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Trial to Evaluate the Efficacy, Safety and Tolerability of BPaMZ in Drug-Sensitive (DS-TB) Adult Patients and Drug-Resistant (DR-TB) Adult Patients

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ClinicalTrials.gov Identifier: NCT03338621
Recruitment Status : Recruiting
First Posted : November 9, 2017
Last Update Posted : August 8, 2018
Sponsor:
Information provided by (Responsible Party):
Global Alliance for TB Drug Development

Brief Summary:
To evaluate the efficacy, safety and tolerability at 8 weeks (2-months), 52 weeks (12-months), and 104 Weeks (24-months) post the start of the following treatment regimens in participants with: Drug Sensitive TB (DS-TB) patients given BPaMZ for 17 Weeks ( or 4 months) vs. Standard HRZE/HR treatment given for 26 weeks (or 6 months) and Drug Resistant TB (DR-TB) patients given BPaMZ for 26 Weeks (or 6 months)

Condition or disease Intervention/treatment Phase
Tuberculosis, Pulmonary Tuberculosis, Multidrug-Resistant Tuberculosis, MDR Tuberculosis Drug-Resistant Tuberculosis Drug: Pretomanid Drug: Bedaquiline Drug: Moxifloxacin Drug: Pyrazinamide Drug: HRZE Drug: HR Phase 2

Detailed Description:

Phase 2c multi-center, open-label, partially randomized clinical trial in DS-TB and DR-TB participants.

All participants in the below arms will have follow-up for a period of 104 weeks (24 months) from the start of therapy.

Participants with Drug Sensitive TB (DS-TB):

Participants with DS-TB will be randomized to one of two treatment arms. These participants will receive either BPaMZ daily for 17 weeks (4 months), or HRZE/HR combination tablets daily for 26 weeks (6 months). participants will be stratified for co-infection with human immunodeficiency virus (HIV) and cavitation.

Participants with Drug Resistant TB (DR-TB):

Participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 months).


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 450 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Phase 2c multi-center, open-label, partially randomized clinical trial in DS-TB and DR-TB participants
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability of a 4-month Treatment of Bedaquiline Plus Pretomanid Plus Moxifloxacin Plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of HRZE/HR (Control) in Adult Participants With Drug-Sensitive Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in Adult Participants With Drug Resistant, Smear-Positive Pulmonary Tuberculosis (DR-TB)
Actual Study Start Date : July 30, 2018
Estimated Primary Completion Date : March 31, 2020
Estimated Study Completion Date : January 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Allergy Tuberculosis

Arm Intervention/treatment
Experimental: Drug Sensitive BPaMZ
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 9 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 17 weeks (Total treatment duration 4 months
Drug: Pretomanid
200 mg tablets
Other Names:
  • PA-824
  • Pa

Drug: Bedaquiline
100 mg tablets
Other Names:
  • B
  • TMC207

Drug: Moxifloxacin
400 mg tablets
Other Name: M

Drug: Pyrazinamide
500 mg tablets
Other Name: Z

Active Comparator: Drug Sensitive Standard Treatment
isoniazid 75 mg + rifampicin 150 mg + pyrazinamide 400 mg + ethambutol 275 mg (HRZE) combination tablets for 8 weeks AND isoniazid 75 mg + rifampicin 150 mg (HR) combination tablets for Weeks 9 to 26
Drug: HRZE
isoniazid 75 mg plus rifampicin 150 mg plus pyrazinamide 400 mg plus ethambutol 275 mg combination tablets
Other Names:
  • isoniazid
  • rifampicin
  • ethambutol

Drug: HR
isoniazid 75 mg plus rifampicin 150 mg combination tablets
Other Names:
  • isoniazid
  • rifampicin

Experimental: Drug Resistant BPaMZ
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 18 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 26 weeks (Total treatment duration 6 months)
Drug: Pretomanid
200 mg tablets
Other Names:
  • PA-824
  • Pa

Drug: Bedaquiline
100 mg tablets
Other Names:
  • B
  • TMC207

Drug: Moxifloxacin
400 mg tablets
Other Name: M

Drug: Pyrazinamide
500 mg tablets
Other Name: Z




Primary Outcome Measures :
  1. Time to culture conversion to negative status over 8 weeks [ Time Frame: Days 0-56 (8 weeks) ]
    Culture conversion is a diagnostic criteria indicating the point at which samples taken from a patient infected with a tuberculosis can no longer produce tuberculosis cell cultures, that point is considered culture negativity


Secondary Outcome Measures :
  1. The proportion of participants experiencing bacteriologic failure or relapse or clinical failure (unfavourable outcome) at 52 weeks (12 months) [ Time Frame: At week 52 of treatment ]
    Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days apart.

