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

NCT ID: NCT07332325

Last Updated: 2026-01-12

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 344 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-04-30
• Study Completion Date: 2029-09-30

Brief Summary

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.

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 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.

Conditions

Sepsis; Tuberculosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

No hydrocortisone/standard antimicrobial therapy

Standard of care

Group Type: NO_INTERVENTION

No interventions assigned to this group

Hydrocortisone/standard antimicrobial therapy

Group Type: EXPERIMENTAL

Hydrocortisone administration

Intervention Type: DRUG

Immediate hydrocortisone at 200 mg IV daily for 7 days and a tapering schedule for an additional 7 days

No hydrocortisone/enhanced spectrum antimicrobial therapy

Group Type: EXPERIMENTAL

Expanded antimicrobial therapy

Intervention Type: DRUG

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

Hydrocortisone/enhanced spectrum antimicrobial therapy

Group Type: EXPERIMENTAL

Hydrocortisone administration

Intervention Type: DRUG

Immediate hydrocortisone at 200 mg IV daily for 7 days and a tapering schedule for an additional 7 days

Expanded antimicrobial therapy

Intervention Type: DRUG

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

Interventions

Hydrocortisone administration

Immediate hydrocortisone at 200 mg IV daily for 7 days and a tapering schedule for an additional 7 days

Intervention Type: 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

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

University of Virginia

OTHER

Sponsor Role: lead

Responsible Party

Scott Heysell, MD

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Scott K Heysell, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of Virginia

Christopher C Moore, MD

Role: PRINCIPAL_INVESTIGATOR

University of Virginia

Locations

Sekou Toure Regional Referral Hospital

Mwanza, , Tanzania

Kibong'oto Infectious Diseases Hospital

Sanya Juu, , Tanzania

Fort Portal Regional Referral Hospital

Fort Portal, , Uganda

Mbarara Regional Referral Hospital

Mbarara, , Uganda

Countries

Tanzania; Uganda

Central Contacts

Scott K Heysell, MD, MPH

Role: CONTACT

SKH8R@uvahealth.org

434-924-0000 ext. 6962

Christopher C Moore, MD

Role: CONTACT

ccm5u@uvahealth.org

434-924-0000 ext. 3489

Facility Contacts

Frederick C Mwita, MD

Role: primary

Cyprianfredy@gmail.com

+255282502171

Stellah G Kibong'oto, MD, PhD

Role: primary

sempagama@yahoo.com

+255272974140

Bibie Said, MD

Role: backup

bibiesd90@gmail.com

+255272974140

Dalton K Munyambalu, MBChB, MMed

Role: primary

daltonkamuda@gmail.com

+256 717 555139

Edwin Nuwagira, MBChB, MMed

Role: primary

enuwagira@must.ac.ug

+256485420030

Other Identifiers

1U01AI192033-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HSR302304

Identifier Type: -

Identifier Source: org_study_id