Triggered Escalating Real-time Adherence Intervention to Promote Rapid HIV Viral Suppression Among Youth Living With HIV Failing Antiretroviral Therapy: The TERA Study
Phase: NA
Conditions: HIV Infections
Sponsor: University of North Carolina, Chapel Hill

   
 
                                                                                                                  
 
ATN 152 
Triggered Escalating Real-time Adherence Intervention to Promote Rapid HIV Viral 
Suppression among Youth Living with HIV Failing Antiretroviral Therapy: The TERA Study 
 
A Multi-Center Study Randomized, Controlled Trial of the Adolescent Medicine Trials 
Network for HIV/AIDS Interventions (ATN) 
 
Version 3.1 
 
 
NCT number NCT03292432 
Document Date 01/21/2020 
 
 
 
 
Sponsored by: 
The Eunice Kennedy Shriver 
National Institute of Child Health and Human Development (NICHD) 
 
 
with co-funding from: 
The National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), and 
National Institute on Minority Health and Health Disparities (NIMHD) 
 
 
 
 
 
 
 
 
Protocol Chair: 
                                                                   K. Rivet Amico, PhD 
 
Protocol Co-Chair: 
                                                                   Aditya H. Gaur, MD 
 
NICHD Health Scientist Administrator: 
                           Sonia S. Lee, PhD 
 
Protocol Manager: 
                                                                   Rachel Goolsby

 
 
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Contents 
Protocol Version History ..............................................................................................................6 
ATN Protocol Team Roster ...........................................................................................................9 
List of Abbreviations .................................................................................................................. 11 
Study Abstract ........................................................................................................................... 14 
Overview of Study Design and Randomization ............................................................................ 15 
Overview of Intervention and Data Collection ............................................................................ 16 
Site Roster ................................................................................................................................. 18 
Study Management .................................................................................................................... 19 
1 
INTRODUCTION 20 
1.1 
Background ...................................................................................................................... 20 
1.2 
Prior Research/Current Evidence Base ............................................................................... 21 
1.2.1 Research and Care Sites .......................................................................................................... 21 
1.2.2 Technology Enhanced and Delivered Interventions ............................................................... 21 
1.2.3 Evidence for Phone-Based Outreach Problem Solving ........................................................... 23 
1.2.4 Evidence for Theory-Based Drivers of ART Adherence in YLWH ............................................ 24 
1.3 
Rationale .......................................................................................................................... 24 
1.4 
Hypotheses ....................................................................................................................... 27 
2 
STUDY OBJECTIVES ............................................................................................................ 28 
2.1 
Primary Objective ............................................................................................................. 28 
2.2 
Secondary Objectives ........................................................................................................ 28 
2.3 
Other Objectives ............................................................................................................... 28 
3 
STUDY DESIGN 29 
3.1 
Study Population .............................................................................................................. 31 
4 
SELECTION AND ENROLLMENT OF STUDY PARTICIPANTS ................................................... 32 
4.1 
Inclusion Criteria ............................................................................................................... 32 
4.2 
Exclusion Criteria .............................................................................................................. 32 
4.3 
Recruitment ...................................................................................................................... 33 
4.4 
Study Informed Consent and Screening ............................................................................. 33 
4.5 
Contact Information .......................................................................................................... 34 
4.6 
Participant Retention ........................................................................................................ 34 
4.7 
Participant Withdrawal or Termination from the Study ...................................................... 34 
4.8 
Co-enrollment Guidelines .................................................................................................. 35 
5 
STUDY PROCEDURES ......................................................................................................... 36 

 
 
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5.1 
Enrollment Procedures ...................................................................................................... 36 
5.2 
Randomization Strategy and Procedures ........................................................................... 36 
5.3 
Intervention and Standard of Care Procedures ................................................................... 36 
5.3.1 TERA Intervention ................................................................................................................... 36 
5.3.2 Standard of Care ..................................................................................................................... 42 
5.3.3 Research Staff Training ........................................................................................................... 43 
5.3.4 Intervention Monitoring/Quality Control ............................................................................... 43 
6 
STUDY MEASURES ............................................................................................................. 44 
6.1 
Computer Assisted Surveys ............................................................................................... 44 
6.2 
Dose Real-Time Adherence Monitoring ............................................................................. 45 
6.3 
Biomarkers ....................................................................................................................... 46 
6.4 
Medical History/Health Status........................................................................................... 46 
6.5 
Demographics ................................................................................................................... 46 
6.6 
Intervention Acceptability and Feasibility Measures .......................................................... 46 
7 
STUDY EVALUATIONS ........................................................................................................ 47 
7.1 
Screening .......................................................................................................................... 47 
7.2 
Enrollment/Entry .............................................................................................................. 48 
7.3 
Week-4 Visit ..................................................................................................................... 49 
7.4 
Week-12 Visit ................................................................................................................... 49 
7.5 
Week-24 Visit ................................................................................................................... 50 
7.6 
Week-36 Visit ................................................................................................................... 50 
7.7 
Week-48 Visit (Off-Study Visit) .......................................................................................... 50 
7.8 
Premature Discontinuation from the Study ........................................................................ 51 
7.9 
Off-schedule Visits ............................................................................................................ 51 
8 
DATA COLLECTION AND SITE MONITORING ....................................................................... 52 
8.1 
Data Records .................................................................................................................... 52 
8.2 
Data Collection ................................................................................................................. 52 
8.2.1 Case Report Forms .................................................................................................................. 52 
8.2.2 AdhereTechTM Electronic Dose Monitor (EDM) .................................................................... 52 
8.2.3 Audio Computer Assisted Self-Interview (ACASI) ................................................................... 53 
8.3 
Qualitative Interviews ....................................................................................................... 54 
8.4 
TERA Dashboard ............................................................................................................... 54 
8.5 
Remote Counseling Data ................................................................................................... 55 
8.6 
Costing Data ..................................................................................................................... 55 
8.7 
Data Submission ............................................................................................................... 57 
8.8 
Case Report Forms/Data Collection Forms ......................................................................... 57 

 
 
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8.9 
AdhereTechTM EDM Data Transmission .............................................................................. 57 
8.10 Data Quality Assurance ..................................................................................................... 58 
8.11 Study Site Monitoring and Record Availability ................................................................... 58 
9 
PARTICIPANT MANAGEMENT ............................................................................................ 59 
9.1 
Tracking Participants/Follow-up ........................................................................................ 59 
9.2 
Study Visit Management ................................................................................................... 59 
9.2.1 Completing the ACASI ............................................................................................................. 59 
9.2.2 ACASI Debriefing and Referral Procedures ............................................................................. 59 
9.3 
Participant Reimbursement ............................................................................................... 60 
9.4 
Intervening on “Social Harms" ........................................................................................... 60 
9.5 
Criteria for Premature Discontinuation .............................................................................. 60 
9.5.1 Premature Discontinuation from Intervention ....................................................................... 60 
9.5.2 Premature Study Discontinuation ........................................................................................... 60 
10 
MONITORING SAFETY EVENTS ........................................................................................... 62 
11 
STATISTICAL/ANALYTIC CONSIDERATIONS ......................................................................... 63 
11.1 Study Design ..................................................................................................................... 63 
11.2 Sample Size and Power Estimates ...................................................................................... 63 
11.2.1 Sample Size ............................................................................................................................. 63 
11.2.2 Accrual..................................................................................................................................... 64 
11.3 Randomization ................................................................................................................. 64 
11.4 Study Outcome Measures ................................................................................................. 64 
11.4.1 Primary Outcome Measures ................................................................................................... 64 
11.4.2 Secondary Outcome Measures ............................................................................................... 65 
11.4.3 Other Outcome Measures ...................................................................................................... 65 
11.5 Study Monitoring .............................................................................................................. 68 
11.5.1 Monitoring by Study Team...................................................................................................... 68 
11.5.2 Study Monitoring Committee ................................................................................................. 68 
11.6 Statistical Analysis Plan ..................................................................................................... 69 
11.6.1 Primary Outcome .................................................................................................................... 70 
11.6.2 Secondary Outcomes .............................................................................................................. 70 
11.6.3 Other Outcomes ...................................................................................................................... 71 
12 
HUMAN SUBJECTS ............................................................................................................ 74 
12.1 Participants’ Confidentiality .............................................................................................. 74 
12.2 Certificate of Confidentiality ............................................................................................. 74 
12.3 Risks and Benefits ............................................................................................................. 74 
12.3.1 Risks......................................................................................................................................... 74 
12.3.2 Benefits ................................................................................................................................... 75 
12.4 Institutional Review Board (IRB) Review and Informed Consent ......................................... 75 
12.5 Risk Category: Minimal Risk .............................................................................................. 76 

 
 
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12.6 Waiver of Requirement for Parental Consent for Special Circumstances ............................. 76 
12.7 Prisoner Participation ....................................................................................................... 77 
12.8 45 CFR Parts 160 and 164 Standards for Privacy of Individually Identifiable Health 
Information ("Privacy Rule" Pursuant to the Health Insurance Portability and Accountability 
Act - HIPAA) ...................................................................................................................... 77 
12.9 Study Discontinuation ....................................................................................................... 77 
13 
ADMINISTRATIVE PROCEDURES ........................................................................................ 78 
13.1 Regulatory Oversight ........................................................................................................ 78 
13.2 Protocol Registration ........................................................................................................ 78 
13.3 Study Implementation ...................................................................................................... 78 
13.4 ClinicalTrials.gov ............................................................................................................... 78 
13.5 Publications ...................................................................................................................... 78 
REFERENCES 
80 
APPENDIX I:  SCHEDULE OF EVALUATIONS ......................................................................................... 84 
 
 
 

 
 
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Protocol Version History 
Version  Date 
Major Changes  
1.0 
21 Jul 2017 
 
1.1 
10 Aug 2017  
 Clarified that text messages will not use the clinic name or any 
reference to the participant’s health status or diagnosis  
 Added Locator Form to Schedule of Evaluations to be collected at 
Baseline and Weeks 4,12, 24, 36, 48 
1.2 
18 Aug 2017 
 Updated Site Roster to include Carrie Chambers, study 
coordinator at the University of Colorado-Denver. 
 Added pregnancy as an exclusion criteria. Pregnancy test (either 
blood or urine) will be performed to determine eligibility after 
consenting to study participation.  
 Modified screening procedures to include rescreening at a later 
date if a participant either did not return for enrollment within 45 
days of latest VL assessment or if HIV VL was <200 copies. 
 Increased information collected in medical chart abstraction to 
include: VL, CD4, and pregnancy test. 
 Modified which visits have a required VL testing as part of the 
study rather than as chart abstraction to include Weeks 12, 24, 
36, and 48 visits. VL testing at Week 4 can be abstracted from 
medical chart if done as standard of care, if not, it is not required 
at this visit.  
 Added pregnancy test (either blood or urine) prior to enrollment 
to the informed consent and parental permission informed 
consent and assent 
1.3 
06 Nov 2017  
 Added Michael Hudgens as the ATN Coordinating Center 
Investigator  
 Updated Site Roster to include Maureen Garcia, study 
coordinator at UCLA 
 Replaced Site PI at Children’s Diagnostic and Treatment Center, 
Inc. with Dr. Lisa-Gaye Robinson on the Site Roster. Removed all 
study coordinators except Amy Inman from this site.  
 Replaced study coordinators at St. Jude with Ryan Heine and 
Colin Quillivan on the Site Roster. 
 Added Ayanna Walters as study coordinator at Wayne State 
University on the Site Roster.   
 Changed timeframe for study enrollment to allow for an HIV VL 
test with HIV RNA ≥200 copies/m from 28 days prior to 45 days 
prior to enrollment.  
 Renamed ‘Locator Form’ to ‘Contact Form.’ 
 Lengthened time window from screening to enrollment visit from 
28 days to 45 days  

 
 
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 Modified VL testing windows for study visits to state: For follow-
up study visits at Weeks 12, 24, 36, and 48, HIV-VL can be +/- 14 
days from the Week 12 follow-up visit and +/- 28 days from the 
Weeks 24, 36, and 48  due date 
 Changed visit windows for Weeks 24, 36, and 48 Visits from a 14 
day to a 28 day window  
 Changed Secondary Outcome Measures (from ± 14 to ± 28 days): 
HIV-1 RNA < 50 copies/ml.  Participants with HIV-1 RNA ≥ 50 
copies/ml or with no HIV-1 RNA measurement within ± 28 days of 
the scheduled visit will be classified as failures  
 Changed Secondary Outcome Measures (from ± 14 to ± 28 days): 
HIV-1 RNA < 200 copies/ml.  Participants with HIV-1 RNA ≥ 200 
copies/ml or with no HIV-1 RNA measurement within ± 28days of 
the scheduled visit will be classified as failures  
 Increased the number of efficacy analyses to take place after at 
least 60 participants have Week 12 HIV-1 RNA results available.  
 Requested a waiver of consent for the coaches and site staff 
interviews.Verbal consent will be given if the waiver is not 
granted. 
 Reported clinicaltrials.gov Identifier Number: NCT03292432 
1.4 
15 Nov 2017  
 Modified language to include ‘written’ in the waiver of written 
consent for all coach and clinic staff interviews.  
 Added the Contact Form information to be collected at screening 
visit and removed this form from the Week 48 Visit.  
 Added the Verbal Consent Form for Staff Interviews.  
2.0 
21 May 2018 
 Modified language of the ‘boot camp’ approach of the 
intervention 
 Added details for the secure audio recording software and 
subsequent audio storage. 
 Updated tables 1 and 2 (Triggered Two-way Outreach and Check 
in Outreach contacts) to reflect the dash functionality. 
 Updated timeline for contacting participants who have been out 
of contact to a 7 day period.  
 Added Protocol Deviation reporting and tracking 
 Modification to inclusion criteria to allow for inclusion of youth 
failing on any line ART regimen provided regimen is once daily. 
Daily can involve more than one ARV medication. 
 Removed option for TERA arm particpants to disable the 1-way 
reminder text near their dose time. 
 Updated protocol team roster and site personnel  
3.0 
06 Mar 2019 
 Edited Monitoring Untoward Events section to refer to 
monitoring both Safety Events and Untoward Events.  The section 

 
 
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also refers to using Chapter 10 of the ATN Manual of Policies and 
Procedures for Safety Event/Untoward Event definitions, 
reporting, and grading requirements. 
 Removed UCLA and UAB from Site Roster.  
 Added Emory University to Site Roster.  
 Clarified in Enrollment visit procedures that pregnancy test must 
occur on day of enrollment. 
 Added sIRB approved telephone script as recruitment method. 
 Clarified that the enrollment visit may not be a split visit. 
3.1 
12 Jan 2020 
 Updated protocol team roster and site roster. 
 Updated email address for Barbara Heckman. 
 Specified location of UNC sIRB SOP 1401: Reporting New Safety 
Information on the ATN secure website. 
https://sites.cscc.unc.edu/atn/tera-grouped 
 Made minor punctuation, spacing, header, and formatting 
changes. 
 Revised 9.4.3 to reflect that staff will only complete interviews 
and not surveys 
 Revised 11.6.3.6 to clarify that the coaches and site staff will be 
interviewed at the end of the intervention phase. 
 
 
 

 
 
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ATN Protocol Team Roster 
Protocol Chair 
K. Rivet Amico, PhD 
University of Michigan 
School of Public Health 
1415 Washington Heights 
Ann Arbor, Michigan 48109-2029 
Phone: 734-763-0051 
Email: ramico@umich.edu  
 
Protocol Co-Chair 
Aditya H. Gaur, MD 
St. Jude Children's Research Hospital  
262 Danny Thomas Place  
Memphis, TN 38105-3678 
Phone: 901-595-5067 
Email: aditya.gaur@stjude.org  
 
Protocol Statistician 
Jane C. Lindsey, ScD 
Statistical Data Analysis Center 
Harvard School of Public Health 
651 Huntington Ave., Boston, MA 02115 
Phone: 617-432-2812 
E-mail: lindsey@sdac.harvard.edu  
 
Protocol Investigator 
Patricia Flynn, MD 
St. Jude Children's Research Hospital  
262 Danny Thomas Place  
Memphis, TN 38105-3678 
Phone: 901-595-4662 
Email: pat.flynn@stjude.org  
 
NICHD Health Scientist Administrator 
Sonia S. Lee, Ph.D  
Eunice Kennedy Shriver National Institute 
of Child Health and Human Development 
(NICHD)  
6710B Rockledge Drive  
Bethesda, MD 20817  
Phone: (301) 594-4783 
E-mail: leesonia@mail.nih.gov  
Protocol Data Manager 
Barbara Heckman, BS 
Frontier Science and Technology Research 
Foundation 4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 x 7231 
E-mail: bheckman@fstrf.org  
Protocol Investigator 
Ronald Dallas, PhD 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place, Mailstop 600 
Memphis, TN 38105-3678 
Phone: 901-595-5972 
E-mail: Ronald.dallas@stjude.org  
 
Protocol Investigator 
Keith Horvath, PhD 
Division of Epidemiology and Community Health 
University of Minnesota 
1300 South 2nd Street 
Suite 300 
Minneapolis, MN 55454 
Phone: (612)626-1799 
E-mail: horva018@umn.edu  

 
 
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Protocol Investigaor  
Anne Neilan, MD, MPH  
Harvard School of Public Health 
677 Huntington Avenue  
Boston, MA 02115 
Phone: 617-495-1000 
E-mail: aneilan@mgh.harvard.edu  
Protocol Investigator  
Andrea L. Ciaranello, MD, MPH 
Harvard School of Public Health 
677 Huntington Avenue  
Boston, MA 02115 
Phone: 617-495-1000 
E-mail: aciaranello@mgh.harvard.edu  
ATN Coordinating Center Investigator 
Michael G. Hudgens, Ph.D. 
Gillings School of Global Public Health 
University of North Carolina at Chapel Hill 
McGavran-Greenberg Hall  
Campus Box 7420  
Chapel Hill, NC 27599 
Phone: (919) 966-7253 
E-mail: mhudgens@bios.unc.edu 
Project Manager 
Jessica Crawford, MPH 
School of Public Health 
University of Michigan 
1415 Washington Heights Room 2850 
Ann Arbor, MI 48109 
Phone:(734) 660-0912 
E-mail: jnicolem@umich.edu  
Protocol Manager 
Rachel Goolsby 
Collaborative Studies Coordinating 
Center 
University of North Carolina at Chapel Hill 
123 W Franklin St, Ste 450  
Chapel Hill, NC 27516 
Phone: (919)843-0685 
E-mail: rwgoolsby@unc.edu  
 

 
 
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List of Abbreviations  
ADMQ 
Adolescent Decision Making Questionnaire 
AE 
Adverse Event  
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine Transaminase 
ART 
Antiretroviral Treatment/Therapy 
ARV 
Antiretroviral  
ASSIST 
Alcohol, Smoking and Substance Involvement Screening Test 
AST 
Aspartate Aminotransferase 
ACASI 
Audio Computer-Assisted Self-Interview 
ATN 
Adolescent Medicine Trials Network for HIV/AIDS Interventions 
ATN MOPP 
ATN Manual of Policies and Procedures 
BID 
Twice per Day 
cART 
Combination Antiretrovial Treatment/Therapy, cART and ART will be used 
interchangeably  
CBC 
Complete Blood Count 
CC 
Coordinating Center 
CE 
European Conformity (Conformité Européene) 
CEPAC 
Cost Effectiveness of Preventing AIDS Complications 
CES-D 
Center for Epidemiologic Studies Depression Scale 
CFR 
Code of Federal Regulations 
CRF  
Case Report Form 
CRF 
Case Report Form 
CSQ-8 
Client Satisfaction Questionnaire 
DHHS 
Department of Health and Human Services 
DNA 
Deoxyribonucleic Acid 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDM 
Electronic Dose Monitoring Device 
EQ-5D-Y 
EuroQol 5 Dimensions Questionnaire – Youth 
ERQ 
Emotional Regulation Questionnaire 
FAQ 
Frequently Asked Question  
FDA 
Food and Drug Administration 
FSTRF 
Frontier Science and Technology Research Foundation 
FTE 
Full Time Equivalent 
GCP 
Good Clinical Practices 
GMS 
Global System for Mobile 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HIV-VL 
HIV Viral Load 
HX 
History  

 
 
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IATA 
International Air Transport Association 
ICF 
Incofmed Consent Form  
ICH 
International Conference on Harmonization 
ICH E6 
International Conference on Harmonization Section E6 – Good Clinical Practice 
ID 
Identification 
IDI 
In depth interview 
IMB 
Information, Motivation, Behavioral Skills Model 
IMB-AAQ 
Information Motivation Behavioral Skills ART Adherence Questionnaire 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
IRB  
Institutional Review Board 
IND 
Investigational New Drug 
IoR 
Investigator of Record  
ITT 
Intent-to-Treat 
LES 
Life Events Scale 
LPC 
Laboratory Processing Chart 
MI 
Motivational Interviewing 
MOP 
Manual of Procedures  
MOS 
Medical Outcomes Study 
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
National Institute of Child Health and Development 
NIDA 
National Institute on Drug Abuse 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NIMHD 
National Institute on Minority Health and Health Disparities 
OHRP 
Office of Human Research Protections 
OI 
Opportunistic Infections  
PCR  
Polymerase Chain Reaction 
PID 
Participant Identification Number 
QA 
Quality Assurance 
QNS 
ATN Query and Notification System 
RE 
Regulatory Entity 
RNA 
Ribonucleic Acid 
RX 
Prescription 
SAP 
Statistical Analysis Plan 
SDAC 
Statistical Data Analysis Center 
SES 
Subject Enrollment System 
SID 
Study Identification Number 
sIMB 
situated-application of the Information Motivation Behavioral Skills Model 
sIRB 
single Institutional Review Board 
SJCRH 
St. Jude’s Children’s Research Hospital 
SMC 
Study Monitoring Committee 
SMS 
Short Message Service 
SOC 
Standard of Care 

 
 
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SOP 
Standard Operating Procedures 
SSL 
Secure Sockets Layer 
TERA 
Triggered Escalating Real-time Adherence Intervention 
UNC-CH 
University of North Carolina at Chapel Hill  
US 
United States 
VL 
Viral Load 
  VLS 
Virologic suppression (HIV-1 RNA at <50 copies/mL or <200 copies/mL as 
specified) 
YLWH  
Youth Living With HIV 

 
 
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Study Abstract 
DESIGN:  
Phase II, two-arm, randomized, open-label study.  Participants will 
be stratified by age (<18 vs. ≥18 years of age) and randomized with 
equal probability to receive either the TERA intervention or 
standard of care (SOC).  Participants will be followed for 48 weeks.   
DURATION: 
Approximately 96 weeks total. Participants will be followed for 48 
weeks.    
SAMPLE SIZE : 
120 youth living with HIV (YLWH) 
POPULATION:  
The study will enroll HIV infected youth 13-24 years of age 
(inclusive) failing antiretroviral therapy (ART) defined as HIV RNA 
PCR ≥ 200 copies/mL at least 24 weeks or more since being 
prescribed ART. 
STUDY INTERVENTION: 
The triggered, escalating, real-time adherence (TERA) intervention 
is a time-limited (12 weeks) approach that includes education and 
motivational skills building from an adherence coach, and 
monitoring with wireless electronic dose monitoring (EDM) for 
identification of delayed and missed doses and related alerts and 
coach phone-based outreach. 
STRATIFICATION:  
Age (<18 years vs. ≥18 years) 
DATA COLLECTION: 
Data will be collected through EDM, ACASI, chart abstraction, 
eCRFs, project implementation dashboard, AdhereTech (EDM), 
secure audio program recordings , and ATN Query & Notification 
System (QNS). 
PRIMARY OBJECTIVES: 
To estimate and compare HIV virologic suppression rates in YLWH 
12 weeks after initiating TERA or continuing SOC. 
SECONDARY OBJECTIVES: 
To estimate and compare virologic suppression rates in YLWH at 
24, 36 and 48 weeks after initiating TERA or continuing SOC. 
 
To estimate and compare proportions of participants initiating 
TERA or continuing SOC who achieve virologic suppression by 12 
weeks and maintain virologic suppression though 48 weeks. 
 
To summarize and compare ART adherence patterns in YLWH 
initiating TERA or continuing SOC during the intervention period 
(weeks 0-12) and the post intervention period (weeks 12-48). 
RISK/BENEFIT CATEGORY: 
Minimal 
MONITORING SAFETY EVENTS Routine team monitoring of any events of potential impact to 
participant’s health or wellbeing are recorded as safety events. 
The study will rely on the ATN Query & Notification System (QNS), 
a real-time, web-based interactive reporting system. The protocol 
chair, study team, protocol manager, and program officials will 
review all new safety events. 
 

 
 
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Overview of Study Design and Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
N=120  
AGE <18 yrs  
AGE ≥18 yrs  
TERA  
SOC  
TERA  
SOC  
STRATIFY 
BY AGE 
RANDOMIZE 

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Overview of Intervention and Data Collection  
 

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Requirements for Site Participation in Protocol 
 
This study is open to US International Maternal Pediatric Adolescent AIDS Clinical Trials Group 
(IMPAACT) and Adolescent Medicine Trials Network (ATN) for HIV/AIDS Interventions sites with 
the following minimum requirements in order to participate:  
Ability to enroll in a one-year period a minimum of five youth (13-24 years of age inclusive) with 
human immunodeficiency virus (HIV) infection failing antiretroviral therapy (ART) defined as 
plasma HIV RNA PCR ≥ 200 copies/mL at least 24 weeks or more since being prescribed an 
effective ART regimen and meeting other inclusion criteria.  
 
Have adequate private space for administration of Audio Computer Assisted Self-Interview 
(ACASI) and an internet-connected, web-cam enabled computer in a private location for remote 
intervention counseling through a two-way video conferencing software program. 
 
 
 

 
 
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Site Roster 
Site PI 
Study Coordinator(s) 
Murli Purswani, MD 
Bronx-Lebanon Hospital Center 
1650 Selwyn Ave, Bronx, NY 10457 
Phone: 718-590-1800 
E-mail: mpurswan@bronxleb.org 
Martha Cavallo 
mcavallo@bronxleb.org 
 
Umer Syed 
usyed@bronxleb.org  
Lisa-Gaye Robinson, MD 
Children’s Diagnostic and Treatment Center, Inc. (CDTC) 
1401 S. Federal Hwy, Fort Lauderdale, FL 33316 
 lerobinson2browardhealth.org 
Kathleen Graham  
kgraham@browardhealth.org 
 
Feiona Heaven 
fheaven@browardhealth.org 
 
Andres F. Camacho-Gonzalez, MD, MSc 
Emory University School of Medicine 
2015 Uppergate Drive, Rm 550, Atlanta, GA 30322 
Phone:  (404)727-5642 
E-mail:  acamac2@emory.edu 
LaTeshia Thomas-Seaton 
lseaton@emory.edu 
 
Will Smith III 
wsmithi@emory.edu 
Allison Agwu, MD 
Johns Hopkins University 
200 N. Wolfe St., Baltimore, MD 21287 
Phone: 410-614-0732 
E-mail: ageorg10@jhmi.edu 
Thuy Anderson 
tander34@jhmi.edu 
 
Aditya Gaur, MD 
St. Jude Children’s Research Hospital 
262 Danny Thomas PL, Memphis, TN 38105 
Phone: 901-595-5067 
E-mail: aditya.gaur@stjude.org 
Ryan Heine 
Ryan.heine@stjude.org 
 
Colin Quillivan 
Colin.quillivan@stjude.org 
Daniel Reirden, MD 
University of Colorado Denver 
Children’s Hospital Colorado 
13123 East 16th Ave., Aurora, CO  80045 
Phone: 720-777-1234 
E-mail: Daniel.Reirden@childrenscolorado.org 
Deina Barton 
Deina.barton@childrensorg 
 
Carrie Chambers  
Carrie.Chambers@childrenscolorado.org 
 
  
Mobeen Rathore, MD 
University of Florida Center for HIV/AIDS, Research, 
Education & Service 
655 West 8th Street, Clinical Center, 3rd Floor, 
Jacksonville, FL  32209 
Phone: (904) 798-4179 
E-mail: mobeen.rathore@jax.ufl.edu 
Alexandrea Borges 
alexandrea.borges@jax.ufl.edu 
 
Saniyyah Mahmoudi 
saniyyah.mahmoudi@jax.ufl.edu 
 
 
Elizabeth Secord, MD 
Wayne State University School of Medicine 
3901 Beaubien St., Detroit, MI 48201 
Phone: 313-745-4450 
Charnell Cromer 
ccromer@med.wayne.edu  
 
Ayanna Walters 

 
 
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E-mail: esecord@med.wayne.edu 
aywalter@med.wayne.edu  
 
Study Management 
Before the recruitment and enrollment of participants, the participating study sites must have 
local Institutional Review Boards (IRBs) enter into reliance agreements with the single IRB (sIRB) 
at the University of North Carolina at Chapel Hill (UNC-CH). All procedures and forms will be 
approved by the sIRB and additional steps required by their local IRBs should be completed as 
appropriate.  In addition, study sites must receive protocol registration approval from the ATN 
Coordinating Center (CC). All original approved documents must be maintained at the clinical 
site. 
 
All queries for this protocol should be sent to the ATN 152 project team using the ATN Query 
Notification System (QNS) accessible via the ATN secure website 
(https://sites.cscc.unc.edu/atn/).  The appropriate team member will address the query 
generally within 2 business days via the ATN QNS and copy the other team members. The 
Protocol Manager, with the help of other ATN CC personnel, FSTRF staff and/or NICHD, if 
necessary, will answer general protocol implementation, eligibility, and CRF completion 
questions. The Protocol Chair or her designee will respond to study and participant 
management, exemptions and/or safety event queries. Queries and replies will automatically 
be archived through the ATN QNS at the CC. The protocol manager will post queries and 
responses deemed relevant to all sites as a frequently asked questions (FAQs) on the ATN 
secure website, where they will be available for future reference.  
 
This study will use the Audio Computer-Assisted Self-Interview (ACASI) to collect study data. All 
questions related to the ACASI should be directed to the FSTRF user support group 
usersprt@fstrf.org. FSTRF User Support is available 24 hours a day, 365 days a year with the 
exception of the holidays which will be provided to sites to ensure no research activity on those 
days and/or appropriate back-up plans as needed. Please contact User Support and provide a 
detailed description of the problem encountered. Phone: 716-834-0900 x7302 
Email: user.support@fstrf.org. 
 
 
For protocol registration issues, contact the ATN CC at ATN152CC@unc.edu.  
For remote data capture issues, contact Barbara Heckman at bheckman@frontierscience.org. 
 
 
 
 

 
 
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1 
INTRODUCTION 
1.1 
Background 
Of the 35 million people living with HIV worldwide, 7 million are below the age of 24. With the 
concerted efforts to increase viral suppression globally and through strategic national plans, the 
unique sequela of youth living with HIV (YLWH) requires specific attention. Successful 
progression through the continuum of HIV care is poorer among adolescents than adults in the 
US, with as many as 43% failing to reach and sustain HIV viral suppression (VLS).1 A sizable 
minority of adolescents and adults who start antiretroviral therapy (ART) fail their first-line ART 
and require transition to second-line ART, while others are re-started on their first-line regimen 
if that regimen is still effective. The odds for continued failure is significantly higher for those 
who fail first-line, particularly those moved to second-line ART due to non-adherence.2-3 
Moreover, evidence suggests that second-line ART failure is not explained by resistant virus for 
many.4 Thus, without intervention, failing on ART signals increased potential for on-going 
failure. For YLWH in the US, there are multiple second- and third-line ART options, however the 
costs and burden are often high and without intervention, repeated failure due to ongoing 
adherence problems is not uncommon. Recent international work found a higher first-line ART 
failure rate among middle, versus early, adolescent Thai youth, 10.8 versus 7.4 per 100 patient 
years5; each higher than the average adult rate. Some 31% of adults demonstrate poor 
adherence to second-line ART regimens,3 which is likely even more dramatic in youth. The call 
for interventions to improve adherence, particularly among YLWH failing first-line ART,6 is well 
understood but remains largely unanswered.  
 
Despite considerable advances in promotion of adherence and factors associated with it (e.g., 
retention in HIV care) in adult populations, the evidence base for interventions to promote 
adherence in YLWH remains sparse and largely inconclusive.78 Skills building may offer 
promise,9 and previous pilots with YLWH have supported problem-solving counseling using cell 
phones.10 Specific to adherence to second- or third-line ART, interventions are near absent 
from the evidence base. International work with adults living with HIV reported null findings for 
a partner-administered directly observed therapy approach11 while a multi-component 
intervention approach including problem-solving counseling12 was effective on viral 
suppression. Given that youth are in developmental phases that are known to challenge the 
kinds of skills needed for adherence-related motivation and skills, we propose combining 
evidence-informed strategies (e.g., phone based problem solving counseling10; wireless drug 
monitoring with texts on delayed dosing [found effective for improving adherence in adults]13) 
in an escalating intensity, triggered intervention approach.   
 
To support YLWH failing ART due to non-adherence, this study will evaluate a novel, evidence-
informed triggered, escalating, real-time adherence intervention (TERA) that leverages 
contemporary technology to address a key area of need as it relates to the care continuum of 
YLWH. TERA is a time-limited (12 weeks) intervention approach that (a) uses wireless electronic 
dose monitoring (EDM) to identify dose-times passing with no bottle opening, (b) sends a text 

 
 
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asking about the delay, (c) evaluates response to text and (d) initiates follow-up by an 
adherence coach depending on response and if the bottle remains unopened for a designated 
period post dosing. Phone based outreach will use problem solving discussion with an 
adherence coach, who can use an agreed-upon contact tree to reach the youth through other 
individuals. With the vast majority of youth on once-daily dosing (single-tablet formulations for 
first line and multiple tablets per dose for second-line), the intervention is tailored to youth 
prescribed once-daily dosing regardless of number of tablets in the regimen. The TERA 
intervention will be compared with standard of care (SOC) on HIV VLS at 12, 24, 36, and 48 
weeks, EDM rates of ART adherence at the same time points, and patterns of adherence over 
time. 
 
1.2 
Prior Research/Current Evidence Base 
1.2.1 Research and Care Sites 
Among the sites participating in the TERA project, a diverse population of YLWH are served, 
with a sizable minority of youth failing ART therapy each year. A review of SOC for YLWH failing 
therapy suggests that all sites implement a medication management approach, where youth 
are advised on the importance of adherence, have a medication-taking plan developed or 
reviewed, and most are encouraged to use their cell-phones for alarm setting; some sites offer 
uni-directional text reminders sent at user-defined dose times automatically. Even in this 
context, optimal outcomes for YLWH failing ART are not realized for the majority of youth at 12-
months. Our detailed exploration of progression from second line therapy to viral suppression 
at the St. Jude Children’s Research Hospital (SJCRH), International Maternal Pediatric 
Adolescent AIDS Clinical Trials Group (IMPAACT) site, identified that only 61% (53/87) of YLWH 
initiating second-line therapy achieved VLS at 3-months, and only 46% (40/87) at 1-year. 
Further, among youth who achieved VLS at 3-months, a progressive loss of suppression 
occurred at 6-months (15% lost VLS), 9-months (30% lost VLS) and 12-months (38% lost VLS). 
Durable VLS from 3-months through 12-months was obtained by only 38%.  
 
Selected sites are well-positioned to implement the proposed research. Each site has a 
demonstrated history in the implementation of high quality/high rigor research protocols. 
Moreover, our polling of sites indicates a high interest in developing effective strategies for 
YLWH who fail to achieve or maintain VLS on daily dosed, effective regimens. 
 
1.2.2 Technology Enhanced and Delivered Interventions 
Evidence supports the use of technology enhanced interventions to promote medication 
adherence among those living with HIV.14 Recent work with adults in Cape Town, South Africa 
evaluated an intervention approach that used text messages to signal late doses according to a 
Wisepill TM device for first-line therapy ART.15 Messages were received for 48 weeks and were 
the same selected message each time a dose was delayed by more than 30 minutes. These text 
messages included “Have you forgotten something,” “Just take it!,” gave the time, or sent just a 
study number. A slight reduction in treatment interruptions was reported, although overall 
adherence, retention in care, and viral suppression did appear improved for this cohort. Other 

 
 
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text-based strategies16 17, that are not yoked to monitoring but are systematically sent, require 
a response from participants, and also seem to suggest that an interactive component is 
particularly beneficial.18-19 Garofalo and colleagues recent work in this area with 105 
adolescents and young adults where two-way daily texts were provided to non-adherent youth 
demonstrated a significant improvement in self-reported adherence and high satisfaction 
scores.20 Furthermore, a pilot study using personalized, interactive, daily text messages 
demonstrated significant improvement among 14-to-29 year olds living with HIV with poor self-
reported adherence rates.21 Texting yoked to known delays in dosing, however, has not been 
rigorously evaluated with YLWH in a randomized, controlled trial.  
 
The TERA study will utilize the AdhereTechTM smart wireless pill bottles to monitor participant 
medication adherence in real-time for those in the TERA intervention arm during the active 
implementation phase of TERA (12 weeks), and to document adherence over 48 weeks of study 
participation in all arms [AdhereTech Inc, 2015]. The smart pill bottle system was designed to 
address previous electronic monitoring tool shortcomings by simplifying the setup process, 
designing a bottle to be used like a regular bottle with a standard child-resistant cap, having 
flexible reminder options, and a long (6 month or more) battery life per charge. The 
AdhereTechTM device is a pill bottle that contains a worldwide cellular communication chip to 
allow for the bottle to passively send real-time adherence data when opened. The smart pill 
bottle sends an electronic medication event record to a central server that is stored on a secure 
server. AdhereTech’sTM system also includes optional adherence promoting tools, including on-
bottle lights and chimes as well as text and phone calls to participants that are delivered in real-
time. Monitoring of dosing events is included for TERA participants for 12 weeks of active 
intervention implementation followed by data collection with the EDM for the remaining 36 
weeks of study participation. During the project, participants in both arms will receive the pill 
bottle with the light-feature activated. The on-bottle light feature is a small band near the 
bottom of the pill-bottle (see Figure 1) that emits soft-blue light pulses 15 minutes prior to dose 
time if the bottle has not yet been opened around a dose-time and continues for a period of 
time after the dose time if the bottle remains unopened. This is intended to act as a ‘soft’ 
reminder. This feature is left active for all participants to enhance engagement with the EDM 
device. Youth in our advisory group noted this feature specifically as engaging and attractive. As 
one aspect of our work focuses on dose monitoring patterns over time, youth in each arm are 
encouraged to dose from the device for the duration of their participation. Allowing the dose-
light feature across arms may help with engagement with the device and refines the active 
intervention to the components under evaluation – eHealth facilitated coaching in real time. 
 
Other features of the pill-bottle EDM are available only to TERA intervention arm participants- 
which include a one-way text at dose time when the device was not opened around dose time 
and an outreach two-way text if the device remains unopened 1.5 hours past the expected 
dose time. Participants have the option of disabling the one-way text but cannot disable the 
SMS two-way (interactive) outreach text. These text messages will not use the clinic name or 
any reference to the participant’s health status or diagnosis.  
 

 
 
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Dosing from the bottle is actively monitored only for TERA intervention arm participants only 
for their 12 weeks on the TERA intervention. Post-intervention for TERA intervention 
participants and for the full study for control arm participants electronic dose monitoring data 
is collected for analysis at end of study. Functionality of the bottles is monitored regularly for all 
participants throughout their 48 weeks of participation.  
 
Available since 2013, AdhereTechTM (Figure 1) is currently being used by multiple industry and 
clinical research trials across a variety of disease and age groups including HIV. Aggregate data 
from AdhereTechTM Inc. suggest high levels of acceptability and feasibility across a diversity of 
treatment regimens (including HIV). Patient surveys among those using AdhereTechTM have also 
demonstrated an 88% satisfaction rate (e.g., satisfied or 
very satisfied) with the entire smart pill bottle system. 
Additionally, 92% of AdhereTechTM users reported the 
smart pill bottle was “easy to use.” The bottle 
communicates wirelessly through cellular networks. 
Regulated by the FDA as a class 1 medical device, the 
entire system is HIPAA-compliant.  The data display for 
aggregate and individual data is customized per project 
and can be used as well to send texts to adherence 
coaches when certain conditions (such as dose delays) occur. The device has received positive 
review from our youth advisory board, which is particularly important given our experiences 
with use of other EDM devices that did not receive positive reviews and had related issues in 
our use of them in clinical trials. We are confident that this EDM will avoid the user-fit issues we 
encountered with other larger devices. 
 
1.2.3 Evidence for Phone-Based Outreach Problem Solving 
Evidence has supported the utility of phone-based outreach using a problem solving 
approach.10,12 In a recent review, harnessing mobile phone technology was identified as a 
promising area for future interventions encouraging optimal adherence among YLWH.20 
Furthermore, evidence suggests using phone-based technology to engage adolescent social 
support networks may promote optimal engagement in care and adherence to medications.22 
22-23 A recent study of a phone-based support intervention among non-adherent YLWH found 
that it was acceptable and feasible among youth and clinic staff.24 The TERA intervention will 
uniquely combine these aspects (distance counseling at the clinical research site on a site 
computer from an adherence coach using HIPAA compliant VSee (https://vsee.com/) remote 
counseling ‘room’ and phone-based problem solving from adherence coach linked to a real-
time electronic adherence monitoring device) to promote optimal adherence among YLWH. 
Although phone-based outreach has been supported in pilot work, it has not been rigorously 
evaluated, nor has triggered outreach been evaluated, as evaluations to date have 
implemented the phone outreach based on time (e.g., daily, weekly) and not tethered to actual 
dosing patterns or potential problems. Additionally, the adherence coaches that will implement 
the phone-outreach are centrally located and are not part of the clinical care team at sites. This 
allows for dedicated counselors/coaches, may offer an elevated sense of privacy among youth, 
Figure 1 
 

 
 
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and assures an on-call system for complete coverage during the intervention arm participants’ 
12 week engagement in the intervention. All correspondence is through VSee, calls, texts, or 
other approved media. The project requires coaches have a strong command of the English 
language- fluency in other languages is not required. Using a central ‘coach’ has a number of 
implementation and generalizability benefits, and fits well with the most common forms of 
communication use among youth presently (texting and cell-phone). Criteria for adherence 
coaches include past counseling experience and advanced training, history of working with 
youth, demonstrate high cultural humility and will engage in advanced MI training and 
supervision while coaching TERA participants. 
 
1.2.4 Evidence for Theory-Based Drivers of ART Adherence in YLWH 
The protocol team has considerable experience in social-behavioral modeling of adherence, as 
well as engagement in HIV-care- known to impact adherence and persistence. The protocol 
chair has co-developed the Information, Motivation, Behavioral Skills (IMB) model of ART 
adherence,25 which has been used extensively in interventional adherence enhancement 
research.26-27 Through a series of studies, the strength of the model, its core constructs, and 
structural relationships have been established through structured equation modeling in diverse 
groups.27-29 Although the IMB-model and the situated-application of the model (sIMB)30 were 
developed to speak to adherence and persistence across populations, the TERA study will be 
the first to apply a sIMB model to YLWH in the context of previous adherence failure. The study 
is well positioned to offer new insights on youth and the impact of their adherence-related 
information, motivation and behavioral skills on VLS, as well as patterns of dose-taking over the 
first 48 weeks. 
1.3 
Rationale 
YLWH are at elevated risks for failure to achieve HIV viral suppression (VLS). Recent reviews 
suggest that a subset of youth achieve VLS post 48 weeks of ART at alarmingly low rates (27% to 
89%).31 Progression through the continuum of care for YLWH in the US suggests that only 6% 
are durably virally suppressed.1 
 
The evidence base for strategies to support adherence and successful VLS in YLWH is lacking. 
The current evidence base is generally lacking in effective adherence improvement 
interventions for YLWH. Despite the fact that youth failing ART because of non-adherence are 
clearly at higher risk for repeated failure, the evidence base remains relatively silent on the 
issues, approaches, and facilitators/barriers for this at-risk group. For YLWH more generally, 
recent reviews provide limited evidence for effective interventions for adherence support. This 
study is responsive to this need specific to YLWH, exceeds standards for rigorous design, 
harnesses contemporary wireless technology and contributes to a higher quality evidence base.   
 

 
 
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Interventions developed specifically for YLWH are needed. With a limited evidence base 
dominated by pilot interventions for effective strategies to use when intervening with YLWH to 
support ART adherence, pulling from the adult intervention literature to guide approaches is 
not uncommon. However, considerable evidence suggests that youth are a unique cohort with 
unique needs. Although literature specific to adults failing first-line ART therapy suggests that 
gender (female) and delayed start of second-line therapy predict lack of suppression by 24-
weeks,32 research unpacking the complex socioecological factors influencing patterns of 
adherence to second-line therapy specifically focused on YLWH is sparse. The evidence base in 
characterizing first- or second-line ART failures and outcomes in resource limited settings33 is 
growing, however such correlates may not generalize to YLWH in the US, nor do surface-level 
demographic factors provide direction of intervention opportunities. Thus, despite nearly two-
decades of available effective ART, drivers of adherence for YLWH and how to best intervene to 
optimize adherence remain poorly understood. 
 
From a developmental perspective, youth would likely benefit most from strategies that 
specifically bridge the gaps common during adolescence cause by normal neuro-cognitive 
development.34 Enhancing salience of dosing through text cues, interactive texts, and ultimately 
human outreach as and when needed matches well with the added desired for autonomy 
characteristics in youth and concomitant need for connection and guidance (see Young and 
colleagues35 for example). Challenges in executive functioning and cognitive abilities are 
common among infected youth, even prior to ART initiation.36 Other factors, such as social 
support, impulsivity constraining prospective planning, lability, increased needs for autonomy, 
and identity development support an approach where intensive involvement in adherence is 
appropriate for a time-limited period. A time intensive approach allows for heavy involvement 
with youth failing ART in developing strong problem solving skills during the first 12 weeks of 
continuing, restarting or starting new ART regimens. A ‘boot camp’ approach offers the 
opportunity to develop strong skills and motivation, and autonomy through emphasis on 
problem solving (versus solution-giving) and self-efficacy in completing a time-limited intensive 
program, which is well-aligned to the developmental processes of youth.  
 
The TERA study addresses gaps in our evidence-base and interventions for youth and will 
dramatically further the scientific understanding of critical factors in the pathway to ART 
adherence and success for YLWH on ART. The TERA study will considerably advance scientific 
understanding of the theory-based dynamics that influence ART adherence in youth. This work 
advances the number of options for highly generalizable strategies to optimize adherence 
among youth living with HIV (YLWH) known to have struggled with ART in the past. 
Interventions that are matched to maturational issues and demands of youth are critically 
needed. Further, TERA contributes to the understanding of ART adherence and non-adherence 
in this population at considerable risk for continued ART failure. We are well positioned to 
advance both science and practice and address ART adherence - a key component of the 
continuum of care for YLWH. Our research has identified an overall lack of rigorous adherence 
enhancing research, which has been echoed in a number of recent research syntheses.722 
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represented in the literature. Although agencies and service providers are advised to adopt 
evidence-based adherence support strategies, there are no strong, rigorously tested 
interventions to consider. Three main strategies, well matched to the developmental and social 
context of adherence among youth, leveraged in the TERA intervention include electronic dose 
monitoring with real-time response, engaging youth in a short-term high-intensity program, 
and centralized adherence coaches.      
                                    
Electronic dose monitoring, real time triggered interventions, and interactive and real-person 
phone-based outreach with use of a contact-tree are all novel components to adherence 
support that promise high impact. The existing evidence base will be leveraged to create a high-
intensity, responsive, time-limited intervention approach. While texting has a strong evidence 
base for adults,16,18,25 use with youth, while intuitively appealing given the widespread use of 
texting, remains supported largely with only pilot studies.21 Similarly, phone-based problem 
solving discussion with adherence coaches has preliminary evidence10 demonstrated in a pilot 
study. Our work leverages the wealth of pilot evidence to create an intervention approach with 
demonstrated promise but not yet rigorously evaluated. Of particular interest, our goal is to 
mesh together an evidence-informed approach that can also be generalizable. Given that sites 
and clinics working with youth will have limitations in resources, we adapted interventions 
implemented over extended periods of time to a discreet, intensive approach implemented 
over a 12-week period and intensified in report to delayed or missed doses. This creates a more 
generalizable program as resources required are similarly time-limited. The key pieces that 
make up the TERA intervention are largely in place; YLWH overwhelmingly have cell phones and 
clinic team members already use or will be trained in problem solving. A system for sending and 
receiving texts can be automated, with costs allocated towards building the system and minor 
costs for maintenance of system. If the intervention is effective, it could have an immediate 
impact on care services provided to YLWH failing ART who are continuing or restarting on a 
once-daily regimen and future applications to other points in the continuum of HIV prevention 
and care that depend on youth adhering to the applicable interventions.   
 
Adoption of a time-limited high-intensity “boot camp” approach is innovative.  Short but 
intensive health promotion approaches are now common in descriptions of professional 
training,37-38 weight loss, and even diabetes control.39 Present day sentiment among our youth 
towards the approach is largely positive, as associations with the term have moved from older 
and unsuccessful applications of correctional boot camps to wilderness and health/fitness boot 
camps. Review by our youth advisory group suggests support for the time-limited, intensive 
approach. For YLWH, a boot camp approach may offer the kind of assurance needed to allow 
for full engagement in an approach that is both demanding and involves monitoring, review and 
guidance. Autonomy is a high priority for many of our youth. Programs that allow youth to 
consider their involvement to be time-limited and the assistance to be similarly time-limited 
may arguably facilitate greater involvement than a program with no visible end. Moreover, 
there is a sense of accomplishment and success with completing an intensive course or 
“training” which can build efficacy and pride. Single session and brief interventions using 
motivational interviewing with youth have been effective in risk reduction in other health areas, 

 
 
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such as alcohol use.40 While a longer intervention may be needed for YLWH failing ART, the 
appeal of a short yet intensive intervention that seeks to establish skills and the development 
and use of adherence promotion strategies that will persist beyond the intervention is clear.  
 
Centralization of adherence coaches is also intended to uniquely apply to youth, where coaches 
may be considered more neutral and also can be available when needed. For the TERA 
intervention, while EDM devices are issued at point of clinical care and research activities (e.g., 
survey) are completed at clinic, the intervention itself is centralized and is not dependent on 
clinic staff or resources at clinic. Adherence coaches can be located anywhere geographically, as 
intervention components do not use in-person contact. Texting and phone-calls can be placed 
from any location. This allows for the intervention to be “stand alone”, making it highly 
generalizable and replicable for youth throughout the US. However, because coaches can 
access and communicate with site staff, local resources for unmet needs and establishing 
referrals can be accomplished. Interventions using phone and web-based applications, versus 
face-to-face, are a growing area in mHealth technologies.  
 
1.4 
Hypotheses 
 Youth in the TERA arm will be more likely to achieve viral suppression at weeks 12, 24, 
36 and 48 compared to youth in the SOC arm 
 Youth in the TERA arm will be more likely to achieve and sustain VLS than those in SOC 
arm 
 Youth in the TERA arm will have higher rates of weekly dosing as measured by EDM over 
48 weeks than those in SOC arm  
 VLS and adherence will be associated with gains in adherence-related information, 
motivation and behavioral skills, which will be higher in youth in the TERA arm than 
those in the SOC arm 
 Youth will report positive attitudes and experiences with the intervention content with 
themes emerging relative to adherence support that are unique from those in the 
control arm 
 
 
 

 
 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
 To estimate and compare HIV virologic suppression rates in YLWH 12 weeks after 
initiating TERA or continuing SOC 
 
2.2 
Secondary Objectives 
 To estimate and compare virologic suppression rates in YLWH 24, 36 and 48 weeks after 
initiating TERA or continuing SOC 
 To estimate and compare proportions of participants initiating TERA or continuing SOC 
who achieve virologic suppression by 12 weeks and maintain virologic suppression up to 
48 weeks 
 To summarize and compare adherence patterns (EDM) in YLWH initiating TERA or 
continuing SOC during the intervention period (weeks 0-12) and the post intervention 
period (week-12 and week-48) 
 
2.3 
Other Objectives 
 To evaluate and compare changes in survey collected social-psychological factors by 
study arm, and establish the extent to which these changes are associated with 
adherence and viral load outcomes 
 To identify profiles (phenotypes) of adherence based on EDM data 
 To describe the resource requirements and costs of the TERA intervention, including the 
AdhereTechTM bottles, virtual coaching software, SMS messages, and personnel time 
and salaries 
 To characterize through qualitative interviews, the main themes youth report for 
adherence support needed, received, and valued at 12 and 48 weeks 
 To evaluate acceptability and feasibility of participation in the intervention with mixed 
methods (interviews and ACASI survey) 
 To gather feedback from intervention coaches and clinic staff on experiences 
implementing the intervention with YLWH 
 
 
 

 
 
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3 
STUDY DESIGN 
This is a phase II, two-arm, randomized, open-label study.  Eligible participants will have failed 
ART, defined as having detectable HIV virus (HIV-1 RNA ≥200 copies/ml) within 45 days of 
enrollment despite having been on ART for at least 24 weeks. They may be continuing the same 
ART regimen or starting a new once daily regimen.  Participants will be stratified by age (<18 vs. 
≥18 years of age) and randomized in equal proportions to receive the study intervention (TERA) 
or standard of care (SOC), with no enrollment limits in each stratum. Institutional balancing will 
ensure roughly equal numbers of participants in each study arm at each site. After being 
randomized to study arm, a second procedure will randomly select a subset of participants to 
engage in the qualitative interviews. To promote ART adherence, participants in the TERA 
intervention arm will receive an intensive, time-limited EDM-based intervention for a 12-week 
period. This “boot camp” strategy is used to unsettle or disrupt established non-adherence 
behaviors and factors promoting ongoing non-adherence. Participants will be followed for 48 
weeks. Both arms will have data collected through the EDM throughout the study. Provided 
below is a brief description of main components of the trial with specific details provided in 
appropriate sections in the remaining sections of the protocol. 
 
YLWH failing antiretroviral therapy (defined as having plasma HIV RNA PCR ≥ 200 copies/mL at 
least 24 weeks on ART) who are either continuing or restarting a once-daily ART regimen will be 
recruited from participating sites. Those who consent to screening and potential study 
participation and who meet the eligibility criteria will be enrolled and randomized. Participants 
will be issued an EDM bottle with training on use and charging provided. Those assigned to the 
TERA intervention will receive additional education about the intervention components they 
will be receiving for the next 12 weeks and will engage in the introduction session with the 
adherence coach via VSee in a private location at the clinic.  
 
There will be six study visits (see Appendix I) -- baseline, 4, 12, 24, 36 and 48 weeks. Audio 
computer assisted self-interview (ACASI) survey data includes adherence related information, 
motivation and skills, with an emphasis on social support and perceived efficacy, depression 
assessment, mental and physical health functioning, and substance use. ACASI surveys occur at 
baseline, 12, 24, 36 and 48 weeks (section 3.3.6). The EDM device is issued at baseline. Only 
one medication will be stored and dispensed from their study assigned AdhereTechTM EDM 
bottle. For those on a one-pill daily ART regimen, the EDM will contain their complete ART 
regimen but for those on a multi-pill once-daily regimen, only one of them will be stored and 
dispensed from the EDM.  Viral load data at weeks 12, 24, 36 and 48 will be collected; HIV viral 
loads done at these time points as per the site’s SOC will be used but in the case that a SOC HIV 
VL is not done, site staff will order one specifically for ATN 152. In addition to granular data 
(e.g., exact time and date of all opening events) collected from EDM daily dosing, social-
behavioral data will be collected via ACASI in 12-week intervals.  
 
All youth (both the TERA and SOC arms) will be asked to dose from their AdhereTechTM EDM 
over the full 48 weeks of the study and therefore will be provided training on use of the EDM. A 
clinic team member will issue the device, assist participants who take multiple ARVs to identify 

 
 
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the one that will be stored in the device (participants are encouraged to pick the ART 
medication they anticipate most difficulty with), and record the dose time. Per protocol, 
participants will be on once-daily dosing. The decision to limit the intervention to youth on a 
once-daily dose schedule was based on information suggesting that youth in participating 
clinics are largely on once-daily regimens, even when on second-line regimens, and to 
streamline the intervention which has multiple active features linked specifically to dose-time. 
If the intervention is effective linked to the once-daily schedule, future work will consider 
impact when youth are negotiating multiple dose-times (eg., those on salvage regimens). FSTRF 
support phone line will be used to collect the data needed to activate a device and FSTRF staff 
will then enter the information on the AdhereTechTM dashboard. The device will likely be fully 
active for the next dose and at the longest 24-hours from set-up. The ATN 152: TERA Manual of 
Procedures (MOP) will detail the exact process the sites will use.  
 
