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

NCT03891901 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: Aim 138518
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Tuberculosis

Keywords

Imatinib; Rifabutin; Isoniazid

Outcome Measures

Primary Outcomes (3)

• 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

Secondary Outcomes (13)

• White Blood Cell Count

  Days 1, 7, 14, 21, 28, 42

• Maximum Concentration (Cmax) of Imatinib

  Day 14, Day 28

• Half-life (T1/2) of Imatinib

  Day 14, Day 28

• Area Under the Curve (AUC) for Imatinib

  Day 14, Day 28

• Elimination Rate Constant (Ke) of Imatinib

  Day 14, Day 28

Study Arms (9)

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.

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.

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.

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.

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.

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.

Drug: Imatinib; Drug: Isoniazid; Drug: Rifabutin

Imatinib (100 mg)

EXPERIMENTAL

Participants will receive 100 mg imatinib daily for 28 days.

Drug: Imatinib

Imatinib (200 mg)

EXPERIMENTAL

Participants will receive 200 mg imatinib daily for 28 days.

Drug: Imatinib

Imatinib (400 mg)

EXPERIMENTAL

Participants will receive 400 mg imatinib daily for 28 days.

Drug: Imatinib

Interventions

Imatinib DRUG

Tablets, administered orally

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)

Isoniazid DRUG

300 mg tablets, administered orally

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

Rifabutin DRUG

300 mg capsules, administered orally

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

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Emory University: collaborator
• University of Pennsylvania: collaborator
• Aurum Institute: collaborator
• University of Florida: collaborator

Study Sites (1)

Emory University DAIDS TB Non-Network CRS

Atlanta, Georgia, 30332, United States

Location

MeSH Terms

Conditions

Tuberculosis

Interventions

Imatinib Mesylate; Isoniazid; Rifabutin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Dr. Cynthia Giver
• Organization: Emory University

cgiver@emory.edu

404-778-5806

Study Officials

• Edmund K. Waller, MD, PhD, FACP

  Emory University School of Medicine, Winship Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 25, 2019
• First Posted: March 27, 2019
• Study Start: October 27, 2020
• Primary Completion: August 30, 2022
• Study Completion: August 30, 2022
• Last Updated: October 23, 2023
• Results First Posted: September 28, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)