Intensified Short Course Regimen for TBM in Adults

Tuberculous Meningitis Clinical Trial

— INSHORT  

Official title:

Comparative Evaluation of Intensified Short Course Regimen and Standard Regimen for Adults TB Meningitis : an Open-label Randomized Controlled Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05917340
• Other study ID #: NIRT-IEC No:2023 003
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: March 2024
• Est. completion date: September 2027

Study information

• Verified date: December 2023
• Source: Indian Council of Medical Research
• Contact: Dr Leeberk Raja Inbaraj, MBBS MD
• Phone: 044-28369527
• Email: leeberk.raja[@]icmr.gov.in
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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. Investigators 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. The investigators 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

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 372
• Est. completion date: September 2027
• Est. primary completion date: September 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

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

Exclusion Criteria:

Patients will not be eligible for the trial if they meet ANY of the following criteria

1. Known current/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 >450 ms in males and >460 ms in females measured in 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

• All participants with Rifampicin resistance will be excluded at baseline from the study. Participants with H, FQ and Z resistance identified from MGIT results done at baseline will be referred back to NTEP for appropriate management and their numbers will be compensated.

Related Conditions & MeSH terms

• Meningitis
• Tuberculosis, Meningeal
• Tuberculous Meningitis

Intervention

Drug:
• High dose rifampicin (25mg/kg)
Given for 2 months
• Moxifloxacin 400mg
Given for 2 months
• Aspirin 150 mg
Given for 2 months
• Isoniazid
Given for 6 months
• Pyrazinamide
Given for 6 months
• Steroid
Tapering dose of dexamethasone or prednisolone upto 8 weeks
• Rifampicin
Standard dose for 4 months after the initial treatment with high dose
• HRZE
2 months
• HRE
7-10 months as per TB program guidelines

Locations

Country	Name	City	State
India	ICMR- National Institute for Research in Tuberculosis	Chennai	Tamil Nadu

Sponsors (7)

Lead Sponsor	Collaborator
Indian Council of Medical Research	All India Institute of Medical Sciences, Jodhpur, Christian Medical College, Vellore, India, Jawaharlal Institute of Postgraduate Medical Education & Research, Madras Medical College, North Eastern Indira Gandhi Regional Institute of Health ans Medical Sciences, Rural Development Trust Hospital

Country where clinical trial is conducted

India, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mortality rate	Between two groups	12 months
Primary	Disability rate	Measured by Modified Rankin scale. A score of 0 to 2 will be considered as no disability and 3-5 will be considered as disability. 0 - no symptoms ; 5 - severe disability	12 months
Primary	Mortality rate		12 months
Primary	Disability rate	Measured by Modified Rankin scale. A score of 0 to 2 will be considered as no disability and 3-5 will be considered as disability. 0 - no symptoms ; 5 - severe disability	24 months
Secondary	Maximum Plasma Concentration [Cmax] of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients)	Plasma Cmax, cerebrospinal fluid [CSF] Cmax, and plasma/CSF Cmax ratio	Between week 1 & 2
Secondary	Time for maximal concentration of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients)	Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma/CSF Tmax ratio	Between week 1 & 2
Secondary	Area Under the Curve (AUC) of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients)	Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma/CSF Tmax ratio	Between week 1 & 2
Secondary	Grade 3 & 4 adverse events	Comparison of the number of participants who develop Grade 3 or Grade 4 adverse events (according to Division of AIDS (DAIDS) criteria) during treatment. Grade 1 - mild event ; Grade 2 - moderate event; Grade 3- severe event ;Grade 4 - potentially life-threatening	12 months
Secondary	Grade 3 & 4 adverse events	Comparison of the number of participants who develop Grade 3 or Grade 4 adverse events (according to Division of AIDS (DAIDS) criteria) during treatment. Grade 1 - mild event ; Grade 2 - moderate event; Grade 3- severe event ;Grade 4 - potentially life-threatening	24 months
Secondary	Quality of life (QoL) in both the arms and change in QoL during the follow up	Using WHO Short form -36 (SF-36), a questionnaire to assess health related outcomes	6,12 & 24 months