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Safety and Efficacy of Various Doses and Treatment Durations of Linezolid Plus Bedaquiline and Pretomanid in Participants With Pulmonary TB, XDR-TB, Pre- XDR-TB or Non-responsive/Intolerant MDR-TB (ZeNix)

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ClinicalTrials.gov Identifier: NCT03086486
Recruitment Status : Recruiting
First Posted : March 22, 2017
Last Update Posted : September 27, 2018
Sponsor:
Information provided by (Responsible Party):
Global Alliance for TB Drug Development

Brief Summary:
To evaluate the efficacy, safety and tolerability of various doses and durations of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in participants with either pulmonary XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB.

Condition or disease Intervention/treatment Phase
Tuberculosis, Pulmonary Tuberculosis, Multidrug-Resistant Tuberculosis, MDR Tuberculosis Extensively Drug-Resistant Tuberculosis Pre-XDR-TB Drug: Pretomanid Drug: Linezolid Drug: Bedaquiline Drug: Placebo Linezolid Phase 3

Detailed Description:

A phase 3, multi-center, partially-blinded, randomized clinical trial in four parallel treatment groups. Bedaquiline and pretomanid treatment will not be blinded. Linezolid treatment dose and duration will be double-blinded.

Participants will have a screening period of up to 9 days and will be randomized to receive one of the 4 active treatment arms. Participants will be randomized to one of the four regimens in a 1:1:1:1 ratio, using an interactive web response system (IWRS) which will utilize a dynamic randomization system using minimization with a random element to allocate participants evenly across the arms by HIV status and type of TB.

Each participant will receive 26 weeks of treatment. If participant's week 16 sample remains culture positive, Investigator may consider extending current treatment to 39 weeks, in consultation with the Sponsor Medical Monitor

Participants will be followed for 78 weeks after end of treatment.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3 Partially-blinded, Randomized Trial Assessing the Safety and Efficacy of Various Doses and Treatment Durations of Linezolid Plus Bedaquiline and Pretomanid in Participants With Pulmonary Infection of Either Extensively Drug-resistant Tuberculosis (XDR-TB), Pre-XDR-TB or Treatment Intolerant or Non-responsive Multi-drug Resistant Tuberculosis (MDR-TB)
Actual Study Start Date : November 21, 2017
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Experimental: 1200mg L x 26 weeks + Pa + B + 300 mg placebo

2 linezolid 600 mg active tablets once daily for 26 weeks plus 1 placebo linezolid 300 mg half tablet once daily for 26 weeks plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks

The above treatment schemes may require modification due to toxicities as noted below. All dose modifications should be discussed with the Sponsor Medical Monitor prior to implementation, unless a pause or dose reduction is required urgently for a safety concern; the Medical Monitor should be informed within 24 hours of the change if not discussed prior to implementation

Drug: Pretomanid
200mg tablets
Other Names:
  • PA-824
  • Pa

Drug: Linezolid
Scored 600mg tablets
Other Names:
  • L
  • Lin
  • Zyvox

Drug: Bedaquiline
100mg tablets
Other Names:
  • TMC-207
  • B
  • Sirturo

Drug: Placebo Linezolid
Scored 600 mg tablets

Experimental: 1200 mg L x 9 weeks + Pa + B + 300 mg placebo

2 linezolid 600 mg active tablets once daily for 9 weeks, 1 placebo linezolid 300 mg half tablet once daily for 9 weeks (for Weeks 1-9); 2 placebo linezolid 600 mg tablets once daily for 17 weeks, 1 placebo linezolid 300 mg half tablet once daily for 17 weeks (for Weeks 10-26) plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks

The above treatment schemes may require modification due to toxicities as noted below. All dose modifications should be discussed with the Sponsor Medical Monitor prior to implementation, unless a pause or dose reduction is required urgently for a safety concern; the Medical Monitor should be informed within 24 hours of the change if not discussed prior to implementation

Drug: Pretomanid
200mg tablets
Other Names:
  • PA-824
  • Pa

Drug: Linezolid
Scored 600mg tablets
Other Names:
  • L
  • Lin
  • Zyvox

Drug: Bedaquiline
100mg tablets
Other Names:
  • TMC-207
  • B
  • Sirturo

Drug: Placebo Linezolid
Scored 600 mg tablets

Experimental: 600 mg L x 26 weeks + Pa + B + 300 mg placebo

1 linezolid 600 mg active tablet once daily for 26 weeks, 1 placebo linezolid 600 mg tablet once daily for 26 weeks, 1 placebo linezolid 300 mg half tablet once daily for 26 weeks plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks

The above treatment schemes may require modification due to toxicities as noted below. All dose modifications should be discussed with the Sponsor Medical Monitor prior to implementation, unless a pause or dose reduction is required urgently for a safety concern; the Medical Monitor should be informed within 24 hours of the change if not discussed prior to implementation

Drug: Pretomanid
200mg tablets
Other Names:
  • PA-824
  • Pa

Drug: Linezolid
Scored 600mg tablets
Other Names:
  • L
  • Lin
  • Zyvox

Drug: Bedaquiline
100mg tablets
Other Names:
  • TMC-207
  • B
  • Sirturo

Drug: Placebo Linezolid
Scored 600 mg tablets

Experimental: 600 mg L x 9 weeks + Pa + B + 300 mg placebo

1 linezolid 600 mg active tablets once daily for 8 weeks, 1 placebo linezolid 600 mg half tablet once daily for 9 weeks, 1 placebo linezolid 300 mg half tablet once daily for 9 weeks (for Weeks 1-9); 2 placebo linezolid 600 mg tablets once daily for 17 weeks, 1 placebo linezolid 300 mg half tablet once daily for 17 weeks (for Weeks 10-26) plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks

The above treatment schemes may require modification due to toxicities as noted below. All dose modifications should be discussed with the Sponsor Medical Monitor prior to implementation, unless a pause or dose reduction is required urgently for a safety concern; the Medical Monitor should be informed within 24 hours of the change if not discussed prior to implementation

Drug: Pretomanid
200mg tablets
Other Names:
  • PA-824
  • Pa

Drug: Linezolid
Scored 600mg tablets
Other Names:
  • L
  • Lin
  • Zyvox

Drug: Bedaquiline
100mg tablets
Other Names:
  • TMC-207
  • B
  • Sirturo

Drug: Placebo Linezolid
Scored 600 mg tablets




Primary Outcome Measures :
  1. Incidence of bacteriologic failure or relapse or clinical failure through follow up until 26 weeks after the end of treatment [ Time Frame: 26 weeks ]
    Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days apart.


Secondary Outcome Measures :
  1. Incidence of bacteriologic failure or relapse or clinical failure through follow up until 78 weeks after the end of treatment. [ Time Frame: 78 weeks ]
    Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days apart.

  2. Time to sputum culture conversion to negative status through the treatment period [ Time Frame: 26 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

  3. Proportion of participants with sputum culture conversion to negative status at week 4 [ Time Frame: 4 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

  4. Proportion of participants with sputum culture conversion to negative status at week 6 [ Time Frame: 6 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

  5. Proportion of participants with sputum culture conversion to negative status at week 8 [ Time Frame: 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

  6. Proportion of participants with sputum culture conversion to negative status at week 12 [ Time Frame: 12 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

  7. Proportion of participants with sputum culture conversion to negative status at week 16 [ Time Frame: 16 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

  8. Proportion of participants with sputum culture conversion to negative status at week 26 [ Time Frame: 26 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

  9. Change from baseline TB symptoms [ Time Frame: 26 weeks ]
    Severity of symptoms compared to start of treatment

  10. Change from baseline in Patient Reported Health Status [ Time Frame: 26 weeks ]
    Comparison of Patient Reported Health Status to start of treatment

  11. Change from baseline weight. [ Time Frame: 26 weeks ]
    Comparison of weight from start of treatment until end of treatment



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.


