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

NCT04618198 | Unknown Phase 3

• 2 other identifiers: 22611U01AI150508-01A1
• Study Type: interventional
• Target: 436
• Locations: 2 countries
• Sites: 2

Brief 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.

Conditions

Tuberculosis; HIV I Infection; Sepsis

Outcome Measures

Primary Outcomes (1)

• 28-day mortality

  number of participants with mortality

  28 days from enrollment

Secondary Outcomes (14)

• In-hospital mortality

  28 days from enrollment

• 6-month mortality

  6 months from enrollment

• Time to death

  6 months from enrollment

• Duration of hospitalization

  6 months from enrollment

• Time to anti-TB therapy

  28 days from enrollment

Study Arms (4)

Diagnosis dependent / conventional dose anti-TB therapy

NO INTERVENTION

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

Immediate anti-TB therapy/conventional dose anti-TB therapy

EXPERIMENTAL

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

Diagnosis dependent/sepsis specific dose anti-TB therapy

EXPERIMENTAL

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

Immediate anti-TB therapy/sepsis specific dose anti-TB therapy

EXPERIMENTAL

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; Other: Sepsis-specific dose anti-TB therapy

Interventions

Immediate anti-TB therapy OTHER

Study participants will receive immediate empiric anti-TB therapy

Immediate anti-TB therapy/conventional dose anti-TB therapy; Immediate anti-TB therapy/sepsis specific dose anti-TB therapy

Sepsis-specific dose anti-TB therapy OTHER

Study participants will receive conventional WHO weight-based dose anti-TB therapy

Diagnosis dependent/sepsis specific dose anti-TB therapy; Immediate anti-TB therapy/sepsis specific dose anti-TB therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Virginia: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (2)

Kibong'oto Infectious Diseases Hospital

Sanya Juu, Tanzania

RECRUITING

Mbarara University Science Technology

Mbarara, Uganda

RECRUITING

Related Publications (7)

• 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.

  PMID: 29868873 BACKGROUND

• 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.

  PMID: 31024977 BACKGROUND

• 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.

  PMID: 24247125 BACKGROUND

• 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.

  PMID: 21968363 BACKGROUND

• 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.

  PMID: 31793499 BACKGROUND

• Heysell SK, Mpagama SG, Nuwagira E, Said B, Conaway M, Null M, Thomas TA, Boulware DR, Otoupalova E, Arinaitwe R, Mushagara R, Edwards L, Buzaare P, Ngoma AM, Muganzi D, Gidoi G, Jjunju S, Gulinja A, Rimoy AG, Mwita FC, Kidola J, Atwiine O, Ocaaki D, Munyambalu DK, Liu J, Ampaire L, Mujaga B, Rao P, Liyoyo A, Sariko M, Muzoora C, Moore CC. Immediate or high-dose antituberculosis therapy for HIV-related sepsis in Tanzania and Uganda (ATLAS): a phase 3, open-label, randomised, controlled, 2 x 2 factorial, superiority trial. Lancet Infect Dis. 2026 Jan 28:S1473-3099(25)00747-9. doi: 10.1016/S1473-3099(25)00747-9. Online ahead of print.

  PMID: 41619753 DERIVED

• Said B, Nuwagira E, Liyoyo A, Arinaitwe R, Gitige C, Mushagara R, Buzaare P, Chongolo A, Jjunju S, Twesigye P, Boulware DR, Conaway M, Null M, Thomas TA, Heysell SK, Moore CC, Muzoora C, Mpagama SG. Early empiric anti-Mycobacterium tuberculosis therapy for sepsis in sub-Saharan Africa: a protocol of a randomised clinical trial. BMJ Open. 2022 Jun 6;12(6):e061953. doi: 10.1136/bmjopen-2022-061953.

  PMID: 35667721 DERIVED

MeSH Terms

Conditions

Tuberculosis; Sepsis

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Christopher Moore, MD

  University of Virginia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Christopher Moore, MD

CONTACT

434-924-9678; ccm5u@hscmail.mcc.virginia.edu

Scott Heysell, MD

CONTACT

434-243-9064; skh8r@hscmail.mcc.virginia.edu

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor, Infectious Disease

Model Details: 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.

Study Record Dates

• First Submitted: October 26, 2020
• First Posted: November 5, 2020
• Study Start: December 10, 2021
• Primary Completion: March 25, 2025
• Study Completion: June 25, 2025
• Last Updated: March 14, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Within 1 year from study conclusion
• Access Criteria: Reasonable request to the PIs

Locations

TA (1); UG (1)