Please select the eligibility criteria that correspond to the clinical trial below.
Title: TBTC Study 28: Evaluation of a Moxifloxacin-based, Isoniazid-sparing Regimen for Tuberculosis Treatment
Brief Summary: This double-blind, randomized controlled trial evaluates moxifloxacin versus isoniazid in daily treatment during the first two months of treatment with rifampin, pyrazinamide and ethambutol for sputum smear-positive pulmonary tuberculosis.


Options:
A: Inclusion Criteria:

* Signed written consent or witnessed oral consent in the case of illiteracy, before undertaking any trial related activity.
* Two sputum specimens positive for tubercle bacilli on smear microscopy at least one of which must be processed and positive at the study laboratory.
* Aged 18 years or over.
* No previous anti-tuberculosis chemotherapy.
* A firm home address 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.
* Agreement to participate in the study and to give a sample of blood for HIV testing (see appendices 1 \& 2).
* Pre-menopausal women must be using a barrier form of contraception or be surgically sterilised or have an IUCD in place.
* Laboratory parameters performed up to 14 days before enrolment.

  * Serum aspartate transaminase (AST) and alanine transaminase (ALT) activity less than 3 times the upper limit of normal.
  * Serum total bilirubin level less than 2.5 times upper limit of normal. Creatinine clearance (CrCl) level greater than 30 mls/min.
  * Haemoglobin level of at least 7.0 g/dL.
  * Platelet count of at least 50x109cells/L.
  * Serum potassium greater than 3.5 mmol/L.
* Negative pregnancy test (women of childbearing potential).

Exclusion Criteria:

* Unable to take oral medication.
* Previously enrolled in this study.
* Received any investigational drug in the past 3 months.
* Received an antibiotic active against M. tuberculosis in the last 14 days (fluoroquinolones, macrolides, standard anti-tuberculosis drugs).
* Any condition that may prove fatal during the first two months of the study period.
* TB meningitis or other forms of severe tuberculosis with high risk of a poor outcome
* Pre-existing non-tuberculosis disease e.g. diabetes, liver or kidney disease, blood disorders,peripheral neuritis, chronic diarrhoeal disease in which the current clinical condition of the patient is likely to prejudice the response to, or assessment of treatment.
* Pregnant or breast feeding.
* Suffering from a condition likely to lead to uncooperative behaviour e.g. psychiatric illness or alcoholism.
* Contraindications to any medications in the study regimens.
* Known to have congenital or sporadic syndromes of QTc prolongation or receiving concomitant medication reported to increase the QTc interval (e.g. amiodarone, sotalol, disopyramide, quinidine, procainamide, terfenadine).
* Known allergy to any fluoroquinolone antibiotic or history of tendinopathy associated with quinolones.
* Patients already receiving anti-retroviral therapy.
* Patients whose initial isolate is shown to be multiple drug resistant (i.e. resistant to rifampicin and isoniazid) or monoresistant to rifampicin, or resistant to any fluoroquinolone)
* Weight less than 35kg
* HIV infection with CD4 count less than 250 cells/µL.
* End stage liver failure (class Child-Pugh C).
B: Inclusion Criteria:

* Provide written, informed consent prior to all trial-related procedures
* Male and female participants aged between 18 and 64 years, inclusive.
* Either mycobacterial culture of sputum positive for growth of Mycobacterium tuberculosis or sputum smear positive for acid fast bacilli within 60 days prior to the expected date of enrollment.
* Participant with TB caused by isolates of Mycobacterium tuberculosis complex confirmed to be resistant to treatment with isoniazid and rifampicin, or with positive rapid test for rifampicin resistance on direct sputum positive for acid fast bacilli within 60 days prior to the expected date of enrollment.
* Findings on chest radiograph consistent with TB.
* Able to produce sputum for mycobacterial culture.
* Female participants of childbearing potential must have a negative urine pregnancy test and agree to use a highly effective method of birth control (for example, two of the following precautions: tubal ligation, vaginal diaphragm, intrauterine device, oral contraceptives, contraceptive implant, combined hormonal patch, combined injectable contraceptive or depot-medroxyprogesterone acetate) throughout the participation in the trial and for 22 weeks after last dose (to cover duration of ovulation).
* Male participants must agree to use an adequate method of contraception (double barrier) throughout the participation in the trial and for 30 weeks after last dose (to cover duration of spermatogenesis).

Exclusion Criteria:

