Preventing Injection Initiation: The Change the Cycle Randomized Controlled Trial.
Phase: NA
Conditions: Substance Abuse, Intravenous, HIV, Heroin Dependence, Opioid Dependence, Cocaine Dependence, Amphetamine Dependence
Sponsor: University of Southern California

Version date: 02/22/201806/9/2016 
 
1
 
 
 
PROTOCOL NUMBER: 
NCT02774954 
 
 
TITLE: 
Training and adaptation of the Change the Cycle 
intervention - Phase 1 and phase 2 
 
 
STUDY PHASE: 
Intervention training and RCT implementation 
 
 
STUDY ARMS: 
2 
 
 
IND OR IDE #: 
Not applicable 
 
 
PRINCIPAL INVESTIGATOR(S): 
Ricky N. Bluthenthal, Ph.D. 
 
SOTO STREET BUILDING, RM 302R 
 
323-442-8236 
 
FAX – 323-442-8201 
 
 
 
CO-INVESTIGATOR(S): 
Alex H. Kral, Ph.D. RTI International  
 
 
SPONSOR: 
National Institute on Drug Abuse (grant#RO1DA038965) 
 
 
PARTICIPANTS/LOCATONS: 
Health Science Campus and community settings 
 
 
AMENDMENTS/REVISIONS: 
Amendment 1 
 
Elucidation substudy 
 
 
 
 
 
 

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2
TABLE OF CONTENTS 
 
SCHEMA, SYNOPSIS, OR STUDY SUMMARY 
 
 
 
 
 
PAGE 
 
1.0 
BACKGROUND AND HYPOTHESES  
__3___ 
 
2.0 
OBJECTIVES AND PURPOSE 
__4___ 
 
3.0 
STUDY DESIGN  
_5-8  _ 
 
4.0 
DRUG/DEVICE INFORMATION 
__8__ 
 
5.0  
SELECTION AND WITHDRAWAL OF SUBJECTS 
__8__ 
 
6.0 
DESCRIPTIVE FACTORS/STRATIFICATION/RANDOMIZATION SCHEME 
__8-9_ 
 
7.0  
STUDY AGENT ADMINISTRATION OR INTERVENTION AND TOXICITY     MANAGEMENT PLAN 
 
 
 
_9-10_  
 
 
 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY 
__10-12_ 
 
 
 
9.0 
CLINICAL AND LABORATORY EVALUATIONS 
__12_ 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS  
 
__12_  
 
11.0 
SPECIAL INSTRUCTIONS  
 
 
 
 
 
 
__12_ 
 
12.0 
DATA COLLECTION AND MONITORING 
_12-13  
 
13.0 
STATISTICAL CONSIDERATIONS  
_13-16_ 
 
14.0 
REGISTRATION GUIDELINES  
_16___ 
 
15.0 
BIOHAZARD CONTAINMENT 
__16_ 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
__16_ 
 
17.0 
REFERENCES 
 
 
 
 
 
 
 
 
_17-23_ 
 
APPENDICES 
 
 

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3
1.0 
BACKGROUND AND HYPOTHESES 
 
 
There are an estimated 1.2 million people who inject drugs (PWID) in the US.29,30 Injection drug use 
dramatically increases risk for blood borne infectious diseases, endocarditis, soft tissue infections, drug 
overdose, psychiatric disorders, and mortality.31-38 Despite this, there are few interventions to prevent drug 
injection initiation, and we are not aware of any that have been proven to be efficacious in a rigorous, large 
randomized controlled trial (RCT).39-43 
To address this critical public health need, we propose to conduct a large-scale RCT of “Change the Cycle” 
(CTC),7,44 an hour long, single-session, one-on-one intervention that aims to reduce injection initiation by 
encouraging active PWID to not promote drug injection, model injection behavior, describe how to inject, or 
assist in injection initiations of non-injectors. This approach is informed by social learning theory, which 
postulates that people learn behaviors through interaction, observation, behavioral experimentation, and 
reinforcement.1,2 These constructs are all highly relevant to the prevention of injection initiation; existing 
research convincingly demonstrates that interactions with active PWID who describe injection, observations of 
injection drug use, and reinforcing conversations that promote the advantages of drug injection (e.g., the better 
“high” to be gained from injecting) contribute to injection initiation.45-56 Further, retrospective accounts of 
injection initiation episodes have found that between 68% and 88% of non-injectors were assisted in their first 
injection by an active PWID.48,57 Therefore, intervening on active PWID to reduce describing how to inject to 
non-injectors (interaction), injecting in front of non-injectors (observation), speaking positively about injection 
drug use (reinforcement), and assisting in first injection (experimentation) could be a promising approach for 
reducing uptake of injection drug use.   
CTC uses the Information-Motivation-Behavioral skills (IMB) model3,4 to achieve changes among active 
PWID through seven short modules. Information and motivational domains are addressed in guided 
conversations about (1) their own first injection episode and consequences, (2) past experiences initiating 
injection-naive people and consequences, (3) health, legal, and social risks related to injection drugs, (4) 
health, legal, social risks of initiating people, and (5) identifying their own behaviors that might promote 
injection among others. The behavioral skills domain is addressed through a (6) skill-building discussion and 
rehearsal of responses to possible initiation scenarios, and (7) safer injection education. CTC pilot study 
results found significant reductions in injection initiation episodes; however, the study did not have a control 
group.7 Our specific aims are: 
Aim 1: To test the efficacy of CTC on reducing the number of non-injectors initiated into injection (counts) 
by PWID. Hypothesis 1: PWID who receive CTC will report initiating fewer non-injectors into drug injection 
at 6 and 12 months as compared with PWID in the equal attention control condition. 
Aim 2: To test the efficacy of CTC on reducing the number of times PWID are asked to initiate (counts) 
someone into injection. Hypothesis 2: PWID who receive CTC will report having been asked fewer times to 
initiate someone into drug injection at 6 and 12 months as compared with PWID in the equal attention 
control condition. 
Aim 3: To test whether injection initiation social learning risks (injecting in front of, describing injection to, 
and speaking positively about injection to non-injectors) act as mediational mechanisms for the efficacy of 
the CTC intervention on initiation and request-to-initiate outcomes. Hypothesis 3: Social learning variables 
will significantly mediate the association between the CTC intervention and episodes of initiating and being 
requested to initiate someone into drug injection at 6 and 12 months. 
 
Following completion of 12-month follow-up interviews, we will collect elucidation interviews with up to 100 
PWID for purposes of providing preliminary data on key issues related to 1) Hepatitis A and C risk, needs, and 
services collected through a quantitative survey, and 2) experiences with drug effects and withdrawal and 
symptoms management in a qualitative audio-recorded interview. 
 
The elucidation interview topics were selected to investigate key issues related to health promotion 
among PWID.  A brief justification for each topic is provided below.  1) HCV/HAV module: A recent outbreak of 
HAV in Los Angeles highlighted the inadequacy of both sanitation services (toilets and showers) for homeless 
populations in Los Angeles and HAV vaccination interventions 
(http://publichealth.lacounty.gov/eprp/Health%20Alerts/DPH%20HAN%20Hep%20A%20Outbreak%20091917.
pdf).  Items related to the HAV will include access to toilets and showers, HAV vaccination, and preferences for 
sanitation services for homeless PWID.  New direct-acting HCV treatments are now available, but inducing and 
completing treatment for PWID has proven to be difficult.  Items on knowledge, attitudes, beliefs, and 

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4
preferences for HCV treatment will be asked of participants.  2) Drug effects and withdrawal module: Anaylses 
of our prior study data (2011-13) indicated that polyroute (injection and non-injection -71%) and polysubstance 
(use of two or more illicit substance – 70%) use was common in our sample, yet little is known about reasons 
for specific drug use combination and/or sequences.  To begin to understand these common phenomena, we 
will ask open-ended items on common drug use combinations and sequences and elicit reasons for using 
substances in these combinations or sequences.  Lastly, preliminary data from the baseline interviews indicate 
that withdrawal symptoms in the last 6 months were reported by 85% of eligible heroin users and 54% of 
methamphetamine users.  Management of withdrawal symptoms by PWID has not been extensively studied 
and may related to polyroute and polysubstance use behaviors.  We will ask open-ended (i.e., qualitative) 
questions about how PWID handle withdrawal symptoms when they occur.  Study resuls will contribute to 
efforts to address HAV and HCV infections and to inform substance use treatment approaches.  Participants 
will be offered the opportunity to complete the Hepatitis survey and the qualitative interview separately.  We 
have developed separate consent forms for each.  Participants will be selected by convenience and data 
collect for the separate modules will not be linked together or linked to the parent study.  Participants will be 
given $10 to complete each module. 
 
 2.0 
OBJECTIVES AND PURPOSE 
 
 
To achieve these aims, people who inject drugs (PWID) who report having initiated someone or having 
injection initiation social learning risks in the past 6 months (N=1,076) will be randomly assigned to receive 
CTC or an equal attention control condition in Los Angeles (LA) and San Francisco (SF), CA. Injection initiation 
and injection initiation social learning variables will be 
collected at baseline, 6 months, and 12 months. CTC is 
brief, easy to implement, and novel in its focus on active 
PWID as a conduit for preventing injection initiation. If 
proven efficacious, CTC will be a much-needed, practical 
approach to preventing drug injection initiation.39-43  
The main outcomes by Aim are as follows: 1) Counts 
of non-injectors initiated into drug injection at 6 and 12 
months; 2) Counts of request to initiate a non-injector into 
drug injection at 6 and 12 months; and 3) Counts of non-
injectors initiated into drug injection and request to initiate 
non-injectors at 6 and 12 months. The study will be 
implemented in 2 phases.  Phase 1 involves adaptation 
and training of intervention personnel and Phase 2 
involves implementing the full study.  
Elucidation goals are to better understand issues 
related to 1) HAV/HCV effects and 2) drug effects and 
withdrawal and symptoms management PWID.  
 
 
3.0 
STUDY DESIGN 
 
3.1. CTC training and piloting. Intervention staff from 
LA and SF will participate in a week-long CTC training led 
by Co-I Strike and consultant Hunt. The goal of the 
training is to develop the knowledge and skills necessary 
to faithfully and effectively deliver the CTC intervention. 
Training modules include information about active 
listening, safer injection practices, overdose prevention, 
and risk associated with injection initiation. The peer 
handbook training manual is provided in Appendix A. 
Training will be completed by the four interventionists (2 
from each site), study coordinator/directors at each site, 
and the MPIs.  
Targeted sampling 
(n~1,200) 
Eligible (n=1,076) 
Baseline interview and 
random assignment 
Ineligible (n~124) 
Adapted Change the 
Cycle Intervention 
(n=538) 
Equal Attention 
Control (Nutrition 
intervention) (n=538) 
Monthly Retention 
Check in 
6 month follow-up 
interview 
Monthly Retention 
check in 
12 month follow-up 
interview 

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5
Following training, each interventionist will pilot the CTC intervention with four PWID at each site (2 
interventionists per site, 4 PWID per interventionist, 16 PWID total). The CTC information Guide (Appendix B) 
was developed by Drs. Strike and Hunt. Participants will be recruited for community settings and undergo 
informed consent prior to undergoing the intervention session (see Appendix C for informed consent form).  
Each practice session will be audio-recorded and reviewed by the MPIs and project directors for fidelity to 
intervention protocols. A brief semi-structured exit interview will be conducted with the PWID participants to 
solicit their input on feasibility, acceptability, and satisfaction with the intervention session (Appendix D). PWID 
will receive $30 for completing the pilot CTC session and exit interview.  Modifications to terminology used in 
the intervention and other minor changes will be considered based on this feedback. Following completion of 
training and piloting, a cross-site meeting with staff from each site and Drs. Strike and Hunt will be held to 
finalize any changes to the CTC curriculum.   
Interventionists will also devote a week to learning and practicing the equal attention control intervention 
(see Section 7.0). To prevent interventionist contamination, one interventionist from each site will conduct the 
CTC intervention for the first half of data accrual while the other interventionist will implement the equal 
attention control. Interventionists will then switch for the second half of data collection. 
We will also conduct up to 20 pilot interviews (10 in each site) of the baseline questionnaire (Appendix H).  
Pilot interview participants will be self-identified persons who inject drugs and are 18 years of age or older.  
The pilot interview will occur in a private one-on-one session with a trained research interviewer.  Participants 
will receive $15 USD for completing the interview.  Information from these interviews will be used to revise 
specific questionnaire items for comprehension and clarity.   
 
3.2. Sampling. We will use targeted sampling methods developed by Watters and Biernacki to recruit PWID 
into the screening component of this study (N~1,200).75-78 This method is a systematic approach to sampling 
hidden and uncounted populations when true random sampling 
is not feasible and has been widely used in epidemiological 
studies of drug users including our own.58-60 We chose targeted sampling for four reasons: (1) in San 
Francisco, targeted sampling has been found to reach a more diverse population of PWID than RDS;79 (2) 
several unresolved methodological issues regarding the analysis of RDS data could potentially obfuscate 
findings;80-82 (3) in cohort studies, RDS referral chains can get easily broken through loss to follow-up, thus 
requiring a large amount of data imputation; and (4) it is not possible to analyze data across two cities because 
the referral chains cannot extend between cities.  
3.3. Field sites and interview setting. Data collection will occur at community-based field sites conveniently 
located for PWID to access and conducive to private confidential interviews and intervention sessions. In the 
past, we have rented space in community-based agencies and single-room occupancy hotels.  
3.4. Recruitment and screening for eligibility. Subjects will be recruited into the study by community 
outreach workers with extensive experience working in LA and SF PWID communities. The outreach workers 
will walk through specified recruitment areas delineated in the targeted sampling plan, engage potential study 
participants in conversation, and distribute socks, water, other supplies and referral information when 
necessary. The outreach workers will briefly describe the study procedures to potentially eligible subjects. 
Individuals interested in participating will be given a card with the hours and location of the local community 
field site. Upon arrival at the community field site, potential study participants will be taken to a private space to 
meet briefly with the Study Coordinator, who will ask a series of questions evaluating age and ability to provide 
informed consent to determine eligibility for the study. Eligible study participants will be given a same-day 
appointment, either immediately or very shortly thereafter for the screening interview. Figure 1 describes the 
participant flow through the study. 
Recruitment for the elucidation sub-study will be from the parent study.  Participants returning for follow-up 
interview or check-ins will be told about the sub-studies and offered an opportunity to participant in one or both 
of the sub-studies.  Eligibility for the parent study will be the same for the sub-studies. However, we will not re-
screen potential participants for recent drug use. 
3.5. Eligibility and inclusion/exclusion criteria: To be eligible to participate in the study potential subjects 
must report: (1) Recent injection of illicit drugs (past 30 days) as verified by checking for signs of venipuncture 
(“tracks”);84 (2) age 18 years or older; (3) ability to speak English, and (4) ability to provide informed consent.  
Exclusion criteria less than 18 years of age, no physical evidence of recent injection drug use, insufficient 
English language comprehension, and intoxication.  Intoxicated potential participants will be invited to return for 
eligibility screening once they are sober.  Eligibility screening will be conducted by Project Coordinators. 
 

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6
3.6. Biometrics data collection to prevent duplicate participation. To prevent duplicate participation, all 
screening-eligible participants will provide the following biometric information: race/ethnicity, age, eye color, 
height, circumference of wrist and length of forearms, and the location of notable scars and tattoos (Appendix 
F). Use of these measures has been found to be acceptable to PWID and provide sufficient information to 
deter, detect, and prevent duplicate enrollment of participants.85 These same procedures were successfully 
implemented in the pilot study conducted by Dr. Strike.7 
No biometric data will be collected as part of the elucidation study. 
 3.7. Informed consent. Informed consent will be obtained in a confidential space prior to the baseline 
interview (Appendix E). The Study Coordinator or research interviewer will read the consent form aloud 
individually to each participant. Questions and concerns will be addressed throughout the consent process. All 
study procedures will be approved by the Institutional Review Boards at the University of Southern California. 
Elucidation information consent forms are provided in Appendix L (HAV/HCV) and M (Drug effects and 
withdrawal). 
3.8. Locator form. For retention purposes, participants will be asked to provide contact information (phone 
number, e-mail address, day-time hangouts), the names and phone numbers of up to three contact persons, 
and the names and locations of social service agencies they utilize (Appendix B). Participants will be 
requested to sign releases authorizing the staff to contact these agencies to locate them if they miss an 
appointment (see Appendix J). They can refuse to provide this information and still participate in the study. 
We have regularly asked and obtained this information in studies with PWID in LA and SF.  No identifying 
information will be collected from elucidation sub-study participants. 
3.9. Baseline interviewing. Baseline interviews will be conducted in English using computer assisted 
personal interview. The interview will occur in an one-on-one session with a trained research interviewer.  
Participants will receive $15 for completing the screening interview. We will conduct approximately 48 baseline 
interviews per month (24 interviews at each site per month) until 538 participants have completed the CTC 
intervention and 538 participants have completed the equal attention control intervention (Timeline, Table 1 
see below). 
The elucidation study interviews will be offered to current study participants.  Study 1 (HAV/HCV) is a 
quantitative survey that covers topics related to HAV risk (sanitation issues) and HCV treatment (Appendix N).  
Study 2 is qualitative in nature and addresses effects and withdrawal symptoms (Appendix O).  Procedures in 
section 3.10 to 4.0 do not apply to the elucidation study. 
3.10. Randomization. Following completion of the interview each participant will be randomly assigned 
(using urn,89 see Section 6.0) to receive either the CTC intervention or the equal attention control nutrition 
intervention session, according to a computer-generated random numbers program. 3.11. Intervention fidelity 
and quality control. All intervention trainings will be audio-recorded. To ensure intervention fidelity, the Study 
Coordinator will listen to all recorded trainings for the first month and then a 10% random sample thereafter. 
The Study Coordinator will score intervention fidelity on a standardized form that will include a list of all 
intervention manual components. Interventionists will receive reports from these sessions. If interventionists 
score less than 95% fidelity on any session, they will be retrained by the Study Coordinator and tape 
recordings of their next sessions will be reviewed until a 95% fidelity rate is obtained. Given our past 
experience, training plan and oversight, we expect fidelity to rarely fall below 95%. Participants will also 
complete a short questionnaire on their satisfaction with the intervention session to which they were exposed 
(see Appendix K). 
3.12. Cohort maintenance and recapture strategies. We will use multiple proven strategies to retain cohort 
members at the 6-month and 12-month follow-up interviews. First, during enrollment for the proposed study, 
we will collect detailed tracking information, as described in Section 3.8. The Study Coordinator will enter 
tracking information into a Microsoft Access database on a password-protected laptop computer. We will use 
this information to locate participants who miss appointments. Second, participants will have a monthly check-
in appointment with study staff, which will be held at field sites in the recruitment communities, and will receive 
a $10 incentive for attending. At check-in, tracking information will be verified and updated. Dr. Kral has 
conducted two NIDA-funded cohort studies that compared the effectiveness of incentivized check-in 
appointments with that of standard tracking by outreach workers67,90 and found that paying each cohort 
member $10 monthly yields much higher return rates and is less costly than relying on staff outreach alone. 
Third, we will use graduated incentives for the interviews: $15 for the screener/baseline and $20 for each of the 
6-month and 12-month follow-up interviews. We will also allow the participants to return for up to one month 
past their study appointments. Study participants will continue to be eligible for the study throughout the follow-

