Preventing Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome in High-risk Patients: a Randomized Placebo-controlled Trial of Prednisone
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 240
- 试验地点
- 1
- 主要终点
- Development of paradoxical TB-IRIS
研究概览
简要总结
Tuberculosis (TB) is the most common opportunistic infection amongst HIV-infected patients starting antiretroviral therapy (ART) in developing countries and thus the most frequent form of immune reconstitution inflammatory syndrome (IRIS). Paradoxical TB-IRIS occurs in 8- 43% of patients starting ART while on TB treatment and results in morbidity, hospitalisation, consumes health care resources and TB-IRIS may be fatal. We have previously demonstrated in a clinical trial that prednisone reduces morbidity when used for treatment of paradoxical TB-IRIS. This trial is a double-blind placebo-controlled trial of prophylactic prednisone (40mg/day for 2 weeks followed by 20mg/day for 2 weeks, started on the same day as ART) in patients with TB who are identified as being at high risk for paradoxical TB-IRIS (starting ART within 30 days of initiating TB treatment and CD4 < 100/μL). The trial will enroll 240 participants, randomised 1:1 (prednisone:placebo). The primary endpoint is development of paradoxical TB-IRIS, defined using international consensus case definitions. Secondary endpoints include time to IRIS event, severity of IRIS, quality of life assessment, mortality and corticosteroids adverse events. The trial is powered to determine a reduction in TB-IRIS events.
详细描述
Objective: To determine whether the addition of prednisone to the first 4 weeks of antiretroviral therapy (ART) reduces the risk of paradoxical TB-IRIS in HIV-infected patients being treated for TB who are at high risk of developing TB-IRIS (CD4 <100 cells/μl and starting ART within 30 days of TB treatment).
Design: A randomized double-blind placebo-controlled trial to evaluate the incidence of paradoxical TB-IRIS over the first 12 weeks of ART in participants who receive a 4 week course of prednisone versus participants who receive a 4 week course of placebo.
Primary efficacy endpoint:
The development of paradoxical TB-IRIS within 12 weeks of starting ART (defined using the International Network for the Study of HIV-associated IRIS (INSHI) consensus case definition).
Secondary efficacy endpoints:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •HIV-infected HIV infection will be confirmed by two different rapid tests (as per South African national Department of Health guidelines) and an HIV viral load test.
- •CD4 count < 100/μL One CD4 count taken within 3 months prior to enrolment less than 100/μL will qualify, even if other CD4 counts are greater than 100/μL
- •ART-naïve Patients who report having been treated with triple drug or dual drug ART previously will be excluded. Single dose nevirapine or short term AZT monotherapy for PMTCT is not an exclusion.
- •Confirmed diagnosis of TB (smear, culture, Xpert MTB/RIF test or compatible histology) or strong clinical and radiological evidence of TB with symptomatic response to TB treatment
- •On TB treatment for less than 30 days prior to study entry.
- •Eligible for ART and patient consents to starting ART within 30 days of starting TB treatment.
- •Written informed consent for trial
排除标准
- •Kaposi's sarcoma (KS) A thorough examination for KS lesions will be performed and any suspicious lesion will be biopsied. Any history of treatment for KS will also be an exclusion.
- •Pregnant All female participants of child-bearing potential will have a pregnancy test performed prior to enrollment and will be counseled to use to two reliable methods of contraception for the duration of the trial.
- •<18 years old
- •TB meningitis or tuberculoma at TB diagnosis
- •Clinical syndrome of pericardial TB at TB diagnosis (a pericardial effusion noted on ultrasound scan alone is not an exclusion criterion)
- •Rifampicin-resistant TB diagnosed by Xpert MTB/RIF test or a drug susceptibility test performed on a culture isolate.
- •On corticosteroids for another indication or on any other immunosuppressive medication within the past 7 days.
- •Uncontrolled diabetes mellitus
- •The following abnormal laboratory values:
- •Alanine aminotransferase > 200 IU/l Absolute neutrophil count < 500/mm3
- •Not on standard intensive phase TB treatment (Rifampicin, isoniazid, pyrazinamide and ethambutol)
- •Poor clinical response to TB treatment prior to ART as judged by the clinical investigators.
- •Hepatitis B surface antigen positive
研究组 & 干预措施
Prednisone
Prednisone oral tablets 40mg daily for 2 weeks followed by 20mg daily for 2 weeks
干预措施: Prednisone (Drug)
Placebo
Placebo oral tablets 40mg daily for 2 weeks followed by 20mg daily for 2 weeks
干预措施: Placebo (Drug)
结局指标
主要结局
Development of paradoxical TB-IRIS
时间窗: 12 weeks
The development of paradoxical TB-IRIS within 12 weeks of starting ART (defined using the International Network for the Study of HIV-associated IRIS (INSHI) consensus case definition)
次要结局
- Laboratory safety data: Glucose(12 weeks)
- Mortality attributed to TB and TB-IRIS(12 weeks)
- All-cause mortality(12 weeks)
- Laboratory safety data: Serum sodium(12 weeks)
- Laboratory safety data: White cell count(12 weeks)
- Discontinuation of either ART or TB treatment for > 5 days due to adverse events(12 weeks)
- Number of hospitalizations(12 weeks)
- Time to IRIS event(12 weeks)
- Severity of IRIS events(12 weeks)
- Duration of TB-IRIS event(Average 8-12 weeks from onset)
- Composite endpoint of death, hospitalization, or hepatotoxicity (using the protocol-specified definition of Grade 3 or 4 increase in ALT or bilirubin)(12 weeks)
- Other (non-TB) IRIS events(12 weeks)
- Adverse events and severe adverse events ascribed to TB treatment, ART or co-trimoxazole(12 weeks)
- Other infections (AIDS-related, bacterial, fungal and viral) and malignancies (Kaposi's sarcoma)(12 weeks)
- Corticosteroid-associated adverse events, classified by severity and relation to study drug(12 weeks)
- All grade 1, 2, 3 and 4 adverse events (clinical and laboratory using the ACTG grading system)(12 weeks)
- Total number of days hospitalised(12 weeks)
- Laboratory safety data: Haemoglobin(12 weeks)
- Laboratory safety data: Serum potassium(12 weeks)
研究者
Graeme Meintjes
Principal Investigator
University of Cape Town