Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised Placebo - Controlled Double Blind Trial Comparing 1) a Two Month Intensive Phase of Ethambutol, Moxifloxacin, Rifampicin, Pyrazinamide Versus the Standard Regimen (Ethambutol, Isoniazid, Rifampicin, Pyrazinamide) and 2) a Treatment Shortening Regimen Comparing Two Months Moxifloxacin, Isoniazid, Rifampicin, Pyrazinamide Followed by Two Months Moxifloxacin, Isoniazid, Rifampicin Versus the Standard Regimen (Two Months Ethambutol, Isoniazid, Rifampicin, Pyrazinamide Followed by Four Months Isoniazid and Rifampicin) for the Treatment of Adults With Pulmonary Tuberculosis
Brief Summary: REMoxTB is a study for the "Rapid Evaluation of Moxifloxacin in the treatment of sputum smear positive tuberculosis". REMoxTB aims to find and evaluate new drugs and regimens that shorten the duration of tuberculosis therapy.

The purpose of REMoxTB is to evaluate the efficacy, safety and acceptability of two moxifloxacin-containing treatment combinations to determine whether substituting ethambutol with moxifloxacin in one combination, and/or substituting isoniazid with moxifloxacin in another combination, makes it possible to reduce the duration of treatment for TB.


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:

* 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
C: Inclusion Criteria

1. The patient has given free, signed written or witnessed oral informed consent for study participation prior to all trial-related procedures, including HIV testing if HIV serostatus is not known or the last documented negative is more than four weeks ago.
2. The patient has a diagnosis of pulmonary tuberculosis from a health clinic established by sputum smear and/or GeneXpert MTB/RIF® and/or chest X-ray.
3. An adequate sputum bacterial load is confirmed by a Ziehl-Neelsen stained smear in the study laboratory, done from concentrated sputum found at least 1+ on the IUATLD/WHO scale.
4. The patient has a valid rapid test result (GeneXpert MTB/RIF®) from the sputum positive for MTB complex, and indicating susceptibility to Rifampicin. This test must be done in the study laboratory.
5. The patient is aged at least 18 years at the day of informed consent.
6. The patient has a body weight in light clothing and without shoes of at least 35 kg, but not more than 90 kg.
7. Female patients of childbearing potential must have a negative serum pregnancy test, and consent to practise an effective method of birth control until week 26. Effective birth control for female patients has to include two methods, including methods that the patient's sexual partner(s) use. At least one must be a barrier method. Female patients are considered not to be of childbearing potential if they are post-menopausal with no menses for the last 12 months, or surgically sterile (this condition is fulfilled by bilateral oophorectomy, hysterectomy, and by tubal ligation which is done at least 12 months prior to enrolment).
8. Male patients must consent to use an effective contraceptive method, if their sexual partner(s) is/are of childbearing potential, and if they are not surgically sterile (see 6.). Contraception by male participants must be practised until at least week 24 to cover the period of spermatogenesis. Contraceptive methods used by male participants may include hormonal methods used by the partner(s).
9. The patient has a firm home address that is readily accessible for visiting and willingness to inform the study team of any change of address during trial participation, or will be compliant to study schedule, in the discretion of the investigator.

Exclusion Criteria

1. Circumstances that raise doubt about free, uncoerced consent to study participation (e.g. in a prisoner or mentally handicapped person)
2. Poor General Condition where delay in treatment cannot be tolerated or death within three months is likely.
3. The patient is pregnant or breast-feeding.
4. The patient has an HIV infection and is receiving antiretroviral treatment (ART), and/or is likely to require ART during the twelve weeks of experimental study treatment as per local guidelines.
5. The patient has a known intolerance to any of the study drugs, or concomitant disorders or conditions for which SQ109, rifampicin, moxifloxacin, or standard TB treatment are contraindicated.
6. The patient has an history or evidence of clinically relevant metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or any other condition that will influence treatment response, study adherence or survival in the judgement of the investigator, especially:

