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Azacytidine During Anti-tuberculosis Therapy (AZA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03941496
Recruitment Status : Not yet recruiting
First Posted : May 8, 2019
Last Update Posted : July 20, 2021
Bristol-Myers Squibb
Information provided by (Responsible Party):
Andrew Dinardo, Baylor College of Medicine

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Tuberculosis, Pulmonary Drug: Azacitidine Injection Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description: This study is a Phase Ib/IIa single-institution, open-label, non-randomized clinical trial of using azacitidine in pulmonary TB patients during the continuation phase of ATT.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1b/2a Safety and Immunogenicity of the DNMT Inhibitor Azacitidine During Anti-Tuberculosis Therapy
Estimated Study Start Date : August 2021
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : May 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis
Drug Information available for: Azacitidine

Arm Intervention/treatment
Experimental: 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:

  1. 5 mg/m^2 subcutaneous (SQ) once daily x 5 days for 8 individuals
  2. 15 mg/m^2 subcutaneous (SQ) once daily x 5 days for 8 individuals
  3. 30 mg/m^2 subcutaneous (SQ) once daily x 5 days for 8 individuals
  4. 50 mg/m^2 SQ once daily x 5 days for 8 individuals
  5. 75 mg/m^2 once daily x 5 days for 8 individuals
Drug: Azacitidine Injection

In Phase Ib dose escalation stage, 24 participants will receive AZA subcutaenously once a day for 5 days as follows:

  1. 5 mg/m^2
  2. 15 mg/m^2
  3. 30 mg/m^2
  4. 50 mg/m^2
  5. 75 mg/m^2

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). Subjects in Phase II will receive a dose that induces two of the three following:

  1. a decrease DNA methylation levels in genes previously identified to be persistently hyper-methylated despite successful anti-TB therapy
  2. an increase in TNF and IFN-γ signaling pathways
  3. an increase in ex vivo mycobacterial growth inhibition assay
Other Name: AZA Group

Primary Outcome Measures :
  1. Overall incidence of all IP-related adverse events [ Time Frame: 2 years ]
    using Common Terminology Criteria for Adverse Events (CTCAE) v 5.0.

  2. Overall severity of all IP-related adverse events [ Time Frame: 4 months ]
    using Common Terminology Criteria for Adverse Events (CTCAE) v 5.0

  3. Measurement of epigenetic-mediated immune exhaustion [ Time Frame: 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

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  1. Age 18 years or older
  2. Microbiologically confirmed pulmonary Tuberculosis, including cavitary, lymph node or military pulmonary TB
  3. Asymptomatic by the end of intense phase ATT (8 weeks) and remains asymptomatic until AZA dosing.
  4. Acid-Fast Bacilli (AFB)-smear negative at the end of intensive phase.
  5. 1-month sputum culture negative and 2-month sputum with no growth at time of study entry.
  6. HIV-negative.
  7. 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.
  8. Adequate renal function (creatinine 2 mg/dl or less and glomular filtration rate (GFR) 60 or greater).
  9. Written informed consent obtained
  10. 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.

Exclusion Criteria:

  1. HIV-infection
  2. Pre-existing liver disease as defined by imaging or pathology consistent with moderate or worse firbrosis or cirrhosis (Metavir scoring system F2)
  3. Smear-positive at 2 months
  4. 1-month or 2 month sputum culture positive at time of study entry.
  5. Participants with extrapulmonary TB.
  6. History or current drug-resistant tuberculosis
  7. 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 platelets/mm3) will be excluded.
  8. Any concurrent uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place the patient at unacceptable risk of study treatment.
  9. Pregnant or breast feeding females.
  10. 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)
  11. 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
  12. Cancer (excluding surgically treated skin cancer) or hematologic malignancy currently active or active in the past three years.
  13. Abnormal coagulation parameters (Prothrombin Time (PT) >15 seconds, Partial Thromboplastin (PTT) >40 seconds, and/or international normalized ratio (INR) >1.5)
  14. Significant active cardiac disease within the previous 6 months including:

    1. New York Heart Association (NYHA) class 4 congestive heart failure (CHF)
    2. Unstable angina
    3. Myocardial infarction
  15. Active viral infection with HIV or hepatitis type B or C
  16. Known or suspected hypersensitivity to azacytidine or mannitol
  17. Inability to give informed consent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03941496

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Contact: Andrew DiNardo 832.822-1331
Contact: Zoe Spieler

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United States, Texas
Harris Health System - Ben Taub Hospital
Houston, Texas, United States, 77030
Contact: Andrew DiNardo, MD         
Contact: Zoe Spieler   
Sub-Investigator: Elizabeth Guy, MD         
Sub-Investigator: Elizabeth Chiao, MD         
Sub-Investigator: Cristian Coarfa, PhD         
Principal Investigator: Andrew DiNardo, MD         
Sponsors and Collaborators
Andrew Dinardo
Bristol-Myers Squibb
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Principal Investigator: Andrew DiNardo Baylor College of Medicine

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Responsible Party: Andrew Dinardo, Principal Investigator / Assistant Professor, Baylor College of Medicine Identifier: NCT03941496    
Other Study ID Numbers: H-45051
First Posted: May 8, 2019    Key Record Dates
Last Update Posted: July 20, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Andrew Dinardo, Baylor College of Medicine:
Mycobacterium tuberculosis
anti-TB therapy
rifampin (R), isoniazid (H) pyrazinamide (Z) ethambutol (E)
rifampin (R), isoniazid (H)
Additional relevant MeSH terms:
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Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Respiratory Tract Infections
Lung Diseases
Respiratory Tract Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors