Trial Outcomes & Findings for A Clinical Trial of the Safety, Pharmacokinetics and Hematologic Effects of Imatinib on Myelopoiesis in Adults When Given With and Without Isoniazid and Rifabutin (NCT NCT03891901)

NCT ID: NCT03891901

Last Updated: 2023-10-23

Results Overview

Immunologic effects of the study treatment are assessed by counting myelomonocytic cells in blood samples. An increase in myelomonocytic cells is used to determine the appropriate therapeutic dose of imatinib.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 24 participants
• Primary outcome timeframe: Days 1, 7, 14, 21, 28, 42
• Results posted on: 2023-10-23

Participant Flow

Participants were recruited through the Winship Cancer Institute, Georgia Clinical & Translational Science Alliance (Georgia CTSA) Clinical Research Center, and Emory University Hospital in Atlanta, Georgia, USA. Participant enrollment began on October 27, 2020 and study visits were completed by August 30, 2022.

A total of 42 individuals were screened and 18 did not meet eligibility criteria or withdrew prior to the baseline assessment, resulting in 24 study participants initiating study activities.

Participant milestones

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. Imatinib: Tablets, administered orally Isoniazid: 300 mg tablets, administered orally Rifabutin: 300 mg capsules, administered orally	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. Imatinib: Tablets, administered orally Isoniazid: 300 mg tablets, administered orally Rifabutin: 300 mg capsules, administered orally	Cohort 1c: Imatinib (200 mg) + Rifabutin + Isoniazid Participants receiving 200 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. Imatinib: Tablets, administered orally Isoniazid: 300 mg tablets, administered orally Rifabutin: 300 mg capsules, administered orally	Cohort 1d: Imatinib (400 mg) + Rifabutin + Isoniazid Participants receiving 400 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. Imatinib: Tablets, administered orally Isoniazid: 300 mg tablets, administered orally Rifabutin: 300 mg capsules, administered orally	Cohort 2a: Imatinib + Rifabutin + Isoniazid Participants receiving isoniazid and rifabutin for 14 days, followed by 14 days of combination isoniazid, rifabutin, and imatinib. Imatinib dose will be determined after analyzing data from Cohort 1. Imatinib: Tablets, administered orally Isoniazid: 300 mg tablets, administered orally Rifabutin: 300 mg capsules, administered orally	Cohort 2b: Imatinib + Rifabutin + Isoniazid Participants receiving isoniazid and rifabutin for 14 days, followed by 14 days of combination isoniazid, rifabutin, and imatinib. Imatinib dose will be determined after analyzing data from Cohort 1. Imatinib: Tablets, administered orally Isoniazid: 300 mg tablets, administered orally Rifabutin: 300 mg capsules, administered orally	Imatinib (100 mg) Participants receiving 100 mg imatinib daily for 28 days. Imatinib: Tablets, administered orally	Imatinib (200 mg) Participants receiving 200 mg imatinib daily for 28 days. Imatinib: Tablets, administered orally	Imatinib (400 mg) Participants receiving 400 mg imatinib daily for 28 days. Imatinib: Tablets, administered orally
Overall Study STARTED	16	6	0	0	0	0	2	0	0
Overall Study Began Imatinib Plus Rifabutin and Isoniazid Portion of the Intervention (if Applicable)	14	3	0	0	0	0	0	0	0
Overall Study COMPLETED	12	2	0	0	0	0	2	0	0
Overall Study NOT COMPLETED	4	4	0	0	0	0	0	0	0

Reasons for withdrawal

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. Imatinib: Tablets, administered orally Isoniazid: 300 mg tablets, administered orally Rifabutin: 300 mg capsules, administered orally	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. Imatinib: Tablets, administered orally Isoniazid: 300 mg tablets, administered orally Rifabutin: 300 mg capsules, administered orally	Cohort 1c: Imatinib (200 mg) + Rifabutin + Isoniazid Participants receiving 200 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. Imatinib: Tablets, administered orally Isoniazid: 300 mg tablets, administered orally Rifabutin: 300 mg capsules, administered orally	Cohort 1d: Imatinib (400 mg) + Rifabutin + Isoniazid Participants receiving 400 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. Imatinib: Tablets, administered orally Isoniazid: 300 mg tablets, administered orally Rifabutin: 300 mg capsules, administered orally	Cohort 2a: Imatinib + Rifabutin + Isoniazid Participants receiving isoniazid and rifabutin for 14 days, followed by 14 days of combination isoniazid, rifabutin, and imatinib. Imatinib dose will be determined after analyzing data from Cohort 1. Imatinib: Tablets, administered orally Isoniazid: 300 mg tablets, administered orally Rifabutin: 300 mg capsules, administered orally	Cohort 2b: Imatinib + Rifabutin + Isoniazid Participants receiving isoniazid and rifabutin for 14 days, followed by 14 days of combination isoniazid, rifabutin, and imatinib. Imatinib dose will be determined after analyzing data from Cohort 1. Imatinib: Tablets, administered orally Isoniazid: 300 mg tablets, administered orally Rifabutin: 300 mg capsules, administered orally	Imatinib (100 mg) Participants receiving 100 mg imatinib daily for 28 days. Imatinib: Tablets, administered orally	Imatinib (200 mg) Participants receiving 200 mg imatinib daily for 28 days. Imatinib: Tablets, administered orally	Imatinib (400 mg) Participants receiving 400 mg imatinib daily for 28 days. Imatinib: Tablets, administered orally
Overall Study Exposure to coronavirus disease 2019 (COVID-19)	1	0	0	0	0	0	0	0	0
Overall Study Adverse Event	2	2	0	0	0	0	0	0	0
Overall Study Poor venous access	1	0	0	0	0	0	0	0	0
Overall Study Withdrawal by Subject	0	2	0	0	0	0	0	0	0

Baseline Characteristics

A Clinical Trial of the Safety, Pharmacokinetics and Hematologic Effects of Imatinib on Myelopoiesis in Adults When Given With and Without Isoniazid and Rifabutin

Baseline characteristics by cohort

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=16 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=6 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) n=2 Participants Participants receiving 100 mg imatinib daily for 28 days.	Total n=24 Participants Total of all reporting groups
Age, Customized 18-25 years	7 Participants n=93 Participants	3 Participants n=4 Participants	0 Participants n=27 Participants	10 Participants n=483 Participants
Age, Customized 26-35 years	7 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants	9 Participants n=483 Participants
Age, Customized 36-45 years	2 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	2 Participants n=483 Participants
Age, Customized 46-55 years	0 Participants n=93 Participants	2 Participants n=4 Participants	1 Participants n=27 Participants	3 Participants n=483 Participants
Sex: Female, Male Female	11 Participants n=93 Participants	3 Participants n=4 Participants	2 Participants n=27 Participants	16 Participants n=483 Participants
Sex: Female, Male Male	5 Participants n=93 Participants	3 Participants n=4 Participants	0 Participants n=27 Participants	8 Participants n=483 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=93 Participants	1 Participants n=4 Participants	0 Participants n=27 Participants	2 Participants n=483 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	15 Participants n=93 Participants	5 Participants n=4 Participants	2 Participants n=27 Participants	22 Participants n=483 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Asian	3 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	3 Participants n=483 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Black or African American	5 Participants n=93 Participants	2 Participants n=4 Participants	0 Participants n=27 Participants	7 Participants n=483 Participants
Race (NIH/OMB) White	8 Participants n=93 Participants	4 Participants n=4 Participants	2 Participants n=27 Participants	14 Participants n=483 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Region of Enrollment United States	16 Participants n=93 Participants	6 Participants n=4 Participants	2 Participants n=27 Participants	24 Participants n=483 Participants

PRIMARY outcome

Timeframe: Days 1, 7, 14, 21, 28, 42

Population: The analysis population includes participants who completed the study.

