STeroids and Enhanced Spectrum Antibiotics for the Treatment of Patients in Africa With Refractory Sepsis (STARS Trial)
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 344
- 试验地点
- 4
- 主要终点
- Mortality
研究概览
简要总结
Sepsis, a life-threatening condition due to a dysregulated response to infection, is the leading cause of global mortality and is frequently driven by tuberculosis (TB) and drug-resistant bacteria in sub-Saharan Africa, particularly among people living with HIV. The prevailing standard of care in the region, ceftriaxone alone, is insufficient as it does not address TB, drug-resistant bacteria, or adrenal insufficiency, which is common in HIV-related sepsis. Therefore, the investigators propose a randomized 2x2 factorial clinical trial to compare 28-day survival from sepsis between study participants who along with a standard of care that includes immediate conventional anti-TB treatment receive 1) hydrocortisone to treat septic shock and 2) rifampin, isoniazid, levofloxacin and linezolid to treat TB and other drug-resistant bacteria in order to deliver important and scalable knowledge that may alter the standard of care for sepsis in HIV endemic settings of sub-Saharan Africa. Improving understanding of the physiology and treatment alternatives for HIV related critical illness globally will have reciprocal benefit for health in the U.S.
详细描述
Sepsis is defined as life-threatening organ dysfunction due to a dysregulated host response to infection and is the leading cause of global mortality. The World Health Organization has declared sepsis a global priority. Yet, little is known about sepsis in the global South and specifically sub-Saharan Africa where there are an estimated 17 million cases and 3.5 million attributable deaths per year. The majority of these patients are living with human immunodeficiency virus (HIV). The investigators have determined the leading cause of sepsis in this region is tuberculosis (TB) which is responsible for 25-30% of bloodstream infections in septic patients. TB sepsis is associated with 20-50% mortality rates with the majority of deaths occurring within the first 4-5 days of admission. Other causative pathogens include bacteria commonly or intrinsically resistant to third-generation cephalosporins which are the standard antimicrobial treatment for sepsis adopted from the global North. The investigators have also studied anti-TB pharmacokinetics/pharmacodynamics in septic patients and discovered considerably low circulating drug concentrations that are suboptimal for microbial kill. Concurrently, the investigators have also found a high burden of corticosteroid insufficiency in people with critical illness at collaborative study sites in Uganda and Tanzania. HIV and TB, independently and in combination, contribute to adrenal infection and endogenous steroid insufficiency. In further observational study, adults with sepsis at the collaborative study sites treated with corticosteroids have significantly improved survival from septic shock in-line with some, but not all, trials of adjunctive steroids in infection associated critical illness. Therefore, hypotheses are that immediate hydrocortisone administered over 7 days followed by a 7-day taper will improve 28 day mortality compared to the standard of care where corticosteroids are not administered, and that an enhanced antimicrobial regimen for 14 days to target TB and other drug-resistant bacteria of sepsis (rifampin, isoniazid, levofloxacin and linezolid) will improve 28 day mortality compared to the standard of care of immediate conventional anti-TB treatment and ceftriaxone alone. These hypotheses will be tested through a randomized 2x2 factorial clinical trial where participants hospitalized with HIV and sepsis will be randomized to 1) hydrocortisone or the standard care without hydrocortisone, and 2) the enhanced antimicrobial regimen plus ceftriaxone or the standard care with ceftriaxone alone. This randomized 2x2 factorial clinical trial is strongly endorsed by Tanzanian and Ugandan stakeholders, utilizes drugs that are available within national formularies and regional pharmacies, and if successful will be scalable for adults with sepsis in HIV endemic regions of sub-Saharan Africa. Improved understanding of the physiology and treatment alternatives for HIV related critical illness globally will have reciprocal benefit for health in the U.S.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provision of signed and dated informed consent form
- •Stated willingness to comply with all study procedures and availability for the duration of the study
- •Male or female aged ≥18 years living with HIV
- •Admitted to hospital with 1) clinical concern for infection; 2) ≥2 qSOFA score criteria (Glasgow Coma Scale score <15, a respiratory rate ≥22, or a systolic blood pressure ≤90 mmHg or a mean arterial pressure of ≤65 mmHg)
- •Resident within a pre-defined geographic area to ensure TB clinic follow-up
- •For females of reproductive potential: use of highly effective contraception through 28 days
排除标准
- •Known active TB or receiving anti-TB therapy
- •Pregnancy or lactation. Women will undergo urine pregnancy screening. Pregnant people will be excluded due to lack of pharmacokinetic data for the expanded antibiotic regimen in pregnancy.
- •Known allergic reactions to the components of the interventional therapy
- •Treatment with another investigational drug or other intervention within one month
- •Known liver disease
- •Alcohol use > 14 standardized drinks per week and/or > 4 drinks per day for men and >7 standardized drinks per week and/or >3 drinks per day for women, defined as 14 grams of ethanol, as found in example 5 ounces of wine, 12 ounces of beer, or 1.5 ounces of 80 proof spirits
- •Positive serum cryptococcal antigen test
- •Current treatment with a drug known to have significant, non-correctable interaction with anti-TB therapy
- •Already receiving corticosteroids at the time of presentation to the hospital
研究组 & 干预措施
Hydrocortisone/enhanced spectrum antimicrobial therapy
干预措施: Expanded antimicrobial therapy (Drug)
No hydrocortisone/enhanced spectrum antimicrobial therapy
干预措施: Expanded antimicrobial therapy (Drug)
Hydrocortisone/enhanced spectrum antimicrobial therapy
干预措施: Hydrocortisone administration (Drug)
结局指标
主要结局
Mortality
时间窗: 28 days from date of randomization
Primary outcome measure
次要结局
- In-hospital mortality(from enrollment through hospitalization, an average of 14 days)
- 6-month mortality(From the date of randomization until death or 180 days from randomization)
- Time to death(From date of randomization to death or 180 days from randomization)
- Incidence of new post-admission shock(From the time of enrollment through hospital discharge, an average of 14 days)
- Duration of hospitalization(From the time of randomization until date of hospital discharge up to 180 days, or death if before hospital discharge)
- Volume of IV fluids received(From the date of randomization until date of hospital discharge up to 180 days, or date of death if occurring before discharge)
- Adverse drug events during the 28-day study period(From date of randomization to 28 days post randomization or date of death if death occurred before 28 days)
- Time to ambulation(From date of randomization until the date of first documented ambulation during hospitalization, or date of death from any cause, whichever came first, on average over 14 days, but up to 180 days)
- Time to temperature normalization(From date of randomization until the date of first documented normal temperature during hospitalization, or date of death from any cause, whichever came first, on average over 14 days, but up to 180 days)
- Lactate/delta lactate(From the date of randomization until the date of hospital discharge or the date of death if death occurred before discharge, on average 14 days)
- Capillary fill time/delta capillary fill time(From the date of randomization until the date of hospital discharge or the date of death if death occurred before discharge, on average 14 days)
- Universal Vital Assessment score and delta Universal Vital Assessment score: component number one, heart rate(From the time of randomization to 72 hours after randomization)
- Universal Vital Assessment mortality risk score at randomization and 72 hours after randomization: component number two, respiratory rate(From time to randomization to 72 hours)
- Calculation of initial Universal Vital Assessment mortality risk score at randomization and 72 hours after randomization: component number three, systolic blood pressure(From time to randomization to 72 hours)
- Calculation of initial Universal Vital Assessment mortality risk score at randomization and 72 hours after randomization: component number four, oxygen saturation(From time to randomization to 72 hours)
- Calculation of initial Universal Vital Assessment mortality risk score at randomization and 72 hours after randomization: component number five, glascow coma scale(From time to randomization to 72 hours)
研究者
Scott Heysell, MD
Professor of Medicine
University of Virginia