Toward a Safe and Reachable Preventive Therapy for LTBI: a Multicenter Randomized Controlled Study in Taiwan

Background:

Tuberculosis (TB) remains the most important infectious disease in the world. Keys to successful control of TB is rapid diagnosis, prompt treatment, as well as effective preventive therapy for contacts with latent TB infection (LTBI). Current methods for the diagnosis of LTBI are tuberculin skin test (TST) and interferon-gamma release assay (IGRA). For preventive therapy, the recommended regimens include daily isoniazid for 9 months and daily rifampicin for 4 months. By incorporating long-acting rifapentine, a new regimen combining weekly rifapentine and high-dose isoniazid for a total of 12 doses has been proven of equal potency and toxicity. However, the treatment completion rate is much higher in weekly treatment for 3 months than daily treatment for 9 months. It is reasonable that using rifapentine-based preventive therapy can markedly increase the completion rate. However, study is lacking, especially in Asia, the high endemic area of TB.

With the effort of all health care workers and public health personnel, the incidence of TB in Taiwan has gradually declined in recent 10 years. In order to maintain the trend of decreasing in incidence, preventive therapy for LTBI become more and more important. However, which is the best preventive regimen for LTBI is still unknown. Therefore, we conduct the prospective randomized multicenter studies to compare the treatment completion rate of two regimens in Taiwan. The first regimen is daily isoniazid for 9 months. The second is weekly rifapentine plus high-dose isoniazid for 3 months.

Study Overview

• Status: Unknown
• Conditions: Latent Tuberculosis Infection
• Intervention / Treatment: Drug: Rifapentine and Isoniazid for 3 months; Drug: Isoniazid for 9 months

Detailed Description

Background:

Tuberculosis (TB) remains the most important infectious disease in the world. Keys to successful control of TB is rapid diagnosis, prompt treatment, as well as effective preventive therapy for contacts with latent TB infection (LTBI). Current methods for the diagnosis of LTBI are tuberculin skin test (TST) and interferon-gamma release assay (IGRA). For preventive therapy, the recommended regimens include daily isoniazid for 9 months and daily rifampicin for 4 months. By incorporating long-acting rifapentine, a new regimen combining weekly rifapentine and high-dose isoniazid for a total of 12 doses has been proven of equal potency and toxicity. However, the treatment completion rate is much higher in weekly treatment for 3 months than daily treatment for 9 months. It is reasonable that using rifapentine-based preventive therapy can markedly increase the completion rate. However, study is lacking, especially in Asia, the high endemic area of TB.

With the effort of all health care workers and public health personnel, the incidence of TB in Taiwan has gradually declined in recent 10 years. In order to maintain the trend of decreasing in incidence, preventive therapy for LTBI become more and more important. However, which is the best preventive regimen for LTBI is still unknown. Therefore, we conduct the prospective randomized multicenter studies to compare the treatment completion rate of two regimens in Taiwan. The first regimen is daily isoniazid for 9 months. The second is weekly rifapentine plus high-dose isoniazid for 3 months.

Specific Aims:

1. Understanding which of the two preventive regimens has the highest completion rate under supervision.
2. Understanding the reasons of interruption in preventive therapy.
3. Comparing the side effect profile of the two preventive regimens in Taiwan.

Methods:

In this prospective multicenter study, we will enroll close contacts aged >=12 with positive TST. Chest radiography and sputum studies, if necessary, will be performed to exclude active pulmonary TB. After performing baseline IGRA, participants will be randomized into 2 groups with different preventive regimens. The first regimen is daily isoniazid for 9 months. The second is weekly rifapentine plus high-dose isoniazid for 3 months. The primary outcome is treatment completion rate of the two preventive regimens. The secondary outcome is toxicity. All participant will be followed for 2 years and screen for the development of active pulmonary TB by chest radiography and sputum studies if necessary. The reasons for treatment incompletion will be recorded.

• Study Type: Interventional
• Enrollment (Actual): 283
• Phase: Phase 3

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Household contacts of TB or TB contacts in schools or densely-populated institutes
• Age ≥12 year-old
• Index case having smear-positive pulmonary TB
• Contact with index case for >8 hours within single day or >40 hours within total transmissible period
• TST ≥10 mm within one month
• Born in 1986 or after (not applicable in the National Taiwan University Hospital Hsin-Chu branch and Chang-Hua Hospital)

Exclusion Criteria:

• Clinical or radiographic evidence of active TB
• Index case having culture-negative pulmonary TB
• Index case having Isoniazid or Rifampin-resistant TB
• Receiving medications with significant interactions with Isoniazid, Rifampin, or Rifapentine
• Allergy to Isoniazid, Rifampin, or Rifapentine
• Sero-positive for hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
• Documented liver cirrhosis
• Human immunodeficiency virus (HIV) infection
• Receiving immunosuppressants
• Receiving biological agents
• Hemoglobin <8 g/dL
• Neutrophil <750000 /mL
• Total bilirubin >2.5 mg/dL
• Aspartic transaminase (AST) or alanine transaminase (ALT) >2 folds of upper limit of normal (ULN)
• Pregnant or breast-feeding
• Life expectancy <3 years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 3M_RH; Rifapentine and Isoniazid for 3 months: weekly oral rifapentine 15 mg/kg plus isoniazid 15 mg/kg for 12 doses	Drug: Rifapentine and Isoniazid for 3 months; weekly oral Rifapentine 15 mg/kg plus Isoniazid 15 mg/kg for 12 doses; Other Names: Priftin; Isoniazid
Active Comparator: 9M_INH; Isoniazid for 9 months: daily oral isoniazid 5 mg/kg for 9 months	Drug: Isoniazid for 9 months; daily oral Isoniazid 5 mg/kg for 9 months under supervision (conventional IPT); Other Names: Isoniazid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
completion rate	This prospective randomized interventional study is aimed to assess the completion rate of two different preventive regimens for LTBI by intent-to-treat analysis. Interruption of preventive therapy due to any reasons will be considered as incompletion.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
side effect	To evaluate the side effect profile (especially hepatotoxicity, defined as AST and/or ALT ≥2 ULN) of the two preventive regimens	3 months in the 3M_RH group and 9 months in the 9M_INH group
interruption	To calculate the number of participants with interruption in preventive therapy and to know the reasons of interruption by questionnaire	3 months in the 3M_RH group and 9 months in the 9M_INH group
active TB	To know the rate of active TB within subsequent 2 years	2 years after enrollment

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Investigators: Principal Investigator: Jann-Yuan Wang, MD. PhD., National Taiwan University Hospital

Publications and helpful links

General Publications

• Sun HY, Huang YW, Huang WC, Chang LY, Chan PC, Chuang YC, Ruan SY, Wang JY, Wang JT. Twelve-dose weekly rifapentine plus isoniazid for latent tuberculosis infection: A multicentre randomised controlled trial in Taiwan. Tuberculosis (Edinb). 2018 Jul;111:121-126. doi: 10.1016/j.tube.2018.05.013. Epub 2018 Jun 7.

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Anticipated): December 1, 2016
• Study Completion (Anticipated): December 1, 2016

Study Registration Dates

• First Submitted: July 31, 2014
• First Submitted That Met QC Criteria: August 3, 2014
• First Posted (Estimate): August 5, 2014

Study Record Updates

• Last Update Posted (Estimate): December 15, 2016
• Last Update Submitted That Met QC Criteria: December 14, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: isoniazid, LTBI, rifapentine, TST
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Latent Infection; Tuberculosis; Latent Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Leprostatic Agents; Antitubercular Agents; Antibiotics, Antitubercular; Fatty Acid Synthesis Inhibitors; Rifapentine; Isoniazid
• Other Study ID Numbers: 201309055MINC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided