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Trial record 62 of 73 for:    "Bacterial Infectious Disease" | "Polyestradiol phosphate"

Shortening Treatment by Advancing Novel Drugs (STAND)

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ClinicalTrials.gov Identifier: NCT02342886
Recruitment Status : Completed
First Posted : January 21, 2015
Results First Posted : March 26, 2019
Last Update Posted : March 26, 2019
Sponsor:
Information provided by (Responsible Party):
Global Alliance for TB Drug Development

Tracking Information
First Submitted Date  ICMJE October 14, 2014
First Posted Date  ICMJE January 21, 2015
Results First Submitted Date  ICMJE February 2, 2019
Results First Posted Date  ICMJE March 26, 2019
Last Update Posted Date March 26, 2019
Actual Study Start Date  ICMJE February 2015
Actual Primary Completion Date January 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 1, 2019)
  • Incidence of Combined Bacteriologic Failure or Relapse or Clinical Failure at Month 12 From Start of Therapy (Day 1) (Modified Intent to Treat [MITT] Population) [ Time Frame: From Day 1 to Month 12. ]
    Patients were classified as having a favorable, unfavorable or unassessable status at 12 months from the start of therapy. A favourable status was a negative culture status at 12 months from start of therapy in patients who had not already been classified as having an unfavorable outcome, and whose last positive culture result was followed by at least 2 negative culture results. Patients with an unfavorable status did not achieve/maintain culture negative status, or previously had culture negative status who following end of treatment (EOT), had 2 positive cultures, or had a positive culture not followed by 2 negative cultures, or were dying from any cause during treatment (except accidental cause not including suicide), or were dying from TB related causes during follow-up, or required an extension, restart or change of treatment except for reinfection/pregnancy, or failed to complete adequate treatment who were unassessable at 12 months or lost to follow-up/withdrawn before EOT.
  • Incidence of Combined Bacteriologic Failure or Relapse or Clinical Failure at Month 12 From Start of Therapy (Day 1) (Per Protocol [PP] Population) [ Time Frame: From Day 1 to Month 12. ]
    Patients were classified as having a favorable, unfavorable or unassessable status at 12 months from the start of therapy. A favourable status was a negative culture status at 12 months from start of therapy in patients who had not already been classified as having an unfavorable outcome, and whose last positive culture result was followed by at least 2 negative culture results. Patients with an unfavorable status did not achieve/maintain culture negative status, or previously had culture negative status who following EOT, had 2 positive cultures, or had a positive culture not followed by 2 negative cultures, or died from any cause during treatment (except accidental cause not including suicide), or were dying from TB related causes during follow-up, or required a restart or change of treatment because of an unfavorable outcome with or without bacteriological confirmation, ie, on bacteriological, radiographic or clinical grounds.
Original Primary Outcome Measures  ICMJE
 (submitted: January 15, 2015)
Incidence of combined bacteriologic failure or relapse of clinical failure at 12 months from start of therapy. [ Time Frame: 12 Months ]
  • Bacteriologic failure: During the treatment period, failure to attain culture conversion to negative status in liquid culture.
  • Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to negative status in liquid culture, with culture conversion to positive status with a Mycobacterium tuberculosis (MTB) strain that is genetically identical to the infecting strain at baseline.
  • Bacteriologic reinfection: During the follow-up period, failure to maintain culture conversion to negative status in liquid culture, with culture conversion to positive status with a MTB strain that is genetically different from the infecting strain at baseline.
  • Clinical failure: A change from protocol-specified TB treatment due to treatment failure, retreatment for TB during follow up, or TB-related death.
Change History Complete list of historical versions of study NCT02342886 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: January 15, 2015)
  • Incidence of bacteriologic failure or relapse or clinical failure at 24 months from the start of therapy as a confirmatory analysis. [ Time Frame: 24 Months ]
  • The 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. [ Time Frame: Screening, Day 1, 7, Week 2-7, Month 2-6, 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. [ Time Frame: Screening, Day 1, 7, Week 2-7, Month 2-6, 9, 12, 15, 18, 24 ]
  • Proportion of subjects 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. [ Time Frame: Weeks 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. [ Time Frame: Day 1, 7, Week 2-7, Month 2-6, 9, 12, 15, 18, 24 ]
  • Clinical laboratory safety measurements of hematology and chemistry, including observed and change from baseline. [ Time Frame: Screening, Day 1, Week 1, 2, 4, Month 2, 3, 4, 6 ]
  • Trough plasma concentrations will be used to evaluate the effects of baseline subject covariates on trial drug pharmacokinetics and associated bacteriological endpoints. [ Time Frame: Week 2, Month 2 ]
  • Minimum inhibitory concentration (MIC) against Moxifloxacin and PA-824 [ Time Frame: Day 1, Week 17 or Week 26 ]
    MIC: The lowest concentration of Moxifloxacin or PA-824 that will inhibit visible growth in culture.
  • Change from baseline in sperm concentration by group. [ Time Frame: Screening, Day 1, Week 12, 13, 26, 27, 39, 40 ]
  • Change from baseline in male FSH by group. [ Time Frame: 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. [ Time Frame: Screening, Day 1, Week 12, 13, 26, 27, 39, 40 ]
  • Change from baseline in male Testosterone by group. [ Time Frame: Screening, Day 1, Week 12, 13, 26, 27, 39, 40 ]
  • Change from baseline in male Inhibin B by group. [ Time Frame: Screening, Day 1, Week 12, 13, 26, 27, 39, 40 ]
  • Change from baseline in proportion of total motile sperm by group. [ Time Frame: Screening, Day 1, Week 12, 13, 26, 27, 39, 40 ]
  • Change from baseline in sperm morphology by group. [ Time Frame: Screening, Day 1, Week 12, 13, 26, 27, 39, 40 ]
  • Change from baseline in sperm volume by group. [ Time Frame: Screening, Day 1, Week 12, 13, 26, 27, 39, 40 ]
  • Change from baseline in total sperm numbers by group. [ Time Frame: Screening, Day 1, Week 12, 13, 26, 27, 39, 40 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Shortening Treatment by Advancing Novel Drugs
Official Title  ICMJE A Phase 3 Open-Label Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability of the Combination of Moxifloxacin Plus PA-824 Plus Pyrazinamide After 4 and 6 Months of Treatment in Adult Subjects With Drug-Sensitive Smear-Positive Pulmonary Tuberculosis and After 6 Months of Treatment in Adult Subjects With Multi-Drug Resistant, Smear-Positive Pulmonary Tuberculosis.
Brief Summary