Immunologic effects of the study treatment are assessed by counting myelomonocytic cells in blood samples. An increase in myelomonocytic cells is used to determine the appropriate therapeutic dose of imatinib.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=12 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=2 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) n=2 Participants Participants receiving 100 mg imatinib daily for 28 days.
Number of Myelomonocytic Cells in the Blood Day 1	3197 cells per microliter (µL) Standard Deviation 933	4340 cells per microliter (µL) Standard Deviation 480	3390 cells per microliter (µL) Standard Deviation 283
Number of Myelomonocytic Cells in the Blood Day 7	3241 cells per microliter (µL) Standard Deviation 1393	3680 cells per microliter (µL) Standard Deviation 1414	3075 cells per microliter (µL) Standard Deviation 64
Number of Myelomonocytic Cells in the Blood Day 14	3418 cells per microliter (µL) Standard Deviation 1640	3195 cells per microliter (µL) Standard Deviation 1265	3195 cells per microliter (µL) Standard Deviation 21
Number of Myelomonocytic Cells in the Blood Day 21	3021 cells per microliter (µL) Standard Deviation 1479	2560 cells per microliter (µL) Standard Deviation 721	2785 cells per microliter (µL) Standard Deviation 332
Number of Myelomonocytic Cells in the Blood Day 28	2356 cells per microliter (µL) Standard Deviation 1059	1140 cells per microliter (µL) Standard Deviation 98	2480 cells per microliter (µL) Standard Deviation 198
Number of Myelomonocytic Cells in the Blood Day 42	3629 cells per microliter (µL) Standard Deviation 1548	4425 cells per microliter (µL) Standard Deviation 403	3255 cells per microliter (µL) Standard Deviation 841

PRIMARY outcome

Timeframe: Measured through Day 50

The number of grade 3 or 4 adverse events occurring among study participants is presented here. Adverse events are graded using the FDA Guidance Document, "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials Guidance for Industry," September 2007, or other guidance, as applicable.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=16 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=6 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) n=2 Participants Participants receiving 100 mg imatinib daily for 28 days.
Frequency of Grade 3 or 4 Adverse Events (AEs)	4 Grade 3 or 4 adverse events	6 Grade 3 or 4 adverse events	0 Grade 3 or 4 adverse events

PRIMARY outcome

Timeframe: Measured through Day 50

The number of serious adverse events occurring among study participants is presented here. Adverse events are graded using the FDA Guidance Document, "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials Guidance for Industry," September 2007, or other guidance, as applicable.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=16 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=6 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) n=2 Participants Participants receiving 100 mg imatinib daily for 28 days.
Frequency of Serious Adverse Events (SAEs)	0 serious adverse events	0 serious adverse events	0 serious adverse events

SECONDARY outcome

Timeframe: Days 1, 7, 14, 21, 28, 42

Population: The analysis population includes participants who completed the study.

The normal range for white blood cell counts is between 4,000 and 11,000 cells per microliter. White blood cell counts increase during infections, autoimmune diseases and some types of cancer. Low white blood cell counts occur with immune system diseases and certain types of cancer.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=12 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=2 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) n=2 Participants Participants receiving 100 mg imatinib daily for 28 days.
White Blood Cell Count Day 21	4875 cells/µL Standard Deviation 1430	3650 cells/µL Standard Deviation 636	4750 cells/µL Standard Deviation 212
White Blood Cell Count Day 1	5558 cells/µL Standard Deviation 1099	6300 cells/µL Standard Deviation 1272	5900 cells/µL Standard Deviation 566
White Blood Cell Count Day 7	5391 cells/µL Standard Deviation 1222	5900 cells/µL Standard Deviation 1697	5500 cells/µL Standard Deviation 283
White Blood Cell Count Day 14	5841 cells/µL Standard Deviation 1648	5150 cells/µL Standard Deviation 2192	5400 cells/µL Standard Deviation 1273
White Blood Cell Count Day 28	4141 cells/µL Standard Deviation 1295	1600 cells/µL Standard Deviation 282	4800 cells/µL Standard Deviation 424
White Blood Cell Count Day 42	5841 cells/µL Standard Deviation 1684	5800 cells/µL Standard Deviation 282	5300 cells/µL Standard Deviation 1414

