Tuberculosis Clinical Trial
— IMPACT-TBOfficial title:
IMPACT-TB (Imatinib Mesylate Per Oral as a Clinical Therapeutic for TB): A Phase II Clinical Trial of the Safety, Pharmacokinetics and Hematologic Effects of Imatinib on Myelopoiesis in Adults When Given With and Without Isoniazid and Rifabutin
Verified date | August 2023 |
Source | National Institute of Allergy and Infectious Diseases (NIAID) |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 24 |
Est. completion date | August 30, 2022 |
Est. primary completion date | August 30, 2022 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | All |
Age group | 18 Years to 55 Years |
Eligibility | 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): - Use of a double-barrier method of contraception: condoms (male or female) and a diaphragm or cervical cap with spermicide; - Use of an intrauterine device (IUD) and a barrier method: condoms (male or female, with or without spermicide) or a diaphragm or cervical cap with spermicide; - For those in the imatinib only study arms: use of hormone-based contraceptives (pill, patch, implant, ring, or injectable) and a barrier method: condoms (male or female, with or without spermicide) or a diaphragm or cervical cap with spermicide (participants in study arms receiving isoniazid and rifabutin are not eligible if they are relying hormonal contraceptives other than an IUD) - Tubal ligation. - Women who are post-menopausal, defined as age greater than 45 and no menses for at least 1 year, or who have had a hysterectomy, are considered not of reproductive potential. 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: - White blood cell count: 3.4 10E3/microliter (mcL) - 11 10E3/mcL - Hemoglobin: Female- 11.1 - 16.7 gm/dL, Male- 12.5 - 16.5 gm/dL - Platelet count: 150-400 10E3/mcL - Absolute neutrophil count: Female- 0.91-5.53 10E3/mcL, Male- 0.67-6.41 10E3/mcL - Absolute lymphocyte count: Female- 0.65-3.05 10E3/mcL, Male- 0.72-3.29 10E3/mcL - Any of the following chemistry panel and liver function test readings that fall outside the normal ranges as listed here: - Serum potassium: 3.5-5.4 mmol/L - Alkaline phosphatase (ALP): 34 - 104 unit/L - Alanine aminotransferase (ALT): 4 - 52 unit/L - Aspartate aminotransferase (AST): 13 - 39 unit/L - Total Bilirubin: 0.2 - 1.0 mg/dL - Creatinine: Female- 0.60-1.20 mg/dL, Male- 0.7-1.3mg/dL - 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 |
Country | Name | City | State |
---|---|---|---|
United States | Emory University DAIDS TB Non-Network CRS | Atlanta | Georgia |
Lead Sponsor | Collaborator |
---|---|
National Institute of Allergy and Infectious Diseases (NIAID) | Aurum Institute, Emory University, University of Florida, University of Pennsylvania |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
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. | Days 1, 7, 14, 21, 28, 42 | |
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. | Measured through Day 50 | |
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. | Measured through Day 50 | |
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. | Days 1, 7, 14, 21, 28, 42 | |
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. | Day 14, Day 28 | |
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. | Day 14, Day 28 | |
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. | Day 14, Day 28 | |
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. | Day 14, Day 28 | |
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. | Day 28 | |
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. | Day 28 | |
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. | Day 28 | |
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. | Day 28 | |
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. | Day 28 | |
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. | Day 28 | |
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. | Day 28 | |
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. | Day 28 |
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