Annex 2. Trial population in ZeNix and TB-PRACTECAL trials

ZeNix inclusion and exclusion criteria

Inclusion criteria

  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 a documented result can be provided, such as ELISA and/or western blot and/or electro-chemiluminescence). If HIV status is a confirmed known positive, a repeated HIV test is not needed if ELISA and/or western blot and/or electro-chemiluminescence documentation of presence of HIV infection is available.
  4. Male or female, aged 14 years and older.

Disease characteristics:

  1. Participants with one of the following pulmonary tuberculosis (TB) conditions:
    1. XDR-TB54 with:
      1. a documented culture positive or a molecular test positive (for M. tuberculosis) 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
      2. documented resistance to rifamycins, a fluoroquinolone AND an injectable during the current TB diagnosis/disease course any time prior to or during screening period (may be sensitive or resistant to isoniazid);
    2. Pre-XDR-TB55 with:
      1. 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
      2. documented resistance to rifamycins, and to a fluoroquinolone OR an injectable during the current TB diagnosis/disease course any time prior to or during screening period (may be sensitive or resistant to isoniazid);
    3. MDR-TB with:
      1. a documented 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
      2. documented resistance to rifamycins during the current TB diagnosis/disease course any time prior to or during screening period (may be sensitive or resistant to isoniazid); and
      3. 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;
    4. MDR-TB with:
      1. 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
      2. documented resistance to rifamycins during the current TB diagnosis/disease course any time prior to or during screening period (may be sensitive or resistant to isoniazid); and
      3. the inability 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 the participant eligible for the study in the investigator’s opinion.
  2. Chest X-ray within 6 months prior to or at screening, obtained and read locally by the investigator or designee with results consistent with pulmonary TB in the opinion of the investigator.

Contraception:

  1. Be of non-childbearing potential or using effective methods of birth control, as defined below: Non-childbearing potential:
    1. participant – not heterosexually active or practises sexual abstinence; or
    2. female participant or male participant’s 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 participant’s male sexual partner – vasectomized or has had a bilateral orchidectomy at least 3 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 intrauterine device for the female participant; or
  3. male participant’s female sexual partner: double barrier method or hormone-based contraceptives or an intrauterine device for the female partner;

and are willing to continue practising birth control methods throughout treatment and for 6 months (female participants) and 12 weeks (male participants) after the last dose of study medication.

Exclusion criteria

Medical history and concurrent conditions:

  1. Any condition in the investigator’s opinion (e.g. an unstable disease such as uncontrolled diabetes or cardiomyopathy, extrapulmonary 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 the 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 a participant’s safety or ability to follow through with all protocol-specified restrictions, visits and evaluations.
  3. In the judgement of the investigator, the participant 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 historic drug susceptibility testing (DST) or the minimum inhibitory concentration (MIC) results with values suggesting likely resistance to pretomanid, delamanid, linezolid or bedaquiline; the Sponsor Medical Monitor must be consulted to help interpret any available historic results.
  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:
    1. corrected QT interval by Fredericia (QTcF) interval on electrocardiogram (ECG) >500 msec. Participants with QTcF >450 must be discussed with and approved by the Sponsor Medical Monitor before enrolment (per measurements and reading done from screening central ECG);
    2. heart failure;
    3. a personal or family history of congenital QT prolongation;
    4. a history of or known, untreated, ongoing hypothyroidism;
    5. a history of or ongoing bradyarrhythmia; or
    6. a history of torsades de pointes.
  11. Females who have a positive pregnancy test at screening or are already known to be pregnant, breastfeeding or planning to conceive a child during the study or within 6 months of cessation of treatment; and 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 . Or participants with a Grade 1 or 2 neuropathy which is likely to progress or worsen over the course of the study, in the opinion of the investigator.

