Empirical Treatment Against Cytomegalovirus and Tuberculosis in HIV-infected Infants With Severe Pneumonia: a Multicenter, Open-label Randomized Controlled Clinical Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 563
- 试验地点
- 13
- 主要终点
- Mortality
研究概览
简要总结
This trial will evaluate whether empirical treatment against cytomegalovirus and tuberculosis improves survival of HIV-infected infants with severe pneumonia.
详细描述
Pneumonia is the main cause of death in Human Immunodeficiency Virus (HIV)-infected children. A significant number of undiagnosed or poorly treated HIV-infected children present to health services with severe pneumonia. World Health Organization (WHO) guidelines to treat severe pneumonia in HIV-infected infants include empirical treatment against common bacteria plus Pneumocystis jirovecii. Although this approach has contributed to reducing overall case fatality rates, mortality in this particularly vulnerable group remains unacceptably high. Autopsy studies in Africa have shown that cytomegalovirus (CMV) infection and tuberculosis (TB) are important underdiagnosed and undertreated causes of deaths. Our objective is to evaluate whether empirical treatment against cytomegalovirus and tuberculosis improves survival of HIV-infected infants with severe pneumonia. A randomized factorial clinical trial will be conducted in six sub-Saharan African countries to evaluate the safety and efficacy of empirical treatment against cytomegalovirus and tuberculosis in HIV-infected infants aged 28 days to 365 days admitted to hospital with severe pneumonia. The primary outcome is mortality. All HIV-infected infants will receive standard of care (SoC) pneumonia treatment, including antibiotics, cotrimoxazole, and prednisolone. A group of patients will receive SoC, another group will receive valganciclovir plus SoC, another group will receive tuberculosis treatment plus SoC, and another group will receive valganciclovir, tuberculosis treatment, and SoC.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 28 Days 至 365 Days（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 28 days to 365 days of age
- •Pneumonia defined as chest indrawing or fast breathing for age, for infants 28 to 60 days of age ≥60 breaths per minute and for infants 61 to 365 days of age, ≥50 breaths per minute.
- •Current hospitalization due to pneumonia with criteria for parenteral antibiotics (1 or more criteria)
- •Chest indrawing with HIV infection
- •No improvement with oral treatment.
- •One or more danger signs according to WHO 5,44,45
- •Central cyanosis or saturation of O2 <90%
- •Severe respiratory distress, e.g. grunting or very severe chest indrawing
- •Signs of pneumonia with a general danger sign:
- •Unable to drink or breastfeed
- •Persisting vomiting
- •Convulsions in the last 24 hours
- •Lethargic or unconscious
- •Stridor while calm
- •Severe malnutrition
- •HIV-confirmed infection (with at least one molecular method: DNA polymerase chain reaction (PCR) or RNA PCR/viral load).
- •Informed consent obtained
排除标准
- •Clinical TB (pulmonary or extrapulmonary) diagnosis, defined as the necessity of TB-T prescribed by a physician, at the moment of randomization
- •Known bacteriologically confirmed TB case (at least one biological specimen positive by culture or Xpert MTB/RIF) at the moment of randomization
- •Patient previously treated for TB or currently on treatment for TB
- •Documented evidence of close TB exposure (household contact of a patient with documented TB during the lifetime of the child, or currently receiving TB-T)
- •Pure wheezers defined as a clear clinical improvement after a bronchodilator test (give a challenge of rapid-acting inhaled bronchodilator for up to three times 15-20 minutes apart. Count the breaths and look for chest indrawing again, and then re-classify)
- •Active malignancies
- •Systemic immunosuppressive medications. Steroids will be considered to be immunosuppressing only if >2 mg/kg of prednisone or equivalent during >15 days
- •Evidence of condition other than HIV and pneumonia which precludes, to the judgment of the clinical researcher, enrollment in this trial due to risk for the patient. In case of doubt, the Trial Management Team will be contacted to assess eligibility
- •Less than 2.5 kg of weight
- •Hb <6 g/dL in the screening blood test or in a test done in the last 48 hours. Transfusion is permitted to achieve >6 g/dL if the patient's state allows it. In case a transfusion is administered, the patient can be enrolled
- •Neutropenia <500 /mm3 in the screening blood test or in a test done in the last 48 hours. Repeating the test is allowed to check eligibility
研究组 & 干预措施
Tuberculosis Treatment plus Valganciclovir plus SoC
Treatment for CMV and for tuberculosis. Fixed-dose dispersible tablet of rifampicin, isoniazid, pyrazinamide (75/50/150 mg) Fixed-dose dispersible tablet of rifampicin/isoniazid (75/50 mg) Ethambutol 100 mg dispersible tablet Valganciclovir (powder for suspension, 50 mg/mL) oral, 16 mg/kg/12 hours for 15 days, Plus Standard of Care described in the Control Group
Doses of tuberculosis treatment:
Isoniazid 10 mg/kg (range 7-15 mg/kg)/day; maximum dose 300 mg/day for 6 months.