SECONDARY outcome

Timeframe: Day 14, Day 28

Population: The analysis population includes those who were participating in the study at the indicated time point. Participants in the Imatinib (100 mg) group, who received imatinib alone, had a single PK analysis.

Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter Cmax is the highest concentration of imatinib in blood following dosing.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=14 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=4 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) n=2 Participants Participants receiving 100 mg imatinib daily for 28 days.
Maximum Concentration (Cmax) of Imatinib After 14 days of imatinib	0.41 micrograms per milliliter (mcg/mL) Interval 0.27 to 0.69	0.69 micrograms per milliliter (mcg/mL) Interval 0.46 to 0.75	0.51 micrograms per milliliter (mcg/mL) Interval 0.48 to 0.54
Maximum Concentration (Cmax) of Imatinib After 14 days of imatinib plus rifabutin and isoniazid	0.71 micrograms per milliliter (mcg/mL) Interval 0.23 to 1.47	0.69 micrograms per milliliter (mcg/mL) Interval 0.66 to 0.72	—

SECONDARY outcome

Timeframe: Day 14, Day 28

Population: The analysis population includes those who were participating in the study at the indicated time point. Participants in the Imatinib (100 mg) group, who received imatinib alone, had a single PK analysis.

Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter T1/2 is the time when imatinib in blood is half of the maximum concentration.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=14 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=4 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) n=2 Participants Participants receiving 100 mg imatinib daily for 28 days.
Half-life (T1/2) of Imatinib After 14 days of imatinib	11.32 hours Interval 8.2 to 16.47	15.01 hours Interval 9.66 to 16.62	11.00 hours Interval 10.62 to 11.37
Half-life (T1/2) of Imatinib After 14 days of imatinib plus rifabutin and isoniazid	9.91 hours Interval 7.85 to 11.29	7.83 hours Interval 7.01 to 8.65	—

SECONDARY outcome

Timeframe: Day 14, Day 28

Population: The analysis population includes those who were participating in the study at the indicated time point. Participants in the Imatinib (100 mg) group, who received imatinib alone, had a single PK analysis.

Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter AUC is the overall exposure to imatinib.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=14 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=4 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) n=2 Participants Participants receiving 100 mg imatinib daily for 28 days.
Area Under the Curve (AUC) for Imatinib After 14 days of imatinib	4.76 hour*mcg/mL Interval 3.32 to 10.21	9.46 hour*mcg/mL Interval 6.42 to 12.53	5.80 hour*mcg/mL Interval 5.48 to 6.12
Area Under the Curve (AUC) for Imatinib After 14 days of imatinib plus rifabutin and isoniazid	7.52 hour*mcg/mL Interval 2.69 to 16.59	7.49 hour*mcg/mL Interval 6.99 to 7.98	—

SECONDARY outcome

Timeframe: Day 14, Day 28

Population: The analysis population includes those who were participating in the study at the indicated time point. Participants in the Imatinib (100 mg) group, who received imatinib alone, had a single PK analysis.

Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The elimination rate constant is the rate that imatinib is removed from the body.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=14 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=4 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) n=2 Participants Participants receiving 100 mg imatinib daily for 28 days.
Elimination Rate Constant (Ke) of Imatinib After 14 days of imatinib	0.06 1/hour Interval 0.04 to 0.08	0.05 1/hour Interval 0.04 to 0.07	0.06 1/hour Interval 0.06 to 0.07
Elimination Rate Constant (Ke) of Imatinib After 14 days of imatinib plus rifabutin and isoniazid	0.07 1/hour Interval 0.06 to 0.09	0.09 1/hour Interval 0.08 to 0.1	—

SECONDARY outcome

Timeframe: Day 28

Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.

Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter Cmax is the highest concentration of the drug in blood following dosing.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=11 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=2 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) Participants receiving 100 mg imatinib daily for 28 days.
Maximum Concentration (Cmax) of Isoniazid	3.14 mcg/mL Interval 1.88 to 4.97	3.66 mcg/mL Interval 2.72 to 4.59	—

SECONDARY outcome

Timeframe: Day 28

Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.

Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter T1/2 is the time when the drug in blood is half of the maximum concentration.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=11 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=2 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) Participants receiving 100 mg imatinib daily for 28 days.
Half-life (T1/2) of Isoniazid	1.59 hours Interval 1.15 to 2.05	2.44 hours Interval 2.33 to 2.55	—

SECONDARY outcome

Timeframe: Day 28

Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.

Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter AUC is the overall exposure to the drug.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=11 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=2 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) Participants receiving 100 mg imatinib daily for 28 days.
Area Under the Curve (AUC) for Isoniazid	9.79 hour*mcg/mL Interval 7.22 to 15.03	16.11 hour*mcg/mL Interval 12.74 to 19.48	—

SECONDARY outcome

Timeframe: Day 28

Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.

Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The elimination rate constant is the rate that the drug is removed from the body.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=11 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=2 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) Participants receiving 100 mg imatinib daily for 28 days.
Elimination Rate Constant (Ke) of Isoniazid	0.44 1/hour Interval 0.34 to 0.6	0.28 1/hour Interval 0.27 to 0.3	—

SECONDARY outcome

Timeframe: Day 28

Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.

Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter Cmax is the highest concentration of the drug in blood following dosing.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=11 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=2 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) Participants receiving 100 mg imatinib daily for 28 days.
Maximum Concentration (Cmax) of Rifabutin	0.37 mcg/mL Interval 0.34 to 0.51	0.53 mcg/mL Interval 0.47 to 0.6	—

SECONDARY outcome

Timeframe: Day 28

Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.

Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter T1/2 is the time when the drug in blood is half of the maximum concentration.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=11 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=2 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) Participants receiving 100 mg imatinib daily for 28 days.
Half-life (T1/2) of Rifabutin	9.65 hours Interval 7.38 to 10.91	8.14 hours Interval 7.78 to 8.5	—

SECONDARY outcome

Timeframe: Day 28

Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.

Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter AUC is the overall exposure to the drug.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=11 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=2 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) Participants receiving 100 mg imatinib daily for 28 days.
Area Under the Curve (AUC) for Rifabutin	3.68 hour*mcg/mL Interval 2.89 to 5.2	5.11 hour*mcg/mL Interval 4.24 to 5.98	—

SECONDARY outcome

Timeframe: Day 28

Population: The analysis population includes those who completed the study. One participant was excluded from the Imatinib 50mg group due to unreliable PK parameters for isoniazid and rifabutin.

Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The elimination rate constant is the rate that the drug is removed from the body.

Outcome measures

Measure	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=11 Participants Participants receiving 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=2 Participants Participants receiving 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.	Imatinib (100 mg) Participants receiving 100 mg imatinib daily for 28 days.
Elimination Rate Constant (Ke) of Rifabutin	0.07 1/hour Interval 0.06 to 0.09	0.09 1/hour Interval 0.08 to 0.09	—

Adverse Events

Cohort 1a: Imatinib (50 mg)

Serious events: 0 serious events

Other events: 16 other events

Deaths: 0 deaths

Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Cohort 1b: Imatinib (100 mg)

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Imatinib (100 mg)

