Drug Interaction Study

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00646776
• Collaborator: (none)
• Enrollment: 85
• Location: 1
• Arms: 2
• Duration (Months): 4
• Patients Per Site Per Month: 21.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the exposure of rifabutin (RIB) when administered with atazanavir and ritonavir (ATV/RTV)

Condition or Disease	Intervention/Treatment	Phase
Antivirals/HIV	Drug: Rifabutin; Drug: Rifabutin + Atazanavir + Ritonavir	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Study to Evaluate the Exposure of Rifabutin Administered in an Alternate Regimen in Combination With Atazanavir and Ritonavir Healthy Subjects
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Aug 1, 2008
• Actual Study Completion Date: Aug 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: A	Drug: Rifabutin; Capsule, Oral, 150 mg, once daily, 11 Days
Active Comparator: B	Drug: Rifabutin + Atazanavir + Ritonavir; Capsules, Oral, 18 Days Rifabutin (150 mg, 2x/wk) Atazanavir (300 mg, once daily) Ritonavir (100 mg, once daily); Other Names: Reyataz

Outcome Measures

Primary Outcome Measures

1. Average Area Under the Plasma Concentration-time Curve for 24 Hours (AUC24avg) for Rifabutin (RIB) [Pre-dose (0 hours [h]) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   AUC24avg is AUC(0-24 hour) following dosing on Day 10 for RIB 150mg once daily (QD); AUC24avg is the area under the plasma concentration-time curve in 1 dosing interval (AUC[TAU]) divided by the number of days over the sampling duration for ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly, i.e. AUC(TAU)/7.

2. Maximum Plasma Concentration (Cmax) of RIB [Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   Cmax was derived from plasma concentration versus time for RIB and was recorded directly from experimental observations for each treatment period.

3. Minimum Plasma Concentration (Cmin) of RIB [Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   Cmin was derived from plasma concentration versus time for RIB.

4. AUC24avg for 25-O-Desacetyl-RIB [Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   AUC24avg is AUC(0-24 hour) following dosing on Day 10 for RIB 150 mg QD; AUC24avg is the area under the plasma concentration-time curve in 1 dosing interval (AUC[TAU]) divided by the number of days over the sampling duration for ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly, i.e. AUC(TAU)/7

5. Cmax of 25-O-Desacetylrifabutin (25-O-Desacetyl-RIB) [Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   Cmax was derived from the plasma concentration versus time for 25-O-Desacetyl-RIB (a metabolite of RIB) and was recorded directly from experimental observations for each treatment period.

6. Cmin of 25-O-Desacetyl-RIB [Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   Cmin was derived from plasma concentration versus time for 25-O-Desacetyl-RIB.

7. Total Area Under the Plasma Concentration-time Curve (AUCtot) [Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   AUCtot represents the total free RIB plus 25-O-Desacetyl-RIB output. It is calculated as: AUCtot (micromolar[µM]*h) = AUC24avg(RIB)(ng*h/mL)/847.016 (g/mole) + AUC24avg(25-O-Desacetyl-RIB)(ng*h/mL)/804.979(g/mole). The 300 mg RIB arm represents an extrapolation from the 150 mg RIB group.

Secondary Outcome Measures

1. Cmax of ATV [Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   Cmax was derived from the plasma concentration versus time for ATV and was recorded directly from experimental observations for each treatment period.

2. Cmin of ATV [Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   Cmin was derived from the plasma concentration versus time for ATV.

3. AUC(TAU) for ATV [Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   AUC(TAU) was derived from the plasma concentration versus time for ATV, and was calculated by linear and log-linear trapezoidal summations using a mixed log-linear algorithm.

4. Time to Reach Maximum Observed Plasma Concentration (Tmax) of ATV [Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   Tmax was derived from the plasma concentration versus time for ATV and was recorded directly from experimental observations for each treatment period.

5. Terminal Elimination Half-life (T-half) of ATV [Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   T-half was obtained directly from the concentration-time data. T-half following doses administered for treatment ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly.

6. Cmax of RTV [Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   Cmax was derived from the plasma concentration versus time for RTV and was recorded directly from experimental observations for each treatment period.

7. Cmin of RTV [Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   Cmin was derived from the plasma concentration versus time for RTV.

8. AUC(TAU) for RTV [Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   AUC(TAU) was derived from the plasma concentration versus time for RTV, and was calculated by linear and log-linear trapezoidal summations using a mixed log-linear algorithm.

9. Tmax of RTV [Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

   Tmax was derived from the plasma concentration versus time for RTV and was recorded directly from experimental observations for each treatment period.

10. T-half of RTV [Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.]

    T-half was obtained directly from the concentration-time data.

11. Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation. [From Day 1 to 30 days after the last dose of study drug.]

    AEs were defined as new, untoward medical occurrences/worsening of pre-existing medical condition, whether drug-related or not. SAEs were defined as any AE that: resulted in death; was life threatening; resulted in a persistent or significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; was a cancer; or was an overdose. Discontinuation from the study was due either to an AE or was conducted at the investigator's discretion.

12. Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Platelet Count and Leukocytes [Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly.]

    MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Hemoglobin/hematocrit: <0.85 x pre-treatment (pre-Rx) value. Platelet count: <0.85 x lower limit of normal (LLN) (or, if pre-Rx value <LLN, then <0.85 x pre-Rx value) or >1.5 x upper limit of normal (ULN). Leukocytes: <0.9 x LLN or >1.2 x ULN (or, if pre-Rx value <LLN, then <0.85 x pre-Rx or >ULN. If pre-Rx value >ULN, then >1.15 x pre-Rx or <LLN).

13. Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) [Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly.]

    MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Neutrophils+bands (absolute): <=1.50 x 10^3 cells/microliter (uL). Lymphocytes (absolute): <0.75 x 10^3 cells/uL or >7.50 x 10^3 cells/uL. Monocytes (absolute): >2.00 x 10^3 cells/uL. Basophils (absolute): >0.40 x 10^3 cells/uL. Eosinophils (absolute): >0.75 x 10^3 cells/uL.

14. Number of Participants With MAs in Serum Chemistry: Alkaline Phosphatase (ALP),Aspartate Aminotransferase (AST),Alanine Aminotransferase (ALT),Bilirubin (Total),Bilirubin (Direct),Blood Urea Nitrogen (BUN),Creatinine,Sodium (Serum),Potassium (Serum) [Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly.]

    MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. ALP, AST, ALT:>1.25xULN (if pre-Rx >ULN, then >1.25xpre-Rx). Bilirubin (total), bilirubin (direct), BUN:>1.1xULN (if pre-Rx >ULN, then >1.25xpre-Rx). Creatinine:>1.33xpre-Rx. Sodium (serum):<0.95xLLN or >1.05xULN (if pre-Rx <LLN, then <0.95xpre-Rx or >ULN. If pre-Rx >ULN, then >1.05xpre-Rx or <LLN). Potassium (serum):<0.9xLLN or >1.1xULN (if pre-Rx <LLN, then <0.9xpre-Rx or >ULN. If pre-Rx >ULN, then >1.1xpre-Rx or <LLN).

15. Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic) [Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly.]

    MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. Chloride (serum), calcium (total), protein (total):<0.9xLLN or >1.1xULN (if pre-Rx <LLN, then <0.9xpre-Rx or >ULN. If pre-Rx >ULN, then >1.1xpre-Rx or <LLN). Bicarbonate:<0.8xLLN or >1.2xULN (if pre-Rx value <LLN, then <0.8xpre-Rx value or >ULN. If pre-Rx >ULN, then >1.2xpre-Rx value or <ULN). Phosphorous (inorganic):<0.85xLLN or >1.25xULN (if pre-Rx <ULN, then <0.85xpre-Rx or <ULN. If pre-Rx >ULN, then >1.25x re-Rx or <LLN).

16. Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH) [Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly.]

    MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. Glucose (fasting serum): <0.8 x LLN or >1.5 ULN (if pre-Rx <LLN, then <0.8 x pre-Rx or >ULN. If pre-Rx >ULN, then >2.0 x pre-Rx or <LLN. Albumin: <0.9 x LLN (if pre-Rx <LLN, then <0.9 x pre-Rx). Creatine kinase: >1.5 x ULN (if pre-Rx >ULN, then >1.5 x pre-Rx). Uric acid: >1.2 x ULN (if pre-Rx >ULN, then >1.25 x pre-Rx). LDH: >1.25 x ULN (if pre-Rx >ULN, then >1.5 x pre-Rx).

17. Number of Participants With MAs in Urinalysis [Pre-dose on Day -1, Day 7 and discharge.]

    MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following definitions specify the criteria for MAs. Protein, glucose and blood: >=2+ (or, if pre-treatment value >=1+, then >= 2 x pre-treatment value).

18. Number of Participants With Identified Electrocardiogram (ECG) Abnormalities [Pre-dose on Day -1 and study discharge.]

