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Trial record 1 of 1 for:    NCT02958709
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Optimizing Treatment to Improve TBM Outcomes in Children (TBM-KIDS)

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ClinicalTrials.gov Identifier: NCT02958709
Recruitment Status : Recruiting
First Posted : November 8, 2016
Last Update Posted : August 9, 2019
Sponsor:
Collaborators:
National Institute for Research in Tuberculosis, Chennai, India
University of North Carolina
B. J. Medical College, Pune
Information provided by (Responsible Party):
Johns Hopkins University

Brief Summary:
In this open-labeled, randomized clinical trial, the Investigator will assess the safety and pharmacokinetics (PK) of model-optimized doses of rifampicin (RIF) with or without levofloxacin (LEVO) given to children as part of multidrug treatment for tuberculous meningitis (TBM) versus standard treatment. The Investigators will also assess functional and neurocognitive outcomes by treatment group, as measured by the Pediatric Modified Rankin Score (MRS) and the Mullen Scales of Early Learning (MSEL), respectively.

Condition or disease Intervention/treatment Phase
Tuberculosis, Meningeal Drug: High-dose: RIF, INH, PZA, EMB Drug: High dose: RIF, INH, PZA, LEVO Drug: Standard of care: RIF, INH, PZA, EMB Phase 1 Phase 2

Detailed Description:
Open-label, randomized clinical trial in three treatment groups. Patients with probable or definite TB meningitis (TBM) will all receive isoniazid and pyrazinamide at standard doses for 8 weeks. Arm 1 participants will receive high-dose rifampicin plus ethambutol (EMB) at standard doses for 8 weeks. Arm 2 participants will receive high-dose rifampicin plus levofloxacin for 8 weeks. Arm 3 participants will receive rifampicin plus ethambutol at standard doses for 8 weeks (control arm). Patients will be screened to confirm TBM diagnosis, will receive 8 weeks of study treatment, and then will receive isoniazid (INH)/rifampicin for an additional 40 weeks, to complete 12 months of TBM treatment. All participants will receive oral steroids. PK sampling will be performed within first week and 6 (+/- 2) weeks following treatment initiation. Participants will have scheduled follow-up visits to assess safety and clinical status. In addition, functional and neurocognitive outcomes up to 18 months following treatment initiation will be assessed. Interim PK and safety analyses will be performed to ensure dosing is producing predefined PK targets and safety is acceptable. It is anticipated that a majority of children will be hospitalized for the initial 2-8 weeks of the study.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Randomized, Open-label Trial to Evaluate the PK, Safety, and Outcomes of Treatment Including High Dose Rifampicin +/- Levofloxacin vs Standard Treatment for Pediatric Tuberculous Meningitis (TBM)
Actual Study Start Date : February 22, 2017
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2020


Arm Intervention/treatment
Experimental: high dose RIF, INH, PZA, EMB
Arm 1 participants will receive high-dose rifampicin for 8 weeks plus ethambutol at standard doses, in addition to standard doze pyrazinamide (PZA) and isoniazid.
Drug: High-dose: RIF, INH, PZA, EMB
high-dose rifampicin plus standard dose H,Z,E, given for 8 weeks in treatment Arms 1 and 2
Other Name: Rifampin

Experimental: high dose RIF, INH, PZA, LEVO
Arm 2 participants will receive high-dose rifampicin plus levofloxacin for 8 weeks, in addition to standard doze pyrazinamide and isoniazid.
Drug: High dose: RIF, INH, PZA, LEVO
high-dose rifampicin plus standard dose H,Z, with levofloxacin substituted for ethambutol for 8 weeks in treatment Arm 2
Other Name: Levaquin

Active Comparator: standard dose RIF, INH, PZA, EMB
Arm 3 participants will receive standard of care dose rifampicin plus ethambutol for 8 weeks, in addition to standard doze pyrazinamide and isoniazid.
Drug: Standard of care: RIF, INH, PZA, EMB
standard doses of R,H,Z,E given for 8 weeks in treatment Arm 3, control arm.
Other Name: control group




Primary Outcome Measures :
  1. Characterize the Volume of Distribution (Vd) in plasma of rifampicin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Weeks 1-16 ]
    Apparent volume of distribution estimated using population PK model

  2. Characterize the Oral Clearance (CL/F) in plasma of rifampicin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Weeks 1-16 ]

    Examines the apparent total clearance of rifampicin from plasma after oral administration.

