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)
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Tuberculosis, Meningeal
- Sponsor
- Johns Hopkins University
- Enrollment
- 38
- Locations
- 3
- Primary Endpoint
- 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.
- Status
- Completed
- Last Updated
- 4 years ago
Overview
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.
Investigators
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.
Outcomes
Primary Outcomes
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
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.
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)
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
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
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
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),
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
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
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.
Secondary Outcomes
- 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(72 weeks)
- 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(Week 72)
- 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(Week 72)
- 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(Week 72)
- 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(Week 72)
- 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.(48 weeks)