    ECG abnormalities were defined as findings that are clinically meaningful as judged by the investigator. A 12-lead ECG was recorded at least 5 minutes after the participant had been lying down and all ECG recordings were evaluated by the investigator. Abnormalities, if present at any study time point, were listed.

19. Number of Participants With Clinically Significant Vital Signs or Physical Examination Findings [Vital signs:screening, prior to dosing on Day 1, Day 7, study discharge. Physical examination:screening, Day -1, Day 7, study discharge]

    Vital signs assessments and physical examination were conducted throughout the study. Vital signs assessments included body temperature, respiratory rate, blood pressure (systolic and diastolic), and heart rate. Physical examination included a neurological examination (if ocular signs or symptoms occurred, a reflex to slit lamp exam was performed by an ophthalmologist). The investigator used his/her clinical judgment to decide whether or not abnormalities in vital signs or physical examination were clinically meaningful.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy male and female subjects between the ages of 18 to 50 years old with a body mass index (BMI) of 18 to 32 kg/m²

• Prior to enrollment, subjects must have physical and laboratory test findings within the normal limits, and women of childbearing potential (WOCBP) must have a negative pregnancy test

Exclusion Criteria:

• Any significant acute or chronic medical illness

• Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, electrocardiogram (ECG) or clinical laboratory determinations

• Use of any prescription drugs or over-the-counter acid controllers within 4 weeks prior to study drug administration

• Use of any other drugs, including over-the-counter medications of herbal preparations within 1 week prior to study drug administration

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Bristol-Myers Squibb Clinical Pharmacology Unit	Hamilton	New Jersey	United States	08690

Sponsors and Collaborators

• Bristol-Myers Squibb

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT00646776
• Other Study ID Numbers: AI424-360
• First Posted: Mar 31, 2008
• Last Update Posted: Jan 31, 2013
• Last Verified: Jan 1, 2013

• Additional relevant MeSH terms: Ritonavir; Atazanavir Sulfate; Rifabutin

Study Results

Participant Flow

Pre-assignment Detail	Of 85 enrolled participants, 52 participants did not receive the study drug (49 did not meet the study criteria and 3 were not needed as study was fully enrolled).

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Period Title: Overall Study
STARTED	15	18
COMPLETED	14	5
NOT COMPLETED	1	13

Baseline Characteristics

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly	Total
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Total of all reporting groups
Overall Participants	15	18	33
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36 (5)	37 (9)	36 (7)
Age, Customized (participants) [Number]
<65 years	15 100%	18 100%	33 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	2 13.3%	4 22.2%	6 18.2%
Male	13 86.7%	14 77.8%	27 81.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 33.3%	4 22.2%	9 27.3%
Not Hispanic or Latino	10 66.7%	14 77.8%	24 72.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	9 60%	5 27.8%	14 42.4%
Black or African American	3 20%	12 66.7%	15 45.5%
Asian	2 13.3%	0 0%	2 6.1%
Other Race	1 6.7%	1 5.6%	2 6.1%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.1 (3.2)	26.6 (3.5)	26.4 (3.3)
Height Continuous (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	173.7 (7.3)	174.4 (10.0)	174.1 (8.8)
Weight Continuous (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	79.1 (12.0)	81.3 (14.9)	80.3 (13.5)

Outcome Measures

1. Primary Outcome

Title	Average Area Under the Plasma Concentration-time Curve for 24 Hours (AUC24avg) for Rifabutin (RIB)
Description	AUC24avg is AUC(0-24 hour) following dosing on Day 10 for RIB 150mg once daily (QD); AUC24avg is the area under the plasma concentration-time curve in 1 dosing interval (AUC[TAU]) divided by the number of days over the sampling duration for ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly, i.e. AUC(TAU)/7.
Time Frame	Pre-dose (0 hours [h]) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis.

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	14	7
Geometric Mean (Full Range) [nanograms*hour /milliliters (ng*h/mL)]	1565 (528.49)	2311 (507.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RIB 150 mg Once Daily (QD), ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	1.477
	Confidence Interval	(2-Sided) 90%; 1.188 to 1.835
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimates and 90% confidence intervals of treatment differences on the log scale were exponentiated to obtain estimates on the original scale.

2. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) of RIB
Description	Cmax was derived from plasma concentration versus time for RIB and was recorded directly from experimental observations for each treatment period.
Time Frame	Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis.

