Clinical trial NCT02208427: Toward a Safe and Reachable Preventive Therapy for LTBI: a Multicenter Randomized Controlled Study in Taiwan
Official title: Toward a Safe and Reachable Preventive Therapy for LTBI: a Multicenter Randomized Controlled Study in Taiwan
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Latent Tuberculosis Infection
Keywords: isoniazid, LTBI, rifapentine, TST
Lead sponsor: National Taiwan University Hospital
Sponsor class: OTHER
First posted: 2014-08-05
Enrollment: 283
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: completion rate
timeFrame: 2 years
Secondary outcomes:
measure: side effect
timeFrame: 3 months in the 3M_RH group and 9 months in the 9M_INH group
measure: interruption
timeFrame: 3 months in the 3M_RH group and 9 months in the 9M_INH group
measure: active TB
timeFrame: 2 years after enrollment
Other outcomes:
Locations:
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
affiliation: National Taiwan University Hospital
name: Jann-Yuan Wang, MD. PhD.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.