| CTRI Number |
CTRI/2017/03/008004 [Registered on: 03/03/2017] Trial Registered Prospectively |
| Last Modified On: |
01/09/2026 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
|
Type of Study
|
Drug |
| Study Design |
Randomized, Parallel Group, Multiple Arm Trial |
|
Public Title of Study
|
Optimizing Treatment to Improve TBM Outcomes in Children (TBM-KIDS) |
|
Scientific Title of Study
|
A Phase I/II Randomized, Open-label Trial to Evaluate the Pharmacokinetics, Safety, and Treatment Outcomes of Multidrug Treatment Including High Dose Rifampicin with or without Levofloxacin versus Standard Treatment for
Pediatric Tuberculous Meningitis
|
| Trial Acronym |
|
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| IRB00051196, V 5.0 12 October 2016 |
Protocol Number |
| NCT02958709 |
ClinicalTrials.gov |
|
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
|
| Name |
Dr Bella Devaleenal D |
| Designation |
Scientist C |
| Affiliation |
National Institute for Research in Tuberculosis |
| Address |
Department of Clinical Research, National Institute for Research in Tuberculosis No.1 Mayor Sathiyamoorthy Road, Chetpet Chennai
Chennai
TAMIL NADU
600031
India |
| Phone |
914428369600 |
| Fax |
914428362528 |
| Email |
bella.d@nirt.res.in |
|
Details of Contact Person
Scientific Query
|
| Name |
Dr Vidya Mave MD MPH |
| Designation |
CRS Leader and Director, BJMC CTU |
| Affiliation |
B.J. Government Medical College and Sassoon General Hospital |
| Address |
B.J. Government Medical College and Sassoon General Hospital,
Jai Prakash Narayan Road, Pune
Pune
MAHARASHTRA
411001
India |
| Phone |
919503646148 |
| Fax |
|
| Email |
vidyamave@gmail.com |
|
Details of Contact Person
Public Query
|
| Name |
Dr Nishi Suryavanshi PhD |
| Designation |
CRS Coordinator, BJMC CTU |
| Affiliation |
B.J. Government Medical College and Sassoon General Hospital |
| Address |
B.J. Government Medical College and Sassoon General Hospital
Jai Prakash Narayan Road
Pune
Pune
MAHARASHTRA
411001
India |
| Phone |
919823248979 |
| Fax |
|
| Email |
nishisuryavanshi@hotmail.com |
|
|
Source of Monetary or Material Support
|
| Eunice Kennedy Shriver National Institute for Child Health and Human Development,
National Institutes of Health,
6100 Executive Boulevard,
Rm. 4B11Bethesda,
MD 20892-7510
|
|
|
Primary Sponsor
|
| Name |
Johns Hopkins University School of Medicine |
| Address |
Division of Clinical Pharmacology
Johns Hopkins University School of Medicine
600 N. Wolfe Street, Osler 527
Baltimore, MD 21287
Phone: 011-410-955-3100
Fax: 011-410-614-9978
Email: kdooley1@jhmi.edu
|
| Type of Sponsor |
Research institution and hospital |
|
|
Details of Secondary Sponsor
|
| Name |
Address |
| BJ Government Medical College and Sassoon General Hospital |
Jai Prakash Narayan Road
Pune 411001. Maharashtra , India
|
| National Institute for Research in Tuberculosis |
No.1, Mayor Sathiyamoorthy Road, Chetpet, Chennai-600031 |
|
|
Countries of Recruitment
|
India
Malawi |
|
Sites of Study
|
| No of Sites = 3 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr Sandhya Khadse |
B.J. Government Medical College and Sassoon General Hospital |
Department of Pediatrics, B J Medical College & Sassoon General hospitals,
Jai Prakash Narayan Road
Pune-411001
Maharashtra, India
Pune
MAHARASHTRA |
91-20-26128000
sandhyakhadse@yahoo.com |
| DrElilarasi |
Institute of Child Health (ICH) and Hospital for Children |
Department of Pulmonology,
Institute of Child Health (ICH) and Hospital for Children
Halls Road, Egmore, Chennai 600008, India
Chennai
TAMIL NADU |
919840348891
unga_elil@yahoo.com |
| DrDBella Devaleenal |
National Institute for Research in Tuberculosis |
National Institute for Research in Tuberculosis,
No: 1, Mayor Sathyamoorthy Road, Chetpet, Chennai, 600031
Chennai
TAMIL NADU |
91-44-28369600
91-44-28362528
bella.d@nirt.res.in |
|
|
Details of Ethics Committee
|
| No of Ethics Committees= 3 |
| Name of Committee |
Approval Status |
| B J Medical College Sassoon General Hospitals |
Approved |
| Madras Medical college |
Approved |
| National Institute for Research in Tuberculosis |
Approved |
|
|
Regulatory Clearance Status from DCGI
|
|
|
Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
Tuberculosis Meningitis in Children, |
|
|
Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Comparator Agent |
2 months of Rifampicin, Isoniazid, Pyrazinamide, Ethambutol followed by 10 months of Rifampicin and Isoniazid |
During Weeks 9-48, patients will receive standard TB treatment Rifampicin (Rh): High dose, 30 mg/kg orally once daily Rifampicin (Rs): Standard dose, 15 mg/kg oral once daily(range 10-20 mg/kg) Levofloxacin (L):Age 6 months to 2 years 15 mg/kg Age 2 to 12 years, 20 mg/kg once daily Ethambutol (E): 20 mg/kg once daily (range 15-25 mg/kg) Isoniazid (H): 10 mg/kg once daily (range 7-15 mg/kg) Pyrazinamide (Z): 35 mg/kg once daily (range 30-40 mg/kg) |
| Intervention |
2 months of High dose Rifampicin, Isoniazid, Pyrazinamide, Ethambutol followed by 10 months of Rifampicin (Standard dose) and Isoniazid |
