TuberculosisPhase 1TBTC S29BNCT01162486
Pharmacokinetics, Safety and Tolerability of Escalating Rifapentine Doses in Healthy Volunteers
A Phase 1 study testing Rifampin & midazolam, rifapentine & midazolam and rifapentine and midazolam in people with Tuberculosis and Tuberculosis, Pulmonary, run by Johns Hopkins University at 1 site in United States.
Trial summary
The aim of this study is to evaluate (1) the safety and tolerability of escalating doses of rifapentine (RPT) administered daily by oral; (2) the effect of increasing doses of RPT on cytochrome P450 isoform 3A (CYP3A) enzyme metabolizing activity, using single-dose midazolam (MDZ); and (3) the effect of increasing… Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Tuberculosis, Tuberculosis, Pulmonary
- What is being tested?
- Rifampin & midazolam, rifapentine & midazolam and rifapentine and midazolam
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 37 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2010to Mar 2011
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Ability and willingness to provide written informed consent.
- Age greater than or equal to 18 years, and less than or equal to 65 years.
- Weight of 50-100 kg for enrollment into the RPT cohorts
- Weight of 50-80 kg for enrollment into the RIF cohort
- Within 28 or fewer days prior to enrollment, a complete blood count with differential, comprehensive serum chemistry profile, HIV antibody test, and Hepatitis C antibody test will be performed, with the following laboratory values:
- Serum amino aspartate transferase (AST) less than the upper limit of normal
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- Total bilirubin level less than the upper limit of normal
- Serum creatinine <1.5 mg/dL
- Hemoglobin greater than 12.0 for men, greater than 11.0 for women
- Platelet count greater than or equal to 125,000 /cu mm
- Absolute neutrophil count greater than or equal to 1250 /cu mm
- Serum albumin greater than 3.5 g/dL
- HIV antibody test negative
- Hepatitis C antibody negative
- For women of childbearing potential, a negative serum bHCG pregnancy test, performed at screening.
- During the study and for 14 days after the last dose of study medication, women of childbearing potential must agree to practice barrier contraception for the duration of the study.
Who cannot join
- Pregnant or breastfeeding
- Known intolerance of or allergy to rifamycins
- Allergy to benzodiazepines
- Use of rifamycin antibiotics in the 30 days prior to enrollment
- Inability to take oral medications
- Renal, hepatic, cardiac (except benign heart murmur), or endocrine disorder; or malignancy; or immunocompromise.
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- History of any acute or chronic illness that requires current medical therapy.
- Prior gastrointestinal surgery involving stomach, biliary system, pancreas, or small intestine.
- Any medical condition that, in the opinion of the investigator, would interfere with the subject's ability to participate in the protocol.
- Any illicit drug use within the preceding 2 months. Subjects must agree to abstain from alcohol and illicit drug use during the study. Smokers must agree to abstain from cigarettes or to smoke fewer than 5 cigarettes per day.
- Current use of any prescription medication(s), including oral contraceptives.
- Planned use, during the study from Day 0 through the last PK blood draw, of any of the following: prescription medication(s), herbal supplement(s), vitamin(s), mineral supplement(s), over-the-counter medication(s), or grapefruit juice. Subjects must agree to abstain from grapefruit juice during the study.
- Participation in any other investigational drug study within 30 days prior to study entry and during study.
- Inability to participate in pharmacokinetic visits
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase I Dose Escalation Study of the Pharmacokinetics, Safety and Tolerability of Rifapentine and the Effects of Increasing Doses of Rifapentine on Induction of Metabolizing Enzymes in Healthy Volunteers
The aim of this study is to evaluate (1) the safety and tolerability of escalating doses of rifapentine (RPT) administered daily by oral; (2) the effect of increasing doses of RPT on cytochrome P450 isoform 3A (CYP3A) enzyme metabolizing activity, using single-dose midazolam (MDZ); and (3) the effect of increasing doses of RPT on autoinduction of RPT metabolism.
