Optimizing Treatment to Improve TBM Outcomes in Children

NCT02958709 | Completed Phase 1 DMC

• 2 other identifiers: IRB000511961R01HD074944-01A1
• Study Type: interventional
• Target: 38
• Locations: 2 countries
• Sites: 3

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.

Conditions

Tuberculosis, Meningeal

Outcome Measures

Primary Outcomes (17)

• 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.

  Apparent volume of distribution estimated using population PK model

  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.

  Examines the apparent total clearance of rifampicin from plasma after oral administration. Unit of Measure: Volume/time or volume/time/kg

  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.

  Examines the absorption rate constant for orally administered rifampicin. Unit of Measure: will be represented as a decimal.

  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.

  Examines the ratio of CSF concentration to Plasma concentration of rifampicin Unit of Measure: will be represented as a decimal

  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.

  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)

  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.

  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)

  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.

  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)

  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.

  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)

  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.

  Examines the apparent total clearance of levofloxacin from plasma after oral administration. Unit of Measure: Volume/time or volume/time/kg

  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.

  Examines the apparent total clearance of levofloxacin from plasma after oral administration. Unit of Measure: Volume/time or volume/time/kg

  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.

  Examines the apparent total clearance of levofloxacin from plasma after oral administration. Unit of Measure: Volume/time or volume/time/kg

  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.

  Examines the absorption rate constant for orally administered levofloxacin. Unit of Measure: will be represented as a decimal.

  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.

  Examines the absorption rate constant for orally administered levofloxacin. Unit of Measure: will be represented as a decimal.

  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.

  Examines the absorption rate constant for orally administered levofloxacin. Unit of Measure: will be represented as a decimal.

  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.

  Examines the ratio of CSF to Plasma concentration of levofloxacin Unit of Measure: will be represented as a decimal

  Weeks 1 and 6

• Assess the relationship between RIF concentrations and longitudinal functional outcomes as measured by longitudinal Modified Rankin Score (MRS) for children

  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),

  48 weeks

• To evaluate the safety of TBM treatment over eight weeks, by treatment Arm, as measured by Grade 3 or higher adverse events

  Grade 3 Adverse Events as defined by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events

  8 weeks

Secondary Outcomes (6)

• 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

Study Arms (3)

high dose RIF, INH, PZA, EMB

EXPERIMENTAL

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 RIF, INH, PZA, LEVO

EXPERIMENTAL

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

standard dose RIF, INH, PZA, EMB

ACTIVE COMPARATOR

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

Interventions

High-dose: RIF, INH, PZA, EMB DRUG

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

Also known as: Rifampin

high dose RIF, INH, PZA, EMB

High dose: RIF, INH, PZA, LEVO DRUG

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

Also known as: Levaquin

high dose RIF, INH, PZA, LEVO

Standard of care: RIF, INH, PZA, EMB DRUG

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

Also known as: control group

standard dose RIF, INH, PZA, EMB

Eligibility Criteria

• Age: 6 Months - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (3)

Byramji Jeejeebhoy Government Medical College and Sassoon Hospital

Pune, Maharashtra, 411001, India

Location

National Institute of Research in TB and Institute of Child Health

Chennai, Tamil Nadu, 600031, India

Location

UNC Project- Malawi

Lilongwe, Lilongwe District, Malawi

Location

Related Publications (1)

• 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.

  PMID: 35291004 DERIVED

MeSH Terms

Conditions

Tuberculosis, Meningeal

Interventions

Rifampin; Isoniazid; NSC 366140; Levofloxacin; Control Groups

Condition Hierarchy (Ancestors)

Meningitis, Bacterial; Central Nervous System Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Tuberculosis, Central Nervous System; Tuberculosis, Extrapulmonary; Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Ofloxacin; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Epidemiologic Research Design; Epidemiologic Methods; Investigative Techniques; Research Design; Methods

Study Officials

• Kelly Dooley, MD,PhD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 13, 2016
• First Posted: November 8, 2016
• Study Start: February 22, 2017
• Primary Completion: November 15, 2020
• Study Completion: November 15, 2020
• Last Updated: October 28, 2021

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will not share

Locations

IN (2); MA (1)