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| ID | Type | Description | Link |
|---|---|---|---|
| 38518 | Registry Identifier | DAIDS-ES Registry Number |
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| Name | Class |
|---|---|
| Emory University | OTHER |
| University of Pennsylvania | OTHER |
| Aurum Institute | OTHER |
| University of Florida |
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The purpose of this study is to evaluate the safety, pharmacokinetics, and effects of imatinib on myelopoiesis in adults when given with and without isoniazid and rifabutin. The results of this trial will determine the imatinib dose to be studied in a subsequent Phase IIB treatment trial of imatinib as an adjunctive therapy with an antimicrobial regimen (rifabutin, pyrazinamide (PZA), isoniazid (INH) and ethambutol) for drug-sensitive TB.
With existing anti-tubercular drug therapies, treatment of drug-susceptible TB takes at least 6 months and success rates for multi-drug resistant tuberculosis (MDR-TB) and extensively drug resistant TB (XDR-TB) are a dismal 50 and 20%, respectively, highlighting the urgent need for new TB drugs. The cancer drug imatinib limits mycobacterial infections in culture and animal models by reducing both entry into macrophages and augmenting phagolysosomal fusion (autophagy), which may facilitate antigen presentation and pathogen killing. Additionally, imatinib induces increases in myeloid cells (myelopoiesis), and an innate immune response to infection that mimics so-called "emergency hematopoiesis," a response that Mycobacterium tuberculosis (Mtb) appears to suppress. Importantly, these mechanisms can be induced in animal models by oral doses substantially lower than those used in people to combat cancer. The dose-dependence has important implications for TB clinical studies in humans, as it suggests that imatinib could improve TB treatment using doses that impart minimal, if any, toxicity.
This study will evaluate the safety, pharmacokinetics, and effects of imatinib on myelopoiesis in adults when given with and without isoniazid and rifabutin (antibiotics to treat mycobacterial infections).
Participants will be enrolled into one of two cohorts. In Cohort 1, participants will be enrolled in a dose-escalating fashion to receive one of four doses of imatinib alone for 14 days, followed by imatinib in combination with rifabutin and isoniazid for another 14 days.
In Cohort 2, participants will receive rifabutin and isoniazid for 14 days, followed by 14 days of rifabutin and isoniazid in combination with one of the two selected doses of imatinib. The exact doses of imatinib administered in Cohort 2 will be determined after analyzing data from Cohort 1.
After safety evaluations of participants enrolled into the first two dose levels of Cohort 1, the intervention of imatinib followed by imatinib in combination with rifabutin and isoniazid was discontinued. The study protocol was amended to evaluate the effects of imatinib alone, at 3 escalating doses.
Total study duration for participants will be 50 days, during which time participants will attend several study visits. Study visits may include a physical exam, electrocardiogram, blood and urine collection, and pharmacokinetic assessments.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Experimental | Participants will receive 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. |
|
| Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Experimental | Participants will receive 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. |
|
| Cohort 1c: Imatinib (200 mg) + Rifabutin + Isoniazid | Experimental | Participants will receive 200 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. |
|
| Cohort 1d: Imatinib (400 mg) + Rifabutin + Isoniazid | Experimental | Participants will receive 400 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. |
|
| Cohort 2a: Imatinib + Rifabutin + Isoniazid | Experimental |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Imatinib | Drug | Tablets, administered orally |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Myelomonocytic Cells in the Blood | 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. | Days 1, 7, 14, 21, 28, 42 |
| Frequency of Grade 3 or 4 Adverse Events (AEs) | 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. | Measured through Day 50 |
| Frequency of Serious Adverse Events (SAEs) | 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. | Measured through Day 50 |
| Measure | Description | Time Frame |
|---|---|---|
| White Blood Cell Count | 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. | Days 1, 7, 14, 21, 28, 42 |
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Inclusion Criteria:
Adult age between 18 years and 55 years
Body mass index (BMI) greater than 18.5 kg/m^2
At least 8 years formal education, with appropriate reading and comprehension skills
Able and willing to provide written informed consent
Males must agree to using contraception during the study and for 2 weeks after the last dose of study drug.