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7
up period even if they miss their check-in appointments. To minimize any potential participation biases during 
check-ins, research staff will only update contact information and not discuss any substantive topics. 
3.13. Follow-up interviews at 6 and 12 months. Similar to baseline/screening interviews, 6- and 12- month 
follow-up interviews will be conducted using CAPI in a one-on-one session with a trained research interviewer. 
Participants will be remunerated $20 for each follow-up interview they complete.  
3.14. Timeline: As described in Table 1, below, following training and piloting, baseline data collection will 
commence in May 2016 and continue until December 2018.  
Table 1. Project Timeline 
Activity 
Year 01 
Year 02 
Year 03 
Year 04 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Calendar year ‘15 
‘15 
‘16 
‘16 
‘16 
‘16 
‘17 
‘17 
‘17 
‘17 
‘18 
‘18 
‘18 
‘18 
‘19 
‘19 
RCT Baseline 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
6-month follow-up 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
12-month follow-up 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
3.15. Data collection measures. Data collection measures were selected based on their relevance to 
evaluating CTC, applicability to social learning theory and IMB model, and potential as confounders. Items 
from each area are described below and a draft of the baseline questionnaire is included in Appendix H.  
3.16. Main outcome measures for Aims 1 & 3 will be the number of people initiated in the past 6 months. 
This item will be assessed by asking the following questions: “In the past 6 months, have you helped someone 
get their first hit (the first time they ever injected)?” If participants respond Yes, they will be asked the following 
question: “How many people (total) have you helped get their first hit (inject for the first time) in the past 6 
months?” Not applicable responses (or No on the first item) will be recoded as zeros for data analysis 
purposes. For Aims 2 & 3 we will ask the following items: “In the past 6 months, have you been asked to help 
someone inject an illicit drug for the first time?”  Participants responding ‘yes’, were then asked how many 
people had asked them to provide their first injection. The time frame of 6 months allows us to assess changes 
in the outcome at 6 months (as was done in the pilot) and 12 months. The use of a count approach for 
outcome variables enables us to account for changes even if they only occur among high volume initiators and 
those with multiple injection initiation social learning risk. We will also collect data on sex risk, specifically, 
unprotected sex, multiple sex partners, and sex risk by partner type91,92 for purposes of determining the 
efficacy of the attention control condition although this is not an aim of the proposed study. 
3.17. Main independent measures will be intervention condition: CTC or equal attention control group for 
Aims 1 & 2. For Aim 3, we will also evaluate three injection initiation social learning risks as mediating 
variables. These items are intended to capture social learning constructs (i.e., observation of behavior, 
supportive interactions, and reinforcement) within the social processes of injection initiation. To capture 
observing, we will ask current PWID the following item: “In the past 6 months, have you injected drugs in front 
of someone who has never injected an illicit drug?” To capture interaction, we will ask “In the past 6 months 
have you explained or described how to inject to someone who has never injected an illicit drug (i.e., a non-
injector)?” To measure reinforcement we will ask, “In the past 6 months, have you spoken positively about 
injecting with someone who has never injected an illicit drug?” Each item is a binary variable (Yes/No) where 
Yes denotes endorsing the injection initiation social learning risk assessed.  
We will also collect IMB constructs related to injection initiation and sex risk. For the information construct, 
we will collect true or false knowledge items on sex-related HIV prevention provided by Kalichman, Simbayi 
and others5,6 and develop similar items for injection initiation risks.  To develop injection initiation risk 
motivation and behavioral skill items we will follow procedures outlined by Kalichman, Simbayi and others.5,6 
For sex-risk related motivation and behavioral skill items we will draw from existing studies.5,6  All injection 
initiation risk and sex-related IMB skill items will all be pilot tested. Psychometric properties of existing 
measures are known and acceptable, however, we will test both existing and new measures for their 
applicability to this study population.  Drafts of all items are provided in the baseline survey (Appendix H). 
3.18. Potential confounding variables or covariates will be selected from the following domains: socio-
demographics/economics, current drug use patterns, blood borne infectious disease risks, experimental 
condition contamination, and social desirable responding. Socio-demographic and socioeconomic 
characteristics will be collected from each participant, including race/ethnicity (with options for multiple 
racial/ethnic identification), age, education, income/income sources, living arrangements (including 
homelessness), and relationship status. Drug use history and current use patterns have previously been 

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shown to be associated with initiation of injection-naive people.59 In the proposed study, we will assess 
frequency of injection and non-injection in the past 30 days for the following drugs: crack cocaine, cocaine, 
heroin, methamphetamines, speedball (admixture of heroin/cocaine), goofball (admixture of 
heroin/methamphetamines), prescription drug misuse (e.g., opiates, tranquilizers, stimulants, sedatives, 
methadone, and buprenorphine), and marijuana. The drug use items have been found to be valid and 
reliable.16,17 Injection-related HIV and HBV/HCV risk will be captured using modified items from NIDA’s 
cooperative agreement study of the 1990s (the “RBA”).96 These items have been found to be valid and 
reliable.15,17 Socially desirable response set measure (SDRS-5) contains five items adapted from the Marlowe-
Crowne Form A measure of social desirability. Respondents rank each item on a 4-point scale ranging from 1 
(strongly disagree) to 4 (strongly agree).97  
3.19. Six-month and 12-month follow-up measures will include all main outcome (Section 3.16.) and 
independent variables (Section 3.17) as well as socio-demographic and economic variables that could change 
during the 6-month follow-up periods (e.g., relationship status, homelessness, income). We will also assess 
contamination at 6-month follow-up interview. It is possible that skills learned by the CTC participants may be 
shared with participants in the equal attention control group. This type of contamination cannot be prevented, 
but it can be measured. At 6-month interview, participants in both conditions will be asked if they have had 
conversations with other PWID on a variety of health issues, including injection initiation, initiation injection 
social learning risk, sex risk, and other items to mask the intent of the question. We will also ask them about 
intervention phrases such as “Change the Cycle” to assess whether control group participants are familiar with 
them.  A similar approach has been used in other intervention studies among PWID to identify exposure to an 
intervention.98 We will ask questions about satisfaction with and usefulness of the CTC intervention or the 
equal attention control intervention at 6 month follow-up interview. Lastly, we will ask questions from several 
other domains on either the 6 month or 12 month survey.  The domain lists for items to be included in the 6 
and 12 month survey are provided in Appendix I. 
 
4.0 
DRUG/DEVICE INFORMATION 
 
 
4.1 
Not applicable. 
 
 
5.0  
SELECTION AND WITHDRAWAL OF SUBJECTS 
  
 
5.1 
Inclusion Criteria:  Inclusion criteria for the baseline/screening interview are (1) recent injection 
of illicit drugs (past 30 days), as verified by checking for venipuncture marks,84 (2) age 18 years 
or older, and (3) ability to provide informed consent.  
5.2 
Exclusion Criteria:  Less than 18 years of age, no evidence of recent drug injection, inability to 
provide informed consent, and non-English speaking. 
5.3 
Withdrawal Criteria:  Participants who unable to complete either the experimental or control 
condition intervention may be asked to withdraw from the study.  Each participant will be given 
at least 2 opportunities to complete the one-hour educational session to which they were 
assigned. 
 
6.0 
 STRATIFICATION/DESCRIPTIVE FACTORS/RANDOMIZATION SCHEME 
 
  
6.1 
Stratification factors. Not applicable. 
 
 
6.2 
Descriptive factors. Based on prior studies with PWID, we anticipate the following 
characteristics: The majority will be over the age of 50, roughly a third will be white, a third will 
be African American, and 25% will be Latino.  About 25% will be female.  The vast majority will 
be heroin injectors although a third will also report methamphetamine use, and 10% will report 
cocaine and opiate prescription injection in the last 30 days. 
 
 
6.3 
For participants in the RCT, randomization will be accomplished using urn.  Urn randomization 
is an adaptive biased-coin randomization method.89 In brief, it means you not only replace the 
ball that is chosen out of a hat (for example: blue for experimental and red for control condition), 
but you add a ball from the opposite color as well. The urn design forces balance for studies 

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9
with a large number of confounders as it approaches complete randomization and full balance 
as the size of the trial increases. Consequently, the urn design is not as vulnerable to 
experimental bias as are other restricted randomization procedures. 
 
