Optimizing Treatment to Improve TBM Outcomes in Children

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)

Sponsors

Lead Sponsor: Johns Hopkins University

Collaborator: National Institute for Research in Tuberculosis, Chennai, India
University of North Carolina
B. J. Medical College, Pune
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Source 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.

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.

Overall Status Completed
Start Date 2017-02-22
Completion Date 2020-11-15
Primary Completion Date 2020-11-15
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
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. Weeks 1-16
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. Weeks 1-16
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. Weeks 1-16
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. Weeks 1 and 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. Weeks 1-16
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. Week 4
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. Week 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. Week 16
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. Weeks 1-16
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. Week 4
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. Week 8
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. Weeks 1-16
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. Week 4
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. Week 16
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. Weeks 1 and 6
Assess the relationship between RIF concentrations and longitudinal functional outcomes as measured by longitudinal Modified Rankin Score (MRS) for children 48 weeks
To evaluate the safety of TBM treatment over eight weeks, by treatment Arm, as measured by Grade 3 or higher adverse events 8 weeks
Secondary Outcome
Measure Time Frame
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
Enrollment 38
Condition
Intervention

Intervention Type: Drug

Intervention Name: High-dose: RIF, INH, PZA, EMB

Description: high-dose rifampicin plus standard dose H,Z,E, given for 8 weeks in treatment Arms 1 and 2

Arm Group Label: high dose RIF, INH, PZA, EMB

Other Name: Rifampin

Intervention Type: Drug

Intervention Name: High dose: RIF, INH, PZA, LEVO

Description: high-dose rifampicin plus standard dose H,Z, with levofloxacin substituted for ethambutol for 8 weeks in treatment Arm 2

Arm Group Label: high dose RIF, INH, PZA, LEVO

Other Name: Levaquin

Intervention Type: Drug

Intervention Name: Standard of care: RIF, INH, PZA, EMB

Description: standard doses of R,H,Z,E given for 8 weeks in treatment Arm 3, control arm.

Arm Group Label: standard dose RIF, INH, PZA, EMB

Other Name: control group

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.

Gender:

All

Minimum Age:

6 Months

Maximum Age:

12 Years

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Kelly Dooley, MD,PhD Principal Investigator Johns Hopkins University
Location
Facility:
Byramji Jeejeebhoy Government Medical College and Sassoon Hospital | Pune, Maharashtra, 411001, India
National Institute of Research in TB and Institute of Child Health | Chennai, Tamil Nadu, 600031, India
UNC Project- Malawi | Lilongwe, Lilongwe District, Malawi
Location Countries

India

Malawi

Verification Date

2020-08-01

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 3
Arm Group

Label: high dose RIF, INH, PZA, EMB

Type: Experimental

Description: 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.

Label: high dose RIF, INH, PZA, LEVO

Type: Experimental

Description: Arm 2 participants will receive high-dose rifampicin plus levofloxacin for 8 weeks, in addition to standard doze pyrazinamide and isoniazid.

Label: standard dose RIF, INH, PZA, EMB

Type: Active Comparator

Description: Arm 3 participants will receive standard of care dose rifampicin plus ethambutol for 8 weeks, in addition to standard doze pyrazinamide and isoniazid.

Acronym TBM-KIDS
Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

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