Rifampicin 15 mg/kg (range 10-20 mg/kg)/day; maximum dose 600 mg/day for 6 months.
Pyrazinamide 35 mg/kg (range 30-40 mg/kg)/day for 2 months. Ethambutol 20 mg/kg (range 15-25 mg/kg)/day for 2 months.
干预措施: Valganciclovir Oral Solution [Valcyte] (Drug)
Valganciclovir plus SoC
Treatment for cytomegalovirus (CMV) Valganciclovir (powder for suspension, 50 mg/mL) oral, 16 mg/kg/12 hours for 15 days, and Standard or Care as described in Control Group
干预措施: Valganciclovir Oral Solution [Valcyte] (Drug)
Tuberculosis Treatment plus SoC
Treatment for tuberculosis Fixed-dose dispersible tablet of rifampicin, isoniazid, pyrazinamide (75/50/150 mg) Fixed-dose dispersible tablet of rifampicin/isoniazid (75/50 mg) Ethambutol 100 mg dispersible tablet Plus Standard of Care described in the Control Group
Doses of tuberculosis treatment:
Isoniazid 10 mg/kg (range 7-15 mg/kg)/day; maximum dose 300 mg/day for 6 months.
Rifampicin 15 mg/kg (range 10-20 mg/kg)/day; maximum dose 600 mg/day for 6 months.
Pyrazinamide 35 mg/kg (range 30-40 mg/kg)/day for 2 months. Ethambutol 20 mg/kg (range 15-25 mg/kg)/day for 2 months.
干预措施: Tuberculostatic Agents (Drug)
Tuberculosis Treatment plus Valganciclovir plus SoC
Treatment for CMV and for tuberculosis. Fixed-dose dispersible tablet of rifampicin, isoniazid, pyrazinamide (75/50/150 mg) Fixed-dose dispersible tablet of rifampicin/isoniazid (75/50 mg) Ethambutol 100 mg dispersible tablet Valganciclovir (powder for suspension, 50 mg/mL) oral, 16 mg/kg/12 hours for 15 days, Plus Standard of Care described in the Control Group
Doses of tuberculosis treatment:
Isoniazid 10 mg/kg (range 7-15 mg/kg)/day; maximum dose 300 mg/day for 6 months.
Rifampicin 15 mg/kg (range 10-20 mg/kg)/day; maximum dose 600 mg/day for 6 months.
Pyrazinamide 35 mg/kg (range 30-40 mg/kg)/day for 2 months. Ethambutol 20 mg/kg (range 15-25 mg/kg)/day for 2 months.
干预措施: Tuberculostatic Agents (Drug)
结局指标
主要结局
Mortality
时间窗: 1 year
The primary endpoint of the study is all-cause mortality, focusing on the short term (up to 15-days) and long-term (up to 1-year) mortality. Mortality will be calculated using all-cause mortality after the admission over all the trial time.
次要结局
- Days with oxygen therapy(60 days)
- Days of hospitalization(1 year)
- Serious Adverse Events(1 year)
- Adverse Reactions(1 year)
- Notable Adverse Events(1 year)
- Immune-reconstitution inflammatory syndrome(6 months)
- Baseline cytomegalovirus prevalence(30 days)
- Baseline tuberculosis prevalence(60 days)
- Tuberculosis incidence(1 year)
- Deaths attributable to tuberculosis(1 year)
- CMV prevalence in died participants(1 year)
- CMV Molecular response to treatment(1 year)
- TB-lipoarabinomannan (LAM) sensitivity and specificity(1 year)
- Quality-adjusted life expectancy(1 year)
- Per-patient cost(1 year)