7.0 
STUDY AGENT ADMINISTRATION OR INTERVENTION AND TOXICITY MANAGEMENT PLAN 
 
 
7.1. 
CTC can be viewed as integration of social learning theory and the Information-Motivation-
Behavioral skill model (IMB). CTC uses social learning theory to explain how active PWID might influence 
directly (by assisting in first injection) and indirectly (through promoting and exposing non-injectors to injection) 
injection initiation among non-injectors.1,2 It uses IMB to promote behavior change among active PWID by 
providing them with information, motivation and behavioral skills related to direct and indirect influences of 
injection initiation.3,4 Figure 2, graphically illustrates these theories are integrated within CTC. 
Figure 2. Integration of IMB skill model with social learning theory for purposes of reducing injection 
initiation as operationalized in CTC. 
 
In the figure, the IMB model constructs of information and motivation (the 2 left-most bubbles) reinforce 
each other; enhance behavioral skills acquisition; and contribute to reductions in injection initiation social 
learning risk (top bubble on the right), requests for injection initiation, and actual injection initiation episodes 
(bubbles below social learning risk bubble). CTC modules are listed within IMB construct bubbles. We expect 
IMB-related changes to influence social learning risk, including interactions with (describing how to inject), 
observations/exposure to injection (injecting in front of non-injectors), and reinforcement (encouraging injection 
drug use). Reductions in social learning risk should lead to lower incidence of both requests to initiate and 
actual injection initiation episodes (behavioral experimentation).  The integrated model targets the injection 
initiation social learning risks documented in the literature to be involved in the transition to injection drug use, 
by providing information, motivation, and behavioral skills to reduce injecting in front of, describing injection to, 
and speaking positively about injecting to non-injectors.45-56 Aim 1 will test the impact of CTC on counts of 
injection episodes, while Aim 2 tests CTC effect on injection initiation request. Aim 3 will explore the 
theoretically and empirically supported mediational mechanism between CTC, social learning risk, and request 
for and episodes of injection initiation.  
7.1.1. 
The Change the Cycle intervention  
The CTC intervention is an hour-long, guided conversation with a trained interventionist. Copies of the Peer 
Educator Handbook and Intervention Guide that were developed by Drs. Strike and Hunt and adapted for this 
study are included in Appendices A and B, respectively. Using the Intervention Guide, the interventionist 
introduces and summarizes CTC goals and then delivers the following seven modules in one session:  
1. Discussion of the participant’s own experience the first time they injected, including when it occurred, 
motivations for initiation, who was present, and feelings about initiation (~5 minutes). 
2. Discussion of the participant’s experiences of initiating others, focusing on the participant’s thoughts about 
the experience, the relationship to the person they initiated, the context of initiation, and descriptions of 
those times they refused to initiate someone (~5 minutes). 
3. The participant’s perceptions of the health, legal, and social risks of initiating non-injectors (~5 minutes). 
4. The participant’s perceptions of the health, legal, and social risks of initiation for themselves (~5 minutes). 
5. Identification of aspects of the participant’s own behavior and the behaviors of other PWID that may 
promote injecting to non-injectors and linking those behaviors back to the participant’s own initiation 
experience (~10 min). Includes discussion of: (A) Talking about the physical benefits of injecting in front of 

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10 
injection-naive people; (B) Talking about the economic benefits of injecting compared with using drugs 
other ways (e.g., snorting, smoking); and (C) Describing how preparing drugs for injection in front of non-
injectors might inadvertently promote injection initiation. 
6. Skill-building session to prevent future initiation events.  We have developed 9 different scenarios covering 
a range of possible events based on the relationship and drug use characteristics of the participant.   
7. A safer injection education session focusing on topics such as hygiene, risks of sharing needles and other 
injection equipment, rotating veins to avoid abscesses, etc. (~5 min). 
  
 
7.1.2 The equal attention control intervention. To ensure that the participants in the intervention and 
control groups are having the same study-related experiences, control participants will receive an intervention 
that mimics the experience but differs in content. The equal attention control intervention will focus on 
improving health eating among PWID.  We have developed a single-session, 60- minute Information-
Motivation-Behavioral (IMB) skills-based intervention addressing healthy eating (Appendix J). Similar to the 
CTC, the healthy eating intervention uses a one-on-one guided conversation between the interventionist and 
the participant.  The intervention addresses (1) information about current eating patterns and 
recommendations for healthy alternatives (20 minutes), (2) motivations for improving healthy eating by 
providing feedback to participants on personal responsibility, a menu of alternative change options, a decision 
balance exercise, and eating goal setting (10 minutes), and (3) Behavioral Self-Management Component (30 
minutes) that covers eating scenarios, participant responses, and healthy alternatives to the scenario and the 
participants feedback.  The participant is also remunerated $15 for completing the session.  
7.2. Elucidation studies: The elucidation studies are pilot interviews.  We anticipate interviewing 60 PWID 
for study 1 and 40 PWID for study 2. 
 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY 
 
 
8.1 
Side effects/Toxicities to be monitored. NOT APPLICABLE 
 
 
 
8.2 
Dosage change based on toxicity.  NOT APPLICABLE 
 
 
8.3 
Adverse Event Reporting: Although the occurrence of adverse events as a direct result of 
the research is unlikely, such events may occur because the research population includes 
people who are  current drug users, involved in illegal activities that make them vulnerable. Any 
serious adverse event will be reported verbally within 24 hours and a written report will follow 
within 72 hours of an adverse event.  Reports will be made to the IRB at USC and RTI 
international.  The program official at NIDA will also be notified. 
 
 
8.4 
Data Monitoring Committee: 
 
The Data Safety and Monitoring Board (DSMB) for this study consists of the following members.  
Name 
Affiliation 
Areas of expertise 
Keith Heinzerling, MD, MPH 
UCLA 
Dr. Heinzerling is a graduate of Stanford University School 
of Medicine, the NYU/Bellevue Internal Medicine Primary 
Care Program, where he was a Medicine Chief Resident, 
and the Robert Wood Johnson Clinical Scholars Program 
at UCLA. Dr. Heinzerling is currently an Associate 
Professor in Residence in the UCLA Department of Family 
Medicine and Medical Director of the UCLA Center for 
Behavioral and Addiction Medicine. His research and 
clinical practice focus on the development and 
dissemination of anti-addiction medications.  
Mary Howe 
Homeless 
Youth 
Alliance 
Ms. Howe is a formerly homeless youth who has 
dedicated her career to developing and implementing 
interventions that empower young people to improve their 
own lives and those of their peers, and to addressing the 
structural causes of poverty and homelessness. Mary 

