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

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01162486
• Collaborator: Sanofi (Industry), Centers for Disease Control and Prevention (U.S. Fed)
• Enrollment: 37
• Location: 1
• Arms: 6
• Duration (Months): 11
• Patients Per Site Per Month: 3.4

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis; Tuberculosis, Pulmonary	Drug: Rifampin & midazolam; Drug: rifapentine & midazolam; Drug: rifapentine & midazolam; Drug: rifapentine & midazolam; Drug: rifapentine and midazolam; Drug: rifapentine and midazolam	Phase 1

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

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Apr 1, 2010
• Actual Primary Completion Date: Feb 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Rifampin control Rifampin + midazolam	Drug: Rifampin & midazolam; rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Experimental: RPT 1 RPT Cohort 1 - 5 mg/kg	Drug: rifapentine & midazolam; rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Experimental: RPT 2 RPT Cohort 2 - 10 mg/kg	Drug: rifapentine & midazolam; rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Experimental: RPT 3 RPT Cohort 3 - 15 mg/kg	Drug: rifapentine & midazolam; rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Experimental: RPT 4 RPT Cohort 4 - 20 mg/kg	Drug: rifapentine and midazolam; rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Experimental: RPT 5 RPT Cohort 5 - Maximal tolerated dose, if dose limiting toxicities are observed	Drug: rifapentine and midazolam; rifapentine - tablet, 2.5 mg/kg lower than previously tolerated dose cohort, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Grade 2 or Higher Adverse Events Over the Course of the 26 Day Trial [26 days]

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

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

Secondary Outcome Measures

1. Midazolam, AUC Over 12 Hours Post-dose [days: 1, 15]

   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)

2. Transporter Genes [day 3]

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

3. Rifapentine Concentrations From Dried Blood Spots [days 2, 3, 7, 10, 15, 16, 17, 18]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Ability and willingness to provide written informed consent.

2. Age greater than or equal to 18 years, and less than or equal to 65 years.

3. Weight of 50-100 kg for enrollment into the RPT cohorts

4. Weight of 50-80 kg for enrollment into the RIF cohort

5. 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:

6. Serum amino aspartate transferase (AST) less than the upper limit of normal

7. Total bilirubin level less than the upper limit of normal

8. Serum creatinine <1.5 mg/dL

9. Hemoglobin greater than 12.0 for men, greater than 11.0 for women

10. Platelet count greater than or equal to 125,000 /cu mm

11. Absolute neutrophil count greater than or equal to 1250 /cu mm

12. Serum albumin greater than 3.5 g/dL

13. HIV antibody test negative

14. Hepatitis C antibody negative

15. For women of childbearing potential, a negative serum bHCG pregnancy test, performed at screening.

16. 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:

1. Pregnant or breastfeeding

2. Known intolerance of or allergy to rifamycins

3. Allergy to benzodiazepines

4. Use of rifamycin antibiotics in the 30 days prior to enrollment

5. Inability to take oral medications

6. Renal, hepatic, cardiac (except benign heart murmur), or endocrine disorder; or malignancy; or immunocompromise.

7. History of any acute or chronic illness that requires current medical therapy.

8. Prior gastrointestinal surgery involving stomach, biliary system, pancreas, or small intestine.

9. Any medical condition that, in the opinion of the investigator, would interfere with the subject's ability to participate in the protocol.

10. 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.

11. Current use of any prescription medication(s), including oral contraceptives.

12. 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.