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	14	7
Geometric Mean (Full Range) [ng/mL]	159.0 (50.52)	395.6 (54.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RIB 150 mg Once Daily (QD), ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	2.489
	Confidence Interval	(2-Sided) 90%; 2.025 to 3.060
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimates and 90% confidence intervals of treatment differences on the log scale were exponentiated to obtain estimates on the original scale.

3. Primary Outcome

Title	Minimum Plasma Concentration (Cmin) of RIB
Description	Cmin was derived from plasma concentration versus time for RIB.
Time Frame	Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis.

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	14	7
Geometric Mean (Full Range) [ng/mL]	28.89 (14.08)	40.49 (11.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RIB 150 mg Once Daily (QD), ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	1.402
	Confidence Interval	(2-Sided) 90%; 1.052 to 1.867
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimates and 90% confidence intervals of treatment differences on the log scale were exponentiated to obtain estimates on the original scale.

4. Secondary Outcome

Title	Cmax of ATV
Description	Cmax was derived from the plasma concentration versus time for ATV and was recorded directly from experimental observations for each treatment period.
Time Frame	Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis.

Arm/Group Title	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were randomized to receive Atazanavir/Ritonavir 300/100mg orally once daily on Days 1 to 17. Participants also received oral dose of Rifabutin 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Participants were dosed in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	9
Geometric Mean (Full Range) [ng/mL]	5633 (940.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RIB 150 mg Once Daily (QD)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	0.947
	Confidence Interval	(2-Sided) 90%; 0.817 to 1.098
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Cmin of ATV
Description	Cmin was derived from the plasma concentration versus time for ATV.
Time Frame	Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis.

Arm/Group Title	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were randomized to receive Atazanavir/Ritonavir 300/100mg orally once daily on Days 1 to 17. Participants also received oral dose of Rifabutin 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Participants were dosed in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	9
Geometric Mean (Full Range) [ng/mL]	920.69 (497.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RIB 150 mg Once Daily (QD)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0963
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	0.7450
	Confidence Interval	(2-Sided) 90%; 0.5569 to 0.9967
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	AUC(TAU) for ATV
Description	AUC(TAU) was derived from the plasma concentration versus time for ATV, and was calculated by linear and log-linear trapezoidal summations using a mixed log-linear algorithm.
Time Frame	Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis.

Arm/Group Title	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were randomized to receive Atazanavir/Ritonavir 300/100mg orally once daily on Days 1 to 17. Participants also received oral dose of Rifabutin 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Participants were dosed in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	9
Geometric Mean (Full Range) [ng*h/mL]	51795 (12680.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RIB 150 mg Once Daily (QD)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	0.857
	Confidence Interval	(2-Sided) 90%; 0.723 to 1.015
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax) of ATV
Description	Tmax was derived from the plasma concentration versus time for ATV and was recorded directly from experimental observations for each treatment period.
Time Frame	Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis.

Arm/Group Title	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were randomized to receive Atazanavir/Ritonavir 300/100mg orally once daily on Days 1 to 17. Participants also received oral dose of Rifabutin 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Participants were dosed in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	9
Median (Full Range) [Hour]	2.00 (0.88)

8. Secondary Outcome

Title	Terminal Elimination Half-life (T-half) of ATV
Description	T-half was obtained directly from the concentration-time data. T-half following doses administered for treatment ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly.
Time Frame	Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis.

Arm/Group Title	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were randomized to receive Atazanavir/Ritonavir 300/100mg orally once daily on Days 1 to 17. Participants also received oral dose of Rifabutin 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Participants were dosed in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	9
Mean (Standard Deviation) [Hour]	11.89 (3.65)

9. Secondary Outcome

Title	Cmax of RTV
Description	Cmax was derived from the plasma concentration versus time for RTV and was recorded directly from experimental observations for each treatment period.
Time Frame	Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis.

Arm/Group Title	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were randomized to receive Atazanavir/Ritonavir 300/100mg orally once daily on Days 1 to 17. Participants also received oral dose of Rifabutin 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Participants were dosed in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	9
Geometric Mean (Full Range) [ng/mL]	1466 (467.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RIB 150 mg Once Daily (QD)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	0.660
	Confidence Interval	(2-Sided) 90%; 0.538 to 0.809
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Cmin of RTV
Description	Cmin was derived from the plasma concentration versus time for RTV.
Time Frame	Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis.

Arm/Group Title	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were randomized to receive Atazanavir/Ritonavir 300/100mg orally once daily on Days 1 to 17. Participants also received oral dose of Rifabutin 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Participants were dosed in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	9
Geometric Mean (Full Range) [ng/mL]	40.54 (34.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RIB 150 mg Once Daily (QD)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	0.651
	Confidence Interval	(2-Sided) 90%; 0.430 to 0.986
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	AUC(TAU) for RTV
Description	AUC(TAU) was derived from the plasma concentration versus time for RTV, and was calculated by linear and log-linear trapezoidal summations using a mixed log-linear algorithm.
Time Frame	Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis.

