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Trial record 1 of 1 for:    SimpliciTB
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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 : Active, not recruiting
First Posted : November 9, 2017
Last Update Posted : May 11, 2020
Sponsor:
Information provided by (Responsible Party):
Global Alliance for TB Drug Development

Tracking Information
First Submitted Date  ICMJE November 3, 2017
First Posted Date  ICMJE November 9, 2017
Last Update Posted Date May 11, 2020
Actual Study Start Date  ICMJE July 30, 2018
Actual Primary Completion Date April 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 8, 2017)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 8, 2017)
  • 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.
  • 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.
  • 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
  • Change from baseline in weight [ Time Frame: Day 0 - Day 364 (Week 52) ]
  • 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) ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Trial to Evaluate the Efficacy, Safety and Tolerability of BPaMZ in Drug-Sensitive (DS-TB) Adult Patients and Drug-Resistant (DR-TB) Adult Patients
Official Title  ICMJE 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)
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)
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE 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
Condition  ICMJE
  • Tuberculosis, Pulmonary
  • Tuberculosis, Multidrug-Resistant
  • Tuberculosis, MDR
  • Tuberculosis
  • Drug-Resistant Tuberculosis
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • 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
    Interventions:
    • Drug: Pretomanid
    • Drug: Bedaquiline
    • Drug: Moxifloxacin
    • Drug: Pyrazinamide
  • 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
    Interventions:
    • Drug: HRZE
    • Drug: HR
  • 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)
    Interventions:
    • Drug: Pretomanid
    • Drug: Bedaquiline
    • Drug: Moxifloxacin
    • Drug: Pyrazinamide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 16, 2020)
455
Original Estimated Enrollment  ICMJE
 (submitted: November 8, 2017)
450
Estimated Study Completion Date  ICMJE February 22, 2022
Actual Primary Completion Date April 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Brazil,   Georgia,   Malaysia,   Philippines,   Russian Federation,   South Africa,   Tanzania,   Uganda
Removed Location Countries Ethiopia,   Thailand
 
Administrative Information
NCT Number  ICMJE NCT03338621
Other Study ID Numbers  ICMJE SimpliciTB (B-Pa-M-Z) NC-008
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Global Alliance for TB Drug Development
Study Sponsor  ICMJE Global Alliance for TB Drug Development
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Morounfolu Olugbosi, MD MSc Global Alliance for TB Drug Development
PRS Account Global Alliance for TB Drug Development
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP