Precision Rifampin Trial for Personalized Dosing

NCT06318416 | Recruiting Phase 1 DMC

• 1 other identifier: HSR230382
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

Individual pharmacokinetic variability is an important driver of tuberculosis (TB) treatment failure particularly among undernourished populations, and that suboptimal serum drug concentrations are associated with delayed response to treatment, death, and acquired bacterial drug resistance. Serum drug exposures can be approximated by urine excretion as measured by spectrophotometry, replacing the need for specialized equipment for serum testing. Anti-TB pharmacokinetic variability has also been associated with enteric pathogen burden. The overall hypothesis is that urine spectrophotometry will identify people with below-target rifampin serum concentrations, which can be corrected to target levels after dose adjustment as confirmed by serum mass spectrometry. Therefore, this protocol includes a clinical trial to assess efficacy and safety of rifampin dose adjustment based on urinary excretion levels among adults and children who are being treated for drug-sensitive pulmonary TB at our longstanding collaborative research site in Haydom Lutheran Hospital, Tanzania.

Conditions

Tuberculosis

Outcome Measures

Primary Outcomes (2)

• Rifampin serum area under the concentration time curve for the 24 hour dosing interval

  Primary efficacy endpoint is the proportion of subjects in the early and delayed group that reach serum target AUC0-24 (35 ug/mL for adults; 31.7 ug/mL for children).

  21 days

• Adverse events

  Primary safety endpoint is the number of serious adverse events

  56 days

Secondary Outcomes (4)

• Time to sputum culture conversion to negative

  56 days

• Weight change

  56 days

• Enteropathogen burden

  14, 21 and 28 days after enrollment

• Biomarkers of intestinal inflammation, permeability and intestinal mass

  14, 21, 28 days after enrollment

Study Arms (2)

Early

EXPERIMENTAL

Urine spectrophotometry for rifampin absorbance and rifampin dose adjustment at Day 14

Diagnostic Test: urine spectrophotometry for rifampin absorbance

Delayed

EXPERIMENTAL

Urine spectrophotometry for rifampin absorbance and rifampin dose adjustment at Day 21

Diagnostic Test: urine spectrophotometry for rifampin absorbance

Interventions

urine spectrophotometry for rifampin absorbance DIAGNOSTIC_TEST

All participants will received conventional weight-based TB therapy, standard of care for active TB disease. After enrollment, participants will be randomized to early Day 14 or delayed Day 21 dose modification of rifampin informed by urine spectrophotometry where absorbance is determined above or below a threshold. Below a threshold, single tablets of rifampin are added to conventional fixed drug combination standard of care, above a threshold, no additional rifampin is added. Dose adjustment of rifampin may be up to \~30mg/kg and will be continued through day-56.

Delayed; Early

Eligibility Criteria

• Age: 3 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 3 or older
• Diagnosed with active, rifampin-susceptible, pulmonary TB- sputum positive for M. tuberculosis complex without rpoB mutation, or culture for M. tuberculosis with conventional rifampin susceptibility OR among children unable to expectorate, meeting confirmed or probable consensus clinical case definitions for intrathoracic childhood TB
• Initiating combination anti-TB therapy with isoniazid, rifampin, pyrazinamide, and ethambutol
• Subject or guardian is able to provide informed consent; and for children 7 years or older, provide assent
• Stated willingness to comply with all trial procedures and availability for the duration of the trial
• Resident within a pre-defined geographic area to ensure TB clinic follow-up

You may not qualify if:

• Urinary incontinence: may complicate urine collection
• Oliguria: may complicate urine collection and limit correlation of urinary excretion and serum concentrations
• Kidney disease, defined as a glomerular filtration rate (GFR) \< 60 mL/min: In 5R01 AI137080, those adults with GFR \< 60 mL/min had reduced correlation or urinary rifampin excretion and serum concentrations.
• Severe anemia, defined as a hemoglobin level less than 7 g/dL: given planned phlebotomy
• Elevated liver function tests, defined as DAIDS grade 3 or above (ALT or AST \>/= 5 x upper limit of normal): may confound potential toxicity signals of dose adjustment strategy
• Pregnancy: Urine rifampin spectrophotometry has not been studied in pregnant people, higher dose rifampin also less studied in pregnancy, and may confound potential toxicity signals (e.g. elevated liver function tests in pregnancy). Urine pregnancy test will be completed at screening in people of child-bearing potential. Child-bearing potential is defined as a person able to menstruate (menstruation in the last 12 months) and not receiving a form of contraception with less than \<1% failure rate (oral levonorgestrel, IUD or etonogestrel implant).
• Weight \<10.0 kg (dose increase may exceed 30mg/kg/dose)
• Current treatment with a drug known to have significant interaction with anti-TB therapy
• Excessive alcohol use? (for example, Men consuming \> 14 standardized drinks per week and/or \> 4 drinks per day OR women consuming \>7 standardized drinks per week, and/or \>3 drinks per day, or at the discretion of the investigator(s).

Sponsors & Collaborators

• University of Virginia: lead
• Rutgers University: collaborator
• Haydom Lutheran Hospital: collaborator

Study Sites (1)

Haydom Lutheran Hospital

Haydom, Tanzania

RECRUITING

Related Publications (2)

• Xie YL, Modi N, Handler D, Yu S, Rao P, Kagan L, Petros de Guex K, Reiss R, Siemiatkowska A, Narang A, Narayanan N, Hearn J, Khalil A, Woods P, Young L, Lardizabal A, Subbian S, Peloquin CA, Vinnard C, Thomas TA, Heysell SK. Simplified urine-based method to detect rifampin underexposure in adults with tuberculosis: a prospective diagnostic accuracy study. Antimicrob Agents Chemother. 2023 Nov 15;67(11):e0093223. doi: 10.1128/aac.00932-23. Epub 2023 Oct 25.

  PMID: 37877727 BACKGROUND

• Thomas TA, Lukumay S, Yu S, Rao P, Siemiatkowska A, Kagan L, Augustino D, Mejan P, Mosha R, Handler D, Petros de Guex K, Mmbaga B, Pfaeffle H, Reiss R, Peloquin CA, Vinnard C, Mduma E, Xie YL, Heysell SK. Rifampin urinary excretion to predict serum targets in children with tuberculosis: a prospective diagnostic accuracy study. Arch Dis Child. 2023 Aug;108(8):616-621. doi: 10.1136/archdischild-2022-325250. Epub 2023 Apr 25.

  PMID: 37171408 BACKGROUND

MeSH Terms

Conditions

Tuberculosis

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Central Study Contacts

Scott Heysell, MD, MPH

CONTACT

4342439064; skh8r@uvahealth.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: March 12, 2024
• First Posted: March 19, 2024
• Study Start: October 1, 2025
• Primary Completion (Estimated): December 30, 2027
• Study Completion (Estimated): June 1, 2028
• Last Updated: January 27, 2026

Record last verified: 2026-01

Locations

TA (1)