Ages Eligible for Study:   14 Years and older   (Child, 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. Provide written, informed consent prior to all trial-related procedures (including any additional consent required for participants considered as minors per applicable regulatory authority or ethics committee).
  2. Willingness and ability to attend scheduled follow-up visits and undergo study assessments
  3. HIV testing (if an HIV test was performed within 1 month prior to screening, it should not be repeated as long as documentation can be provided [ELISA and/or Western Blot]. If HIV status is a confirmed known positive, repeated HIV test is not needed provided documentation is available.
  4. Male or female, aged 14 years or older.

    Disease Characteristics:

  5. Participants with one of the following pulmonary TB conditions:

    a. XDR-TB with i. A documented culture positive or a molecular test positive (for MTB) from a sputum specimen collected within 3 months prior to screening or MTB confirmed in sputum based on molecular test within 3 months prior to or at screening and: ii. historical documented resistance to isoniazid, rifamycins, a fluoroquinolone AND an injectable during the current TB diagnosis/disease course; b. Pre-XDR-TB with i. A documented culture positive or a molecular test positive (for MTB) from a sputum specimen collected within 3 months prior to screening or MTB confirmed in sputum based molecular test within 3 months prior to or at screening and; ii. historical documented resistance to isoniazid, rifamycins, and to a fluoroquinolone OR an injectable during the current TB diagnosis/disease course.

    c. MDR-TB with i. documented by culture positive or a molecular test positive (for MTB) from a sputum specimen collected results within 3 months prior to screening or MTB confirmed in sputum based on molecular test within 3 months prior to or at screening and; ii. historical documented resistance to isoniazid and rifamycins during the current TB diagnosis/disease course; iii. with documented non-response to treatment with the best available regimen for 6 months or more prior to enrolment who in the opinion of the Investigator have been adherent to treatment and will be adherent to study regimen.

    d. MDR-TB with i. documented by culture positive or a molecular test positive (for MTB) from a sputum specimen collected within 3 months prior to screening or MTB confirmed in sputum based on molecular test within 3 months prior to or at screening and: ii. historical documented resistance to isoniazid and rifamycins during the current TB diagnosis/disease course and; iii. who are unable to continue second line drug regimen due to a documented intolerance to:

    1. PAS, ethionamide, aminoglycosides or fluoroquinolones or ;
    2. Current treatment not listed above that renders participant eligible for the study in the Investigator's opinion.
  6. Chest X-Ray within one month prior to screening, obtained and read locally by investigator or designee with results consistent with pulmonary TB in the opinion of the Investigator.

    Contraception:

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

Non-childbearing potential:

  1. Participant - not heterosexually active or practices sexual abstinence; or
  2. Female participant/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/sexual partner - vasectomised or has had a bilateral orchidectomy at least three months prior to Screening.

Effective birth control methods:

A double contraceptive method should be used as follows:

  1. Double barrier method which can include any 2 of the following: a male condom, diaphragm, cervical cap, or female condom (male and female condoms should not be used together); or
  2. Barrier method (one of the above) combined with hormone-based contraceptives or an intra-uterine device for the female participant/partner;

And are willing to continue practicing birth control methods throughout treatment and for 6 months (both male and female participants) after the last dose of study medication.

Exclusion Criteria:

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

Medical History and Concurrent Conditions

  1. Any condition in the Investigator's opinion (i.e., an unstable disease such as uncontrolled diabetes or cardiomyopathy, extra-pulmonary TB requiring extended treatment, cancer that could affect survival through the protocol-specified follow up period), where participation in the trial would compromise the well-being of participant or prevent, limit or confound protocol specified assessments.
  2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would compromise the participants' safety or ability to follow through with all protocol-specified restrictions, visits and evaluations.
  3. In the judgment of the Investigator, the patient is not expected to survive for more than 6 months.
  4. Karnofsky score < 60 at screening.
  5. History of allergy or known hypersensitivity to any of the trial Investigational Medicinal Products or related substances.
  6. Body mass index (BMI) < 17 kg/m2
  7. TB infection with known resistance to pretomanid, delamanid, linezolid or bedaquiline.
  8. Participants who, upon the evaluation of their pulmonary disease, are expected to require a surgical procedure.
  9. Having participated in other clinical studies with dosing of investigational agents within 8 weeks prior to screening or currently enrolled in an investigational study that includes treatment with medicinal agents. Participants who are participating in observational studies or who are in a follow up period of a trial that included drug therapy may be considered for inclusion.
  10. Participants with any of the following at Screening:

