Clinical trial NCT02958709: Optimizing Treatment to Improve TBM Outcomes in Children
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Tuberculosis, Meningeal
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: National Institute for Research in Tuberculosis, Chennai, India
name: University of North Carolina
name: B. J. Medical College, Pune
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2016-11-08
Enrollment: 38
Sex: ALL
Minimum age (years): 6
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: 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.
timeFrame: Weeks 1-16
measure: 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.
timeFrame: Weeks 1-16
measure: 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.
timeFrame: Weeks 1-16
measure: 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.
timeFrame: Weeks 1 and 6
measure: 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.
timeFrame: Weeks 1-16
measure: 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.
timeFrame: Week 4
measure: 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.
timeFrame: Week 8
measure: 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.
timeFrame: Week 16
measure: 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.
timeFrame: Weeks 1-16
measure: 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.
timeFrame: Week 4
measure: 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.
timeFrame: Week 8
measure: 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.
timeFrame: Weeks 1-16
measure: 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.
timeFrame: Week 4
measure: 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.
timeFrame: Week 16
measure: 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.
timeFrame: Weeks 1 and 6
measure: Assess the relationship between RIF concentrations and longitudinal functional outcomes as measured by longitudinal Modified Rankin Score (MRS) for children
timeFrame: 48 weeks
measure: To evaluate the safety of TBM treatment over eight weeks, by treatment Arm, as measured by Grade 3 or higher adverse events
timeFrame: 8 weeks
Secondary outcomes:
measure: 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
timeFrame: 72 weeks
measure: 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
timeFrame: Week 72
measure: 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
timeFrame: Week 72
measure: 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
timeFrame: Week 72
measure: 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
timeFrame: Week 72
measure: 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.
timeFrame: 48 weeks
Other outcomes:
Locations:
city: Pune
country: India
facility: Byramji Jeejeebhoy Government Medical College and Sassoon Hospital
state: Maharashtra
city: Chennai
country: India
facility: National Institute of Research in TB and Institute of Child Health
state: Tamil Nadu
city: Lilongwe
country: Malawi
facility: UNC Project- Malawi
state: Lilongwe District
Study officials:
affiliation: Johns Hopkins University
name: Kelly Dooley, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Paradkar MS, Devaleenal D B, Mvalo T, Arenivas A, Thakur KT, Wolf L, Nimkar S, Inamdar S, Giridharan P, Selladurai E, Kinikar A, Valvi C, Khwaja S, Gadama D, Balaji S, Yadav Kattagoni K, Venkatesan M, Savic R, Swaminathan S, Gupta A, Gupte N, Mave V, Dooley KE; TuBerculous Meningitis in Kids (TBM-KIDS) Study Team. Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial. Clin Infect Dis. 2022 Oct 29;75(9):1594-1601. doi: 10.1093/cid/ciac208.