Evaluation of SQ109, High-dose Rifampicin, and Moxifloxacin in Adults With Smear-positive Pulmonary TB in a MAMS Design
Evaluation of SQ109, High-dose Rifampicin, and Moxifloxacin in Adults With Smear-positive Pulmonary TB in a MAMS Design
This study is a multiple-arm, multiple-stage (MAMS), phase 2, open label, randomized,
 controlled clinical trial that will compare the efficacy and safety of four experimental four
 drug regimens with a standard control regimen in patients with smear positive, pulmonary
 tuberculosis (TB). Patients will be randomly allocated to the control or one of the four
 experimental regimens in the ratio 2:1:1:1:1. Experimental regimens will be given for 12
 weeks. Thereafter, participants in the experimental arms will receive continuation phase
 treatment for 14 weeks containing standard-dose rifampicin and isoniazid. All participants
 will receive 25 mg of vitamin B6 (pyridoxine) with every dose of INH to prevent INH-related
 neuropathy. Interim analyses will be conducted during the trial for efficacy, with the aim of
 identifying experimental arms that perform below a pre-specified efficacy threshold; these
 arms will then be stopped from further recruitment.

 Following the first scheduled interim analysis on March 3rd, the Trial Steering Committee
 (TSC) followed a recommendation of the independent data monitoring committee (IDMC) and has
 stopped the enrolment into two of the arms in the MAMS-TB trial: HRZQ and HR20ZQ, based on
 these arms not meeting the pre-specified gain in efficacy over control. Importantly, there
 was no safety concern that prompted stopping recruitment to these arms. They recommended that
 recruitment to arm 2 (HRZQ) and 3 (HR20ZQ) be terminated as there was insufficient evidence
 that these regimens could shorten treatment. Importantly, there was no evidence that either
 arm was inferior to standard treatment (the control arm) with regards to efficacy. There was,
 however, sufficient evidence that the other intervention arms HR35ZE and HR20ZM could shorten
 treatment to continue enrolling patients.
This Phase II, multi-arm, multi-stage, open label, prospectively randomized, controlled
 clinical trial will compare the efficacy and safety of four experimental regimens with the
 control, standard treatment regimen in patients with smear positive, pulmonary tuberculosis
 (TB). There will be four experimental regimens. Participants will be randomly allocated to
 control or one of the four experimental intensive phase regimens in the ratio 2:1:1:1:1. The
 control and 4 experimental regimens are:

 Control: HRZE isoniazid, rifampicin standard, pyrazinamide, ethambutol Arm 1: HRZQlow
 isoniazid, rifampicin standard, pyrazinamide, SQ109 150 mg Arm 2: HRZQhigh isoniazid,
 rifampicin standard, pyrazinamide, SQ109 300 mg Arm 3: HR20ZQhigh isoniazid, rifampicin 20
 mg/kg, pyrazinamide, SQ109 300 mg Arm 4: HR20ZM isoniazid, rifampicin 20 mg/kg, pyrazinamide,
 moxifloxacin 400mg

 Up to 372 participants will be randomized into this study, with 124 participants being
 randomized to the control arm and 62 participants to each experimental arm. With an expected
 loss to follow-up of 5%, the final power of the study to detect a hazard ratio of 1.8 for
 culture conversion to negative will be 90%, at the 5% significance level.

 Participants will be randomised using a probabilistic minimisation algorithm based on site,
 baseline bacterial load as measured by GeneXpert MTB/RIF®, and HIV status. The allocated
 intensive phase of the four experimental arms will be administered daily for twelve weeks.
 During this time, participants will visit the study clinic on a weekly basis for sputum
 collection, safety monitoring and receipt of study medication. After the completion of the
 experimental treatment, participants in the experimental arms will receive daily standard
 continuation phase treatment for 14 weeks containing standard-dose RIF and INH to complete
 their TB treatment course. Participants in the control arm will receive eight weeks of
 intensive four-drug treatment (HRZE, followed by 18 weeks of the HR continuation phase
 treatment in line with the current WHO recommendations.

 All participants will receive 25mg of Vitamin B6 (pyridoxine) with every dose of treatment in
 order to prevent INH-related neuropathy.

 Interim analyses will be conducted during the trial for efficacy at predetermined times, with
 the aim of identifying experimental arms that perform below a pre-specified efficacy
 threshold. There will be no further recruitment to these arms.
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.