Previous and concomitant therapy

  1. Known (during screening) requirement for future concomitant (during treatment) use of any prohibited and/or avoided medications noted in Section 5.3 (of the trial protocol).
  2. Prior use of monoamine oxidase inhibitors (MAOIs) within 2 weeks of randomization.
  3. Prior use of serotonergic antidepressants within 3 days of randomization if the investigator foresees potential risks for serotonin syndrome when combined with linezolid.
  4. Participants who have received more than 2 weeks of bedaquiline, linezolid or delamanid prior to the first dose of IMP.
  5. Participants with newly diagnosed TB and HIV that require initiation of appropriate HIV therapy before the participant has received at least 2 weeks of an antituberculosis regimen.
  6. HIV infected participants with planned continued use of zidovudine, stavudine or didanosine. The antiretroviral therapy (ART) booster cobicistat should not be used. Please reference restrictions Section 5.3.3 (of the trial protocol) Antiretroviral Therapy, for guidance on ART treatment during the treatment period.

Diagnostic and laboratory abnormalities

  1. Participants with any of the following toxicities at screening (laboratories may be repeated during the screening period) as defined by the enhanced (DMID) adult toxicity table (November 2007):
    1. viral load >1 000 copies/mL (unless newly diagnosed HIV and not yet on ART and 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. haemoglobin <9.0 g/dL or <90 g/L;
    5. platelets <100 000/mm3 or <100 × 10^9/L;
    6. absolute neutrophil count (ANC) <1 500/mm3 or <1.5 × 10^9/L;
    7. aspartate aminotransferase (AST):
      • Grade 3 or greater (>3.0 × ULN) to be excluded;
      • results between 1.5 × ULN and 3 × ULN must be discussed with and approved by the Sponsor Medical Monitor;
    8. alanine aminotransferase:
      • Grade 3 or greater (>3.0 × ULN) to be excluded;
      • results between 1.5 × ULN and 3 × ULN must be discussed with and approved by the Sponsor Medical Monitor;
    9. total bilirubin:
      • greater than 1.5 × ULN to be excluded;
      • 1–1.5 × 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; and
    12. albumin <3.0 g/dl or <30 g/L.
TB-PRACTECAL inclusion and exclusion criteria

Inclusion criteria

  • Male or female patients aged 15 years or above (where locally approved), regardless of HIV status.
  • Microbiological test (molecular or phenotypic) confirming the presence of M. tuberculosis in sputum.
  • Resistant to at least rifampicin by either molecular or phenotypic drug susceptibility test.
  • Completed informed consent form (ICF).

Exclusion criteria

  • Known allergies, hypersensitivity or intolerance to any of the study drugs.
  • Pregnant, breastfeeding or unwilling to use appropriate contraceptive measures if of childbearing potential.
  • Alanine transaminase (ALT) and/or aspartate transaminase (AST) and/or bilirubin >3 times the upper limit of normal.
  • Taking any medications contraindicated with the medicines in the trial.
  • QTcF >450 ms.
  • One or more risk factors for QTc prolongation (excluding age and gender) or other uncorrected risk factors for torsades de pointes.
  • History of cardiac disease, syncopal episodes, symptomatic or significant asymptomatic arrhythmias (with the exception of sinus arrhythmia).
  • Any baseline laboratory value consistent with Grade 4 toxicity.
  • Moribund.
  • Known resistance to bedaquiline, pretomanid, linezolid or delamanid.
  • Any other condition (social or medical) which, in the opinion of the investigator, would make study participation unsafe.
  • Prior use of bedaquiline and/or pretomanid and/or linezolid and/or delamanid for 1 or more months.
  • Patients not eligible to start a new course of MDR-TB or XDR-TB56 treatment according to local protocol, for reasons including but not limited to:
    1. currently on MDR-TB treatment for at least 2 weeks (and not failing);
    2. no permanent physical address;
    3. loss to follow-up in previous treatment with no change in circumstance and motivation.
  • Tuberculous meningoencephalitis, brain abscesses, osteomyelitis or arthritis.

54 In 2021, the definition of XDR-TB changed (see Definitions).

55 In 2021, the definition for pre-XDR-TB changed (see Definitions).

56 In 2021, the definition for pre-XDR-TB changed (see Definitions).

Book navigation