IMPAACT 2002: Combined Cognitive Behavioral Therapy and a Medication Management Algorithm for Treatment of Depression Among Youth Living With HIV in the United States
Phase: NA
Conditions: HIV, Depression
Sponsor: International Maternal Pediatric Adolescent AIDS Clinical Trials Group

IMPAACT 2002 
(DAIDS Document ID 12051) 
Combined Cognitive Behavioral Therapy and a Medication 
Management Algorithm for Treatment of Depression among Youth 
Living with HIV in the United States 
 
A Multi-center International Trial of the 
International Maternal Pediatric Adolescent AIDS 
Clinical Trials Group (IMPAACT) 
 
 
This file contains the current IMPAACT 2002 protocol, 
which is comprised of the following documents, 
presented in reverse chronological order: 
 
 
• 
Letter of Amendment #1, dated 27 April 2018 
• 
Clarification Memorandum #2, dated 4 October 2017 
• 
Clarification Memorandum #1, dated 6 March 2017 
• 
Protocol Version 1.0, dated 19 August 2016 

Letter of Amendment # 1 
      Page 1 of 5 
27 April 2018 
IMPAACT 2002 Protocol Version 1.0 
 
Letter of Amendment #1 for: 
 
IMPAACT 2002 
Combined Cognitive Behavioral Therapy and a Medication Management 
Algorithm for Treatment of Depression among Youth Living with HIV in the 
United States 
 
Version 1.0, dated 19 August 2016 
DAIDS Study ID #12051  
 
Letter of Amendment Date: 27 April 2018 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) affects the IMPAACT 2002 study and 
must be submitted to site Institutional Review Boards (IRBs) as soon as possible for their review and 
approval. Approval must also be obtained from site regulatory entities if applicable per the policies and 
procedures of the regulatory entities. All IRB and regulatory entity requirements must be followed. 
 
Upon obtaining IRB approval and any other applicable regulatory entity approvals, each site should 
immediately begin implementing this LoA.  
 
Sites are required to submit an LoA registration packet to the DAIDS Protocol Registration Office 
(DAIDS PRO) at the Regulatory Support Center (RSC). Sites will receive a registration notification for 
the LoA after the DAIDS PRO verifies that all required registration documents have been received and 
are complete. Sites should not await this notification before implementing this LoA  
 
Please file this LoA, all associated IRB and regulatory entity correspondence, and all correspondence with 
the DAIDS PRO in your essential documents files for IMPAACT 2002. If the IMPAACT 2002 protocol 
is amended in the future, the contents of this LoA will be incorporated into the next version of the 
protocol. 
 
 
 
 
 

Letter of Amendment # 1 
      Page 2 of 5 
27 April 2018 
IMPAACT 2002 Protocol Version 1.0 
 
IMPAACT 2002 
 
Combined Cognitive Behavioral Therapy and a Medication Management Algorithm for 
Treatment of Depression among Youth Living with HIV in the United States 
Version 1.0, dated 19 August 2016 
 
DAIDS Study ID #12051 
 
 
Version 1.0, Letter of Amendment #1 
dated 27 April 2018 
 
 
 
 
LETTER OF AMENDMENT SIGNATURE PAGE 
 
 
I will conduct this study in accordance with the current version of this protocol, including this Letter of 
Amendment, and all applicable protocol-related documents. I agree to conduct this study in compliance 
with United States (U.S.) Health and Human Service regulations (45 CFR 46); applicable U.S. Food and 
Drug Administration regulations; standards of the International Conference on Harmonization Guideline 
for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee determinations; all 
applicable in-country, state, and local laws and regulations; and other applicable requirements (e.g., U.S. 
National Institutes of Health, Division of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 
 
 
 
 
 
 
 
 
 
 

Letter of Amendment # 1 
      Page 3 of 5 
27 April 2018 
IMPAACT 2002 Protocol Version 1.0 
 
Summary of Modifications and Rationale 
 
The purpose of this LoA is to: 
 
1. Modify the procedures for the screening and enrollment process in addition to the clarifications 
applied to protocol Section 4.4 in Clarification Memoranda (CM) #1 and #2 to remove barriers to 
recruitment and allow for more timely enrollment. The requirement that sites approach 
participants in a randomly assigned order is removed; potentially eligible participants may be 
approached for screening, as available.  
2. Provide other minor administrative updates. 
 
Implementation 
 
The modifications included in this Letter of Amendment are listed below by modification and will be 
incorporated into the next protocol amendment as specified below. Additions to the text are indicated in 
bold; deletions are indicated by strikethrough.  
 
1. Screening and Enrollment Process  
 
Section 4.4, Recruitment, Screening, and Enrollment Process 
 
As noted in Sections 3.0 and 9.1, selection bias is a concern. The protocol includes design 
features to minimize selection bias, including requiring sites to obtain screening numbers for all 
potentially eligible participants and randomizing the order in which the site will approach 
potential participants for enrollment; and collectsing limited data on patients who do not enroll so 
that their characteristics can be compared to those of participants who did enroll (to assess the 
potential extent of selection bias). New randomized lists will be created for sites as needed. 
 
It is expected that site staff will approach all potentially eligible youth for possible study 
participation. Patients will be recruited, and proceed with the screening process as follows: 
 
1. Sites create a list of all potentially eligible youth at their site and complete a Screening Log in the 
Subject Enrollment System (SES) for each patient who is potentially eligible for the study. from 
their list. Completion of the Screening Log will generate a screening number. 
2. Prior to site initiation of formal screening and enrollment into the study, the Statistical Data 
Management Center (SDMC) will retrieve the lists of potential participants entered, and 
randomly order all of the screening numbers within each site into blocks. The DMC 
randomization department will load these blocks into the randomization system and send the 
blocks to the sites; the team will then notify sites that this process has been completed and that 
they can begin screening and enrollment. 
2. Sites may approach any patient in care at the study site whom they consider to be potentially 
eligible for the study and who has a screening number. anyone from their first block of 
screening numbers. Patients from the subsequent blocks may not be approached until all patients 
from the previous block are enrolled or have been approached but will not enroll into the study 
(for any reason). If a patient is interested in the study, they will undergo the informed 
assent/consent process and be assigned a PID. 
3. Sites will submit a “Screening Failure and Non-Enrollment Results Form” using the screening 
number in the following circumstances: 1) If a potential participant is approached but not 
interested in enrolling in the study, in this case, only the fact that the participant does not want to 
consent to the study will be recorded; 2) If a potential participant is approached and is interested 

Letter of Amendment # 1 
      Page 4 of 5 
27 April 2018 
IMPAACT 2002 Protocol Version 1.0 
 
in being in the study, but fails the eligibility criteria or does not enroll for another reason; in 
this case, the form will collect the reason(s) for not enrolling (i.e., ineligibility and associated 
reasons for ineligibility), in addition to the patient’s gender, race, ethnicity age, viral suppression 
status, depression severity estimate, and mode of transmission. This record will not include other 
patient-identifying data. 
4. When a participant is enrolled into IMPAACT 2002, the screening number, in addition to the 
eligibility criteria, will be entered into the data base. The DMC randomization system will 
verify that the screening number is on the list. Enrollment will occur upon successful entry of 
required eligibility data into the SES. Successful entry into the SES will generate a study 
identification number (SID). 
5. Once enrolled, if a participant is no longer able to participate in the study, an off-study 
form will be completed. 
 
 
Ideally, screening and enrollment into the study will be conducted on one day, if the participant is 
 
willing and found to be eligible. 
 
 
Ineligible participants may rescreen for study participation provided their initial reason for 
ineligibility has changed or is thought by site staff to have changed. In addition, those participants 
listed on the pre-screening list Participants who do not screen for the study or do not enroll for any 
reason may be subsequently assigned new screening numbers, and new potential participants will be 
assigned screening numbers as they are identified. The SDMC will regularly retrieve the lists of 
potential participants and steps 2 through 5 above will be repeated as needed to achieve the target 
study enrollment. Steps 1 through 5 above will be repeated as needed to achieve the target study 
enrollment. 
 
Section 9.1, General Design Issues, fourth paragraph  
 
In addition, the protocol includes several design features to minimize selection bias, including 
defining eligibility criteria that apply equally to both study arms; requiring sites to obtain screening 
numbers for all potentially eligible participants and randomizing the order in which the site can 
approach potential participants for enrollment; and collecting limited data on patients who do not 
enroll so that their characteristics can be compared to those of participants who did enroll, to assess 
the potential extent of selection bias. 
 
2. Updates to the Protocol Team and Site Roster.
 
Protocol Vice-Chairs 
Patricia Emmanuel, MD Lewis A. Barness 
Endowed Chair Professor and Chair of 
Pediatrics USF Health; Morsani College of 
Medicine 2 Tampa General Circle, 5th 
Floor, Rm 5016 Tampa, FL 33606 Phone: 
(813) 259-8867 Email: 
pemmanue@health.usf.edu 
 
NIAID Medical Officers 
Adeola Adeyeye MD, MPA, CCFP, 
LCDR, U.S. Public Health Service 
Medical Officer, Clinical Prevention 
Research Branch, 
Prevention Science Program, DAIDS, 
NIAID, NIH 
Room 8B36 MSC 9831, 5601 Fishers Lane 
Rockville, MD 20852-9831 
Phone: (240) 669-5005 
BB: (240) 421-8446  
Email: adeola.adeyeye@nih.gov  
Cell: (240) 619-9365 
Email: adeyeyeao@niaid.nih.gov 
 
Protocol Data Managers 
Korianne Sulzbach, MPH 
Frontier Science and Technology 
Research Foundation, Inc 
4033 Maple Road  
Amherst, NY  14226-1056 

Letter of Amendment # 1 
      Page 5 of 5 
27 April 2018 
IMPAACT 2002 Protocol Version 1.0 
 
Phone: 716-834-0900 x7219 
Email: sulzbach@fstrf.org 
 
Study Site Roster 
Site 5055, Children’s Diagnostic and 
Treatment Center 
Ana Puga,  
CFAP Medical Director 
Children’s Diagnostic & Treatment Center 
1401 S Federal Highway 
Fort Lauderdale, Florida 33316 
Phone: 954-728-1017 
Email: apuga@browardhealth.org 
 
Kathleen Graham, PharmD 
Study Coordinator 
Children’s Diagnostic & Treatment 
Center 
1401 S Federal Highway 
Fort Lauderdale, Florida 33316 
Phone: 954-728-1111   
Email: kgraham@browardhealth.org 
 
Lisa-Gaye Robinson, MD, MPH  
IoR 
Children’s Diagnostic & Treatment 
Center 
1401 S Federal Highway 
Fort Lauderdale, Florida 33316  
Phone: (954)728-1136  
Email: lerobinson@browardhealth.org 
 
Site 5030, Emory University School of 
Medicine 
Bridget Wynn, MPH 
Study Coordinator 
Family & Youth Clinic at Ponce, Room 201 
341 Ponce de Leon Avenue NE 
Atlanta, GA 30308 
Phone: (404) 966-1487 
Email: Bridget.wynn@emory.edu 
 
LaTeshia Seaton, MS, APRN, CCRC 
Senior Research Nurse 
Study Coordinator 
Children's Healthcare of Atlanta 
Grady-Family and Youth Clinic at Ponce 
341 Ponce de Leon Avenue, Room 201 
Atlanta, GA 30308 
Phone: 404-616-5936 
Email: lseaton@emory.edu 
Site 4601, UCSD  
Daniel Szpak, RN, CCRC 
Study Coordinator 
UCSD Mother-Child-Adolescent HIV 
Program 
4076 Third Avenue, Suite 301 
San Diego, CA 92103 
Phone: (858) 534-9216 
Email: dszpak@ucsd.edu 
 
Megan Loughran B.A. 
Study Coordinator  
4076 Third Avenue, Suite 301  
San Diego, CA 92103  
 
Phone: (858)-534-9218 
 
Email: meloughran@ucsd.edu  

Clarification Memorandum #2       
Page 1 of 2 
4 October 2017 
IMPAACT 2002 Protocol Version 1.0 
Clarification Memorandum #2 for: 
 
IMPAACT 2002 
Combined Cognitive Behavioral Therapy and a Medication Management 
Algorithm for Treatment of Depression among Youth Living with HIV in the 
United States 
 
Version 1.0, dated 19 August 2016 
DAIDS ES # 12051  
 
Clarification Memorandum Date: 4 October 2017 
 
Summary of Clarifications and Rationale  
 
The primary purposes of this Clarification Memorandum (CM) are: 
1. To clarify that the Off-Study Form (F1601) may only be completed for participants that enrolled 
in the study. 
2. To clarify that if the 1-Week visit occurs on the same day as the Screen/Entry visit, COMB-R 
sites must complete both the ACASI and paper QIDS-SR questionnaire. 
3. To specify use of Version 2.1 of the Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events for grading severity of adverse events in IMPAACT 2002 (instead 
of Version 2.0). 
4. To update the Protocol Team Roster to reflect current membership and responsibilities. 
 
