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

Study Overview
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Brief Summary
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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
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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: 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. 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. 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. 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. To determine the safety of increased dose sepsis-specific anti-TB therapy for patients with sepsis 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.

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

Conditions
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Tuberculosis, HIV I Infection, Sepsis

Intervention / Treatment
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* Other: Immediate anti-TB therapy
* Other: Sepsis-specific dose anti-TB therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: Known active TB or receiving anti-TB therapy Pregnancy or lactation. Women will undergo urine pregnancy screening. Pregnant women will be excluded due to the possible toxicity and teratogenicity of high dose rifampin and isoniazid included in anti-TB therapy as well as possible teratogenicity of dolutegravir which is recommended as first-line antiretroviral therapy in this study. Known allergic reactions to the components of the anti-TB 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 interaction with anti-TB therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: This is a phase 3, multi-site, open-label, randomized controlled clinical 2x2 factorial superiority trial of a) immediate initiation of anti-TB therapy and b) sepsis-specific dose anti-TB therapy for people living with HIV and presenting with sepsis to our regional study sites in Tanzania and Uganda.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Diagnosis dependent / conventional dose anti-TB therapy<br>Standard care per admitting team including ceftriaxone x 7 days If subsequent TB test positive, then WHO recommended weight-based anti-TB therapy x 28 days | |
| Experimental: Immediate anti-TB therapy/conventional dose anti-TB therapy<br>Standard care per admitting team including ceftriaxone x 7 days plus immediate empiric WHO recommended weight-based dose anti-TB therapy x 28 days | Other: Immediate anti-TB therapy<br>* Study participants will receive immediate empiric anti-TB therapy<br>|
| Experimental: Diagnosis dependent/sepsis specific dose anti-TB therapy<br>Standard care per admitting team including ceftriaxone x 7 days If subsequent TB test positive, then sepsis specific dose anti-TB therapy x 28 days | Other: Sepsis-specific dose anti-TB therapy<br>* Study participants will receive conventional WHO weight-based dose anti-TB therapy<br>|
| Experimental: Immediate anti-TB therapy/sepsis specific dose anti-TB therapy<br>Standard care per admitting team including ceftriaxone x 7 days plus immediate empiric sepsis specific dose anti-TB therapy x 28 days | Other: Immediate anti-TB therapy<br>* Study participants will receive immediate empiric anti-TB therapy<br>Other: Sepsis-specific dose anti-TB therapy<br>* Study participants will receive conventional WHO weight-based dose anti-TB therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-day mortality | number of participants with mortality | 28 days from enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In-hospital mortality | number of participants with mortality while admitted to the hospital | 28 days from enrollment | 
| 6-month mortality | number of participants with mortality | 6 months from enrollment | 
| Time to death | time from enrollment to date of mortality | 6 months from enrollment | 
| Duration of hospitalization | time from enrollment to date of discharge from hospital | 6 months from enrollment | 
| Time to anti-TB therapy | Time to administration of anti-TB therapy | 28 days from enrollment | 
| Adverse events | Number of adverse events per participant associated with anti-TB therapy | 28 days from enrollment | 
| Sepsis etiology | pathogen identified in blood by molecular TAC platform | baseline specimen collection | 
| Time to ambulation | time from enrollment to date of first ambulation | 28 days from enrollment | 
| Time to temperature normalization | Time until participant has a normal temperature (above 36C and below 38C) | 28 days from enrollment | 
| Karnofsky score | Karnofsky score at discharge or death, scale 0 (worst) to 100 (best) | 28 days from enrollment | 
| Peak drug concentration isoniazid | Serum isoniazid peak concentration (Cmax) | 2 days from enrollment | 
| Peak drug concentration rifampin | Serum rifampin peak concentration (Cmax) | 2 days from enrollment | 
| Total drug exposure isoniazid | Serum isoniazid total area under the concentration time curve (AUC) | 2 days from enrollment | 
| Total drug exposure rifampin | Serum total area under the concentration time curve (AUC) | 2 days from enrollment |