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

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ClinicalTrials.gov Identifier: NCT03891901
Recruitment Status : Not yet recruiting
First Posted : March 27, 2019
Last Update Posted : April 7, 2020
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE March 25, 2019
First Posted Date  ICMJE March 27, 2019
Last Update Posted Date April 7, 2020
Estimated Study Start Date  ICMJE June 2020
Estimated Primary Completion Date June 15, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 3, 2019)
  • Change in the number of myelomonocytic cells in the blood between baseline and Day 14 of imatinib (imatinib alone) [ Time Frame: Measured through Day 14 (Cohort 1) ]
    Based on laboratory evaluations
  • Change in the number of myelomonocytic cells in the blood between Day 14 and Day 28 of imatinib (imatinib given to participants already taking isoniazid and rifabutin) [ Time Frame: Measured through Day 28 (Cohort 2) ]
    Based on laboratory evaluations
  • Frequency of grade 3 or 4 adverse events (AEs) [ Time Frame: Measured through Day 50 ]
    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 ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 25, 2019)
  • Change in the number of myelomonocytic cells in the blood between baseline and Day 14 of imatinib (imatinib alone) [ Time Frame: Measured through Day 14 (Cohort 1) ]
    Based on laboratory evaluations
  • Change in the number of myelomonocytic cells in the blood between Day 14 and Day 28 of imatinib (imatinib given to subjects already taking isoniazid and rifabutin) [ Time Frame: Measured through Day 28 (Cohort 2) ]
    Based on laboratory evaluations
  • Frequency of grade 3 or 4 adverse events [ Time Frame: Measured through Day 49 ]
    Graded using the DAIDS table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017
  • Frequency of serious adverse events (SAEs) [ Time Frame: Measured through Day 49 ]
    Graded using the DAIDS table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 3, 2019)
  • Difference between the change in the numbers of myelomonocytic cells from baseline to Day 14 in Cohort 1 [ Time Frame: Measured through Day 14 (Cohort 1) ]
    Based on laboratory evaluations
  • Change in the numbers of myelomonocytic cells from Day 14 to Day 28 in Cohort 2 (to evaluate the effect of TB drugs on imatinib-induced myelopoesis) [ Time Frame: Measured through Day 28 (Cohort 2) ]
    Based on laboratory evaluations
  • Change in the numbers of myelomonocytic cells from baseline to Day 28 in Cohort 1 [ Time Frame: Measured through Day 28 (Cohort 1) ]
    Based on laboratory evaluations
  • Change in the numbers of myelomonocytic cells from baseline to Day 28 in Cohort 2 [ Time Frame: Measured through Day 28 (Cohort 2) ]
    Based on laboratory evaluations
  • Pooled change in both cohorts in the numbers of myelomonocytic cells in the blood between baseline and Day 28 [ Time Frame: Measured through Day 28 ]
    Based on laboratory evaluations
  • Change in the numbers of myelomonocytic cells during the imatinib-exposed periods [ Time Frame: Measured through Day 28 (Cohort 1) ]
    Based on laboratory evaluations
  • Change in the numbers of myelomonocytic cells during the imatinib-exposed periods [ Time Frame: Measured through Day 28 (Cohort 2) ]
    Based on laboratory evaluations
  • Change in the numbers of myelomonocytic cells during the imatinib-exposed periods in the pooled cohorts [ Time Frame: Measured through Day 28 ]
    Based on laboratory evaluations
Original Secondary Outcome Measures  ICMJE
 (submitted: March 25, 2019)
  • Difference between the change in the numbers of myelomonocytic cells from baseline to Day 14 in Cohort 1 [ Time Frame: Measured through Day 14 (Cohort 1) ]
    Based on laboratory evaluations
  • Change in the numbers of myelomonocytic cells from Day 14 to Day 28 in Cohort 2 (to evaluate the effect of TB drugs on imatinib-induced myelopoesis) [ Time Frame: Measured through Day 28 (Cohort 2) ]
    Based on laboratory evaluations
  • Change in the numbers of myelomonocytic cells from baseline to Day 28 in Cohort 1 [ Time Frame: Measured through Day 28 (Cohort 1) ]
    Based on laboratory evaluations
  • Change in the numbers of myelomonocytic cells from baseline to Day 28 in Cohort 2 [ Time Frame: Measured through Day 28 (Cohort 2) ]
    Based on laboratory evaluations
  • Pooled change in both cohorts in the numbers of myelomonocytic cells in the blood between baseline and Day 28 [ Time Frame: Measured through Day 28 ]
    Based on laboratory evaluations
  • Change in the numbers of myelomonocytic cells during the imatinib-exposed periods [ Time Frame: Measured through Day 28 (Cohort 1) ]
    Based on laboratory evaluations
  • Change in the numbers of myelomonocytic cells during the imatinib-exposed periods [ Time Frame: Measured through Day 28 (Cohort 2) ]
    Based on laboratory evaluations
  • Change in the numbers of myelomonocytic cells during the imatinib-exposed periods in the pooled cohorts [ Time Frame: Measured through Day 28 ]
    Based on laboratory evaluations
  • Mtb-killing activity of Day 14 leukocytes in the whole blood assay (WBA) or on phagocytosis [ Time Frame: Measured through Day 14 ]
    Assessed by fluorogenic BioParticles uptake (FBPU)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Clinical Trial of the Safety, Pharmacokinetics and Hematologic Effects of Imatinib on Myelopoiesis in Adults When Given With and Without Isoniazid and Rifabutin
Official Title  ICMJE 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
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, PZA, INH and ethambutol) for drug-sensitive TB.
Detailed Description

This study will evaluate the safety, pharmacokinetics, and effects of imatinib on myelopoiesis in adults when given with and without isoniazid and rifabutin.

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.

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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Tuberculosis
Intervention  ICMJE
  • Drug: Imatinib
    Tablets, administered orally
  • Drug: Isoniazid
    300 mg tablets, administered orally
  • Drug: Rifabutin
    300 mg capsules, administered orally
Study Arms  ICMJE
  • Experimental: Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid
    Participants will receive 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.
    Interventions:
    • Drug: Imatinib
    • Drug: Isoniazid
    • Drug: Rifabutin
  • Experimental: Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid
    Participants will receive 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.
    Interventions:
    • Drug: Imatinib
    • Drug: Isoniazid
    • Drug: Rifabutin
  • Experimental: Cohort 1c: Imatinib (200 mg) + Rifabutin + Isoniazid
    Participants will receive 200 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.
    Interventions:
    • Drug: Imatinib
    • Drug: Isoniazid
    • Drug: Rifabutin
  • Experimental: Cohort 1d: Imatinib (400 mg) + Rifabutin + Isoniazid
    Participants will receive 400 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid.
    Interventions:
    • Drug: Imatinib
    • Drug: Isoniazid
    • Drug: Rifabutin
  • Experimental: Cohort 2a: Imatinib + Rifabutin + Isoniazid
    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.
    Interventions:
    • Drug: Imatinib
    • Drug: Isoniazid
    • Drug: Rifabutin
  • Experimental: Cohort 2b: Imatinib + Rifabutin + Isoniazid
    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.
    Interventions:
    • Drug: Imatinib
    • Drug: Isoniazid
    • Drug: Rifabutin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: March 25, 2019)
72
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 28, 2020
Estimated Primary Completion Date June 15, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03891901
Other Study ID Numbers  ICMJE Aim 1
38518 ( Registry Identifier: DAIDS-ES Registry Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Edmund K. Waller, MD, PhD, FACP Emory University School of Medicine, Winship Cancer Institute
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP