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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: Understanding which of the two preventive regimens has the highest completion rate under supervision. Understanding the reasons of interruption in preventive therapy. 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.

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

Conditions
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Latent Tuberculosis Infection

Intervention / Treatment
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* Drug: Rifapentine and Isoniazid for 3 months
* Drug: Isoniazid for 9 months


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 3M_RH<br>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<br>* weekly oral Rifapentine 15 mg/kg plus Isoniazid 15 mg/kg for 12 doses<br>* Other names: Isoniazid;|
| Active Comparator: 9M_INH<br>Isoniazid for 9 months: daily oral isoniazid 5 mg/kg for 9 months | Drug: Isoniazid for 9 months<br>* daily oral Isoniazid 5 mg/kg for 9 months under supervision (conventional IPT)<br>* Other names: Isoniazid;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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isoniazid, LTBI, rifapentine, TST