The purpose of this study is to assess the efficacy, safety and tolerability of a combination of moxifloxacin, PA-824, and pyrazinamide treatments with varying doses and treatment lengths from 4 to 6 months in subjects with drug-sensitive (DS) pulmonary TB compared to standard HRZE treatment.

This study will also assess the efficacy, safety and tolerability of a combination of moxifloxacin, PA-824, and pyrazinamide treatments after 6 months of treatment in subjects with multi drug-resistant (MDR) pulmonary TB compared to a combination of moxifloxacin, PA-824, and pyrazinamide treatments in DS-TB subjects.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Tuberculosis, Pulmonary, Drug Sensitive
  • Tuberculosis, Pulmonary, Multi Drug-resistant
Intervention  ICMJE
  • Drug: Moxifloxacin
    Oral
    Other Names:
    • BAY 12-8039
    • Avelox
    • Avalon
    • Avelon
  • Drug: PA-824
    Oral
  • Drug: Pyrazinamide
    Oral
  • Drug: HRZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol combination)
    Oral
    Other Name: Rifafour e-275
  • Drug: HR (rifampicin plus isoniazid combination tablets)
    Oral
Study Arms  ICMJE
  • Experimental: MDR-TB
    moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg for 26 weeks.
    Interventions:
    • Drug: Moxifloxacin
    • Drug: PA-824
    • Drug: Pyrazinamide
  • Active Comparator: DS-TB (HRZE), HR

