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Tuberculosis, PulmonaryPhase 1/2AZANCT03941496

Azacytidine During Anti-tuberculosis Therapy

A Phase 1/2 study testing Azacitidine Injection in people with Tuberculosis, Pulmonary, run by Andrew Dinardo at 1 site in United States.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and olderHealthy volunteers can take part
Conditions the study is for
Tuberculosis, Pulmonary
What is being tested?
Azacitidine Injection
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
1 siteUnited States
Study dates
Oct 2022to May 2023
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • 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.
Show all 10Show fewer
  • 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.

Who cannot join

  • 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
Show all 20Show fewer
  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Harris Health System - Ben Taub Hospital

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: Phase 1b/2a Safety and Immunogenicity of the DNMT Inhibitor Azacitidine During Anti-Tuberculosis Therapy

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.

Read the detailed description

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.

  1. Informed consent
  2. Full History and Exam
  3. Concomitant medications
  4. Allergies
  5. Alcohol and substance use
  6. Vital signs and physical exam
  7. Review of baseline laboratory results including complete blood count (CBC) with differential, liver function, renal function and microbiology studies
  8. After consent, CBC, coagulation and Renal and liver function studies will occur within 14-days prior to study drug.
  9. CBC: WBC, Hemoglobin, Hematocrit, Platelet count ii. Coagulation studies: PT and PTT iii. Sodium, potassium, blood urea nitrogen, creatinine, glucose, AST, ALT, alkaline phosphatase, total bilirubin b. After screening labs, participants with cytopenias or inappropriate coagulation, renal or liver function (see inclusion and exclusion criteria), will not receive study drug
  10. Pregnancy test (within 24 hours prior to AZA dosing)

PHASE IB: AZACITIDINE AFTER 10 WEEKS OF ATT; PRE-TREATMENT EVALUATION

1-Month pre-study drug: Recruitment, consent and completion of the Case Report Form (CRF) including baseline history and physical exam will occur between week 4-10 of Anti-TB therapy.

0-2 weeks pre-study drug: Blood draw for baseline immune correlates and to screen for eligibility criteria (CBC, CMP and coagulation) will occur 1-14 days prior to azacitidine dosing. A pregnancy test will occur within 24 hours prior to AZA dosing. (A CMP will include measurement of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, total bilirubin, creatinine, chloride, carbon dioxide/bicarbonate, sodium, potassium and glucose. A CBC will include a differential and includes red blood cell count, white blood cell count, hemoglobin, hematocrit, platelet count, percent and absolute neutrophil count, percent and absolute lymphocyte count, percent and absolute monocyte count, and percent and absolute eosinophil count.)

CYCLE 1 DAYS 1-21 AZA dosing will occur during weeks 10-13 of ATT (+/- 1 week). Pretreatment enrollment labs will be reviewed, and a symptom screen and a focused exam will occur before each sub-cutaneous dosing of azacitidine. Administration includes inverting 2-3 times to homogenize contents, rolling the syringe in the palms for 30 seconds and then administering subcutaneously at a maximum of 4mL. (On subsequent days, injection sites will be > 1 inch from a previous site and only at intact and healthy skin). Subjects will come to the clinic each day (10 minute visit) for 5 days to receive the injection. A weekly telephone call will screen for symptoms with clinically relevant symptoms triggering a clinical visit and in-person evaluation.

POST DOSE FOLLOW UP Additional screenings for cytopenias, renal and liver function will occur weekly (between days 4-11, 10-18, 17-25, and 24-32). Two mL of plasma will be collected at the same time for pharmacokinetic analysis (between days 4-11, 10-18, 17-25, and 24-32). Follow up study visits and clinical evaluation will occur monthly for the last 4 months of anti-TB therapy as standard of care. Additional blood draws for PBMCs, and immune correlates will occur at week 16 of ATT (week 6 post commencing AZA).

PHASE II: AZACITIDINE AFTER 10 WEEKS OF ATT; PRE-TREATMENT EVALUATION

1-Month pre-study drug: Recruitment, consent and completion of the CRF including baseline history and physical exam will occur between week 4-10 of Anti-TB therapy.

0-2 weeks pre-study drug: Blood draw for baseline immune correlates and to screen for eligibility criteria (CBC, CMP and coagulation) will occur within 1-14 days prior to azacitidine dosing. A pregnancy test will occur within 24 hours prior to AZA dosing.

CYCLE 1 DAYS 1-21 AZA dosing will occur during weeks 10-13 of ATT (+/- 1 week). Pretreatment enrollment labs will be reviewed, and a symptom screen and a focused exam will occur before administering AZA. Subjects will come to the clinic each day (10 minute visit) for 5 days to receive the injection. A weekly telephone call will screen for symptoms with clinically relevant symptoms triggering a clinical visit and in-person evaluation.

POST DOSE FOLLOW UP Additional screenings for cytopenias, renal and liver function will occur weekly (between days 4-11, 10-18, 17-25 and 24-32). Follow up study visits and clinical evaluation will occur at week 12 (at the peak of AZA induced toxicity), 16, 20 and 24. Additional blood draws for PBMCs and immune correlates will occur at week 16 of ATT (week 6 post commencing AZA).

Being tested
Azacitidine Injection
Keywords
Tuberculosis, TB, Mycobacterium tuberculosis, Mtb, anti-TB therapy, ATT, rifampin (R), isoniazid (H) pyrazinamide (Z) ethambutol (E), RHZE, rifampin (R), isoniazid (H), RH
Medical subject headings
Tuberculosis, Pulmonary, Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Azacitidine InjectionDrug

    Also called AZA Group

    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
Study groups in NCT03941496
Study groupRoleWhat they receive
AZA TreatmentExperimentalIn 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
Receives: Drug: Azacitidine Injection

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall incidence of all IP-related adverse events

    using Common Terminology Criteria for Adverse Events (CTCAE) v 5.0.

    Measured: 2 years

  2. Overall severity of all IP-related adverse events

    using Common Terminology Criteria for Adverse Events (CTCAE) v 5.0

    Measured: 4 months

  3. Measurement of epigenetic-mediated immune exhaustion

    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

    Measured: baseline and Week 16

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 May 2019
  2. Study startOct 2022 (estimated)
  3. Primary completionMay 2023 (estimated)
  4. Study completionMay 2023 (estimated)

Why it stopped: The study was halted prematurely due to Bristol-Myers Squibb's (BMS) decision to withdraw support for this study.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Sequential
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)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03941496
Sponsor's protocol ID
H-45051
Acronym
AZA
Status last verified
Feb 2023
First submitted
6 May 2019
Last updated
8 Feb 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • DiNardo AR, Mace EM, Lesteberg K, Cirillo JD, Mandalakas AM, Graviss EA, Orange JS, Makedonas G. Schistosome Soluble Egg Antigen Decreases Mycobacterium tuberculosis-Specific CD4+ T-Cell Effector Function With Concomitant Arrest of Macrophage Phago-Lysosome Maturation. J Infect Dis. 2016 Aug 1;214(3):479-88. doi: 10.1093/infdis/jiw156. Epub 2016 Apr 18.

    PubMed 27389351

  • Starke JR. Mortality in childhood tuberculosis: has there been progress? Lancet Infect Dis. 2017 Mar;17(3):239-241. doi: 10.1016/S1473-3099(16)30537-0. Epub 2016 Dec 8. No abstract available.

    PubMed 27964821

  • van der Walt M, Lancaster J, Shean K. Tuberculosis Case Fatality and Other Causes of Death among Multidrug-Resistant Tuberculosis Patients in a High HIV Prevalence Setting, 2000-2008, South Africa. PLoS One. 2016 Mar 7;11(3):e0144249. doi: 10.1371/journal.pone.0144249. eCollection 2016.

    PubMed 26950554

  • Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-gamma immunity. Semin Immunol. 2014 Dec;26(6):454-70. doi: 10.1016/j.smim.2014.09.008. Epub 2014 Oct 26.

    PubMed 25453225

  • DiNardo AR, Rajapakshe K, Nishiguchi T, Grimm SL, Mtetwa G, Dlamini Q, Kahari J, Mahapatra S, Kay A, Maphalala G, Mace EM, Makedonas G, Cirillo JD, Netea MG, van Crevel R, Coarfa C, Mandalakas AM. DNA hypermethylation during tuberculosis dampens host immune responsiveness. J Clin Invest. 2020 Jun 1;130(6):3113-3123. doi: 10.1172/JCI134622.

