Evaluation of SQ109, High-dose Rifampicin, and Moxifloxacin in Adults With Smear-positive Pulmonary TB in a MAMS Design
Condition: Tuberculosis, Pulmonary
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Intervention: SQ109; Rifampicin; Moxifloxacin; isoniazid; pyrazinamide; ethambutol; pyridoxine
Intervention description: SQ109 300 mg; Rifampicin 10 to 35 mg/kg; Moxifloxacin 400mg; isoniazid 75 mg; pyrazinamide 400 mg; ethambutol 275 mg; pyridoxine 25 mg
Intervention MeSH terms: Pyridoxine; Moxifloxacin; Rifampin; Isoniazid; Pyrazinamide; Ethambutol
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 365.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: TB; Tuberculosis; MAMS - Multiple-arm, multiple-stage; Pulmonary; SQ109; High dose rifampicin; moxifloxacin

Summary:

      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.
    

Eligibility criteria:

        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.