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

Sepsis Clinical Trial

— ATLAS  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04618198
• Other study ID #: 22611
• Secondary ID: U01AI150508-01A1
• Status: Recruiting
• Phase: Phase 3
• Start date: December 10, 2021
• Est. completion date: June 25, 2025

Study information

• Verified date: March 2023
• Source: University of Virginia
• Contact: Christopher Moore, MD
• Phone: 434-924-9678
• Email: ccm5u[@]hscmail.mcc.virginia.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 436
• Est. completion date: June 25, 2025
• Est. primary completion date: March 25, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 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.

3. Known allergic reactions to the components of the anti-TB 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 interaction with anti-TB therapy

Related Conditions & MeSH terms

• HIV I Infection
• Sepsis
• Toxemia
• Tuberculosis

Intervention

Other:
• Immediate anti-TB therapy
Study participants will receive immediate empiric anti-TB therapy
• Sepsis-specific dose anti-TB therapy
Study participants will receive conventional WHO weight-based dose anti-TB therapy

Locations

Country	Name	City	State
Tanzania	Kibong'oto Infectious Diseases Hospital	Sanya Juu
Uganda	Mbarara University Science Technology	Mbarara

Sponsors (2)

Lead Sponsor	Collaborator
University of Virginia	National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

Tanzania,  Uganda, 

References & Publications (5)

Byashalira K, Mbelele P, Semvua H, Chilongola J, Semvua S, Liyoyo A, Mmbaga B, Mfinanga S, Moore C, Heysell S, Mpagama S. Clinical outcomes of new algorithm for diagnosis and treatment of Tuberculosis sepsis in HIV patients. Int J Mycobacteriol. 2019 Oct-Dec;8(4):313-319. doi: 10.4103/ijmy.ijmy_135_19. — View Citation

Hazard RH, Kagina P, Kitayimbwa R, Male K, McShane M, Mubiru D, Welikhe E, Moore CC, Abdallah A. Effect of Empiric Anti-Mycobacterium tuberculosis Therapy on Survival Among Human Immunodeficiency Virus-Infected Adults Admitted With Sepsis to a Regional Referral Hospital in Uganda. Open Forum Infect Dis. 2019 Mar 14;6(4):ofz140. doi: 10.1093/ofid/ofz140. eCollection 2019 Apr. — View Citation

Heysell SK, Mtabho C, Mpagama S, Mwaigwisya S, Pholwat S, Ndusilo N, Gratz J, Aarnoutse RE, Kibiki GS, Houpt ER. Plasma drug activity assay for treatment optimization in tuberculosis patients. Antimicrob Agents Chemother. 2011 Dec;55(12):5819-25. doi: 10.1128/AAC.05561-11. Epub 2011 Oct 3. — View Citation

Moore CC, Jacob ST, Banura P, Zhang J, Stroup S, Boulware DR, Scheld WM, Houpt ER, Liu J. Etiology of Sepsis in Uganda Using a Quantitative Polymerase Chain Reaction-based TaqMan Array Card. Clin Infect Dis. 2019 Jan 7;68(2):266-272. doi: 10.1093/cid/ciy472. — View Citation

Mpagama SG, Ndusilo N, Stroup S, Kumburu H, Peloquin CA, Gratz J, Houpt ER, Kibiki GS, Heysell SK. Plasma drug activity in patients on treatment for multidrug-resistant tuberculosis. Antimicrob Agents Chemother. 2014;58(2):782-8. doi: 10.1128/AAC.01549-13. Epub 2013 Nov 18. — View Citation

Outcome

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