    Unit of Measure: Volume/time or volume/time/kg


  3. Characterize the Rate of Absorption (ka) in plasma of rifampicin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Weeks 1-16 ]
    Examines the absorption rate constant for orally administered rifampicin. Unit of Measure: will be represented as a decimal.

  4. Characterize the Penetration Coefficient in CSF of rifampicin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Weeks 1 and 6 ]
    Examines the ratio of CSF concentration to Plasma concentration of rifampicin Unit of Measure: will be represented as a decimal

  5. Characterize the Volume of Distribution (Vd) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Weeks 1-16 ]

    Examines the apparent volume in which levofloxacin is distributed (i.e., the parameter relating drug concentration to drug amount in the body).

    Unit of measure: Liter (L)


  6. Characterize the Volume of Distribution (Vd) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Week 4 ]

    Examines the apparent volume in which levofloxacin is distributed (i.e., the parameter relating drug concentration to drug amount in the body).

    Unit of measure: Liter (L)


  7. Characterize the Volume of Distribution (Vd) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Week 8 ]

    Examines the apparent volume in which levofloxacin is distributed (i.e., the parameter relating drug concentration to drug amount in the body).

    Unit of measure: Liter (L)


  8. Characterize the Volume of Distribution (Vd) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Week 16 ]

    Examines the apparent volume in which levofloxacin is distributed (i.e., the parameter relating drug concentration to drug amount in the body).

    Unit of measure: Liter (L)


  9. Characterize the Oral Clearance (CL/F) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Weeks 1-16 ]

    Examines the apparent total clearance of levofloxacin from plasma after oral administration.

    Unit of Measure: Volume/time or volume/time/kg


  10. Characterize the Oral Clearance (CL/F) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Week 4 ]

    Examines the apparent total clearance of levofloxacin from plasma after oral administration.

    Unit of Measure: Volume/time or volume/time/kg


  11. Characterize the Oral Clearance (CL/F) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Week 8 ]

    Examines the apparent total clearance of levofloxacin from plasma after oral administration.

    Unit of Measure: Volume/time or volume/time/kg


  12. Characterize the Rate of Absorption (ka) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Weeks 1-16 ]
    Examines the absorption rate constant for orally administered levofloxacin. Unit of Measure: will be represented as a decimal.

  13. Characterize the Rate of Absorption (ka) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Week 4 ]
    Examines the absorption rate constant for orally administered levofloxacin. Unit of Measure: will be represented as a decimal.

  14. Characterize the Rate of Absorption (ka) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Week 16 ]
    Examines the absorption rate constant for orally administered levofloxacin. Unit of Measure: will be represented as a decimal.

  15. Characterize the Penetration Coefficient in CSF of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. [ Time Frame: Weeks 1 and 6 ]
    Examines the ratio of CSF to Plasma concentration of levofloxacin Unit of Measure: will be represented as a decimal

  16. Assess the relationship between RIF concentrations and longitudinal functional outcomes as measured by longitudinal Modified Rankin Score (MRS) for children [ Time Frame: 48 weeks ]
    At the end of treatment, all participants' RIF concentrations (Cmax and AUC) will be compared across time against their MRS scores. MRS parameters and their scores (in parentheses) as follows: No symptoms at all (0),No significant disabilities despite symptoms in clinical examination; age appropriate behaviour and further development (1),Slight disability; unable to carry out all previous activities, but same independence as other age- and sex-matched children (no reduction of levels on the gross motor function scale) (2),Moderate disability; requiring some help, but able to walk without assistance; in younger patients adequate motor development despite mild functional impairment (reduction of one level on the gross motor function scale) (3), Moderately severe disability; unable to walk without assistance; in younger patients reduction of at least 2 levels on the gross motor function scale (4),Severe disability; bedridden, requiring constant nursing care and attention (5),

  17. To evaluate the safety of TBM treatment over eight weeks, by treatment Arm, as measured by Grade 3 or higher adverse events [ Time Frame: 8 weeks ]
    Grade 3 Adverse Events as defined by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events


Secondary Outcome Measures :
  1. Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Gross Motor Scale [ Time Frame: 72 weeks ]

    The Gross Motor Scale is used to assess infants who are 33 months of age or younger and provides information about the child's kinesthetic experience.

    Maximum Raw Scores of Gross Motor Scale: 36 Raw scores are converted to T Scores (A type of standardized score) based on the child's age.

    A T Score has a mean of 50 and a standard deviation of 10. A T Score between 20 and 30 (or less than 20) has a descriptive category of "Very Low" A T Score between 31 and 39 has a descriptive category of "Below Average" A T Score between 40 and 60 has a descriptive category of "Average" A T Score between 61 and 69 has a descriptive category of "Above Average" A T Score between 70 and 80 has a descriptive category of "Very High"


  2. Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Visual Reception Scale [ Time Frame: Week 72 ]

    A cognitive score that may be derived from children ages birth to 68 months of age.

    The Visual Reception Scale assesses visual processing skills through isolation of oculomotor and visual-motor operations. This scale minimizes the motor output required to execute the response and eliminates the need for verbalized responses.

    Maximum Raw Scores of the Visual Reception Scale: 50 Raw scores are converted to T Scores (A type of standardized score) based on the child's age.

    A T Score has a mean of 50 and a standard deviation of 10. A T Score between 20 and 30 (or less than 20) has a descriptive category of "Very Low" A T Score between 31 and 39 has a descriptive category of "Below Average" A T Score between 40 and 60 has a descriptive category of "Average" A T Score between 61 and 69 has a descriptive category of "Above Average" A T Score between 70 and 80 has a descriptive category of "Very High"


  3. Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Fine Motor Scale [ Time Frame: Week 72 ]

    A cognitive score that may be derived from children ages birth to 68 months of age.

    The Fine Motor Scale emphasizes the output aspect of visual organization by assessing visual-motor skills, such as motor planning, motor control, and writing readiness.

    Maximum Raw Scores of the Fine Motor Scale: 49 Raw scores are converted to T Scores (A type of standardized score) based on the child's age.

    A T Score has a mean of 50 and a standard deviation of 10. A T Score between 20 and 30 (or less than 20) has a descriptive category of "Very Low" A T Score between 31 and 39 has a descriptive category of "Below Average" A T Score between 40 and 60 has a descriptive category of "Average" A T Score between 61 and 69 has a descriptive category of "Above Average" A T Score between 70 and 80 has a descriptive category of "Very High"


  4. Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Receptive Language Scale [ Time Frame: Week 72 ]

    A cognitive score that may be derived from children ages birth to 68 months of age.

    The Receptive Language Scale evaluates the ability to decode verbal input through tasks requiring auditory discrimination, linguistic conceptualization, sequencing, and use of spatial concepts.

    Maximum Raw Scores of the Fine Motor Scale: 48 Raw scores are converted to T Scores (A type of standardized score) based on the child's age.

    A T Score has a mean of 50 and a standard deviation of 10. A T Score between 20 and 30 (or less than 20) has a descriptive category of "Very Low" A T Score between 31 and 39 has a descriptive category of "Below Average" A T Score between 40 and 60 has a descriptive category of "Average" A T Score between 61 and 69 has a descriptive category of "Above Average" A T Score between 70 and 80 has a descriptive category of "Very High"


  5. Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Expressive Language Scale [ Time Frame: Week 72 ]

    A cognitive score that may be derived from children ages birth to 68 months of age.

    The Expressive Language Scale focuses on the child's use of spoken language for communication and expression during spontaneous utterances and during specific vocal or verbal responses to tasks.

    Maximum Raw Scores of the Fine Motor Scale: 50 Raw scores are converted to T Scores (A type of standardized score) based on the child's age.

