A Clinical Trial of the Safety, Pharmacokinetics and Hematologic Effects of Imatinib on Myelopoiesis in Adults When Given With and Without Isoniazid and Rifabutin
Condition: Tuberculosis
MeSH terms: Tuberculosis
Intervention: Imatinib; Isoniazid; Rifabutin
Intervention description: Tablets, administered orally; 300 mg tablets, administered orally; 300 mg capsules, administered orally
Intervention MeSH terms: Isoniazid; Rifabutin; Imatinib Mesylate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Imatinib; Rifabutin; Isoniazid

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 therapy with an antimicrobial regimen
      (rifabutin, pyrazinamide (PZA), isoniazid (INH) and ethambutol) for drug-sensitive TB.
    

Eligibility criteria:

        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