Implementation  
 
This Clarification Memorandum (CM) has been approved by the NIAID and NICHD Medical Officers. 
Institutional Review Board/Ethics Committee (IRB/EC) approval of this CM is not required by the 
sponsor prior to implementation; however, sites may submit it to the responsible IRBs/ECs for their 
information or, if required by the IRBs/ECs, for their approval prior to implementation. 
 
The contents of the CM do not impact the sample informed consent forms for the study or the benefit-to-
risk ratio for study participants. This CM should be maintained in each site’s essential documents file for 
IMPAACT 2002. It is the responsibility of the Investigator of Record to ensure that all study staff are 
made aware of and follow this CM. The content of this CM will be incorporated into any future 
amendment of the IMPAACT 2002 protocol. 
 
The modifications included in this CM are listed by modification. Deletions in the protocol text are 
indicated by strikethrough and additions shown in bold text. 
1. To clarify that an Off-Study Form should only be completed for enrolled participants who are no 
longer able to participate in the study, a correction to the text included in CM #1 is made below. 
 
Section 4.4 Recruitment, Screening and Enrollment Process, 3rd Paragraph, CM #1, #6   
 
6. Once consented enrolled, if a participant is no longer able to participate in the study, an Off-
Study Form will be completed. 

Clarification Memorandum #2       
Page 2 of 2 
4 October 2017 
IMPAACT 2002 Protocol Version 1.0 
 
2. Updated Section 6.2 1 Week Visit to clarify the procedures to be completed if the Week 1 visit 
occurs on the same day as Entry.  
The 1-Week Visit is targeted to take place on Day 7, counted from the date of enrollment as Day 
0, with an allowable window of -7 and +14 days. Sites may conduct the 1-Week visit procedures 
on the same day as the Screen/Entry visit, if the participant and site staff have adequate time. If 
the 1-Week Visit is conducted on the same day as the Screen/Entry visit, then sites should not 
repeat procedures, such as the QIDS-SR and collecting medical and medication history. The 
primary purpose in this case, would be to provide therapy and medication management as 
indicated below. Note per Section 5.3.2, if the 1-Week visit occurs on the same day as Entry, 
COMB-R sites must complete both the ACASI and paper QIDS-SR questionnaire; ESC 
sites are not required to repeat the QIDS-SR. If the 1-Week Visit is not conducted on the same 
day as Screen/Entry, then all the procedures listed below must be performed. 
3. Updated protocol Section 7.4.3 to specify the use of Version 2.1 of the DAIDS Table for grading 
severity of adverse events  
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table), Version 2.0, dated November 2014 Corrected Version 2.1, dated July 2017, 
will be used to grade the severity of most adverse events in this study. This table is available on 
the RSC website at: http://rsc.tech-res.com/docs/default-
source/safety/daids_ae_grading_table_v2_nov2014.pdf?sfvrsn=8 http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids-grading-tables. 
 
4. Updated the Protocol Team Roster to reflect current membership:  
 
Clinical Trials Specialists 
 
 
 
Westat Clinical Research Associate 
 
JL Ariansen, MS Anna LeViere, MPH  
 
Rita Patel, MS Aundria Charles 
IMPAACT Operations Center, FHI 360  
 
Westat, Inc. 
359 Blackwell Street, Suite 200  
 
 
1441 W. Montgomery Ave. 
Durham, NC 27701, USA 
 
 
 
Rockville, MD 20850 
Phone: (919) 544-7040 x11185 919-475-11585  
Phone: (240) 453-2693 2758 
Email: jariansen@fhi360.org  
 
 
 
Email: ritapatel@westat.com  
ALeViere@fhi360.org   
 
 
 
AundriaCharles@westat.com 
 
Protocol Data Managers 
Elise Tjaden, MPH Chelsea Krotje, MPH 
Frontier Science & Technology Research Foundation 
4033 Maple Road  
Amherst, NY 14226-1056 
Phone: (716) 834-0900 x 7272 7368 
Email: tjaden@fstrf.org krotje@fstrf.org  
 
Laboratory Data Managers 
Kaitley Wozer, BS Frederic Bone 
Frontier Science & Technology 
Research Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: (716) 834-0900 x7224 7306 
Email: wozer@fstrf.org bone@fstrf.org  

Clarification Memorandum #1  
     Page 1 of 5 
6 March 2017 
IMPAACT 2002 Protocol Version 1.0 
Clarification Memorandum #1 for: 
 
IMPAACT 2002 
Combined Cognitive Behavioral Therapy and a Medication Management 
Algorithm for Treatment of Depression among Youth Living with HIV in the 
United States 
 
Version 1.0, dated 19 August 2016 
 DAIDS ES # 12051 
 
Clarification Memorandum Date: 6 March 2017   
 
 
Information/Instructions to Study Sites 
 
This Clarification Memorandum (CM) has been approved by the NIAID and NICHD Medical Officers. 
Institutional Review Board/Ethics Committee (IRB/EC) approval of this CM is not required by the study 
sponsor prior to implementation. However, sites may submit this CM to the responsible IRBs/ECs for 
their information or, if required by the IRBs/ECs, for their approval prior to implementation. 
 
The content of the CM does not impact the sample informed consent forms for the study or the benefit-to-
risk ratio for study participants. 
 
This CM should be maintained in each site’s essential documents file for IMPAACT 2002. It is the 
responsibility of the Investigator of Record (IoR) to ensure that all study staff are made aware of this CM. 
The content of this CM will be incorporated into any future amendment of the IMPAACT 2002 protocol. 
 
 
Summary of Clarifications and Rationale 
 
The purpose of this CM is to: 1) clarify the study recruitment, screening and enrollment processes with 
respect to defining the scenarios in which a site will submit a Screening Failure and Non-Enrollment 
Results Form 2) clarify the forms specific to the Clinician Satisfaction Scales and 3) update the Protocol 
Team and Site Roster. 
 
 
Implementation 
 
The modifications included in this CM are listed below by update and in order of appearance in the 
protocol and will be incorporated into the next protocol amendment as specified below. Additions to the 
text are indicated in bold; deletions are indicated by strikethrough. 
 
1. Clarification of the screening and enrollment processes for potential participants  
 
Section 4.4 Recruitment, Screening and Enrollment Process, 3rd Paragraph 

Clarification Memorandum #1  
     Page 2 of 5 
6 March 2017 
IMPAACT 2002 Protocol Version 1.0 
It is expected that site staff will approach all potentially eligible youth for possible study participation. 
Patients will be recruited, and proceed with the screening process as follows: 
[…] 
3. Sites may approach start screening and enrolling anyone from their first block of screening 
numbers. Patients from the subsequent blocks may not be approached until all patients from the 
previous block are enrolled or have been approached but will not enroll into the study (for any 
reason). If a patient is interested in the study, they will undergo the informed assent/consent 
process and be assigned a PID. 
4. If a patient is interested in the study, they will undergo the informed assent/consent process and 
be assigned a PID. Sites will submit a “Screening Failure and Non-Enrollment Results 
Form” using the screening number in the following circumstances: 1) If a potential 
participant patient is approached but not interested in enrolling in the study, in this case, only 
the fact that the participant does not want to consent to the study will be recorded; 2) If a 
potential participant is approached and is interested in being in the study, but fails the 
eligibility criteria; in this case, the This form will collect the reason(s) for not enrolling (i.e., 
ineligibility, refusal, and associated reasons for ineligibility or refusal), in addition to the patient’s 
gender, race, ethnicity, age, viral suppression status, depression severity estimate, and mode of 
transmission. This record will not include other patient-identifying data. 
5. When a participant patient is enrolled into IMPAACT 2002, the screening number, in addition to 
the eligibility criteria, will be entered into the data base. The DMC randomization system will 
verify that the screening number is on the list. Enrollment will occur upon successful entry of 
required eligibility data into the SES. Successful entry into the SES will generate a study 
identification number (SID). 
6. Once consented, if a participant is no longer able to participate in the study, an off-study 
form will be completed.  
 
