Study 33: Adherence to Latent Tuberculosis Infection Treatment 3HP SAT Versus 3HP DOT

Study Overview
=================
Brief Summary
-----------------
The study is an open label, multicenter, randomized (three arms: DOT (standard control), SAT, SAT with SMS reminders) controlled clinical trial. The trial is conducted in patients diagnosed with latent tuberculosis infection (LTBI) who are recommended for treatment. The primary objective is to evaluate adherence to a three-month (12-dose) regimen of weekly rifapentine and isoniazid (3RPT/INH) given by directly observed therapy (DOT) compared to self-administered therapy (SAT). The secondary objectives: To compare the treatment completion rates between participants randomized to SAT without reminders versus SAT with weekly SMS reminders To evaluate the timing of doses and patterns of adherence to once weekly RPT/INH among participants who complete treatment and those who discontinue therapy prior to completion. To determine the availability and acceptability of using SMS reminders among all patients consenting to participate in the study. To determine the toxicity and tolerability by comparing the rates of any drug-related grade 3 or 4 adverse events or death between the DOT arm and the SAT arms (both combined and individually) To compare the frequency, timing, and causes for failure to complete treatment between the DOT arm and the SAT arms To collect patient-specific cost data related to the 3 treatment arms To describe the pattern of antituberculosis drug resistance among Mycobacterium tuberculosis strains cultured from participants who develop active TB.

Detailed Description
-----------------
The World Health Organization (WHO) estimates that approximately 2.3 billion people are infected with Mycobacterium tuberculosis. Approximately 1.7 million people die of TB each year, the second most common infectious cause of death in the world. In order to improve TB control worldwide, an affordable, effective, short course treatment for latent TB infection (LTBI) is a global priority. Candidates for LTBI treatment are those persons with a positive TST or IGRA, particularly if they also have risk factors for progressing to active TB, including individuals likely to be recently infected. The Prevent TB Study (TBTC Study 26) was an open-label, randomized, phase III controlled clinical trial with over 8,000 high risk TST reactors enrolled. The study compared rifapentine and INH (3RPT/INH) given once-weekly by directly observed treatment (DOT) for 3 months (12 doses) compared with 9 months of daily, self-administered INH. The results demonstrated the safety and efficacy of the shorter regimen. Moreover, the once weekly therapy had significantly higher treatment completion rates than the standard 9 INH regimen. One of the most effective strategies for assuring adherence with therapy is to have each dose of medication directly administered by a health care worker who observes and records the ingestion of the drugs. DOT for active TB has been successfully used in many settings to improve treatment completion, however cost and logistical constraints of DOT remain. The estimated cost of giving 12 weekly DOT doses to all LTBI patients is likely prohibitive for TB control programs worldwide. This may lead to a decreased uptake of the new regimen or implementation using SAT where adherence has not been studied. Therefore, to apply the Prevent TB study results more broadly, a new study evaluating treatment completion of 3 RPT/INH given as SAT is conducted. Medication adherence is defined by whether patients take a treatment as prescribed. The effectiveness of any treatment is determined largely by adherence. In clinical practice and research, indirect measures of adherence are commonly used. Indirect measures of adherence include patient self-report, evaluation of pharmacy dispensation records, pill counts, and the use of electronic prescription bottle monitors. Patient self-reported adherence is accurate when non-adherence is reported but tends to overestimate true adherence. Self-report is not discerning enough to be utilized as a sole measure of adherence in research settings where adherence is the primary outcome. Pill counts have been utilized successfully in research and clinical settings for real-time assessment but also tend to overestimate adherence. Electronic drug monitors such as the Medication Event Monitoring System (MEMS) are the best available tools to assess the timing and patterns of adherence. This study uses a combination of indirect measures including MEMS, pill counts, and self-report to provide the most accurate assessment of adherence to once weekly, self-administered RPT/INH. The number of cellular phone users globally has increased dramatically in the last decade. Cell phones and SMS reminders have been used successfully in randomized controlled clinical trials to improve adherence to vaccines, HIV medications, and asthma treatment. SMS appear to be cost-effective ways to reach patients in remote locations. This study examines effect of SMS on medication adherence. The goal of this open label clinical trial is to compare the adherence to 3RPT/INH given by DOT versus SAT or SAT with a weekly SMS reminder. The primary assessment of adherence will be treatment completion which is defined as taking at least 90% of the doses (11/12 doses of each drug) within 16 weeks of initiation. Secondary objectives include evaluating the patterns of adherence in participants who fail to complete, determining the feasibility and impact of using SMS reminders on treatment completion with SAT, evaluating the tolerability and any adverse events associated with each treatment arm, monitoring for the development of active TB, determining the drug susceptibility for participants who develop active TB, and measuring important patient-related expenditures associated with each study arm. The trial will be conducted in patients diagnosed with LTBI and recommended for treatment.

Official Title
-----------------
TBTC Study 33. An Evaluation of Adherence to Latent Tuberculosis Infection (LTBI) Treatment With 12 Doses of Once Weekly Rifapentine (RPT) and Isoniazid (INH) Given as Self-administered (SAT) Versus Directly-observed Therapy (DOT): iAdhere.

Conditions
-----------------
Latent Tuberculosis Infection

Intervention / Treatment
-----------------
* Behavioral: Self Administered Therapy (SAT)
* Behavioral: SMS reminders
* Drug: isoniazid and rifapentine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and non-pregnant, non-nursing females Age > 18 years Weight > 45kg and considered appropriate to receive RPT 900mg and INH 900mg once weekly by the local site investigator Willingness to provide signed informed consent. Clinical indication for LTBI treatment such as: 1) persons with a positive tuberculin skin test (TST) as defined by CDC criteria or a positive interferon-gamma release assay (IGRA) defined per the manufacturers' guidelines AND one of the following: close contact to someone with culture confirmed TB, HIV infection, or > 2 cm2 of pulmonary parenchymal fibrosis on chest X-ray and no prior history of TB treatment; 2) TST or IGRA converters defined as a documented change from negative to positive within a two-year period; 3) Persons with any other clinical indication for LTBI treatment as locally defined including persons with a negative TST and/or IGRA (e.g. HIV-infected close contacts to an active pulmonary TB cases) Exclusion Criteria: Confirmed or suspected active TB Contacts to a source case with known resistance to isoniazid or rifampin Persons with a history (by written documentation or self-report) of ever receiving > 1 week of treatment for active or latent TB, regardless of whether the course was completed, because adherence may be different in people who previously took TB treatment Persons who are not considered candidates for SAT by the local investigator History of sensitivity or intolerance to isoniazid or rifamycins Serum alanine aminotransferase (ALT, SGPT) > 5x upper limit of normal among persons in whom an ALT is determined Persons with HIV-infection who 1) have a CD4 < 350 or 2) are currently receiving or planning to receive antiretroviral therapy in the first 120 days after study initiation (e.g., HIV-1 protease inhibitors, nucleoside or non-nucleoside reverse transcriptase inhibitors, CCR5 inhibitors or integrase inhibitors)

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 3HP Directly Observed Therapy (DOT)<br>900mg of isoniazid plus 900mg of rifapentine given weekly for 3 months (12 weeks, 12 doses) under Directly Observed Therapy (DOT) | Drug: isoniazid and rifapentine<br>* rifapentine (PRIFTIN, RPT) 900 mg and isoniazid (INH) 900mg, once-weekly, for 12 weeks (12 doses)<br>* Other names: I;|
| Experimental: 3HP Self Administered Therapy (SAT)<br>900mg of isoniazid plus 900mg of rifapentine given weekly for 3 months (12 weeks, 12 doses) as patient Self Administered Therapy (SAT) | Behavioral: Self Administered Therapy (SAT)<br>* Self Administered Therapy (SAT)<br>* Other names: SAT;Drug: isoniazid and rifapentine<br>* rifapentine (PRIFTIN, RPT) 900 mg and isoniazid (INH) 900mg, once-weekly, for 12 weeks (12 doses)<br>* Other names: I;|
| Experimental: 3HP SAT with SMS Reminders<br>900mg of isoniazid plus 900mg of rifapentine given weekly for 3 months (12 weeks, 12 doses) as patient Self Administered Therapy (SAT). In addition, patient receives phone Short Message Service (SMS) reminders weekly. | Behavioral: Self Administered Therapy (SAT)<br>* Self Administered Therapy (SAT)<br>* Other names: SAT;Behavioral: SMS reminders<br>* Short Message Service (SMS) text reminders<br>* Other names: phone text reminder;Drug: isoniazid and rifapentine<br>* rifapentine (PRIFTIN, RPT) 900 mg and isoniazid (INH) 900mg, once-weekly, for 12 weeks (12 doses)<br>* Other names: I;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment completion rate. | Treatment completion rates between participants randomized to DOT vs SAT without reminders and DOT versus SAT with weekly SMS reminders. Treatment completion is defined as taking at least 90% of the doses (11/12 doses of each drug) within 16 weeks of treatment initiation. | Up to 16 weeks from start of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment completion rates between the DOT arm and the SAT arm with SMS reminders |  | Up to 16 weeks from start of treatment. | 
| Treatment completion rates between the DOT arm and the SAT arm without SMS reminders. |  | Up to 16 weeks from start of treatment. | 
| Treatment completion rates between the SAT arm with SMS reminders and the SAT arm without SMS reminders. |  | Up to 16 weeks from start of treatment. | 
| Rates of treatment discontinuation by category. | Categories of treatment discontinuation include: due to adverse events due to patient choice due to inability to locate patient other | Up to 16 weeks from start of treatment. | 
| Rates of SMS reminders utilization. |  | Up to 16 weeks from start of treatment. | 
| Rates of any drug-related grade 3, 4, or 5 adverse events between the DOT arm and the SAT arms (both combined and individually) |  | Up to 20 weeks from start of treatment. | 
| Rates and timing of treatment discontinuations between the DOT arm and the SAT arms (both combined and individually). | This includes discontinuations due to: non-adherence any adverse event (AE) a diagnosis of active TB other reasons | Up to 16 weeks from start of treatment. | 
| Cost of treatment (in USD or QALY) associated with adverse events between the DOT arm and the SAT arms (both combined and individually). |  | Up to 20 weeks from start of treatment. | 
| Rates of antituberculosis drug resistance among Mycobacterium tuberculosis strains cultured from patients who develop active TB between the DOT arm and the SAT arms (both combined and individually). |  | up to 2 years from start of treatment. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
LTBI, LTB, Latent TB, TB infection