13. Participation in any other investigational drug study within 30 days prior to study entry and during study.

14. Inability to participate in pharmacokinetic visits

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

• Johns Hopkins University
• Sanofi
• Centers for Disease Control and Prevention

Investigators

• Principal Investigator: Kelly Dooley, MD, PhD, Johns Hopkins University
• Principal Investigator: Susan Dorman, MD, Johns Hopkins Univeristy

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT01162486
• Other Study ID Numbers: CDC-NCHHSTP-5779
• First Posted: Jul 14, 2010
• Last Update Posted: May 7, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by Johns Hopkins University: Anti-infective agents; Anti-bacterial agents; Rifampin; Rifapentine; Midazolam; Molecular mechanisms of pharmacological action; Antitubercular agents; Pharmacologic actions
• Additional relevant MeSH terms: Tuberculosis; Tuberculosis, Pulmonary; Rifampin; Rifapentine; Midazolam

Study Results

Participant Flow

Arm/Group Title	Rifampin Control	RPT 1	RPT 2	RPT 3	RPT 4
Arm/Group Description	Rifampin + midazolam Rifampin & midazolam: rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 1 - 5 mg/kg rifapentine & midazolam: rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 2 - 10 mg/kg rifapentine & midazolam: rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 3 - 15 mg/kg rifapentine & midazolam: rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 4 - 20 mg/kg rifapentine and midazolam: rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Period Title: Overall Study
STARTED	8	6	6	7	6
Took at Least One Dose Study Drug	8	6	6	7	6
COMPLETED	6	6	5	6	6
NOT COMPLETED	2	0	1	1	0

Baseline Characteristics

Arm/Group Title	Rifampin Control	RPT 1	RPT 2	RPT 3	RPT 4	Total
Arm/Group Description	Rifampin + midazolam Rifampin & midazolam: rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 1 - 5 mg/kg rifapentine & midazolam: rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 2 - 10 mg/kg rifapentine & midazolam: rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 3 - 15 mg/kg rifapentine & midazolam: rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 4 - 20 mg/kg rifapentine and midazolam: rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	Total of all reporting groups
Overall Participants	8	7	7	7	8	37
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	8 100%	7 100%	7 100%	7 100%	8 100%	37 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	39	50	44	41	47	44
Sex: Female, Male (Count of Participants)
Female	1 12.5%	1 14.3%	0 0%	3 42.9%	1 12.5%	6 16.2%
Male	7 87.5%	6 85.7%	7 100%	4 57.1%	7 87.5%	31 83.8%
Region of Enrollment (participants) [Number]
United States	8 100%	7 100%	7 100%	7 100%	8 100%	37 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Four withdrew prior to receiving study rifamycin so were not included in the safety population

Arm/Group Title	Rifampin Control	RPT 1	RPT 2	RPT 3	RPT 4
Arm/Group Description	Rifampin + midazolam Rifampin & midazolam: rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 1 - 5 mg/kg rifapentine & midazolam: rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 2 - 10 mg/kg rifapentine & midazolam: rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 3 - 15 mg/kg rifapentine & midazolam: rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 4 - 20 mg/kg rifapentine and midazolam: rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Measure Participants	8	6	6	7	6
Count of Participants [Participants]	1 12.5%	0 0%	1 14.3%	1 14.3%	0 0%

2. Primary Outcome

Title	Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose)
Description	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)
Time Frame	days: 2, 15

Outcome Measure Data

Analysis Population Description

These patients completed PK visits on Day 2 and 15 (Three participants in this non-control group - subdivided into 4- did not complete the study). Reasons provided in the participant flow session

Arm/Group Title	RPT 1	RPT 2	RPT 3	RPT 4
Arm/Group Description	RPT Cohort 1 - 5 mg/kg rifapentine & midazolam: rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 2 - 10 mg/kg rifapentine & midazolam: rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 3 - 15 mg/kg rifapentine & midazolam: rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 4 - 20 mg/kg rifapentine and midazolam: rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Measure Participants	5	5	6	6
RPT AUC, Day 2 single dose	128	242	363	403
RPT AUC, Day 15 multiple dose	218	330	560	483

3. Secondary Outcome

Title	Midazolam, AUC Over 12 Hours Post-dose
Description	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)
Time Frame	days: 1, 15

Outcome Measure Data

Analysis Population Description

29 participants completed both midazolam PK visits; one person in RPT1 visit was not analyzed because his samples were zero and was found to have been non-compliant with regimen

Arm/Group Title	Rifampin Control	RPT 1	RPT 2	RPT 3	RPT 4
Arm/Group Description	Rifampin + midazolam Rifampin & midazolam: rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 1 - 5 mg/kg rifapentine & midazolam: rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 2 - 10 mg/kg rifapentine & midazolam: rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 3 - 15 mg/kg rifapentine & midazolam: rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 4 - 20 mg/kg rifapentine and midazolam: rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Measure Participants	6	5	5	6	6
AUC 0-12 Midazolam alone (Day 1)	151	150	114	204	173
AUC 0-12 Midazolam with RIF (Day 15)	26.9	14.2	10.2	14.0	11.7

4. Secondary Outcome

Title	Transporter Genes
Description	To determine the effects of polymorphisms of transporter genes on rifampin and rifapentine PK parameters
Time Frame	day 3

Outcome Measure Data

Analysis Population Description

This outcome was not assessed because data was not collected

Arm/Group Title	Rifampin Control	RPT 1	RPT 2	RPT 3	RPT 4
Arm/Group Description	Rifampin + midazolam Rifampin & midazolam: rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 1 - 5 mg/kg rifapentine & midazolam: rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 2 - 10 mg/kg rifapentine & midazolam: rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 3 - 15 mg/kg rifapentine & midazolam: rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 4 - 20 mg/kg rifapentine and midazolam: rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Measure Participants	0	0	0	0	0

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

This outcome was not assessed because data was not collected

Arm/Group Title	Rifampin Control	RPT 1	RPT 2	RPT 3	RPT 4
Arm/Group Description	Rifampin + midazolam Rifampin & midazolam: rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 1 - 5 mg/kg rifapentine & midazolam: rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 2 - 10 mg/kg rifapentine & midazolam: rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 3 - 15 mg/kg rifapentine & midazolam: rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15	RPT Cohort 4 - 20 mg/kg rifapentine and midazolam: rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Measure Participants	0	0	0	0	0

Adverse Events

Arm/Group Title	Rifampin Control		RPT 1		RPT 2		RPT 3		RPT 4
Arm/Group Description	Rifampin + midazolam Rifampin & midazolam: rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15		RPT Cohort 1 - 5 mg/kg rifapentine & midazolam: rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15		RPT Cohort 2 - 10 mg/kg rifapentine & midazolam: rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15		RPT Cohort 3 - 15 mg/kg rifapentine & midazolam: rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15		RPT Cohort 4 - 20 mg/kg rifapentine and midazolam: rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
All Cause Mortality
	Rifampin Control		RPT 1		RPT 2		RPT 3		RPT 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/6 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)
Serious Adverse Events
	Rifampin Control		RPT 1		RPT 2		RPT 3		RPT 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/6 (0%)		0/6 (0%)		0/7 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Rifampin Control		RPT 1		RPT 2		RPT 3		RPT 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/8 (62.5%)		2/6 (33.3%)		3/6 (50%)		4/7 (57.1%)		2/6 (33.3%)
Endocrine disorders
Hyperglycemia	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	0/6 (0%)	0
Gastrointestinal disorders
Gas	0/8 (0%)	0	2/6 (33.3%)	2	0/6 (0%)	0	0/7 (0%)	0	0/6 (0%)	0
Constipation	0/8 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	2/7 (28.6%)	2	0/6 (0%)	0
Vomitting	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0
General disorders
fever	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0
Dizziness	0/8 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/7 (14.3%)	1	0/6 (0%)	0
Neutropenia	2/8 (25%)	2	0/6 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0	0/6 (0%)	0
Lymphopenia	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/7 (28.6%)	2	0/6 (0%)	0
Hypertransaminasemia	0/8 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0	0/6 (0%)	0
Leukopenia	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	0/6 (0%)	0
Hepatobiliary disorders
Hyperbilirubinemia	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	1/6 (16.7%)	1
Nervous system disorders
Headache	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	1/6 (16.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.