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11 
assumed leadership of HYA in 2006 when two 
longstanding grassroots programs—Haight Ashbury Youth 
Outreach Team and San Francisco Needle Exchange—
ended their affiliation with Haight Ashbury Free Clinics, 
Inc. and merged to form a single organization under the 
name “Homeless Youth Alliance.” Prior to serving as 
Executive Director of HYA, Mary was an outreach worker 
and later the Center Manager for Haight Ashbury Youth 
Outreach Team, Program Coordinator for San Francisco 
Needle Exchange, and Trainer for the Drug Overdose 
Prevention and Education Project of the City and County 
of San Francisco. She is the recipient of a 2009 Bay Area 
Unsung Hero Award from KQED Northern California. 
Paula Lum, MD, MPH 
UCSF 
Dr. Paula J. Lum graduated from the Case Western 
Reserve University School of Medicine in 1993. She works 
in San Francisco, CA and specializes in Internal Medicine. 
Dr. Lum is affiliated with San Francisco General Hospital 
Medical Center and UCSF Medical Center Parnassus. 
Cathy Reback 
Friends 
Research 
Institute, 
Inc 
Dr. Reback is executive Director of Friends Community 
Center and a Senior Research Scientist with Friends 
Research Institute, Inc.  Her work focuses on the 
intersection of HIV risk behaviors, substance use, sexual 
identity and gender identity.  Dr. Reback is also a 
Research Sociologist with UCLA Integrated Substance 
Abuse Programs (UCLA ISAP) and a Core Scientist with 
the UCLA Center for HIV Identification, Prevention and 
Treatment Services (UCLA CHIPTS). 
Shoshanna Scholar 
Los 
Angeles 
Community 
Health 
Outreach 
Project 
Ms. Scholar is the executive director of LA Community 
Health Project. LACHP reaches some of Los Angeles' 
most vulnerable populations through three specific, 
evidence-based public health interventions: LA's oldest 
syringe exchange program, which operates in Hollywood, 
downtown LA/ Skid Row, Pico Union and Watts; the 
Overdose Outreach Project, which trains doctors, medical 
workers, people who use drugs and their communities in 
overdose prevention and response; and Transition 
Partners, a pilot project seeking to integrate drug users 
and homeless clients into the emerging community clinic 
health system. Since 2003, Scholar has developed, tested 
and adapted innovative public health strategies for drug-
using populations. She is especially focused on activating 
peer networks to reach hard-to-find populations, working 
with government to implement better public health policies 
and raising public awareness around overdose prevention. 
She currently serves as a Los Angeles County HIV 
Commissioner. 
Steve Shoptaw 
UCLA 
Dr. Shoptaw is a licensed psychologist and Director of 
the Center for Behavioral and Addiction Medicine at 
UCLA. I am a Professor in the UCLA Departments of 
Family Medicine and Psychiatry and Biobehavioral 
Sciences and Vice Chair of Research in Family Medicine. 
He is also a member of the DAIDS-funded, HIV 
Prevention Trials Network (HPTN) Executive Committee, 
and site Principal Investigator for HPTN-073, a feasibility 

Version date: 02/22/201806/9/2016 
 
12 
study of Pre-Exposure Prophylaxis (Truvada) in Black 
men who have sex with men.  Lastly, Dr. Shoptaw is Co-
Director for the UCLA Center for HIV Identification 
Prevention and Treatment Services (CHIPTS; Rotheram-
Borus PI) where he works with a team of colleagues to 
develop funded research on application of the next 
generation of technological advances and biomedical 
approaches to prevent HIV transmission.  
 
The charge of the DSMB includes advising the multi-PIs on study procedures related to risk to subjects, 
consideration of the interim results from the study, and providing reports to the IRBs at USC and RTI 
International as requested from this bodies.  No members of the board have any conflicts of interest with the 
study or its key personnel.  Members will meet at least annually.  In the event that a serious adverse event 
occurs, the DSMB will be notified of the event within 10 days and convened within a month to review the case.  
The multiple PIs acknowledge the requirement to provide a report on DSMB activities in the annual progress 
report to NIDA. 
 
9.0 
CLINICAL AND LABORATORY EVALUATIONS AND STUDY CALENDAR 
 
 
Not applicable 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
 
 
NOT APPLICABLE 
 
11.0 
SPECIAL INSTRUCTIONS: 
 
 
NOT APPLICALBE. 
 
12.0 
DATA COLLECTION AND MONITORING 
 
Data Security. On all data records, participants will be identified by unique ID numbers rather than names. 
Forms containing participants’ names (release of information, and consent form) will be kept in separate and 
locked file cabinets. The tracking database, containing participants’ names and contact information will be 
kept in a password protected database on an encrypted laptop that is backed up nightly to a server at each of 
the study sites (USC and RTI). Both the forms and the database will be, accessible only to the Study 
Coordinators, Project Director and Principal Investigators. 
 
Data Storage. The data will be stored as follows: 
 
Informed consent 
Locked file cabinet (Study Coordinator, Project Director and Principal 
Investigators will have access). 
Release forms 
Locked file cabinet with informed consent. (Study Coordinator, Project Director
and Principal Investigators will have access) 
Tracking database 
(computerized) 
Locked file cabinet (Study Coordinator, Project Director and Principal 
Investigator will have access). 
Biometric Information 
database (computerized) 
On Study Coordinator’s laptop, used in office and at field site. Laptop will be 
encrypted and files will be password protected and backed up to an FTP 
secure server at RTI at the end of each day.  
Interview data – Screener, 
6 and 12 month follow-up 
(computerized) 
On field laptops. Encrypted and password protected. Data will be uploaded to 
an FTP site at RTI at the end of each day and automatically deleted from 
laptops. 
 
Paper forms and databases containing identifying information will be destroyed within 30 days of the 
completion of the study. 

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13 
 
Data transfer will occur through the use of password protected USB jump drives. Completed interviews will be 
copied and pasted into the USB storage device. These devices will then be immediately transported to USC 
or RTI where they will be downloaded onto a secure computer. Data files on field site computers will be 
deleted and the recycling bin emptied. One advantage of using the Questionnaire Development System for 
data collection and transfer is that in the unlikely event that interview computers are stolen or the USB storage 
device is misplaced, the actual data files cannot be viewed without a data warehouse module. The data 
warehouse module will not be installed on computers used for the collection of data or on the USB device. 
Once data is stored on USC/RTI computers, these computers will be maintained in secured, password-
protected folders, accessible only to designated staff through the USC file server. The surveys will be securely 
downloaded and maintained in the database of Dr. Bluthenthal. Drs. Bluthenthal and Kral have successfully 
used similar methods for data management in other multisite NIDA-funded studies. 
 
Elucidation data will consist of pen and paper survey forms for Study 1 and digitally recorded, qualitative 
interviews for Study 2.  Study 1 forms will contain no identifying information and limited demographic 
information (sex, race, age).  After data has been entered into a data entry form, paper versions of the survey 
will be destroyed. Study 2 will only include identification number on recording.  Participants will be asked to use 
a fake name to refer to themselves and others in the recording.  This has worked well in the past.  No 
information will be collected that connects an individual by name to the audio recording.  Following 
transcription, audio files will be deleted for audio-recorders and study computers. 
 
13.0 
STATISTICAL CONSIDERATIONS 
 
13.1.  Data analysis will involve (a) understanding the structure of all of the variables, (b) assessing 
whether randomization worked, (c) assessing and addressing intervention fidelity, and (d) testing the three 
hypotheses proposed in Aims 1, 2, and 3. First, we will employ exploratory data analytic techniques using the 
survey data collected at baseline and the 6- and 12-month follow-up. Dispersion and central tendency 
measures (e.g., means, standard deviations, medians, proportions) will be calculated for all items. The 
distributional properties and reliability of continuously scaled variables will be examined. We will also create 
longitudinal plots to identify trends in the key variables. We will also assess whether there is any statistically 
significant differential loss to follow-up between the two conditions. Any variable that is statistically significantly 
associated with loss to follow-up between conditions will also be included as a covariate in the hypothesis 
testing analyses. Next, we will examine fidelity to ensure compliance to the intervention based on observed 
intervention check lists that document the receipt of the intervention as manualized, compared with any 
changes that may occur. We can treat fidelity in the model as parameterized as a covariate in the observed 
model. Finally, we will test the three hypotheses.  Similar procedures will be used to determine if the sex risk 
reduction intervention was efficacious.  
Aim 1: To test the efficacy of CTC on reducing the number of non-injectors initiated into injection 
(counts) by PWID. Hypothesis 1(H1): PWID who receive CTC will report initiating fewer non-injectors into drug 
injection at 6 and 12 months as compared with PWID in the equal attention control condition. To test H1, we 
will conduct structural equation modeling (SEM) using Mplus (release 7.11).99 Our primary outcome analysis is 
based on an outcome that is distributed as counts of the number of episodes initiating someone into drug 
injection. This is a standard Poisson count variable with a potential inflation of the number of zeros as there will 
likely be many who do not initiate others (e.g., zero-inflation). This Poisson count outcome can essentially be 
thought of as consisting of two separate, yet interrelated, processes—one in which the participant engaged in 
the behavior of initiating someone else at all (i.e., binary yes/no) and another in which we assess the number 
of times the participant initiated someone (ranging from 1 to j, where j=the number of episodes initiating 
someone. In SEM literature, this is referred to as a two-part process for zero inflated Poisson, as SEM models 
these two processes separately as unique latent processes.100 As this outcome is collected as part of an 
intervention with a baseline (T0) and two follow-ups (T1, T2), the model is parameterized to accommodate 
three time points, following Olsen and Schafer (2001).100 Note that with three time points, the implied model is 
mis-identified given the number of measured variables in the variance-covariance from the observed data in an 
SEM measurement model with an intercept (i) and slope (s) for 3 observations.101-103 However, joint modeling 
the ZIP as a two-part process redresses the identification problem, and results in 6 measured variables, one 
for the process in which the participant actually initiated another person (0 for no, 1 for yes) and another for the 

Version date: 02/22/201806/9/2016 
 
14 
change/reduction in the number of initiations over the 3 
observation times (1 to j). The first part of the analysis will 
involve characterization of the measurement model for the 
change over time from T0 to T1 and from T1 to T2. As 
shown in Figure 3, the model will include a treatment 
covariate representing the effect of the CTC intervention 
on changes over time for the binary (sU) and count (sZ) 
latent variables, and it may contain other covariates 
identified as having been distributed differentially by 
condition at baseline or associated with loss to follow-up. 
Note that if there are no differences at baseline in 
preliminary bivariate analyses, there is no need to include 
a treatment effect on the intercept for the SEM because 
with no differences at baseline, the intercept test for 
difference is likely to be non-significant so there is no value 
in risking the extra degrees of freedom. Through model 
constraints, we will also examine specific differences 
between conditions within time points (e.g., T1 or T2) and 
between time points (e.g., change over time from T0 to 
T1). There will be little need for additional covariates to control for potential inflation of the correlations due to 
recruitment sites, as the targeted sampling will ensure full coverage across the locations where PWID 
congregate in LA and SF. We will, however, explore differences between the two sites, and may introduce a 
control variable to account for large-scale environmental differences between the two sites. To avoid any 
analytic decisions being driven by a desire for a certain result, the statistician and data analysis team will be 
blinded as to whether 0 or 1 denotes the treatment or control condition until the analyses are completed. There 
is also potential for contamination, which we will assess by asking the respondents in the control condition their 
level of exposure to intervention components, as described in Section 3.5.17.3. We will follow procedures 
outlined by Keogh-Brown et al. (2007) using complier average causal models (CACE),104 in which the bias 
associated with contamination is significantly reduced by averaging the estimated causal effect over classes of 
participants that differ in the level of exposure to contamination. Each person in the control group will be 
assigned to a class, depending on their level of exposure and type of exposure, using latent classification 
techniques utilized by Dr. Novak in previous publications.105 Lastly, we will compare differences in examining 
the rate of change versus the standardized difference at each follow-up point (e.g., compare counts of injection 
initiation at 6m and 12m) and test for differences by condition. The latent change model has more power than 
the raw difference approach, and we will present differences in our published work if the outcome is sensitive 
to model estimation.     
Aim 2: To test the efficacy of CTC on reducing the number of times PWID are asked to initiate 
(counts) someone into injection. H2: PWID who receive CTC will report having been asked fewer times to 
initiate someone into drug injection at 6 and 12 months as compared with PWID in the equal attention control 
condition. This model will be estimated in the same manner as the model for the outcome of the actual number 
of reported counts, save that this one will estimated using the self-reported counts by the respondent regarding 
being asked to initiate another person. 
Aim 3: To test whether injection initiation social learning risks (injecting in front of, describing 
injection to, and speaking positively about injection to non-injectors) act as mediational mechanisms 
for the efficacy of the CTC intervention on initiation and request-to-initiate outcomes. H3: Social 
learning variables will significantly mediate the association between the CTC intervention and episodes of 
initiating and being requested to initiate someone into drug injection at 6 and 12 months. The outcome variable 
will remain counts of the number of episodes initiating someone into drug injection (Aim 1) and the counts of 
request to initiate another person (Aim 2). The mediational models will be specified following the work of Baron 
and Kenny and newer generalizations.106-108 With only three time points, we can examine the effect of baseline 
randomization to treatment status on 12-month counts of injection initiation as the outcome and 6-month 
injection-risk behavior variables as the mediators. The lagged approach can be used as static measures at 6 
months and 12 months, or changes in injection initiation social learning risks and IMB skills constructs that 
precede changes in the number of counts of initiation as outcome. This latter approach is strong in that the 
change in a variable, created by difference scores, is isolated so that it precedes the subsequent outcome. 
Figure 3. Two-Part Zero-Inflated Poisson SEM 

Version date: 02/22/201806/9/2016 
 
15 
There are also techniques for estimating mediational models with only 2 time-points;109 consequently, we will 
examine mediation from randomization to 6-month follow-up with the mediator and outcome measured 
concurrently. We can estimate separate mediational models for each injection initiation social learning risk and 
IMB skills construct, or enter the mediation mechanisms together into a single model, while examining overfit 
due to multiple mediational paths.110 Omnibus measures of model fit (chi-square, root mean square error of 
approximation, Tucker Lewis Index [TLI]), and specific path coefficients will be used to assess the treatment 
effect and test for the mediational pathways. The null hypothesis will be rejected if the p value for the variable 
that denotes treatment condition is below 0.05. Proposed Co-I Dr. Novak has extensive experience with these 
techniques as part of longitudinal community-based interventions.105,111,112  
13.2. Sample size/ power analyses 
Power calculations were estimated using Mplus by creating a Monte Carlo Simulation by generating a 
synthetic data set based on the expected parameter values, such as slopes, standard errors, and correlations 
among measured variables, for the anticipated treatment effect.113,114 Power was estimated assuming an 
intracluster correlation of 0.5, which is similar to our previous NIDA-funded studies.105,112,115 Statistical tests 
were two-sided, allowing detection of effects in either direction, and an alpha of .05 and power at 80%, 
corresponding to moderate effect sizes. Because the outcome is a count (i.e., Poisson), standard errors were 
estimated as non-normal via a sandwich estimator in Mplus.116 Co-Is Strike and Hunt found that the number of 
participants who initiated people into injection was halved at follow-up.7 Preliminary data from MPIs Bluthenthal 
and Kral’s study in LA and SF indicated that 809 active PWID were found to have initiated 431 people in the 
past year. Using the same proportion, we expect that 573 people would be initiated by our proposed sample 
size of 1,076 participants at baseline (286 in each arm). If the number of people initiated by intervention group 
participants is halved, as suggested by Strike and Hunt’s pilot data, that would represent a reduction of 143 
people not being initiated into injection.  
We also calculated the effect under different assumptions of attrition, subgroups (e.g., 25% Latino), sex, 
and age. For brevity, we illustrate power for primary outcome and most conservative—changes in the number 
of injection initiation events. We also account for 25% attrition—our worst-case scenario. To test the three 
hypotheses given our alpha and power specifications, we would need a baseline recruitment of 1,076 (n=538 
per condition). We will recruit 1,076 participants to achieve the final sample of approximately 800 at the 12- 
month data point. The sample power for Cohen’s effect sizes for small (2 percentage point difference), medium 
(5% difference) and large (10%−15% difference) effect sizes are plotted in Figure 4, revealing that after 
accounting for attrition, a final study of 800 participants at the 12-
month follow-up, evenly randomized, will have excellent power 
to detect small (0.82), moderate (0.88), and large (0.99) effect 
sizes. We also examined power for our mediational analyses in 
which the injection initiation risk variables will be differentially 
associated with treatment assignment. Following data from Co-I 
Strike for the mediational models, we expect that there was a 
37% change in transition from initiation to non-initiation, and a 
38% reduction in the participants injecting in front of injection-
naive people. These parameter estimates were converted to a 
Monte-Carlo simulation in Mplus, and we will have power to 
detect a mediational effect of for moderate to large pathways 
(TxMediatorOutcome). Note that we will not have sufficient 
power for small mediational effects with our proposed sample, 
which may be clinically insignificant anyway.  
13.3 
Missing data 
The likelihood of missing data at the item level will be reduced by using CAPI. Therefore, much of the 
missing data will likely be due to participant-attrition. We will attempt to gather detailed tracking information to 
mitigate the likelihood of dropout, which has been approximately 25% at 12 months in our prior NIDA-funded 
studies of this population in LA and SF. We will censor data at the point of loss to follow-up. Other options, 
such as last-observation carried forward, will also be explored. As the team has done in previous studies, 
separate intent to treat (ITT) analyses will be conducted by treating the dropouts as the unfavorable outcome. 
We will explore mechanism of attrition, and can explore model-based extrapolations, such as pattern mixture 
modeling to account for data that are non-missing at random and the selection mechanism cannot be 
explained by observed covariates.103,117-119 Regardless of the method used to redress missing data, we will 
Figure 4. Statistical Power (Y axis) for 
Sample Size (Total N) for Small, 
Medium, and Large Effect Sizes  

Version date: 02/22/201806/9/2016 
 
16 
conduct sensitivity analyses by comparing results using these procedures to those that exclude missing data 
altogether so that reviewers may incorporate any differences in the evaluation of our work.  
13.4. 
Elucidation Study 1 
We will use descriptive statistics to characterize participants responses to these items. 
13.5. 
Elucidation Study 2 
Interviews and data analysis will be conducted by experienced qualitative interviewers (Drs. Bluthenthal, 
Karina Dominguez-Gonzalez, Johnathan Zhao).  We anticipate qualitative interviews taking no more than 60 
minutes.  All interviews will be audio-recorded.  Participants will receive $10 for completing the interview.  The 
interviews will be digitally recorded and later transcribed verbatim by a professional transcription service that 
the investigative team has worked with successfully for four years.  Transfer of audio files is accomplished 
through Hightail website.  Audio files on digital recorders are erased after been transferred to Dr. Bluthenthal’s 
password protected computer.  Thematic analysis of transciptions will be conducted in an iterative fashion.  
After the completion of sets of 5 to 7 interviews, transcribed interviews will be coded and read to determine if 
new questions need to be added to explore emerging themes.  This iterative analytic meeting will occur every 
other week until all 40 interviews are completed or therotical saturation has been achieved.    Coding of 
interviews involves reading transcripts in their entirety, coding them and meeting with the research team to 
refine codes and check for inter-coder reliability.  Coding will be conducted using Atlas-Ti qualitative data 
analysis software.   
 
 
14.0 
REGISTRATION GUIDELINE 
 
 
Not applicable.  
 
15.0 
BIOHAZARD COMTAINMENT 
 
 
Not applicable  
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
All institutional and Federal regulations concerning the Informed Consent form will be fulfilled.  The 
study will be conducted in adherence to ICH Good Clinical Practice. 
 
 

Version date: 02/22/201806/9/2016 
 
17 
17.0 
REFERENCES 
 
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APPENDICES (Include any desired tables, scales, questionnaires, etc.) 
 
 
Appendix A: Peer Handbook Training Manual 
 
Appendix B: Change the Cycle (CTC) Information Guide 
 
Appendix C: Pilot informed consent 
 
Appendix D: Assessment of pilot intervention 
 
Appendix E: Screening interview informed consent 
 
Appendix F: Randomized controlled trial informed consent 
 
Appendix G: Contact form 
 
Appendix H: Baseline questionnaire 
 
Appendix I: Follow-up interview questionnaire domains 
 
Appendix J: Releases of information forms for USC and RTI International 
 
Appendix K: Exit interview questionnaire 
 
Appendix L: Elucidation study 1 (HAV/HCV) consent form 
 
Appendix M: Eluciation study 2 (Drug effects and withdrawal symptoms) consent form 
 
Appendix N: HAV/HCV survey 
 
Appendix O: Drug effects and withdrawal symptoms interview guide