Tuberculosis Clinical Trial
— P-RIFOfficial title:
Precision Rifampin (P-RIF) Trial for Personalized Dosing in Active Tuberculosis Disease
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.
Status | Not yet recruiting |
Enrollment | 200 |
Est. completion date | January 30, 2028 |
Est. primary completion date | January 30, 2027 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 3 Years and older |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
n/a |
Lead Sponsor | Collaborator |
---|---|
University of Virginia | Haydom Lutheran Hospital, Rutgers University |
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. — View Citation
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. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | |
Primary | Adverse events | Primary safety endpoint is the number of serious adverse events | 56 days | |
Secondary | Time to sputum culture conversion to negative | Time to sputum culture conversion to negative from pretreatment, Day 0, and serial sample collection | 56 days | |
Secondary | Weight change | Percent of weight change of total body weight in kilograms | 56 days |
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