2. Clarify the forms to be completed as part of the clinician satisfaction measures   
 
Section 5.3.8 Clinician Satisfaction Scales, 4th and 5th paragraphs 
 
At the COMB-R sites, the clinician conducting the H&W CBT sessions will complete a six seven item 
survey (H&W CBT Clinician Satisfaction Questionnaire) to assess the appropriateness, effectiveness, 
flexibility, ease of use, and “fit” of the H&W CBT treatment approach for the patient and the clinic 
(responses: Excellent, Good, Fair, Poor). 
 
At the ESC sites, the clinician conducting the counseling sessions will complete a five seven item survey 
(Counseling Clinician Satisfaction Questionnaire) to assess the appropriateness, effectiveness, 
flexibility, ease of use, and “fit” of their treatment strategies for the patient and the clinic (responses: 
Excellent, Good, Fair, Poor). 
 
 
 
 
 
 
 
 
 

Clarification Memorandum #1  
     Page 3 of 5 
6 March 2017 
IMPAACT 2002 Protocol Version 1.0 
 
Section 6.4 24 Week Follow-up Visit  
 
24 Week Visit Procedures  
Study Day 168 (+/- 14 days) 
Behavioral  
and Counseling 
 Administer QIDS-SR 
 Administer behavioral questionnaire  
 Administer Client Satisfaction Questionnaire 
 Administer Physician Prescribing Clinician Satisfaction 
Questionnaire (COMB-R Sites Only) 
Clinical 
 Collect/update medical and medications history; including 
assessments for suicidality and number of kept and missed 
medical and mental health visits 
 Assess CDC HIV disease category 
 Identify/review/update adverse events (signs, symptoms, 
diagnoses) 
 COMB-R Sites Only: 
 Administer CBT Session and complete the CBT 
Adherence Checklist 
 Administer the MM Session and complete the MM 
Checklist 
 Complete H&W CBT Clinician Satisfaction 
Questionnaire 
 ESC Sites Only: 
 Psychotherapy as indicated by symptoms 
 Medication management as indicated by symptoms 
 Complete the ESC therapy Checklist 
 Complete Counseling Clinician Satisfaction 
Questionnaire 
Laboratory 
 
Blood 
Collect blood for: 
 CD4+ T-Cell Count^  
 HIV-1 RNA^ 
 Plasma storage, for inflammatory markers  
 
Appendix I:  Schedule of Evaluations for All Participants 
 
Study Visit 
Week 24 
Visit Window 
±14 d 
Behavioral and Counseling 
 
Site Prescribing Clinician Physician Satisfaction 
Questionnaire (COMB-R Sites Only) 
X 
Clinical 
 
COMB-R Sites ONLY: 
 
 
H&W CBT Clinician Satisfaction 
Questionnaire 
X 
ESC Sites ONLY: 
 
 
Counseling Clinician Satisfaction 
Questionnaire 
X 
 
Have re-named “Physician Satisfaction Questionnaire” to “Site Prescribing Clinician Satisfaction 
Questionnaire” and removed (COMB-R sites only). 
 

Clarification Memorandum #1  
     Page 4 of 5 
6 March 2017 
IMPAACT 2002 Protocol Version 1.0 
Have added the following line for COMB-R Sites ONLY: “H&W CBT Clinician Satisfaction 
Questionnaire.” To be completed at Week 24 only. 
 
Have added the following line for ESC Sites ONLY: “Counseling Clinician Satisfaction Questionnaire.” 
To be completed at Week 24 only. 
 
3. Updates to Protocol Team and Site Roster.  
 
Protocol Data Managers 
Michael Basar, BA Elise Tjaden, MPH 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: (716) 834-0900 x7271 7272 
E-mail:  basar.michael@fstrf.org 
tjaden@fstrf.org 
 
Study Site Roster Updates 
Site 4001, Chicago Children’s  
Melanie Koch, LPC  
Health and Wellness CBT  
Lurie Children's Memorial Hospital  
225 East Chicago Ave Box 155  
Chicago, IL 60611-2605  
Phone: (312) 227-8269  
Email: mkoch@luriechildrens.org 
 
Site 5040, The Research Foundation of 
SUNY-Stony Brook University Medical 
Center 
Michele Kelly, CPNP, NPP 
Study Coordinator 
Department of Pediatrics 
Stony Brook University School of Medicine 
Stony Brook, NY 11794-8225 
Phone: (631) 632-3736 444-8832 
Email: 
Michele.kelly@stonybrookmedicine.edu 
 
Site 5030, Emory University School of 
Medicine 
Chandra C. Graves, PhD, ABPP 
Department of Psychiatry and Behavioral 
Sciences 
Emory University School of Medicine 
Pediatric Infectious Disease Program 
Atlanta, GA 30307 
Phone: (404) 616-9380 
Email:  ccgrave@emory.edu 
 
LaTeshia Thomas-Seaton, RN, BSN, 
CCRC 
Children’s Healthcare of Atlanta 
Grady-Family and Youth Clinic at Ponce 
341 Ponce de Leon Avenue, Room 201 
Atlanta, GA 30308 
Phone: (404) 616-5936 
Email: leaston@emory.edu 
 
Site 5052, The Regents of the University of 
Colorado 
Daniel Reirdan, MD 
Director, Combined Internal Medicine-
Pediatrics Residency 
Sections of Adolescent Medicine and 
Infectious Disease 
Center for Bioethics and Humanities 
13123 East 16th Avenue, Box 025 
Aurora, CO 80045 
Phone: (720) 777-4971 
Email:  
Daniel.reirdan@childrenscolorado.org 
 
Amber Bunch, MA, LPC, LAC 
Mental Health and Substance Abuse 
Specialist 
Children’s Hospital of Immunodeficiency 
Program (CHIP) 
13123 East 16th Avenue, Box 055 
Aurora, CO 80045 
Phone: (720) 777-6758 

Clarification Memorandum #1  
     Page 5 of 5 
6 March 2017 
IMPAACT 2002 Protocol Version 1.0 
Email: 
amber.bunch@childrenscolorado.org 
 
Site 5083, Rush University Medical Center 
Ixchell Ortiz-Estes, RN, MSN 
Study Coordinator 
2020 W. Hrrison 
Chicago, IL 60612 
Phone: (312) 572-4541 
Email: iortiz-estes@cookcountyhhs.org 
 
Site 5013, Jacobi Medical Center 
Michael G. Rosenberg, MD, PhD 
Jacobi Medical Center 
1400 Pelham Parkway South 
Building #1, Suite 1W5 
Bronx, NY 10461 
Phone: (718) 918-4677 
Email:  michael.rosenberg@nbhn.net 
 
Joanna Dobroszycki, MD 
Jacobi Medical Center 
1400 Pelham Parkway South 
Building #1, Suite 1W5 
Bronx, NY 10461 
Phone: (718) 918-4667 
Email: Joanna.dobroszycki@nbhn.net 
 
Jacobo Abadi, MD  
Pediatrician  
Jacobi Medical Center  
1400 Pelham Parkway South  
Building #1, Suite 1W5  
Bronx, NY 10461  
Phone: (718) 918-4108  
Email: Jacob.abadi@nbhn.net 
 
 
 
 
 

IMPAACT 2002 
 
 
Combined Cognitive Behavioral Therapy and a Medication 
Management Algorithm for Treatment of Depression among Youth 
Living with HIV in the United States 
 
 
A Study of the International Maternal Pediatric Adolescent 
AIDS Clinical Trials Network 
 
 
 
Sponsored by: 
The National Institute of Allergy and Infectious Diseases 
Eunice Kennedy Shriver 
National Institute of Child Health and Human Development 
National Institute of Mental Health 
 
 
 
 
DAIDS ES #12051 
Non-IND Study 
 
 
 
 
Protocol Chair: 
 
 
 
Larry Brown, M.D.  
 
Protocol Vice-Chairs:  
 
 
Patricia Emmanuel, M.D. 
 
 
 
 
 
 
 
Betsy Kennard, Ph.D. 
 
 
 
NIAID Medical Officer:  
 
 
Ellen Townley, MSN, FNP  
 
 
 
 
 
 
 
Adeola Adeyeye, M.D., MPA  
 
NICHD Medical Officer:   
 
Sonia Lee, Ph.D. 
 
