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

• Status: Recruiting
• Trial end date: 2021-11-01
• Target enrollment: 0
• Participant gender: All

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, PZA, INH and ethambutol) for drug-sensitive TB.

• Phase: Phase 2
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Treatments: Imatinib Mesylate; Isoniazid; Rifabutin

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;

• Tubal ligation.

• Important Note: Due to documented effects of rifabutin on effectiveness of hormonal contraceptives (16-18), these are not included as options here with the exception of an IUD. 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 (Emory Medical Lab Reference Ranges, 2019, with some variation for different ethnic groups incorporated in the system):

• White blood cell count: Female- 4.0-10.0 10E3/mcL, Male- 4.2-9.1 10E3/mcL

• Hemoglobin: Female-11.4-14.4 gm/dL, Male-12.9-16.1 gm/dL

• Platelet count: Female-150-400 10E3/mcL, Male-150-400 10E3/mcL

• Absolute neutrophil count: Female- 0.91-5.53 10E3/mcL, Male- 0.67-6.4110E3/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 (Emory Medical Lab Reference Ranges, 2019):

• Serum potassium: Female- 3.5-5.1 mmol/L, Male- 3.5-5.1 mmol/L

• Alkaline phosphatase (ALP): Female- 34-104unit/L, Male- 34-104unit/L

• Alanine aminotransferase (ALT): Female- 7-52 unit/L, Male-7-52 unit/L

• Aspartate aminotransferase (AST): Female-13-39 unit/L, Male-13-39 unit/L

• Gamma-glutamyl transferase (GGT): Female- 9-64 unit/L, Male- 9-64 unit/L

• Total Bilirubin: Female- 0.3-1.0 mg/dL, Male- 0.3-1.0 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