- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04618198
Early Empiric Anti-Mycobacterium Tuberculosis Therapy for Sepsis in Sub-Saharan Africa (ATLAS)
A Randomized Clinical Trial of Early Empiric Anti-Mycobacterium Tuberculosis Therapy for Sepsis in Sub-Saharan Africa
Study Overview
Status
Conditions
Intervention / Treatment
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:
- 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.
Study Type
Enrollment (Anticipated)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: Christopher Moore, MD
- Phone Number: 434-924-9678
- Email: ccm5u@hscmail.mcc.virginia.edu
Study Contact Backup
- Name: Scott Heysell, MD
- Phone Number: 434-243-9064
- Email: skh8r@hscmail.mcc.virginia.edu
Study Locations
-
-
-
Sanya Juu, Tanzania
- Recruiting
- Kibong'oto Infectious Diseases Hospital
-
Contact:
- Stellah Mpagama, MD, PhD
- Email: sempagama@yahoo.com
-
-
-
-
-
Mbarara, Uganda
- Recruiting
- Mbarara University Science Technology
-
Contact:
- Conrad Muzoora, MD
- Email: conradmuzoora@yahoo.com
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Factorial Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
No Intervention: Diagnosis dependent / conventional dose anti-TB therapy
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
Standard care per admitting team including ceftriaxone x 7 days plus immediate empiric WHO recommended weight-based dose anti-TB therapy x 28 days
|
Study participants will receive immediate empiric anti-TB therapy
|
Experimental: Diagnosis dependent/sepsis specific dose anti-TB therapy
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 |
Study participants will receive conventional WHO weight-based dose anti-TB therapy
|
Experimental: Immediate anti-TB therapy/sepsis specific dose anti-TB therapy
Standard care per admitting team including ceftriaxone x 7 days plus immediate empiric sepsis specific dose anti-TB therapy x 28 days
|
Study participants will receive immediate empiric anti-TB therapy
Study participants will receive conventional WHO weight-based dose anti-TB therapy
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
28-day mortality
Time Frame: 28 days from enrollment
|
number of participants with mortality
|
28 days from enrollment
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
In-hospital mortality
Time Frame: 28 days from enrollment
|
number of participants with mortality while admitted to the hospital
|
28 days from enrollment
|
6-month mortality
Time Frame: 6 months from enrollment
|
number of participants with mortality
|
6 months from enrollment
|
Time to death
Time Frame: 6 months from enrollment
|
time from enrollment to date of mortality
|
6 months from enrollment
|
Duration of hospitalization
Time Frame: 6 months from enrollment
|
time from enrollment to date of discharge from hospital
|
6 months from enrollment
|
Time to anti-TB therapy
Time Frame: 28 days from enrollment
|
Time to administration of anti-TB therapy
|
28 days from enrollment
|
Adverse events
Time Frame: 28 days from enrollment
|
Number of adverse events per participant associated with anti-TB therapy
|
28 days from enrollment
|
Sepsis etiology
Time Frame: baseline specimen collection
|
pathogen identified in blood by molecular TAC platform
|
baseline specimen collection
|
Time to ambulation
Time Frame: 28 days from enrollment
|
time from enrollment to date of first ambulation
|
28 days from enrollment
|
Time to temperature normalization
Time Frame: 28 days from enrollment
|
Time until participant has a normal temperature (above 36C and below 38C)
|
28 days from enrollment
|
Karnofsky score
Time Frame: 28 days from enrollment
|
Karnofsky score at discharge or death, scale 0 (worst) to 100 (best)
|
28 days from enrollment
|
Peak drug concentration isoniazid
Time Frame: 2 days from enrollment
|
Serum isoniazid peak concentration (Cmax)
|
2 days from enrollment
|
Peak drug concentration rifampin
Time Frame: 2 days from enrollment
|
Serum rifampin peak concentration (Cmax)
|
2 days from enrollment
|
Total drug exposure isoniazid
Time Frame: 2 days from enrollment
|
Serum isoniazid total area under the concentration time curve (AUC)
|
2 days from enrollment
|
Total drug exposure rifampin
Time Frame: 2 days from enrollment
|
Serum total area under the concentration time curve (AUC)
|
2 days from enrollment
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Christopher Moore, MD, University of Virginia
Publications and helpful links
General Publications
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 22611
- U01AI150508-01A1 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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