   clinically significant evidence of severe TB (e.g. miliary TB, TB meningitis. Limited lymph node involvement will not lead to exclusion); serious lung conditions other than TB or severe respiratory impairment in the discretion of the investigator; neuropathy, epilepsy or significant psychiatric disorder; uncontrolled and/or insulin-dependent diabetes; cardiovascular disease such as myocardial infarction, heart failure, coronary heart disease, uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure of ≥100 mmHg on two occasions), arrhythmia, or tachyarrhythmia; long QT syndrome (see criterion 9.), or family history of long QT syndrome or sudden death of unknown or cardiac-related cause; Plasmodium spp. parasitemia as indicated by thick blood smear or a positive rapid test present at screening; Alcohol or other drug abuse that is sufficient to significantly compromise the safety or cooperation of the patient, includes substances prohibited by the protocol, or has led to significant organ damage at the discretion of the investigator.
7. History of previous TB within the last five years.
8. Laboratory: at screening one or more of the following abnormalities were observed for the patient in screening laboratory: Serum amino aspartate transferase (AST) and/or serum alanine aminotransferase (ALT) activity \>3x the upper limit of normal; Serum total bilirubin level \>2.5 times the upper limit of normal; Creatinine clearance (CrCl) level lower than 30 mls/min; Complete blood count with hemoglobin level \<7.0 g/dL; Platelet count \<50,000/mm3; Serum potassium below the lower level of normal;
9. ECG findings in the screening ECG: QTcB and/or QTcF of \>0.450 s; atrioventricular (AV) block with PR interval \> 0.20 s; prolongation of the QRS complex over 120 milliseconds; other changes in the ECG that are clinically relevant as per discretion of the investigator.
10. The patient has had treatment with any other investigational drug within 1 month prior to enrolment, or enrolment into other clinical (intervention) trials is planned during week 1-26
11. Previous anti-TB treatment: the patient has had previous treatment with drugs active against M. tuberculosis within the last 3 months, including but not limited to INH, EMB, RIF, PZA, amikacin, cycloserine, rifabutin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, thioacetazone, capreomycin, fluoroquinolones, thioamides.
12. QT prolonging medications: Administration within 30 days prior to study start, anticipated administration during the study period, or during the 12 weeks of experimental treatment, of any QT-prolonging agents such as, but not limited to, azithromycin, bepridil chloroquine, chlorpromazine, cisapride, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, lumefantrine, mefloquine, mesoridazine, methadone, moxifloxacin, pentamidine, pimozide, procainamide, quinidine, quinine, roxithromycin, sotalol, sparfloxacin, terfenadine, thioridazine. Exceptions may be made for participants who have received 3 days or less of one of these drugs or substances, if there has been a wash-out period equivalent to at least 5 half-lives of that drug or substance.

    Patients who have ever received amiodarone will be excluded from study participation.
13. CYP 450 inducers/inhibitors: administration within 30 days prior to dosing, or planned administration until the end of week 12, of any drug(s) or substance(s) known to be strong inhibitors or inducers of cytochrome P450 enzymes, or specific inhibitors/inducers of SQ109-metabolizing enzymes as Exceptions may be made for subjects that have received 3 days or less of one of these drugs or substances, if a wash-out period equivalent to at least 5 half-lives of that drug or substance prior to study treatment is granted.
D: Inclusion Criteria:

* Presumptive diagnosis of sputum smear-positive pulmonary TB.
* Age: ≥18 years
* Seven (7) or fewer days of multidrug therapy for TB disease in the preceding 6 months.
* Seven (7) or fewer days of fluoroquinolone therapy in the preceding 3 months.
* Documentation of HIV infection status.
* For HIV seropositive individuals, a CD4 T lymphocyte count of greater than or equal to 200 cells/mm3.
* Documentation of study baseline laboratory parameters done at, or ≤ 14 days prior to screening:

  * AST less than or equal to 2.5 times upper limit of normal.
  * Total bilirubin level less than 2.5 times upper limit of normal.
  * Creatinine level less than 2 times upper limit of normal.
  * Hemoglobin level of at least 8.0 g/dl.
  * Platelet count of at least 75,000 mm3.
  * Potassium level of at least 3.5.
  * Negative pregnancy test (women of childbearing potential).
* Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs).
* Male or nonpregnant, nonnursing female.
* Provision of informed consent.

Exclusion Criteria:

* CD4 count \< 200 cells/cu mm.
* Presence of active AIDS-related opportunistic infection (other than TB) or active AIDS-related malignancy.
* Known intolerance to any of the study drugs.
* Concomitant disorders or conditions for which any of the study drugs is contraindicated. These include severe hepatic damage, acute liver disease of any cause, and acute uncontrolled gouty arthritis.
* Inability to take oral medication.
* Central nervous system TB.
* Pulmonary silicosis.
* Current or planned therapy, during study phase (intensive phase of TB treatment), with any one or more of the following drugs: quinidine, procainamide, amiodarone, sotalol, disopyramide, terfenadine, cisapride, erythromycin, clarithromycin, phenothiazines, haloperidol, olanzapine, ziprasidone, tricyclic antidepressants, chronic corticosteroids administered either orally or intravenously, chronic fluconazole,chronic itraconazole, chronic ketoconazole, oral or intravenous tacrolimus, oral or intravenous cyclosporine, HIV protease inhibitor, HIV non-nucleoside reverse transcriptase inhibitor.
* Concurrent severe and/or uncontrolled medical or psychiatric condition that, in the opinion of the investigator, could cause unacceptable safety risks or compromise compliance with the protocol.
* Unable or unwilling to receive directly observed therapy and/or adhere with follow-up (e.g. due to residence remote from the study site).
* Refusal of consent.

Answer: A