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Pharmacokinetics, Safety and Tolerability of Escalating Rifapentine Doses in Healthy Volunteers (TBTC S29B)

Primary Purpose

Tuberculosis, Tuberculosis, Pulmonary

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Rifampin & midazolam

rifapentine & midazolam

rifapentine and midazolam

About this trial

This is an interventional treatment trial for Tuberculosis focused on measuring Anti-infective agents, Anti-bacterial agents, Rifampin, Rifapentine, Midazolam, Molecular mechanisms of pharmacological action, Antitubercular agents, Pharmacologic actions

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

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:
1. Serum amino aspartate transferase (AST) less than the upper limit of normal
2. Total bilirubin level less than the upper limit of normal
3. Serum creatinine <1.5 mg/dL
4. Hemoglobin greater than 12.0 for men, greater than 11.0 for women
5. Platelet count greater than or equal to 125,000 /cu mm
6. Absolute neutrophil count greater than or equal to 1250 /cu mm
7. Serum albumin greater than 3.5 g/dL
8. HIV antibody test negative
9. 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.

Exclusion Criteria:

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.
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

Sites / Locations

Johns Hopkins University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Active Comparator

Experimental

Arm Label

Rifampin control

RPT 1

RPT 2

RPT 3

RPT 4

RPT 5

Arm Description

Rifampin + midazolam

RPT Cohort 1 - 5 mg/kg

RPT Cohort 2 - 10 mg/kg

RPT Cohort 3 - 15 mg/kg

RPT Cohort 4 - 20 mg/kg

RPT Cohort 5 - Maximal tolerated dose, if dose limiting toxicities are observed

Outcomes

Primary Outcome Measures

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

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)

Secondary Outcome Measures

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)

Transporter Genes

To determine the effects of polymorphisms of transporter genes on rifampin and rifapentine PK parameters

Rifapentine Concentrations From Dried Blood Spots

To develop methods for determination of rifapentine concentrations from dried blood spots on sampling paper

Full Information

NCT ID

NCT01162486

First Posted

July 13, 2010

Last Updated

January 29, 2019

Sponsor

Johns Hopkins University

Collaborators

Sanofi, Centers for Disease Control and Prevention

1. Study Identification

Unique Protocol Identification Number

NCT01162486

Brief Title

Pharmacokinetics, Safety and Tolerability of Escalating Rifapentine Doses in Healthy Volunteers

Acronym

TBTC S29B

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2019

Overall Recruitment Status

Completed

Study Start Date

April 2010 (undefined)

Primary Completion Date

February 2011 (Actual)

Study Completion Date

March 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Johns Hopkins University

Collaborators

Sanofi, Centers for Disease Control and Prevention

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief 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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tuberculosis, Tuberculosis, Pulmonary

Keywords

Anti-infective agents, Anti-bacterial agents, Rifampin, Rifapentine, Midazolam, Molecular mechanisms of pharmacological action, Antitubercular agents, Pharmacologic actions

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

37 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Rifampin control

Arm Type

Active Comparator

Arm Description

Rifampin + midazolam

Arm Title

RPT 1

Arm Type

Experimental

Arm Description

RPT Cohort 1 - 5 mg/kg

Arm Title

RPT 2

Arm Type

Experimental

Arm Description

RPT Cohort 2 - 10 mg/kg

Arm Title

RPT 3

Arm Type

Experimental

Arm Description

RPT Cohort 3 - 15 mg/kg

Arm Title

RPT 4

Arm Type

Experimental

Arm Description

RPT Cohort 4 - 20 mg/kg

Arm Title

RPT 5

Arm Type

Experimental

Arm Description

RPT Cohort 5 - Maximal tolerated dose, if dose limiting toxicities are observed

Intervention Type

Drug

Intervention Name(s)

Rifampin & midazolam

Intervention Description

rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15

Intervention Type

Drug

Intervention Name(s)

rifapentine & midazolam

Intervention Description

rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15

Intervention Type

Drug

Intervention Name(s)

rifapentine & midazolam

Intervention Description

rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15

Intervention Type

Drug

Intervention Name(s)

rifapentine & midazolam

Intervention Description

rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15

Intervention Type

Drug

Intervention Name(s)

rifapentine and midazolam

Intervention Description

rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15

Intervention Type

Drug

Intervention Name(s)

rifapentine and midazolam

Intervention Description

rifapentine - tablet, 2.5 mg/kg lower than previously tolerated dose cohort, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15

Primary Outcome Measure Information:

Title

Number of Participants With Grade 2 or Higher Adverse Events Over the Course of the 26 Day Trial

Description

Number of Participants with Grade 2 or higher adverse events over 26 days

Time Frame

26 days

Title

Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose)

Description

Time Frame

days: 2, 15

Secondary Outcome Measure Information:

Title

Midazolam, AUC Over 12 Hours Post-dose

Description

Time Frame

days: 1, 15

Title

Transporter Genes

Description

To determine the effects of polymorphisms of transporter genes on rifampin and rifapentine PK parameters

Time Frame

day 3

Title

Rifapentine Concentrations From Dried Blood Spots

Description

To develop methods for determination of rifapentine concentrations from dried blood spots on sampling paper

Time Frame

days 2, 3, 7, 10, 15, 16, 17, 18

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 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. Exclusion Criteria: 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. 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kelly Dooley, MD, PhD

Organizational Affiliation

Johns Hopkins University

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Susan Dorman, MD

Organizational Affiliation

Johns Hopkins Univeristy

Official's Role

Principal Investigator

Facility Information:

Facility Name

Johns Hopkins University

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21287

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

24614383

Citation

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.

Results Reference

derived

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Pharmacokinetics, Safety and Tolerability of Escalating Rifapentine Doses in Healthy Volunteers

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