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

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.

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.

Study Overview

• Status: Completed
• Conditions: Latent Tuberculosis Infection
• Intervention / Treatment: Drug: isoniazid and rifapentine; Behavioral: Self Administered Therapy (SAT); Behavioral: SMS reminders

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.

• Study Type: Interventional
• Enrollment (Actual): 1002
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Hong Kong, China
    • TB and Chest service of Hong Kong
• South Africa
  • Soweto, South Africa
    • Wits Health Consortium
• Spain
  • Barcelona, Spain, 08023
    • Agencia de Salut Publica - Barcelona, Spain and UNTHSC
• United States
  • California
    • San Francisco, California, United States, 94110
      • University of California, San Francisco
  • Colorado
    • Denver, Colorado, United States, 80204
      • Denver Public Health Department
  • District of Columbia
    • Washington, District of Columbia, United States, 20422
      • Washington DC Veterans Affairs Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University College of Physicians and Surgeons and New York City Department of Health
  • North Carolina
    • Durham, North Carolina, United States, 27713
      • Duke University
  • Tennessee
    • Nashville, Tennessee, United States, 37232-0146
      • Vanderbilt University Medical Center and Nashville Metro Public Health Department
  • Texas
    • Fort Worth, Texas, United States, 76104-4802
      • University of North Texas Health Science Center at Fort Worth
    • San Antonio, Texas, United States, 78229-4404
      • Audie L. Murphy VA Hospital
    • San Antonio, Texas, United States, 78229-4404
      • South Texas - Department of State Health Services

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

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

3

Arms and Interventions

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

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.

Collaborators and Investigators

• Sponsor: Centers for Disease Control and Prevention
• Investigators: Study Director: Andrey S Borisov, MD, MPH, U.S. Centers for Disease Control and Prevention (CDC), Atlanta, USA.; Study Chair: Robert Belknap, MD, Division of Infectious Diseases, University of Colorado, Denver, USA.; Principal Investigator: Robert Belknap, MD, Division of Infectious Diseases, University of Colorado, Denver, USA.

Publications and helpful links

General Publications

• 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.
• 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.
• 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. Erratum In: MMWR Morb Mortal Wkly Rep. 2012 Feb 3;61:80.
• 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.
• 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.
• 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.

Helpful Links

• Home page of the Tuberculosis Trials Consortium (TBTC) funded by the U.S. Centers for Disease Control and Prevention (CDC)

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: February 10, 2012
• First Submitted That Met QC Criteria: April 19, 2012
• First Posted (Estimate): April 23, 2012

Study Record Updates

• Last Update Posted (Estimate): August 3, 2015
• Last Update Submitted That Met QC Criteria: July 30, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: Latent TB; LTBI; LTB; TB infection
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Latent Infection; Infections; Communicable Diseases; 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: CDC-NCHHSTP 6222; TBTC Study 33 (Other Identifier: CDC)