A Pilot Clinical Trial Characterizing Use of Ingestion Sensor Enabled Rifamate in Comparison to Directly Observed Therapy for the Treatment of Tuberculosis
Phase: PHASE4
Conditions: Tuberculosis
Sponsor: University of California, San Diego

 
 
 
 
AHF TB 001 
 
Wirelessly Observed Therapy in Comparison to Directly Observed Therapy for the 
Treatment of Tuberculosis 
 
A Pilot Clinical Trial Characterizing Use of Ingestion Sensor Enabled Rifamate 
in Comparison to Directly Observed Therapy 
for the Treatment of Tuberculosis 
 
 
 
A Clinical Trial Funded by: 
The Alliance Healthcare Foundation & Specialists in Global Health 
 
Technology Provided by: 
Proteus Digital Health, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Chair: Sara H. Browne, MD, MPH 
 
 
 
Version 2.3 
March 25, 2015 
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
2 
CONTENTS 
 
PROTOCOL TEAM ROSTER ................................................................................................... 4 
ABBREVIATIONS USED ........................................................................................................... 6 
SITES PARTICIPATING IN THE STUDY .............................................................................. 8 
SCHEMA ..................................................................................................................................... 10 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES .............................................................. 12 
1.1 
Hypotheses ............................................................................................................ 12 
1.2 
Study Objectives ................................................................................................... 12 
2.0 
INTRODUCTION .......................................................................................................... 13 
2.1 
Background ........................................................................................................... 13 
2.2 
Rationale ............................................................................................................... 14 
3.0 
STUDY DESIGN ............................................................................................................. 17 
3.1 
Non-Significant Risk Study .................................................................................. 18 
3.2 
Study Population ................................................................................................... 18 
3.3 
Recruitment ........................................................................................................... 19 
3.4 
Study Conduct and Data Collection ...................................................................... 20 
3.5 
Study Design ......................................................................................................... 20 
3.6 
Study Outcome Data ............................................................................................. 24 
3.7 
Discontinuation for Medication Related Toxicity ................................................ 24 
3.8 
Plasma Storage ...................................................................................................... 24 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS ................................................ 25 
4.1 
Inclusion Criteria .................................................................................................. 25 
4.2 
Exclusion Criteria ................................................................................................. 25 
4.3 
Study Enrollment Procedures ............................................................................... 26 
5.0 
STUDY TREATMENT .................................................................................................. 26 
5.1 
The Ingestible Sensor System ............................................................................... 26 
5.2 
Regimens, Administration, and Duration ............................................................. 26 
5.3 
Study Treatment (DHFS IS-RM) Formulation and Preparation ........................... 27 
5.4 
Study Product Supply, Distribution, and Accountability ...................................... 28 
5.5 
Concomitant Medications ..................................................................................... 28 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ................................................. 31 
6.1 
Schedule of Events ................................................................................................ 31 
6.2 
Evaluations ............................................................................................................ 33 
6.3 
Special Instructions and Definitions of Evaluations ............................................. 36 
6.4 
Off-Drug Requirements ........................................................................................ 38 
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
3 
7.0 
CLINICAL MANAGEMENT ISSUES ........................................................................ 39 
7.1 
Adverse Events ..................................................................................................... 39 
7.2 
Toxicity Management ........................................................................................... 41 
8.0 
CRITERIA FOR DISCONTINUATION ..................................................................... 43 
8.1 
Criteria for Treatment Discontinuation ................................................................. 43 
8.2 
Criteria for Discontinuation from the Study ......................................................... 43 
9.0 
STATISTICAL CONSIDERATIONS .......................................................................... 44 
9.1 
General Design Issues ........................................................................................... 44 
9.2 
Endpoints .............................................................................................................. 44 
9.3 
Randomization ...................................................................................................... 45 
9.4 
Sample Size and Accrual ...................................................................................... 45 
9.5 
Monitoring ............................................................................................................ 46 
9.6 
Analyses ................................................................................................................ 46 
10.0 
PHARMACOLOGY PLAN INCLUDING INTENSIVE PK SUBSTUDY ............... 49 
10.1 
Pharmacology Substudy Objectives ..................................................................... 49 
10.2 
Pharmacology Substudy Design ........................................................................... 49 
10.3 
Primary and Secondary Data, Modeling, and Data Analysis ................................ 52 
10.4 
Preliminary Results ............................................................................................... 52 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EXPERIENCE 
REPORTING .................................................................................................................. 52 
11.1 
Records to Be Kept ............................................................................................... 52 
11.2 
Project Management by BIT Core ........................................................................ 56 
11.3 
Role of Data Management .................................................................................... 57 
11.4 
Clinical Site Monitoring and Record Availability ................................................ 57 
11.5 
Serious Adverse Experience Reporting ................................................................ 57 
12.0 
HUMAN SUBJECTS ...................................................................................................... 57 
12.1 
Institutional Review Board Review and Informed Consent ................................. 57 
12.2 
Subject Confidentiality ......................................................................................... 58 
12.3 
Study Discontinuation ........................................................................................... 58 
13.0 
PUBLICATION OF RESEARCH FINDINGS ............................................................ 58 
14.0 
BIOHAZARD CONTAINMENT .................................................................................. 58 
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
4 
PROTOCOL TEAM ROSTER 
 
Chair 
Sara H. Browne, MD, MPH 
Assoc. Professor of Clinical Medicine, 
Div. of Infectious Diseases, 
George Palade Labs, Rm 125 
University of California, San Diego 
9500 Gilman Drive 
La Jolla, CA 92093 
Phone  858-534- 2230 
Email shbrowne@ucsd.edu  
 
Co-Investigators: 
Constance A. Benson, MD 
Professor of Medicine 
Division of Infectious Diseases 
I.D. Training Program Director 
Director, Antiviral Research Center 
PI/Director, HIV/AIDS Clinical Trials Unit 
University of California, San Diego 
220 Dickinson Street, Suite A 
San Diego, CA 92103 
Phone 619-543-8080 
Fax 
619-543-5066 
Email cbenson@ucsd.edu  
 
Kathleen S. Moser, MD 
Public Health Services 
San Diego County HHSA 
P.O. Box 85222 (P511D) 
San Diego, CA 92186 
Phone 619-692-8613 
Fax 
619-692-5581 
Email kathleen.moser@sdcounty.ca.gov  
 
Julie Low MD 
County of Orange Health Care Agency 
Pulmonary Disease Services 
1725 W 17th Street, 
Santa Ana, CA 92706 
Phone 714- 834- 8787 
Email jlow@ochca.com 
 
Terrence F. Blaschke, 
Emeritus Professor of Medicine and 
Pharmacology, Stanford University,  
291 Campus Drive, 
Stanford, 
CA 94305 
Email:blaschke@stanford.edu 
 
Charles Peloquin, Pharm.D. 
College of Pharmacy 
University of Florida 
1600 SW Archer Road, P4-33 
Gainesville, FL 32610 
Phone 352-273-6266 
Email peloquin@cop.ufl.edu 
 
Project Management:  
Amanda Tucker Maytom, MD 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson Street, Suite A 
San Diego, CA 92103 
Phone 619-543-8080 
Email a1tucker@ucsd.edu 
 
Study Co-ordinator: 
Jonathan Gonzalez-Garcia 
Staff Research Associate 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson Street, Suite A 
San Diego, CA 92103 
Phone 691-543-8080 
Fax 
619-543-5066 
Email jgg@ucsd.edu  
 
 
Study Nurse 
Jill Kunkel, RN 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson Street, Suite A 
San Diego, CA 92103 
Phone 619-543-8080 
Email jkunkel@ucsd.edu 
 
Data Management   
Amanda Tucker Maytom, MD 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
5 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson Street, Suite A 
San Diego, CA 92103 
Phone 619-543-8080 
Email a1tucker@ucsd.edu 
 
Anya Umlauf, PhD 
Senior Statistician, 
HNRC, Rm 344, 
220 Dickinson Street,  
San Diego CA 92103 
Phone: 619-543-5000 
 
Statisticians 
Anya Umlauf, PhD 
Senior Statistician, 
HNRC, Rm 344, 
220 Dickinson Street,  
San Diego CA 92103 
Phone: 619-543-5000 
 
Florin Vaida, PhD 
Prof. Family Medicine & Public Health 
University of California, San Diego 
9500 Gilman Drive, 
La Jolla, CA 92093 
Phone 858-543-2230 
 
 
Pharmacokinetic Analysis 
Charles Peloquin, Pharm.D. 
College of Pharmacy 
University of Florida 
1600 SW Archer Road, P4-33 
Gainesville, FL 32610 
Phone 352-273-6266 
Email peloquin@cop.ufl.edu 
 
Pharmacist 
Leticia Muttera 
Investigational Pharmacist 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson Street, Suite A 
San Diego CA 92103 
Phone 619-543-8080 
Fax 
619-543-5072 
Email lmuttera@ucsd.edu  
 
Laboratory Technologist 
DeeDee Pacheco 
Phlebotomist and Lab Manager 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson Street, Suite A 
San Diego, CA 92103 
Phone 619-543-8080 
Fax 
619-543-5067 
Email dmpacheco@ucsd.edu  
 
Industry Representative: 
George Savage, MD 
Chief Medical Officer, 
Proteus Digital Health, Inc. 
2600 Bridge Parkway, Suite 101 
Redwood City, CA 94065 
Phone 650-632-4031 
Fax 
650-632-4071 
 
 
 
 
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
6 
ABBREVIATIONS USED 
 
AAE 
anticipated adverse event 
ACTG 
AIDS Clinical Trials Group 
AE 
adverse event 
AFB 
acid-fast bacilli 
AHF 
Alliance Healthcare Foundation 
ALT 
alanine transaminase 
ANC  
absolute neutrophil count 
AST 
aspartate transaminase 
AUDIT 
Alcohol Use Disorders Identification Test 
AVRC 
Antiviral Research Center 
BIT Core 
UCSD Center for AIDS Research Bioinformatics and Information Technologies 
Core 
BUN 
blood urea nitrogen 
CBC  
complete blood count 
CDC 
Centers for Disease Control and Prevention 
CMD 
Core Medical Device 
CMP  
comprehensive panel 
DAST-10 
Drug Abuse Screening Test 
DHFS 
digital health feedback system 
DOT 
directly observed therapy 
FDA 
U.S. Food and Drug Administration 
β-HCG  
human chorionic gonadotropin 
HLA 
human leukocyte antigen 
HHSA  
County of San Diego Health and Human Services Agency 
HIV 
human immunodeficiency virus 
IEM 
ingestible event markers 
IRB 
institutional review board 
IS-RM 
ingestion sensor-enabled Rifamate  
MDR-TB 
multi-drug-resistant tuberculosis 
NIH 
National Institutes of Health 
OCCAMS Open Source Clinical Content Management System 
OCHCA 
County of Orange Health Care Agency Pulmonary Disease Services 
PDA 
positive detection accuracy 
PDH 
Proteus Digital Health 
PHI 
protected health information 
PHQ-9 
Patient Health Questionnaire-9 
PHS 
County of San Diego Public Health Services 
PI 
Principal Investigator 
QD 
once a day 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SGOT  
serum glutamic oxaloacetic transaminase 
SGPT  
serum glutamic pyruvic transaminase 
SOC 
standard of care 
TB 
Mycobacterium tuberculosis complex 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
7 
UA  
urinalysis 
UADE 
Unanticipated Adverse Device Effect 
UCSD 
University of California, San Diego 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
WHO  
World Health Organization 
WOT 
wirelessly observed therapy 
 
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
8 
SITES PARTICIPATING IN THE STUDY 
 
UCSD Antiviral Research Center  
 
The University of California, San Diego (UCSD) is among the world’s leading institutions for 
HIV patient care and clinical, basic, and behavioral HIV research. The UCSD Antiviral Research 
Center (AVRC), founded in 1986 by Drs. Douglas Richman, Stephen Spector, and Allen 
McCutchan, has been at the forefront of clinical training and research since the beginning of the 
HIV epidemic in the U.S. The AVRC is engaged in multiple studies funded by the National 
Institutes of Health (NIH), including trials with the AIDS Clinical Trials Group (ACTG), the 
Centers for Disease Control (CDC), and California Research Programs. This highly 
distinguished center has performed investigational clinical trials with most of major international 
pharmaceutical companies including Merck, Pfizer, GlaxoSmithKline, Gilead, Bristol-Myers 
Squibb, Tibotec, Roche, Abbott, Boehringer Ingelheim, Vertex, Dupont, and Egron. The AVRC 
participates in approximately 60 clinical trials per year. 
 
AVRC researchers have also been active in clinical trials related to Mycobacterium tuberculosis 
complex (TB) infection with the Tuberculosis Trials Consortium, the CDC, and the ACTG. 
Current TB trials at the AVRC include studies of pulmonary disease in TB infected subjects 
(with and without HIV), pharmacokinetics of higher doses of standard treatments for TB, and 
cross border TB infection. In partnership with the CDC, County of San Diego Health and Human 
Services Agency (HHSA), and the University of California, San Francisco, the AVRC is 
currently running a study to assess the relative performance and cost of three U.S. Food and 
Drug Administration (FDA)-approved diagnostic tests for latent TB infection. In addition, the 
AVRC collaborates with the La Jolla Institute for Allergy and Immunology and the San Diego 
Blood Bank in an NIH study to identify, characterize, and validate human leukocyte antigen 
(HLA) class II epitopes derived from Mycobacterium tuberculosis. In collaboration with the 
HHSA, investigators at the AVRC have completed a proof of concept study on use of video 
directly observed therapy (DOT) in TB, a novel mobile technology. 
 
San Diego County Public Health 
 
County of San Diego Public Health Services (PHS) is dedicated to community wellness and 
health protection for the people of San Diego County. The PHS, part of the HHSA, works to 
prevent epidemics and the spread of disease, protect against environmental hazards, prevent 
injuries, promote and encourage healthy behaviors, respond to disasters, and assist communities 
in recovery and assure the quality and accessibility of health services throughout the county. 
Diagnostic and treatment services for TB are provided at the main TB Clinic, located at the 
Health Services Complex on Rosecrans Street in San Diego. The AVRC and HHSA have a long 
track record of collaborating on clinical studies of TB within San Diego County. 
 
County of Orange Health Care Agency Pulmonary Disease Services 
 
County of Orange Health Care Agency (OCHCA) is dedicated to community wellness and health 
protection for the people of Orange County. The OCHCA works to prevent epidemics and the 
spread of disease, protect against environmental hazards, prevent injuries, promote and 
encourage healthy behaviors, respond to disasters, and assist communities in recovery and assure 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
9 
the quality and accessibility of health services throughout the county. Orange County TB Control 
is housed within the Pulmonary Disease Services Program. TB screening, diagnosis, and 
treatment services are offered to Orange County residents at the TB Treatment and Prevention 
Services Clinic on West 17th Street in Santa Ana. 
 
 
 
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
 
SCHEMA 
AHF TB 001 
 
Wirelessly Observed Therapy in Comparison to Directly Observed Therapy for the 
Treatment of Tuberculosis 
 
A pilot feasibility trial characterizing use of a digital health feedback system (DHFS) using 
ingestion sensor-enabled fixed-dose combination of isoniazid-rifampin (Rifamate) and 
comparing this to directly observed therapy (DOT) for treatment of Mycobacterium tuberculosis 
complex (TB). 
 
Design: 
AHF TB 001 is a multi-site, randomized, open-label, controlled 
interventional pilot feasibility study comparing the efficacy, characteristics 
of use, persistence and safety of a digital health feedback system (DHFS) 
(Proteus Digital Health, Inc., Redwood City, CA, USA) using ingestion 
sensor-enabled fixed-dose combination Rifamate (IS-RM) in comparison to 
directly observed therapy (DOT) using standard of care (SOC) with 
isoniazid plus rifampin, or Rifamate in TB-infected subjects. Subjects will 
be ineligible if they have any evidence of drug resistant TB or prior 
intolerance to study drug. Those who are found to be eligible will participate 
in a two-week investigation (Phase 1) of the positive detection accuracy and 
characteristics of use of the DHFS in the TB patient population. Eligible 
patients who elect to continue in Phase 2 will then be randomized 2:1 to 
monitoring intervention with the ingestion sensor-enabled Rifamate (IS-
RM), or to DOT SOC. This study will be conducted at the UCSD AVRC, 
the San Diego County TB Clinic, and the County of Orange Health Care 
Agency Pulmonary Services Clinic. 
 