    PubMed 32125282

  • Youngblood B, Noto A, Porichis F, Akondy RS, Ndhlovu ZM, Austin JW, Bordi R, Procopio FA, Miura T, Allen TM, Sidney J, Sette A, Walker BD, Ahmed R, Boss JM, Sekaly RP, Kaufmann DE. Cutting edge: Prolonged exposure to HIV reinforces a poised epigenetic program for PD-1 expression in virus-specific CD8 T cells. J Immunol. 2013 Jul 15;191(2):540-4. doi: 10.4049/jimmunol.1203161. Epub 2013 Jun 14.

    PubMed 23772031

  • Durzynska J, Lesniewicz K, Poreba E. Human papillomaviruses in epigenetic regulations. Mutat Res Rev Mutat Res. 2017 Apr-Jun;772:36-50. doi: 10.1016/j.mrrev.2016.09.006. Epub 2016 Sep 19.

    PubMed 28528689

  • Li H, Chiappinelli KB, Guzzetta AA, Easwaran H, Yen RW, Vatapalli R, Topper MJ, Luo J, Connolly RM, Azad NS, Stearns V, Pardoll DM, Davidson N, Jones PA, Slamon DJ, Baylin SB, Zahnow CA, Ahuja N. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget. 2014 Feb 15;5(3):587-98. doi: 10.18632/oncotarget.1782.

    PubMed 24583822

  • Mikovits JA, Young HA, Vertino P, Issa JP, Pitha PM, Turcoski-Corrales S, Taub DD, Petrow CL, Baylin SB, Ruscetti FW. Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-gamma) promoter and subsequent downregulation of IFN-gamma production. Mol Cell Biol. 1998 Sep;18(9):5166-77. doi: 10.1128/MCB.18.9.5166.

    PubMed 9710601

  • Wen H, Dou Y, Hogaboam CM, Kunkel SL. Epigenetic regulation of dendritic cell-derived interleukin-12 facilitates immunosuppression after a severe innate immune response. Blood. 2008 Feb 15;111(4):1797-804. doi: 10.1182/blood-2007-08-106443. Epub 2007 Nov 30.

    PubMed 18055863

  • Sahiratmadja E, Alisjahbana B, de Boer T, Adnan I, Maya A, Danusantoso H, Nelwan RH, Marzuki S, van der Meer JW, van Crevel R, van de Vosse E, Ottenhoff TH. Dynamic changes in pro- and anti-inflammatory cytokine profiles and gamma interferon receptor signaling integrity correlate with tuberculosis disease activity and response to curative treatment. Infect Immun. 2007 Feb;75(2):820-9. doi: 10.1128/IAI.00602-06. Epub 2006 Dec 4.

    PubMed 17145950

  • Zumla A, Rao M, Dodoo E, Maeurer M. Potential of immunomodulatory agents as adjunct host-directed therapies for multidrug-resistant tuberculosis. BMC Med. 2016 Jun 15;14:89. doi: 10.1186/s12916-016-0635-1.

    PubMed 27301245

  • Tough DF, Tak PP, Tarakhovsky A, Prinjha RK. Epigenetic drug discovery: breaking through the immune barrier. Nat Rev Drug Discov. 2016 Dec;15(12):835-853. doi: 10.1038/nrd.2016.185. Epub 2016 Oct 21.

    PubMed 27765940

  • Maio M, Covre A, Fratta E, Di Giacomo AM, Taverna P, Natali PG, Coral S, Sigalotti L. Molecular Pathways: At the Crossroads of Cancer Epigenetics and Immunotherapy. Clin Cancer Res. 2015 Sep 15;21(18):4040-7. doi: 10.1158/1078-0432.CCR-14-2914.

    PubMed 26374074

  • Tumes DJ, Onodera A, Suzuki A, Shinoda K, Endo Y, Iwamura C, Hosokawa H, Koseki H, Tokoyoda K, Suzuki Y, Motohashi S, Nakayama T. The polycomb protein Ezh2 regulates differentiation and plasticity of CD4(+) T helper type 1 and type 2 cells. Immunity. 2013 Nov 14;39(5):819-32. doi: 10.1016/j.immuni.2013.09.012.

    PubMed 24238339

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Azacitidine Injection in people with Tuberculosis, Pulmonary, run by Andrew Dinardo at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 8 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall incidence of all IP-related adverse events (time frame: 2 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03941496, which also lists 69 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Feb 2023.

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