TuberculosisPhase 2IMPACT-TBNCT03891901
A Clinical Trial of the Safety, Pharmacokinetics and Hematologic Effects of Imatinib on Myelopoiesis in Adults When Given With and Without Isoniazid and Rifabutin
A Phase 2 study testing Imatinib, Isoniazid and Rifabutin in people with Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Tuberculosis
- What is being tested?
- Imatinib, Isoniazid and Rifabutin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteUnited States
- Study dates
- 27 Oct 2020to 30 Aug 2022
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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):
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- 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.
Who cannot join
- 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)
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- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Emory University DAIDS TB Non-Network CRS
Atlanta, Georgia, 30332
About this study
Official 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
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.
Read the detailed description
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.
- Conditions
- Tuberculosis
- Being tested
- Imatinib, Isoniazid, Rifabutin
- Keywords
- Imatinib, Rifabutin, Isoniazid
- Medical subject headings
- Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ImatinibDrug
Tablets, administered orally
IsoniazidDrug
300 mg tablets, administered orally
RifabutinDrug
300 mg capsules, administered orally
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Imatinib; Drug: Isoniazid; Drug: Rifabutin |
| 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. Receives: Drug: Imatinib; Drug: Isoniazid; Drug: Rifabutin |
| 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. Receives: Drug: Imatinib; Drug: Isoniazid; Drug: Rifabutin |
| 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. Receives: Drug: Imatinib; Drug: Isoniazid; Drug: Rifabutin |
| Cohort 2a: 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. Receives: Drug: Imatinib; Drug: Isoniazid; Drug: Rifabutin |
| 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. Receives: Drug: Imatinib; Drug: Isoniazid; Drug: Rifabutin |
| Imatinib (100 mg) | Experimental | Participants will receive 100 mg imatinib daily for 28 days. Receives: Drug: Imatinib |
| Imatinib (200 mg) | Experimental | Participants will receive 200 mg imatinib daily for 28 days. Receives: Drug: Imatinib |
| Imatinib (400 mg) | Experimental | Participants will receive 400 mg imatinib daily for 28 days. Receives: Drug: Imatinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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: 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: Measured through Day 50
Secondary outcomes (13)
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.
Measured: Days 1, 7, 14, 21, 28, 42
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Day 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Mar 2019
- Study start27 Oct 2020
- Primary completion30 Aug 2022
- Study completion30 Aug 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Collaborators
- Emory University, University of Pennsylvania, Aurum Institute, University of Florida
- Responsible party
- Sponsor
- Investigators
- Edmund K. Waller, MD, PhD, FACP, Principal investigator, Emory University School of Medicine, Winship Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03891901
- Sponsor's protocol ID
- Aim 1
- Other IDs
- 38518
- Acronym
- IMPACT-TB
- Status last verified
- Aug 2023
- First submitted
- 25 Mar 2019
- Last updated
- 23 Oct 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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
- ClinicalTrials.gov ID
- NCT03891901
- Acronym / sponsor ID
- IMPACT-TB / Aim 1
- Conditions
- Tuberculosis
- Keywords
- Imatinib, Rifabutin, Isoniazid
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Collaborators
- Emory University, University of Pennsylvania, Aurum Institute, University of Florida
- Study start
- 27 Oct 2020 (actual)
- Primary completion
- 30 Aug 2022 (actual)
- Study completion
- 30 Aug 2022 (actual)
- First posted
- 27 Mar 2019 (actual)
- Results
- Posted 28 Sep 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 9
| Arm | Type | Receives |
|---|---|---|
| Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid | Experimental | Drug: Imatinib, Drug: Isoniazid, Drug: RifabutinParticipants 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 | Drug: Imatinib, Drug: Isoniazid, Drug: RifabutinParticipants 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 | Drug: Imatinib, Drug: Isoniazid, Drug: RifabutinParticipants 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 | Drug: Imatinib, Drug: Isoniazid, Drug: RifabutinParticipants 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 | Drug: Imatinib, Drug: Isoniazid, Drug: RifabutinParticipants 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 | Drug: Imatinib, Drug: Isoniazid, Drug: RifabutinParticipants 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 | Drug: ImatinibParticipants will receive 100 mg imatinib daily for 28 days. |
| Imatinib (200 mg) | Experimental | Drug: ImatinibParticipants will receive 200 mg imatinib daily for 28 days. |
| Imatinib (400 mg) | Experimental | Drug: ImatinibParticipants will receive 400 mg imatinib daily for 28 days. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (11 listed)
- 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.
Key exclusion criteria (40 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ImatinibTablets, administered orally | Drug | Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid, Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid, Cohort 1c: Imatinib (200 mg) + Rifabutin + Isoniazid, Cohort 1d: Imatinib (400 mg) + Rifabutin + Isoniazid, Cohort 2a: Imatinib + Rifabutin + Isoniazid, Cohort 2b: Imatinib + Rifabutin + Isoniazid, Imatinib (100 mg), Imatinib (200 mg), Imatinib (400 mg) |
| Isoniazid300 mg tablets, administered orally | Drug | Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid, Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid, Cohort 1c: Imatinib (200 mg) + Rifabutin + Isoniazid, Cohort 1d: Imatinib (400 mg) + Rifabutin + Isoniazid, Cohort 2a: Imatinib + Rifabutin + Isoniazid, Cohort 2b: Imatinib + Rifabutin + Isoniazid |
| Rifabutin300 mg capsules, administered orally | Drug | Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid, Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid, Cohort 1c: Imatinib (200 mg) + Rifabutin + Isoniazid, Cohort 1d: Imatinib (400 mg) + Rifabutin + Isoniazid, Cohort 2a: Imatinib + Rifabutin + Isoniazid, Cohort 2b: Imatinib + Rifabutin + Isoniazid |
Primary outcome
Number of Myelomonocytic Cells in the Blood
Time frame: Days 1, 7, 14, 21, 28, 42
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.
Frequency of Grade 3 or 4 Adverse Events (AEs)
Time frame: 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.
Frequency of Serious Adverse Events (SAEs)
Time frame: 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.
13 secondary outcomes
White Blood Cell Count
Time frame: Days 1, 7, 14, 21, 28, 42
Maximum Concentration (Cmax) of Imatinib
Time frame: Day 14, Day 28
Half-life (T1/2) of Imatinib
Time frame: Day 14, Day 28
Area Under the Curve (AUC) for Imatinib
Time frame: Day 14, Day 28
Elimination Rate Constant (Ke) of Imatinib
Time frame: Day 14, Day 28
Maximum Concentration (Cmax) of Isoniazid
Time frame: Day 28
Half-life (T1/2) of Isoniazid
Time frame: Day 28
Area Under the Curve (AUC) for Isoniazid
Time frame: Day 28
Elimination Rate Constant (Ke) of Isoniazid
Time frame: Day 28
Maximum Concentration (Cmax) of Rifabutin
Time frame: Day 28
Half-life (T1/2) of Rifabutin
Time frame: Day 28
Area Under the Curve (AUC) for Rifabutin
Time frame: Day 28
Elimination Rate Constant (Ke) of Rifabutin
Time frame: Day 28
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Oct 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Edmund K. Waller, MD, PhD, FACP principal investigator
Emory University School of Medicine, Winship Cancer Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Imatinib, Isoniazid and Rifabutin in people with Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 40 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 28 Sep 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Myelomonocytic Cells in the Blood (time frame: Days 1, 7, 14, 21, 28, 42). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Oct 2023.