Read the detailed description
On day 1, volunteers will receive a single dose of MDZ dosed at 15 mg delivered orally, and a 24-hour PK analysis of MDZ and its metabolite, 1-OH-midazolam (1-OH-MDZ) will be performed. RPT (or RIF) will be given as a single daily dose (5, 10, 15, or 20 mg/kg, depending on the dose cohort) on days 2-15 (14 doses). A 24-hour PK analysis of RPT (or RIF) and its 25-deacetyl metabolite (25-des-RPT) will be performed after the first dose (day 2). On day 15, volunteers receive a second single dose of MDZ. A 72-hour RPT (or RIF) and 24-hour MDZ (and 1-OH-MDZ) PK analysis will be performed after the second dose of MDZ beginning on day 15. The PK sampling will occur both on an in-patient basis in the General Clinical Research Center (GCRC) and on an out-patient basis in the study clinic. Volunteers will undergo assessments for adverse events (AEs) several times throughout the study.
Each dose cohort will contain 6 subjects. RPT dosing will begin at 5 mg/kg (6 volunteers) and increase by 5 mg/kg increments (6 volunteers each at 10, 15, and 20 mg/kg) to a maximum dose of 20 mg/kg unless dose-limiting toxicities (DLT) are seen in two or more patients within a dose cohort, in which case a dose that is 2.5 mg/kg lower than the previous dose will be enrolled to determine the maximal tolerated dose (MTD). In addition, one cohort of 6 subjects will receive RIF at 10 mg/kg daily, rather than RPT, as a comparator arm.
- Conditions
- Tuberculosis, Tuberculosis, Pulmonary
- Being tested
- Rifampin & midazolam, rifapentine & midazolam, rifapentine and midazolam
- Keywords
- Anti-infective agents, Anti-bacterial agents, Rifampin, Rifapentine, Midazolam, Molecular mechanisms of pharmacological action, Antitubercular agents, Pharmacologic actions
- Medical subject headings
- Tuberculosis, Tuberculosis, Pulmonary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Rifampin & midazolamDrug
rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
rifapentine & midazolamDrug
rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
rifapentine & midazolamDrug
rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
rifapentine & midazolamDrug
rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
rifapentine and midazolamDrug
rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
rifapentine and midazolamDrug
rifapentine - tablet, 2.5 mg/kg lower than previously tolerated dose cohort, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
| Study group | Role | What they receive |
|---|---|---|
| Rifampin control | Active comparator | Rifampin + midazolam Receives: Drug: Rifampin & midazolam |
| RPT 1 | Experimental | RPT Cohort 1 - 5 mg/kg Receives: Drug: rifapentine & midazolam |
| RPT 2 | Experimental | RPT Cohort 2 - 10 mg/kg Receives: Drug: rifapentine & midazolam |
| RPT 3 | Experimental | RPT Cohort 3 - 15 mg/kg Receives: Drug: rifapentine & midazolam |
| RPT 4 | Experimental | RPT Cohort 4 - 20 mg/kg Receives: Drug: rifapentine and midazolam |
| RPT 5 | Experimental | RPT Cohort 5 - Maximal tolerated dose, if dose limiting toxicities are observed Receives: Drug: rifapentine and midazolam |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Grade 2 or Higher Adverse Events Over the Course of the 26 Day Trial
Number of Participants with Grade 2 or higher adverse events over 26 days
Measured: 26 days
Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose)
To determine and compare the steady-state pharmacokinetics and dose linearity of escalating daily doses of rifapentine in dose cohorts of 5 mg/kg, 10 mg/kg, 15 mg/kg and 20 mg/kg in healthy volunteers after a single dose (Day 2) or multiple doses (Day 15)
Measured: days: 2, 15
Secondary outcomes (3)
Midazolam, AUC Over 12 Hours Post-dose
To compare and describe, the pharmacokinetics of single-dose midazolam alone (Day 1) versus midazolam co-administered with either steady-state rifapentine at multiple daily doses (5, 10, 15, and 20 mg/kg) or rifampin at 10 mg/kg daily (Day 15)
Measured: days: 1, 15