If a female participant is of reproductive potential, the participant (and her partner) must agree to use of one of the following combinations of birth control during the study and for 2 weeks after the last dose of study drug (or tubal ligation as a single method):
Exclusion Criteria:
Current or imminent treatment for significant infection
Pregnant or breastfeeding
HIV positive status as determined by a U.S. Food and Drug Administration (FDA)-approved HIV assay
Hepatitis B infection, as determined by an FDA-approved hepatitis B surface antigen assay
Hepatitis C infection, as determined by an FDA-approved positive Hepatitis C antibody assay
Known infection with Mycobacterium tuberculosis (MTB)
History of allergy or hypersensitivity to imatinib, isoniazid or rifabutin.
History of enrollment in other clinical trials with investigational agents within 8 weeks
Cardiac arrhythmia requiring medication, or any clinically significant electrocardiogram (ECG) abnormality
Exam consistent with congestive heart failure (e.g., edema)
Random blood glucose greater than 140 mg/dL or history of unstable diabetes mellitus requiring hospitalization for hyper or hypoglycemia within the past year prior to start of screening
Use of systemic corticosteroids within the past 28 days
Any of the following readings from a complete blood count that fall outside the normal ranges as listed here:
Any of the following chemistry panel and liver function test readings that fall outside the normal ranges as listed here:
Cirrhosis of the liver, or any known active or chronic liver disease
Current or past alcohol or elicit/recreational drug use, which in the expert judgment of the Investigator, will interfere with the participant's ability to comply with the protocol requirements.
Any experimental medications for less than 8 weeks prior to screening or anticipated use during the trial
Current (within 30 days prior to the first dose of study drug) or anticipated use of antimetabolites; alkylating agents; or other drugs or herbal preparations (including St. John's wort), known to affect activity of the CYP3A4 enzyme pathway
Consumption of grapefruit, grapefruit juice, or grapefruit-related citrus fruits (e.g., pomelos) within 7 days before assessment for eligibility
Unwilling to avoid grapefruit or grapefruit-related citrus fruits/pomelo during the course of the study
Unwilling to avoid alcohol for the duration of the study
Unwilling to abstain from taking acetaminophen-containing medications during the 28-day study drug dosing period, due to increased risk of liver toxicity
History of major medical disorders including metabolic, endocrine, hypothyroid, hepatic, renal, hematologic, pulmonary, gastrointestinal, autoimmune or cardiovascular disorders
Uncontrolled hypertension (persistent measurements at or above 150/100)
Participants who are, in the opinion of the Investigator, unable to comply with the dosing schedule and protocol evaluations
Diarrhea defined as 4 or more stools per day
Active involvement (by the participant or the participant's partner) in In Vitro Fertilization or another assisted reproductive technology procedure
Emory students currently enrolled in a course taught by the principal investigator (PI) or a Co-Investigator
Emory employees currently working under supervision of the PI or a Co-Investigator
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| Name | Affiliation | Role |
|---|---|---|
| Edmund K. Waller, MD, PhD, FACP | Emory University School of Medicine, Winship Cancer Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Emory University DAIDS TB Non-Network CRS | Atlanta | Georgia | 30332 | United States |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 22, 2022 |
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| OTHER |
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Participants will receive 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.
|
| Cohort 2b: Imatinib + Rifabutin + Isoniazid | Experimental | Participants will receive 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 (100 mg) | Experimental | Participants will receive 100 mg imatinib daily for 28 days. |
|
| Imatinib (200 mg) | Experimental | Participants will receive 200 mg imatinib daily for 28 days. |
|
| Imatinib (400 mg) | Experimental | Participants will receive 400 mg imatinib daily for 28 days. |
|
| Isoniazid | Drug | 300 mg tablets, administered orally |
|
| Rifabutin | Drug | 300 mg capsules, administered orally |
|
| Maximum Concentration (Cmax) of Imatinib |
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. |
| Day 14, Day 28 |
| Half-life (T1/2) of Imatinib | 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. | Day 14, Day 28 |
| Area Under the Curve (AUC) for Imatinib | 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. | Day 14, Day 28 |
| Elimination Rate Constant (Ke) of Imatinib | 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. | Day 14, Day 28 |
| Maximum Concentration (Cmax) of Isoniazid | 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. | Day 28 |
| Half-life (T1/2) of Isoniazid | 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. | Day 28 |
| Area Under the Curve (AUC) for Isoniazid | 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. | Day 28 |
| Elimination Rate Constant (Ke) of Isoniazid | 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. | Day 28 |
| Maximum Concentration (Cmax) of 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. | Day 28 |
| Half-life (T1/2) of 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. | Day 28 |
| Area Under the Curve (AUC) for 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. | Day 28 |
| Elimination Rate Constant (Ke) of 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. | Day 28 |
| 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 |
| FG002 | 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 |
| FG003 | 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 |
| FG004 | 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 |
| FG005 | 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 |
| FG006 | Imatinib (100 mg) | Participants receiving 100 mg imatinib daily for 28 days. Imatinib: Tablets, administered orally |
| FG007 | Imatinib (200 mg) | Participants receiving 200 mg imatinib daily for 28 days. Imatinib: Tablets, administered orally |
| FG008 | Imatinib (400 mg) | Participants receiving 400 mg imatinib daily for 28 days. Imatinib: Tablets, administered orally |
| Began Imatinib Plus Rifabutin and Isoniazid Portion of the Intervention (if Applicable) |
|
| COMPLETED |
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| NOT COMPLETED |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 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. |
| BG002 | Imatinib (100 mg) | Participants receiving 100 mg imatinib daily for 28 days. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Myelomonocytic Cells in the Blood | 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. | The analysis population includes participants who completed the study. | Posted | Mean | Standard Deviation | cells per microliter (µL) | Days 1, 7, 14, 21, 28, 42 |
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| Primary | Frequency of Grade 3 or 4 Adverse Events (AEs) | 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. | Posted | Number | Grade 3 or 4 adverse events | Measured through Day 50 |
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| Primary | Frequency of Serious Adverse Events (SAEs) | 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. | Posted | Number | serious adverse events | Measured through Day 50 |
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| Secondary | White Blood Cell Count | 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. | The analysis population includes participants who completed the study. | Posted | Mean | Standard Deviation | cells/µL | Days 1, 7, 14, 21, 28, 42 |
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| Secondary | Maximum Concentration (Cmax) of Imatinib | 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. | 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. | Posted | Median | Inter-Quartile Range | micrograms per milliliter (mcg/mL) | Day 14, Day 28 |
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| Secondary | Half-life (T1/2) of Imatinib | 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. | 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. | Posted | Median | Inter-Quartile Range | hours | Day 14, Day 28 |
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| Secondary | Area Under the Curve (AUC) for Imatinib | 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. | 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. | Posted | Median | Inter-Quartile Range | hour*mcg/mL | Day 14, Day 28 |
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| Secondary | Elimination Rate Constant (Ke) of Imatinib | 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. | 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. | Posted | Median | Inter-Quartile Range | 1/hour | Day 14, Day 28 |
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| Secondary | Maximum Concentration (Cmax) of Isoniazid | 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. | 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. | Posted | Median | Inter-Quartile Range | mcg/mL | Day 28 |
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| Secondary | Half-life (T1/2) of Isoniazid | 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. | 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. | Posted | Median | Inter-Quartile Range | hours | Day 28 |
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| Secondary | Area Under the Curve (AUC) for Isoniazid | 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. | 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. | Posted | Median | Inter-Quartile Range | hour*mcg/mL | Day 28 |
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| Secondary | Elimination Rate Constant (Ke) of Isoniazid | 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. | 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. | Posted | Median | Inter-Quartile Range | 1/hour | Day 28 |
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| Secondary | Maximum Concentration (Cmax) of 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. | 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. | Posted | Median | Inter-Quartile Range | mcg/mL | Day 28 |
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| Secondary | Half-life (T1/2) of 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. | 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. | Posted | Median | Inter-Quartile Range | hours | Day 28 |
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| Secondary | Area Under the Curve (AUC) for 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. | 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. | Posted | Median | Inter-Quartile Range | hour*mcg/mL | Day 28 |
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| Secondary | Elimination Rate Constant (Ke) of 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. | 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. | Posted | Median | Inter-Quartile Range | 1/hour | Day 28 |
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Information on adverse events was collected from the time of the baseline visit through Day 50.
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cohort 1a: Imatinib (50 mg) | Participants in Cohort 1a while receiving 50 mg imatinib for 14 days. | 0 | 16 | 0 | 16 | 16 | 16 |
| EG001 | Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Participants in Cohort 1a while receiving 50 mg imatinib for 14 days together with rifabutin and isoniazid. | 0 | 14 | 0 | 14 | 12 | 14 |
| EG002 | Cohort 1b: Imatinib (100 mg) | Participants in Cohort 1b while receiving 100 mg imatinib for 14 days. | 0 | 6 | 0 | 6 | 5 | 6 |
| EG003 | Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid | Participants in Cohort 1b while receiving 100 mg imatinib for 14 days together with rifabutin and isoniazid. | 0 | 3 | 0 | 3 | 3 | 3 |
| EG004 | Imatinib (100 mg) | Participants receiving 100 mg imatinib daily for 28 days. | 0 | 2 | 0 | 2 | 2 | 2 |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Low Hemoglobin | Blood and lymphatic system disorders | Non-systematic Assessment |
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| Lymphopenia (low absolute lymphocyte count (ALC)) | Blood and lymphatic system disorders | Non-systematic Assessment |
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| Neutropenia (low absolute neutrophil count (ANC)) | Blood and lymphatic system disorders | Non-systematic Assessment |
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| White blood cell count decrease | Blood and lymphatic system disorders | Non-systematic Assessment |
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| Eosinophils increase | Blood and lymphatic system disorders | Non-systematic Assessment |
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| Neutrophil decrease | Blood and lymphatic system disorders | Non-systematic Assessment |
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| Conjunctivitis | Eye disorders | Non-systematic Assessment |
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| Photophobia | Eye disorders | Non-systematic Assessment |
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| Constipation | Gastrointestinal disorders | Non-systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | Non-systematic Assessment |
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| Edema localized | General disorders | Non-systematic Assessment |
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| Fatigue | General disorders | Non-systematic Assessment |
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| Elevated bilirubin | Hepatobiliary disorders | Non-systematic Assessment |
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| Hyperglycemia | Metabolism and nutrition disorders | Non-systematic Assessment |
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| Hypocalcemia | Metabolism and nutrition disorders | Non-systematic Assessment |
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| Hypoglycemia | Metabolism and nutrition disorders | Non-systematic Assessment |
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| Hypoproteinemia | Metabolism and nutrition disorders | Non-systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
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| Paresthesia | Nervous system disorders | Non-systematic Assessment |
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| Menstrual disturbances | Reproductive system and breast disorders | Non-systematic Assessment |
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| Protein in urine | Renal and urinary disorders | Non-systematic Assessment |
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| Urine discoloration | Renal and urinary disorders | Non-systematic Assessment |
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| Visual changes | General disorders | Non-systematic Assessment |
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| Bicarbonate low | General disorders | Non-systematic Assessment |
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| Blood urea nitrogen abnormal | General disorders | Non-systematic Assessment |
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| eGFR Decrease | General disorders | Non-systematic Assessment |
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| eGFR Decrease from Baseline | General disorders | Non-systematic Assessment |
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| Hypokalemia | General disorders | Non-systematic Assessment |
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| Hyponatremia | General disorders | Non-systematic Assessment |
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| Pruritus | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
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| Abdominal pain | General disorders | Non-systematic Assessment |
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| Chills | General disorders | Non-systematic Assessment |
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| Headache | General disorders | Non-systematic Assessment |
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| Fever | General disorders | Non-systematic Assessment |
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| Mild heartburn | Gastrointestinal disorders | Non-systematic Assessment |
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| Estimated creatinine clearance decrease from baseline | General disorders | Non-systematic Assessment |
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| Alkaline phosphatase (ALP) increase | General disorders | Non-systematic Assessment |
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Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Cynthia Giver | Emory University | 404-778-5806 | cgiver@emory.edu |
| Aug 25, 2023 |
| Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | May 4, 2023 | Aug 23, 2023 | ICF_001.pdf |
| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| ID | Term |
|---|---|
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
Not provided
Not provided
| ID | Term |
|---|---|
| D000068877 | Imatinib Mesylate |
| D007538 | Isoniazid |
| D017828 | Rifabutin |
| ID | Term |
|---|---|
| D001549 | Benzamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D001565 | Benzoates |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D010879 | Piperazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011743 | Pyrimidines |
| D006834 | Hydrazines |
| D007539 | Isonicotinic Acids |
| D000147 | Acids, Heterocyclic |
| D011725 | Pyridines |
| D012294 | Rifamycins |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
Not provided
Not provided
| 26-35 years |
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| 36-45 years |
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| 46-55 years |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Day 14 |
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| Day 21 |
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| Day 28 |
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| Day 42 |
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| Participants |
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| Participants |
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| Participants |
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Participants receiving 100 mg imatinib daily for 28 days.
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Participants receiving 100 mg imatinib daily for 28 days.
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