Please select the eligibility criteria that correspond to the clinical trial below.
Title: Multicentre Clinical Trial to Assess the Performance of the Xpert MTB/XDR Assay for INH- and Second-line Resistance Detection
Brief Summary: FIND and partners intend to address the need for a multi- and extensively drug-resistant tuberculosis (M/XDR-TB) diagnostic solution for patients in settings with a high burden of drug-resistant tuberculosis (DR-TB) though the development, evaluation and introduction of an Xpert MTB/XDR assay


Options:
A: 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.
B: Inclusion Criteria:

* Men and women of ≥18 years of age
* Presence of cough, fever, night sweats or weight loss
* Ability and willingness to give written informed consent
* Documentation of positive HIV status (test conducted at GHESKIO)
* Acceptance of HIV diagnosis, defined as affirmative responses to two questions: "I believe that HIV and AIDS exist" and "I believe that the results of my HIV test show that I am infected".

Exclusion Criteria:

* Any use of ART in the past
* Treatment for TB in the year prior to screening visit
* Pregnancy or breastfeeding at the screening visit
* Active drug, alcohol use, or mental condition that would interfere with the ability to adhere to study requirements, in the opinion of the study physician
* Score of \<3 for any of the 7 questions on the ART readiness survey
* Planning to transfer care to another clinic during the study period
* Symptoms consistent with WHO stage 4 neurologic disease (cryptococcal meningitis, TB meningitis; central nervous system toxoplasmosis; HIV encephalopathy; progressive multifocal leukoencephalopathy)
* Severe illness, classified as one of the WHO "danger signs" of temperature \>39 degrees Celsius, pulse \>120 beats/minutes, respiratory rate \>30, or inability to walk unaided.
C: 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
D: Inclusion Criteria:

* • Age 18 years or above;

  * Symptoms suggesting pulmonary TB, i.e. persistent cough (generally ≥3 weeks or as per local definition of TB suspect), and at least one of the following:

    * Previously received \>1 month of treatment for a prior TB episode or
    * Failing TB treatment with positive sputum smear or culture after ≥3 months of a standard TB treatment or
    * Had close contact with a known drug-resistant TB case or
    * Newly diagnosed with MDR-TB within the last 30 days or
    * Previously diagnosed with MDR-TB and failed TB treatment with positive sputum smear or culture after ≥3 months of a standard MDR-TB treatment regimen

Patients meeting the above criteria will be screened by Xpert MTB/RIF or Xpert MTB/RIF Ultra. TB patients meeting the following criteria will be included in the study:

* A clear Mtb-positive and RIF-resistant or RIF-sensitive result by Xpert MTB/RIF or Xpert MTB/RIF Ultra
* Provision of informed consent;
* Production of an adequate quantity (\>3mL) of sputum

Exclusion Criteria:

* Participants will be excluded from the study if informed consent is not provided.

Answer: D