    • QTcF interval on ECG >500 msec. Participants with QTcF > 450 must be discussed with the Sponsor Medical Monitor before enrolment.
    • Heart failure
    • A personal or family history of congenital QT prolongation
    • A history of or known, untreated, ongoing hypothyroidism
    • A history of or ongoing bradyarrhythmia
    • A history of Torsade de Pointe
  11. Females who have a positive pregnancy test at Screening or already known to be pregnant, breast-feeding, or planning to conceive a child during the study or within 6 months of cessation of treatment. Males planning to conceive a child during the study or within 6 months of cessation of treatment.
  12. A peripheral neuropathy of Grade 3 or 4, according to DMID (Appendix 2). Or, participants with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the course of the study, in the opinion of the Investigator.

    Previous and Concomitant Therapy

  13. Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) or prior use within 2 weeks of randomization.
  14. Concomitant use of serotonergic antidepressants or prior use within 3 days of randomization if Investigator foresees potential risks for serotonin syndrome when combined with linezolid.
  15. Concomitant use of any drug known to prolong QTc interval (including, but not limited to, amiodarone, bepridil, chloroquine, chlorpromazine, cisapride, cyclobenzaprine, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, fluoroquinolones, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine).
  16. Concomitant use of any drug known to induce myelosuppression.
  17. Concomitant use of any drugs or substances known to be strong inhibitors or inducers of cytochrome P450 enzymes (including but not limited to efavirenz, quinidine, tyramine, ketoconazole, fluconazole, testosterone, quinine, gestodene, metyrapone, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine, dextromethorphan). Exceptions may include use of lopinavir/ritonavir regimen as noted in section 5.3.3.
  18. Participants who have received more than 2 weeks of bedaquiline, linezolid or delamanid prior to first dose of IMP.
  19. Participants with an existing TB diagnosis (a diagnosis made > 4 weeks prior to screening) and HIV co-infection, must have been on an ART for at least 4 weeks prior to screening.
  20. Participants with newly diagnosed tuberculosis and HIV may be enrolled provided that appropriate HIV therapy will not be initiated until participant has received at least 2 weeks of study medication.
  21. HIV infected participants: the following antiretroviral therapies should not be used: zidovudine, stavudine, didanosine. The antiretroviral therapy (ART) booster cobicistat should not be used. Please reference restrictions Section 5.3.3 Antiretroviral Therapy, for guidance on ART treatment during the treatment period.

    Diagnostic and Laboratory Abnormalities

  22. Participants with any of the following toxicities at Screening (labs may be repeated during screening period) as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007):

    1. Viral load >1000 IU/ml (Unless newly diagnosed HIV and not yet on ART who otherwise qualify for participation);
    2. CD4+ count < 100 cells/µL (HIV positive participants);
    3. Serum potassium less than the lower limit of normal for the laboratory;
    4. Hemoglobin < 9.0 g/dL;
    5. Platelets <100,000/mm3;
    6. Absolute neutrophil count (ANC) < 1500/ mm3;
    7. Aspartate aminotransferase (AST)

      • Grade 3 or greater (> 3.0 x ULN) to be excluded;
      • Results between 1.5 x ULN and 3 x ULN must be discussed with and approved by the Sponsor Medical Monitor
    8. Alanine aminotransferase

      • Grade 3 or greater (> 3.0 x ULN) to be excluded;
      • Results between 1.5 x ULN and 3 x ULN must be discussed with and approved by the Sponsor medical monitor;
    9. Total bilirubin