* A history of allergy to any nitro-imidazoles or nitro-imidazole derivates at any time.
* Use of the medications including: use of amiodarone at any time during the previous 12 months, use of other anti-arrhythmics for the previous 30 days, and use of certain other medications, including certain anti-depressants, anti-histamines, and macrolides, for the previous 14 days.
* Any current serious concomitant conditions or renal impairment characterized by serum creatinine levels ≥265 micromol/L or hepatic impairment characterized by alanine transaminase (ALT) and/or aspartate transferase (AST) levels 3 times the upper limit of the laboratory reference range.
* Current clinically relevant changes in the electrocardiogram (ECG) such as any atrioventricular (AV) block, prolongation of the QRS complex over 120 milliseconds (in both male and female participants), or of either the QT interval corrected by Fridericia's formula (QTcF) or QT interval corrected by Bazett's formula (QTcB) interval over 430 milliseconds in male participants and 450 milliseconds in female participants.
* Current clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction.
* For participants with human immunodeficiency virus (HIV) infection, cluster of differentiation 4 helper/inducer T cell\[s\] (CD4) cell count \< 350/mm3 or on treatment with anti-retroviral medication for HIV infection.
* Karnofsky score \< 60%.
* Any diseases or conditions in which the use of nitro-imidazoles or nitro-imidazole derivates is contra-indicated.
* Evidence of clinically significant metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied).
* Known or suspected alcohol abuse, that is, abuse sufficient enough to compromise the safety or cooperation of the participant in the opinion of the investigator.
* Administered an investigational medicinal product (IMP) within 1 month prior to Visit 1 (Screening \[Days -9 to -3\]).
* Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described in the informed consent form.
* Recent use of methadone, benzodiazepines, cocaine, amphetamine/metamphetamine, tetrahydrocannabinol, barbiturates, tricyclic antidepressants, and opiates as determined by a urine drug screen unless evidence is provided that the positive drug screen is the result of authorized medications products prescribed by a physician for a non-abuse-related indication.
* Any disorder that in the judgment of the investigator makes the participant not a good candidate for the trial or may prevent the participant from reliably participating in the entire course of the trial.
C: Inclusion Criteria:

* Suspected pulmonary tuberculosis with acid-fast bacilli in a stained smear of expectorated or induced sputum. Patients whose sputum cultures do not grow M. tuberculosis and those having an M. tuberculosis isolate resistant to (one or more) isoniazid, rifampin, fluoroquinolones, will be discontinued from the study, but followed for 14 days to detect late toxicities from study therapy. Patients having extra-pulmonary manifestations of tuberculosis, in addition to smear-positive pulmonary disease, are eligible for enrollment. Sputum must be expectorated or induced; smear results from respiratory secretions obtained by bronchoalveolar lavage or bronchial wash may not be used for assessment of study eligibility.
* Willingness to have HIV testing performed, if HIV serostatus is not known or if the last documented negative HIV test was more than 6 months prior to enrollment. HIV testing does not need to be repeated if there is written documentation of a positive test (positive ELISA and Western Blot or a plasma HIV-RNA level greater than 5000 copies/ml) at any time in the past.
* 7 (seven) or fewer days of multidrug therapy for tuberculosis disease in the 6 months preceding enrollment.
* 7 (seven) or fewer days of fluoroquinolone therapy in the 3 months preceding enrollment.
* Age \> 18 years
* Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs; see Appendix B).
* Signed informed consent
* Women with child-bearing potential must agree to practice an adequate (barrier) method of birth control or to abstain from heterosexual intercourse during study therapy.
* Laboratory parameters done at, or \<14 days prior to, screening:
* Serum amino aspartate transferase (AST) activity ≤ 3 times the upper limit of normal
* Serum total bilirubin level ≤ 2.5 times the upper limit of normal
* Serum creatinine level ≤ 2 times the upper limit of normal
* Complete blood count with hemoglobin level of at least 7.0 g/dL
* Complete blood count with platelet count of at least 50,000/mm3
* Serum potassium \> 3.5 meq/L
* Negative pregnancy test (women of childbearing potential)

Exclusion Criteria:

* Breast-feeding
* Known intolerance to any of the study drugs
* Known allergy to any fluoroquinolone antibiotic
* Concomitant disorders or conditions for which moxifloxacin (MXF), isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), or ethambutol (EMB) are contraindicated. These include severe hepatic damage, acute liver disease of any cause, and acute uncontrolled gouty arthritis.
* Current or planned therapy during the intensive phase of therapy using drugs having unacceptable interactions with rifampin (rifabutin can be substituted for rifampin during the continuation phase of therapy).
* Current or planned antiretroviral therapy during the intensive phase of therapy.
* History of prolonged QT syndrome or current or planned therapy with quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine during the intensive phase of therapy.
* Pulmonary silicosis
* Central nervous system TB
D: Inclusion Criteria:

* Presumptive diagnosis of smear-positive pulmonary TB within 2 weeks of study entry. Patients with both pulmonary and extrapulmonary disease are eligible.
* Documentation of HIV infection status. If HIV status is unknown at study entry, the participant must consent to testing and results must be available prior to study participation.
* Agree to use acceptable methods of contraception

Exclusion Criteria:

* History of adverse drug reaction to MOX, INH, RIF, PZA, or EMB
* Disease or condition for which MOX, INH, RIF, PZA, or EMB is contraindicated
* History of more than 14 days of continuous antituberculosis therapy during the previous 2 years or more than 2 months of antituberculosis therapy ever
* Active AIDS-related opportunistic infection or malignancy
* Currently receiving or planning to receive HIV protease inhibitors or nonnucleoside reverse transcriptase inhibitors in the first 2 months after study entry
* Silicotuberculosis
* Central nervous system TB
* Pregnant or breastfeeding
* Unable to take oral medication
* Electrocardiogram (EKG) QTc interval greater than 450 msec
* Taking classes IA or III antiarrhythmic agents (quinidine, procainamide, amiodarone, sotalol), cisapride, erythromycin, perphenazine/amitriptyline, phenothiazines, or tricyclic antidepressant
* Diseases or conditions for which treatment with other drugs with antituberculosis activity (e.g., rifabutin for MAC prophylaxis) is anticipated during the course of the study

Answer: C