Arm/Group Title	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were randomized to receive Atazanavir/Ritonavir 300/100mg orally once daily on Days 1 to 17. Participants also received oral dose of Rifabutin 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Participants were dosed in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	9
Geometric Mean (Full Range) [ng*h/mL]	8699 (3002.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RIB 150 mg Once Daily (QD)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	0.696
	Confidence Interval	(2-Sided) 90%; 0.563 to 0.862
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Tmax of RTV
Description	Tmax was derived from the plasma concentration versus time for RTV and was recorded directly from experimental observations for each treatment period.
Time Frame	Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis.

Arm/Group Title	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were randomized to receive Atazanavir/Ritonavir 300/100mg orally once daily on Days 1 to 17. Participants also received oral dose of Rifabutin 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Participants were dosed in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	9
Median (Full Range) [Hour]	4.00 (0.87)

13. Secondary Outcome

Title	T-half of RTV
Description	T-half was obtained directly from the concentration-time data.
Time Frame	Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis.

Arm/Group Title	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were randomized to receive Atazanavir/Ritonavir 300/100mg orally once daily on Days 1 to 17. Participants also received oral dose of Rifabutin 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Participants were dosed in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	9
Mean (Standard Deviation) [Hour]	4.45 (0.65)

14. Secondary Outcome

Title	Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation.
Description	AEs were defined as new, untoward medical occurrences/worsening of pre-existing medical condition, whether drug-related or not. SAEs were defined as any AE that: resulted in death; was life threatening; resulted in a persistent or significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; was a cancer; or was an overdose. Discontinuation from the study was due either to an AE or was conducted at the investigator's discretion.
Time Frame	From Day 1 to 30 days after the last dose of study drug.

Outcome Measure Data

Analysis Population Description

All treated participants.

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	15	18
Deaths	0 0%	0 0%
Other SAEs	0 0%	2 11.1%
AEs	5 33.3%	13 72.2%
AE leading to discontinuation	1 6.7%	9 50%
Discontinuation due to investigator discretion	0 0%	4 22.2%

15. Secondary Outcome

Title	Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Platelet Count and Leukocytes
Description	MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Hemoglobin/hematocrit: <0.85 x pre-treatment (pre-Rx) value. Platelet count: <0.85 x lower limit of normal (LLN) (or, if pre-Rx value <LLN, then <0.85 x pre-Rx value) or >1.5 x upper limit of normal (ULN). Leukocytes: <0.9 x LLN or >1.2 x ULN (or, if pre-Rx value <LLN, then <0.85 x pre-Rx or >ULN. If pre-Rx value >ULN, then >1.15 x pre-Rx or <LLN).
Time Frame	Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly.

Outcome Measure Data

Analysis Population Description

All treated participants. If a value had "not evaluable" in the dataset, then these participants were not counted (hemoglobin and hematocrit).

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	15	18
Hemoglobin	0 0%	1 5.6%
Hematocrit	0 0%	1 5.6%
Platelet count	0 0%	0 0%
Leukocytes	1 6.7%	7 38.9%

16. Secondary Outcome

Title	Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute)
Description	MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Neutrophils+bands (absolute): <=1.50 x 10^3 cells/microliter (uL). Lymphocytes (absolute): <0.75 x 10^3 cells/uL or >7.50 x 10^3 cells/uL. Monocytes (absolute): >2.00 x 10^3 cells/uL. Basophils (absolute): >0.40 x 10^3 cells/uL. Eosinophils (absolute): >0.75 x 10^3 cells/uL.
Time Frame	Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly.

Outcome Measure Data

Analysis Population Description

All treated participants. If a value had "not evaluable" in the dataset, then these participants were not counted(neutrophils + bands [absolute], monocytes [absolute], basophils [absolute] and eosinophils [absolute]).

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	15	18
Neutrophils+bands (absolute)	1 6.7%	10 55.6%
Lymphocytes (absolute)	1 6.7%	5 27.8%
Monocytes (absolute)	0 0%	0 0%
Basophils (absolute)	0 0%	0 0%
Eosinophils (absolute)	0 0%	0 0%

17. Primary Outcome

Title	AUC24avg for 25-O-Desacetyl-RIB
Description	AUC24avg is AUC(0-24 hour) following dosing on Day 10 for RIB 150 mg QD; AUC24avg is the area under the plasma concentration-time curve in 1 dosing interval (AUC[TAU]) divided by the number of days over the sampling duration for ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly, i.e. AUC(TAU)/7
Time Frame	Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis.

