| Trial name or title |
Shortening treatment by advancing novel drugs (STAND) |
| Methods |
Phase 3 open‐label, partially randomized, controlled clinical trial |
| Participants |
Inclusion criteria:
Signed written consent or witnessed oral consent in the case of illiteracy, before undertaking any trial‐related procedures Male or female, aged 18 years or older Body weight (in light clothing and no shoes) ≥ 30 kg Sputum positive for tubercle bacilli (at least 1+ on the International Union Against Tuberculosis and Lung Disease (IUATLD) and World Health Organization (WHO) scales on smear microscopy at the trial laboratory) Drug‐sensitive tuberculosis treatment arm participants should be:sensitive to rifampicin by rapid sputum‐based test (may be sensitive or resistant to isoniazid) AND either newly diagnosed with TB or with patient history of being untreated for at least 3 years after cure from a previous episode of TB. If they are entered into the trial because they are sensitive to rifampicin by rapid sputum‐based test, however, if receipt of rifampicin resistance testing via an indirect susceptibility test in liquid culture shows they are rifampicin resistant, they will be. excluded as late exclusions; possibly replaced as determined by the sponsor MDR‐TB treatment arm participants should be resistant to rifampicin by rapid sputum‐based test (may be sensitive or resistant to isoniazid) Chest X‐ray that in the opinion of the investigator is compatible with pulmonary TB Non‐childbearing potential or using effective methods of birth control, as defined below
Non‐childbearing potential:
Participant not heterosexually active or practicing sexual abstinence; or Female participant or male participant with female sexual partner ‐ bilateral oophorectomy, bilateral tubal ligation, and/or hysterectomy; or postmenopausal with a history of no menses for at least 12 consecutive months; or Male participant or female participant with male sexual partner ‐ vasectomized or with bilateral orchidectomy minimally 3 months before screening
Effective birth control methods:
Double‐barrier method, which can include male condom, diaphragm, cervical cap, or female condom; or Female participant: barrier method combined with hormone‐based contraceptives or an intrauterine device for the female participant Male participant's female sexual partner: double‐barrier method or hormone‐based contraceptives or an intrauterine device for the female participant
Willing to continue practising birth control methods and not planning to conceive throughout treatment and for 12 weeks (male participants) or 1 week (female participants) after last dose of trial medication or discontinuation from trial medication in case of premature discontinuation
Exclusion criteria:
Any non‐TB‐related condition (including myasthenia gravis) where participation in the trial, as judged by the investigator, could compromise the well‐being of the participant or could prevent, limit, or confound protocol‐specified assessments Being or about to be treated for malaria Critically ill and, in the judgement of the investigator, with a diagnosis likely to result in death during the trial or the follow‐up period TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor outcome, or likely to require a longer course of therapy (such as TB of the bone or joint), as judged by the investigator History of allergy or hypersensitivity to any of the trial IMP or related substances, including known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with quinolones, or suspected hypersensitivity to any rifampicin antibiotics For HIV‐infected participants, any of the following: CD4+ count < 100 cells/µL; Karnofsky score < 60%; received intravenous antifungal medication within the last 90 days; WHO clinical stage 4 HIV disease Resistant to fluoroquinolones (rapid, sputum‐based molecular screening tests). If they are entered into the trial because they are sensitive to fluoroquinolones by rapid sputum‐based test, but on receipt of the fluoroquinolone resistance test via an indirect susceptibility test in liquid culture, they show they are fluoroquinolone resistant, they will be excluded as late exclusions; possibly replaced as determined by the sponsor Resistant to pyrazinamide (rapid, sputum‐based molecular screening tests). Drug‐sensitive TB treatment arm participants may be entered before receipt of the rapid, sputum‐based molecular pyrazinamide resistance screening test result. On receipt of the result, if resistant, they will be excluded as late exclusions; possibly replaced as determined by the sponsor. MDR‐TB treatment arm participants may not be entered before receipt of the rapid, sputum‐based molecular pyrazinamide resistance screening test result showing they are sensitive to pyrazinamide Having participated in other clinical trials with investigational agents within 8 weeks before trial start or currently enrolled in an investigational trial With any of the following at screening (per measurements and reading done by central electrocardiogram (ECG) where applicable): cardiac arrhythmia requiring medication; prolongation of QT/QTc interval with QTcF (Fridericia correction) > 450 ms; history of additional risk factors for torsade de pointes (e.g. heart failure, hypokalaemia, family history of long QT syndrome); any clinically significant ECG abnormality, in the opinion of the investigator -
Unstable diabetes mellitus that required hospitalization for hyperglycaemia or hypoglycaemia within the past year before the start of screening. Specific treatments:
