| CTRI Number |
CTRI/2023/05/053314 [Registered on: 31/05/2023] Trial Registered Prospectively |
| Last Modified On: |
21/12/2023 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
|
Type of Study
|
Drug |
| Study Design |
Randomized, Parallel Group, Active Controlled Trial |
|
Public Title of Study
|
Intensified short course regimen for adults with TB meningitis |
|
Scientific Title of Study
|
Comparative evaluation of intensified short course regimen and standard regimen for adults TB meningitis : an open label randomized controlled trial (INSHORT trial) |
| Trial Acronym |
INSHORT TRIAL |
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| NIL |
NIL |
|
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
|
| Name |
Dr Leeberk RajaI |
| Designation |
Scientist- E (Medical) |
| Affiliation |
ICMR-National Institute for Research in Tuberculosis |
| Address |
ICMR-National Institute for Research in Tuberculosis
No.1 Mayor Sathyamoorthy Road
Chethpet
Chennai
TAMIL NADU
600031
India |
| Phone |
044-28369527 |
| Fax |
|
| Email |
leeberk.raja@icmr.gov.in |
|
Details of Contact Person
Scientific Query
|
| Name |
Dr Leeberk RajaI |
| Designation |
Scientist- E (Medical) |
| Affiliation |
ICMR-National Institute for Research in Tuberculosis |
| Address |
ICMR-National Institute for Research in Tuberculosis
No.1 Mayor Sathyamoorthy Road
Chethpet
Chennai
TAMIL NADU
600031
India |
| Phone |
044-28369527 |
| Fax |
|
| Email |
leeberk.raja@icmr.gov.in |
|
Details of Contact Person
Public Query
|
| Name |
Dr Leeberk RajaI |
| Designation |
Scientist- E (Medical) |
| Affiliation |
ICMR-National Institute for Research in Tuberculosis |
| Address |
ICMR-National Institute for Research in Tuberculosis
No.1 Mayor Sathyamoorthy Road
Chethpet
Chennai
TAMIL NADU
600031
India |
| Phone |
044-28369527 |
| Fax |
|
| Email |
leeberk.raja@icmr.gov.in |
|
|
Source of Monetary or Material Support
|
| ICMR- National Institute for Research in Tuberculosis |
|
|
Primary Sponsor
|
| Name |
Dr Leeberk RajaI |
| Address |
No.1, Mayor Sathyamoorthy Road,
Chethpet
Chennai -31 |
| Type of Sponsor |
Research institution |
|
|
Details of Secondary Sponsor
|
|
|
Countries of Recruitment
|
India |
|
Sites of Study
|
| No of Sites = 6 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr Deepak |
AIIMS,Jodhpur |
Marudhar Industrial Area,
2nd Phase MIA 1st Phase,
Basni,
Jodhpur
Jodhpur
RAJASTHAN |
9116396922
deepak1007sharma@gmail.com |
| Dr Karthik G |
Christian Medical College |
Ida scudder Road, Vellore
Vellore
TAMIL NADU |
9894566467
karthikgunasekaran@yahoo.com |
| Dr Kadhiravan |
JIPMER |
JIPMER Campus Rd, Gorimedu,
Dhanvantari Nagar,
Pondicherry
PONDICHERRY |
9488819978
kadhir@jipmer.ac.in |
| Dr Nancy Glory Prof Balasubramanian |
Madras Medical College |
Near central Railway Station, Poonamallee High Rd, Park Town, Chennai, Tamil Nadu 600003
Chennai
TAMIL NADU |
9841123088
nancy_ranjit@yahoo.co.in |
| Dr Baiakmenlang synmon |
North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences |
Mawdiangdiang, Shillong
East Khasi Hills
MEGHALAYA |
9957641467
baiakmenlabaiakmenlangsynmon@gmail.com |
| Dr Gerardo Uria Alvarez |
Rural Development Trust Hospital |
Bathalapalli
Anantapur
Anantapur
ANDHRA PRADESH |
8897916035
gerardouria@hotmail.com |
|
Details of Ethics Committee
Modification(s)
|
| No of Ethics Committees= 7 |
| Name of Committee |
Approval Status |
| AIIMS, Jodhpur, Institutional Ethics Committee |
Submittted/Under Review |
| CMC,Vellore- Institutional Ethics Committee |
Submittted/Under Review |
| JIPMER, Institutional Ethics Committee |
Submittted/Under Review |
| MMC, Institutional Ethics Committee |
Submittted/Under Review |
| NEIGRIHMS, Institutional Ethics Committee |
Approved |
| NIRT-Institutional Ethics Committee |
Approved |
| Rural Development Trust Hospital |
Not Applicable |
|
|
Regulatory Clearance Status from DCGI
|
|
|
Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
(1) ICD-10 Condition: G01||Meningitis in bacterial diseases classified elsewhere, |
|
Intervention / Comparator Agent
Modification(s)
|
| Type |
Name |
Details |
| Intervention |
Arm - 1 (Intensified ATT with aspirin) |
Patients in this arm will receive a High dose of Rifampicin (Single dose - Once daily 25 mg/kg) and a weight based dose of Moxifloxacin (400mg once daily) along with Isoniazid and Pyrazinamide. They will also receive dexamethasone or equivalent dose of prednisolone as a tapering dose beginning with parenteral administration and switching over to orally later. Patients with MRC grade-1, grade-2 and 3 will receive steroids for 6 weeks and 8 weeks respectively. This regimen will also be intensified with 150mg of Aspirin once daily. This regimen will be continued for 2 months after which the patients will receive standard doses of Isoniazid, Rifampicin and Pyrazinamide for the next 4 months |
| Comparator Agent |
Arm -3 (Control arm) |
The control arm will receive treatment according to the standard national guidelines for EPTB. They will receive a first-line regimen consisting of 2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in fixed-dose combination (FDC) pills followed by 7-10 months of Rifampicin, isoniazid, and ethambutol (HRE) daily in a fixed-dose combination as per various weight bands in NTEP. They will also receive tapering dose of steroids at the discretion of treating clinician |
| Intervention |
Arm- 2 (Intensified ATT without aspirin) |
Participants in this arm will receive intensified ATT regimen similar to arm 1, but without aspirin. Aspirin (150mg) will be given once daily for 2 months along with intensified ATT. They will also receive dexamethasone or equivalent dose of prednisolone as a tapering dose beginning with parenteral administration and switching over to orally later. Patients with MRC grade-1, grade-2 and 3 will receive steroids for 6 weeks and 8 weeks respectively. This regimen will be continued for 2 months after which the patients will receive standard doses of Isoniazid, Rifampicin and Pyrazinamide for the next 4 months |
|
|
Inclusion Criteria
|
| Age From |
18.00 Year(s) |
| Age To |
99.00 Year(s) |
| Gender |
Both |
| Details |
A patient will be eligible for entry to the trial if ALL of the following conditions are satisfied
1.Adults (> 18 years) with or without HIV infection
2.Possible, probable or definite TBM according to Lancet consensus diagnostic criteria
3.Willing to give written informed consent
4.Is willing to have an HIV test.
5.Residing within 100 km of the study sites
6. Express willingness to attend the treatment centre for supervised treatment
7. Express willingness to adhere to the trial procedures and follow-up schedule.
8.Agrees to use effective barrier contraception during the period of the treatment in case of female participants
|
|
| ExclusionCriteria |
| Details |
Patients will not be eligible for the trial if they meet ANY of the following criteria
1. Known current or previous drug resistance to ATT (Rifampicin, INH, FQ)
2. Concurrent or known diagnosis any other meningitis such as bacterial, viral, and fungal.
3. Currently having an uncontrolled cardiac arrhythmia or ECG abnormalities which are
contradiction for the administration of moxifloxacin including prolonged QTc. QTc value define as more than 450 ms in males and more than 460 ms in females measured in the lead II or V5 on a standard 12-lead ECG.
4.Has clinical icterus or hepatic impairment characterized by serum bilirubin level above the normal laboratory reference range with abnormal liver enzymes or isolated alanine
aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels above 5 times the upper limit of the normal laboratory reference range
5. Previous history of anti-TB treatment, If any, should not exceed one month in the past and not more than 7 days in the preceding one month.
6. pregnant or lactating women
7. rapid clinical deterioration or very sick and moribund during the screening process, renal failure, liver disease or any condition (social or medical) that in the opinion of the investigator would make trial participation unreliable or unsafe.
8. Has a known allergy to any of the drugs proposed to be used in the trial regimen
|
|
|
Method of Generating Random Sequence
|
Permuted block randomization, fixed |
|
Method of Concealment
|
An Open list of random numbers |
|
Blinding/Masking
|
Open Label |
|
Primary Outcome
|
| Outcome |
TimePoints |
| Mortality and disability |
The primary outcome will be mortality and disability as measured by modified Rankin scale at 12 months and 24 months. i.e., time from randomization to death during the follow-up period. Survivors will be censored at the date they were last known to be alive (i.e., date of last follow-up visit, loss to follow-up or withdrawal). |
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
1. Pharmacokinetic parameters
2.Grade 3 and 4 adverse events
3. Quality of life |
1.Plasma concentrations of HRhZ and Moxifloxacin will be estimated and the effects of baseline patient covariates on trial drug pharmacokinetics and associated clinical endpoints will be evaluated.
2.Comparison of the number of participants who develop Grade 3 or Grade 4 adverse events during treatment.
3.QoL at baseline and at 6 months, 12 months, and 24 months will be assessed using a WHO Short form -36 (SF-36) questionnaire. |
|
Target Sample Size
Modification(s)
|
Total Sample Size="372"
Sample Size from India="372"
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" |
|
Phase of Trial
|
Phase 3 |
|
Date of First Enrollment (India)
|
01/09/2023 |
| Date of Study Completion (India) |
Applicable only for Completed/Terminated trials |
| Date of First Enrollment (Global) |
Date Missing |
| Date of Study Completion (Global) |
Applicable only for Completed/Terminated trials |
|
Estimated Duration of Trial
|
Years="3"
Months="6"
Days="0" |
|
Recruitment Status of Trial (Global)
|
Not Yet Recruiting |
| Recruitment Status of Trial (India) |
Not Yet Recruiting |
|
Publication Details
|
Nil |
|
Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
|
|
Brief Summary
|
Tuberculous meningitis (TBM) is the most lethal form of extra pulmonary tuberculosis. This devastating disease kills almost a third of its sufferers and disables a significant proportion of the survivors. TBM poses one of the most difficult diagnostic and therapeutic challenges in modern clinical practice. High-quality robust clinical trials have made a considerable contribution to the treatment of pulmonary tuberculosis in the last four decades. However, evidence from such clinical trials is lacking in TBM and the treatment remains uncertain. There is a significant variation in the choice, dose and duration of drugs between countries, institutions and clinicians. We propose a multi-centric open-label clinical trial to assess the efficacy of short-course anti-TB drugs with high dose rifampicin, and moxifloxacin along with conventional anti-TB drugs and adjuvant therapy with aspirin and corticosteroids. Controls will receive standard treatment as per national guidelines for TBM. We also aim to assess the safety and tolerability of high-dose Rifampicin and Moxifloxacin and the Pharmacodynamics and Pharmacokinetics parameters of ATT (Rifampicin, INH, Moxifloxacin and Pyrazinamide) in CSF between the two groups |