STeroids and Enhanced Spectrum Antibiotics for the Treatment of Patients in Africa With Refractory Sepsis (STARS)

University of Virginia

Status and phase: Begins enrollment in 1 month; Phase 3

Conditions: Tuberculosis; Sepsis

Treatments: Drug: Expanded antimicrobial therapy; Drug: Hydrocortisone administration

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT07332325

HSR302304

1U01AI192033-01 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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 current standard of care in the region, ceftriaxone, 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 the standard of care 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.

Full description

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 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.

Enrollment: 344 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male or female aged ≥18 years living with HIV
4. 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)
5. Resident within a pre-defined geographic area to ensure TB clinic follow-up
6. For females of reproductive potential: use of highly effective contraception through 28 days

Exclusion criteria

1. Known active TB or receiving anti-TB therapy
2. 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.
3. Known allergic reactions to the components of the interventional therapy
4. Treatment with another investigational drug or other intervention within one month
5. Known liver disease
6. 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
7. Positive serum cryptococcal antigen test
8. Current treatment with a drug known to have significant, non-correctable interaction with anti-TB therapy
9. Already receiving corticosteroids at the time of presentation to the hospital

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: None (Open label)

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344 participants in 4 patient groups

No hydrocortisone/standard antimicrobial therapy

No Intervention group

Description:

Standard of care

Hydrocortisone/standard antimicrobial therapy

Experimental group

Treatment:

Drug: Hydrocortisone administration

No hydrocortisone/enhanced spectrum antimicrobial therapy

Experimental group

Treatment:

Drug: Expanded antimicrobial therapy

Hydrocortisone/enhanced spectrum antimicrobial therapy

Experimental group

Treatment:

Drug: Expanded antimicrobial therapy

Drug: Hydrocortisone administration