    26 consecutive weeks to DS-TB subjects only, as follows:

    HRZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol combination) Weeks 1-8 with daily dose per the subjects weight

    HR (Rifampicin plus isoniazid combination tablets) Weeks 9 - 26 with daily dose per the subjects weight

    Daily dose per the subjects weight as follows: 30-39kg: 2 tablets; 40-54kg: 3 tablets; 55 - 70kg: 4 tablets; 71kg and over: 5 tablets.

    Interventions:
    • Drug: HRZE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol combination)
    • Drug: HR (rifampicin plus isoniazid combination tablets)
  • Experimental: DS-TB PA-824 200mg 26 weeks
    moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg orally once daily for 26 weeks
    Interventions:
    • Drug: Moxifloxacin
    • Drug: PA-824
    • Drug: Pyrazinamide
  • Experimental: DS-TB PA-824 200mg 17 weeks
    moxifloxacin 400 mg + PA-824 200 mg + pyrazinamide 1500 mg orally once a day for 17 weeks
    Interventions:
    • Drug: Moxifloxacin
    • Drug: PA-824
    • Drug: Pyrazinamide
  • Experimental: DS-TB PA-824 100mg 17 weeks
    moxifloxacin 400 mg + PA-824 100 mg + pyrazinamide 1500 mg orally once daily for 17 weeks
    Interventions:
    • Drug: Moxifloxacin
    • Drug: PA-824
    • Drug: Pyrazinamide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 1, 2019)
284
Original Estimated Enrollment  ICMJE
 (submitted: January 15, 2015)
1500
Actual Study Completion Date  ICMJE May 2018
Actual Primary Completion Date January 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Signed written consent or witnessed oral consent in the case of illiteracy, prior to undertaking any trial-related procedures.
  2. Male or female, aged 18 years or over.
  3. Body weight (in light clothing and no shoes) ≥ 30 kg.
  4. Sputum positive for tubercule bacilli (at least 1+ on the International Union Against Tuberculosis and Lung Disease (IUATLD) and World Health Organization (WHO) scale on smear microscopy at the trial laboratory.
  5. Drug‐Sensitive TB treatment arms subjects should be:

    • sensitive to rifampicin by rapid sputum based test (may be sensitive or resistant to isoniazid) AND
    • either newly diagnosed for TB or have a 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 due to being sensitive to rifampicin by rapid sputum based test, however on receipt of the rifampicin resistance testing using an indirect susceptibility test in liquid culture this shows they are rifampicin resistant, they will be:
    • Excluded as late exclusions;
    • Possibly replaced as determined by the sponsor.
  6. MDR‐TB treatment arm subjects should be resistant to rifampicin by rapid sputum based test (may be sensitive or resistant to isoniazid).
  7. A chest x-ray which in the opinion of the investigator is compatible with pulmonary TB.
  8. Be of non‐childbearing potential or using effective methods of birth control, as defined below:

Non‐childbearing potential:

  • Subject ‐ not heterosexually active or practice sexual abstinence; or
  • Female subject or male subjects female sexual partner ‐ bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive months; or
  • Male subject or female subjects male sexual partner ‐ vasectomised or has had a bilateral orchidectomy minimally three months prior to screening;

Effective birth control methods:

  • Double barrier method which can include a male condom, diaphragm, cervical cap, or female condom; or
  • Female subject: Barrier method combined with hormone‐based contraceptives or an intra‐uterine device for the female patient.
  • Male subjects' female sexual partner: Double barrier method or hormone‐based contraceptives or an intra‐uterine device for the female partner.

and are willing to continue practising birth control methods and are not planning to conceive throughout treatment and for 12 weeks (male subjects) or 1 week (female subjects) after the last dose of trial medication or discontinuation from trial medication in case of premature discontinuation.