  2. Incidence of bacteriologic failure or relapse or clinical failure at 104 weeks from the start of therapy. [ Time Frame: Day 0 - Day 728 (Week 104) ]
    Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days apart.

  3. Proportion of participants with sputum culture conversion to negative status in liquid culture (MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 52 weeks from start of therapy. [ Time Frame: Week 4, Week 6, Week 12, Week 17, and Week 52 ]
    Culture conversion is a diagnostic criteria indicating the point at which samples taken from a patient infected with a tuberculosis can no longer produce tuberculosis cell cultures, that point is considered culture negativity

  4. Change from baseline in weight [ Time Frame: Day 0 - Day 364 (Week 52) ]
  5. Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, severity, drug relatedness, seriousness, leading to early withdrawal, and leading to death. [ Time Frame: Day 0 - Day 364 (Week 52) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Participants are required to meet all of the following inclusion criteria during the screening period in order to be randomized.

  1. Signed written consent prior to undertaking any trial-related procedures.
  2. Male or female, aged 18 years or over.
  3. Body weight (in light clothing and no shoes) ≥ 30 kg.
  4. Sputum positive for tubercule bacilli (at least 1+ on the International Union Against Tuberculosis and Lung Disease [IUATLD]/WHO scale (Appendix 1) on smear microscopy) at the trial laboratory.
  5. Disease Characteristics:

    • Participants with one of the following pulmonary TB conditions:

DS-TB treatment arm participants should be:

  1. sensitive to rifampicin and isoniazid by rapid sputum based test AND
  2. either newly diagnosed for TB or have a history of being untreated for at least 3 years after cure from a previous episode of TB.

If they are entered into the trial due to being sensitive to rifampicin and isoniazid by rapid molecular sputum based test, however on receipt of the rifampicin and/or isoniazid phenotypic resistance testing in liquid culture this shows they are rifampicin or isoniazid resistant, they will be:

  1. Excluded as late exclusions;
  2. Possibly replaced as determined by the Sponsor.

DR-TB treatment arm participants should be:

a. Resistant to rifampicin and/or isoniazid. A chest x-ray which in the opinion of the investigator is compatible with pulmonary TB.

1. Contraception:

Be of non-childbearing potential or using effective methods of birth control, as defined below:

Non-childbearing potential:

  1. Participant - not heterosexually active or practice sexual abstinence; or
  2. Female participant or male participants female sexual partner - bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive months; or
  3. Male participant or female participants male sexual partner - vasectomised or has had a bilateral orchidectomy minimally three months prior to screening;

Effective birth control methods:

  1. Double barrier method which can include a male condom, diaphragm, cervical cap, or female condom; or
  2. Female participant: Barrier method combined with hormone-based contraceptives or an intra-uterine device for the female participant.
  3. Male participants' female sexual partner: Double barrier method or hormone-based contraceptives or an intra-uterine device for the female partner.

And both male and female participants are willing to continue practicing birth control methods and are not planning to conceive throughout treatment and for 12 weeks after the last dose of trial medication or discontinuation from trial medication in case of premature discontinuation.

(Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, hormone-based contraceptives alone cannot be used by female participants to prevent pregnancy).

Exclusion Criteria:

Participants will be excluded from participation if they meet any of the following criteria:

Medical History and Concurrent Conditions:

  1. Any non-TB related condition where participation in the trial, as judged by the investigator, could compromise the well-being of the participant or prevent, limit or confound protocol specified assessments.
  2. Being, or about to be, treated for Malaria.
  3. Is critically ill and, in the judgment of the investigator, has a diagnosis likely to result in death during the trial or the follow-up period.
  4. TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor outcome, or likely to require a longer course of therapy (such as TB of the bone or joint), as judged by the investigator.
  5. History of allergy or hypersensitivity to any of the trial IMP or related substances, including known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with quinolones or suspected hypersensitivity to any rifampicin antibiotics.
  6. For HIV infected participants any of the following:

    1. CD4+ count <100 cells/µL
    2. Karnofsky score <60% (Appendix 5)
    3. Received intravenous antifungal medication within the last 90 days
    4. WHO Clinical Stage 4 HIV disease (Appendix 3)
  7. Participants recently started or expected to need to start ART within 1 month after randomization. Participants may be included who have been on ARTs for greater than 30 days prior to start of screening, or who are expected to start ART greater than 30 days after randomization.
  8. Resistant to fluoroquinolones (rapid, sputum-based molecular screening tests).

    a. If they are entered into the trial due to being sensitive to fluoroquinolones by rapid sputum based test, however on receipt of the moxifloxacin phenotypic resistance testing in liquid culture they are found to be fluoroquinolones resistant, they will be excluded as late exclusions;

  9. Having participated in other clinical trials with investigational agents within 8 weeks prior to start of trial medication or currently enrolled in an investigational trial;
  10. Participants with any of the following at screening (per measurements and reading done by ECG):
  11. Cardiac arrhythmia requiring medication;
  12. Prolongation of QT/QTc interval with QTcF (Fridericia correction) >450 ms;
  13. History of additional risk factors for Torsade de Pointes, (e.g., heart failure, hypokalemia, family history of Long QT Syndrome);
  14. Any clinically significant ECG abnormality, in the opinion of the investigator.
  15. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening.

Previous and Concomitant Therapy

  1. Previous treatment with pretomanid or bedaquiline as part of a clinical trial.
  2. Previous treatment for TB which includes, but is not limited to, gatifloxacin, amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, thioacetazone, capreomycin, quinolones, thioamides, and metronidazole:
  3. For DS-TB treatment arms: Previous treatment for tuberculosis within 3 years prior to Day -9 to -1 (Screening). Participants who have previously received isoniazid prophylactically may be included in the trial as long as that treatment is/was discontinued at least 7 days prior to randomization into this trial.
  4. For the DR-TB/MDR-TB participants: Previous treatment for DR-TB/MDR-TB, although may have been on a DR-TB treatment regimen for no longer than 7 days at start of screening.
  5. Any diseases or conditions in which the use of the standard TB drugs or any of their components is contra-indicated, including but not limited to drug allergy.
  6. Use of any drug within 30 days prior to randomisation known to prolong QTc interval (including, but not limited to, amiodarone, amitriptyline, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinacrine, quinidine, sotalol, sparfloxacin, thioridazine).
  7. Use of systemic glucocorticoids within one year of start of screening (inhaled or intranasal glucocorticoids are allowed) due to visual opacities or cataracts
  8. For HIV infected participants, only the following types of ART are permissible:

    • Nevirapine (NVP) based regimen consisting of NVP in combination with any two nucleosidase reverse transcriptase inhibitors (NRTIs) tenofovir (TDF)/abacavir (ABC) and emtricitabine (FTC)/lamivudine (3TC).
    • Lopinavir/ritonavir based regimen consisting of lopinavir/ritonavir in combination with any two NRTI. TDF/ABC and FTC/3TC.
    • Integrase inhibitor (e.g., dolutegravir) in combination with TDF/ABC and FTC/3TC.
    • In participants who have viral load suppressed on efavirenz at the time of screening, their ART can be changed to rilpivirine in combination with TDF/ABC and FTC/3TC. If possible, the same nucleoside backbone should be used.
  9. In the case where participants are randomized to a rifampicin containing regime

    • EFV can be used with rifampicin.
    • LPV needs to be double dosed.
    • Rilpivirine cannot be given with rifampicin

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 ClinicalTrials.gov identifier (NCT number): NCT03338621


Contacts
Contact: Leandra Lombard 27833076784 Leandra.Lombard@tballiance.org

Locations
Georgia
National Center for Tuberculosis and Lung Diseases Recruiting
Tbilisi, Georgia, 0101
Contact: Marike Eristavi, MD    +99 559 954 0393    ma.eristavi@gmail.com   
Contact: Nestan Tukvadze         
Sponsors and Collaborators
Global Alliance for TB Drug Development
Investigators
Study Chair: Morounfolu Olugbosi, MD MSc Global Alliance for TB Drug Development

Responsible Party: Global Alliance for TB Drug Development
ClinicalTrials.gov Identifier: NCT03338621     History of Changes
Other Study ID Numbers: SimpliciTB (B-Pa-M-Z) NC-008
First Posted: November 9, 2017    Key Record Dates
Last Update Posted: August 8, 2018
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Global Alliance for TB Drug Development:
tuberculosis
drug-resistant tuberculosis
TB
DR-TB
pretomanid
PA-824
bedaquiline
TMC207
moxifloxacin
pyrazinamide
HRZE
TB Alliance
NC-008
drug-sensitive tuberculosis
DS-TB

Additional relevant MeSH terms:
Tuberculosis
Hypersensitivity
Tuberculosis, Multidrug-Resistant
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Immune System Diseases
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Moxifloxacin
Fluoroquinolones
Rifampin
Isoniazid
Pyrazinamide
Ethambutol
Bedaquiline
Diarylquinolines
Norgestimate, ethinyl estradiol drug combination
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Contraceptives, Oral, Combined
Contraceptives, Oral