For YLWH who do not have their medication available for loading into the EDM at baseline, they 
will receive training and set-up but will be asked to load the device within 24-hours. These 
situations will be attended to on a case by case basis, however site-staff will call each YLWH 
who self-loaded the device outside of clinic within 24-48 hours to confirm the bottle is filled 
and answer questions. The EDM will collect dose (device opening) data for all participants 
centrally; only participants in the TERA arm will have their data automatically reviewed in real-
time to identify delays or potential missed doses during the 12-week active intervention period. 
For youth in both the SOC arm and TERA arm after the 12-week intervention, data will be 
collected and stored for analyses. For all youth, the EDM data is not intended for use by the 
clinic site - rather, the data will be maintained centrally, and adherence coaches - also remote 
from the clinic site – working with youth in the intervention arm during the first 12 weeks of 
their participation will actively review and respond to EDM data. As such, the intervention will 
be evaluated as a “stand alone” approach. The research team will monitor EDM functionality 
and work with sites to replace or repair any EDMs that appear to be malfunctioning. The study 
project manager will monitor for malfunctioning devices on the dashboard throughout the 
study.   
 
In addition to the TERA and standard of care control arm procedures, a subset of participants 
(20 in each arm) will be randomly selected to engage in in-depth interviews about their 
experiences at week-12 and week-48. Confirmation of desire to participate in the qualitative 
portion is requested at baseline (when randomly selected). The participant is expected to 
engage in both the week-12 and week-48 interview. Selection probabilities will be increased 
during accrual if refusal rates at week-12 are higher than expected. Every effort to engage 
week-12 interview participants in the week-48 interviews will be made- including phone based 
interviewing. Strategies to add new participants to the week-48 interviews will be considered if 
loss to follow-up reduces the originally selected sample size. To facilitate feasibility of collecting 
interviews, participant interviews can occur any time in the week-12 visit and week-48 visit 
windows after completion of study visit. (See Appendix I for visit window timeframes.) 
 
Participants remain on-study for approximately 48 weeks with a window of ±28 days.  

 
 
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3.1 
Study Population 
This study will be conducted among approximately 120 YLWH at ATN and IMPAACT sites in the 
US. Each of these sites has existing populations of YLWH and will continue to receive new 
referrals over the course of the study through linkages to their communities. These sites are 
located in key cities around the US, representing areas of high rates of newly infected and high-
risk youth. Participants will be selected for the study according to the criteria in Sections 4.1 
and 4.2 and the guidelines in Section 4.3.   
 
 
 

 
 
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4 
SELECTION AND ENROLLMENT OF STUDY PARTICIPANTS 
4.1 
Inclusion Criteria 
Potential participants must meet all of the following criteria in order to be included in this 
study: 
 
1. Age 13 through 24 years (inclusive) 
2. Confirmation of HIV-1 Infection as documented in the participant’s medical record by at 
least two of the following criteria: 
a. Reactive HIV screening test result with an HIV antibody or HIV antibody/antigen-
based, Food and Drug Administration (FDA)-licensed assay followed by a positive 
supplemental assay (e.g., HIV-1 Western Blot, HIV-1 indirect immunofluorescence, 
HIV-1/HIV-2 discriminatory immunoassay) 
b. Plasma HIV-1 quantitative ribonucleic acid (RNA) assay >1,000 copies/mL 
c. Positive HIV-1 deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) 
assay 
d. Positive plasma HIV-1 RNA qualitative assay 
3. Participant aware of his or her HIV infection, as determined by site staff 
4. Documented plasma HIV-1 RNA plasma ≥200 copies/mL within 45 days of the date of 
the enrollment visit 
5. Prescribed antiretroviral therapy for at least 24 weeks or more prior to documented 
plasma HIV-1 RNA plasma ≥200 copies/mL.  
6. Prescribed a once-daily  (one or more pills once a day) ART regimen with at least two 
active agents (per clinician judgment or genotype evidence) at enrollment 
7. Able to communicate in spoken and written English   
8. Currently has a cellular phone that is also able to send and receive text messages 
9. Willing and able to provide at least one additional contact phone number (preferably 
two) to contact participant  
10. Able and willing to provide written informed assent/consent and able to obtain written 
parental or guardian permission (if required as specified by the site, by state law, and/or 
IRB policy, and detailed in each site’s Protocol Implentation Plan [PIP])to be screened for 
and to enroll in this study 
 
4.2 
Exclusion Criteria 
To be considered eligible for enrollment, an individual must not meet any of the criteria listed 
below. 
1. Gross cognitive limitations, acute emotional instability, or medical or mental health 
illness that in the opinion of site personnel would impair the individual’s ability to 
provide informed consent and/or interfere with the protocol’s objectives.  
2. Concurrent participation in interventional studies addressing adherence unless 
approved in advance by study team 

 
 
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3. Positive pregnancy test at the time of enrollment.  If participant becomes pregnant 
while on study, they may continue on study 
4. Currently using or planning to use an electronic dose monitoring and reminder device 
outside of the study 
 
4.3 
Recruitment  
Sites will generate a list of potentially eligible participants based on medical chart review. 
Potential participants will be approached for the study through the clinics by trained clinic staff, 
research staff or other means, as the per the site’s recruitment strategy. Sites may also use the 
sIRB-approved recruitment flyers to identify interested participants. To contact current clinic  
patients who have been out of care for some time, sites may use the sIRB-approved telephone 
scripts to gauge potential interest in the study and conduct a few pre-screening procedures. 
Potential participants will need to visit the site to complete a formal screening.  
Potential participants will be informed of the nature of the study, the information to be 
collected, and the evaluations and assessments that are involved. No procedures, other than 
preliminary verbal assessment of eligibility or medical chart review to assess potential 
eligibility, are included in initial screening. 
Those who are approached for participation, outcomes of approach (accept, decline, reasons 
for decline) will be recorded in the recruitment log. This log may include name or initials, date 
of birth or age, birth sex, race, and ethnicity and will be stored in a secure location at site. See 
the appendix of the current MOP for the recruitment log. When study accrual ends, site study 
staff will remove all names or initials and dates of birth belonging to individuals who did not 
consent to participate in the study. The protocol team may request tabulated information on 
individuals who participated in the recruitment process, but did not provide informed consent 
and the reasons these individuals refused to participate. These data will provide general 
information on the population that is recruited at the study site.  
Those who are approached and express interest may lack viral load data in their charts that are 
within the acceptable time interval for eligibility. In these cases a viral load test supported by 
the study will be obtained.  In addition, a pregnancy test (blood or urine) supported by the 
study will be obtained, if not included in standard of care. Consent for study participation must 
be obtained prior to study-supported viral load test and/or pregnancy test.    
4.4 
Study Informed Consent and Screening 
Potential participants meeting study criteria will engage in full consent procedures for study 
participation. Study details will be discussed, and questions answered during the informed 
consent process. Signed informed consent from the individuals or assent with signed parental 
permission, as determined by the sIRB (and local IRBs where required), will be obtained before 
any study related medical chart data are recorded or study procedures are performed.    
 
A waiver of parental/legal guardian consent will be requested from the sIRB given that minor 

 
 
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individuals often seek HIV care and treatment without parental/legal guardian permission, 
depending on each site’s state laws.  
After consent, the site uses one of its participant identification numbers provided by the study 
to enter all screening data into the Subject Enrollment System (SES). At the end of screening, 
eligible participants are enrolled (see section 7.1 and 7.2). If a participant fails screening for any 
reason, the ATN152 Screening Failure form is completed using the screen number provided by 
SES and the PID used is retired from the site’s list of available TERA participant IDs, unless this 
participant is rescreened at a later time.   
4.5 
Contact Information  
Once consented, designated study staff will complete the ATN 152 Contact Form with the 
participant. Participants will be asked to provide contact information where they can be 
reached. Participants will also be asked to provide valid contact information for a family 
member and/or friend who can be contacted in the event the participant cannot be reached. 
Participants will be asked if voice and/or text messages can be left at the numbers provided. 
Study staff will not leave any messages unless expressly permitted to do so by the participant, 
which will also be documented on the contact form. If permission is given to leave messages, 
site staff will assure participants that messages left with a family member and/or friend will 
only ask the participant to contact study staff and will not include any protected health 
information or information related to study participation. We will also ask participants what 
message they would like for us to leave and how we should identify ourselves.  
 
The ATN 152 Contact Form will not contain any study data and will be securely maintained at 
the study site, separate from all study records, with access limited to designated site research 
personnel.  
 
4.6 
Participant Retention 
Once a participant is enrolled in this study, study staff will make every effort to retain him or 
her for the protocol-specified duration of follow-up, thereby minimizing potential biases 
associated with loss to follow-up. Each site must establish and outline study specific procedures 
in their Protocol Implementation Plan (PIP) that target retention rates that are sufficient to 
allow the primary study outcomes to be reliably estimated (a maximum 10% loss to follow-up). 
Refer to Section 9.5 for more information on monitoring participant retention in this study. 
 
4.7 
Participant Withdrawal or Termination from the Study 
Regardless of the participant retention procedures referenced above, participants may 
voluntarily withdraw from the study. Participants may also be terminated from the study by the 
site investigator or designee under the following circumstances: 
 Participant re-locates away from the study site or is otherwise determined to be lost to 
follow-up 
 Investigator or designee determines that continued participation in the study would be 

 
 
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unsafe or otherwise not in the best interest of the participant, after consultation with 
the protocol team 
 The study is stopped or canceled by the sponsors, government or regulatory authorities, 
or sIRB. 
 
For any participant who withdraws/is withdrawn or is terminated from the study prior to 
scheduled completion of follow-up, study staff will document the reason for the withdrawal or 
termination in detail and will make every effort to complete final evaluations as described in 
Section 7.7.  In the event that the circumstances that led to a participant’s withdrawal or 
termination change (e.g., he or she returns to the study site area after having re-located 
previously), the site investigator or designee should contact the protocol team to discuss 
options for resumption of follow-up. 
 
4.8 
Co-enrollment Guidelines  
Concurrent participation in studies addressing adherence interventions is not permitted. Co-
enrollment in other clinical studies may be considered at the discretion of the protocol team.  
Requests for “blanket” co-enrollment approvals into other relevant open protocols during the 
implementation of this protocol will be considered by the protocol team and, if meritorious, will 
be granted prior to implementation of this protocol.  
 
Studies that open after this protocol is implemented can be considered for co-enrollment either 
by requesting a blanket, one-time approval from the protocol team OR by requesting case-by-
case permission for co-enrollment in writing from the protocol chair using the ATN Query and 
Notification System (QNS) located on the ATN website (https://sites.cscc.unc.edu/atn/).  
 
 
 

 
 
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5 
STUDY PROCEDURES 
The Schedule of Evaluations (Appendix I) provides a timeline of when each study 
visit/activity/etc. is to be performed.  
 
5.1 
Enrollment Procedures 
Enrollment must occur no more than 45 days after the screening visit. Screening and 
enrollment can occur (and is preferable) on the same visit, conditional on availability of an HIV 
VL ≥ 200 copies/mL within the prior 45 days1.   
The Frontier Science Data Management Center Subject Enrollment System (SES) will be used to 
assist with tracking the screening and enrollment process. When informed consent is obtained 
for the study, a participant identification number (PID) is assigned by the site using a study 
specific PID list and is used to enter all screening information into the SES. This PID remains with 
the participant and is only reused if a potential participant rescreens. If the same potential 
participant is rescreened at a later time the same PID should be used and a different screening 
number should be obtained Successful screens generate a Study identification number (SID) 
that is used for internal data management procedures and is linked to the PID for study 
procedures detailed below. For participants who are found to be ineligible for the study, or who 
do not enroll in the study for any reason, an eCRF (screening failure form) will be completed to 
record the screening outcome using the screen number provided by SES as an identifier.    
 
5.2 
Randomization Strategy and Procedures  
Participants will be randomized to the TERA or SOC study arms using the Frontier Science Data 
Management Center’s SES. Immediately after randomization to study arm and using the SES, 40 
participants (20 in each arm) will be randomly selected to participate in in-depth interviews 
within 14 days after their week 12 visit and 28 days from their week 48 visit. Refer to Section 
11.3 for details. 
5.3 
Intervention and Standard of Care Procedures 
5.3.1 TERA Intervention 
The TERA intervention is a sequence of adherence support strategies implemented as needed 
and in increasing intensity on the basis of monitoring of dose-taking from the AdhereTechTM 
EDM device. Components of the intervention implemented over the 12-week intervention 
period include: (1) remote education/preparation through counseling and planning with the 
assigned adherence coach (on computer at clinic site at baseline and weeks 4 and 12, as 
needed and as-available between visit coaching sessions); (2) one-way text alert at dose time 
when bottle has not yet been opened for that dosing window; (3) missed dose two-way 
interactive outreach text asking “What’s the plan?”;  and (4) implementation of the coach-
outreach (phone, text, remote counseling) triggered by missed doses or as a check-in. Text 
                                                     
1 Sites can request study specific funding to perform a viral load test for any youth that appears to qualify on other criteria but is missing viral 
load within the timeframe required. Note that consent for participation in the study is needed prior to this viral load testing and confirmation 
of entry into the study cannot be provided until detectable virus criteria is met.  

 
 
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messages will not use the clinic name or any reference to the participant’s health status or 
diagnosis. Each component is implemented for 12 weeks total for intervention arm participants 
and is described below. 
 
5.3.1.1 Face to Face Remote Counseling  
When youth are assigned to the TERA intervention condition at baseline, they meet with their 
assigned adherence coach in a private location via web-enabled virtual counseling (VSee) at 
clinic. These trained coaches are not part of the clinic team; rather they are centrally located at 
the University of Michigan. The first session is anticipated to last up to 60 minutes, and includes 
building rapport, discussing roles and expectations, explaining the intervention components, 
and building engagement. The coach works with the youth to develop a personal adherence 
plan, contact tree and preferences, and problem solving around previous challenges with 
adherence. Specific details about the EDM bottle may be reviewed and how texts are prompted 
will be explained. Details for phone contact tree, black-out times (times when the participant 
does not want to be called), preferred name and appropriate pronouns, and other important 
aspects of the participant’s life that need to be considered throughout the interactions with 
coaches will be documented through “notes” and entered by the coach in a profile area on the 
TERA implementation dashboard for later use. A secure audio recording program records all 
sessions and stores this data on a HIPAA compliant secure website at the University of 
Michigan. Coaches can review their sessions for training purposes and to confirm notes.  
 
When coaches (counselors with training in Motivational Interviewing) review the intervention 
with youth, they will intentionally emphasize intensity, difficulty and short-duration as a way to 
mobilize pride in engaging in and ‘succeeding' in the program. Motivational interviewing (MI) 
strategies will be used to work through ambivalence and garner support for engaging in the 
intervention. Because the coaches have set face-to-face meetings only three times (baseline, 
week-4 and week-12) and the week-12 visit focuses on termination and transition off of active 
intervention, the need for baseline to function as a single session is critical and well-suited to 
MI approaches. Counseling strategies are detailed in the TERA Coach’s Manual. 
 
5.3.1.2 Triggered Outreach 
 The sequential escalation of adherence support follows a set pattern, where late and no dosing 
prompts increased efforts to connect and work with youth. AdhereTech’sTM algorithm identifies 
each opening event as an early, on-time, or late dose for a given expected dose. An opening 
event may be counted as an early dose from an expected dose time that has passed or an early 
dose for an upcoming expected dose based on a computation of time elapsed and remaining 
for doses not yet ‘taken’. 1.5 hours elapsed without an opening event prompts interactive 
outreach. From the moment the two-way outreach is sent, a “ticket” is opened for the event 
with all implementation procedures from that point forward are tracked on the study specific 
implementation dashboard. 
 
Potential outcomes of the two-way outreach text are detailed below in Table 1 and include: (1) 
there is no response within 1-hour; (2) the participant replies he or she is not taking it (each 

 
 
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participant has 1 pass-reply per week where a report of not intending to take the dose is 
permissible with no follow-up); (3) participant replies that the dose is being taken now; (4) 
participant response that says he/she has taken the dose; or (a plan for taking the dose later is 
reported); or (5) reply that dose will be taken later. Note that events such as the dose 
monitoring capturing an opening event between the outreach text and coach involvement may 
occur and negate the need for follow-up. Finally, the response may be uninterpretable and 
require follow-up.   
 
For participants who fail to respond to the two-way outreach text within an hour, the event is 
investigated by the monitor on call and then escalated to coach outreach as needed. The 
adherence coach team member monitoring alerts at that time will escalate the ticket and make 
contact with the participant’s assigned coach when possible or address the ticket as needed 
him or herself if the specific coach is not available. 
 
 
 
 
 

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Table 1. Triggered Two-way Outreach 
Participant 
response 
Action 
MONITOR 
a) taking now 
Text alert sent to Monitor 30 minutes after receipt of reply 
Checks dashboard to see if an opening 
event was registered in past 30 minutes 
Yes Closes ticket 
No Escalate to coach 
b) took already 
Text alert sent to Monitor  
 
Check dashboard to see if an opening 
event was registered that may represent 
the dose already taken 
 
Resolved Closes ticket  
Not resolved Escalate to coach 
c) taking later 
Text alert sent to Monitor  
Get more information regarding planned 
time. 
Check dashboard to see if an opening 
event was registered at planned time. 
 
Resolved Closes ticket  
Not resolved Escalate to coach  
d) other  
Text alert sent to Monitor  
Get more information regarding plan 
→Escalate to coach as needed 
e) pass [only 
when a pass is 
available] 
Ticket is moved to closed automatically by the dashboard 
No action required by monitor 
 
 

 
 
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Participant 
response 
Action 
MONITOR 
“e” or “pass” 
when no pass is 
available 
Automated text from 
dishboard sent to 
participant 
“A pass is not 
available. Please 
respond with 
a)Taking Now b)Took 
Already c)Taking Later 
d) Other” 
Different Selection “corrects” response and 
loops into appropriate row above 
NA 
 
No change in response or no response is 
handled as no reply 
NA 
Uninterpretable  Automated text from 
dishboard sent to 
participant 
“Please reply with 
available options” 
Different Selection “corrects” response and 
loops into appropriate row above 
NA 
 
No change in response or no response is 
handled as no reply 
NA 
No reply after 1 
hour  
Text alert sent to Monitor  
Monitor 
sends 
inquiry 
text 
to 
participant. 
 
Resolved Closes ticket  
Not resolved Escalate to coach 
 
Note: The ticket monitor on-duty creates tickets and determines need for escalation to coach. Monitors watch the system during active hours 7-days a week.  
 
 
 
 

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The adherence coach contacting the participant documents the situation, contact attempts and 
successes, plan, and content of discussion or text for each ticket. Coaches are trained to follow 
site-provided (local) protocols for suicidality or discourse suggesting that the participant is a 
threat to self or other(s). Any interactions that include threat to self/other(s) will also be 
documented as a safety event in the ATN QNS tracking system.  
 
Discourse between participant and coach will be documented in the notes section of the TERA 
implementation dashboard, as will the strategic plan result from the conversation which can 
vary between participants and within participant over time (from dose-taking, to accessing 
other services or using referrals). Documentation is marked with PID and appropriate ticket 
number. Our implementation database will maintain lists of all tickets sent.  Related details and 
tickets are “closed” only when coaches submit documentation and submit tickets for closure= 
which can be closed by approved supervisory staff. In the event that coaches cannot reach 
youth via any agreed upon modality (phone, text, social media), the phone tree will be used in 
the order in which the youth listed contacts. The coach will implement all agreed upon forms of 
outreach to contact the youth, with the final attempt being outreach to the clinical-care team. 
Tickets that are open and unresolved for over a week will be dealt with by the team on a case 
by case basis. While sites are engaged by coaches to resolve contact issues when needed, and 
also to identify appropriate referrals and local resources as needed, sites do not have access to 
EDM monitoring dashboards. It is not possible to blind sites completely on assignment to 
condition, however, because coaches may need to discuss referrals for a given participant. Any 
communications of this nature will be documented.     
 
