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

May 29, 2026 updated by: Scott Heysell, MD, University of Virginia

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

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed 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 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.

Study Type

Interventional

Enrollment (Estimated)

344

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Tanzania
      • Mwanza, Tanzania
        • Sekou Toure Regional Referral Hospital
        • Contact:
        • Principal Investigator:
          • Frederick C Mwita, MD
      • Sanya Juu, Tanzania
        • Kibong'oto Infectious Diseases Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Stellah G Mpagama, MD, PhD
  • Uganda
      • Fort Portal, Uganda
        • Fort Portal Regional Referral Hospital
        • Contact:
        • Principal Investigator:
          • Dalton K Munyambalu, MBChB, MMed
      • Mbarara, Uganda
        • Mbarara Regional Referral Hospital
        • Contact:
        • Principal Investigator:
          • Edwin Nuwagira, MBChB, MMed

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: No hydrocortisone/enhanced spectrum antimicrobial therapy
Drug: Expanded antimicrobial therapy
empiric initiation of the enhanced spectrum antimicrobial therapy regimen (rifampin, isoniazid, linezolid, and levofloxacin) for 14 days plus standard care which includes ceftriaxone for 7 days or diagnosis dependent conventional anti-TB therapy
Experimental: Hydrocortisone/enhanced spectrum antimicrobial therapy
Drug: Hydrocortisone administration
Immediate hydrocortisone at 200 mg IV daily for 7 days and a tapering schedule for an additional 7 days
Drug: Expanded antimicrobial therapy
empiric initiation of the enhanced spectrum antimicrobial therapy regimen (rifampin, isoniazid, linezolid, and levofloxacin) for 14 days plus standard care which includes ceftriaxone for 7 days or diagnosis dependent conventional anti-TB therapy
No Intervention: No hydrocortisone/immediate anti-TB therapy
Standard of care
Experimental: Hydrocortisone/immediate anti-TB therapy
Drug: Hydrocortisone administration
Immediate hydrocortisone at 200 mg IV daily for 7 days and a tapering schedule for an additional 7 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mortality
Time Frame: 28 days from date of randomization
Primary outcome measure
28 days from date of randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
In-hospital mortality
Time Frame: from enrollment through hospitalization, an average of 14 days
Mortality
from enrollment through hospitalization, an average of 14 days
6-month mortality
Time Frame: From the date of randomization until death or 180 days from randomization
Mortality
From the date of randomization until death or 180 days from randomization
Time to death
Time Frame: From date of randomization to death or 180 days from randomization
Mortality
From date of randomization to death or 180 days from randomization
Incidence of new post-admission shock
Time Frame: From the time of enrollment through hospital discharge, an average of 14 days
New post-admission shock
From the time of enrollment through hospital discharge, an average of 14 days
Duration of hospitalization
Time Frame: From the time of randomization until date of hospital discharge up to 180 days, or death if before hospital discharge
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
Time Frame: From the date of randomization until date of hospital discharge up to 180 days, or date of death if occurring before 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
Time Frame: From date of randomization to 28 days post randomization or date of death if death occurred before 28 days
Adverse drug events
From date of randomization to 28 days post randomization or date of death if death occurred before 28 days
Time to ambulation
Time Frame: 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 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
Time Frame: 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
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
Time Frame: 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
Lactate concentration change
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
Time Frame: 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
Change in 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
Time Frame: From the time of randomization to 72 hours after randomization
Calculation of initial Universal Vital Assessment mortality risk score at randomization and 72 hours after randomization: component number one, measure 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
Time Frame: 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 two, measure 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
Time Frame: 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, measure 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
Time Frame: 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, measure 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
Time Frame: 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, record record level of consciousness by glascow come scale
From time to randomization to 72 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Virginia

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

  • Principal Investigator: Scott K Heysell, MD, MPH, University of Virginia
  • Principal Investigator: Christopher C Moore, MD, University of Virginia

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

October 1, 2026

Primary Completion (Estimated)

March 1, 2029

Study Completion (Estimated)

September 1, 2029

Study Registration Dates

First Submitted

January 6, 2026

First Submitted That Met QC Criteria

January 8, 2026

First Posted (Actual)

January 12, 2026

Study Record Updates

Last Update Posted (Actual)

June 1, 2026

Last Update Submitted That Met QC Criteria

May 29, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HSR302304
  • 1U01AI192033-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Sharing Time Frame

Within one year of trial completion

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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