    A T Score has a mean of 50 and a standard deviation of 10. A T Score between 20 and 30 (or less than 20) has a descriptive category of "Very Low" A T Score between 31 and 39 has a descriptive category of "Below Average" A T Score between 40 and 60 has a descriptive category of "Average" A T Score between 61 and 69 has a descriptive category of "Above Average" A T Score between 70 and 80 has a descriptive category of "Very High"


  6. Describe TBM treatment outcomes at 12 months which will be classified as favorable (cured or treatment completed) or unfavorable (death, lost to follow up, treatment failure, transferred out) at 48 weeks. [ Time Frame: 48 weeks ]
    TB treatment outcomes , favorable or unfavorable



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Months to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Weight > 6kg
  • Age ≥ 6 months to < 12 years and, in the opinion of the investigator, can tolerate the treatment and study participation.
  • Probable or definite TBM according to diagnostic criteria or a positive Gene Xpert cerebrospinal fluid (CSF) test.
  • Since participants will all be under legal age of independent consent, a parent or legal guardian must be willing and able to provide informed consent. If the subject is of appropriate age, she/he will also be asked to give assent if developmentally appropriate and clinically possible.
  • Participant can comply with the protocol requirements in the opinion of the site investigator.

Exclusion Criteria:

  • TB treatment for > 7 days
  • Exposure via close contact with someone with multi drug resistant TB (MDR-TB) (or rifampicin mono-resistant TB) or personal history of MDR-TB (or rifampicin mono-resistant TB)
  • Known intolerance or allergy to any of the study drugs
  • Death imminent and expected within 24 hours, as assessed by the site investigator
  • Moderate to severe renal or liver dysfunction (Grade 2 or higher abnormalities of creatinine, alanine aminotransferase (ALT), or direct bilirubin)
  • HIV infection with any of the following:

Planned initiation of antiretroviral treatment (ART) during the experimental treatment phase (first 8 weeks), as initiation of ART is contraindicated in that time period with TBM.

On ART with planned continued use of a protease inhibitor or nevirapine (children can be switched to an acceptable alternative regimen and then participate)

  • Having participated in other clinical studies with investigational agents or treatments within 8 weeks prior to enrollment.
  • A clinically significant active medical condition or the presence of any concomitant severe illness or rapidly deteriorating health condition (outside of TB), which, in the opinion of the site investigator, would prevent appropriate participation in the trial, or that would make implementation of the protocol or interpretation of the study results difficult, or otherwise make the subject a poor candidate for a clinical trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02958709


Contacts
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Contact: Kelly Dooley, MD, PhD 410-955-3100 kdooley1@jhmi.edu
Contact: Lisa Wolf, RN 410-955-7493 lisawolf@jhmi.edu

Locations
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India
Byramji Jeejeebhoy Government Medical College and Sassoon Hospital Recruiting
Pune, Maharashtra, India, 411001
Contact: Chhaya Valvi, MD       chhayavalvi@gmail.com   
Contact: Vidya Mave, MD, MPH & TM    919503646148    vidyamave@gmail.com   
National Institute of Research in TB and Institute of Child Health Not yet recruiting
Chennai, Tamil Nadu, India, 600031
Contact: Bella Devaleenal, MBBS    919841746690    bella.d@nirt.res.in   
Contact: Syed Hissar, MD, MPH    919442927242    syed.hissar@nirt.res.in   
Malawi
UNC Project- Malawi Not yet recruiting
Lilongwe, Lilongwe District, Malawi
Contact: Mina Hosseinipour, MD,MPH    2651750610    mina_hosseinipour@med.unc.edu   
Contact: Tisungane Mvalo, MBBS, FCPaed    2651750610    tmvalo@unclilongwe.org   
Sponsors and Collaborators
Johns Hopkins University
National Institute for Research in Tuberculosis, Chennai, India
University of North Carolina
B. J. Medical College, Pune
Investigators
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Principal Investigator: Kelly Dooley, MD,PhD Johns Hopkins University

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Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT02958709     History of Changes
Other Study ID Numbers: IRB00051196
First Posted: November 8, 2016    Key Record Dates
Last Update Posted: August 9, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Meningeal
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Meningitis, Bacterial
Central Nervous System Bacterial Infections
Tuberculosis, Central Nervous System
Central Nervous System Infections
Central Nervous System Diseases
Nervous System Diseases
Meningitis
Levofloxacin
Ofloxacin
Rifampin
Ethambutol
Anti-Infective Agents, Urinary
Anti-Infective Agents
Renal Agents
Anti-Bacterial Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Antibiotics, Antitubercular
Antitubercular Agents