5.3.1.3 Additional Outreach 
Additional outreach in the form of a texted check in (Checking in. All good?) will be used when 
there has been no contact with the participant for a 7-day period. This is to keep participants 
engaged with the intervention and to offer assistance from a coach before a potential dosing 
delay or skip occurs. Thus, these are not triggered by a no- or late-dosing event. Rather, they 
are gentle check-ins for participants who have not triggered outreach in 7-days. The “ticket” 
approach used in the TERA implementation dashboard will be used for these check-ins where 
the text check-in represents a ticket that must be closed and documented in the dashboard, like 
other tickets. The process is depicted in Table 2 below.  
 
 
 

 
 
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Table 2: Check in outreach contacts “Checking in. All good? Y) yes N) no” 
Participant response 
Action 
MONITOR 
Yes 
Ticket is moved to closed automatically by the 
dashboard 
NA 
No 
Text alert sent to Monitor  
 
→Escalate to coach 
Provide follow-up to 
participant as needed 
No Reply after 24 hours 
Automated text from 
dishboard sent to 
participant 
“Checking in again. All 
OK? Y) Yes N) No” 
Different Selection 
“corrects” response and 
loops into appropriate row 
above 
NA 
 
Ongoing no reply after 24 
hours of second text sends 
an alert text to Monitor 
Monitor investigates 
dashboard data and 
gathers information as 
needed. 
 
Resolved Closes ticket  
Not resolved Escalate to 
coach 
 
5.3.1.4 Participant Requested Contact  
Participant requested contact is possible and will be tracked throughout the 12-week 
intervention. A participant in the TERA condition can text questions or requests for contact to 
the study specific cell phone. Coaches have training in ART related content, but will assist 
participants in linking to their care team should questions center on side-effects, medications, 
or other medical issues best addressed by the clinical care team.  
 
5.3.1.5 Adherence Coaches 
Adherence Coaches will have advanced skills in motivational interviewing and working with 
youth. All coaches will participate in two days of concentrated training and an additional one-
week of practice before starting with youth. Monitoring of skills and implementation will be 
conducted in collaboration with the Protocol Chair. Procedures will be documented in TERA 
Coach’s Manual. 
 
5.3.1.6 SMS 
All text messages are received, reviewed and replied to using the SMS platform located on the 
secure TERA implementation dashboard. Text messages will not use the clinic name or any 
reference to the participant’s health status or diagnosis. 
 
5.3.2 Standard of Care 
Per the eligibility criteria, all youth in both the SOC and TERA arms will be continuing or 
restarting with a once-daily regimen with at least two active agents (per clinician judgment or 

 
 
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genotype evidence) as per their primary care providers prior to randomization. We intentionally 
leave the decision of whether the YLWH are on an “effective” regimen to the primary care 
provider recognizing that these clinical SOC decisions are informed by a number of clinical 
factors including a discussion with the patient and are best individualized and not standardized 
or protocol driven.     
 
SOC relative to adherence support each participant is receiving will be enumerated in detail at 
study start and updated at each study visit.  In previous work we have developed a SOC 
measure for ART adherence support41 that follows international recommendations for 
strategies42, as well as strategies known to have positive effects43 in some populations. We 
anticipate, based on polling of IMPAACT sites, that use of cell-phone reminders, patient-
education, adherence planning (medication management), and checking-in on adherence at 
clinical care visits, as well as VL monitoring with patient feedback on VL, are used at sites. Less 
common, but available as a general service at some sites, on several websites, and at many 
pharmacies, youth may also receive text messages at dose times, for appointment reminders, 
and for refill reminders. Given that these are automated and not generally interactive, and are 
not in response to non-dosing, these do not ‘compete’ with the TERA intervention components. 
 
5.3.3 Research Staff Training 
The protocol chairs and project manager assume primary responsibility for training the 
adherence coaches and the sites regarding the project and TERA intervention. The adherence 
coaches will have training in therapeutic/counseling strategies, have previous experience 
facilitating behavioral interventions with youth, and receive additional formal training and 
supervision in Motivational Interviewing.  
 
5.3.4 Intervention Monitoring/Quality Control 
The intervention facilitators will be trained centrally to carry out the intervention protocol, thus 
providing consistency in training experience. Intervention facilitators will engage in group 
supervision. In addition, intervention facilitators will complete session checklists at the end of 
each interaction with a participant to document the elements of the intervention that were 
delivered and to record unique issues that arise. This method has proven successful in assisting 
interventionists in monitoring their adherence to the protocol and preventing the use of 
proscribed intervention in prior studies. By providing multiple layers of clinical oversight and 
ongoing feedback, deviations from fidelity will be easily detected and addressed. 
 
 
 

 
 
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6 
STUDY MEASURES 
6.1 
Computer Assisted Surveys 
Audio computer assisted surveys (ACASI) will be collected at baseline, week-12, week-24, week-
36, and week-48, during scheduled visits. Table 3 describes each measure used in the ACASI as 
well as the schedule for data collection and a brief description of each measure. The ACASI should 
take approximately 30 minutes or less to complete. 
 
Table 3. ACASI Measures and Collection Time-Points 
Measures 
Time Point 
Description 
Adherence Support During 
Participation 
Week-12, Week-48 
Check list of receipt of specific kinds of support 
during first 12 weeks and at week-48 
Information Motivation 
Behavior Skills ART 
Adherence 
Questionnaire44,45  
Baseline, Week-12, 
Week-24, Week-36, 
Week-48 
Measure of adherence barriers identified by 
the Information, Motivation, Behavioral Skills 
Model of Adherence.  
The HIV Adherence Self-
Efficacy Scale46  
Baseline, Week-12, 
Week-24, Week-36, 
Week-48 
Measures self-efficacy for adherence to HIV 
treatment plans, including, but not limited to 
taking HIV medications.  The overall self-
efficacy scale score as well as integration and 
perseverance subscales will be used for study 
purposes.  
Adolescent Decision 
Making Questionnaire 
(ADMQ)47  
Baseline, Week-12, 
Week-24, Week-36, 
Week-48 
Revised version of the ADMQ that measures 
decision making patterns in adolescence.  
Four subscales will be used for this study: 
avoidance, self-confidence, panic, and 
impulsive/thoughtless 
CESD-1048 
 
 
Baseline, Week-48 
Self-reported 10 item screening instrument 
designed to measure symptoms of depressed 
mood in respondents.  
Higher scores indicate increased depressive 
symptomology.  
Demographics  
Baseline 
Study developed and ATN harmonized items 
assessing socio-demographic characteristics 
Emotional Regulation 
Questionnaire (ERQ)49 
 
Baseline, Week-12, 
Week-24, Week-36, 
Week-48 
10-items scale designed to measure 
respondents’ tendency to regulate their 
emotions in two ways: cognitive reappraisal 
and expressive suppressive.  
Higher scores indicate greater use of emotion 
regulation strategy.  
EQ-5D-Y (Overall health 
status)50 
 
 
Baseline, Week-12, 
Week-24, Week-48 
Standardized measure of overall health status 
designed to provide a simple measure of 
health for clinical appraisal.  
Provides a descriptive score for 5 dimensions: 
mobility, looking after myself, doing usual 
activities, having pain/discomfort, and sad or 

 
 
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Measures 
Time Point 
Description 
happy). A visual analogue scale item records 
respondent’s self-rated health on a vertical 
scale to quantitatively measure respondents’ 
self-reported overall health status.  
HIV Cascade Measure 
(U24) 
Baseline 
ATN harmonized items related to engagement 
in HIV related care.  
HIV Stigma Mechanisms51 
 
Baseline, Week-12, 
Week-24, Week-36, 
Week-48 
Measures stigma mechanisms defined by the 
HIV Stigma Framework including measures of 
internalized, anticipated and enacted HIV 
stigma.  
Higher scores indicate greater stigma.  
Life Events Survey (LES) 
Baseline, Week-12, 
Week-48 
Study adapted measure of significant or 
traumatic life events 
Satisfaction Scale 
(Developed for study) 
Week-12, Week-48 
Study developed measure of TERA arm 
participants’ satisfaction with the TERA 
intervention.  
Self-Reported Adherence52 
 
Baseline, Week-12, 
Week-24, Week-36, 
Week-48 
3-item self-reported measure of adherence to 
HIV medications - Doses taken (0 to 30), 
frequency of doses taken in last 30 days (Likert 
response), and rating of how good of job 
taking medications (Likert response).  
Sex Behavior  
Baseline, Week-12, 
Week-48 
Brief item set to assess rates of condomless 
sex 
Social Support Scale 
(MOS)53 
 
 
Baseline, Week-12, 
Week-24, Week-36, 
Week-48 
Measure designed to assess overall functional 
social support as well as four separate social 
support subscales: emotional/information 
support, tangible support, affectionate 
support, and positive social interaction.  
A higher score for an individual scale or for the 
overall support index indicates more support.  
Substance Use (ASSIST)54 
 
 
Baseline, Week-12, 
Week-48 
Screening measure designed for use in primary 
care settings to screen for problem or risky use 
of tobacco, alcohol, cannabis, cocaine, 
amphetamine-type stimulants, sedatives, 
hallucinogens, inhalants, opioids and “other 
drugs” that do not fall into the previous 
categories.  
Higher scores for each substance use category 
indicate greater risk of experiencing severe 
problems as a result of substance use as well 
as greater risk for substance dependence.   
 
6.2 
Dose Real-Time Adherence Monitoring 
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arms, the TERA intervention and SOC arm. The AdhereTechTM device has a global system for 
mobile (GSM) communication chip and a wireless signal is sent to a central management 
system (AdhereTechTM web server) whenever the device is opened. AdhereTechTM data (unique 
identifier and time/date stamp) will be received on a continual basis and stored on the secured 
AdhereTechTM server. Data from the AdhereTechTM device will be used to assess medication 
adherence and persistence. AdhereTechTM data will be maintained centrally for adherence 
coaches and will not be made available to site clinical staff.  
 
6.3 
Biomarkers 
HIV-VL and CD4+ count and percentage will be abstracted from participant medical records. If a 
recent HIV-VL test is not available, it must be collected. For screening of eligible participants, 
HIV-VL can be up to 45 days before the enrollment (week 0) study visit. For follow-up study 
visits at weeks 12, 24, 36, and 48, HIV-VL can be ±14 days from the week 12 follow-up visit and 
±28 days from the week 24, 36, and 48  due date. All HIV-VL and CD4+ data outside of study 
visit time-points but within the time of participation on study will be abstracted.  
 
The frequency of HIV-VL testing in the study is intended to align with what is the sites’ standard 
of care and hence not require a separate HIV-VL to be done exclusively for the purpose of the 
TERA study. HIV-VL testing done as part of the standard of care should not be labeled or billed 
as a TERA study test. If SOC HIV-VL is not available or planned within the study visit window, 
then it should be done (and billed) within the study visit window as per the TERA study 
schedule of evaluations.  
 
6.4 
Medical History/Health Status 
Date of HIV diagnosis, route of HIV transmission, previous experience with HIV medications, 
AIDS defining illnesses and opportunistic infections (OIs) since diagnosis, and current co-
morbidities and concomitant medications will be abstracted from participant medical records.  
  
6.5 
Demographics  
Descriptive information about participants will be collected including, but not limited to, gender 
assigned at birth, subject’s identified gender, age, and race/ethnicity.  
 
6.6 
Intervention Acceptability and Feasibility Measures 
This satisfaction scale will be completed by participants randomized to the intervention arm via 
ACASI at their week-12 and week-48 visit. Items are rated on a 5-point Likert scale.  
 
A semi-structured interview will also be used to collect information on acceptability and 
feasibility of the TERA intervention. The interview  guide has interviewer prompts that inquire 
about overall experiences with the intervention and with adherence services offered as 
standard of care. (see section 8.2 data collection) 
 
 
 

 
 
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7 
STUDY EVALUATIONS 
An overview of the study visits and evaluation schedule is provided in Appendix I. Presented in 
this section is additional information on visit-specific study procedures. Each site will provide 
detailed study specific procedures in their PIPs for review and sign-off by the ATN CC prior to 
site activation. The PIPs must reflect the required expected procedures as specified in the ATN 
152: TERA MOP.    
 
Although split visits should be avoided as much as possible, the MOP includes guidance for 
strategies for split visits and off-schedule visits. All visits and procedures must be documented 
in accordance with the NICHD policies for source documentation; refer to Section 8 for more 
information on documentation requirements and completion of CRFs. 
 
In addition to the procedures listed in this section, study staff may complete other tasks 
consistent with the site’s standard operating procedures for conducting research and providing 
care, including but not limited to collecting, reviewing, and updating demographic and contact 
information; reviewing elements of informed consent; scheduling telephone contacts and visits; 
providing instructions for contacting study staff between visits; providing visit reminders; and 
following up on missed visits.  All such tasks should be documented consistent with each site’s 
PIP.  Study staff should inform participants of clinically meaningful physical exam findings and 
laboratory test results when available. 
 
7.1 
Screening 
Refer to Section 4.3 for a description of the study recruitment, screening, and enrollment 
process. Screening procedures may be performed up to 45 days prior to enrollment. Multiple 
visits may be conducted to complete all required screening procedures if necessary. For 
potential participants who do not meet the eligibility criteria, screening may be discontinued 
once ineligibility is determined. Potential study participants who did not meet study eligibility 
criteria for reasons such as the latest HIV VL was < 200 copies/ml or who did not return to the 
clinic within the 45 day window from HIV VL assessment to study entry, can be rescreened. 
 
Before screening a potential participant, site staff will conduct a medical record review to 
determine if a VL ≥200 copies/mL within 45 days before the enrollment visit has been or needs 
tobe performed. As previously noted (Section 5.1), study sites may perform a viral load test as 
needed once consent for study participation is obtained. Enrollment/Entry visit can only be 
started once the viral load requirement for participation is confirmed. As stated earlier in 
section 4.3, no procedures, other than preliminary verbal assessment of eligibility or medical 
chart review to assess potential eligibility, may be done before the informed consent process is 
complete. 
 
 
 
 

 
 
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7.2 
Enrollment/Entry 
Refer to Section 4.3 and 4.4 for a description of the study recruitment, screening, and 
enrollment process. The Enrollment/Entry visit should ideally be conducted on the same day as 
the Screening visit. However, if this is not possible (e.g., a pre-screening VL≥200 copies/mL 
within the previous 45 days is not available in the subject’s medical record and needs to be 
collected for study purposes), the enrollment visit must occur no more than 45 days after the 
screening visit.  
 
The enrollment visit may not be a split visit. All Enrollment Visit procedures must be performed 
on the day of enrollment; procedures that may provide information relevant to eligibility for 
the study (e.g., pregnancy test and medical history), should be performed first, prior to final 
eligibility determination. If not included as standard of care, site staff will perform a pregnancy 
test (blood or urine), once consent for study participation is obtained. 
 
Enrollment Visit Procedures (Day 0) 
Administrative 
and Regulatory 
 Complete final eligibility determination and 
confirmation 
 Enter checklist data into SES, print and file a copy 
of the confirmed enrollment file to retain as paper 
or electronic file at site  
   Generate randomization for treatment assignment 
 Generate randomization for offering participation 
in qualitative interview 
 Complete Contact form 
Clinical Data 
 Chart abstraction for VL,  CD4, and pregnancy test1 
 Medical history  
 Medication history  
Participant Surveys and Data 
 Demographics 
 ACASI survey 
 Adherence service utilization form 
EDM (AdhereTechTM Bottle) 
 EDM set up and training 
 Activation of EDM (FSTRF call line) 
 EDM device check and charging 
 Issue EDM 
 Complete EDM tracking log 
Screening Visit Procedures (up to 45 days prior to enrollment) 
Administrative 
and Regulatory 
 Preliminary evaluation of potential eligibility 
 Obtain written informed consent 
 Assign PID from list  
 Obtain screening number from SES 

 
 
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Behavioral and Counseling 
 Adherence counseling per SOC 
TERA Intervention Arm 
 Baseline TERA remote coaching session 
 
1Pregnancy test must be performed on day of enrollment visit 
 
7.3 
Week-4 Visit 
The Week-4 Visit is targeted to take place on Day 28, counted from the date of enrollment as 
Day 0, with an allowable window of ± 14 days.   
 
Visit Procedures (Day 28) 
Administrative 
and Regulatory 
 Check Contact form 
 Safety event assessment 
 Confirm and schedule participants for qualitative 
interviews for those randomized to qualitative 
interview subset 
Clinical Data 
 Chart abstraction for VL and CD4 (as available) 
 Medication history and changes 
EDM (AdhereTechTM Bottle) 
 EDM device check  and charging 
Behavioral and Counseling 
 Adherence counseling per SOC 
TERA Intervention Arm 
 TERA remote coaching session in clinic (visit 2) 
 
7.4 
Week-12 Visit  
The Week-12 Visit is targeted to take place on Day 84, counted from the date of enrollment as 
Day 0, with an allowable window of ± 14 days.   
 
Visit Procedures (Day 84) 
Administrative 
and Regulatory 
 Check Contact form 
 Safety event assessment 
Clinical Data 
 Chart abstraction for VL and CD4 
 Medical history and changes 
 Targeted Medication History 
Participant Surveys and Data 
 ACASI survey 
 Adherence service utilization form 
 Qualitative interviews (schedule at or within 14 
days of Week-12) 
EDM (AdhereTechTM Bottle) 
 EDM device check and charging 
Behavioral and Counseling 
 Adherence counseling per SOC 
TERA Intervention Arm 
 TERA remote coaching clinic session (visit 3/final 
visit) 
 
 
 

 
 
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7.5 
Week-24 Visit 
The Week-24 Visit is targeted to take place on Day 168, counted from the date of enrollment as 
Day 0, with an allowable window of ± 28 days.   
 
Visit Procedures (Day 168) 
Administrative 
and Regulatory 
 Check and/or  update Contact form 
 Safety event assessment 
Clinical Data 
 Chart abstraction for VL and CD4 
 Medical history and changes 
 Targeted Medication History 
Participant Surveys and Data 
 ACASI survey 
 Adherence service utilization form 
EDM (AdhereTechTM Bottle) 
 EDM device check and charging 
Behavioral and Counseling 
 Adherence counseling per SOC 
 
7.6 
Week-36 Visit  
The Week-36 Visit is targeted to take place on Day 252, counted from the date of enrollment as 
Day 0, with an allowable window of ± 28 days.   
 
Visit Procedures (Day 252) 
Administrative 
and Regulatory 
 Check and/or update Contact form 
 Safety event assessment 
 Confirm and schedule participants for qualitative 
interviews for those randomized to qualitative 
interview subset 
Clinical Data 
 Chart abstraction for VL and CD4 
 Medical history and changes 
 Targeted Medication History 
Participant Surveys and Data 
 ACASI survey 
 Adherence service utilization form 
EDM (AdhereTechTM Bottle) 
 EDM device check and charging 
Behavioral and Counseling 
 Adherence counseling per SOC 
 
7.7 
Week-48 Visit (Off-Study Visit) 
The Week-48 Visit is targeted to take place on Day 336, counted from the date of enrollment as 
Day 0, with an allowable window of ± 28 days. At this visit, participants will be informed of how 
to contact study staff with any post-study questions and how to learn about the results of the 
study when available. 
 
 
 

 
 
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Visit Procedures (Day 336) 
Administrative 
and Regulatory 
 Safety event assessment 
 Enter off-study form in Rave when all evaluations 
are complete 
Clinical Data 
 Chart abstraction for VL and CD4 
 Medical history and changes 
 Targeted Medication History 
Participant Surveys and Data 
 ACASI survey (final) 
 Adherence service utilization form 
 Qualitative interviews (schedule at or ±28 days of 
Week-48) 
EDM (AdhereTechTM Bottle) 
 Return EDM 
Behavioral and Counseling 
 Adherence counseling per SOC 
 
7.8 
Premature Discontinuation from the Study  
Participants who discontinue from the study after baseline but prior to their Week-48 visit, will 
have all evaluations scheduled for the Week-48 visit completed at the time of their study 
discontinuation.  
 
7.9 
Off-schedule Visits 
Sites should make every effort to engage participants within the study window. When not 
possible and a participant who has missed a visit(s) can be contact, an off-schedule visit should 
be performed. Sites should query the protocol team for specific instructions on which 
assessments should be prioritized for these off-schedule visits. 
 
 
 

 
 
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8 
DATA COLLECTION AND SITE MONITORING 
8.1 
Data Records  
Data on screening and enrollment in this study will be collected using the FSTRF Subject 
Enrollment System. Study sites must maintain adequate and accurate research records 
containing all information pertinent to the study for all screened and enrolled participants, 
including supporting source data. Electronic CRFs (eCRFs) are completed and keyed using a 
remote data entry system managed by FSTRF known as Rave. In this system, computerized 
checks are applied to the data and when required, data queries are issued for resolution by site 
staff. All data must be keyed and transferred to FSTRF within 21 days. Queries must also be 
resolved within 14 days.  
 
Participant-related study information will be identified through the Patient Identification 
Number (PID) on all participant CRFs and ACASI files. Participant names or other personally-
identifying information will not be used on study documents with the exception of (1) a linking 
sheet located at site that links PID to contact information which is stored in a secure location at 
the local siteand (2) first names or nick names and contact tree information to be used by the 
coaches kept in the TERA implementation dashboard on a secure server. Information required 
to activate the EDM device will include contact phone number and PID, as well as dose times 
for the EDM alerts and optional features. All study-related information at site will be kept in 
double-locked, limited access areas. The log that links the names of participants to their PID 
numbers are accessible only to the study staff, site monitors, and representatives from the 
NICHD. Original source documents for individual participants will be maintained at the 
respective clinic site and will be accessible only to the study staff. Data from original source 
documents will be transcribed into Rave as applicable.   
 
Individuals who do not complete the screening process are reflected in summary data the sites 
will collect and report on to the core team in the form of the recruitment log. Those who 
complete the screening process but screen fail will have anonymous information collected on 
the ATN 152 Screening Failure Form which will be entered into the study database- screening 
numbers are used in data entry, no personally identifying information is collected, there is no 
log that links the screening ID to personally identifying information, and no source 
documentation on incompletely screened or screen failed individuals will be maintained by the 
site staff.    
 
8.2 
Data Collection 
8.2.1 Case Report Forms  
Study monitoring data, including information about eligibility will be collected on eCRFs. All 
eCRFs and tools for this study will be available for download from the FSTRF portal 
(https://www.frontierscience.org/). eCRF completion guidelines will be made available to sites. 
 
8.2.2 AdhereTechTM Electronic Dose Monitor (EDM) 
An AdhereTech bottle will be provided to participants in both arms of the study. This device is a 

 
 
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pill bottle that electronically monitors whenever the bottle is opened and sends an electronic 
medication event record to a central server for real-time medication adherence monitoring. 
These medication event records are stored as data on the secured AdhereTech server and will 
be downloaded by FSTRF as .CSV files to the FSTRF study database per institutional secure 
standards. Interventionists will be provided unique user IDs and passwords to log into the 
AdhereTech server so that they can set up or modify participant specific dose monitoring times 
as well as review any text message responses that are stored when participants’ reply to the 
AdhereTech survey text if they do not take their dose during the specified study dose window.  
 
8.2.3 Audio Computer Assisted Self-Interview (ACASI) 
All ACASI data will be collected on a portable laptop computer or tablet. ACASI responses will 
remain confidential; sessional responses are identified by the participant identification number 
(PID). Data is not shared with clinical team or intervention coaches. The PID will be used in 
order to link the survey responses to the participant’s CRF data. Detailed instructions on the 
operation of the ACASI will be provided to the sites in the ATN 152 TERA MOP.  
 
Table 4. ACASI Individual Measure Schedule 
ACASI Measure 
BL 
W12 
W24 
W36 
W48 
DEMOGRAPHICS/BACKGROUND INFORMATION 
X 
 
 
 
 
MENTAL/PHYSICAL HEALTH FUNCTIONING (EQ-5D-Y) 
X 
X 
X 
 
X 
EMOTIONAL REGULATION QUESTIONNAIRE (ERQ) 
X 
X 
X 
X 
X 
SOCIAL SUPPORT SCALE (MOS) 
X 
X 
X 
X 
X 
CES-D 
X 
 
 
 
X 
HIV STIGMA MEASURE 
X 
X 
X 
X 
X 
SUBSTANCE USE (ASSIST) 
X 
X 
 
 
X 
SEX BEHAVIOR 
X 
X 
 
 
X 
HIV CASCADE MEASURE (Adapted from U24 Harmonized 
Items) 
X 
 
 
 
 
SELF-REPORTED MEDICATION ADHERENCE 
X 
X 
X 
X 
X 
ADHERENCE (IMB-AAQ) 
X 
X 
X 
X 
X 
ADHERENCE SELF EFFICACY 
X 
X 
X 
X 
X 
ADOLESCENT DECISION MAKING QUESTIONNAIRE (ADMQ) X 
X 
X 
X 
X 
LIFE EVENTS SURVEY (LES) 
X 
X 
 
 
X 
SATISFACTION WITH INTERVENTION (CSQ-8) 
 
X 
 
 
X 
ADHERENCE SUPPORT DURING PARTICIPATION 
 
x 
 
 
X 
 
8.2.3.1 ACASI Data Security 
Web-based data collection will be collected via a commercial software tool designed by DatStat, 
Inc. for online data collection instruments. The DatStat software tool (Illume) uses secure HTTPS 
connections that adhere to the Food and Drug Administration (FDA) guidelines for secure 
electronic data capture. The collected data will be stored on DatStat’s server and periodically 

 
 
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copied to the FSTRF database. Access to the database will be limited to those designated by the 
principal investigator.  
 
8.2.3.2 ACASI Data Transmission 
DatStat secure servers are registered with site certificates provided by VeriSign Internet Trust 
Services that provides for advanced encryption over the wire. As users move through the data 
entry forms, the responses are encrypted while in transit between the browser and DatStat's 
server using SSL (Secure Sockets Layer) and Public Key Encryption.  
 
8.2.3.3 Data Access 
Physical access to DatStat servers and data backup is restricted to a minimal number of IT 
professionals. Access to data stored on the server is available only to designated Illume users 
who log in with specified usernames and passwords. Users are logged out after a period of 
time. A listing of the named users with a description of their access privileges is available within 
the application. 
 
8.2.3.4 Participant Confidentiality 
To ensure an even greater level of security and confidentiality, participants/study staff are 
required to enter a Personal Identification Number (PID) to gain access to the data entry forms. 
It is ONLY the PID that is stored with the collected survey data, thus ensuring that under no 
means may the collected survey data reveal a participant’s identity. Participants will also 
complete the ACASI survey in a private clinic room further ensuring their answers remain 
confidential.  
 
8.3 
Qualitative Interviews 
Qualitative interviews will be conducted for 20 randomly selected participants in each arm 
(N=40). The interview will be scheduled by the site team and conducted via Vsee’s remote face-
to-face platform by a study team member not involved with the implementation of the trial but 
well versed in qualitative methodology. Interviews will not exceed 60-minutes and will be 
recorded on the secure audio recording program and stored on the HIPAA-compliant University 
of Michigan Box. All audio will be de-identified and transcribed verbatim by a qualified 
transcription service. Analyses (see section 11) will generate main themes and coded data. De-
identified transcripts will be shared with study team members. Original audio recordings will be 
shared only with the transcription service and will be maintained on the secure server until data 
destruction post trial. 
   
8.4 
TERA Dashboard 
Metrics collected from the TERA implementation dashboard include : 
Date, time, and/or occurrence for: 
 Ticket opening and closing—with reason for ticket opening and conditions surrounding 
closure 
 Escalation 

 
 
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 All Coach contact via SMS and all following texts 
 All Coach contact via phone 
 Use of contact tree 
 Participant requested contact 
 Coach or monitor who handled the event 
 
Tracking can then be summarized for producing summed counts of any of the listed events, 
overall and in specific time intervals, qualitative evaluation of overall themes emerging from 
outreach notes, time elapsing between events (alert, contacts, ticket closure), reasons for alters 
(tickets) and specific outcomes and reasons for closing tickets, and all texts sent and received 
for length, duration of exchange, and content. 
 
8.5 
Remote Counseling Data 
Vsee and a secure audio recording program are  used to collect all face to face remote 
counseling data. VSee and the audio recording program are both hosted on a secure server and 
are  HIPAA compliant. Per the vendor’s website https://vsee.com/telemedicine/, “VSee uses end-to-
end 256-bit AES, FIPS 140-2 certified encryption to guarantee that no servers have access to the 
decryption keys.” Documentation for HIPPA compliance can be found at vsee.com/hipaa. 
 
The interaction will be audio recorded  unless a participant specifically declines audio recording. 
Audio recording is done through Audacity which is an open source software program that 
stores directly to a secure server. The adherence coach controls start and end of recording and 
saving it to the secure server. The research team conducting the qualitative evaluation of 
coaching session content will retrieve the audio recording from the secure server for 
transcription. De-identification of the session will occur during transcription.     
8.6 
Costing Data 
To characterize costs associated with the implementation of the TERA intervention, several 
sources of information/data collection will be used. As indicated in Table 5, several data sources 
are used to generate costing data. 
 
Table 5. Costing Data Sources   
Critical Components of 
Intervention Implementation 
Method of collection 
Timing of assessment 
Electronic Dose Monitoring Device 
Cost per unit 
Study budget 
End of study 
Unit replaced over the trial (loss, 
malfunction) 
EDM tracking log 
End of study 
Time required for profile set up 
Clinic Staff Qualitative Interview 
item 2d 
 
Collected during semi-
structured interviews 
end study 
Devices identified as 
EDM tracking log (retired or 
End of study 

 
 
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Critical Components of 
Intervention Implementation 
Method of collection 
Timing of assessment 
malfunctioning 
returned devices) 
Time required to address 
Project Manager self-report 
End of study 
Device identified as out of battery 
Project manager report (study log 
non-source document) 
End of study 
Time required to address 
Project Manager self-report 
End of study 
Remote Counseling Visits 
Vsee software cost 
Study budget (weighted if needed 
by average minutes for per 
participant costs) 
End of study 
Prep for scheduled patient session 
Coach self-report: 1-week log 
 
Within 3-months of 
study start 
 
During final weeks of 
implementation of 
intervention phase 
Session length in minutes 
Extracted from audio transcription 
data 
End study 
Charting/documentation 
Coach self-report: 1 week log 
Within 3-months of 
study start 
During final weeks of 
implementation of 
intervention phase 
Alerts and follow-up 
Average minutes per monitor shift 
spend watching alerts 
Monitor self-report- 1 week log 
 
Dashboard data for number of 
events 
 
 
Within 3-months of 
study start 
 
During final weeks of 
implementation of 
intervention phase 
Coach time allocated to outreach  
Time between escalation and 
ticket close-out 
 
Coach self-report- 1 week log 
 
Dashboard data for number of 
events 
Within 3-months of 
study start 
 
During final weeks of 
implementation of 
intervention phase 
SMS fees 
Project budget 
End of study 
Staffing 

 
 
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Critical Components of 
Intervention Implementation 
Method of collection 
Timing of assessment 
Project manager FTE adjusted to 
implementation activities/Salary 
Coach FTE/Salary 
 
MI specific training 
 
MI supervision 
 
Supervisory meetings 
 
Supervisory recording reviews 
 
Self-report and study budget 
 
 
End of study 
  
8.7 
Data Submission 
All forms and data collection are electronic. There are no paper forms submitted. 
 
8.8 
Case Report Forms/Data Collection Forms  
Study sites must follow the study CRF/DCF completion and entry that are specified in ATN 152 
MOP. Once the study database is developed, the Rave screens are available for data entry, and 
protocol training has been completed, research staff at the sites will be responsible for ensuring 
that CRF data is entered into Rave within the timeframe specified on the CRF.   
 
Each clinical site is responsible for entering data into Rave. CRFs must be completed and 
entered into Rave within 21 days from the date of the study visit. CRFs must have 
corresponding source documentation on file at the clinical site to substantiate all submitted 
data.  Data edits through range checks and field inconsistencies will be built into the Rave 
system to enable real time correction of key entries and CRF completion errors. 
  
8.9 
AdhereTechTM EDM Data Transmission 
Data from the AdhereTechTM bottle will be received on a continual basis (the wireless signal 
with unique identifier and date/time stamp is activated when the container is opened) and 
stored on a secure server at AdhereTechTM Inc. The AdhereTech device is a FDA Class I 
approved medical device. The entire AdhereTech system (e.g., bottle, dashboard) is HIPAA-
compliant and all bottles are CE marked. The AdhereTech device operates on a worldwide 
cellular data network.  
 
Data captured by the AdhereTech bottle and dashboard will be downloaded to the FSTRF study 
database as CSV files. Participants names will not be included in the AdhereTech data. Instead, 
PIDs will be entered in the database.  
 

 
 
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8.10 Data Quality Assurance 
Investigators receiving federal funding must adhere to the Code of Federal Regulations (CFR) to 
protect research participants and produce reliable study information.  Sites participating in 
research sponsored by the NICHD or co-funding agencies (NIMH, NIDA, and NIMHD) need to 
have an internal quality assurance (QA) plan that will identify problems and correct errors in 
research study records.   
 
8.11 Study Site Monitoring and Record Availability 
Site monitors from the ATN coordinating center will visit participating study sites to review a 
selected portion of the individual participant records, including assent/consent forms, CRFs and 
supporting source documentation to ensure the protection of study participants, compliance 
with the protocol, and accuracy and completeness of records.  Regulatory files, as required, will 
also be inspected to ensure that regulatory requirements are being followed. 
 
The site investigator will make study documents (e.g., consent forms, case report forms) and 
pertinent hospital or clinic records readily available for inspection by the local IRB, the site 
monitors, the NICHD, the Office of Human Research Protection (OHRP), or the sponsor’s 
designee for confirmation of the study data. 
 
 
 

 
 
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9 
PARTICIPANT MANAGEMENT 
9.1 
Tracking Participants/Follow-up 
Study site staff will track participant study recruitment and retention for the intervention and 
follow-up visits. Study interventionists will also track intervention sessions completed by 
participants. 
 
9.2 
Study Visit Management  
Ideally, all study visit related evaluations should be completed on the same day. If a n individual 
is unable to complete their study visit evaluations in one day, he/she will have 7 calendar days 
to complete all evaluations, with the exception of the baseline/enrollment visit which must be 
conducted in one day (see section 7.2). If the evaluations cannot be completed within 7 days, 
the study visit evaluations should be considered missed. Study visit windows are included in the 
schedule of evaluations in Appendix I. Sites should submit a query via the ATN QNS to conduct 
study evaluations outside of the protocol window unless otherwise allowed per protocol 
documentation.  
 
9.2.1 Completing the ACASI 
Study staff should follow the following procedures at each site:    
 Participants should be reminded they may discontinue at any time with no 
penalty, and that they have the right to choose to leave any questions 
unanswered  
 Participants should be given headphones and a laptop or desktop computer in an 
accommodating, private and quiet area 
 Site staff must assist particiants with ACASI tutorials 
 If the participant requires a break, site staff must make sure the computer 
program is exited and re-entered properly so that participant confidentiality is 
maintained 
 
If the ACASI is discontinued for any reason, during the follow-up visits only, the 
participant can plan to return to finish the survey another time, up to 7 days from the 
start of the survey. 
 
9.2.2 ACASI Debriefing and Referral Procedures 
Participants will be debriefed about possible reactions to answering questions of a sensitive 
nature, such as short-term feelings of sadness or anxiety. Participants will be instructed to 
contact study personnel or to consult the list of referrals provided if feelings persist or worsen 
after several days. Referrals for mental health services will be provided to all participants if 
warranted. 
 
Study staff should follow the following debriefing procedures following each ACASI survey:    
 The site staff member facilitating the session will ask “Is there anything else about the 
interview that you would like to discuss?” If the respondent says “no,” she or he should 

 
 
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be thanked for participation. The respondent will be given contact information for 
mental health personnel available at the site and informed that she or he can also 
contact study personnel in the event that issues or concerns arise later.   
 If the response indicates the participant is in urgent need of mental health assistance, 
site staff should follow their individual site procedures for acute mental health referrals. 
Site staff should contact a supervisor immediately and stay with the study participant 
until the supervisor, mental health professional or emergency services, if needed, 
arrives.  
 All such events should be reported in the QNS as a safety event.  
 
9.3 
Participant Reimbursement  
Reimbursement will be provided for participants at each study visit. The amount of such 
reimbursement will be determined by the local study site staff and will be confirmed with the 
single IRB and will be reflected in the site-specific consent form and the recruitment flyers. 
 
9.4 
Intervening on “Social Harms"  
All sites have specific policies governing the treatment of human subjects. These policies specify 
that medical and psychological assistance will be available in the immediate environment in the 
event a participant should experience any adverse reactions resulting from study procedures.  
 
While participants will be informed that they may refuse to answer any question at any time, 
responses or reactions to certain questions may indicate distress on the part of the participants. 
If at any time during the study, a participant divulges that he or she is at risk for harm, including 
but not limited to being abused or experiencing violence, if harm is suspected or likely, or if the 
participant states he or she is suicidal/homicidal, measures will be taken to ensure his or her 
safety. Reporting will be done as appropriate to the situation and the legal statutes, including 
reporting to child protection agencies or other appropriate agencies and referrals will be 
provided to appropriate support, counseling or treatment resources. 
 
9.5 
Criteria for Premature Discontinuation 
9.5.1 Premature Discontinuation from Intervention 
If there is a concern that a participant may need to be discontinued from the study 
intervention, the site must notify the Protocol Team via the ATN Query Notification System 
(QNS). The Protocol Team will make a decision on whether the participant is discontinued from 
the study or only discontinued from the intervention. Site staff will then complete the 
Permanent Study Treatment Discontinuation eCRF.  
 
9.5.2 Premature Study Discontinuation 
Participants may request to discontinue their study participation at any time, and in so doing 
will be considered off-study. Site staff must complete the Study Discontinuation Log eCRF. 
Otherwise, participants may be discontinued prematurely from the study if any of the following 
occurs: 

 
 
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 The participant fails to comply with the study requirements that may seriously interfere 
with the validity of the study results;  
 The site investigator determines that further participation would be detrimental to the 
health or well-being of the participant; 
 The participant becomes incarcerated or detained impeding the ability to adhere to the 
study intervention and causing more than one study visit to be missed; 
 The participant withdraws consent;  
 The participant moves out of the area or is lost to follow-up; 
 The study is stopped by a government agency such as the National Institutes of Health 
or the FDA; 
 The study has to be stopped for other administrative reasons.  
 
 

 
 
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10 MONITORING SAFETY EVENTS 
ATN protocols administratively managed by the CC, such as TERA, follow the ATN Manual of 
Policies and Procedures (MOPP) for safety event reporting, including untoward events (UEs).  
All study staff should report safety events/UEs using the definitions and guidelines stated in 
Chapter 10 Safety and Adverse Event Reporting of the MOPP located on the ATN secure 
website at: https://sites.cscc.unc.edu/atn/.  
 
Events that meet the criteria for New Safety Information will be reported to the UNC sIRB by 
ATN CC Protocol Manager within the designated reporting period.  The safety criteria is found 
in the UNC Office of Human Research Ethics’s SOP 1401: Reporting New Safety Information that 
is available on the ATN secure website in the ATN Manual of Policies and Procedures, Appendix 
10-6:   https://sites.cscc.unc.edu/atn/policies-procedures-grp 
 
 
 
 

 
 
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11 STATISTICAL/ANALYTIC CONSIDERATIONS 
11.1 Study Design 
This is a Phase II, randomized, open-label study designed to assess the effectiveness of using a 
Triggered Escalating Real-time Adherence (TERA) intervention for 12 weeks, in YLWH failing 
ART.  Success of the intervention will be assessed by subsequent viral suppression and 
adherence to the ART regimen being taken at entry to this study.   
 
120 YLWH will be randomized with equal probability to the TERA intervention or continuing 
standard of care (SOC), with stratification by age (<18 years vs. ≥ 18 years).  At entry, 40 
participants (20 from each arm) will be randomly selected to engage in additional in-depth 
interviews about their experiences at weeks 12 and 48.   
 
The primary outcome of virologic suppression is assessed at Week-12. Results for the primary 
outcome are required to be entered into ClinicalTrials.gov within one year of the last 
participant reaching Week-12, which may occur before the full 48 weeks of follow-up is 
complete on all participants. Since this could compromise the integrity of the study, a request 
will be made to ClinicalTrials.gov to delay results entry until one year after the last participant 
completes their 48 week follow-up. 
 
The study will enroll a relatively small number of participants at a large number of sites with 
varying SOC. Power to detect differences may be impacted by variability in SOC across sites, 
although it will increase generalizability of the conclusions. However, even if statistically 
significant differences in virologic suppression rates are not found, the study will provide 
information on feasibility of the TERA intervention and preliminary data on its effectiveness. It 
will also provide information about adherence and its association with behavioral 
characteristics that will inform a predictive model of virologic suppression. This will contribute 
to the overarching goal of increasing numbers of YLWH with sustained virologic suppression. 
11.2 Sample Size and Power Estimates 
11.2.1 Sample Size  
The primary study outcome is percent of participants in each arm with virologic suppression at 
week-12. Prior experience drawn from YLWH initiating second-line ART with SOC adherence 
monitoring indicates that about 60% would likely achieve the primary outcome of HIV-1 RNA < 
200 copies/ml. With 120 participants (60 in each group) and a Type I error of 5%, there will be 
85% power to show a difference of 25% (an 85% success rate in the TERA arm) and 62% power 
to show a difference of 20% (an 80% success rate in the TERA arm). Table 7 shows the power to 
detect differences of 20% to 30% in outcome rates in the two arms with varying success rates in 
the SOC arm. Since participants who are lost to follow-up are inherently likely to have poor 
adherence (an example of informative missingness), calculations assume that participants with 
missing HIV-1 RNA measurements at Week-12 for any reason (lost to follow-up, missed visit, 
etc.) are classified as failures.  
 

 
 
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A key secondary outcome is sustained virologic suppression defined as HIV-1 RNA <200 
copies/ml at weeks 12, 24, 36 and 48. Prior experience indicates that approximately 38% of 
YLWH initiating second-line ART achieve and maintain controlled viral load over 48 weeks on 
SOC. Assuming a 40% success rate in the SOC arm, there will be 89% power to show a 
difference of 30%, and 75% power to show a difference of 25% in success rates between the 
two arms out to Week-48.  As for the primary outcome, these calculations assume that 
participants with missing HIV-1 RNA measurements are classified as failures.   
 
Table 7. Sample Size and Power 
Sample 
size 
% with HIV-1 RNA < 200 cp/ml at Week-
12 
Difference in outcome 
rates 
Power 
120 
60% 
85% 
25% 
85% 
 
 
80% 
20% 
62% 
 
50% 
80% 
30% 
92% 
 
 
75% 
25% 
77% 
 
 
70% 
20% 
62% 
 
40% 
70% 
30% 
89% 
 
 
65% 
25% 
75% 
 
 
60% 
20% 
61% 
 
11.2.2 Accrual 
Accrual of 120 participants is expected to require about 12 months after the first participant is 
enrolled.   
 
11.3 Randomization 
A dynamic permuted block system will be used to randomize approximately 120 participants 
equally to TERA or SOC. Randomization will be stratified by age (<18 vs. ≥ 18 years) to ensure 
balance in treatment assignments, with no enrollment limits on either age stratum.  
Institutional balancing will be used to help ensure roughly equal balance in intervention 
assignments within each site.     
 
Immediately after randomization to study arm, enrolled participations will be randomly 
selected by the FSTRF Randomization system to participate in in-depth interviews at weeks 12 
and 48, implemented until 40 participants (20 in each intervention arm) are identified. If refusal 
rates at Week-12 are higher than expected, probabilities of selection will be increased during 
accrual. Every effort to engage week-12 interview participants in the week-48 interviews will be 
made, including phone based interviewing. Strategies to add new participants to the week-48 
interviews will be considered if loss to follow-up reduces the originally selected sample size. 
 
11.4 Study Outcome Measures 
11.4.1 Primary Outcome Measures 
Primary Objective #1. To estimate and compare HIV virologic suppression rates in YLWH 12 

 
 
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weeks after initiating TERA or continuing SOC  
 
Primary Outcomes: 
 HIV-1 RNA <50 copies/ml. Participants with HIV-1 RNA ≥ 50 copies/ml or with no HIV-1 
RNA measurement within the Week-12 window (± 14 days) will be classified as failures 
 HIV-1 RNA < 200 copies/ml. Participants with HIV-1 RNA ≥ 200 copies/ml or with no HIV-
1 RNA measurement within the Week-12 window (± 14 days) will be classified as failures 
 
11.4.2 Secondary Outcome Measures 
Secondary Objective #1. To estimate and compare virologic suppression rates in YLWH 24, 36, 
and 48 weeks after initiating TERA or continuing SOC  
 
Outcomes: 
 HIV-1 RNA < 50 copies/ml. Participants with HIV-1 RNA ≥ 50 copies/ml or with no HIV-1 
RNA measurement within ± 28 days of the scheduled visit will be classified as failures 
 HIV-1 RNA < 200 copies/ml. Participants with HIV-1 RNA ≥ 200 copies/ml or with no HIV-
1 RNA measurement within ± 28 days of the scheduled visit will be classified as failures  
 
Secondary Objective #2. To estimate and compare proportions of participants initiating TERA 
or continuing SOC who achieve virologic suppression (HIV-1 RNA < 200 copies/ml) by 12 weeks 
and maintain virologic suppression through 48 weeks  
 
Outcome: 
 
 HIV-1 RNA < 200 copies/mL at weeks 12, 24, 36 and 48. Participants will be classified as 
virologic successes if both the Week-12 (± 14 days) and 48 (± 28 days) HIV-1 RNA 
measurements are < 200 copies/mL and at least one of the Week-24 (± 28 days) or 
Week-36 (± 28 days) HIV-1 RNA measurements is < 200 copies/mL.   
 
Secondary Objective #3. To summarize and compare adherence patterns in YLWH initiating 
TERA or continuing SOC during the intervention period (weeks 0-12) and the post intervention 
period (weeks 12-48). 
 
Outcomes: 
 Electronic dose monitored adherence: Percent of days with all doses taken per week.  
 Electronic dose monitored on-time adherence: Percent of days with all doses taken 
within the defined acceptable windows (±4 hours) per week. 
 Electronic dose monitored non-persistence: Number of gaps (at least 7 consecutive days 
(168 hours) between doses) in the intervals: week 0-12, 12-24, 24-36 and 36-48. 
 
11.4.3 Other Outcome Measures 
Other Objective #1. To evaluate and compare changes in survey collected social-psychological 

 
 
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factors by study arm, and establish the extent to which these changes are associated with 
adherence and viral load outcomes. 
 
Outcomes: 
 Emotional Regulation Questionnaire (ERQ) 
 Social Support Scale (MOS) 
 CES-D 
 HIV Stigma Measure 
 Self-reported Medication Adherence  
 Adherence (IMB-AAQ) 
 Adherence Self Efficacy  
 Adolescent Decision Making Questionnaire (ADMQ) 
 EDM measures listed in Secondary Objective #3 
 VL measures listed in Secondary Objective #2 
 
Other Objective #2. To identify profiles (phenotypes) of adherence based on EDM data. 
Outcome: Adherence phenotypes that highlight temporal patterns of use and overall adherence. 
 
Other Objective #3. To describe the resource requirements and costs of the TERA intervention, 
including the AdhereTechTM bottles, virtual coaching software, SMS messages, and personnel 
time and salaries. 
 
Outcomes: 
 Adherence counsellor staff time associated with the intervention through activity logs 
translated into dollar terms using loaded salary data of the personnel involved and 
transformed into a per participant fixed and variable cost estimates 
 Cost of the AdhereTechTM bottle and replacements. 
 Staff time required to maintain the process flow of the TERA intervention translated into 
dollar terms using loaded salary data of the personnel involved and transformed into a 
per participant fixed and variable cost estimates 
 
Other Objective #4: To characterize through qualitative interviews, the main themes youth 
report for adherence support needed, received, and valued at 12 and 48 weeks. 
 
Outcomes: Thematic content of interview inquiries about 
 Facilitators and barriers to adherence 
 Perceptions of received (types of support and value) support for adherence 
 Unaddressed adherence related needs 
 
Other Objective #5: To evaluate acceptability and feasibility of participation in the intervention 
with mixed methods (interviews and ACASI survey).  
 

 
 
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Outcomes: Acceptability 
 Satisfaction Survey at week-12 ACASI (all TERA arm participants) 
 Semi-structured interview with a subset of participants in TERA. 
 Thematic content of interview inquiries about  
 Satisfaction with TERA intervention 
 Experiences with specific components of the intervention 
 Recommendation of intervention to others 
 Perceptions of needs met, unmet needs, and impact 
 Recommendations for changes 
 
Outcomes: Feasibility 
 Ability to enroll: number of youth enrolling in study compared to total number 
approached for enrollment 
 Drop-out rate: number of participants lost to follow-up prior to Week-12 clinic visit 
compared to total enrolled  
 Adherence coach contact failure rate: number of failed attempts to contact participants 
compared to total number of contact attempts made [TERA study arm only] 
 Adherence coach ratings on quality of interactions and contacts [TERA study arm only] 
 AdhereTechTM bottle replacement rate: number of AdhereTechTM bottles requiring 
replacement due to loss, theft, or breakage  
 Participant reported problems with the AdhereTechTM device or any aspects of TERA 
intervention [TERA study arm only] 
 
Other Objective #6. To gather feedback from intervention coaches and clinic staff on 
experiences implementing the intervention with YLWH.  
 
Outcomes: Semi-structured interview with TERA coaches and discussions with site staff after 
completion of intervention phase of research generating thematic content for: 
 
Coaches/Monitors 
 Advantages of TERA 
 Challenges with TERA 
 Skills required from coaches 
 Experiences with monitoring tickets and assigning escalations 
 Experiences with youth in sessions and in outreach  
 Reactions to use of Smart-Bottle 
 Case examples (best and worst) 
 Recommendations for changes 
 Estimation of hours/time allocations for specific activities 
 
Site Staff/team members 
 Advantages of TERA 

 
 
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 Challenges with TERA 
 Skills required for site-level procedures 
 Perceived impacts, facilitators and barriers to youth adherence 
 Perceived impacts, facilitators and barriers to TERA implementation 
 Estimation of hours/time allocations for specific site-level study-related activities 
 Reactions to use of Smart-Bottle 
 Recommendations for changes 
 
11.5 Study Monitoring 
Implementation of the study will be monitored by the Protocol Team and by an independent 
Study Monitoring Committee (SMC) that provides this oversight for other on-going ATN 
protocols.   
 
11.5.1 Monitoring by Study Team 
Full details of the proposed monitoring reports will be described in a separate Study Progress 
Data and Safety Monitoring Plan (SPDSMP).  Accrual and retention based on reports generated 
by FSTRF in collaboration with the Statistical and Data Analysis Center (SDAC) will be presented 
monthly.  If there are any problems with accrual or retention rates at specific sites, the Protocol 
Team will work with the sites to identify operational issues or problems and take appropriate 
action.   
 
The Protocol Team will review other key indicators of study quality monthly, based on reports 
generated by SDAC.  These reports will include information on baseline characteristics as well 
as data completeness.  All reports for the Protocol Teams will present data combined across the 
TERA and SOC arms.  The Protocol Team will also be responsible for reviewing any safety 
events, including untoward events, as they are reported from the ATN QNS. 
 
Protocol deviations will be reported in the Rave data management system and reviewed by the 
Protocol Team on a regular basis.  Protocol related tests, procedures or labs not performed as 
scheduled due to malfunctioning equipment, patient non-compliance, patient need or 
preference (i.e. vacation), patient condition or due to falling on a weekend or holiday will be 
noted in the patient study record but will not be reported as deviations. 
 
Protocol deviations that are required to be reported to the sIRB within 7 days, such as ones that 
harm a participant or others, must also be reported in the ATN QNS for immediate review. The 
list of these deviations is included in the Manual of Procedures (MOP).  
 
11.5.2 Study Monitoring Committee 
An independent SMC will review this study at scheduled, planned points, or as otherwise 
determined by the SMC. Reports for the SMC will include accrual, baseline characteristics, data 
quality and completeness, participant retention, study implementation issues, safety events, 
and summaries of the primary outcome by masked intervention arm.   

 
 
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The primary consideration at any interim review is avoidance of harm to participants. At any 
point, should the SMC or Protocol Team become aware of major unexpected findings that 
impact participant safety or study research integrity, then it may be necessary for the SMC to 
consider recommending prematurely stopping enrollment and/or participant follow-up. 
As this is a Phase II study, there are no a-priori statistical stopping guidelines.  At every interim 
review the SMC should consider the totality of evidence including feasibility assessed by rates 
of enrollment, losses-to-follow-up, and implementation issues using the AdhereTechTM device.  
Efficacy analyses will take place at each interim review after at least 60 participants have Week-
12 HIV-1 RNA results available.  Efficacy analyses will focus on the proportions of participants 
with HIV-1 RNA < 200 copies/mL at Week-12 in the TERA and SOC arms and whether the 95% 
confidence intervals for the two proportions overlap. Non-overlapping confidence intervals 
would indicate large efficacy differences between the two arms.  For example, if one third of 
participants had reached Week-12 (20 in each arm), the difference in proportions between the 
two arms (depending on outcome rates) might need to be as large as 0.5 for the 95% 
confidence intervals to be non-overlapping.  With half the participants reaching Week-12 (30 in 
each arm), the difference could be as large as 0.4.  If the SOC arm is superior to the TERA arm 
based on Week-12 data, the SMC might consider recommending termination of the study.  
However, even if the TERA arm is superior to the SOC arm at Week-12, it is possible the benefit 
of the TERA intervention would not be sustained in the post-intervention phase, so the SMC’s 
discussion should include consideration of recommending continuing enrollment and 
participant follow-up until evidence of the durability of the intervention effect is available.  An 
additional consideration will be outcome rates in the SOC arm, upon which sample size 
calculations are based.  If outcome rates are very different from anticipated, the sample size of 
the study may need to be reassessed.   
 
At each review the SMC may recommend that the study proceed as currently designed, 
proceed with design modifications, or be discontinued.  The SMC may also provide specific 
operational recommendations to help address any study implementation challenges identified 
during their reviews. 
 
11.6 Statistical Analysis Plan 
The primary and secondary goals of this study are to estimate and compare virologic 
suppression rates and adherence over 48 weeks between the TERA and SOC arms. Analyses will 
be intent-to-treat (ITT) using all participants as randomized. Categorical outcomes will be 
summarized using proportions (95% confidence intervals) and continuous outcomes will be 
summarized using means/medians as appropriate. In adjusted analyses, the number of 
covariates used in the models will be limited because of the relatively small sample size. A 
significance level of p < 0.05 will be used with no adjustments for multiple comparisons or 
interim analyses.   
 
Full details of the proposed analyses will be described in separate statistical analysis plans 
(SAPs). The primary SAP will include primary and secondary objectives and outcomes. This will 

 
 
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form the basis of the primary manuscript. Analyses of the other objectives and outcomes will 
be summarized in separate SAPs, grouped together to form separate manuscripts. These 
secondary SAPs will be finalized once the primary analysis is complete as the primary findings 
will inform priorities for the additional analyses.   
 
11.6.1 Primary Outcome  
The primary unadjusted analysis will estimate and compare proportions of participants with 
virologic suppression (HIV-1 RNA < 50 copies/ml and < 200 copies/ml) at Week-12 in the TERA 
and SOC arms. Participants lost-to-follow-up before 12 weeks or with no HIV-1 RNA 
measurement within ±14 days of the Week-12 visit will be classified as failures. Adjusted 
analyses will use logistic regression models adjusted for study arm and may use other 
covariates measured at study entry that differ between arms and associate with outcome (such 
as route of HIV infection, years living with HIV, age, motivation and behavioral skills, mental 
health, substance use, ARV regimen, and others). Adjusted analyses will explore the resilience 
of the intervention effect after adjustment for other covariates, as well as identifying other 
factors associated with the primary outcome. 
 
11.6.2 Secondary Outcomes 
11.6.2.1 To estimate and compare virologic suppression rates (<50 and <200 copies/ml) in 
YLWH 24, 36, and 48 weeks after initiating TERA or continuing SOC.  
 
The analytic approach for this secondary outcome will be similar to that used for the primary 
outcome, with unadjusted comparisons at each time point and using logistic regression for 
adjusted analyses.   
 
11.6.2.2 To estimate and compare proportions of participants initiating TERA or continuing SOC 
who achieve virologic suppression (HIV-1 RNA < 200 copies/ml) by 12 weeks and maintain 
virologic suppression through 48 weeks.   
 
The analytic approach for this secondary outcome will be similar to that used for the primary 
outcome, with unadjusted comparisons of the proportions of participants achieving and 
maintaining documented viral suppression through 48 weeks, and using logistic regression for 
adjusted analyses.   
 
11.6.2.3 To summarize and compare adherence patterns in YLWH initiating TERA or continuing 
SOC during the intervention period (weeks 0-12) and the post intervention period (weeks 12-
48). 
 
The EDM will provide daily information on adherence in each participant. Two outcomes 
(percent of days correctly dosed per week and percent of days dosed within the targeted time 
frame per week) will be summarized by arm by week, in 12-week intervals, and during and 
post-intervention. Differences may be largest during the initial 12 weeks, since that is when the 

 
 
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intervention is administered, with differences waning over time. To address the issue of 
informative censoring induced by losses-to-follow-up, analyses will include (i) available data 
and (ii) imputing weekly adherence of 0% after a participant has been lost-to-follow-up.  
Interventions will be compared using repeated measures rank sum tests.   
 
Alternative outcome definitions may need to be used if there is insufficient variation in percent 
adherence. For example, it might be necessary to define a binary outcome (adherent, not-
adherent) if the majority of percent adherence measures are >95%, in which case analyses 
would be based on comparisons of proportions and logistic regression.   
 
An incidence rate (95% confidence interval) of the number of gaps between dosing of > 7 days 
in each 12-week interval will be calculated and compared between intervention arms.   
 
11.6.3 Other Outcomes 
Analyses of other outcomes will be initiated after results of the primary and secondary 
objectives are known, so the analyses listed below are subject to change. 
 
11.6.3.1  To evaluate and compare changes in survey collected social-psychological factors by 
study arm, and establish the extent to which these changes are associated with adherence and 
viral load outcomes. 
 
Each social-psychological outcome of interest and changes from baseline will be summarized at 
each measured time point by arm.  Correlations among survey measures will be summarized.  
Depending on observed patterns, survey measures may be grouped or combined and used in 
regression models to determine their association with the VL and EDM adherence outcomes. 
 
 
11.6.3.2 To identify profiles (phenotypes) of adherence based on EDM data 
This will be an exploratory analysis based on doses taken per day.  Daily and weekly summaries 
of the data will be explored to see if there are distinct patterns of adherence, such as weekend 
holidays, regular periods of good and poor adherence, extended periods with no doses etc.   
 
11.6.3.3 To describe the resource requirements and costs of the TERA intervention, including 
the AdhereTechTM bottles, virtual coaching software, SMS messages, and personnel time and 
salaries.  
 
Cost and resource use as well as efficacy data from Secondary Objective 1 will serve as inputs 
for model-based analyses to project the longer-term clinical outcomes, costs, and cost-
effectiveness of the TERA intervention. Each resource will be multiplied by its unit cost (e.g., 
coach minutes spent as a proportion of FTE * coach salary; number of SMS messages * per-
message cost) to calculate total costs for the intervention. As data permit, costs will be 
stratified by key participant characteristics, such as demographics and adherence level. 

 
 
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Outcomes will be examined not only for the intervention as implemented in the trial, but also 
under a range of relevant scenarios, including use of alternative virtual coaching and adherence 
monitoring software, as well as if implemented in different populations with different duration 
and magnitude of effectiveness. If resources are available, model-based analyses will be 
conducted in collaboration with the Cost-effectiveness of Preventing AIDS Complications 
(CEPAC) research team, at Massachusetts General Hospital, Boston, MA. 
 
11.6.3.4: To characterize through qualitative interviews, the main themes youth report for 
adherence support needed, received, and valued at 12 and 48 weeks. 
 
Transcripts from qualitative interviews using semi-structured interview guides will be reviewed 
by a qualitative coding team iteratively to identify main themes emerging within specific areas. 
A hybrid approach using framework analysis methodology to sort discourse text into content 
captured in response to specific question areas (eg., questions asking about facilitators of 
adherence, barriers to adherence, perceptions of support received, adherence related needs) 
and thematic content analysis to identify main themes emerging from their areas of inquiries 
will generate the basic coding structure. This also allows for examination of specific content 
codes across the frames, Dedoose (an online coding software program) will be used to import 
the transcript documents and creating coding structures- first with the frames and then 
thematic content. Inter-coding reliability for application of frame themes will be established 
through the testing/training function of Dedoose. Coders will continue training until perfect 
agreement is obtained on initial transcripts. Frames will be iteratively reviewed to identify the 
main themes which will be summarized with sample quotes. Potential differences in themes 
from specific groups of participants (eg., age group, route of HIV infection, gender) and over 
time (12 versus 48-week interviews) will be considered. Quantitizing will be considered, 
although the main focus of these analyses will be on detailing nuanced experiences.  
 
11.6.3.5  To evaluate acceptability and feasibility of participation in the intervention with mixed 
methods (interviews and ACASI survey).  
 
All aspects of TERA implementation will be summarized including: ability to enroll to the study 
(both study arms), drop-out rates by Week-12 and throughout the study (both study arms), 
numbers of participants escalating to different alerts and outreach at least once and numbers 
of alerts per participant (TERA arm only). 
 
Feasibility of using the AdhereTechTM device will assessed by summarizing bottle replacement 
rates (with reasons) and participant-reported problems.    
 
The qualitative data contributing to participant perspectives of the acceptability and feasibility 
of the TERA intervention will come from the interviews specifically with individuals in the TERA 
intervention condition at weeks 12 and 48. The same procedures noted above (11.6.3.4) are 
used for these analyses.  
 

 
 
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11.6.3.6  To gather feedback from intervention coaches and clinic staff on experiences 
implementing the intervention with YLWH.  
 
The same procedure for identification of themes emerging from specific interview guide 
questions and narratives that cut across frames will be used with the interviews of coaches and 
clinic staff. Coaches and clinic staff are free to decline participation. Interviews will take place at 
the end of the intervention phase for coaches and site staff. Interviews are conducted by an 
interviewer trained in qualitative interviewing and will be audio recorded for transcription. 
Transcription will de-identify the data and the qualitative team will code the transcripts 
according to the previously detailed procedures.  
 
 
 

 
 
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12 HUMAN SUBJECTS 
This study will be conducted in compliance with the protocol, ICH Good Clinical Practice 
guidelines, and 45 CFR Part 46. 
 
12.1 Participants’ Confidentiality 
All adherence records, questionnaires, including the ACASI, evaluation forms, reports, and 
other research-related records will be identified by a coded number only, to maintain 
participant confidentiality. All records with personally-identifying information will be kept in a 
locked, limited access area (such as a locked file cabinet or secured electronic folder). All 
computer entry and networking programs will be done with coded numbers only. Clinical 
information will not be released without written permission of the participant (and parent or 
legal guardian, when applicable), except as necessary for monitoring by the ATN CC or NICHD. 
 
12.2 Certificate of Confidentiality 
To further protect the privacy of the study participants, the ATN has obtained a Certificate of 
Confidentiality from the U.S. Department of Health and Human Services (DHHS). With this 
Certificate in place, the ATN researchers cannot be forced to turn over identifying information 
about a study participant in any Federal, State, or local criminal, administrative, legislative, or 
other proceedings. This Certificate does not prevent a study participant from volunteering to 
turn over their research information nor does it prevent researchers from providing research-
related information to others when requested by the study participant. 
 
12.3 Risks and Benefits 
12.3.1 Risks 
Participation in this study poses no more harms or discomforts to research participants than 
they may experience in normal daily life, standard clinical practice, during routine physical or 
psychological examinations or tests.  
 
However, there are some risks of emotional discomfort or distress due to the personal nature 
of some questions asked in the behavioral assessments as well as by the Adherence Coach 
during intervention phone calls and risk of breaching confidentiality during the calls and/or the 
text reminders that the participant receives. Participants will be informed they are free to 
decline to answer any questions, or withdraw from participation at any time without penalty. 
Participants will be instructed to contact study personnel or to consult the list of referrals 
provided if feelings persist or worsen after several days. If the response indicates the 
participant is in urgent need of mental health assistance, site staff should follow their individual 
site procedures for acute mental health referrals. Site staff should contact a supervisor 
immediately and stay with the study participant until the supervisor, mental health professional 
or emergency services, if needed, arrives. 
 
Participants will undergo a debriefing interview after completing the behavioral assessments 

 
 
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and will be offered referrals to speak with mental health professional staff that is available at 
the study site if needed.  
 
The biomarker measurements that are involved in this study requiring a venipuncture to collect 
blood samples are all considered part of SOC and not an additional study specific requirement. 
This procedure may cause local discomfort, bleeding, or bruising; rarely small clot or infection 
can occur at the blood draw site. This measurement should not be considered greater than 
minimal risk in and of itself given its routine use in general health care delivery.  
   
Finally there is a risk of breach of confidentiality related to disclosure of participant information 
as part of the communications (text message, phone call, email) with the participant or 
attempts to reach them through the contacts they provided on the TERA Contact  Form. Every 
effort to avoid an inadvertent breach of confidentiality will be taken. Participants will be asked 
if messages can be left at the contact numbers they provided. Study staff will not leave 
messages unless expressly permitted to do so by the participant. If permission is given to leave 
messages, site staff will assure participants that messages left with a family member or friend 
will only ask the participant to contact study staff and will not include any protected health 
information or information related to study participation. 
 
12.3.2 Benefits   
Information from this study may benefit other youth, now or in the future, by understanding 
methods to motivate HIV-positive young people to start and adhere to their prescribed HIV 
treatments. Possible participant benefits may include: (1) improvements in HIV medication 
adherence and thus, health status, and (2) assisting in identifying a potential intervention to 
improve HIV medication adherence and health outcomes for YLWH.  
 
12.4 Institutional Review Board (IRB) Review and Informed Consent 
This protocol, the informed consent documents and any subsequent modifications will be 
reviewed and approved by the IRB or ethics committee responsible for the oversight of the 
study. The informed consent will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation.   
 
Signed informed consent (or assent as applicable) will be obtained from the participant (or 
parent, legal guardian, or person with power of attorney for participants who cannot consent 
for themselves). The study team is requesting the waiver of parental permission for minor 
participation based on 45 CFR 46.408. If waiver of parent consent is not granted, then a signed 
informed consent from the parent and the minor’s assent will be required. The signed original 
consent/assent form will be kept on file at the site and a copy of the consent/assent form will 
be given to the participant and to the parent or legal guardian, if applicable.  Sample informed 
consent/assent forms are included in Appendix 2.  
 
The study team is also requesting waiver of written consent for the interviews with coaches and 

 
 
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clinic staff. Verbal consent will be requested from all staff participants; therefore, no 
documentation of participation will be recorded, which will enhance participant confidentiality.  
The qualitative interviews will take place at the end of the intervention phase for coaches and 
at the end of the study for clinic staff. They will be asked for feedback regarding their 
experiences implementing the study intervention. The interviews will not contain questions 
regarding sensitive data or protected health information. Their answers will be kept 
confidential and de-identified by the transcription service as previously described.  Coaches and 
clinic staff are free to decline participation.   
 
12.5 Risk Category: Minimal Risk  
Permission will be sought from at least one parent or guardian in accordance with IRB approved 
procedures unless the IRB/EC has waived the requirements for obtaining parental or guardian 
permission in accordance with 45 CFR §46.408 (c).  
 
The study team is requesting the waiver of parental permission for minor participation based 
on 45 CFR 46.408, which provides that the single  IRB may waive parental permission under the 
same circumstances that it may waive individual consent, as described in 45 CFR 46.116 (d):  (1) 
the research involves no more than minimal risk to participants; (2) the waiver or alteration will 
not adversely affect the rights and welfare of the participants; (3) the research could not 
practicably be carried out without the waiver or alteration; and (4) whenever appropriate, the 
participants will be provided with additional pertinent information after participation.  This 
research clearly meets requirements 1 & 2.  Since many YLWH access medical care services 
independently of parental involvement, the requirement to involve parents may adversely 
affect the minor’s decision to participate and thereby potentially bias the sample. 
 
Assent of the children involved in this study will be sought in accordance with the regulations at 
45 CFR §46.408(a) or 21 CFR §50.55 and IRB-approved policies and procedures. 
12.6 Waiver of Requirement for Parental Consent for Special Circumstances 
The single IRB will be requested to grant a waiver of parental/legal guardian consent to 
participate in this research study under the age of legal majority based on state or local laws.  
 
Under 45 CFR Part 46.4116 (c), an IRB has the authority to waive parental permission if it 
determines that “a research protocol is designed for conditions or a subject population for 
which parental or guardian permission is not a reasonable requirement to protect the subjects” 
and “an appropriate mechanism for protecting the children who will participate as research 
subjects is substituted” and “that the waiver is not inconsistent with Federal, state, or local 
law.” 
 
The Protocol Team would submit that:  
 This study is not considered greater than minimal risk. Participants will complete 
surveys, use an electronic pill bottle, and undergo routine HIV viral load monitoring. 
None of the content of this study is beyond what would be covered during routine 

 
 
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medical or psychological visits or procedures related to improving medication 
adherence. The probability of harm from participating in this study is no greater than 
that occurring in routine care.  
 Participating clinic sites and most other community agencies offering HIV-related 
services are confidential and do not require parental/legal guardian notification or 
permission to treat under most state regulations.  
 
 Contacting the parent/legal guardian could constitute a breach of confidentiality for 
these HIV-positive participants at risk for abuse or ousting from the home if 
parents/legal guardians are not aware of their HIV status.  
 It is expected that there will be subjects who have not disclosed their HIV status to 
parents/legal guardians, and the parents/legal guardians will not be aware of the 
subject’s gender identity or risk behaviors. A requirement for parental permission in this 
type of study could not only affect a person’s willingness to participate, but could also 
potentially impact the ability of researchers to engage in this type of HIV-related 
research with youth.  
 Adequate protection has been substituted by the mechanisms in place to protect the 
privacy and confidentiality of subjects and by the treatment referrals offered if needed.  
 
12.7 Prisoner Participation 
The ATN and NICHD have concluded that this protocol does NOT meet Federal requirements 
governing prisoner participation in human subject research and should NOT be considered for 
the recruitment of prisoners. Participants enrolled who subsequently become incarcerated or 
are placed in detention may not continue study participation during incarceration. Study visits 
cannot be conducted during the period of incarceration or detention.  
 
12.8 45 CFR Parts 160 and 164 Standards for Privacy of Individually Identifiable Health 
Information ("Privacy Rule" Pursuant to the Health Insurance Portability and 
Accountability Act - HIPAA) 
Each site is responsible for adherence to their individual institution’s HIPAA policies and 
procedures. 
 
12.9 Study Discontinuation 
This study may be discontinued at any time by the NICHD. 
 
 
 

 
 
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13 ADMINISTRATIVE PROCEDURES 
13.1 Regulatory Oversight 
This study is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD), the National Institute of Mental Health (NIMH), the National 
Institute on Drug Abuse (NIDA) and the National Institute on Minority Health and Health 
Disparities (NIMHD), which are parts of the United States National Institutes of Health (NIH).  
 
The ATN CC is responsible for the oversight of this study and for providing funding support to 
the clinical research sites at which this study will be conducted. ATN clinical site monitors will 
perform on-site monitoring for visits as described in section 8.11. As part of these visits, 
monitors will inspect site files to ensure compliance with both U.S. and local regulatory 
requirements.  
 
13.2 Protocol Registration 
Before the recruitment and enrollment of subjects, sites must have their local IRBs cede to the 
UNC single IRB, which will review the protocol and any subsequent full version amendments, 
and the protocol informed consent form(s). Sites are required to work closely with their IRBs to 
coordinate approval of UNC as the single IRB and submit any material (i.e., approved informed 
consent forms, protocol registration documents) to their IRBs as needed/as requested by their 
local IRB. Staff at the CC will review the submitted protocol registration documents to ensure 
that all of the required materials have been received. Original documents must be maintained 
at the study sites.  
 
For additional information about the initial protocol registration and subsequent protocol 
registration process, please refer to the current version of the study MOP. 
13.3 Study Implementation 
This study will be conducted in accordance with the protocol, international good clinical 
practice guidelines (ICH E6), and all applicable U.S. and local regulations. Study implementation 
at all sites will also be guided by the study-specific procedures and other implementation 
material, which will be available on the ATN website: https://sites.cscc.unc.edu/atn/  
 
Study implementation at each site is based on the study MOP and is articulated by each site in a 
Protocol Implementation Plan and Delegation of Authority and Master Signature Log which will 
describe roles, responsibilities, and procedures for this study.  
13.4 ClinicalTrials.gov 
The trial is registered with ClinicalTrials.gov under Identifier Number: NCT03292432. 
 
13.5 Publications 
NICHD and ATN policies will govern publication of the results of this study. Publication of the 
results of this trial will be governed by the ATN Publications Policy, from the ATN Manual of 

 
 
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Policies and Procedures. Any presentation, abstract or manuscript will be made available for 
review by the core protocol team prior to submission. Scientific publications or presentations 
that result from the study will not mention participants by name or reveal any personal 
information that could potentially compromise participant confidentiality. All publications and 
presentations must clearly report funding source, ATN protocol number, and supporting 
agencies. 
 

 
 
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APPENDIX I:  SCHEDULE OF EVALUATIONS 
1 Entry/Enrollment visit should be within 45 days of screening; 2 Contact information is a site tool and is not collected in Rave;  3 Baseline medical history covers previous 30 days;  4Documented laboratory results 
may be used if available within 45 days of study enrollment visit. This is part of study eligibility criteria;  5Abstract from medical record if done for standard of care; not required to be done for research study 
purpose only;  6Collect for research study purpose if not already planned/available for standard of care;   7 At baseline record most recent CD4 value;  8 Pregnancy test (urine or blood; research test if not also 
planned for standard of care) result required for study entry, pregnancy tests at study visits other than study entry based on site’s standard of care.
Event 
 
Screening1 
Entry/ 
Baseline 
Week-4 
Week-12 
Week-24 
Week-36 
Week-48 
(Off Study) 
Window 
 
 
+/- 14 days +/- 14 days 
+/- 28 days 
+/- 28 days 
+/- 28 days 
Eligibility checklist 
X 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Confirm eligibility 
 
X 
 
 
 
 
 
Contact  Form2 
X 
X 
X 
X 
X 
X 
 
Enrollment and Randomization 
 
X 
 
 
 
 
 
Demographics/Medical History3 
 
X 
 
 
 
 
 
ACASI Surveys 
 
X 
 
X 
X 
X 
X 
Safety Events 
 
 
X 
X 
X 
X 
X 
Viral Load 
X4 
 
X5 (as available) 
X6 
X6 
X6 
X6 
CD4 if available 
X 
X7 
X 
X 
X 
X 
X 
Pregnancy Test8  
 
X8 
 
 
 
 
 
Medication History & Changes Log 
 
X 
X 
X 
X 
X 
X 
Adherence Support Service Utilization Check list 
(past 30 days at baseline; since last visit at follow-up) 
 
X 
 
X 
X 
X 
X 
EDM Device Issue, Follow-up, or return 
 
X 
X 
X 
X 
X 
X 
Remote Coaching In Clinic Session Visit (intervention 
arm) 
 
X 
X 
X 
 
 
 
Qualitative Interviews [subset] 
 
 
 
X 
 
 
X 

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