- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT06318416
Precision Rifampin Trial for Personalized Dosing (P-RIF)
March 19, 2024 updated by: Scott Heysell, MD, University of Virginia
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.
Study Overview
Status
Not yet recruiting
Conditions
Intervention / Treatment
Detailed Description
This is a single-site trial at Haydom Lutheran Hospital, a regional referral hospital level in Manyara Region of northern Tanzania.
The primary objective: Among children and adults in Tanzania initiating treatment for drug-susceptible pulmonary TB, perform urine spectrophotometric testing for rifampin, and collect serum throughout the 24 hour dosing interval for later concentration measurement by gold-standard mass spectrometry and comparative pharmacokinetics.
Patients with urine rifampin excretion below target will undergo incremental dose increase and urine spectrophotometry and serum collection will be repeated.
Stool will also be evaluated at regular intervals to understand the association with enteropathogen burden and effects on rifampin absorption, urine excretion, and serum exposures.
Participants will randomized to an early group where urine spectrophotometry and dose adjustment is performed at Day 14 after treatment initiation, or a delayed group where the intervention is performed at Day 21.
Primary efficacy endpoint is the proportion of subjects in the early and delayed groups that reach serum target AUC0-24 (35 ug/mL for adults; 31.7 ug/mL for children) at Day 21, before the urine based dose adjustment is made in the delayed group.
Primary safety endpoint is the number of severe adverse events.
Secondary endpoints include: time to sputum culture conversion to negative, weight change.
Time to culture conversion and weight change are stratified by age given pediatric populations are more likely to be culture negative and clinically diagnosed with weight gain a central measurement of treatment response.
Study Type
Interventional
Enrollment (Estimated)
200
Phase
- Phase 2
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Contact
- Name: Scott Heysell, MD, MPH
- Phone Number: 4342439064
- Email: skh8r@uvahealth.org
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
- Child
- Adult
- Older Adult
Accepts Healthy Volunteers
No
Description
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Diagnostic
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Early
Urine spectrophotometry for rifampin absorbance and rifampin dose adjustment at Day 14
|
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.
|
Experimental: Delayed
Urine spectrophotometry for rifampin absorbance and rifampin dose adjustment at Day 21
|
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.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Rifampin serum area under the concentration time curve for the 24 hour dosing interval
Time Frame: 21 days
|
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
Time Frame: 56 days
|
Primary safety endpoint is the number of serious adverse events
|
56 days
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Time to sputum culture conversion to negative
Time Frame: 56 days
|
Time to sputum culture conversion to negative from pretreatment, Day 0, and serial sample collection
|
56 days
|
Weight change
Time Frame: 56 days
|
Percent of weight change of total body weight in kilograms
|
56 days
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- 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.
- 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.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Estimated)
July 1, 2024
Primary Completion (Estimated)
January 30, 2027
Study Completion (Estimated)
January 30, 2028
Study Registration Dates
First Submitted
March 12, 2024
First Submitted That Met QC Criteria
March 12, 2024
First Posted (Actual)
March 19, 2024
Study Record Updates
Last Update Posted (Actual)
March 21, 2024
Last Update Submitted That Met QC Criteria
March 19, 2024
Last Verified
March 1, 2024
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Infections
- Bacterial Infections
- Bacterial Infections and Mycoses
- Gram-Positive Bacterial Infections
- Actinomycetales Infections
- Mycobacterium Infections
- Tuberculosis
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Anti-Bacterial Agents
- Leprostatic Agents
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 CYP3A Inducers
- Antitubercular Agents
- Antibiotics, Antitubercular
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2C8 Inducers
- Cytochrome P-450 CYP2C19 Inducers
- Cytochrome P-450 CYP2C9 Inducers
- Rifampin
Other Study ID Numbers
- HSR230382
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
UNDECIDED
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
No
Studies a U.S. FDA-regulated device product
No
product manufactured in and exported from the U.S.
No
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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