      • greater than 1.5 x ULN to be excluded;
      • 1-1.5 x ULN must be discussed with and approved by the Sponsor Medical Monitor
    10. Direct bilirubin

      • Greater than ULN to be excluded

    11. Serum creatinine level greater than 1.5 times upper limit of normal
    12. Albumin <3.0 mg/dl

All inclusion and no exclusion criteria must be met. If no single variable/value is outside of the ranges of acceptability, but when multiple values are close to the limits and/or whenever the Investigator has reason to suspect that there might be a health problem (other than TB), enrolment should only be considered after discussing the case with the sponsor medical monitor.


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): NCT03086486


Contacts
Contact: Erica Egizi 1 212 227 7540 erica.egizi@tballiance.org
Contact: Dan Everitt 1 212 227 7540 dan.everitt@tballiance.org

Locations
Georgia
National Center for Tuberculosis and Lung Diseases Recruiting
Tbilisi, Georgia, 0101
Contact: Lali Mikiashvili         
Principal Investigator: Lali Mikiashvili         
Moldova, Republic of
Institute of Phthisiopneumology Chiril Draganiuc Not yet recruiting
Chisinau, Moldova, Republic of, 2025
Contact: Elena Tudor, MD         
Principal Investigator: Elena Tudor, MD         
Russian Federation
Central TB Research Institute of the Federal Agency of Scientific Organizations Moscow Not yet recruiting
Moscow, Russian Federation, 107564
Contact: Tatevik Bagdasaryan         
Principal Investigator: Tatevik Bagdasaryan         
Research Institute of Phthisiopulmonology of I.M. Sechenov First Moscow State Medical University Not yet recruiting
Moscow, Russian Federation
Contact: Anastasia Samoilova         
Principal Investigator: Anastasia Samoilova         
FSBI "Saint-Petersburg Research Institute of Phthisiopulmonology" Recruiting
Saint Petersburg, Russian Federation, 191036
Contact: Petr Yablonskiy, MD         
Principal Investigator: Petr Yablonskiy, MD         
Ural Research Institute of Phthisiopulmonology Not yet recruiting
Yekaterinburg, Russian Federation, 620039
Contact: Sergey Skornyakov, MD         
Principal Investigator: Sergey Skornyakov, MD         
South Africa
Tshepong Hospital Recruiting
Klerksdorp, North - West, South Africa, 2574
Contact: Ebrahim Variava         
Principal Investigator: Ebrahim Variava         
King DinuZulu Hospital Complex Recruiting
Durban, South Africa, 4015
Contact: Nosipho Ngubane         
Principal Investigator: Nosipho Ngubane         
Clinical HIV Research Unit (CHRU) Sizwe Tropical Diseases Hospital Recruiting
Johannesburg, South Africa, 2131
Contact: Pauline Howell, MD         
Principal Investigator: Pauline Howell, MD         
Empilweni TB Hospital Not yet recruiting
Johannesburg, South Africa, 2194
Contact: Francesca Conradie, MBBS         
Principal Investigator: Francesca Conradie, MBBS         
Sponsors and Collaborators
Global Alliance for TB Drug Development

Responsible Party: Global Alliance for TB Drug Development
ClinicalTrials.gov Identifier: NCT03086486     History of Changes
Other Study ID Numbers: ZeNix (B-Pa-L) NC-007
First Posted: March 22, 2017    Key Record Dates
Last Update Posted: September 27, 2018
Last Verified: February 2018
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
Multi Drug-Resistant Tuberculosis
Extensively Drug-Resistant Tuberculosis
Drug-Resistant Tuberculosis
Pretomanid
PA-824
Bedaquiline
Linezolid
NC-007
TB Alliance
pre-XDR-TB

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Multidrug-Resistant
Tuberculosis, Pulmonary
Extensively Drug-Resistant Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Linezolid
Bedaquiline
Diarylquinolines
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antitubercular Agents