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	14	7
Geometric Mean (Full Range) [ng*h/mL]	117.7 (53.48)	1283 (260.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RIB 150 mg Once Daily (QD), ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	10.902
	Confidence Interval	(2-Sided) 90%; 8.135 to 14.610
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Primary Outcome

Title	Cmax of 25-O-Desacetylrifabutin (25-O-Desacetyl-RIB)
Description	Cmax was derived from the plasma concentration versus time for 25-O-Desacetyl-RIB (a metabolite of RIB) and was recorded directly from experimental observations for each treatment period.
Time Frame	Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis.

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	14	7
Geometric Mean (Full Range) [ng/mL]	13.44 (4.50)	104.36 (21.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RIB 150 mg Once Daily (QD), ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	7.766
	Confidence Interval	(2-Sided) 90%; 6.133 to 9.833
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Primary Outcome

Title	Cmin of 25-O-Desacetyl-RIB
Description	Cmin was derived from plasma concentration versus time for 25-O-Desacetyl-RIB.
Time Frame	Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis.

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	14	7
Geometric Mean (Full Range) [ng/mL]	2.79 (1.40)	31.97 (10.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RIB 150 mg Once Daily (QD), ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	11.451
	Confidence Interval	(2-Sided) 90%; 8.147 to 16.095
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Primary Outcome

Title	Total Area Under the Plasma Concentration-time Curve (AUCtot)
Description	AUCtot represents the total free RIB plus 25-O-Desacetyl-RIB output. It is calculated as: AUCtot (micromolar[µM]*h) = AUC24avg(RIB)(ng*h/mL)/847.016 (g/mole) + AUC24avg(25-O-Desacetyl-RIB)(ng*h/mL)/804.979(g/mole). The 300 mg RIB arm represents an extrapolation from the 150 mg RIB group.
Time Frame	Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB.

Outcome Measure Data

Analysis Population Description

All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis. The RIB 300 mg arm represents an extrapolation of the RIB 150 mg arm and as such, does not have a value for "Number of Participants Analyzed". AUCtot for RIB 300 mg QD was calculated as 2 × AUCtot for RIB 150 mg QD.

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly	RIB 300 mg QD
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QAD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	AUCtot for RIB 300 mg QD was calculated as 2 × AUCtot for RIB 150 mg QD.
Measure Participants	14	7	0
Geometric Mean (Full Range) [µM*h]	2.00 (0.68)	4.38 (0.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RIB 150 mg Once Daily (QD), ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	2.190
	Confidence Interval	(2-Sided) 90%; 1.783 to 2.691
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimates and 90% confidence intervals of treatment differences on the log scale were exponentiated to obtain estimates on the original scale.

21. Secondary Outcome

Title	Number of Participants With MAs in Serum Chemistry: Alkaline Phosphatase (ALP),Aspartate Aminotransferase (AST),Alanine Aminotransferase (ALT),Bilirubin (Total),Bilirubin (Direct),Blood Urea Nitrogen (BUN),Creatinine,Sodium (Serum),Potassium (Serum)
Description	MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. ALP, AST, ALT:>1.25xULN (if pre-Rx >ULN, then >1.25xpre-Rx). Bilirubin (total), bilirubin (direct), BUN:>1.1xULN (if pre-Rx >ULN, then >1.25xpre-Rx). Creatinine:>1.33xpre-Rx. Sodium (serum):<0.95xLLN or >1.05xULN (if pre-Rx <LLN, then <0.95xpre-Rx or >ULN. If pre-Rx >ULN, then >1.05xpre-Rx or <LLN). Potassium (serum):<0.9xLLN or >1.1xULN (if pre-Rx <LLN, then <0.9xpre-Rx or >ULN. If pre-Rx >ULN, then >1.1xpre-Rx or <LLN).
Time Frame	Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly.

Outcome Measure Data

Analysis Population Description

All treated participants. If a value had "not evaluable" in the dataset, then these participants were not counted (ALP, AST, ALT, bilirubin [total], bilirubin [direct], BUN and creatinine).

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	15	18
ALP	0 0%	0 0%
AST	0 0%	0 0%
ALT	0 0%	0 0%
Bilirubin (total)	0 0%	17 94.4%
Bilirubin (direct)	0 0%	16 88.9%
BUN	0 0%	0 0%
Creatinine	0 0%	1 5.6%
Sodium (serum)	0 0%	0 0%
Potassium (serum)	0 0%	0 0%

22. Secondary Outcome

Title	Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic)
Description	MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. Chloride (serum), calcium (total), protein (total):<0.9xLLN or >1.1xULN (if pre-Rx <LLN, then <0.9xpre-Rx or >ULN. If pre-Rx >ULN, then >1.1xpre-Rx or <LLN). Bicarbonate:<0.8xLLN or >1.2xULN (if pre-Rx value <LLN, then <0.8xpre-Rx value or >ULN. If pre-Rx >ULN, then >1.2xpre-Rx value or <ULN). Phosphorous (inorganic):<0.85xLLN or >1.25xULN (if pre-Rx <ULN, then <0.85xpre-Rx or <ULN. If pre-Rx >ULN, then >1.25x re-Rx or <LLN).
Time Frame	Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly.

Outcome Measure Data

Analysis Population Description

All treated participants.

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	15	18
Chloride (serum)	0 0%	0 0%
Calcium (total)	0 0%	0 0%
Protein (total)	0 0%	0 0%
Bicarbonate	0 0%	0 0%
Phosphorous (inorganic)	0 0%	0 0%

23. Secondary Outcome

Title	Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH)
Description	MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. Glucose (fasting serum): <0.8 x LLN or >1.5 ULN (if pre-Rx <LLN, then <0.8 x pre-Rx or >ULN. If pre-Rx >ULN, then >2.0 x pre-Rx or <LLN. Albumin: <0.9 x LLN (if pre-Rx <LLN, then <0.9 x pre-Rx). Creatine kinase: >1.5 x ULN (if pre-Rx >ULN, then >1.5 x pre-Rx). Uric acid: >1.2 x ULN (if pre-Rx >ULN, then >1.25 x pre-Rx). LDH: >1.25 x ULN (if pre-Rx >ULN, then >1.5 x pre-Rx).
Time Frame	Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly.

Outcome Measure Data

Analysis Population Description

All treated participants. If a value had "not evaluable" in the dataset, then these participants were not counted(albumin, creatine kinase, uric acid and LDH).

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	15	18
Glucose (Fasting Serum)	0 0%	0 0%
Albumin	0 0%	0 0%
Creatine Kinase	0 0%	0 0%
Uric Acid	0 0%	0 0%
LDH	0 0%	0 0%

24. Secondary Outcome

Title	Number of Participants With MAs in Urinalysis
Description	MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following definitions specify the criteria for MAs. Protein, glucose and blood: >=2+ (or, if pre-treatment value >=1+, then >= 2 x pre-treatment value).
Time Frame	Pre-dose on Day -1, Day 7 and discharge.

Outcome Measure Data

Analysis Population Description

All participants who received the study drug on Day 1 were included in the analysis. If a value had "not evaluable" in the dataset, then these participants were not counted (for all parameters: protein, glucose and blood).

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	15	18
Protein	0 0%	1 5.6%
Glucose	0 0%	0 0%
Blood	0 0%	1 5.6%

25. Secondary Outcome

Title	Number of Participants With Identified Electrocardiogram (ECG) Abnormalities
Description	ECG abnormalities were defined as findings that are clinically meaningful as judged by the investigator. A 12-lead ECG was recorded at least 5 minutes after the participant had been lying down and all ECG recordings were evaluated by the investigator. Abnormalities, if present at any study time point, were listed.
Time Frame	Pre-dose on Day -1 and study discharge.

Outcome Measure Data

Analysis Population Description

All participants who received the study drug on Day 1 were included in the analysis.

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	15	18
Number [Participants]	0 0%	3 16.7%

26. Secondary Outcome

Title	Number of Participants With Clinically Significant Vital Signs or Physical Examination Findings
Description	Vital signs assessments and physical examination were conducted throughout the study. Vital signs assessments included body temperature, respiratory rate, blood pressure (systolic and diastolic), and heart rate. Physical examination included a neurological examination (if ocular signs or symptoms occurred, a reflex to slit lamp exam was performed by an ophthalmologist). The investigator used his/her clinical judgment to decide whether or not abnormalities in vital signs or physical examination were clinically meaningful.
Time Frame	Vital signs:screening, prior to dosing on Day 1, Day 7, study discharge. Physical examination:screening, Day -1, Day 7, study discharge

Outcome Measure Data

Analysis Population Description

All treated participants.

