NCT01785186.

Trial name or title	Evaluation of SQ109, high‐dose rifampicin, and moxifloxacin in adults with smear‐positive pulmonary TB in a MAMS design (PanACEA‐MAMS‐TB‐01)
Methods	Allocation: randomized; endpoint classification: safety/efficacy study; intervention model: single group Assignment; masking: open label; primary purpose: treatment
Participants	Age minimum: 18 years; age maximum: N/A; gender: both 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 TB 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 M. tuberculosis 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 ART, or is likely to require ART during the twelve weeks of experimental study treatment as per local guidelines, or both. 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, or diastolic blood pressure of =100 mmHg on two occasions, or both), 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. parasitaemia 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), or serum alanine aminotransferase (ALT) activity >3x the upper limit of normal, or both; 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 haemoglobin 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, or QTcF, or both, 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 to 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.
Interventions	Dietary supplement: pyridoxine Drug: ethambutol Drug: isoniazid Drug: moxifloxacin Drug: pyrazinamide Drug: rifampicin Drug: SQ109
Outcomes	Primary outcome: sputum culture conversion (2 negative cultures) using liquid media (time frame: 0 to 12 weeks) Secondary outcomes: changes in baseline laboratory safety parameters during treatment and follow‐up (time frame: 0 to 12 weeks) Frequency of adverse events (time frame: 0 to 12 weeks) Mycobacteriology identification and characterization by PCR and MIC (time frame: 0 to 12 weeks) Occurence of treatment failure (relapse or emergence of drug‐resistance) (time frame: 0 to 12 weeks) Pharmacodynamics including AUC0‐24/MIC (h*ng/mL) and Cmax/MIC (ng/mL) (time frame: 0 to 12 weeks) Pharmacokinetics including AUC, Cl, t1/2, Vd, and protein binding (time frame: 0 to 12 weeks) Proportion of negative sputum cultures (time frame: 0 to 12 weeks) Rate of change in quantitative PCR during therapy (time frame: 0 to 12 weeks) Rate of change in time to positivity (time frame: 0 to 12 weeks) Time to first negative culture on liquid and solid media (time frame: 0 to 12 weeks)
Starting date	February 2013
Contact information	Michael Hoelscher; Klinikum of the University of Munich; 0049 89 2180; hoelscher@lrz.uni‐muenchen.de
Notes	Location: South Africa, Tanzania Secondary sponsor: European and Developing Countries Clinical Trials Partnership (EDCTP), German Federal Ministry of Education and Research, Medical Research Council, Radboud University, Sequella, Inc.