NCT04618198

Early Empiric Anti-Mycobacterium Tuberculosis Therapy for Sepsis in Sub-Saharan Africa

A Randomized Clinical Trial of Early Empiric Anti-Mycobacterium Tuberculosis Therapy for Sepsis in Sub-Saharan Africa

• Status: Unknown
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 436 (estimated)
• Sponsor: University of Virginia · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

In sub-Saharan Africa, tuberculosis (TB) is the etiology of 25-50% of bloodstream infections (BSIs) and the leading cause of sepsis among people living with HIV. TB BSI is associated with 20-50% mortality, and 20-25% of deaths occur within five days of admission. TB BSI is difficult to identify clinically and microbiologically. Given that the high prevalence of TB BSI is under-recognized, most patients with sepsis in sub-Saharan Africa do not receive early anti-TB therapy. The hypothesis of this study is that immediate and optimally dosed anti-TB therapy will improve 28 day mortality in patients with sepsis in Uganda and Tanzania. Therefore, the overall goal is to conduct a phase 3 multi-site open label 2x2 factorial clinical trial of 1) empiric immediate initiation of anti-TB therapy plus standard care compared to diagnosis dependent anti-TB therapy plus standard care and 2) sepsis-specific dose anti-TB therapy plus standard care compared to conventional WHO weight-based dose anti-TB therapy plus standard care for the treatment of sepsis in people living with HIV admitted to our longstanding collaborative research sites at either the Mbarara Regional Referral Hospital in Mbarara, Uganda, or Kilimanjaro region hospitals in Moshi, Tanzania.

Detailed description

The primary objective of this clinical trial is to: 1\) To conduct a randomized 2x2 factorial clinical trial of 1) empiric immediate initiation of anti-TB therapy plus standard care vs diagnosis dependent anti-TB therapy plus standard care, 2) sepsis-specific anti-TB therapy plus standard care vs conventional WHO weight-based anti-TB therapy plus standard care for patients presenting with sepsis in Uganda and Tanzania. 1a) To determine if empiric immediate initiation of anti-TB therapy plus standard care improves 28 day mortality compared to diagnosis dependent anti-TB therapy plus standard care. 1b) To determine if sepsis-specific dose anti-TB therapy plus standard care improves 28 day mortality compared to conventional WHO weight-based anti-TB therapy plus standard care. The secondary objectives include: 1. To determine if empiric immediate initiation of anti-TB therapy plus standard care improves in-hospital mortality compared to diagnosis dependent anti-TB therapy plus standard care. 2. To determine if sepsis-specific dose anti-TB therapy plus standard care improves in-hospital mortality compared to conventional WHO weight-based anti-TB therapy plus standard care. 3. To determine if empiric immediate initiation of anti-TB therapy plus standard care improves 6 month mortality compared to diagnosis dependent anti-TB therapy plus standard care. 4. To determine if sepsis-specific dose anti-TB therapy plus standard care improves 6 month mortality compared to conventional WHO weight-based anti-TB therapy plus standard care. 5. To determine the safety of increased dose sepsis-specific anti-TB therapy for patients with sepsis 6. To determine if early achievement of target serum drug concentrations of isoniazid and rifampin, measured at day-2 of TB treatment, associates with more rapid clinical improvement among patients with confirmed TB. Participants will be men or women aged ≥18 years living with HIV in Tanzania or Uganda who are admitted to one of the study hospitals with sepsis, defined by a clinical concern for infection, a modified quick sepsis-related organ failure assessment (qSOFA) score ≥2 (Glasgow Coma Scale score \<15, a respiratory rate ≥22, or a systolic blood pressure ≤90 mmHg or a mean arterial pressure of ≤65 mmHg). This is a multi-site trial at Kilimanjaro region hospitals in Tanzania (Kibong'oto Infectious Diseases Hospital and Kilimanjaro Christian Medical Centre) and Mbarara Regional Referral Hospital in Mbarara, Uganda. At both regional study sites, clinical trial infrastructure has been developed over multiple TB and non-TB related interventional studies supported by the NIH and other funders including EDCTP, WHO, MRC, and BMGF with associated regulatory standards. Furthermore, both regional hospital systems have large recruitment populations serving mid-sized cities where patients receive local care and as referral hospitals for those from more peripheral settings. The study population will be enrolled from the Emergency or inpatient wards. Admission numbers of eligible patients presenting with sepsis at each site allow for a conservative estimates of 100 patients per country per year to be well within attainment. After enrollment, patients will be randomized to 1) empiric immediate initiation of anti-TB therapy plus standard care vs diagnosis dependent anti-TB therapy plus standard care and 2) conventional WHO recommended weight-based dose anti-TB therapy with rifampin, isoniazid, pyrazinamide, and ethambutol plus pyridoxine, plus standard therapy; or sepsis-specific dose anti-TB therapy with rifampin (\~30mg/kg), isoniazid (\~7.5mg/kg), pyrazinamide, and ethambutol plus pyridoxine, plus standard care. Each individual participant will complete all participant follow-up at 6 months from enrollment.

Conditions

• Tuberculosis
• HIV I Infection
• Sepsis

Interventions

Type	Name	Description
OTHER	Immediate anti-TB therapy	Study participants will receive immediate empiric anti-TB therapy
OTHER	Sepsis-specific dose anti-TB therapy	Study participants will receive conventional WHO weight-based dose anti-TB therapy

Timeline

• Start date: 2021-12-10
• Primary completion: 2025-03-25
• Completion: 2025-06-25
• First posted: 2020-11-05
• Last updated: 2023-03-14

Locations

2 sites across 2 countries: Tanzania, Uganda