RECRUITINGPhase 1INTERVENTIONAL

Precision Rifampin Trial for Personalized Dosing

Precision Rifampin (P-RIF) Trial for Personalized Dosing in Active Tuberculosis Disease

About This Trial

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.

Who May Be Eligible (Plain English)

Who May Qualify: 1. Age 3 or older 2. 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 3. Initiating combination anti-TB therapy with isoniazid, rifampin, pyrazinamide, and ethambutol 4. Subject or guardian is able to provide willing to sign a consent form; and for children 7 years or older, provide assent 5. Stated willingness to comply with all trial procedures and availability for the duration of the trial 6. Resident within a pre-defined geographic area to ensure TB clinic follow-up Who Should NOT Join This Trial: 1. Urinary incontinence: may complicate urine collection 2. Oliguria: may complicate urine collection and limit correlation of urinary excretion and serum concentrations 3. 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. 4. Severe anemia, defined as a hemoglobin level less than 7 g/dL: given planned phlebotomy 5. 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 ...See full criteria on ClinicalTrials.gov Always talk to your doctor about whether this trial is right for you.

Original Eligibility Criteria

View original clinical language

Inclusion Criteria: 1. Age 3 or older 2. 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 3. Initiating combination anti-TB therapy with isoniazid, rifampin, pyrazinamide, and ethambutol 4. Subject or guardian is able to provide informed consent; and for children 7 years or older, provide assent 5. Stated willingness to comply with all trial procedures and availability for the duration of the trial 6. Resident within a pre-defined geographic area to ensure TB clinic follow-up Exclusion Criteria: 1. Urinary incontinence: may complicate urine collection 2. Oliguria: may complicate urine collection and limit correlation of urinary excretion and serum concentrations 3. 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. 4. Severe anemia, defined as a hemoglobin level less than 7 g/dL: given planned phlebotomy 5. 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 6. 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). 7. Weight \<10.0 kg (dose increase may exceed 30mg/kg/dose) 8. Current treatment with a drug known to have significant interaction with anti-TB therapy 9. 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).

Treatments Being Tested

DIAGNOSTIC_TEST

urine spectrophotometry for rifampin absorbance

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.

Locations (1)

Haydom Lutheran Hospital

Haydom, Tanzania