Transporter Genes
To determine the effects of polymorphisms of transporter genes on rifampin and rifapentine PK parameters
Measured: day 3
Rifapentine Concentrations From Dried Blood Spots
To develop methods for determination of rifapentine concentrations from dried blood spots on sampling paper
Measured: days 2, 3, 7, 10, 15, 16, 17, 18
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jul 2010 (estimated)
- Study startApr 2010
- Primary completionFeb 2011
- Study completionMar 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- More trials run by Johns Hopkins UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 37 participants (actual)
Sponsor and investigators
- Lead sponsor
- Johns Hopkins University
- Sponsor type
- University, hospital or other
- Collaborators
- Sanofi, Centers for Disease Control and Prevention
- Responsible party
- Sponsor
- Investigators
- Kelly Dooley, MD, PhD, Principal investigator, Johns Hopkins UniversitySusan Dorman, MD, Principal investigator, Johns Hopkins Univeristy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01162486
- Sponsor's protocol ID
- CDC-NCHHSTP-5779
- Acronym
- TBTC S29B
- Status last verified
- Jan 2019
- First submitted
- 13 Jul 2010
- Last updated
- 7 May 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Savic RM, Lu Y, Bliven-Sizemore E, Weiner M, Nuermberger E, Burman W, Dorman SE, Dooley KE. Population pharmacokinetics of rifapentine and desacetyl rifapentine in healthy volunteers: nonlinearities in clearance and bioavailability. Antimicrob Agents Chemother. 2014 Jun;58(6):3035-42. doi: 10.1128/AAC.01918-13. Epub 2014 Mar 10.
PubMed 24614383
Study at a glance
From the registry record, last updated by the sponsor on 7 May 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Dose Escalation Study of the Pharmacokinetics, Safety and Tolerability of Rifapentine and the Effects of Increasing Doses of Rifapentine on Induction of Metabolizing Enzymes in Healthy Volunteers
- ClinicalTrials.gov ID
- NCT01162486
- Acronym / sponsor ID
- TBTC S29B / CDC-NCHHSTP-5779
- Conditions
- Tuberculosis, Tuberculosis, Pulmonary
- Keywords
- Anti-infective agents, Anti-bacterial agents, Rifampin, Rifapentine, Midazolam, Molecular mechanisms of pharmacological action, Antitubercular agents, Pharmacologic actions
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 37 participants (actual)
- Lead sponsor
- Johns Hopkins UniversityUniversity, hospital or other
- Collaborators
- Sanofi, Centers for Disease Control and Prevention
- Study start
- Apr 2010
- Primary completion
- Feb 2011 (actual)
- Study completion
- Mar 2011 (actual)
- First posted
- 14 Jul 2010 (estimated)
- Results
- Posted 7 May 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aim of this study is to evaluate (1) the safety and tolerability of escalating doses of rifapentine (RPT) administered daily by oral; (2) the effect of increasing doses of RPT on cytochrome P450 isoform 3A (CYP3A) enzyme metabolizing activity, using single-dose midazolam (MDZ); and (3) the effect of increasing doses of RPT on autoinduction of RPT metabolism.
Detailed description
On day 1, volunteers will receive a single dose of MDZ dosed at 15 mg delivered orally, and a 24-hour PK analysis of MDZ and its metabolite, 1-OH-midazolam (1-OH-MDZ) will be performed. RPT (or RIF) will be given as a single daily dose (5, 10, 15, or 20 mg/kg, depending on the dose cohort) on days 2-15 (14 doses). A 24-hour PK analysis of RPT (or RIF) and its 25-deacetyl metabolite (25-des-RPT) will be performed after the first dose (day 2). On day 15, volunteers receive a second single dose of MDZ. A 72-hour RPT (or RIF) and 24-hour MDZ (and 1-OH-MDZ) PK analysis will be performed after the second dose of MDZ beginning on day 15. The PK sampling will occur both on an in-patient basis in the General Clinical Research Center (GCRC) and on an out-patient basis in the study clinic. Volunteers will undergo assessments for adverse events (AEs) several times throughout the study.