Duration: 
Up to 12 months 
 
Sample Size: 
75-100 subjects in Phase 1; 50 intervention and 25 control SOC subjects in 
Phase 2  
 
Study Population: 
Adult men and women being treated for TB with at least isoniazid and 
rifampin who are able to use the DHFS mobile device, and to tolerate a 
wearable sensor patch 
 
Regimen: 
Subjects will be randomized 2:1 to TB treatment using DHFS ingestion 
sensor-enabled Rifamate (IS-RM) or SOC 
 
 
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
11 
 
 
Figure 1. AHF TB 001 Study Schema 
 
 
 
 
 
 
 
 
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
12 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypotheses 
 
1.1.1 Direct confirmation of TB medication dosing by DHFS is feasible for monitoring 
TB treatment. 
 
1.1.2 DHFS can be used as an alternative to SOC DOT for monitoring and 
documenting completion of TB treatment.  
 
1.1.3 The cost of TB target treatment using DHFS is comparable or favorable when 
compared to DOT for monitoring a comparable number of targeted doses. 
 
1.1.4 DHFS is safe for use in TB treatment.  
 
1.1.5 Patient satisfaction with DHFS use for TB treatment is rated as ‘satisfactory’ or 
higher.  
 
1.1.6 Healthcare worker and physician satisfaction with DHFS for TB treatment is rated 
as ‘satisfactory’ or higher. 
 
1.1.7 DHFS subjects have similar or better self-efficacy scores than control subjects 
receiving SOC DOT during and at the end of the trial. 
 
1.2 
Study Objectives  
 
Primary 
 
1.2.1 Phase 1: Determine positive detection accuracy (PDA, direct confirmation of TB 
medication ingestion) of the DHFS when compared to a healthcare worker 
witnessing actual TB medication ingestion. PDA will be based upon proper DHFS 
use. PDA will be determined using an intention-to-treat and an adjusted analysis. 
 
1.2.2 Phase 2: Determine the percentage of witnessed doses by DHFS and SOC, 
respectively. Witnessed doses by DHFS is defined as the total number of dose 
ingestions confirmed by DHFS, divided by the total number of prescribed 
witnessed dose ingestions for TB treatment. Witnessed doses by SOC is defined 
as the total number of dose ingestions that are actually witnessed by a healthcare 
worker, divided by the total number of prescribed witnessed dose ingestions for 
TB treatment. 
 
Secondary 
 
1.2.3 Determine the percentage of subjects completing > 80% prescribed witnessed 
dosing for TB treatment using DHFS and SOC, respectively. 
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
13 
1.2.4 Summarize the total number of lapses in witnessed doses and longest duration of 
witnessed treatment lapse during use of DHFS and SOC, respectively. 
 
1.2.5 Model cost of treatment based upon data obtained during use of DHFS and SOC, 
respectively. 
 
1.2.6 Characterize adverse events for DHFS and SOC using summary statistics. 
 
1.2.7 Characterize subject responses to post-study questionnaires to collect information 
regarding their experience with the DHFS and the usability of the system, using 
summary statistics. Questionnaire responses by subjects will be examined by 
study reviewers from the AVRC to develop recommendations regarding the 
usability of the system.  
 
1.2.8 Characterize provider responses to post-study questionnaires to collect 
information regarding their experience with the DHFS and the usability of the 
system, using summary statistics. Questionnaire responses by providers will be 
examined by study reviewers from the AVRC to develop recommendations 
regarding the usability of the system. 
 
1.2.9 Characterize generalized scores on habitual self-control, self-efficacy beliefs, 
depression scale (PHQ-9), alcohol use (AUDIT), and drug use (DAST-10) 
questionnaires at the start and end of study within the intervention group, and 
between the intervention and control groups. 
 
1.2.10 Define the characteristics of those subjects with < 80% adherence, including 
demographics, disease characteristics, and self-reported metrics by individual 
instruments, for example the PHQ-9. 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
Eradication of disease due to Mycobacterium tuberculosis complex (TB) has been for 
decades a major policy goal of the Centers for Disease Control (CDC), the Global Alliance 
for TB Drug Development, and the World Health Organization (WHO). Poor adherence to 
therapy has long been recognized as a barrier to effective treatment of TB infection. Inconsistent 
and interrupted treatment, in combination with HIV co-infection, has led to rising numbers of TB 
cases and the emergence of drug resistant TB. One third of the world’s population (~2 billion 
people) are infected with latent TB, over 9 million people a year develop active TB, and 
mortality approaches 2 million deaths annually. 
 
Treatment of active TB requires 6-12 months of combined therapy. Public health authorities in 
all countries recommend that TB treatment be administered by short course directly observed 
therapy (DOT), in which a healthcare worker observes medication ingestion events and provides 
written verification of treatment adherence and completion. While highly reliable when 
performed appropriately, DOT is resource intensive, time consuming, and represents the largest 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
14 
single cost of TB treatment [1]. Although DOT is the WHO’s recommended TB treatment 
standard, its implementation has been attenuated due to cost. Even in the U.S., DOT is not 
consistently applied; “modified DOT,” or self-administered therapy, is more often used due to 
budget limitations. Some TB public health programs in the U.S. do not use DOT at all, or use 
DOT only for high-risk patients; in the private sector, self-administered therapy is the rule rather 
than the exception. Bi- and tri-weekly dosing is used to lower the cost of DOT, despite evidence 
that daily dosing of TB medication is more effective [2, 3]. In the absence of DOT, there is no 
method of reliably determining when and if patients actually ingest their medication. 
 
Alternative methods for assessing adherence such as patient questionnaires, pill counts, patient 
diaries, and prescription refill rates have been shown to be inaccurate and to overestimate 
adherence [4-6]. For example, a review of prescription databases can show when refills occur, 
but does not show when dosing errors occurred, or most importantly, the date the patient stopped 
taking the drug [7-10]. Limitations also apply to measurements of drug concentrations in plasma, 
which do not take into account the fact that patients’ drug taking behavior is a dynamic process 
that changes over time and is subject to strong bias, with white coat effects that typically increase 
adherence in the 24-48 hours before a scheduled visit to the clinic or laboratory [11-13]. The 
electronic bottle cap, such as the medication event monitoring system device, has also been used 
as a potential surrogate for drug dosing [14]. However, several limitations have been reported 
with this methodology, including mismatches between electronic cap opening and actual intake 
(more than one dose taken or no dose taken) and patients obviating electronic assessment by 
decanting pills from a bottle having an electronic cap to an alternative daily decanter or a weekly 
pill box [4-6].  
 
Even fully implemented DOT has drawbacks for adherence. DOT by definition does not allow 
naturalistic observation of an individual patient’s drug taking behaviors. One concept 
emphasized in medication adherence literature is the link between a patient’s sense of self-
efficacy, that is, an individual’s perception of their ability to perform a specified behavior or set 
of behaviors [15], and their ability to execute satisfactory adherence. In one recent study 
comparing modified DOT with self-administered drugs, Gross et al. observed that DOT does not 
enable a patient to learn to manage their own drug taking behavior, a factor that may detract from 
improvements in medication compliance in the long term [16].  
 
There is clearly an unmet need for an alternative to DOT that can reliably and efficiently confirm 
medication ingestion events and provide verification of TB treatment adherence and course 
completion. This tool should be accurate and easy for both the patient and healthcare worker to 
use, and ideally should provide feedback to the patient to guide their compliance with TB 
treatment. 
 
2.2 
Rationale 
 
A digital health feedback system (DHFS) (Proteus Digital Health, Inc., Redwood City, CA, 
USA) has been developed to provide wirelessly observed therapy (WOT) as a reliable, efficient, 
scalable, and cost-effective alternative to DOT for sharing complete and accurate medication 
data in near real-time among patients, prescribing physicians, public health workers, 
pharmacists, and other healthcare providers. WOT represents a potential new paradigm for TB 
therapy monitoring, which can be utilized by public health workers and outreach workers to 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
15 
confirm TB treatment. The ultimate goal of this protocol is to utilize WOT as an alternative 
to DOT for daily real-time assessment of TB medication adherence in an ambulatory 
setting, providing individualized mobile healthcare using prompt, targeted feedback for the 
management of TB infected patients. This pilot trial provides an opportunity to lead the way 
forward in the clinical practice of TB control with this innovative U.S.-developed technology. 
The results from this trial will demonstrate the feasibility and the utility of this technology to 
other countries that have a higher TB burden. 
 
DHFS represents the first technology that allows date- and time-stamping of actual ingestions of 
oral medications, instead of surrogate measures of ingestion [17]. It can also provide specific 
information regarding the types and doses of multiple drugs taken simultaneously. DHFS allows 
secure medication-taking data to flow to patients, prescribing physicians, pharmacists, and other 
healthcare providers [17, 18]. The data shared between patients and healthcare providers affords 
the opportunity 1) to assess the regularity of medication-taking and 2) to support patient 
medication taking behavior in near real time to encourage optimal adherence. 
 
DHFS consists of two main components: 1) an ingestion sensor, and 2) a wearable sensor to 
detect and record ingestion and physiological activity. The ingestion sensor is smaller than a 
sesame seed (1.0 mm x 1.0 mm x 0.45 mm) and composed of minerals and metals in the human 
food chain. The sensor can be encapsulated with prescribed medication. When ingested, the 
sensor utilizes gastric fluid and electrolytes to communicate information to an adhesive-backed 
wearable sensor. The wearable sensor is worn on the torso and confirms and records the identity, 
date, and time of sensor ingestion. The wearable sensor interprets each individual ingestion 
sensor’s information as unique. The communication process lasts approximately 5-7 minutes and 
is unnoticed by, and not detectable beyond, the system user. Like an ingested sesame seed, the 
remainder of the ingestion sensor is then passed and excreted with the stool. 
 
In this manner, DHFS is capable of directly confirming when, how much, and how many doses 
of prescribed medication have been ingested. The wearable sensor decodes and records the 
information from the ingestion sensor, and date- and time-stamps ingestions and physiological 
metrics such as rest and activity. All of the recorded data is sent wirelessly using encryption to a 
computing device (such as a mobile device or a personal computer) and is subsequently uploaded 
to a secure, centralized data storage location. The data can then be formatted and directed back in 
a similarly secure manner to the patient or those designated by the patient, so they can keep track 
of their own medication-taking and other activities of daily living [17-19]. 
 
The DHFS has been studied in healthy volunteers, as well as in patients with TB, heart failure, 
hypertension, diabetes, schizophrenia, and bipolar disorder as their primary disease. The 
ingestion sensor has been cleared via the 510(k) pathway and has received the CE mark in the 
EU. The following is an excerpt from the FDA-cleared device label which summarizes the 
technical performance: “A total of 412 study subjects have participated in Pill ingestion studies 
representing 20,993 ingestible sensor ingestions. In comparison with direct observation, the 
ingestible sensor was detected in 97.3% of ingestions, with correct identification in 100%.” The 
latest configuration of the system, which includes wearable sensor version RP4 and the 
Miniature Ingestible Event Marker Tablet dose form, underwent post-approval, formative 
testing, in which sensitivity for ingestion sensor detection versus directly observed ingestion was 
99.4% (95% CI 97.9-99.8%), and there were no false positive detections. Regarding ingestion 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
16 
sensor safety, the following is also abstracted from the FDA-cleared device label: 
“nausea/vomiting occurred in 1%, constipation in 0.5%, asthma attack in 0.2%, abdominal 
cramping in 0.2%, non-cardiac chest pain in 0.2% and bitter taste in mouth in 0.2%. None of 
these adverse events were considered serious and all resolved spontaneously” (Ingestible Sensor 
Investigator’s Brochure, Rev 4). 
 
Wearable sensor version RP2 and RP3 have been cleared via the 510(k) pathway and have 
received the CE mark in the EU. The following is an excerpt from the FDA-cleared device label, 
which summarizes the safety of these earlier wearable sensor versions: “A total of 492 study 
subjects have participated in clinical studies representing 6,407 days of Patch (wearable sensor) 
use with or without ingestible sensor ingestion. Sixty-two (12.6%) of these users experienced 
adverse events related or possibly related to the Patch. Sixty-one of these AE were self-limited 
skin rashes localized to the Patch placement site, and 1 was a self-limited episode of pain at the 
Patch location unassociated with skin rash. None of these adverse events were considered 
serious.” The latest wearable sensor version (RP4), which remains investigational at present, has 
undergone testing in 38 subjects. Four AE were reported (10.5% of subjects), all localized to the 
wearable sensor placement site and mild in severity. Three of these AE were erythematous 
rashes at the wearable sensor location; one of these rashes transiently manifested itself as non-
erythematous skin discoloration (“secondary NESD”) on the path to full resolution. The fourth 
AE was an episode of “primary NESD” (i.e., there was no antecedent erythematous rash reported 
at the wearable sensor location). Primary and secondary NESD have been encountered with 
previous wearable sensor versions. The investigator hypothesized that per-protocol premature 
removal of the wearable sensor in these studies (typically after several hours, as opposed to 
intended 7-day wear) significantly contributed to the occurrence of these four RP4-related AE 
(Wearable Sensor Investigator’s Brochure, Rev 4). 
 
A proof of feasibility study has been conducted in 30 TB patients and published from two 
clinical sites in the U.S., using an earlier prototype of the current WOT system. This was a 
prospective, non-randomized, single-blinded study to evaluate the feasibility and safety of an 
early version of the DHFS in patients with active TB and in the continuation phase of treatment. 
Study participants were monitored during 10 consecutive daily DOT visits where ingestible 
event markers (IEM) were ingested separately at the time of medication dosing. At each visit, 
participants ingested 2 tablets along with their TB medications. Of the 20 tablets ingested by 
each patient (over 10 visits), 18 had IEM attached and 2 placebo tablets contained no IEM. The 
IEM system showed high positive and negative detection accuracies in identifying medication 
ingestions [20]. The DHFS has been updated substantially since this early study. 
 
This pilot trial project will utilize DHFS to assess medication adherence to ingestion sensor-
enabled Rifamate (IS-RM) reliably, in an ambulatory setting in order to accurately characterize 
medication taking behavior of adult patients undergoing treatment for TB that includes at least 
INH and RIF. The system will provide a means of directly confirming medication adherence and 
identifying non-adherent patients to County healthcare workers, who can then provide prompt 
adherence intervention, thereby preventing treatment failure. The system can also provide 
individualized healthcare using prompt-targeted feedback tailored to individual TB patients.  
 
The ingestible sensor will be over-encapsulated with a fixed-dose combination of isoniazid-
rifampin (Rifamate), IS-RM; thus DHFS will capture actual ingestion of IS-RM. In this 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
17 
feasibility study, subjects meeting eligibility criteria will initially have ingestion of IS-RM 
confirmed by DHFS for two weeks with simultaneous healthcare worker witness of actual IS-
RM medication ingestion to evaluate the positive detection accuracy of DHFS. Alternatively, 
during Phase I, subjects may take Rifamate with co-ingestion of an encapsulated edible sensor. 
Subsequently, those eligible subjects who wish to continue will be randomized to either DHFS or 
SOC DOT. DHFS has previously been studied for up to 4 months in patients with chronic 
disease. Phase 2 of this trial will look at persistence of use from 4 weeks until completion of TB 
treatment (up to a maximum of 12 months on study). 
 
Per CDC guidelines, DOT can take place five, three, or two times per week, with the medication 
dose adjusted to the frequency of medication taking. Although DOT is the gold standard for 
monitoring therapy, it can be difficult to execute perfectly, since subjects may miss DOT 
appointments for vacation, work, or other reasons, and conversely DOT workers may miss 
appointments due to overscheduling or transportation failure. Thus, the adherence metrics chosen 
for this study need to carefully take into account the unique nature of DOT, as adherence 
determined by the number of witnessed doses ingested. The optimal adherence metric for this 
study is the total number of actual witnessed dose ingestions divided by the total number of 
prescribed witnessed dose ingestions, captured by DOT or via DHFS. This parameter, the 
percentage of witnessed doses, will be reported for the duration of the study (per week, per 
month and over the entire study period). The percentage of witnessed doses in this trial captures 
effective monitoring of TB treatment via DOT and DHFS, and allows calculation of adherence 
with SOC DOT at varying intervals, e.g., five, three, or two times per week. 
 
TB treatment has largely grown up through convention and analysis of treatment failures in 
traditional clinical practice, rather than extensive clinical trials with pharmacokinetic and 
therapeutic drug monitoring. Thus patterns of drug administration given via DOT five, three, or 
two times per week have been deemed acceptable based on treatment failure rates, with 
adherence > 80% of prescribed dosing estimated by key opinion leaders as adequate for TB 
treatment [21]. Daily DOT may give more favorable pharmacokinetic profiles for isoniazid and 
rifampin with their relatively short half-lives (isoniazid-1.5 hours [fast acetylators] to 4 hours 
[slow acetylators]; rifampin-3 hours). Random and sparse sampling of therapeutic drug 
concentrations may confirm adherence monitoring data obtained via DHFS and SOC DOT; and 
pharmacokinetic evaluation of daily and five, three, and two times weekly dose administration 
may be analyzed. Stored plasma samples in this trial may allow future pharmacokinetic analysis 
with random sampled dosing history data providing the foundation for sound pharmacological 
interpretation of dose- or exposure-dependent variations in drug response in ambulatory care of 
TB.  
 
3.0 
STUDY DESIGN 
 
This study is a prospective, two phase, open-label feasibility study with lead in (Phase 1) and 
randomized (Phase 2) components to evaluate the utility of the DHFS for monitoring TB 
treatment. In Phase 1, all subjects will receive DHFS IS-RM (or Rifamate with co-ingestion of 
an encapsulated edible sensor) and a series of doses will be witnessed in order to determine the 
detection accuracy of the system, as well as to evaluate subject acceptance and ability to use the 
system. In Phase 2, those randomized to intervention will continue to use the DHFS IS-RM and 
control subjects will receive SOC DOT. 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
18 
 
3.1 
Non-Significant Risk Study 
 
To date, all of the clinical investigations in the U.S. of the DHFS and its wearable sensor 
component have been designated as non-significant risk studies, as they have met the established 
regulatory criteria for a non-significant risk device study. Specifically, the system and the 
wearable sensor component are not: 
• an implant used to support or to sustain human life 
• being used for substantially diagnosing, curing, mitigating or treating disease, or 
preventing impairment of human health, or 
• a potential serious risk to the health, safety or welfare of subjects. 
 
No serious adverse events (SAE) and no unanticipated adverse device effects (UADE) have been 
reported. The vast majority of the non-serious, device-related AE that have been reported in 
completed studies have been categorized as mild in severity. Please see Investigator’s Brochure 
for additional details. 
 
3.2 
Study Population 
 
Study participants will be approximately 100 adult patients being treated for TB that includes at 
least isoniazid and rifampin, or Rifamate and who have at least 6 weeks remaining of treatment.  
 
Eligible subjects will be at least 18 years of age, have sputum smear negative or culture negative 
TB, have no evidence of drug resistant TB, and have complete blood count (CBC) and 
comprehensive panel (CMP) values that fall within parameters specified in Section 4.1 
(Inclusion Criteria). In cases where abnormalities in these laboratories exist, the study Principal 
Investigator or co-investigator physicians must be contacted to directly determine whether the 
observed lab abnormalities exclude patient from enrollment. Females of child bearing age must 
be willing to use contraception during the study. Subjects must be able to understand written and 
verbal information regarding DHFS use, be able to use a mobile device and wear a patch sensor, 
and have the ability to give written informed consent. 
 
Criteria for exclusion will include pregnancy, or being fertile and not using a clinically accepted 
means of birth control for the duration of the study, use of prohibited medications (see Sections 
4.2 and 5.4.2), known hypersensitivity to skin adhesives, and inability to understand instructions 
regarding and use of the components of the DHFS. 
 
All eligible subjects willing to participate in the study will sign an informed consent. Following 
consent and pre-study interview, subjects will participate in a Phase 1, two-week investigation of 
the positive detection accuracy and characteristics of use of DHFS in the TB patient population, 
using DHFS IS-RM (or Rifamate with co-ingestion of an encapsulated edible sensor) with 
simultaneous DOT. Patients deemed eligible after Phase 1 and who elect to continue will then be 
randomized to DHFS IS-RM or SOC DOT delivered by County healthcare workers. 
 
The study will be conducted at the UCSD AVRC, at PHS, and OCHCA. Subjects will be 
recruited from County TB clinics in San Diego and Orange Counties, San Ysidro Health Centers, 
and UCSD. Study enrollment will take place from the period of 09/01/2013 through 12/01/2015. 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
19 
Subjects will be enrolled into the study for a minimum of 6 weeks, and will end the study at 
completion of TB treatment (up to a maximum of 12 months on study). 
 
3.3 
Recruitment 
 
The study will be advertised in flyers placed at PHS, OCHCA, San Ysidro Health Centers, and at 
UCSD. County outreach workers and healthcare personnel will inform all of their patients of this 
study, as will San Ysidro Health Centers and UCSD personnel involved in TB care. Interested 
patients will be directed to contact AVRC study personnel by phone. When patients interested in 
participating call, AVRC personnel will describe the study. They will inform patients that they 
may enroll in the study to undergo a two-week investigation of use and accuracy of DHFS IS-
RM and then if willing and eligible, be randomized to the intervention with remote WOT via 
DHFS IS-RM, or to SOC DOT. The AVRC will establish the eligibility of potential participants 
(see above). 
 
If a patient wants to participate, the study coordinator will then conference with the public health 
nurse and DOT outreach workers to review the patient’s suitability for the study, including 
adequacy of living situation and ability to use mobile technology. If the patient is willing to 
participate and is recommended by PHS as able to participate, the patient will be scheduled for 
an appointment with AVRC personnel. At this appointment, AVRC personnel will again 
describe the study to the patient and confirm eligibility criteria (see above). Screening will 
include documentation of TB, smear negative or culture negative status, and resistance status as 
recorded, clinical assessment with targeted exam, concomitant medications and toxicities, and 
laboratory values obtained from CLIA certified clinical laboratories, within the last 30 days, or 
by County or AVRC laboratory if routine labs are unavailable (only lab values drawn by 
OCHCA staff will be used for Orange County participants), including complete blood count 
(CBC) with differential, chemistry panel and liver function tests (CMP), (abnormalities in these 
laboratory values will be reviewed by the PI or physician co-investigators prior to enrollment), 
and pregnancy test (as appropriate). The interviewer will assess the subject’s attitude to mobile 
devices, understanding and experience of TB medications thus far, and whether they would be 
able to understand DHFS instructions of use and be willing to use all the components of the 
system. If the patient is viewed as able and eligible, the AVRC personnel will supervise 
signature of informed consent.  
 
Following informed consent, subjects will be assigned a participant identification number. Data 
will be collected on demographics (age, race/ethnicity, gender, employment, education level), 
co-morbidities, and concurrently administered medications, and will include review of 
information from County records and medical records. Each subject will then participate in a 
two-week investigation of the positive detection accuracy and characteristics of use of DHFS in 
the TB patient population (Phase 1). Following the Phase 1 lead in, subjects who remain eligible 
and who elect to continue will then be randomized in a 2:1 ratio to either an intervention group 
with DHFS IS-RM or a control group receiving SOC DOT with isoniazid plus rifampin, or 
Rifamate. Subjects will be accrued until 50 subjects are in the intervention and 25 subjects are in 
the control arm. 
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
20 
3.4 
Study Conduct and Data Collection 
 
Prior to the commencement of the study, AVRC personnel and County healthcare providers will 
be trained in set up and use of the PDH DHFS medication monitoring system. This includes 
information on the ingestion sensor, the wearable sensor, use of study computerized devices, and 
study drug. Healthcare providers will also be given guided instruction on the provider data view, 
which will display daily patch adhesion, patch sensing, and ingestion data for each study subject 
using DHFS. The study coordinator and County healthcare workers will be shown how to check 
the PDH website containing daily medication ingestion and wearable sensor data. The study 
coordinator will be transcribing this information manually into the study database. All data will 
be entered by study staff under the subject’s participant number. Study data collection is 
described below in Section 10. County healthcare workers will be entering daily medication 
ingestion confirmation information into the County health records as is current practice (see 
below). Whenever possible, data will be collected from County records and medical records, for 
the duration of the subject’s participation in the study.  
 
Following subject consent, the study will proceed as described below. 
 
3.5 
Study Design  
 
Phase 1: A two-week period where the subjects receive DHFS IS-RM (or Rifamate with co-
ingestion of an encapsulated edible sensor), in conjunction with witnessed medication 
doses to determine the positive detection accuracy and characteristics of use of DHFS 
in the TB patient population. 
 
Phase 2: A period of TB treatment monitoring randomized to DHFS IS-RM or SOC DOT, for a 
minimum of 4 weeks and continuing until completion of TB treatment (up to a 
maximum of 12 months on study). 
 
These study periods are designed to capture the following information. Phase 1 will gather 
information on the verification of DHFS ability to capture medication ingestion events alongside 
simultaneous witnessed ingestions. This Phase incorporates DHFS use at the AVRC or OCHCA 
clinic with simultaneous witnessed ingestions by clinic staff to ascertain the positive detection 
accuracy (with calculation of sensitivity and specificity), system function, and the subject’s 
ability to interface with the DHFS system as currently designed. Phase 2 represents a period of 
persistence with DHFS IS-RM or SOC DOT and monitoring of patient medication taking 
behavior until the completion of TB consolidation treatment or termination on the study.  
 
In Phase 1 (Weeks 0-2), all subjects will use DHFS and receive the study drug in conjunction 
with DOT. The wearable sensor will be changed weekly (or earlier if needed) by the subject 
themselves under the supervision of study personnel. Subjects will be required to visit the AVRC 
two times a week during this phase to complete DHFS/DOT doses. In the case of Orange County 
participants, AVRC personnel will conduct all study visits at the OCHCA clinic. County 
outreach workers will also provide at least three visits per week during Phase 1, providing a 
combined minimum of five days of DOT per week in conjunction with study drug ingestion. 
Upon completion of four successful ingestions of Rifamate with concurrent use of DHFS and 
witnessed DOT during study visits, and two successful patch changes performed under 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
21 
observation by study personnel, Phase 1 of the study will be completed. The first patch change 
may include minimal coaching, but no intervention by study personnel. The second patch change 
must occur without any coaching or intervention by study personnel. Subjects deemed eligible by 
study personnel and who wish to continue will be randomized and proceed to Phase 2.  
 
On the last day of Phase 1, the subject will take DHFS IS-RM (or Rifamate with co-ingestion of 
an encapsulated edible sensor). On this same day, the investigator will 1) access the Core 
Medical Device (CMD) viewer that is available on the subject’s mobile study device, and 2) 
obtain the dates and times from the CMD of all Rifamate ingestions that were detected by the 
DHFS, with the exception of the final day of Phase 1. The dates and times of all DHFS 
detections that were logged on the CMD during Phase 1 will be entered into the study database 
for subsequent PDA analysis. 
 
In Phase 2, subjects are randomized 2:1 to the Intervention Group that will use DHFS with IS-
RM without concurrent DOT, or to the Control Group that will receive standard isoniazid plus 
rifampin, or standard Rifamate, per SOC that includes DOT from County healthcare workers. 
 
3.5.1 Intervention Group 
 
In intervention subjects, the patch monitor will be changed weekly by the subject 
themselves or under the supervision of the AVRC/County healthcare worker if 
requested. Subjects will be contacted weekly for review of side effects and any 
questions by AVRC and will be able to contact the AVRC and County healthcare 
worker at any time with questions regarding the intervention. Subjects will 
continued to be followed by County healthcare per their usual routine (i.e., 
County nurse visit once a week, physician visit once a month, and County 
outreach worker visits as directed by County nurse). All phone calls between the 
subject and the AVRC or County healthcare workers including medical 
information, such as physical symptoms possibly associated with side effects or 
other medical complaints, will be recorded as per the Schedule of Events (see 
Section 6) and communicated to PHS, OCHCA, or the physician with primary 
responsibility for the subject’s TB treatment. All phone calls between the subject 
and the AVRC or County healthcare workers related to the function of the DHFS, 
will be directed to and dealt with by the AVRC in conjunction with PDH 
personnel. 
 
The AVRC study coordinator and County healthcare worker will review the 
subject ingestion log on the PDH website daily on business days to record the 
subject’s wirelessly confirmed dosing. This follows current County practices. The 
wirelessly confirmed dose will be entered by AVRC study staff into the study 
database via a secure user-authenticated website designed and hosted by the 
UCSD Center for AIDS Research Bioinformatics and Information Technologies 
(BIT) Core. The identity of staff recording the wirelessly confirmed dose will be 
recorded in the study database as the user who logged into the secure website to 
enter the data. The County healthcare worker will enter the subject’s wirelessly 
confirmed dosing into the County medical records daily, following current 
County practices. Each site should check daily to see that the subject’s data has 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
22 
been recorded properly into the study database (by the AVRC) and medical record 
(by PHS or OCHCA).  
 
In Phase 2, if ingestion of DHFS IS-RM cannot be wirelessly confirmed on any 
business day, the subject will be contacted within 24 hours. During this call, 
information will be obtained to clarify whether there is a malfunction of the 
DHFS or non-adherence to medication has occurred. In case of malfunction of the 
DHFS, the AVRC in conjunction with PDH will address the problem. In the case 
of medication non-adherence in the absence of DHFS malfunction, such as due to 
medication side effects, County healthcare workers will ascertain the reasons for 
non-adherence and follow County protocol. This process is summarized in Figure 
2 below. 
 
Figure 2. AVRC/County Outreach Worker Algorithm Used for Wirelessly Confirmed 
Ingestions  
 
 
 
 
 
Safety laboratory values will be reviewed at Weeks 2, 4, 8, and every 4 weeks 
until the completion of TB treatment (up to a maximum of 12 months on study) 
and at the end of study, or at frequency of PHS or OCHCA SOC. For the full 
schedule of events at these weeks, see Section 6.1. 
 
In Phase 2 on Day 0, Week 8, and at the end of study, subjects will be asked to 
complete the following questionnaires: habitual self-control, self-efficacy beliefs, 
depression scale (PHQ-9), alcohol use (AUDIT), and drug use (DAST-10). 
Questionnaires will be available in English and Spanish; for subjects with other 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
23 
first languages, questionnaires will be administered with the aid of an interpreter, 
if necessary. All self-report questionnaires will be completed via a study tablet 
device. Questionnaires will automatically upload to a secure server after 
completion. 
 
As indicated above, each intervention subject will also be followed by County 
healthcare workers, who will collect and follow data on intervention subjects 
following County routine practice, including data from medical records, 
adherence data as witnessed ingestions, cost data, any toxicity data and side effect 
data pertaining to non-DHFS medical treatment, including number of clinic visits 
and number of hospitalizations related to TB treatment, per patient during the 
study period. AVRC study staff must ensure that data from County records and 
medical records are on study CRFs and entered into the study database. 
 
