Optimizing Treatment to Improve TBM Outcomes in Children

NCT ID: NCT02958709

Last Updated: 2021-10-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 38 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-02-22
• Study Completion Date: 2020-11-15

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.

Conditions

Tuberculosis, Meningeal

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

High-dose: RIF, INH, PZA, EMB

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

High dose: RIF, INH, PZA, LEVO

Intervention Type: DRUG

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

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.

Group Type: ACTIVE_COMPARATOR

Standard of care: RIF, INH, PZA, EMB

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Rifampin; Levaquin; 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.

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute for Research in Tuberculosis, Chennai, India

UNKNOWN

Sponsor Role: collaborator

University of North Carolina

OTHER

Sponsor Role: collaborator

B. J. Medical College, Pune

OTHER

Sponsor Role: collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kelly Dooley, MD,PhD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Locations

Byramji Jeejeebhoy Government Medical College and Sassoon Hospital

Pune, Maharashtra, India

National Institute of Research in TB and Institute of Child Health

Chennai, Tamil Nadu, India

UNC Project- Malawi

Lilongwe, Lilongwe District, Malawi

Countries

India; Malawi

References

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.

Reference Type: DERIVED

PMID: 35291004 (View on PubMed)

Other Identifiers

1R01HD074944-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB00051196

Identifier Type: -

Identifier Source: org_study_id