High-Dose Isoniazid Adjuvant Therapy for Multidrug Resistant Tuberculosis

Study Overview
=================
Brief Summary
-----------------
The need for a standardized treatment protocol for multidrug resistant tuberculosis (MDR-TB) in resource-limited countries is being increasingly recognized. This single center, double blind, randomized controlled trial was designed to compare the time required for sputum culture conversion and extent of radiological improvement in cases of MDR pulmonary tuberculosis when isoniazid was included (both at a regular dose and at a high dose) as an adjuvant to the standardized second line of treatment. The study was designed to test the hypothesis that inclusion of high-dose isoniazid will enhance the effectiveness of the second line of treatment in cases of MDR-TB without significantly increasing the toxicity.

Detailed Description
-----------------
Tuberculosis was declared a global emergency by the World Health Organization (WHO) in 1993. The global problem of tuberculosis is further complicated by a substantial increase in drug resistant tuberculosis. Available data suggest that drug resistant TB especially multi drug resistant may represent a public health threat in areas with a high prevalence of tuberculosis, suboptimal TB control programmes and/ or HIV. The cure rate of these cases has been reported to be lower than for non-drug resistant TB with a failure rate of 44%. New therapies for MDR-TB have not been introduced since the fluoroquinolones in the 1970s. Strains of Mycobacterium Tuberculosis (M. tub.) in H resistant cases often contain mixture of susceptible & resistant organisms. Use of high dose H (16- 20 mg/kg) can eliminate susceptible & those with low level resistance4. This Study was done to evaluate the role of isoniazid (INH) at high & normal dosages as an adjuvant therapy in treatment of patients with persistent culture positive pulmonary tuberculosis despite 6 months of continuous first line antitubercular treatment and on culture at least resistant to isoniazid and rifampicin.

Official Title
-----------------
A Randomized Control Trial Of High-Dose Isoniazid Adjuvant Therapy For Multidrug Resistant Tuberculosis

Conditions
-----------------
Tuberculosis, Multidrug-Resistant

Intervention / Treatment
-----------------
* Drug: Isoniazid
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Consecutive patients reporting to the study center Sputum-positive for acid-fast bacilli HIV-uninfected MDR-TB defined as resistance to at least the following two drugs: Isoniazid and Rifampicin. Exclusion Criteria: Unwilling to give consent Abnormal renal or hepatic profile History suggestive of isoniazid hypersensitivity Pregnancy Lactating mother Previous history of taking any of the following: kanamycin, prothionamide, levofloxacin, cycloserine and p-aminosalicylic acid

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Isoniazid<br>* High-dose isoniazid (16-18 mg/kg/day) in addition to standardized regimen that included the following: kanamycin (15 mg/kg/day), levofloxacin (7.5-15 mg/kg/day), protionamide (10-20 mg/kg/day), cycloserine (10-20 mg/kg/day) and p-aminosalicylic acid (150 mg/kg/day) Regular dose isoniazid (5 mg/kg/day) in addition to standard regimen that included the following: kanamycin (15 mg/kg/day), levofloxacin (7.5-15 mg/kg/day), protionamide (10-20 mg/kg/day), cycloserine (10-20 mg/kg/day) and p-aminosalicylic acid (150 mg/kg/day)<br>|
| Active Comparator: 2<br> | Drug: Isoniazid<br>* High-dose isoniazid (16-18 mg/kg/day) in addition to standardized regimen that included the following: kanamycin (15 mg/kg/day), levofloxacin (7.5-15 mg/kg/day), protionamide (10-20 mg/kg/day), cycloserine (10-20 mg/kg/day) and p-aminosalicylic acid (150 mg/kg/day) Regular dose isoniazid (5 mg/kg/day) in addition to standard regimen that included the following: kanamycin (15 mg/kg/day), levofloxacin (7.5-15 mg/kg/day), protionamide (10-20 mg/kg/day), cycloserine (10-20 mg/kg/day) and p-aminosalicylic acid (150 mg/kg/day)<br>|
| Placebo Comparator: 3<br> | Drug: Placebo<br>* Similar appearing and similarly packaged placebo tablets in addition to the standardized regimen that included the following: kanamycin (15 mg/kg/day), levofloxacin (7.5-15 mg/kg/day), protionamide (10-20 mg/kg/day), cycloserine (10-20 mg/kg/day) and p-aminosalicylic acid (150 mg/kg/day)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to sputum culture conversion |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extent of radiological improvement |  | 1 year | 
| Proportion with peripheral neuropathy |  | 1 year | 
| Proportion with hepatotoxicity |  | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Randomized control trial, multidrug resistant tuberculosis, isoniazid, standardized regimen, adjuvant therapy