During Weeks 9-48, patients will receive standard TB treatment
Rifampicin (Rh): High dose, 30 mg/kg orally once daily
Rifampicin (Rs): Standard dose, 15 mg/kg oral once daily(range 10-20 mg/kg)
Levofloxacin (L):Age 6 months to 2 years 15 mg/kg
Age 2 to 12 years, 20 mg/kg
once daily
Ethambutol (E): 20 mg/kg once daily (range 15-25 mg/kg)
Isoniazid (H): 10 mg/kg once daily (range 7-15 mg/kg)
Pyrazinamide (Z): 35 mg/kg once daily (range 30-40 mg/kg)
|
| Intervention |
2 months of High dose Rifampicin, Isoniazid, Pyrazinamide, Levofloxacin followed by 10 months of Rifampicin (Standard dose) and Isoniazid |
During Weeks 9-48, patients will receive standard TB treatment Rifampicin (Rh): High dose, 30 mg/kg orally once daily Rifampicin (Rs): Standard dose, 15 mg/kg oral once daily(range 10-20 mg/kg) Levofloxacin (L):Age 6 months to 2 years 15 mg/kg Age 2 to 12 years, 20 mg/kg once daily Ethambutol (E): 20 mg/kg once daily (range 15-25 mg/kg) Isoniazid (H): 10 mg/kg once daily (range 7-15 mg/kg) Pyrazinamide (Z): 35 mg/kg once daily (range 30-40 mg/kg) |
|
|
Inclusion Criteria
|
| Age From |
6.00 Month(s) |
| Age To |
12.00 Year(s) |
| Gender |
Both |
| Details |
1. Weight > 6kg
2. Age greater than or equal to 6 months to less than or equal to 12 years and, in the opinion of the investigator, can tolerate the treatment and study participation.
3. Probable or definite TBM according to diagnostic criteria (Appendix II) or a positive Gene Xpert CSF test.
4.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.
4. Participant can comply with the protocol requirements in the opinion of the site investigator.
|
|
| ExclusionCriteria |
| Details |
1. TB treatment for more than 7 days within 30 days prior to enrollment
2. Exposure via close contact with someone with MDR-TB (or rifampicin mono-resistant TB) or personal history of MDR-TB (or rifampicin mono-resistant TB)
3. Known intolerance or allergy to any of the study drugs
4. Death imminent and expected within 24 hours, as assessed by the site investigator
5. Moderate to severe renal or liver dysfunction (Grade 2 or higher abnormalities of creatinine, ALT, or direct bilirubin)
6. 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)
7.Having participated in other clinical studies with investigational agents or treatments within 8 weeks prior to enrollment.
8.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.
|
|
|
Method of Generating Random Sequence
|
Computer generated randomization |
|
Method of Concealment
|
Sequentially numbered, sealed, opaque envelopes |
|
Blinding/Masking
|
Open Label |
|
Primary Outcome
|
| Outcome |
TimePoints |
1.Population plasma and CSF PK of rifampicin and levofloxacin: A population modelling approach will be used to describe pharmacokinetics of rifampicin and levofloxacin in plasma and CSF. This PK model will represent an immediate basis for linkage to the longitudinal efficacy measurements.
2.Population PK/PD model assessing the relationship between PK of rifampicin and the primary efficacy endpoint, Modified Ranking Score (MRS) for children.
3.Grade 3 or higher AEs during treatment phase
|
18 months
|
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
1.Overall longitudinal cognitive score and subscale (gross motor, visual reception, fine motor receptive language, expressive language) MSEL scoring system longitudinally, at baseline, 2, 12, and 18 months.
2.Favorable TB treatment response at 48 weeks will be reported as a binary variable (favorable or unfavorable) at 48 weeks.
|
2,12,18 months |
|
|
Target Sample Size
|
Total Sample Size="120"
Sample Size from India="80"
Final Enrollment numbers achieved (Total)= "37"
Final Enrollment numbers achieved (India)="27" |
|
Phase of Trial
|
Phase 1/ Phase 2 |
|
Date of First Enrollment (India)
|
06/03/2017 |
| Date of Study Completion (India) |
30/06/2021 |
| Date of First Enrollment (Global) |
06/03/2017 |
| Date of Study Completion (Global) |
30/06/2021 |
|
Estimated Duration of Trial
|
Years="2"
Months="6"
Days="0" |
Recruitment Status of Trial (Global)
Modification(s)
|
Completed |
| Recruitment Status of Trial (India) |
Completed |
|
Publication Details
|
none yet |
|
Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
|
Brief Summary
Modification(s)
|
Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had
stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and
3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered
to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and
expressive language domains (P < .01). in this first-ever trial of antimicrobials specifically for pediatric TBM, functional outcomes were favorable, across arms.
Neurocognitive outcomes were statistically better in children who received high-dose rifampicin compared to those who did not, but this finding requires replication in larger trials. There was no discernable benefit of levofloxacin, though small sample size precluded a thorough assessment of the potential risks and benefits of levofloxacin substitution for ethambutol.
|