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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Number of Myelomonocytic Cells in the Blood
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Imatinib (Drug)
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.
干预措施: Isoniazid (Drug)
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.
干预措施: Rifabutin (Drug)
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.
干预措施: Imatinib (Drug)
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.
干预措施: Isoniazid (Drug)
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.
干预措施: Rifabutin (Drug)
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.
干预措施: Imatinib (Drug)
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.
干预措施: Isoniazid (Drug)
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.
干预措施: Rifabutin (Drug)
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.
干预措施: Imatinib (Drug)
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.
干预措施: Isoniazid (Drug)
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.
干预措施: Rifabutin (Drug)
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.
干预措施: Imatinib (Drug)
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.
干预措施: Isoniazid (Drug)
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.
干预措施: Rifabutin (Drug)
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.
干预措施: Imatinib (Drug)
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.
干预措施: Isoniazid (Drug)
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.
干预措施: Rifabutin (Drug)
Imatinib (100 mg)
Participants will receive 100 mg imatinib daily for 28 days.
干预措施: Imatinib (Drug)
Imatinib (200 mg)
Participants will receive 200 mg imatinib daily for 28 days.
干预措施: Imatinib (Drug)
Imatinib (400 mg)
Participants will receive 400 mg imatinib daily for 28 days.
干预措施: Imatinib (Drug)
结局指标
主要结局
Number of Myelomonocytic Cells in the Blood
时间窗: 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 Serious Adverse Events (SAEs)
时间窗: 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.
Frequency of Grade 3 or 4 Adverse Events (AEs)
时间窗: 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.
次要结局
- 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)
- Maximum Concentration (Cmax) of Isoniazid(Day 28)
- Half-life (T1/2) of Isoniazid(Day 28)
- Area Under the Curve (AUC) for Isoniazid(Day 28)
- Elimination Rate Constant (Ke) of Isoniazid(Day 28)
- Maximum Concentration (Cmax) of Rifabutin(Day 28)
- Half-life (T1/2) of Rifabutin(Day 28)
- Area Under the Curve (AUC) for Rifabutin(Day 28)
- Elimination Rate Constant (Ke) of Rifabutin(Day 28)