(Note: Hormone‐based contraception alone may not be reliable when taking IMP; therefore,

Exclusion Criteria:

  1. 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 subject or prevent, limit or confound protocol specified assessments.
  2. Being or about to be treated for Malaria.
  3. Is critically ill and, in the judgment of the investigator, has a diagnosis likely to result in death during the trial or the follow-up period.
  4. 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.
  5. 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.
  6. For HIV infected subjects 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.
  7. Resistant to fluoroquinolones (rapid, sputum - based molecular screening tests). If they are entered into the trial due to being sensitive to fluoroquinolones by rapid sputum based test, however on receipt of the fluoroquinolones resistance testing using an indirect susceptibility test in liquid culture this shows they are fluoroquinolones resistant, they will be:

    • Excluded as late exclusions;
    • Possibly replaced as determined by the sponsor.
  8. Resistant to pyrazinamide (rapid, sputum - based molecular screening tests).

    Drug-Sensitive TB treatment arms subjects may be entered prior to receipt of the rapid, sputum - based molecular pyrazinamide resistance screening test result. On receipt of the result, if they are resistant, they will be:

    • Excluded as late exclusions;
    • Possibly replaced as determined by the sponsor. MDR-TB treatment arm subjects may not be entered prior to receipt of the rapid, sputum - based molecular pyrazinamide resistance screening test result showing they are sensitive to pyrazinamide.
  9. Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial.
  10. Subjects 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, hypokalemia, family history of Long QT Syndrome);
    • Any clinically significant ECG abnormality, in the opinion of the investigator.
  11. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening.

    Specific Treatments

  12. Previous treatment with PA-824 as part of a clinical trial.
  13. For DS-TB treatment arms: Previous treatment for tuberculosis within 3 years prior to Day (-9 to -1)(Screening). Subjects who have previously received isoniazid prophylactically may be included in the trial as long as that treatment is/was discontinued at least 7 days prior to randomization into this trial.

    For the MDR-TB Subjects: Previous treatment for MDR-TB, although may have been on a MDR TB treatment regimen for no longer than 7 days at start of screening.

    Previous treatment for TB includes, but is not limited to, gatifloxacin, amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, thioacetazone, capreomycin, quinolones, thioamides, and metronidazole.

  14. Any diseases or conditions in which the use of the standard TB drugs or any of their components is contra-indicated, including but not limited to allergy to any TB drug, their component or to the IMP.
  15. Use of any drug within 30 days prior to randomisation 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).
  16. Use of systemic glucocorticoids within one year of start of screening (inhaled or intranasal glucocorticoids are allowed).
  17. Subjects recently started or expected to need to start anti-retroviral therapy (ART) within 1 month after randomization. Subjects may be included who have been on ARTs for greater than 30 days prior to start of screening, or who are expected to start ART greater than 30 days after randomization.

    Laboratory Abnormalities

  18. Subjects 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 mLs/min according to the Cockcroft-Gault Formula;
    • haemoglobin grade 4 (<6.5 g/dL);
    • platelets grade 3 or greater (under 50x109 cells/L/ 50 000/mm3);
    • serum potassium less than the 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 - 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 subjects 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 enrollment
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Georgia,   Kenya,   Malaysia,   Philippines,   South Africa,   Tanzania,   Uganda,   Zambia
Removed Location Countries Brazil,   China,   Haiti,   Mozambique,   Peru,   Russian Federation,   Thailand,   Ukraine
 
Administrative Information
NCT Number  ICMJE NCT02342886
Other Study ID Numbers  ICMJE NC-006-(M-PA-Z)
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Global Alliance for TB Drug Development
Study Sponsor  ICMJE Global Alliance for TB Drug Development
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Stephen H Gillespie, MD University of St Andrews
PRS Account Global Alliance for TB Drug Development
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP