A Randomized Controlled Clinical Trial Comparing Daily Vs. Intermittent 6 - Month Short Course Chemotherapy in Reducing Failures & Emergence of Acquired Rifampicin Resistance (ARR) in Patients With HIV and Pulmonary Tuberculosis
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 331
- 试验地点
- 2
- 主要终点
- unfavourable responses during treatment
研究概览
简要总结
Acquired Rifampicin Resistance has emerged as an important issue in the treatment of HIV-TB patients. It has not been a major problem in HIV-negative individuals treated for TB treated with standard intermittent regimens. The study would generate data on the efficacy of daily and thrice weekly regimen of ATT in pulmonary TB patients with HIV in the presence of highly active antiretroviral therapy (HAART). Not many trials have compared sputum conversion and adverse drug reaction between daily and intermittent regimens of ATT in HIV positive patients. This study provides a unique opportunity for comparison of daily and intermittent therapy for HIV patients with pulmonary TB looking into multiple dimensions of HIV-TB treatment namely efficacy, drug resistance, toxicity , drug interaction and immune reconstitution inflammatory syndrome. The primary outcome of the study is to compare the efficacy of three anti-TB regimens in a) reducing bacteriological failures and b) decreasing the emergence of Acquired Rifampicin Resistance (ARR). The secondary outcomes include unfavourable responses (clinical failures, deaths, relapses) as whole, treatment emergent adverse drug reactions, pharmacokinetic levels of ATT and incidence of immune reconstitution syndrome.
详细描述
HIV positive patients (regardless of ART status) with newly diagnosed pulmonary TB attending the TRC clinics at Chennai, Madurai and Vellore will form the study group. Those who fulfill the clinical inclusion criteria will be evaluated for eligibility to the study after signing a screening consent form. Patients willing to participate in the study will undergo the following investigations namely, sputum examination, chest x-ray, liver and renal function tests. Hematological investigations will include CBC, CD4 and viral load, done periodically at baseline, end of intensive phase of ATT, at the end of TB treatment and once in 6 months during follow-up period of 1 year. Patients getting enrolled in Chennai and its subcentres will also be evaluated for immune reconstitution inflammatory syndrome through additional laboratory investigations. If the patients satisfy the inclusion criteria, a house visit will be done by the social worker to ascertain the facts regarding living condition and domiciliary stability and if continues to remain suitable , will be enrolled into the study after a written, signed and dated informed study consent form. All eligible patients, enrolled into the study, will be randomized to receive one of the three regimens mentioned below. Patients who are ART naïve will be referred to National AIDS Control Organization (NACO) ART centres for assessment and eligibility for procurement of ART according to National guidelines Common opportunistic infections that could occur during study period will be managed according to standard NACO guidelines. Cotrimaxozole DS One tablet once a day will be given to all patients with CD4 < 250 along with multivitamins, unless contraindicated. They will be discharged from the study once their 18th month sputum culture is negative.
Treatment regimens and Dosing:
- Regimen 1. Daily - 2EHRZ7/4HR7 (E 800 mg ,H 300 mg, R 450/600 mg depending on Weight < 60, 600 mg for 60 kg and more, Z 1500 mg daily)
- Regimen 2. Part Daily - 2EHRZ7/4HR3 (E 800 mg ,H 300 mg, R 450/600 mg depending on Weight <60, 600mg for 60 kg and more, Z 1500 mg daily in the intensive phase followed by H-600 mg ,R-450/600 mg in the continuation phase thrice weekly)
- Regimen 3. Intermittent - 2EHRZ3/4HR3 (E 1200mg, H 600 mg, R 450/600 mg depending on Weight < 60, 600 mg for 60 kg and more, Z 1500 mg given thrice weekly)
Statistical design:
Stratification and randomization:
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 above 18 years.
- •HIV-1/2 infected patients with Pulmonary TB. This includes sputum smear positive disease.
- •Initially smear negative but Xpert-MTB positive or LPA positive taken as a surrogate marker for culture positivity (e.g. miliary TB, Mediastinal adenitis and Chest x-ray with persistent abnormality after antibiotics). as BACTEC (Becton-Dickinson) has been phased out ,Final inclusion will only be patients positive by LJ culture
- •Persistent X-ray abnormality will be included for allocation. However final inclusion into both ITT and efficacy analysis will depend on positivity in LJ culture.
- •Living within 40 km radius from the nearest sub centre of TRC and willing for attendance as prescribed.
- •Likely to remain in the same area for at least one and half years after start of treatment.
- •Willing for house visits and surprise checks.
- •Willing to participate and give informed consent after going through the terms and conditions of the trial.
排除标准
- •Patients with known hypersensitivity to rifampicin
- •Pregnancy and lactation at initial presentation
- •Major complications like HIV encephalopathy, renal dysfunction (serum creatinine > 1.5 mg% in the absence of dehydration) or jaundice (serum bilirubin > 2 mgs% along with SGOT /SGPT elevation > 2.5 times the upper limit of normal).
- •Previous anti-tuberculosis treatment for more than 1 month. Prophylaxis (non-rifampicin containing regimen) will not be considered as prior antituberculosis treatment.
- •Moribund, bedridden or unconscious patients.
- •Co-morbid conditions like uncontrolled diabetes mellitus, cardiac failure, and malignancy at initial presentation.
- •Major psychiatric illness.
- •Patients on second line ART, mainly protease inhibitors, at initial presentation.
研究组 & 干预措施
2EHRZ3/4HR3
Regimen 3. Intermittent - 2EHRZ3/4HR3 (E 1200mg, H 600 mg, R 450/600 mg depending on Weight <60, 600 mg for 60 kg or more, Z 1500 mg given thrice weekly)
干预措施: ATT (Ethambutol, Pyrazinamide, INH, Rifampicin) (Drug)
2EHRZ7/4HR7
Regimen 1. Daily - 2EHRZ7/4HR7 (E 800 mg ,H 300 mg, R 450/600 mg depending on Weight <60, 600 mg for 60 kg or more, Z 1500 mg daily)
干预措施: ATT (Ethambutol, Pyrazinamide, INH, Rifampicin) (Drug)
2EHRZ7/4HR3
Regimen 2. Part Daily - 2EHRZ7/4HR3 (E 800 mg ,H 300 mg, R 450/600 mg depending on Weight <60, 600 mg for 60 kg or more, Z 1500 mg daily in the intensive phase followed by H-600 mg ,R-450/600 mg in the continuation phase thrice weekly)
干预措施: ATT (Ethambutol, Pyrazinamide, INH, Rifampicin) (Drug)
结局指标
主要结局
unfavourable responses during treatment
时间窗: At the end of 6 months
including bacteriological and failures and ARR, clinical failures, TEADRS requiring premanent discontinuation of the drug , Deaths except unnatural and Defaults during treatment period
次要结局
- Unfavorable responses during follow-up(At the end of 6 months and at the end of follow-up of 1 year)
- TEADR's between the groups(At the end of 6 months and at the end of follow-up of 1 year)
- Incidence of Immune Reconstitution Syndrome among the groups(At the end of 6 months and at the end of follow-up of 1 year)
研究者
Narendran Gopalan
Asst.Director, NIRT
Tuberculosis Research Centre, India