High-Dose Isoniazid Adjuvant Therapy for Multidrug Resistant Tuberculosis

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

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.

Study Overview

• Status: Completed
• Conditions: Tuberculosis, Multidrug-Resistant
• Intervention / Treatment: Drug: Isoniazid; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: Isoniazid; 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)
Active Comparator: 2	Drug: Isoniazid; 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)
Placebo Comparator: 3	Drug: Placebo; 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to sputum culture conversion	1 year

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: GSVM Medical College
• Investigators: Study Chair: Subodh Katiyar, MD, GSVM Medical College, Kanpur, India; Principal Investigator: Shivesh Prakash, MBBS, GSVM Medical College, Kanpur, India; Principal Investigator: Shailesh Bihari, MD, GSVM Medical College, Kanpur, India; Principal Investigator: Hemant Kulkarni, MD, Lata Medical Research Foundation, Nagpur, India; Principal Investigator: Manju Mamtani, MD, Lata Medical Research Foundation, Nagpur, India

Study record dates

Study Major Dates

• Study Start: January 1, 2004
• Study Completion (Actual): December 1, 2006

Study Registration Dates

• First Submitted: August 6, 2007
• First Submitted That Met QC Criteria: August 6, 2007
• First Posted (Estimate): August 8, 2007

Study Record Updates

• Last Update Posted (Estimate): August 8, 2007
• Last Update Submitted That Met QC Criteria: August 6, 2007
• Last Verified: July 1, 2007

More Information

Terms related to this study

• Keywords: adjuvant therapy; isoniazid; Randomized control trial; multidrug resistant tuberculosis; standardized regimen
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Multidrug-Resistant; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Antitubercular Agents; Fatty Acid Synthesis Inhibitors; Isoniazid
• Other Study ID Numbers: TB chest - 1/2005