Clinical Trials Logo

Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT04618198
Other study ID # 22611
Secondary ID U01AI150508-01A1
Status Recruiting
Phase Phase 3
First received
Last updated
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
Health authority
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

Study Design


Related Conditions & MeSH terms


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
See also
  Status Clinical Trial Phase
Active, not recruiting NCT05095324 - The Biomarker Prediction Model of Septic Risk in Infected Patients
Completed NCT02714595 - Study of Cefiderocol (S-649266) or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens Phase 3
Completed NCT03644030 - Phase Angle, Lean Body Mass Index and Tissue Edema and Immediate Outcome of Cardiac Surgery Patients
Completed NCT02867267 - The Efficacy and Safety of Ta1 for Sepsis Phase 3
Completed NCT04804306 - Sepsis Post Market Clinical Utility Simple Endpoint Study - HUMC
Recruiting NCT05578196 - Fecal Microbial Transplantation in Critically Ill Patients With Severe Infections. N/A
Terminated NCT04117568 - The Role of Emergency Neutrophils and Glycans in Postoperative and Septic Patients
Completed NCT03550794 - Thiamine as a Renal Protective Agent in Septic Shock Phase 2
Completed NCT04332861 - Evaluation of Infection in Obstructing Urolithiasis
Completed NCT04227652 - Control of Fever in Septic Patients N/A
Enrolling by invitation NCT05052203 - Researching the Effects of Sepsis on Quality Of Life, Vitality, Epigenome and Gene Expression During RecoverY From Sepsis
Terminated NCT03335124 - The Effect of Vitamin C, Thiamine and Hydrocortisone on Clinical Course and Outcome in Patients With Severe Sepsis and Septic Shock Phase 4
Recruiting NCT04005001 - Machine Learning Sepsis Alert Notification Using Clinical Data Phase 2
Completed NCT03258684 - Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Sepsis and Septic Shock N/A
Recruiting NCT05217836 - Iron Metabolism Disorders in Patients With Sepsis or Septic Shock.
Completed NCT05018546 - Safety and Efficacy of Different Irrigation System in Retrograde Intrarenal Surgery N/A
Completed NCT03295825 - Heparin Binding Protein in Early Sepsis Diagnosis N/A
Not yet recruiting NCT06045130 - PUFAs in Preterm Infants
Not yet recruiting NCT05361135 - 18-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in S. Aureus Bacteraemia N/A
Not yet recruiting NCT05443854 - Impact of Aminoglycosides-based Antibiotics Combination and Protective Isolation on Outcomes in Critically-ill Neutropenic Patients With Sepsis: (Combination-Lock01) Phase 3