Each dose cohort will contain 6 subjects. RPT dosing will begin at 5 mg/kg (6 volunteers) and increase by 5 mg/kg increments (6 volunteers each at 10, 15, and 20 mg/kg) to a maximum dose of 20 mg/kg unless dose-limiting toxicities (DLT) are seen in two or more patients within a dose cohort, in which case a dose that is 2.5 mg/kg lower than the previous dose will be enrolled to determine the maximal tolerated dose (MTD). In addition, one cohort of 6 subjects will receive RIF at 10 mg/kg daily, rather than RPT, as a comparator arm.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Rifampin control | Active comparator | Drug: Rifampin & midazolamRifampin + midazolam |
| RPT 1 | Experimental | Drug: rifapentine & midazolamRPT Cohort 1 - 5 mg/kg |
| RPT 2 | Experimental | Drug: rifapentine & midazolamRPT Cohort 2 - 10 mg/kg |
| RPT 3 | Experimental | Drug: rifapentine & midazolamRPT Cohort 3 - 15 mg/kg |
| RPT 4 | Experimental | Drug: rifapentine and midazolamRPT Cohort 4 - 20 mg/kg |
| RPT 5 | Experimental | Drug: rifapentine and midazolamRPT Cohort 5 - Maximal tolerated dose, if dose limiting toxicities are observed |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- Ability and willingness to provide written informed consent.
- Age greater than or equal to 18 years, and less than or equal to 65 years.
- Weight of 50-100 kg for enrollment into the RPT cohorts
- Weight of 50-80 kg for enrollment into the RIF cohort
- Within 28 or fewer days prior to enrollment, a complete blood count with differential, comprehensive serum chemistry profile, HIV antibody test, and Hepatitis C antibody test will be performed, with the following laboratory values:
Key exclusion criteria (14 listed)
- Pregnant or breastfeeding
- Known intolerance of or allergy to rifamycins
- Allergy to benzodiazepines
- Use of rifamycin antibiotics in the 30 days prior to enrollment
- Inability to take oral medications
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Rifampin & midazolamrifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 | Drug | Rifampin control |
| rifapentine & midazolamrifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 | Drug | RPT 1 |
| rifapentine & midazolamrifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 | Drug | RPT 2 |
| rifapentine & midazolamrifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 | Drug | RPT 3 |
| rifapentine and midazolamrifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 | Drug | RPT 4 |
| rifapentine and midazolamrifapentine - tablet, 2.5 mg/kg lower than previously tolerated dose cohort, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 | Drug | RPT 5 |
Primary outcome
Number of Participants With Grade 2 or Higher Adverse Events Over the Course of the 26 Day Trial
Time frame: 26 days
Number of Participants with Grade 2 or higher adverse events over 26 days
Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose)
Time frame: days: 2, 15
To determine and compare the steady-state pharmacokinetics and dose linearity of escalating daily doses of rifapentine in dose cohorts of 5 mg/kg, 10 mg/kg, 15 mg/kg and 20 mg/kg in healthy volunteers after a single dose (Day 2) or multiple doses (Day 15)
3 secondary outcomes
Midazolam, AUC Over 12 Hours Post-dose
Time frame: days: 1, 15
Transporter Genes
Time frame: day 3
Rifapentine Concentrations From Dried Blood Spots
Time frame: days 2, 3, 7, 10, 15, 16, 17, 18
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 May 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 24614383Savic RM, Lu Y, Bliven-Sizemore E, Weiner M, Nuermberger E, Burman W, Dorman SE, Dooley KE. Population pharmacokinetics of rifapentine and desacetyl rifapentine in healthy volunteers: nonlinearities in clearance and bioavailability. Antimicrob Agents Chemother. 2014 Jun;58(6):3035-42. doi: 10.1128/AAC.01918-13. Epub 2014 Mar 10.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kelly Dooley, MD, PhD principal investigator
Johns Hopkins University
Susan Dorman, MD principal investigator
Johns Hopkins Univeristy
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Rifampin & midazolam, rifapentine & midazolam and rifapentine and midazolam in people with Tuberculosis and Tuberculosis, Pulmonary, run by Johns Hopkins University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 May 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 7 May 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Grade 2 or Higher Adverse Events Over the Course of the 26 Day Trial (time frame: 26 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01162486, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 May 2019.