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Cohort 1a: Imatinib (50 mg) n=16 participants at risk Participants in Cohort 1a while receiving 50 mg imatinib for 14 days.	Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid n=14 participants at risk Participants in Cohort 1a while receiving 50 mg imatinib for 14 days together with rifabutin and isoniazid.	Cohort 1b: Imatinib (100 mg) n=6 participants at risk Participants in Cohort 1b while receiving 100 mg imatinib for 14 days.	Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid n=3 participants at risk Participants in Cohort 1b while receiving 100 mg imatinib for 14 days together with rifabutin and isoniazid.	Imatinib (100 mg) n=2 participants at risk Participants receiving 100 mg imatinib daily for 28 days.
Blood and lymphatic system disorders Low Hemoglobin	56.2% 9/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	16.7% 1/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	33.3% 1/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	50.0% 1/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Blood and lymphatic system disorders Lymphopenia (low absolute lymphocyte count (ALC))	12.5% 2/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	28.6% 4/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	16.7% 1/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	100.0% 3/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	50.0% 1/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Blood and lymphatic system disorders Neutropenia (low absolute neutrophil count (ANC))	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	100.0% 3/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	50.0% 1/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Blood and lymphatic system disorders White blood cell count decrease	12.5% 2/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	35.7% 5/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	66.7% 2/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Blood and lymphatic system disorders Eosinophils increase	12.5% 2/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Blood and lymphatic system disorders Neutrophil decrease	37.5% 6/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	21.4% 3/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Eye disorders Conjunctivitis	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Eye disorders Photophobia	12.5% 2/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	33.3% 1/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Gastrointestinal disorders Constipation	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Gastrointestinal disorders Diarrhea	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	33.3% 1/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Gastrointestinal disorders Nausea	12.5% 2/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders Edema localized	6.2% 1/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders Fatigue	6.2% 1/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Hepatobiliary disorders Elevated bilirubin	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	50.0% 3/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Metabolism and nutrition disorders Hyperglycemia	12.5% 2/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Metabolism and nutrition disorders Hypocalcemia	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	35.7% 5/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	66.7% 2/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	50.0% 1/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Metabolism and nutrition disorders Hypoglycemia	18.8% 3/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	50.0% 1/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Metabolism and nutrition disorders Hypoproteinemia	6.2% 1/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	50.0% 1/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Nervous system disorders Paresthesia	12.5% 2/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Reproductive system and breast disorders Menstrual disturbances	6.2% 1/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Renal and urinary disorders Protein in urine	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Renal and urinary disorders Urine discoloration	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	28.6% 4/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders Visual changes	6.2% 1/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders Bicarbonate low	37.5% 6/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	14.3% 2/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders Blood urea nitrogen abnormal	6.2% 1/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	16.7% 1/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	50.0% 1/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders eGFR Decrease	43.8% 7/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	14.3% 2/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	33.3% 2/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders eGFR Decrease from Baseline	18.8% 3/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders Hypokalemia	43.8% 7/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	14.3% 2/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	33.3% 2/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	50.0% 1/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders Hyponatremia	6.2% 1/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Skin and subcutaneous tissue disorders Rash	6.2% 1/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders Abdominal pain	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders Chills	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders Headache	6.2% 1/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	33.3% 1/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders Fever	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	7.1% 1/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
Gastrointestinal disorders Mild heartburn	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	50.0% 1/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders Estimated creatinine clearance decrease from baseline	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	50.0% 1/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.
General disorders Alkaline phosphatase (ALP) increase	0.00% 0/16 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/14 • Information on adverse events was collected from the time of the baseline visit through Day 50.	16.7% 1/6 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/3 • Information on adverse events was collected from the time of the baseline visit through Day 50.	0.00% 0/2 • Information on adverse events was collected from the time of the baseline visit through Day 50.

Additional Information

Dr. Cynthia Giver

Emory University

Phone: 404-778-5806

Email: cgiver@emory.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place