Clinical trial NCT01582711: Study 33: Adherence to Latent Tuberculosis Infection Treatment 3HP SAT Versus 3HP DOT
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Latent Tuberculosis Infection
Keywords: LTBI
LTB
Latent TB
TB infection
Lead sponsor: Centers for Disease Control and Prevention
Sponsor class: FED
First posted: 2012-04-23
Enrollment: 1002
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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)

Primary outcomes:
measure: Treatment Completion Rate.
timeFrame: Up to 16 weeks from start of treatment.
Secondary outcomes:
measure: Treatment Completion Rates Between Participants Randomized to SAT Without Reminders Versus SAT With Weekly SMS Reminders
timeFrame: Up to 16 weeks from start of treatment.
measure: The Percentage of Participants Who Completed Treatment Based on SOC vs SOC Plus MEMS
timeFrame: Up to 16 weeks from start of treatment.
measure: Availability and Acceptability
timeFrame: Up to 16 weeks from start of treatment.
measure: Number and Percentage of Participants With Drug-related Grade 3 or 4 Adverse Events or Death
timeFrame: Up to 16 weeks from start of treatment.
measure: Number and Percentage of Participants Reason for Failure to Complete Treatment
timeFrame: Up to 16 weeks from start of treatment.
measure: Patient-specific Cost
timeFrame: Up to 20 weeks from start of treatment.
measure: Antituberculosis Drug Resistance
timeFrame: Up to 16 weeks from start of treatment.
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Denver
country: United States
facility: Denver Public Health Department
state: Colorado
city: Washington
country: United States
facility: Washington DC Veterans Affairs Medical Center
state: District of Columbia
city: New York
country: United States
facility: Columbia University College of Physicians and Surgeons and New York City Department of Health
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center and Nashville Metro Public Health Department
state: Tennessee
city: Fort Worth
country: United States
facility: University of North Texas Health Science Center at Fort Worth
state: Texas
city: San Antonio
country: United States
facility: Audie L. Murphy VA Hospital
state: Texas
city: San Antonio
country: United States
facility: South Texas - Department of State Health Services
state: Texas
city: Hong Kong
country: China
facility: TB and Chest service of Hong Kong
city: Soweto
country: South Africa
facility: Wits Health Consortium
city: Barcelona
country: Spain
facility: Agencia de Salut Publica - Barcelona, Spain and UNTHSC
Study officials:
affiliation: U.S. Centers for Disease Control and Prevention (CDC), Atlanta, USA.
name: Andrey S Borisov, MD, MPH
role: STUDY_DIRECTOR
affiliation: Division of Infectious Diseases, University of Colorado, Denver, USA.
name: Robert Belknap, MD
role: STUDY_CHAIR
affiliation: Division of Infectious Diseases, University of Colorado, Denver, USA.
name: Robert Belknap, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E, Hackman J, Hamilton CD, Menzies D, Kerrigan A, Weis SE, Weiner M, Wing D, Conde MB, Bozeman L, Horsburgh CR Jr, Chaisson RE; TB Trials Consortium PREVENT TB Study Team. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011 Dec 8;365(23):2155-66. doi: 10.1056/NEJMoa1104875.
citation: Centers for Disease Control and Prevention (CDC). Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep. 2011 Dec 9;60(48):1650-3.
citation: Shepardson D, Marks SM, Chesson H, Kerrigan A, Holland DP, Scott N, Tian X, Borisov AS, Shang N, Heilig CM, Sterling TR, Villarino ME, Mac Kenzie WR. Cost-effectiveness of a 12-dose regimen for treating latent tuberculous infection in the United States. Int J Tuberc Lung Dis. 2013 Dec;17(12):1531-7. doi: 10.5588/ijtld.13.0423.
citation: Sterling TR, Moro RN, Borisov AS, Phillips E, Shepherd G, Adkinson NF, Weis S, Ho C, Villarino ME; Tuberculosis Trials Consortium. Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study. Clin Infect Dis. 2015 Aug 15;61(4):527-35. doi: 10.1093/cid/civ323. Epub 2015 Apr 22.
citation: Moro RN, Scott NA, Vernon A, Tepper NK, Goldberg SV, Schwartzman K, Leung CC, Schluger NW, Belknap RW, Chaisson RE, Narita M, Machado ES, Lopez M, Sanchez J, Villarino ME, Sterling TR. Exposure to Latent Tuberculosis Treatment during Pregnancy. The PREVENT TB and the iAdhere Trials. Ann Am Thorac Soc. 2018 May;15(5):570-580. doi: 10.1513/AnnalsATS.201704-326OC.
citation: Belknap R, Holland D, Feng PJ, Millet JP, Cayla JA, Martinson NA, Wright A, Chen MP, Moro RN, Scott NA, Arevalo B, Miro JM, Villarino ME, Weiner M, Borisov AS; TB Trials Consortium iAdhere Study Team. Self-administered Versus Directly Observed Once-Weekly Isoniazid and Rifapentine Treatment of Latent Tuberculosis Infection: A Randomized Trial. Ann Intern Med. 2017 Nov 21;167(10):689-697. doi: 10.7326/M17-1150. Epub 2017 Nov 7.