Arm/Group Title	RIB 150 mg Once Daily (QD)	ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly
Arm/Group Description	Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.	Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study.
Measure Participants	15	18
Number [Participants]	0 0%	0 0%

Adverse Events

Arm/Group Title	ATV/RTV 300/100mg+RIB 150mg		RIB 150mg
Arm/Group Description
All Cause Mortality
	ATV/RTV 300/100mg+RIB 150mg		RIB 150mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	ATV/RTV 300/100mg+RIB 150mg		RIB 150mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/18 (11.1%)		0/15 (0%)
Investigations
NEUTROPHIL COUNT DECREASED	2/18 (11.1%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	ATV/RTV 300/100mg+RIB 150mg		RIB 150mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/18 (72.2%)		5/15 (33.3%)
Cardiac disorders
PALPITATIONS	1/18 (5.6%)		0/15 (0%)
VENTRICULAR EXTRASYSTOLES	1/18 (5.6%)		0/15 (0%)
Eye disorders
EYE PAIN	1/18 (5.6%)		0/15 (0%)
EYE PRURITUS	1/18 (5.6%)		0/15 (0%)
Gastrointestinal disorders
ABDOMINAL DISTENSION	1/18 (5.6%)		0/15 (0%)
ABDOMINAL PAIN	2/18 (11.1%)		0/15 (0%)
ABDOMINAL PAIN UPPER	1/18 (5.6%)		0/15 (0%)
DIARRHOEA	4/18 (22.2%)		0/15 (0%)
DRY MOUTH	1/18 (5.6%)		0/15 (0%)
FREQUENT BOWEL MOVEMENTS	1/18 (5.6%)		0/15 (0%)
GINGIVAL PAIN	0/18 (0%)		1/15 (6.7%)
LIP SWELLING	1/18 (5.6%)		0/15 (0%)
MOUTH ULCERATION	1/18 (5.6%)		0/15 (0%)
NAUSEA	1/18 (5.6%)		1/15 (6.7%)
SWOLLEN TONGUE	1/18 (5.6%)		0/15 (0%)
VOMITING	1/18 (5.6%)		1/15 (6.7%)
General disorders
CHEST DISCOMFORT	1/18 (5.6%)		0/15 (0%)
CHEST PAIN	1/18 (5.6%)		0/15 (0%)
CHILLS	2/18 (11.1%)		1/15 (6.7%)
FATIGUE	1/18 (5.6%)		0/15 (0%)
FEELING COLD	1/18 (5.6%)		0/15 (0%)
PAIN	3/18 (16.7%)		1/15 (6.7%)
PYREXIA	6/18 (33.3%)		1/15 (6.7%)
Hepatobiliary disorders
JAUNDICE	3/18 (16.7%)		0/15 (0%)
Infections and infestations
CELLULITIS	1/18 (5.6%)		0/15 (0%)
Investigations
NEUTROPHIL COUNT DECREASED	5/18 (27.8%)		1/15 (6.7%)
Musculoskeletal and connective tissue disorders
PAIN IN JAW	0/18 (0%)		2/15 (13.3%)
Nervous system disorders
DIZZINESS	3/18 (16.7%)		0/15 (0%)
HEADACHE	3/18 (16.7%)		2/15 (13.3%)
HYPOAESTHESIA	1/18 (5.6%)		0/15 (0%)
Psychiatric disorders
SLEEP DISORDER	1/18 (5.6%)		0/15 (0%)
Renal and urinary disorders
POLLAKIURIA	2/18 (11.1%)		0/15 (0%)
Respiratory, thoracic and mediastinal disorders
CHOKING SENSATION	1/18 (5.6%)		0/15 (0%)
COUGH	1/18 (5.6%)		1/15 (6.7%)
NASAL CONGESTION	1/18 (5.6%)		0/15 (0%)
PHARYNGEAL OEDEMA	1/18 (5.6%)		0/15 (0%)
PHARYNGOLARYNGEAL PAIN	0/18 (0%)		1/15 (6.7%)
THROAT IRRITATION	1/18 (5.6%)		0/15 (0%)
THROAT TIGHTNESS	2/18 (11.1%)		0/15 (0%)
Skin and subcutaneous tissue disorders
ERYTHEMA	0/18 (0%)		1/15 (6.7%)
RASH	1/18 (5.6%)		2/15 (13.3%)
Vascular disorders
FLUSHING	1/18 (5.6%)		0/15 (0%)
HOT FLUSH	1/18 (5.6%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.