Please select the eligibility criteria that correspond to the clinical trial below.
Title: Evaluating Newly Approved Drugs for Multidrug-resistant TB (endTB): A Clinical Trial
Brief Summary: endTB Clinical Trial a Phase III, randomized, controlled, open-label, non-inferiority, multi-country trial evaluating the efficacy and safety of five new, all-oral, shortened regimens for multidrug-resistant tuberculosis (MDR-TB).


Options:
A: Key Inclusion Criteria

1. Provide written, informed consent prior to all trial-related procedures (if under 18, include consent of legal guardian).
2. Body weight of ≥35 kg (in light clothing and no shoes).
3. Male or female, aged 14 years or above.
4. Subjects with one of the following pulmonary TB conditions (WHO definitions prior to 2021):

   a. Extensively Drug Resistant Tuberculosis (XDR-TB) with

   i. documented culture positive (for M.tb.) results within 3 months prior to screening or M.tb. confirmed in sputum based on molecular test within 3 months prior to or at screening;

   ii. documented resistance to isoniazid, rifamycins, a fluoroquinolone and an injectable historically at any time or at screening;

   b. Multi-Drug Resistant Tuberculosis (MDR-TB) documented by culture positive results (for M.tb.) within 3 months prior to or at screening 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;

   c. MDR-TB documented by culture positive (for M.tb.) results within 3 months prior to or at screening who are unable to continue second line drug regimen due to a documented intolerance to:

   i. PAS, ethionamide, aminoglycosides or fluoroquinolones;

   ii. Current treatment not listed above that renders subject eligible for the study in the Investigator's opinion.

6. Chest X-Ray picture (taken within a year prior to screening) consistent with pulmonary TB in the opinion of the Investigator.

Key Exclusion Criteria

1. Karnofsky score \< 50 within 30 days prior to entry.
2. Body Mass index (BMI) \< 17 kg/m²
3. History of allergy or known hypersensitivity to any of the trial Investigational Medicinal Products or related substances.
4. HIV infected Subjects having a CD4+ count ≤ 50 cells/μL
5. Having participated in other clinical studies with dosing of investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational study that includes treatment with medicinal agents. Subjects 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.
6. Significant cardiac arrhythmia requiring medication.
7. Subjects with the following at Screening:

   1. QTcF interval on ECG \>500 msec.
   2. History of additional risk factors for Torsade de Pointes, (e.g., heart failure, hypokalemia, family history of Long QT Syndrome);
   3. Clinically significant ventricular arrhythmias;
   4. Subjects with other cardiac abnormalities that may place them at risk of arrhythmias must be discussed with the sponsor medical monitor before enrolment. Such abnormalities include: Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome); Electrocardiographic evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; Evidence of second or third degree heart block; Intraventricular conduction delay with QRS duration more than 120 msec.
8. Females who have a positive pregnancy test at Screening or already known to be pregnant, breastfeeding, 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.
9. A peripheral neuropathy of Grade 3 or 4, according to DMID (Appendix 2). Or, subjects 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.
10. Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) or prior use within 2 weeks of treatment assignment.
11. Subjects with the following toxicities at Screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007):

    a. serum potassium less than the lower limit of normal for the laboratory; b. Hemoglobin level grade 2 or greater (\< 8.0 g/dL); c. Platelets grade 2 or greater(\<75,000/mm3); d. Absolute neutrophil count (ANC) \< 1000/ mm3; e. Aspartate aminotransferase (AST) \> 3 x ULN g. Total bilirubin \> or = to 2xULN h. Direct bilirubin \> ULN i. Serum creatinine level greater than 2 times upper limit of normal j. Albumin \<32 g/L
B: Inclusion Criteria:

* Suspected pulmonary tuberculosis plus one or both of the following: a) at least one sputum specimen positive for acid-fast bacilli on smear microscopy OR b) at least one sputum specimen positive for M. tuberculosis by Xpert MTB/RIF testing, with semiquantitative result of 'medium' or 'high' and rifamycin resistance not detected.
* Age twelve (12) years or older
* A verifiable address or residence location that is readily accessible for visiting, and willingness to inform the study team of any change of address during the treatment and follow-up period.
* Women of child-bearing potential who are not surgically sterilized must agree to practice a barrier method of contraception or abstain from heterosexual intercourse during study drug treatment.
* Documentation of HIV infection status.
* For HIV-positive individuals, CD4 T cell count greater than or equal to 100 cells/mm3 based on testing performed at or within 30 days prior to screening.
* Laboratory parameters done at or within 14 days prior to screening:

  * Serum or plasma alanine aminotransferase (ALT) less than or equal to 3 times the upper limit of normal
  * Serum or plasma total bilirubin less than or equal to 2.5 times the upper limit of normal
  * Serum or plasma creatinine level less than or equal to 2 times the upper limit of normal
  * Serum or plasma potassium level greater than or equal to 3.5 meq/L
  * Hemoglobin level of 7.0 g/dL or greater
  * Platelet count of 100,000/mm3 or greater
* For women of childbearing potential, a negative pregnancy test at or within seven (7) days prior to screening
* Karnofsky score greater than or equal to 60
* Written informed consent

Exclusion Criteria:

* Pregnant or breast-feeding.
* Unable to take oral medications.
* Previously enrolled in this study.
* Received any investigational drug in the past 3 months.
* More than five (5) days of treatment directed against active tuberculosis within 6 months preceding initiation of study drugs.
* More than five (5) days of systemic treatment with any one or more of the following drugs within 30 days preceding initiation of study drugs: isoniazid, rifampin, rifabutin, rifapentine, ethambutol, pyrazinamide, kanamycin, amikacin, streptomycin, capreomycin, moxifloxacin, levofloxacin, gatifloxacin, ofloxacin, ciprofloxacin, other fluoroquinolones, ethionamide, prothionamide, cycloserine, terizidone, para-aminosalicylic acid, linezolid, clofazimine, delamanid or bedaquiline.
* Known history of prolonged QT syndrome.
* Suspected or documented tuberculosis involving the central nervous system and/or bones and/or joints, and/or miliary tuberculosis and/or pericardial tuberculosis.
* Current or planned use within six months following enrollment of one or more of the following medications: HIV protease inhibitors, HIV integrase inhibitors, HIV entry and fusion inhibitors, HIV non-nucleoside reverse transcriptase inhibitors other than efavirenz, quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine. Individuals who are currently taking efavirenz-based antiretroviral treatment or for whom initiation of efavirenz-based antiretroviral treatment is planned within 17 weeks following enrollment may participate.
* Weight less than 40.0 kg.
* Known allergy or intolerance to any of the study medications.
* Individuals will be excluded from enrollment if, at the time of enrollment, their M. tuberculosis isolate is already known to be resistant to any one or more of the following: rifampin, isoniazid, pyrazinamide, ethambutol, or fluoroquinolones.
* Other medical conditions, that, in the investigator's judgment, make study participation not in the individual's best interest.
* Current or planned incarceration or other involuntary detention.
C: Inclusion criteria:

* Being ≥ 15 year old
* Having a positive test on GeneXpert (M. tuberculosis) with or without resistance detected to rifampicin
* Willing and able to provide written informed consent, or for minors: assent from and consent from a legal representative

Exclusion Criteria: None
D: Inclusion Criteria:

A patient will be eligible for randomization if s/he:

1. Has documented pulmonary tuberculosis due to strains of M. tuberculosis resistant to rifampin (RIF) and susceptible to fluoroquinolones, diagnosed by validated rapid molecular test;
2. Is ≥ 15 years of age;
3. Is willing to use contraception: pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilized must agree to use contraception unless their partner has had a vasectomy; men who have not had a vasectomy must agree to use condoms;
4. Provides informed consent for study participation; additionally a legal representative of patients considered minor per local laws should also provide consent;
5. Lives in a dwelling that can be located by study staff and expects to remain in the area for the duration of the study.

Exclusion Criteria:

A patient will not be eligible for randomization if s/he:

1. Has known allergies or hypersensitivity to any of the investigational drugs;
2. Is known to be pregnant or is unwilling or unable to stop breast-feeding an infant;
3. Is unable to comply with treatment or follow-up schedule;
4. Any condition (social or medical) which, in the opinion of the site principal investigator, would make study participant unsafe;
5. a. Has had exposure (intake of the drug for 30 days or more) in the past five years to bedaquiline, delamanid, linezolid, or clofazimine, or has proven or likely resistance to bedaquiline, delamanid, linezolid, or clofazimine (e.g., household contact of a DR-TB index case who died or experienced treatment failure after treatment containing bedaquiline, delamanid, linezolid, or clofazimine or had resistance to one of the listed drugs); exposure to other anti-TB drugs is not a reason for exclusion.

   b. Has received second-line drugs for 15 days or more prior to screening visit date in the current MDR/RR-TB treatment episode. Exceptions include: (1) patients whose treatment has failed according to the WHO definition151 and who are being considered for a new treatment regimen; (2) patients starting a new treatment regimen after having been "lost to follow-up" according to the WHO definition149 and, (3) patients in whom treatment failure is suspected (but not confirmed according to WHO definition), who are being considered for a new treatment regimen, and for whom the Clinical Advisory Committee (CAC) consultation establishes eligibility.
6. Has one or more of the following:

   * Hemoglobin ≤ 7.9 g/dL;
   * Uncorrectable electrolytes disorders:
   * Calcium \< 7.0 mg/dL;
   * Potassium \< 3.0 or ≥6.0 mEq/L;
   * Magnesium \< 0.9 mEq/L;
   * Serum creatinine \> 3 x ULN;
   * Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3 x ULN;
   * Total bilirubin ≥ 1.5 x ULN if accompanied by AST or ALT \> ULN or total bilirubin ≥ 2 x ULN when other liver function results are in the normal range;
   * Grade 4 result on any of the specified laboratory tests as defined by the MSF Severity Scale.
7. Has cardiac risk factors defined as:

   * A confirmed QTc interval of greater than or equal to 450 ms. Retesting to reassess eligibility will be allowed once using an unscheduled visit during the screening phase;
   * Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome);
   * Electrocardiographic evidence of either:

     * Complete left bundle branch block or right bundle branch block; OR
     * Incomplete left bundle branch block or right bundle branch block and QRS complex duration greater or equal to 120 msec on at least one ECG;
   * Having a pacemaker implant;
   * Congestive heart failure;
   * Evidence of second or third degree heart block;
   * Bradycardia as defined by sinus rate less than 50 bpm;
   * Personal or family history of Long QT Syndrome;
   * Personal history of arrhythmic cardiac disease, with the exception of sinus arrhythmia;
   * Personal history of syncope (i.e. cardiac syncope not including syncope due to vasovagal or epileptic causes).
8. Concurrent participation in another trial of any medication used or being studied for TB treatment, as defined in cited documents.
9. Is taking any medication that is contraindicated with the medicines in the trial regimen which cannot be stopped (with or without replacement) or requires a wash-out period longer than 2 weeks.

Answer: D