Clinical trial NCT04618198: Early Empiric Anti-Mycobacterium Tuberculosis Therapy for Sepsis in Sub-Saharan Africa
Official title: A Randomized Clinical Trial of Early Empiric Anti-Mycobacterium Tuberculosis Therapy for Sepsis in Sub-Saharan Africa
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Tuberculosis
HIV I Infection
Sepsis
Lead sponsor: University of Virginia
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2020-11-05
Enrollment: 436
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention 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.
Primary purpose: TREATMENT

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.

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.

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 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

Primary outcomes:
measure: 28-day mortality
timeFrame: 28 days from enrollment
Secondary outcomes:
measure: In-hospital mortality
timeFrame: 28 days from enrollment
measure: 6-month mortality
timeFrame: 6 months from enrollment
measure: Time to death
timeFrame: 6 months from enrollment
measure: Duration of hospitalization
timeFrame: 6 months from enrollment
measure: Time to anti-TB therapy
timeFrame: 28 days from enrollment
measure: Adverse events
timeFrame: 28 days from enrollment
measure: Sepsis etiology
timeFrame: baseline specimen collection
measure: Time to ambulation
timeFrame: 28 days from enrollment
measure: Time to temperature normalization
timeFrame: 28 days from enrollment
measure: Karnofsky score
timeFrame: 28 days from enrollment
measure: Peak drug concentration isoniazid
timeFrame: 2 days from enrollment
measure: Peak drug concentration rifampin
timeFrame: 2 days from enrollment
measure: Total drug exposure isoniazid
timeFrame: 2 days from enrollment
measure: Total drug exposure rifampin
timeFrame: 2 days from enrollment
Other outcomes:
Locations:
city: Sanya Juu
country: Tanzania
facility: Kibong'oto Infectious Diseases Hospital
city: Mbarara
country: Uganda
facility: Mbarara University Science Technology
Study officials:
affiliation: University of Virginia
name: Christopher Moore, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
citation: 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.
citation: 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.