3.5.2 Control Group 
 
Subjects randomized to the control arm will receive SOC DOT with isoniazid plus 
rifampin, or Rifamate via the County healthcare workers. Safety laboratory values 
will be reviewed as per County SOC. At Phase 2 Day 0, Week 8, and at subject’s 
termination on the study, the following questionnaires will be administered: 
habitual self-control, self-efficacy beliefs, depression scale (PHQ-9), alcohol use 
(AUDIT), and drug use (DAST-10). Questionnaires will be available in English 
and Spanish; for subjects with other first languages, questionnaires will be 
administered with the aid of an interpreter, if necessary. These data will be 
identified by subject’s participant number only and will not be associated with the 
subject’s name. All self-report questionnaires will be completed via a study tablet 
device. Questionnaires will automatically upload to a secure server after 
completion. 
 
County healthcare workers will collect and follow data on control subjects 
following County routine practice, including data from medical records, 
adherence data as prescribed DOT (two, three, or five times per week), actual 
witnessed ingestions, cost data, any toxicity data and side effect data pertaining to 
treatment, including number of clinic visits and number of hospitalizations related 
to TB treatment, per patient during the study period. AVRC study staff must 
ensure that data from County records and medical records are on study CRFs and 
entered into the study database. 
 
3.5.3 Study Medication 
 
In Phase 1, oral Rifamate will be supplied by the AVRC pharmacy. All 
medications will be over-encapsulated by the AVRC pharmacist. PDH will supply 
the ingestible sensor and the AVRC pharmacist will over-encapsulate Rifamate 
with the ingestible sensor (or in Phase I, the ingestible sensor alone) using an 
appropriate size capsule, manufactured by Capsugel Inc., according to Standard 
Operating Procedures. Thus the AVRC will dispense over-encapsulated IS-RM or 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
24 
Rifamate with co-ingestion of an encapsulated edible sensor to all Phase 1 
subjects. 
 
In Phase 2, subjects in the intervention arm will be dispensed study drug, IS-RM, 
following the process described above, by the AVRC pharmacy to coincide with 
AVRC visits or study visits with AVRC personnel in Orange County. Control 
subjects will have medications per SOC prescribed by PHS or OCHCA and 
dispensed by a public health pharmacy for two, three, or five times a week DOT. 
 
3.6 
Study Outcome Data  
 
Detection Rates: Detection rates of ingested study drug, sensitivity and specificity calculation 
using data derived from Phase 1 of study. 
 
Positive Detection Accuracy (PDA): PDA is defined as DHFS detection of the ingestion of a 
dose of IS-RM when compared to a witnessed ingestion of the same dose of medication. For 
purposes of PDA analysis, a dose is as a single IS-RM capsule. A minimum of 280 dose 
ingestions are required to generate sensitivity and specificity of the System. The expected 
treatment for study subjects is two IS-RM capsules daily. 
 
Persistence of WOT signal transfer and patch function over period of study providing confirmed 
ingestion of TB medication will be reported as the percentage of witnessed doses captured. For 
the DHFS, the percentage of witnessed doses by DHFS is defined as the total number of dose 
ingestions confirmed by DHFS, divided by the total number of prescribed witnessed dose 
ingestions for TB treatment. For SOC DOT, the percentage of witnessed doses is defined as the 
total number of dose ingestions that are actually witnessed by a healthcare worker, divided by the 
total number of prescribed witnessed dose ingestions for TB treatment. This endpoint will be 
calculated from baseline to Weeks 4, 8 and end of follow-up. 
 
For additional details, see Primary Endpoints in Section 9.2.1, and Secondary Endpoints in 
Section 9.2.2. 
 
3.7 
Discontinuation for Medication Related Toxicity 
 
If the subject develops a toxicity that results in discontinuation of isoniazid and rifampin, or 
Rifamate, then an alternative medication regimen will be found and started as soon as feasible. 
The medication will not be supplied by the study. These patients will be required to permanently 
discontinue their study regimens but will continue to be followed for the duration of the study. 
 
3.8 
Plasma Storage 
 
Patients seen at the AVRC (this excludes subjects drawn from OCHCA) will undergo random 
collection of plasma, which will be stored to later run drug levels of rifampin. The time and date 
of the three previous doses of TB medications should be recorded.  
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
25 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 Basic competency in understanding written and verbal information as it applies to 
DHFS use. 
 
 
4.1.2 Persons undergoing treatment for TB that includes at least isoniazid and rifampin 
at the time of entry to Phase 1; of note, patients must be sputum smear negative or 
culture negative at the time of study entry. 
 
4.1.3 Laboratory values obtained by screening laboratories within 30 days of entry: 
• Absolute neutrophil count (ANC) ≥ 1,000/mm3. 
• Hemoglobin ≥ 9.0 g/dL. 
• Platelet count ≥ 75,000/mm3. 
• AST (SGOT), ALT (SGPT), and alkaline phosphatase ≤ 3 x ULN. 
• Total bilirubin ≤ 1.5 x ULN and direct bilirubin. 
 
4.1.5 Females of childbearing potential must agree to use contraception throughout the 
study period. 
 
4.1.6 Men and women age ≥ 18 years. 
 
4.1.7 Eligible for anti-mycobacterial medications and in possession of prescriptions for 
isoniazid and rifampin, or Rifamate, as appropriate. 
 
4.1.8 Willing to follow all protocol requirements. 
 
4.1.9 Ability to use mobile device per investigator determination, and to wear PDH 
wearable sensor (i.e., no skin conditions precluding use). 
 
4.1.10 Ability and willingness of subjects to give written informed consent. 
 
4.2 
Exclusion Criteria 
 
4.2.1 Female who is pregnant or breast-feeding, or of childbearing potential and has a 
tuberculin positive test at screening and disagrees to use contraception throughout 
the study period. 
 
4.2.2 Use of any of the prohibited medications or other non-informed medications 
(Section 5.4.2) within 30 days of study entry. 
 
4.2.3 Known hypersensitivity to any of the study drugs. 
 
4.2.4 Known sensitivity to skin adhesives. 
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
26 
4.2.5 Serious illness requiring systemic treatment and/or hospitalization until subject 
either completes therapy or is clinically stable on therapy, in the opinion of the 
investigator, for at least 30 days prior to study entry (Day 0). 
 
4.2.6 Evidence of any anti-mycobacterial resistance, clinical or genetic, prior to study 
entry. Resistance testing results must be available for review by the site 
investigator and study protocol team prior to enrollment to ensure that no 
exclusionary resistance exists. 
 
4.2.7 Active drug or alcohol use, or dependence, or other conditions that, in the opinion 
of the site investigator, would interfere with adherence to study requirements. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, sites must have the protocol and consent 
form approved by their local institutional review board (IRB). Once a candidate 
for study entry has been identified, details will be carefully discussed with the 
subject. The subject will be asked to read and sign the consent form that was 
approved by the local IRB. 
 
4.3.2 A patient identification number (PID) will be assigned to each patient screened 
for the study. PIDs should not be reassigned even if the patient fails to enter the 
study. The PID must be included on every CRF and patient blood sample. BIT 
Core must maintain a master list of PIDs in a central location. The patient 
registration and inclusion/exclusion CRF must be completed on the online system 
(cfar.ucsd.edu/intranet).  
 
5.0 
STUDY TREATMENT  
 
5.1 
The Ingestible Sensor System 
 
The system consists of 1.0 mm x 1.0 mm x 0.45 mm ingestible sensor and an on-body wearable 
sensor. The ingestible sensors are activated by gastric fluids, independent of the acidity level, 
and communicate unique identifying signatures to the body surface. The system uses a 
conductive method of communication, not radio frequency, which ensures the information is 
confined to the body of the user and preserves privacy. The wearable sensor counts the number 
of times each unique signature is received. For pre-study, the ingestible sensors were attached to 
inert tablets and co-ingested with the TB medications. The system recorded the date and time of 
an ingestion event after a unique signature was received 10 times. The ingestible sensors are 
designed to communicate for approximately 7 minutes after which they are inactive and get 
eliminated in the feces. The system is capable of identifying and differentiating among multiple 
simultaneously ingested sensors. 
 
5.2 
Regimens, Administration, and Duration 
 
Study Treatment is defined as:  
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
27 
DHFS Group: over-encapsulated ingestion sensor plus a fixed-dose combination of isoniazid-
rifampin (Rifamate) (study supplied) (alternatively in Phase 1, Rifamate with co-ingestion of an 
encapsulated edible sensor) 
 
SOC Control Group: isoniazid plus rifampin, or Rifamate (by prescription) 
 
5.2.1 Regimens  
 
DHFS Group: 
Rifamate (combination of isoniazid 150 mg and rifampin 300 mg) over-
encapsulated with ingestion sensor - 2 capsules orally QD (provided by the study 
through the AVRC pharmacy) 
 
SOC Control Group: 
isoniazid 300 mg -1 tablet orally QD plus rifampin 300 mg - 2 capsules orally 
QD, or Rifamate (combination of isoniazid 150 mg and rifampin 300 mg) - 2 
capsules orally QD (provided by the PHS, OCHCA, or study physician) 
 
5.2.2 Administration 
 
Isoniazid and rifampin, or Rifamate, will be administered orally as described 
above, preferably on an empty stomach (at least one hour prior to or two hours 
after a meal) first thing in the morning. 
 
5.2.3 Duration 
 
Subjects will receive study treatment for a minimum of 6 weeks up to a maximum 
of 12 months on study, depending on time left to complete treatment. 
 
5.3 
Study Treatment (DHFS IS-RM) Formulation and Preparation  
 
5.3.1 Formulation 
 
Isoniazid-rifampin (Rifamate) fixed dose formulation capsules over-encapsulated 
with ingestible PDH sensor. Store at 250C (770F), excursion permitted to 15-300C 
(59-860F) (see USP Controlled Room Temperature); protect from excessive heat 
and humidity.  
 
5.3.2 Preparation 
 
Ingestible PDH sensor and isoniazid-rifampin (Rifamate) will be over-
encapsulated with Capsugel gelatin capsules, and dispensed by the AVRC 
pharmacy. The final study product will be packaged in white, high density 
polyethylene bottles. Each bottle will contain a sufficient quantity of study drug to 
last until the subject’s next scheduled visit. 
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
28 
5.4 
Study Product Supply, Distribution, and Accountability 
 
5.4.1 Study Product Supply/Distribution 
 
For the DHFS group, ingestion sensors will be purchased from Proteus Digital 
Health, Inc. and anti-TB drugs (Rifamate) and over-encapsulation will be 
provided by the AVRC pharmacy. The study product (IS-RM) will be supplied by 
the study. 
 
For the control group receiving SOC, isoniazid and rifampin, or Rifamate, will 
not be supplied by the study, but will be made available to subjects via 
prescription at a public health pharmacy. 
 
5.4.2 Study Product Accountability 
 
The clinical site pharmacist is required to maintain complete records of all study 
products received, compounded (over-encapsulated), and subsequently dispensed 
for this study. All unused study products must be returned to the sponsors after 
the study is completed or terminated. 
 
5.5 
Concomitant Medications 
 
5.5.1 Required Medications 
 
WHILE PARTICIPANTS ARE TAKING ISONIAZID OR RIFAMATE 
(isoniazid in combination with rifampin), PYRIDOXINE (VITAMIN B6) 25 MG 
OR 50 MG MUST ALSO BE GIVEN ONCE DAILY. 
 
5.5.2 Prohibited Medications: 
 
  
• All investigational drugs.  
• Any immunomodulators. 
• Systemic cytotoxic chemotherapy. 
• The following antiviral drugs: ritonavir, Stribild®, atazanavir, darunavir, 
fosamprevavir, saquinavir, tipranavir, delavirdine, etravirine, and rilpivirine.  
• All herbal products should be avoided because of the unknown drug 
interactions between herbal products and TB drugs used in this study. 
 
5.5.3 Precautionary Medications  
 
 
5.5.3.1 Precautionary Medications with Rifampin 
Medication Class 
Precautionary Medications 
ACE Inhibitors 
Enalapril 
Antiarrhythmics 
Disopyramide 
Mexiletine 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
29 
Medication Class 
Precautionary Medications 
Quinidine 
Tocainide 
Antibiotics 
Chloramphenicol 
Clarithromycin 
Dapsone 
Doxycycline 
Fluoroquinolones 
Anticoagulants 
Warfarin 
Anticonvulsants 
Phenytoin 
Antimalarials 
Quinine 
Atovaquone 
Antiretrovirals 
Efavirenz 
Nevirapine 
Raltegravir 
Zidovudine 
Dolutegravir 
Antipsychotics 
Haloperidol 
Azole Antifungals 
Fluconazole 
Itraconazole 
Ketoconazole 
Barbiturates 
Phenobarbital 
Benzodiazepines 
Diazepam 
Beta-Blockers 
Propranolol 
Calcium Channel Blockers 
Diltiazem 
Nifedipine 
Verapamil 
Cardiac Glycoside Preparations 
Digoxin 
Corticosteroids 
Prednisone 
Fibrates 
Clofibrate 
Hormonal Contraceptives/Progestins 
Ethinyl estradiol 
Levonorgestrel 
Oral hypoglycemic agents 
Sulfonylureas 
Immunosuppressants 
Cyclosporine 
Tacrolimus 
Methylxanthines 
Theophylline 
Narcotic analgesics 
Methadone 
Phosphodiesterase-5 (PDE-5) Inhibitors 
Sildenafil 
Thyroid preparations 
Levothyroxine 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
30 
Medication Class 
Precautionary Medications 
Tricyclic Antidepressants 
Amitriptyline 
Nortriptyline 
 
 
5.5.3.2 Precautionary Medications with Isoniazid: 
• Carbamazepine 
• Chlorzoxazone 
• Disulfiram 
• Ketoconazole 
• Phenytoin 
 
The physician responsible for prescribing TB medications to subjects 
should be made aware of the following: It may be necessary to adjust the 
dosages of some medications when given concurrently with 
isoniazid/rifampin. To avoid adverse drug interactions, package inserts 
of anti-TB agents and other concomitant medications should be 
referenced whenever a concomitant medication is initiated or dose 
changed, to avoid drug interaction AEs. 
 
5.5.4 Food Interactions  
 
 
Prescribing physicians should be aware that since isoniazid has some monoamine 
oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, 
red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated 
response (e.g., headache, sweating, palpitations, flushing, hypotension) to foods 
containing histamine (e.g., tuna, other tropical fish). Tyramine- and histamine-
containing foods should be avoided. 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
31 
6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Events 
 
Table 1.  
Evaluation 
Screening 
Phase 1 
Randomization 
Phase 2 
Completion of 
Treatment/ 
End of Study 
or Premature 
Discontinuation 
Week 1 
Day 0 
Week 1 
Visit 1 
Week 2 
Visit 2 
Week 2 
Visit 3 
Day 0 
Daily 
Weekly 
Wk 2 
Wk 4 
Wk 8 
Wk 12 
and 
every 4 
weeks 
Visit Window 
 
Within 45 
days of 
Screening 
 
 
 
 
 
 
 
+ 7 
days 
+ 7 
days 
+ 14 
days 
+ 14 
days 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Language 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of TB 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History (last 30 days) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Toxicity/AE Evaluation 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
Targeted Exam 
X 
X 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
Concomitant Meds (since last 
visit) 
 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
Initiation of study medication 
 
X 
 
 
 
 
X* 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
PDH System 
Subject training 
 
X 
X 
 
 
 
X* 
 
 
 
 
 
 
 
Observation with PDH Patch 
 
X 
X 
X 
X 
 
X* 
 
 
X* 
X* 
X* 
X* 
X* 
Patch change (by subject) 
 
X 
 
X 
 
 
X* 
 
X* 
 
 
 
 
 
Witnessed Rifamate doses 
 
X 
X 
X 
X 
 
X* 
 
 
 
 
 
 
 
Adherence Intervention Based on 
PDH Sensor**  
 
 
 
 
 
 
 
X* 
 
 
 
 
 
 

 
 
AHF TB 001 
 
 
Protocol Version 2.3 
 
 
March 25, 2015 
32 
Evaluation 
Screening 
Phase 1 
Randomization 
Phase 2 
Completion of 
Treatment/ 
End of Study 
or Premature 
Discontinuation 
Week 1 
Day 0 
Week 1 
Visit 1 
Week 2 
Visit 2 
Week 2 
Visit 3 
Day 0 
Daily 
Weekly 
Wk 2 
Wk 4 
Wk 8 
Wk 12 
and 
every 4 
weeks 
Laboratory Evaluations 
Hematology§ 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
Liver Function Tests§ 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
Chemistry§ 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
Pregnancy Testing (and whenever 
pregnancy is suspected) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Stored Plasma/Serum λ 
 
 
 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Assessments 
Adherence Self-Report 
 
X 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
Self-Report Questionnaires §§ 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Usability and Satisfaction Survey 
 
 
 
 
X 
 
 
 
 
 
 
X* 
X* 
X* 
 
* 
Subjects randomized to intervention arm only 
** Three visits for witnessed doses; phase1: Week 1 and Week 2 
§ 
Done per standard of care within 30 days of screening and captured whenever done during the course of the study 
§§ Habitual self-control, self-efficacy beliefs, depression scale (PHQ-9), alcohol use (AUDIT) and drug use (DAST-10) questionnaires 
λ 
Only subjects seen at UCSD AVRC will undergo collection of plasma for storage. 
 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
33 
6.2 
Evaluations 
 
6.2.1 Pre-Entry Evaluations 
 
Occur prior to the subject taking any study medications, treatments, or 
interventions.  
 
6.2.1.1 Patient Registration 
 
 
A coded patient identification number (PID) will be assigned to each 
patient screened for the study. PIDs should not be reassigned even if the 
patient fails to enter the study. The PID must be included on every case 
report form (CRF) and patient blood sample. BIT Core must maintain a 
master list of PIDs in a central location. The patient registration and 
inclusion/exclusion CRF must be completed on the online system.  
 
6.2.1.2 Screening Clinical Labs 
 
If plasma sputum, resistance testing, biochemistry, and hematology 
laboratories were obtained at a CLIA-approved lab no more than 90 days 
prior to screening and results are available then these labs do not need to 
be repeated. If these laboratories are not available from County records 
or medical records, then hematology, microbiology, chemistry, and 
pregnancy testing will be coordinated through the public health or 
AVRC laboratory and results will be tracked on the online database. 
 
Screening entry evaluations in addition to screening laboratories will 
include documentation of TB, and medical and medication history with 
report of clinical assessment, including toxicity to TB treatment.   
Attitudes to mobile devices and internet usage, and ability to have a 
mobile device housed and charged at home will be ascertained. County 
healthcare workers will be asked about suitability of individual for 
inclusion in study. Once the screening laboratories and other evaluations 
have been done, the patient will be evaluated for study eligibility if all 
other entry criteria are satisfied.  
 
If any laboratory values are outside the eligible range, the site may re-
screen a patient on one occasion. However, the study will not pay for 
additional re-screening laboratories.  
 
6.2.1.3 Enrollment 
  
Once a subject is deemed as eligible at screening they will be consented 
for enrollment into the study.  
 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
34 
6.2.1.4 Phase 1 
 
 
The Day 0 evaluation should be scheduled within 45 days of the 
screening visit. Subjects will undergo training and instruction on the 
DHFS system and initiation of study drug with DOT. A clinical 
assessment including toxicity will take place on Day 0, Week 1, and 
Week 2. Subjects will be trained with the PDH system by study staff, 
including placing the patch under observation Day 0, Week 1, and Week 
2. Subjects will begin DHFS IS-RM (or Rifamate with co-ingestion of 
an encapsulated edible sensor) on Day 0, which will be directly 
observed. Patients will have two study visits per week in Week 1 and 
Week 2 for directly observed ingestion of DHFS IS-RM (or Rifamate 
with co-ingestion of an encapsulated edible sensor). Monitoring for side 
effects will take place at visits. At the end of Week 2 the subject will 
have their plasma drawn and stored. All subjects will complete items on 
PDH system usability and satisfaction. 
 
6.2.1.5 Randomization  
 
Subjects who wish to continue and remain eligible will be randomized 
2:1 to DHFS IS-RM or to the control group receiving standard of care 
(SOC). Randomization for treatment assignment will be done centrally 
via the electronic database. 
 
If the subject is randomized to the control arm, public health will 
provide isoniazid and rifampin, or Rifamate and DOT as per their 
routine. Please remind the subject to fill medication and contact public 
health as soon as possible. Please contact public health to inform them 
subject has been randomized to SOC DOT. The public health nurse 
assigned to this case should be handed the cost analysis data collection 
materials. The public health nurse will collect and perform quality 
control of the DOT forms used, but the outreach workers that actually 
perform the DOT.  
 
If the subject is randomized to the intervention arm they will be given a 
14-30-day supply of treatment medication, DHFS IS-RM, from the 
AVRC pharmacy on the entry day.  
 
6.2.2 On-Study Evaluations, Phase 2 
 
6.2.2.1 Day 0 
 
 
Subjects randomized to the intervention will undergo clinical assessment 
including toxicity. They will receive training and instruction will take 
place on home use of DHFS, continuous patch wearing, use of mobile 
device with application screen. They will be monitored for correct patch 
use. Pre-study interviews will collect subject attitudes to mobile devices 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
35 
and internet usage, as well as their understanding of taking anti-
mycobacterial medications thus far and what they would like to gain 
from use of the PDH monitoring system. Self-report questionnaires will 
be administered on a mobile device. The subject’s plasma will be drawn 
and stored only if they are subjects seen at the AVRC. Cost data 
collected. The patient will be instructed to take IS-RM at the clinic. 
From this point on study personnel and public health workers will check 
adherence data provided by DHFS daily and perform adherence 
intervention as necessary. 
 
6.2.2.2 Week 2 to Completion of Treatment/End of Study 
 
 
All subjects will receive a clinical assessment with toxicity and side 
effect evaluation, completion of a self-report adherence questionnaire 
and cost data collection. In the intervention arm, adherence will be 
checked (by reviewing DHFS logs) by study staff and public health daily 
and intervention will be performed as appropriate. At Weeks 2, 4, 8, and 
every 4 weeks until treatment is completed/end of study, adherence 
questionnaires will be collected; for subjects seen at the AVRC, Phase 2 
visits will include a blood draw with stored plasma. In the intervention 
arm, the DHFS system usability and satisfaction questionnaires will be 
collected at Week 8, Week 12, and every 4 weeks until treatment is 
completed/end of study. For all subjects, at Week 8 and at the end of 
study, self-report questionnaires will be completed on a mobile device. 
 
6.2.3 Change in Anti-Mycobacterial Regimen 
 
Intervention subjects who require a change their treatment regimen from DHFS 
IS-RM for any reason will be required to permanently discontinue their study 
regimens.  
 
If the regimen change is due to microbiologic failure, the subject would be 
evaluated for microbiologic failure during physician clinic visits (Section 6.1). 
 
6.2.4 Post-Treatment Evaluations 
 
All randomized subjects will complete an end of study visit, which will occur 
when a subject has completed their TB treatment (up to a maximum of 12 months 
on study). If the sponsor ends the study early, the end of study visit evaluation 
will be completed, regardless of week number.  
 
6.2.5 Premature Treatment Discontinuation 
 
These evaluations are required at the subject’s final visit if they stop the study any 
time before the end of their treatment. 
 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
36 
6.2.6 Pregnancy  
 
Women who become pregnant during the study will be required to permanently 
discontinue their study regimens and will not continue to be followed on study. 
They should be advised to seek best available medical care for their pregnancy 
according to U.S. TB treatment guidelines. 
 
6.3 
Special Instructions and Definitions of Evaluations 
 
6.3.1 Documentation of TB 
 
 
The research coordinator will obtain results of any TB cultures, smears, cytology, 
and histopathology, from County records and medical records, and record them in 
the CRF. 
 
6.3.2 TB Drug Resistance Definition 
 
 
Multi-drug-resistant tuberculosis (MDR-TB) is defined as tuberculosis that is 
resistant to at least isoniazid and rifampicin (RMP). Isolates that are multiply 
resistant to any other combination of anti-TB drugs but not to isoniazid and RMP 
are not classed as MDR-TB. Extensively drug-resistant tuberculosis is defined as 
TB that has developed resistance to at least rifampicin and isoniazid (resistance to 
these first line anti-TB drugs defines multi-drug-resistant tuberculosis, or MDR-
TB), as well as to any member of the quinolone family and at least one of the 
following second-line anti-TB injectable drugs: kanamycin, capreomycin, or 
amikacin [22]. 
 
6.3.3 TB Drug Resistance Testing 
 
 
MDR-TB is defined by clinical, microbiologic, or molecular testing [23]. 
 
6.3.4 Medical and Laboratory History 
 
 
At screening, a medical history will be obtained and must be recorded in the 
source documents. The medical history should include detailed information on 
mycobacterial infection, clinical course, and drug susceptibilities. 
 
6.3.5 Medication History 
 
 
At screening, a medication history (only if within last 30 days prior to entry) 
with actual or estimated start and stop dates should be obtained and recorded in 
the source documents and the concomitant medication CRF, including:  
 
• All prescription medications. Including medications taken for the treatment or 
prophylaxis of opportunistic infections. 
• Non-prescription medications.  

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
37 
• Alternative therapies and/or dietary supplements.  
• Allergies to any medications and their formulations must be documented. 
 
6.3.6 Concomitant Medications 
 
 
During study visits (see Section 6.1 for specific dates) all concomitant 
medications taken since the last visit will be recorded in the source documentation 
and entered into the concomitant medication log CRF. 
 
6.3.7 Study Treatment Modifications 
 
 
All modifications to study drug(s) including initial doses, patient-initiated and/or 
protocol-mandated interruptions, modifications, and permanent discontinuation of 
anti-mycobacterials need be recorded on the CRFs at each visit. 
 
6.3.8 Clinical Assessments 
 
 
Targeted Physical Exam 
 
 
A targeted physical examination will be based on any signs or symptoms 
previously identified that the subject has experienced within 30 days of entry or 
since the last visit. This examination will be performed at Day 0 and at study 
visits, as specified in the Schedule of Events, and in instances of microbiologic 
failure/toxicity or premature treatment discontinuation if they should occur. 
 
Height and Weight 
 
Height and weight should be measured at study entry. Weight will be measured at 
every study visit. 
 
Signs and Symptoms 
 
All signs, symptoms, deaths, and toxicities must be documented in the subject’s 
record. At entry, record all signs/symptoms experienced within 30 days of entry 
on the CRFs. For all other visits and at the time of occurrence of microbiologic 
failure, record all Grade > 2 signs and symptoms and deaths on the CRFs that 
have occurred since the last visit. Any signs or symptoms that lead to a change in 
DHFS treatment or the investigator thinks could possibly be due to DHFS 
treatment, regardless of Grade, must be recorded on the CRF. The source 
document must include date of onset and date of resolution, but the CRF will only 
record prevalence of a given adverse event since the previous study visit. 
 
Refer to the Division of AIDS Table for Grading Adult Adverse Experiences.  
 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
38 
Diagnoses 
 
The following should be recorded on the CRFs: TB diagnosis and co-morbidities. 
Any other diagnosis that is, in the opinion of the site investigator, associated with 
study product or DHFS system, should be recorded on the adverse event CRF. 
The source document must include date of diagnosis and date of resolution. 
 
Vital Signs 
 
Temperature, pulse, and blood pressure will be collected at all visits and kept as a 
part of the source document. 
 
6.3.9 Laboratory Evaluations 
 
For all visits record all Grade ≥ 2 laboratory values on the CRFs throughout the 
course of the study. All values, regardless of toxicity, of specific laboratories will 
also be recorded on the laboratory CRF; including: white blood cell count, 
neutrophil count, hemoglobin, platelets, blood urea nitrogen, creatinine, glucose, 
AST/ALT, alkaline phosphatase, total bilirubin. 
 
Any laboratory toxicities that lead to a change in TB or DHFS treatment, 
regardless of Grade, must be recorded on the adverse event CRF. 
 
Refer to the Division of AIDS Table for Grading Adult Adverse Experiences, 
which can be found on the ACTG website: https://actgnetwork.org/ 
 
Hematology  
 
Laboratory values will be done per SOC at public health and recorded in the CRF. 
 
Liver & Kidney Function Tests 
 
Total bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase, BUN, 
creatinine and electrolytes (sodium, potassium, chloride, and bicarbonate) will be 
collated from the public health laboratory. 
 
Pregnancy Test 
 
For women with reproductive potential: Urine β-HCG (urine test must have a 
sensitivity of < 50 mIU/mL) should be done at the site’s local laboratory during 
screening, at study entry and whenever clinically suspected. 
 
6.4 
Off-Drug Requirements 
 
Additional safety monitoring and reporting of serious adverse events (SAEs) thought to 
be at least possibly related to DHFS will be required upon completion or discontinuation 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
39 
of study protocol regardless of whether a protocol follow-up visit is scheduled to occur. 
Follow-up will continue until the adverse event is resolved or stabilized.  
 
7.0 
CLINICAL MANAGEMENT ISSUES  
 
7.1 
Adverse Events 
 
Adverse events will be captured by study personnel throughout a patient’s participation in both 
the active portion of the protocol as well as the follow-up period. Wearable sensor-related 
adverse events will be captured from the onset of exposure (e.g. first patch application) to the 
end of device exposure (e.g. removal of last patch, or resolution of last wearable sensor-related 
AE, whichever is later). Ingestible sensor-related adverse events will be captured from the onset 
of exposure (e.g. first ingestion) to the end of device exposure (e.g. last ingestion, or resolution 
of last ingestible-sensor related adverse event). 
 
Table 2. Adverse Event-Related Definitions 
Adverse Event (AE) 
Any undesirable medical event occurring in research 
subject, whether or not the event is considered related to 
the investigational device.  
Serious Adverse Event (SAE) 
An AE that results in death, is life-threatening (even if 
temporary in nature), results in a permanent impairment of 
body function or permanent damage to body structure, 
hospitalization, prolongation of hospitalization, or medical 
or surgical intervention to preclude permanent impairment 
of a body function or permanent damage to a body 
structure, or represent a serious medical event. An SAE 
may or may not be considered related to the investigational 
device. 
Anticipated Adverse Event (AAE) An AE that is listed in the clinical protocol or other study-
related document that has been identified as a potential AE 
related to the investigational device or procedure being 
studied. 
Unanticipated Adverse Device 
Effect (UADE) 
Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated 
with, a device, if that effect, problem or death was not 
previously identified in nature, severity or degree of 
incidence in the investigational plan or application or any 
other unanticipated serious problem associated with a 
device that relates to the rights, safety or welfare of 
subjects. 
 
In some adverse event reports, the cause of the adverse event may not be immediately apparent, 
due to the overlapping nature of the anticipated adverse events from the DHFS and from the 
concomitant medications with which the patients will enroll in the study. In these cases, it is the 
investigator’s responsibility to appropriately adjudicate the cause of the adverse events, taking 
into consideration the location, nature, onset, and duration of the adverse event, as well as the 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
40 
known safety profiles of both the study device, study drug, and other concomitant drugs. The 
following table outlines the reporting algorithm to be used for Adverse Events. 
 
Table 3. Adverse Event Reporting Algorithm, Investigator’s (or Designee’s) Responsibilities 
Type 
Action 
Communication 
Non-Serious Adverse Event 
§ Record on the CRFs 
Written on CRF 
Serious Adverse Event 
(SAE), unrelated to the 
device 
§ Record on the CRFs 
Written on CRF 
Serious Adverse Event 
(SAE), possibly or 
definitively related to the 
device, anticipated 
§ Record on the CRFs  
§ Preliminary report to Proteus Digital 
Health within 3 days (reporting days) 
of the investigator/site’s becoming 
aware 
§ Full report submitted as additional 
information becomes available.  
§ Full report submitted to the IRB within 
10 working days of the 
investigator/site’s becoming aware 
Verbal and written 
Unanticipated Adverse 
Device Effect (UADE) 
§ Record on the CRFs 
§ Preliminary report to Proteus Digital 
Health within 3 days of the 
investigator/site’s becoming aware 
§ Full report to Proteus Digital Health as 
additional information becomes 
available. Report to the IRB as soon as 
possible, but within 10 working days 
of the investigator/site’s becoming 
aware 
Verbal and written 
 
Investigators should make the required reports to the manufacturer’s Safety Officer: 
 
Greg Moon, MD 
Director of Clinical Affairs 
Proteus Digital Health, Inc. 
2600 Bridge Parkway, Suite 101, Redwood City, California 94065 
Phone: (Office) 650-637-6111, (Mobile) 415-939-6425, Fax: 650-632-4071 
Email: gmoon@proteusdh.com 
 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
41 
Once the manufacturer has been notified of an adverse event, it will fulfill its reporting 
requirements to regulatory authorities per Proteus Digital Health SOP000794, Adverse Events: 
Reporting Requirements for Investigational and Approved Devices. 
 
7.2 
Toxicity Management 
 
Adverse events due to Tuberculosis or the medical treatment of TB (Rifamate) will be handled 
per SOC and County criteria. Laboratories to monitor toxicity will be done per County criteria 
and will be recorded by study forms.  
 
Toxicity Events Related to DHFS  
 
No adverse effects have been observed after administering the PDH ingestible sensors to rats in a 
dose 1,000 times the maximum human daily dose (see Investigator’s Brochure). Human testing 
to date has included more than 250 subjects, including healthy human subjects and subjects with 
TB and other chronic diseases, with more than 14,000 PDH ingestible sensors ingestions. More 
recent studies have occurred with no exclusion for pre-existing gastrointestinal diseases. 
Ingestions have occurred twice daily for as long as 12 weeks, and as many as 30 PDH ingestible 
sensors have been ingested in a single day with no adverse gastrointestinal effect. A single 
occurrence of nausea and vomiting (3.5% of all subjects) has been reported after multiple earlier 
prototype PDH ingestible sensors ingestions in a single day. Self-limited, minor, and localized 
skin irritation has occurred in 17.7% wearing the adhesive backed monitor. Adhesives with 
improved skin tolerability are being incorporated into newer versions of the PDH system. There 
have been no unanticipated adverse events and no serious adverse events related, or possibly 
related, to the PDH System.  
 
Skin-related issues can occur with any adhesive medical product, including the common 
adhesive bandage, and the wearable sensor is no exception. To date, some subjects have 
experienced cutaneous AEs, in the form of transient, mild, macular, papular, or maculopapular 
erythematous rash at the wearable sensor site. These rashes appear to be consistent with irritant 
(i.e., non-immune mediated) contact dermatitis, a well-characterized and common phenomenon. 
(It is the same phenomenon that underlies the colloquially named “dishpan hands”). Each rash in 
prior system studies either resolved or was resolving significantly by the time of the final safety 
follow-up. Experience has shown that risk of rash can be significantly mitigated by rotating 
wearable sensor sites with no areas of overlap. 
 
The sponsor is committed to the rigorous capture of skin AEs related to use of the system. 
However, not all issues are clinically significant. Thus, the following skin-related issues shall not 
be captured as AEs by study investigators: 
 
1. Pruritis, if not associated with: a) visible skin changes, including excoriation or b) 
interruption of system use > 1 day. 
 
 
2. Skin changes that would be routinely encountered through the wear of a common 
adhesive bandage (e.g., transient wrinkling/whitening of the skin under a bandage, mild 
hyperemia). 
 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
42 
Verification that a Skin Issue has Occurred 
 
Before being classified as an AE, skin issues must be verified. Verification can consist of either: 
a) direct visualization by the investigator or his/her designee or b) a photograph taken of the 
affected area. The most convenient means to accomplish the latter will be use of the mobile 
device issued to each study subject; site staff should train each subject regarding the mobile 
device camera feature as he/she enters a given study. The only exception is pruritis that leads to 
interruption of system use > 1 day, as there likely will be nothing to visualize.  
 
Documenting Skin AE Evolution and Chronicity 
 
Skin AEs frequently last longer than 1 day, so a means to document the course of the AE is 
described below. Skin findings that occur in the same location should be treated as a single AE, 
unless complete resolution at that location has been visualized and documented by the 
investigator. Moreover, a skin AE may evolve over its course (e.g., erythema progressing to 
papules, followed by scaling). The investigator should therefore name the skin AE based upon 
findings first encountered (e.g., “macular rash”). For each assessment episode that occurs in 
follow-up, record the following on the Adverse Events Form case report form: 
 
1. Date of assessment 
 
2. Actions taken 
 
3. Outcome, using the Table TBD 
 
4. Any new features of the same skin AE that emerge on its course to resolution (e.g., 
scaling, non-erythematous skin discoloration) captured within the “additional skin 
findings” data field for a given skin AE 
 
5. Date of onset and date of resolution 
 
Table 4. Procedure for Documenting Device-Related Skin AE Outcome 
Outcome 
Definition 
Action 
CRF Used 
Resolved 
No remaining signs of 
skin changes 
Document date of 
resolution 
Adverse Event form 
used (for interim visits) 
OR Follow-up Visit 
form (for final study 
visit) 
Resolving 
Skin changes have 
improved but are still 
discernible 
Document as “resolving” 
List any new skin 
findings 
Must continue 
surveillance through last 
study visit 
Adverse Event form 
used (for interim visits) 
OR Follow-up Visit 
form (for final study 
visit) 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
43 
Outcome 
Definition 
Action 
CRF Used 
Unresolved 
Skin changes have not 
improved or have 
worsened 
Document as 
“unresolved” 
List any new skin 
findings 
Must continue 
surveillance through last 
study visit 
Adverse Event form 
used (for interim visits) 
OR Follow-up Visit 
form (for final study 
visit) 
Resolved with 
Sequelae 
Original skin issues and 
all subsequent skin 
features that were 
present throughout 
course have resolved, 
but a condition as a 
consequence of the skin 
AE emerged 
Document as “resolved 
with sequelae” 
List the sequelae 
Adverse Event form 
used (for interim visits) 
OR Follow-up Visit 
form (for final study 
visit) 
 
On the CRF used for the last study visit (usually the safety follow-up visit), all skin AEs—except 
those that have not previously been documented as “resolved”—shall have a final categorization 
of outcome (“resolved,” “resolving,” “unresolved,” or “resolved with sequelae”). 
 
Non-Erythematous Skin Discoloration 
 
This finding has been noted infrequently in studies of the system. Following an initially 
erythematous rash, the skin can take on a brownish hue in the areas of prior erythema. This 
should not be considered a new skin AE, as it is a continuation of the previous AE. If detected, 
the investigator should list “non-erythematous skin discoloration” as a new skin finding in the 
associated data field. On each subsequent assessment, the investigator must make the 
determination of “resolved,” “resolving,” “unresolved,” or “resolved with sequelae.” 
 
8.0 
CRITERIA FOR DISCONTINUATION 
 
8.1 
Criteria for Treatment Discontinuation 
 
• Drug-related toxicity (see Section 7.2, Toxicity Management). 
• Requirement for prohibited concomitant medications (see Section 5.5.2) 
 
8.2 
Criteria for Discontinuation from the Study 
 
• Pregnancy or breast-feeding. 
• Active drug or alcohol use or dependence that, in the opinion of the investigator, 
would interfere with adherence to study requirements. 
• Failure by the subject to attend three consecutive clinic visits during the follow-up 
portion may result in discontinuation. 
• Request by the subject to withdraw. 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
44 
• Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the subject. 
• Clinical reasons believed life threatening by the physician, even if not addressed in 
the toxicity management of the protocol. 
• Subject judged by the investigator to be at significant risk of failing to comply with 
the provisions of the protocol as to cause harm to self or seriously interfere with the 
validity of the study results. 
• At the discretion of the AVRC, investigator, or sponsors. 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues 
 
This study is a prospective, two phase, open-label feasibility study with lead in (Phase 1) and 
randomized (Phase 2) components to evaluate the utility of the DHFS for monitoring TB 
treatment. In the first phase, all subjects will receive DHFS IS-RM (or Rifamate with co-
ingestion of an encapsulated edible sensor) and a series of doses will be witnessed in order to 
determine the detection accuracy of the system as well as to evaluate subject acceptance and 
ability to use the system. In the randomized phase, those randomized to intervention will 
continue to use the DHFS IS-RM and control subjects will receive SOC DOT. 
 
9.2 
Endpoints 
 
9.2.1 Primary Endpoints  
 
Phase 1 (1.2.1) Positive Detection Accuracy (PDA) 
 
PDA is defined as DHFS detection of the ingestion of a dose of IS-RM (or 
Rifamate with co-ingestion of an encapsulated edible sensor) when compared to a 
witnessed ingestion of the same dose of medication. For purposes of PDA 
analysis, a dose is defined as a single IS-RM capsule. PDA will be based upon 
dose ingestions that occur during concurrent use of DHFS and DOT during the 
planned Phase 1 study visits. A minimum of 280 dose ingestions are required to 
generate sensitivity and specificity of the System.  
 
Phase 2 (1.2.2) Percentage of Witnessed Doses 
 
This will be calculated as the total number of witnessed doses ingestions divided 
by the total number of prescribed witnessed dose ingestions. For the DHFS, 
witnessed doses by DHFS is defined as the total number of dose ingestions 
confirmed by DHFS, divided by the total number of prescribed witnessed dose 
ingestions for TB treatment. For SOC, witnessed doses will be defined as the total 
number of dose ingestions that are actually witnessed by a healthcare worker, 
divided by the total number of prescribed witnessed dose ingestions for TB 
treatment. This endpoint will be calculated from Phase 2, Day 0 to  
Weeks 4, 8 and end of study. 
 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
45 
9.2.2 Secondary Endpoints  
 
(1.2.3) The definition of 80% adherence will be completion of ≥ 80% of 
witnessed doses.  
 
(1.2.4) Lapse in prescribed witnessed doses will be defined by missing 1 or more 
prescribed witnessed doses; the duration of lapses will be defined by the number 
of sequential missed prescribed witnessed doses in a row.  
 
(1.2.5) The total cost of treatment for DHFS IS-RM and SOC DOT will be 
defined based on specific data collected for that purpose.  
  
(1.2.6) Adverse events of the DHFS system or DOT will be defined as any grade 
1 or higher DHFS or DOT related adverse clinical and laboratory events.  
 
(1.2.7) Responses to individual questions and grouped question responses (i.e., 
summary metrics across questions) will be defined to evaluate subject satisfaction 
with the DHFS system.  
 
(1.2.8) Responses to individual questions and grouped question responses (i.e., 
summary metrics across questions) will be defined to evaluate healthcare worker 
and physician satisfaction with DHFS and DOT. 
  
(1.2.9) Individual question and summary metrics will be defined for each of the 
self-reported instruments: 1) habitual self-control, 2) self-efficacy beliefs, 3) 
PHQ-9, 4) AUDIT, and 5) DAST-10. If standardized scores exist (e.g., for the 
PHQ-9), these scoring systems will be used to define the endpoint. 
 
(1.2.10) The definition of 80% adherence will be completion of > 80% of 
witnessed doses.  
 
9.3 
Randomization 
 
Subjects will be randomized 2:1 to DHFS or SOC. Randomization will be done centrally via the 
study database. 
 
9.4 
Sample Size and Accrual 
 
Phase 1: For phase 1, both groups will use the DHFS for 2 weeks, and we will estimate the 
confidence interval around an estimate of the detection accuracy of the DHFS by taking the ratio 
of the sensor-enabled ingestion recorded events compared to the witnessed doses. Assuming that 
each of 75 subjects completes 2 weeks of DHFS dosing and has a total of three witnessed doses 
each week (a total of 450 dosing events) and that the overall rate of positive detection is 95%, 
then the 95% confidence interval around the point estimate of 95% accurate detection would be 
+/- 2.0%. If the detection accuracy was 97%, then the 95% confidence interval around the point 
estimate of 97% accurate detection would be +/- 1.6%.  
 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
46 
Phase 2: The primary aim of phase 2 is to assess the percentage of prescribed witnessed doses 
completed over the entire study period for each subject and to compare the DHFS arm to the 
DOT arm. This metric captures the persistent efficacy of the DHFS ingestion sensor system and 
allows comparison to SOC DOT of varying intervals (5 times, 3 times, or 2 times per week that 
may occur in the SOC). Sample size calculations were based on a two-sided, two-sample t-test to 
compare the differences in adherence percentages by treatment arm using different 
mean/standard deviation scenarios. Calculations were performed using the R statistical package 
(version 2.14.0) (www.r-project.org).  
 
In choosing a sample size for this pilot study, we considered issues of cost, feasibility, as well as 
how large an effect size would be of interest to spur further study of this intervention in this 
population. Assuming a two-sided alpha of 0.05, an adherence percentage in the DOT arm of 
90%, and a common standard deviation of 6%, we will need 75 participants (50 DHFS arm and 
25 DOT arm) to detect a 5% difference (i.e. 95% adherence percentage in DHFS arm) with 92% 
power.  
 
9.5 
Monitoring 
 
 
The study team will review all adverse events during the study by cumulative reports, on a 
monthly basis. Adverse events will be graded using the ACTG toxicity grading scale and 
recorded using standard AE electronic data capture. The study investigators will monitor safety 
events in aggregate on monthly team calls. An independent Data Safety and Monitoring Board 
will not be used for this study.  
 
9.6 
Analyses 
 
This section briefly describes the planned statistical analysis. The Statistical Analysis Plan 
(SAP), which will be finalized prior to database lock, provides further details. In case the 
language in this section differs from the language in the SAP, the SAP takes precedence. 
 
In general, analyses will incorporate the modified intent-to-treat principle, namely, all 
randomized participants dispensed at least one dose of medication will be included in the 
analysis. No adjustments for multiple comparisons will be made for secondary analyses, and a p-
value of 0.05 will be considered statistically significant. 
 
Demographic data, concomitant medications, site of TB infection, adverse events prior to entry 
into study due to TB medications and past medical history will be collated and described for all 
study subjects and presented in aggregate for phase 1 and by randomized group for phase 2. 
  

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
47 
9.6.1 Analysis for Primary Outcomes 
 
Phase 1 (Detection Accuracy of the DHFS) 
 
The primary analysis of the positive detection accuracy will be done by 
calculating the number of correct sensor detected IS-RM (or Rifamate with co-
ingestion of an encapsulated edible sensor) ingestions divided by the total number 
of actual witnessed ingestion events with a 95% confidence interval. The data will 
be reviewed to detect false positive events (recorded ingestion when none should 
have occurred), especially on days where an observed dose is given and ingestion 
was recorded at another time. False positive and false negative ingestions will be 
determined as well as true positive ingestions. An intent-to-treat (all inclusive 
analysis) will be done that includes all events but will exclude doses that were 
either known to be not ingested or ingested during the period of time when the 
patch was known not to be worn. An additional adjusted analysis will use the 
same definition, but will exclude doses that were taken during a time period when 
the patch was not functioning properly, either by malfunction or user error. 
 
Phase 2 (Percentage of Witnessed Doses) 
 
A mixed effects regression model will be used to determine if the WOT 
intervention arm will produce greater percentage of witnessed doses compared to 
the DOT standard of care arm at treatment end. This model will include time, 
treatment arm, and time-by-treatment arm interaction terms. In addition, any 
covariates, which are simultaneously unbalanced at baseline and associated with 
the outcome, will be included in the model. Time will be treated as a categorical 
variable. A signiﬁcant treatment eﬀect will be concluded if the p-value for the 
time-by-treatment interaction contrast in the model is <=0.05. Permutation tests 
may be implemented to verify that valid p-values will be obtained even if model 
assumptions are not correct. Note that the linear mixed model seamlessly 
accommodates diﬀerent times of measurement as well as missed measurements 
and data from subjects who are lost to follow-up. Generalized estimating equation 
(GEE) models will be used as the sensitivity analysis method.  
 
Note that when considering percentages of witnessed doses over the entire study 
period in aggregate, this model reduces to a multiple linear regression, and the 
independent variable of interest is the treatment arm.  
 
9.6.2 Analysis for Secondary Outcomes 
 
All secondary measures will be summarized descriptively by study arm and 
overall. Mixed effects regression models analogous to the primary analysis 
methodology will be applied for the secondary outcomes. There will be no 
adjustments made for multiple testing corrections for secondary outcomes. P-
values less than 0.05 will be considered statistically significant. 
 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
48 
The percentage of subjects completing > 80% prescribed witnessed dosing for TB 
treatment using DHFS and SOC, respectively will be calculated and compared 
using two sample t-tests (or non-parametric equivalent) for the duration of follow-
up. The time to first evidence of < 80% adherence will be calculated in the DHFS 
only as this may not be available in the SOC data. 
 
The number of lapses in witness doses will be compared between DHFS and SOC 
using Wilcoxon rank sum test. The longest duration of lapse in witnessed 
treatment will be calculated and compared between the DHFS and SOC groups. 
 
Data collected and model considerations for the costs analyses will include: 1) 
number of visits from outreach worker divided by length of time on study, 2) 
outreach worker hours spent per subject divided by length time on study; 3) 
distanced traveled per subject divided by length of time on study; 4) distance 
traveled by outreach worker divided by length of time on study, and 6) number of 
hospitalizations divided by length of time on study. Patient travel costs and lost 
wages will be reported. Wage costs with benefits of County workers and time 
spent per case will be calculated. Sensitivity analyses as appropriate with 
variation of costs and rates of failure derived from pre-existing County data will 
be performed of DHFS and DOT and will include all costs related to TB 
treatment, laboratory monitoring, assessment and treatment of adverse events, 
costs of DHFS and equipment associated with DHFS. 
 
Adverse events related to study procedures (either DHFS or SOC DOT) will be 
graded using standard ACTG grading tables and listed by organ system and 
severity. Of note, GI symptoms, hepatic enzyme abnormalities, or other expected 
toxicities of Rifamate or TB disease itself that were pre-existing and were not 
exacerbated during the study will be recorded, but will not be adjudicated as 
related or possibly related to DHFS.  
 
Subject responses regarding satisfaction with the DHFS and DOT will be reported 
on post study questionnaires regarding their experience with the DHFS and the 
usability of the system, using summary statistics. Questionnaire responses by 
subjects will be examined by study reviewers from AVRC and will present a set 
of recommendations regarding the usability of the system. Areas evaluated may 
include ease of use, time needed to use the system, perceived personal benefit, 
negative impressions, risk of disclosure of health status and changes to quality of 
life. Analyses of individual questions as well as summary metrics across questions 
will be explored. Analyses will use descriptive statistics. If there is variation in 
satisfaction with the DHFS, the demographic characteristics potentially related to 
different levels of satisfaction will be explored. 
 
Healthcare and physician satisfaction with the DHFS will be reported 
quantitatively, using non-standard customized questionnaires to collect 
information regarding their experience with the DHFS and the usability of the 
system, using summary statistics. Questionnaire responses by providers will be 
examined by study reviewers from AVRC and make a set of recommendations 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
49 
regarding the usability of the system. DOT satisfaction will be reported using 
questionnaires. 
 
Summary statistics will be used to define the results of self-reported instruments. 
Comparisons between groups will use Fisher’s exact test or Wilcoxon rank sum 
test as appropriate.  
 
Reported clinical and demographic characteristics, as well as responses to self-
reported questionnaires, will be compared for subjects with < 80% adherence to 
those with greater than 80% adherence. Comparisons will include: demographics, 
disease characteristics, and self- reported metrics. Self-reported metrics will be 
defined based on the individual instrument. For example, depression will be 
defined as a PHQ-9 score > 5. 
 
10.0 
PHARMACOLOGY PLAN INCLUDING INTENSIVE PK SUBSTUDY 
 
The PK substudy described in this Section was completed in November 2014, and will not 
enroll any additional participants. See below Section 10.4 Preliminary Results for early data 
from this substudy. 
 
The focus of the pharmacology substudy of AHF TB 001 is to prospectively evaluate the PK 
parameters, determined by sequential, within subject intensive PK sampling, of isoniazid (INH) 
and rifampin concentrations derived from dosing with Rifamate when given in native format 
compared to when dosed with the over-encapsulated PDH IS system. 
 
10.1 
Pharmacology Substudy Objectives 
 
10.1.1 To determine if pharmacokinetic parameters (CL/F, AUC, Cmin, and Cmax) for 
INH and rifampin are similar within subjects when dosed with over-encapsulated 
ingestion sensor-enabled Rifamate (IS-RM) compared to dosing with non-
encapsulated Rifamate. 
 
10.1.2 To explore whether the distributions of these parameters are comparable to 
published (i.e., historical) data. 
 
10.1.3 To explore the associations between these parameters and measurements of 
adherence as measured by the IS-RM.  
 
10.2 
Pharmacology Substudy Design 
 
A subset of 12 patients on rifampin and isoniazid will be enrolled in this two-period, randomized 
intensive pharmacokinetic (PK) substudy. They will meet all the inclusion/exclusion criteria 
detailed in this protocol. Prior to entry into the PK substudy, subjects will be required to be on 
five times per week DOT with 300mg isoniazid and 600mg rifampin for a minimum of one 
week. Upon entry, subjects will be randomized to one of two different sequences of initiating 
over-encapsulated versus native Rifamate. Thus, subjects will complete one of the following: 1) 
Complete 14 days of treatment with the study medication (over-encapsulated Rifamate with IS), 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
50 
undergo pharmacokinetic sampling, then go onto 2 weeks of native Rifamate, followed by a 
second PK sampling. 2) Complete 14 days of treatment with native Rifamate, undergo 
pharmacokinetic sampling, then go onto two weeks of over-encapsulated Rifamate with IS 
followed by a second PK sampling. The schema below describes the two PK sampling sequences 
and timeframe: 
 
Table 5. PK Substudy Sampling Sequences 
 
 
Randomize 
Period 1: study 
day 0 to 14  
PK sampling 
Day 14 
Period 2: day 
15 to day 28 
PK sampling 
Day 28 
PK sub-
study; N = 
12 subjects 
 
Rifamate over-
encapsulated 
IS  
24 hr intensive 
PK sampling 
Rifamate 2 
capsules daily  
24 hr PK 
sampling 
Rifamate 2 
capsules daily 
24 hr PK 
sampling 
Rifamate over-
encapsulated 
IS  
24 hr intensive 
PK sampling 
 
If necessary, subjects may separate Period 1 and Period 2 of the PK substudy at the discretion of 
the Study PI. 
 
Subjects who have previously completed Phase 1 alone may elect to participate in the PK 
substudy after individual case review and at the discretion of the Study PI. In this case the 
subject would repeat Phase 1. 
 
10.2.1 Recruitment 
 
 
Public health nurses will inform their eligible patients of the PK substudy and 
refer interested patients to the study coordinators for more information and/or 
screening. The study coordinator will ensure that patients understand that 
participation in the PK substudy is voluntary and that PK substudy visits are in 
addition to the main study clinic visits. Recruitment for this sub-study will only 
take place in San Diego County.  
 
10.2.2 Informed Consent 
 
 
Eligible subjects choosing to participate in the PK substudy will sign a separate 
consent form for the substudy. The PK substudy informed consent form is in 
addition to the main protocol consent form. Subjects must first sign the main 
study consent form before signing the PK substudy consent form.  
 
10.2.3 Sampling 
 
 
In this substudy, subjects will either initiate Phase 1 of the main study, taking 
over-encapsulated Rifamate with the ingestible sensor (IS), or initiate native 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
51 
Rifamate for 14 days. On Day 14, when the subject has taken at least 14 
uninterrupted doses of over-encapsulated Rifamate with IS, they will have an 
intensive PK sampling with blood draws occurring over a 24-hour period. The 
date and time of the previous three doses of Rifamate will be recorded on the 
CRF. An IV lock will be placed for blood draws. A pre-dose Ctrough blood sample 
will be obtained and the daily dose of over-encapsulated Rifamate with IS, or 
native Rifamate will be administered with 8 ounces of water. The subject should 
remain fasting for 2 hours and then can eat as desired. PK samples will be 
collected at eight time points: 0 (prior to dosing), 1, 2, 3, 4, 6, 8 and 24 hrs. Two 
6ml heparin tubes will be drawn per time point. Also, we will have 1 ml of 
discard per time point to clear the IV lock. Therefore, about 100 ml of blood will 
be drawn per participant per study day (24 hrs).  
 
 
 
Table 6. PK Substudy Schedule of Events 
 
 
 
Plasma sampling for INH + RIF 
Visit 
Switch to 
native 
Rifamate OR 
over-
encapsulated 
Rifamate 
with IS 
0 
hour 
(pre-
dose) 
Witnessed 
dose of 
Rifamate 
1 
2 
3 
4 
6 
8 24 
Day 14  
 
X 
X 
X X 
X 
X 
X X 
X 
Day 15 
X 
 
 
 
 
 
 
 
 
 
Day 28 
 
X 
X 
X X 
X 
X 
X X 
X 
 
 
 
After the first intensive PK sampling, subjects will be placed on native Rifamate 
or over-encapsulated Rifamate with IS for two weeks. After at least 14 days on 
native Rifamate, or over-encapsulated Rifamate with IS, the PK substudy patients 
will again have blood samples drawn for an intensive PK analysis. Once again, an 
IV lock will be placed, and blood samples taken at 0 (prior to dosing), 1, 2, 3, 4, 
6, 8 and 24 hrs. The fasting and medication dosing directions will be the same as 
above. 
 
Plasma will be collected and processed from all subjects at the time points noted 
above. Samples will be stored at -70°C (or colder) until shipped frozen on dry ice 
to the laboratory, where they will be maintained at -70°C (or colder) until 
analysis. All samples will be stored. They may be processed individually or in 
batches. Only subjects with two weeks of uninterrupted, over-encapsulated 
Rifamate dosing witnessed by the DHFS and DOT will be sampled. Any subject 
who has missed any doses of study treatment within the 3 days prior to a 
scheduled PK sampling visit should have the PK sampling visit rescheduled 
within 1 week.  
  
Samples will be analyzed for isoniazid and rifampin drug concentration levels 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
52 
either individually or in batches at a central specialized laboratory. Substudy 
subjects who demonstrate bioequivalence for isoniazid and rifampin levels 
between the native Rifamate and over-encapsulated Rifamate with IS will be 
allowed to continue onto Phase 2, if they remain eligible, at the discretion of the 
Study PI. 
 
10.2.4 Required Data 
  
 
At each sampling visit, the subject’s weight, and time of administration of the last 
three doses of each of the Rifamate doses will be collected. Height will be 
recorded for all subjects at the first PK visit. Information about the last intake of 
food/drink must also be recorded for all subjects. 
  
10.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
All samples will be identified by a unique patient ID and study number only at the specialized 
testing laboratory. The plasma concentrations of isoniazid and rifampin in the plasma of subjects 
from the study will be measured using validated assays (such as HPLC or UV) as appropriate. 
De-identified data will be compiled and analyzed using non-compartmental and, as appropriate, a 
compartmental pharmacokinetic model. Individual estimates of primary and secondary 
parameters (t1/2, CL/F, Cmax, Ctrough and AUC) will be determined.  
 
The individual PK parameters will be compared within subjects by calculating the geometric 
mean ratio of isoniazid and rifampin PK parameters from the native to the over-encapsulated 
dosing intervals. The 90 percent confidence interval will be calculated around these ratios using 
appropriate models, including those that include factors for gender, weight, and BMI. 
  
10.4 
Preliminary Results 
  
Patients were enrolled in a substudy of AHF TB 001 to evaluate the PK parameters for both 
native isoniazid and rifampin (combined together in Rifamate) compared to over-encapsulated 
IS-RM. Twelve patients were enrolled in the PK study and had blood drawn for sampling after 
completing 14 days of both native Rifamate and IS-RM. Results show that levels of both 
isoniazid and rifampin in IS-RM compared to isoniazid and rifampin levels in native Rifamate 
met the criteria for bioequivalence. Given these findings of bioequivalence, the PK substudy is 
complete and no longer enrolling patients. 
 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EXPERIENCE 
REPORTING 
 
11.1 
Records to Be Kept 
 
Electronic Case report forms (eCRF) will be provided via a secure, user-authenticated study 
website hosted by the UCSD Center for AIDS Research Bioinformatics and Information 
Technologies (BIT) Core. These eCRFs will be used by study staff with proper permissions to 
enter patient data into the study database as needed. Subjects will not be identified by name on 
any CRFs, but rather by a confidential PID provided by the BIT Core upon study screening. 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
53 
 
The following describes the capacity and function of the UCSD BIT Core for all study-related 
data security and management: 
 
The BIT Core is comprised of three faculty members, five professional programmers, and 
several other support staff with world-class expertise in infectious disease bioinformatics, 
computational biology, software development, website design and hosting, and clinical study 
data management. In addition to this experienced staff, the BIT Core also possesses extensive 
computational resources including a +700 processor Linux Beowulf MPI cluster, seven rack-
mounted web servers, and two fault-tolerant encrypted 16TB RAID6 data storage arrays. This 
hardware is hosted in a secure computing environment co-located at the UCSD San Diego 
Supercomputing Center (SDSC) and AVRC. The collective resources of the BIT Core will be 
made available to this study under the direction of Dr. Jason A. Young, the BIT Core biomedical 
data management scientific lead. 
 
11.1.1 Central Database System 
 
All data management for this study will be provided by the Open Source Clinical 
Content Management System (OCCAMS) developed by the BIT Core. OCCAMS 
provides integrated, flexible, and secure tools for complex clinical study data 
management using only a web browser. This includes: 1) an intuitive drag-and-
drop eCRF editor, 2) methods for automatically displaying these eCRFs according 
to user-defined study protocol schedules, 3) easy-to-use interfaces for direct 
online data entry with integrated QA workflows and accrual monitoring, 4) a 
powerful database backend with data and form auditing capabilities, 5) an 
integrated specimen collection and tracking system with optional use of barcode 
labeling, and 6) flexible data import and export modules compatible with popular 
statistical packages such as R, SAS, etc. Furthermore, OCCAMS is built atop 
Plone, the most mature (first launched in 2001), secure (best record of any major 
CMS), compatible (runs on every major operating system), and actively 
developed (+340 core developers worldwide) open source content management 
system available today (plone.org). As such, OCCAMS utilizes built-in Plone 
functionalities including secure login and robust user management with granular 
permissions that are under continual security scrutiny by the open source 
community as a whole. 
 
11.1.2 Clinical Data Receipt, Storage, Quality Control, Retrieval 
 
Study personnel will use OCCAMS from a web browser to manage all data and 
specimen collection, storage, quality control, and retrieval. Each staff member 
will be provided a login and password and will be assigned to the appropriate 
role-based groups using the UCSD campus active directory. Membership in these 
role-based groups will provide users with the necessary web views to complete 
their assigned tasks on a need to know basis. For example, nurse permissions will 
only allow for viewing and entering of data into eCRFs, QC permissions will only 
allow for editing and verification of data entry, and laboratory permissions will 
only allow the collection and management of specimens. However, these roles 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
54 
and views are extremely flexible, are not mutually exclusive, and can be easily 
managed from within OCCAMS by study supervisors with appropriate 
permissions, to meet specific study needs. 
 
11.1.3 Receipt 
 
Data and specimens will be directly entered into the database by clinical staff via 
OCCAMS eCRF and specimen collection workflows. Electronic CRFs will be 
designed using the occams.form module, whereas specimen collection and aliquot 
procedures will be defined in the occams.lab module. Following review, the 
eCRFs and specimen types will be assigned for collection to study visits as 
outlined in the Schedule of Events (see Section 6.1). Upon study initiation, 
OCCAMS will then automatically queue clinical staff to enter/collect the 
appropriate data and specimen(s) for each patient visit.  
 
11.1.4 Storage 
 
All data will be stored in an Entity-Attribute-Value database similar to standards 
used in commercial clinical data systems, but implemented using the open source 
database software postgreSQL and SQLAlchemy. Designed specifically for 
OCCAMS, this database (occams.datastore) allows for the precise tracking of all 
changes to eCRFs and data over time, providing exhaustive auditing functionality. 
The database is also split into two components: a protected health information 
(PHI) component for storage of personally identifiable data as defined by the 
Privacy Rule of the HIPAA Section 164.154, and a non-PHI component for all 
other data storage needs. This separation enhances data security by limiting access 
to sensitive parts of the database whenever possible. Furthermore, all databases 
are hosted from fault-tolerant encrypted RAID6 data storage arrays, with secure 
nightly synchronization between co-located sites. 
 
11.1.5 Quality Control 
 
Built-in OCCAMS quality control workflows and views will be used to ensure 
data accuracy throughout the study. Specifically, OCCAMS provides eCRF status 
descriptions that indicate where in the quality control workflow a particular eCRF 
resides. The “Pending-Entry” status denotes a patient visit has occurred and the 
clinical staff has yet to enter data for the eCRF required at that visit. Upon entry 
of this data, the eCRF is automatically moved to a “Pending-Review” status 
where it then becomes accessible to quality assurance staff for verification. Once 
verified for accuracy by quality assurance staff, the eCRF then enters a 
“Reviewed” status indicating it is ready to be included in data analysis. The flow 
of eCRFs through these statuses can be monitored in real-time from various 
reporting views accessible to staff with the appropriate permissions. 
 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
55 
11.1.6 Retrieval 
 
OCCAMS provides methods for both viewing and downloading data collected 
though eCRFs on a form-by-form basis. Files can be downloaded in csv format, 
which can then be easily imported into standard statistical packages (R, SAS, etc.) 
for offline analysis. By default, data viewing and download permissions are 
restricted to investigator and analyst roles, but can be expanded to others as 
needed. Regarding specimen retrieval, the occams.lab module provides query 
functionality allowing specimen search by type, date, and PID, as well as a 
specimen inventory system that supports the tracking of specimens using 
computer-generated barcoded labels. 
 
11.1.7 Data Security Plans 
 
The BIT Core ensures data security though a robust security model consisting of a 
multi-level hardware/software firewalled network, secure hardware and software 
encryption, data auditing and access tracking procedures, and completely 
redundant services hosted from two physically separated server facilities. All 
primary production machines are located behind a hardware firewall at the SDSC 
on the UCSD main campus in a server facility with biometric-based restricted 
access, temperature and humidity monitoring, seismic protection, 24/7 generator 
power backup, and continuous CCTV camera surveillance. For data and service 
redundancy in case of hardware or power failure at SDSC, secondary backup 
machines are located behind a hardware firewall at the AVRC on the UCSD 
medical campus in a server room with key card-based restricted access, 
temperature and humidity monitoring, and 24/7 CCTV camera surveillance. All 
communication between server facilities occurs over a gigabit UCSD line, 
encrypted using secure shell (SSH) on a Virtual Private Network (VPN) with 
strict access control. All web servers hosted by the BIT Core are virtualized and 
backed up routinely so they can be reinstated quickly on new hardware if needed. 
The BIT Core systems administrator and other key personnel are automatically 
notified by e-mail and SMS of any server abnormalities. 
 
11.1.8 HIPAA/FISMA Compliance 
 
Our approach to research information security is designed to comply with the 
latest requirements of HIPAA and FISMA regulations. For FISMA compliance, 
this includes documentation of management, operational, and technical processes 
used to secure the physical and virtual infrastructure based on the National 
Institute of Standards and Technology (NIST) Special Publication 800-53 and 
compliance with the Revision 3 standards for the Security Categories and Levels 
of “Moderate” as outlined by FIPS 199. To date, we have instituted: 1) a detailed 
categorization of information and information systems comprising our network, 2) 
a network map detailing all systems and services, 3) standardization of server 
images using CentOS-6 with SELinux enabled, 4) clear documentation of file 
permissions, 5) centralized user authentication using Active Directory, 6) 
encryption of all user desktop OSX file systems and data backup, 7) nightly 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
56 
encrypted backup of all data to secure co-located sites at the SDSC and AVRC, 8) 
extensive logging of user access, and 9) a sandboxed environment for all software 
development. 
 
11.1.9 Data Labeling, Storage, Handling, and Disposal 
 
Specimens collected throughout the proposed contract will be managed using the 
specimen management component of OCCAMS, called occams.lab. This 
component provides integrated workflows to clinical staff for facilitating the 
collection of specimen(s) per study visit, splitting of these specimens into user-
defined numbers of aliquot, generation of barcoded labels for aliquot and 
specimen tracking, and specimen check-out workflows for shipment and disposal 
as required. For example, occams.lab has already been successfully used to 
manage over 200,000 specimens collected as part of HIV studies at the AVRC 
(including PBMCs, plasma, serum, urine, anal swabs, and CSF). For this study, 
lab assistants and phlebotomists will be responsible for reviewing and organizing 
the collection, processing, barcode labeling, transporting, and cryostoring of all 
samples. Lab assistants will be responsible for data entry and maintenance of the 
specimen inventories using occams.lab specimen query tools and auditing tools. 
 
11.2 
Project Management by BIT Core 
 
11.2.1 Data Management and Tracking 
 
Clinical site monitoring will be done by AVRC staff. Well-developed data 
monitoring operating procedures include monitored elements and timelines, 
procedures for generation and resolution of data queries, and reporting, including 
quality assurance workflows built into OCCAMS and available to appropriate 
study staff via the web. Review of regulatory documents and individual patient 
records and consent forms will occur bi-annually. Queries from the eCRF will be 
resolved and compared to source documentation. Clinical monitoring for all 
patients will include review of regulatory files, consent forms, inclusion criteria, 
and major endpoint verification. Monthly reports showing patients screened, early 
terminations, and late visits are shared with the protocol team, as well as listings 
of adverse events and assessment of data quality reports. 
 
11.2.2 Previous Experience and Timeliness 
 
The BIT Core has extensive experience in biomedical data management for 
infectious disease-related clinical trials. Dr. Young, the BIT Core scientific and 
strategy lead for biomedical informatics projects, has hands-on experience 
managing data needs for complex, multi-site clinical studies. Under the 
supervision of Dr. Young, other BIT Core team members that will be actively 
involved in this contract will include Mr. Marco Martinez (senior programmer) 
and Ms. Fang Wan (data manager), both of whom have relevant private sector and 
academic work experience. OCCAMS currently handles all data management 
needs for three ongoing clinical research studies at the AVRC, consisting of more 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
57 
than 10,000 patient screens, 1,000 patient enrollments, 200,000 specimens, and 
5GB clinical data originating as far back as 1996. Collectively, these projects 
currently support more than 50 clinical staff working at four sites throughout 
Southern California (UCSD, USC, UCLA, and Long Beach Department of Health 
and Human Services). Furthermore, OCCAMS is continually being expanded and 
refined to meet new clinical research needs as they arise, having been designed 
from the beginning to be modular and extensible. 
 
11.3 
Role of Data Management  
 
Instructions concerning the recording of study data on eCRFs will be provided by the BIT Core. 
It is the responsibility of the BIT Core to assure the quality of computerized data for this study. 
 
11.4 
Clinical Site Monitoring and Record Availability 
 
Monitors will review the individual participant records, including consent forms, eCRFs, 
supporting data, laboratory specimen records, and medical records (physician progress notes, 
nurse notes, hospital charts), to ensure protection of study subjects, compliance with the 
protocol, and accuracy and completeness of records. The monitors also will inspect regulatory 
files to ensure that regulatory requirements are being followed, and the site pharmacy to review 
product storage and management. 
 
The investigator will make study documents (e.g., consent forms, drug distribution forms, CRFs) 
and pertinent hospital or clinic records readily available for inspection by the local Institutional 
Review Board (IRB), the site monitors, the Food and Drug Administration (FDA), the 
pharmaceutical sponsor(s), or the sponsor’s designee for confirmation of the study data. 
 
11.5 
Serious Adverse Experience Reporting 
 
Serious adverse experiences must be documented on the Serious Adverse Event (SAE) Reporting 
Form and submitted to the BIT Core. 
 
12.0 
HUMAN SUBJECTS 
 
12.1 
Institutional Review Board Review and Informed Consent 
 
This protocol and the informed consent document and any subsequent modifications will be 
reviewed and approved by the Institutional Review Board (IRB) or ethics committee responsible 
for oversight of the study. A signed consent form will be obtained from the subject (or parent, 
legal guardian, or person with power of attorney for subjects who cannot consent for themselves, 
such as those below the legal age of consent). The consent form will describe the purpose of the 
study, the procedures to be followed, and the risks and benefits of participation. A copy of the 
consent form will be given to the subject, parent, or legal guardian, and this fact will be 
documented in the subject’s record. 
 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
58 
12.2 
Subject Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified by coded number only to maintain subject confidentiality. All records will be kept 
locked. All computer entry and networking programs will be done with coded numbers only. 
Clinical information will not be released without written permission of the subject, except as 
necessary for monitoring by the IRB, AVRC, BIT Core, or Proteus Biomedical.  
 
12.3 
Study Discontinuation 
 
The study may be discontinued at any time by the BIT Core, IRB, and the industry supporter(s). 
 
13.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by AVRC policies. Any presentation, 
abstract, or manuscript will be made available for review by Proteus Biomedical prior to 
submission.  
 
14.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV, TB and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study, as currently recommended by the Centers for Disease Control and 
Prevention and the National Institutes of Health. 
 
All dangerous goods materials, including diagnostic specimens and infectious substances, must 
be transported using packaging mandated by CFR 42 Part 72. Please refer to instructions detailed 
in the International Air Transport Association Dangerous Goods Regulations. 
 
15.0 
REFERENCES 
1. 
Weis SE, Foresman B, Matty KJ, Brown A, Blais FX, Burgess G, King B, Cook PE, 
Slocum PC. Treatment costs of directly observed therapy and traditional therapy for 
Mycobacterium tuberculosis: a comparative analysis. Int J Tuberc Lung Dis 1999; 3:976-
984. 
2. 
Vernon AA, Iademarco MF. In the treatment of tuberculosis, you get what you pay for. 
Am J Respir Crit Care Med 2004; 170:1040-1042. 
3. 
Chang KC, Leung CC, Yew WW, Chan SL, Tam CM. Dosing schedules of 6-month 
regimens and relapse for pulmonary tuberculosis. Am J Respir Crit Care Med 2006; 
174:1153-1158. 
4. 
Bova CA, Fennie KP, Knafl GJ, Dieckhaus KD, Watrous E, Williams AB. Use of 
electronic monitoring devices to measure antiretroviral adherence: practical 
considerations. AIDS Behav 2005; 9:103-110. 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
59 
5. 
Wendel CS, Mohler MJ, Kroesen K, Ampel NM, Gifford AL, Coons SJ. Barriers to use 
of electronic adherence monitoring in an HIV clinic. Ann Pharmacother 2001; 35:1010-
1015. 
6. 
Olivieri NF, Matsui D, Hermann C, Koren G. Compliance assessed by the Medication 
Event Monitoring System. Arch Dis Child 1991; 66:1399-1402. PMCID: PMC1793394 
7. 
Laine C, Newschaffer CJ, Zhang D, Cosler L, Hauck WW, Turner BJ. Adherence to 
antiretroviral therapy by pregnant women infected with human immunodeficiency virus: 
a pharmacy claims-based analysis. Obstet Gynecol 2000; 95:167-173. 
8. 
Young-Xu Y, Chan KA. Pooling overdispersed binomial data to estimate event rate. 
BMC Med Res Methodol 2008; 8:58. PMCID: PMC2538541 
9. 
Wu JR, Moser DK, Chung ML, Lennie TA. Objectively measured, but not self-reported, 
medication adherence independently predicts event-free survival in patients with heart 
failure. J Card Fail 2008; 14:203-210. PMCID: PMC2751635 
10. 
Stroupe KT, Teal EY, Tu W, Weiner M, Murray MD. Association of refill adherence and 
health care use among adults with hypertension in an urban health care system. 
Pharmacotherapy 2006; 26:779-789. 
11. 
Feinstein AR. On white-coat effects and the electronic monitoring of compliance. Arch 
Intern Med 1990; 150:1377-1378. 
12. 
Feldman SR, Camacho FT, Krejci-Manwaring J, Carroll CL, Balkrishnan R. Adherence 
to topical therapy increases around the time of office visits. J Am Acad Dermatol 2007; 
57:81-83. 
13. 
Alcoba M, Cuevas MJ, Perez-Simon MR, Mostaza JL, Ortega L, Ortiz de Urbina J, Carro 
JA, Raya C, Abad M, Martin V. Assessment of adherence to triple antiretroviral 
treatment including indinavir: role of the determination of plasma levels of indinavir. J 
Acquir Immune Defic Syndr 2003; 33:253-258. 
14. 
Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed 
antihypertensive drug treatments: longitudinal study of electronically compiled dosing 
histories. BMJ 2008; 336:1114-1117. PMCID: PMC2386633 
15. 
Wolf MS, Davis TC, Osborn CY, Skripkauskas S, Bennett CL, Makoul G. Literacy, self-
efficacy, and HIV medication adherence. Patient Educ Couns 2007; 65:253-260. 
16. 
Gross R, Tierney C, Andrade A, Lalama C, Rosenkranz S, Eshleman SH, Flanigan T, 
Santana J, Salomon N, Reisler R, Wiggins I, Hogg E, Flexner C, Mildvan D, Team 
ACTGAS. Modified directly observed antiretroviral therapy compared with self-
administered therapy in treatment-naive HIV-1-infected patients: a randomized trial. Arch 
Intern Med 2009; 169:1224-1232. PMCID: PMC2771688 

 
 
AHF TB 001  
 
 
Protocol Version 2.3 
 
 
 March 25, 2015 
60 
17. 
DiCarlo L, Moon G, Intondi A, Duck R, Frank J, Hafazi H, Behzadi Y, Robertson T, 
Costello B, Savage G, Zdeblick M. A digital health solution for using and managing 
medications: wirelessly observed therapy. IEEE Pulse 2012; 3:23-26. 
18. 
Au-Yeung KY, Robertson T, Hafezi H, Moon G, DiCarlo L, Zdeblick M, Savage G. A 
networked system for self-management of drug therapy and wellness. Available in: 
Proceedings of Wireless Health 2010. doi 10.1145/1921081.1921083 
19. 
Au-Yeung KY, Moon GD, Robertson TL, Dicarlo LA, Epstein MS, Weis SE, Reves RR, 
Engel G. Early clinical experience with networked system for promoting patient self-
management. Am J Manag Care 2011; 17:e277-287. 
20. 
Belknap R, Weis S, Brookens A, Au-Yeung KY, Moon G, DiCarlo L, Reves R. 
Feasibility of an ingestible sensor-based system for monitoring adherence to tuberculosis 
therapy. PloS One 2013; 8:e53373. PMCID: PMC3538759 
21. 
Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, Fujiwara 
P, Grzemska M, Hopewell PC, Iseman MD, Jasmer RM, Koppaka V, Menzies RI, 
O'Brien RJ, Reves RR, Reichman LB, Simone PM, Starke JR, Vernon AA. American 
Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society 
of America: Treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167:603-662. 
22. 
World Health Organization. WHO global task force outlines measures to combat XDR-
TB worldwide. 2006. Available at www.who.int/mediacentre/news/notes/2006/np29.  
23. 
Centers for Disease Control and Prevention Division of Tuberculosis Elimination. Report 
of expert consultations on rapid molecular testing to detect drug-resistant tuberculosis in 
the United States. Last updated September 1, 2012. Available at 
www.cdc.gov/tb/topic/laboratory/rapidmoleculartesting.