion rates. However the effectiveness of this treatment is unclear, and is being studied in an ongoing study. The investigators plan to compare the safety as well as the acceptability and effectiveness of 4 months Rifampin with 9 months Isoniazid (standard treatment) in children in several sites in Canada and other countries.
It is hypothesized that among children at high risk for development of active TB, intolerance/adverse events will not be worse (non-inferiority), among those randomized to 4RIF compared to those randomized to 9INH. In addition completion of latent tuberculosis infection (LTBI) therapy will be significantly greater (superiority), and subsequent rates of active TB will not be significantly higher (non-inferiority) in children taking 4RIF.
详细描述
On a global scale tuberculosis (TB) is the single most important infectious cause of morbidity and mortality in individuals aged 15-49. The World Health Organization has estimated that one third of the entire population of the world carries dormant or latent TB infection (LTBI). Of these, 9 million develop active disease and 2 million die from TB each year. In Canada and other industrialized countries, TB continues to cause significant morbidity and mortality, particularly in minorities, immigrants and other disadvantaged populations.
A key TB control strategy is therapy of LTBI. The current standard regimen is 9 months of daily Isoniazid (9INH). This has excellent efficacy if taken regularly, but the long duration of treatment as well as potential for serious side effects, substantially reduces provider prescription, patient acceptance, and completion. A shorter alternative of 4 months of daily Rifampin (4RIF) has been recommended based on limited evidence in LTBI, but extensive experience using Rifampin for treatment of active TB. However the efficacy of 4RIF in preventing active TB is not known, especially in children.
The investigators have initiated a research program to evaluate 4RIF for the treatment of LTBI. In a first study, 4RIF was associated with significant higher completion rates than 9INH. In a second study, all suspected adverse events were judged by an independent 3-member review panel, who were blinded to study drug. Incidence of Grade 3-4 serious adverse events was significantly lower among the 420 subjects randomized to 4RIF then among the 427 randomized to 9INH (2.4 % vs. 5.6%, P=.02). Grade 3-4 hepatotoxicity was also significantly lower with 4RIF than 9INH (0.7% vs. 3.8%, P=.003), and completion rates were significantly higher with 4RIF.
Therefore, a large scale multi-center trial was launched, with CIHR funding, to compare the efficacy and effectiveness in preventing active TB of 4RIF and 9INH in adults (see NCT00931736). In total 5,850 adults will be randomized at 4 sites in Canada as well as sites in Australia, Brazil, Benin, Ghana, Indonesia, Korea and Saudi Arabia. The primary outcome of this trial is the occurrence of microbiologically confirmed active TB within 28 months after randomization.
As an addition to this ongoing study, the investigators are conducting an open label randomized trial in children at some of these same sites with the primary objectives of comparing tolerability and safety. Secondary outcomes will be completion of therapy (defined as taking more than 80% of planned doses), and active TB. Eligible children will be HIV infected, household contacts of active pulmonary TB cases, or other high risk group, with a positive Tuberculin skin test (TST) reaction. Active TB must be excluded before enrollment.
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
- — 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Children (age <18) with documented positive TST (or in the absence of TST, a positive QFT or T-Spot) and prescribed 9INH for LTBI for the following indications:
- •HIV positive (TST >5 mm or QFT+)
- •Age 5 or less (TST >5 mm or QFT+)
- •Other reason for immuno-compromised state - such as therapy for malignancy or post-transplant (TST >5 mm or QFT+)
- •Contact: with adult or adolescent with active contagious pulmonary TB. (TST >5 mm or QFT +)
- •Have both of the following factors if TST = 10-14mm or QFT + or one factor if TST >15mm :
- •Arrival in Canada, Australia, or Saudi Arabia in the past 2 years from countries with estimated annual incidence of active TB greater than 100 per 100,000
- •Body mass index (BMI) less than 10th percentile for their age
排除标准
- •Patients who were contacts of TB cases known to be resistant to Isoniazid, Rifampin, or both.
- •Known HIV-infected individuals on anti-retroviral agents whose efficacy would be substantially reduced by Rifampin, unless therapy can safely be changed to agents not affected by Rifampin.
- •Pregnant women - Rifampin and Isoniazid are considered safe in pregnancy but therapy is usually deferred until 2-3 months post-partum to avoid fetal risk and the potential for increased hepato-toxicity immediately post partum.
- •Patients on any medication with clinically important drug interactions with Isoniazid or Rifampin, which their physician believes would make either arm contra-indicated.
- •Patients with a history of allergy/hypersensitivity to Isoniazid or to Rifampin, Rifabutin, or Rifapentine.
- •Patients with active TB. Patients initially suspected to have active TB can be randomized once this has been excluded.
- •Prior complete LTBI therapy or if children have taken >1 week and are still taking the treatment. Children will be eligible if they took an incomplete LTBI therapy (less than 80% of recommended total dose) but > 6 months ago.
研究组 & 干预措施
Isoniazid
The standard therapy will be daily self-administered INH, 10-15 mg/kg/day (max=300mg/day) for 9 months (9INH).
干预措施: Isoniazid (Drug)
Rifampin
The experimental arm will be daily self-administered RIF 10-20 mg/kg/day for 4 months (4RIF).
干预措施: Rifampin (Drug)
结局指标
主要结局
Adverse events of all grades
时间窗: Treatment duration
The outcome of intolerability/adverse events (or the 'inverse' of safety) will include adverse events of all levels of severity (Grades 1 to 5) that resulted in permanent discontinuation of study drug, that were judged probably related to the study drug by a majority (2 out of 3) of the independent review panel members.
次要结局
- Rates of drug completion (compliance)(Treatment duration)
- Confirmed active TB during 16 months after randomization (efficacy)(16 months post-randomization)
- Occurrence of drug resistance in confirmed cases of active TB(16 months post-randomization)
研究者
Dr. Dick Menzies
Director of Respiratory Medicine
McGill University