Phase 1b/2a Safety and Immunogenicity of the DNMT Inhibitor Azacitidine During Anti-Tuberculosis Therapy
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 发起方
- 试验地点
- 1
- 主要终点
- Overall incidence of all IP-related adverse events
研究概览
简要总结
Tuberculosis has been shown to make immune genes inaccessible and slows immune response The purpose of this research is to see if if azacitidine is safe and can return the ability of the body to resist tuberculosis (TB), a contagious infection that attacks the lungs. Individuals with tuberculosis are being asked to participate. Some will receive a drug to restore a host immunity while others can choose to receive standard of care. All patients will continue to receive standard of care tuberculosis therapy regardless of whether they chose to participate in the study.
This study is a Phase Ib/IIa single-institution, open-label, non-randomized clinical trial of sub-cutaneous azacitidine in pulmonary TB patients during the continuation phase of ATT.
详细描述
All study participants will have drug-sensitive TB and successfully complete 2 months of standard intensive phase 4-drug RHZE (rifampin, isoniazid, pyrazinamide, ethambutol). By definition, to have uncomplicated TB, participants will have become asymptomatic and smear-negative by the end of intense phase anti-Tb therapy and be ready to transition from standard 4-drug (INH, RIF, ETH, PZA) intense phase to the 2-drug continuation phase (INH and RIF). All participants will have 1 and 2-month cultures "no growth to date" at the time of AZA administration (1-month cultures will therefore be no growth at ~6 weeks and 2-month cultures will be no growth at ~2 weeks).
Eligible study participants will be allocated to the AZA in sequential blocks of 8 study participants.
The following will be performed during screening and work up. These procedures will be performed within 4 weeks prior to administration of study drug. A signed and dated IRB approved consent form will be obtained before study specific procedures are performed. Procedures part of routine care are not considered study specific. All subjects will be screened for eligibility before enrollment.
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Informed consent
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Full History and Exam
-
Concomitant medications
-
Allergies
-
Alcohol and substance use
-
Vital signs and physical exam
-
Review of baseline laboratory results including complete blood count (CBC) with differential, liver function, renal function and microbiology studies
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age 18 years or older
- •Microbiologically confirmed pulmonary Tuberculosis, including cavitary, lymph node or military pulmonary TB
- •Asymptomatic by the end of intense phase ATT (8 weeks) and remains asymptomatic until AZA dosing.
- •Acid-Fast Bacilli (AFB)-smear negative at the end of intensive phase.
- •1-month sputum culture negative and 2-month sputum with no growth at time of study entry.
- •HIV-negative.
- •Adequate hepatic function (direct bilirubin 1.5 x upper limit of normal (ULN) or less, alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 1.5 x ULN or less) at the end of ATT intensive phase.
- •Adequate renal function (creatinine 2 mg/dl or less and glomular filtration rate (GFR) 60 or greater).
- •Written informed consent obtained
- •Women and men of childbearing potential must agree to use 2 clinically effective methods of contraception (e.g., oral, intrauterine device [IUD], diaphragm plus spermicide, injectable, transdermal or implantable contraception) during the study and at least 3 months after the last treatment.
排除标准
- •HIV-infection
- •Pre-existing liver disease as defined by imaging or pathology consistent with moderate or worse firbrosis or cirrhosis (Metavir scoring system F2)
- •Smear-positive at 2 months
- •1-month or 2 month sputum culture positive at time of study entry.
- •Participants with extrapulmonary TB.
- •History or current drug-resistant tuberculosis
- •After consent and within two weeks before Investigational Product (IP), a study complete blood count (CBC) will be performed and individuals with cytopenias (Hemoglobin <12 g/dL, WBC < 3 cells/ mm3, Absolute Neutrophil Count (ANC) < 2,000 cells/mm3, or platelets < 110,000 platelets/mm3) will be excluded.
- •Any concurrent uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place the patient at unacceptable risk of study treatment.
- •Pregnant or breast feeding females.
- •Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment)
- •History of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), celiac disease (ie. sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity
- •Cancer (excluding surgically treated skin cancer) or hematologic malignancy currently active or active in the past three years.
- •Abnormal coagulation parameters (Prothrombin Time (PT) >15 seconds, Partial Thromboplastin (PTT) >40 seconds, and/or international normalized ratio (INR) >1.5)
- •Significant active cardiac disease within the previous 6 months including:
- •New York Heart Association (NYHA) class 4 congestive heart failure (CHF)
- •Unstable angina
- •Myocardial infarction
- •Active viral infection with HIV or hepatitis type B or C
- •Known or suspected hypersensitivity to azacytidine or mannitol
- •Inability to give informed consent.
研究组 & 干预措施
AZA Treatment
In Phase Ib dose escalation stage, participants will receive subcutaneous (SQ) AZA once daily x 5 days. Results from Phase Ib are sent to FDA/IRB for approval before proceeding to Phase IIa. 36 subjects will receive AZA treatment in total (Phase Ib/IIa). All participants receive standard of care antibiotics against tuberculosis.
Dose Escalation Strategy to identify the lowest dose of AZA that decreases DNA methylation and restores immune function is listed below. Proceeding to Phase IIa will proceed if stopping criteria are met at any of the steps below and FDA/IRB approval is obtained:
- 5 mg/m^2 subcutaneous (SQ) once daily x 5 days for 8 individuals
- 15 mg/m^2 subcutaneous (SQ) once daily x 5 days for 8 individuals
- 30 mg/m^2 subcutaneous (SQ) once daily x 5 days for 8 individuals
- 50 mg/m^2 SQ once daily x 5 days for 8 individuals
- 75 mg/m^2 once daily x 5 days for 8 individuals
干预措施: Azacitidine Injection (Drug)
结局指标
主要结局
Overall incidence of all IP-related adverse events
时间窗: 2 years
using Common Terminology Criteria for Adverse Events (CTCAE) v 5.0.
Overall severity of all IP-related adverse events
时间窗: 4 months
using Common Terminology Criteria for Adverse Events (CTCAE) v 5.0
Measurement of epigenetic-mediated immune exhaustion
时间窗: baseline and Week 16
measured by using 1) a standardized mycobacterial growth inhibition assay (MGIA) that measures ex vivo mycobacterial killing; 2) 18-parameter flow cytometry based multi-dimensional immune profiling (MDIP); and 3) epigenetic assays
次要结局
未报告次要终点
研究者
Andrew Dinardo
Principal Investigator / Assistant Professor
Baylor College of Medicine