Previous treatment with PA‐824 as part of a clinical trial For DS‐TB treatment arms: previous treatment for tuberculosis within 3 years before Day (‐9 to ‐1) (screening). Participants who have previously received isoniazid prophylactically may be included in the trial as long as that treatment is/was discontinued at least 7 days before randomization into this trial. For MDR‐TB participants: previous treatment for MDR‐TB, although may have been on MDR‐TB treatment regimen for no longer than 7 days at the start of screening. Previous treatment for TB includes, but is not limited to, gatifloxacin, amikacin, cycloserine, rifabutin, kanamycin, para‐aminosalicylic acid, rifapentine, thiacetazone, capreomycin, quinolones, thioamides, and metronidazole Any disease or condition for which use of standard TB drugs or any of their components is contraindicated, including but not limited to allergy to any TB drugs, their components, or the IMP Use of any drug within 30 days before randomization known to prolong QTc interval (including, but not limited to, amiodarone, amitriptyline, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinacrine, quinidine, sotalol, sparfloxacin, thioridazine) Use of systemic glucocorticoids within 1 year of start of screening (inhaled or intranasal glucocorticoids are allowed) Participants recently started or expected to need to start antiretroviral therapy (ART) within 1 month after randomization. Patients may be included who have been on ARTs for longer than 30 days before the start of screening, or who are expected to start ART more than 30 days after randomization. Laboratory abnormalities
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Participants with the following toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007), where applicable:
Creatinine grade 2 or greater (> 1.5 times upper limit of normal (ULN)) Creatinine clearance (CrCl) level less than 30 mL/min according to the Cockcroft‐Gault formula Haemoglobin grade 4 (< 6.5 g/dL); platelets grade 3 or greater (under 50 x 10⁹ cells/L 50,000/mm³) Serum potassium less than lower limit of normal for the laboratory; this may be repeated once Aspartate aminotransferase (AST) grade 3 or greater (≥ 3.0 x ULN) Alanine aminotransferase (ALT) grade 3 or greater (≥ 3.0 x ULN) Alkaline phosphatase (ALP): grade 4 (> 8.0 x ULN) to be excluded; grade 3 (≥ 3.0 to 8.0 x ULN) must be discussed with and approved by the sponsor medical monitor Total bilirubin: 2.0 x ULN, when other liver functions are in the normal range; 1.50 x ULN when accompanied by any increase in other liver function tests among participants with total bilirubin > 1.25 x ULN and accompanied by any increase in other liver function tests must be discussed with the sponsor medical monitor before enrolment
Recruited sample size = 1500 |
| Interventions |
Interventions:
Moxifloxacin 400 mg + PA‐824 200 mg + pyrazinamide 1500 mg orally once daily for 26 weeks Moxifloxacin 400 mg + PA‐824 200 mg + pyrazinamide 1500 mg orally once a day for 17 weeks Moxifloxacin 400 mg + PA‐824 100 mg + pyrazinamide 1500 mg orally once daily for 17 weeks
Control:
(Additional MDR‐TB arm: moxifloxacin 400 mg + PA‐824 200 mg + pyrazinamide 1500 mg for 26 weeks) |
| Outcomes |
Primary outcome:
Secondary outcomes:
Incidence of bacteriologic failure or relapse or clinical failure at 24 months from the start of therapy as a confirmatory analysis Rate of change in time to culture positivity (TTP) over time in liquid culture MGIT in sputum, represented by the model‐fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. [Screening; Day 1, 7; Week 2 to 7; Month 2 to 6, 9, 12, 15, 18, 24] MGIT is defined as mycobacterial growth indicator tube Time in days to sputum culture conversion to negative status in liquid culture (MGIT) through the treatment period to be explored as a potential biomarker of definitive outcome. [Screening; Day 1, 7; Week 2 to 7; Month 2 to 6, 9, 12, 15, 18, 24] Proportion of participants with sputum culture conversion to negative status in liquid culture (MGIT) at 4, 8, 12, and 17 weeks to be explored as a potential biomarker of definitive outcome. [Week 4, 8, 12, and 17] Incidence of treatment‐emergent adverse events (TEAEs) presented by incidence and seriousness, leading to TB‐related or non‐TB‐related death. [Day 1, 7; Week 2 to 7; Month 2 to 6, 9, 12, 15, 18, 24] Clinical laboratory safety measurements of haematology and chemistry, including observed and change from baseline. [Screening; Day 1; Week 1, 2, 4; Month 2, 3, 4, 6] Trough plasma concentrations will be used to evaluate effects of baseline subject covariates on trial drug pharmacokinetics and associated bacteriologic endpoints. [Week 2, Month 2] Minimum inhibitory concentration (MIC) against moxifloxacin and PA‐824 [Day 1; Week 17 or Week 26 ]. MIC: lowest concentration of moxifloxacin or PA‐824 that will inhibit visible growth in culture Change from baseline in sperm concentration by group. [Screening; Day 1; Week 12, 13, 26, 27, 39, 40] Change from baseline in male FSH by group. [Screening; Day 1; Week 12, 13, 26, 27, 39, 40] Reproductive hormones: FSH, LH, testosterone, inhibin B Change from baseline in male LH by group. [Screening; Day 1; Week 12, 13, 26, 27, 39, 40] Change from baseline in male testosterone by group. [Screening; Day 1; Week 12, 13, 26, 27, 39, 40] Change from baseline in male inhibin B by group. [Screening; Day 1; Week 12, 13, 26, 27, 39, 40] Change from baseline in proportion of total motile sperm by group. [Screening; Day 1; Week 12, 13, 26, 27, 39, 40] Change from baseline in sperm morphology by group. [Screening; Day 1; Week 12, 13, 26, 27, 39, 40] Change from baseline in sperm volume by group. [Screening; Day 1; Week 12, 13, 26, 27, 39, 40] Change from baseline in total sperm numbers by group. [Screening; Day 1; Week 12, 13, 26, 27, 39, 40]
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| Starting date |
February 2015; completed May 2018 (no results posted) |
| Contact information |
Stephen H Gillespie, MD
School of Medicine, University of St. Andrews, North Haugh, St. Andrews KY16 9TF, United Kingdom
Email: shg3@st‐andrews.ac.uk |
| Notes |
Study locations: Georgia, Kenya, Malaysia, Philippines, South Africa, Tanzania, Uganda, Zambia
Registration number:NCT02342886
Sponsors: Global Alliance for TB Drug Development |