Clinical Trials Specialists:  
 
Kathryn Lypen, MPH 
 
 
JL Ariansen, MS 
 
 
 
Version 1.0 
19 August 2016

 
IMPAACT 2002, Version 1.0                   Page 2 of 95                                   19 August 2016 
IMPAACT 2002 
Combined Cognitive Behavioral Therapy and a Medication Management 
Algorithm for Treatment of Depression among Youth Living with HIV in the United 
States  
 
TABLE OF CONTENTS 
 
 
ABBREVIATIONS AND ACRONYMS ..............................................................................  
PROTOCOL TEAM ROSTER ...........................................................................................  
SCHEMA ...........................................................................................................................  
1 
INTRODUCTION ................................................................................................ 14 
1.1 
Background ...........................................................................................................14 
1.2 
Prior Research .......................................................................................................15 
1.3 
Rationale ..............................................................................................................17 
1.4 
Hypotheses ...........................................................................................................18 
2 
OBJECTIVES ..................................................................................................... 18 
2.1 
Primary Objectives ..................................................................................................18 
2.2 
Secondary Objectives ..............................................................................................19 
2.3 
Exploratory Objectives .............................................................................................19 
3 
STUDY DESIGN ................................................................................................. 20 
4 
STUDY POPULATION ....................................................................................... 20 
4.1 
Inclusion Criteria .....................................................................................................21 
4.2 
Exclusion Criteria ....................................................................................................22 
4.3 
Co-Enrollment Considerations ....................................................................................22 
4.4 
Recruitment, Screening, and Enrollment Process ............................................................22 
4.5 
Participant Retention................................................................................................24 
5 
STUDY INTERVENTIONS ................................................................................. 24 
5.1 
COMB-R Study Sites ...............................................................................................24 
5.2 
ESC Study Sites .....................................................................................................29 
5.3 
Study Evaluations and Measures ................................................................................30 
5.4 
Intervention Monitoring/Quality Control .........................................................................34 
5.5 
Research Staff Training ............................................................................................35 
5.6 
Concomitant Medications ..........................................................................................36 
6 
STUDY VISITS AND PROCEDURES ................................................................ 36 
6.1 
Screening and Entry Visit ..........................................................................................38 
6.2 
1 Week Visit ..........................................................................................................39 
6.3 
6 and 12 Week Visits ...............................................................................................40 
6.4 
24 Week Follow-up Visit ...........................................................................................41 
6.5 
36 and 48 Week Follow-up Visits ................................................................................42 
6.6 
Interim Follow-up Visits ............................................................................................43 
6.7 
Premature Discontinuation of Study Participation Visit ......................................................43 
6.8 
Procedures for Participants Who Become Pregnant .........................................................43 
6.9 
Additional Considerations for Laboratory Procedures .......................................................44 

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7 
SAFETY ASSESSMENT AND REPORTING ..................................................... 45 
7.1 
Safety-Related Roles and Responsibilities for Site Investigators .........................................45 
7.2 
Recording of Pre-Existing Conditions ...........................................................................45 
7.3 
Safety Data on Case Report Forms .............................................................................45 
7.4 
Expedited Adverse Event (EAE) Reporting ....................................................................46 
8 
PARTICIPANT SAFETY MANAGEMENT ......................................................... 47 
8.1 
Management of Adverse Events .................................................................................47 
8.2 
Criteria for Premature Discontinuation of Study Participation ..............................................48 
9 
STATISTICAL CONSIDERATIONS ................................................................... 49 
9.1 
General Design Issues .............................................................................................49 
9.2 
Outcome Measures .................................................................................................50 
9.3 
Randomization .......................................................................................................51 
9.4 
Sample Size and Accrual ..........................................................................................52 
9.5 
Monitoring .............................................................................................................58 
9.6 
Analyses ...............................................................................................................61 
9.6.1  
Primary Objectives ..................................................................................................61 
9.6.2  
 Secondary and Exploratory Objectives ........................................................................62 
10 
DATA HANDLING AND RECORD KEEPING ................................................... 64 
10.1 
Data Management Responsibilities ..............................................................................64 
10.2 
Essential and Source Documents and Access to Source Data ............................................65 
10.3 
Quality Control and Quality Assurance .........................................................................65 
11 
CLINICAL SITE MONITORING .......................................................................... 65 
12 
HUMAN SUBJECTS PROTECTIONS ............................................................... 66 
12.1 
Institutional Review Board/Ethics Committee Review and Approval .....................................66 
12.2 
Vulnerable Participants .............................................................................................66 
12.3 
Informed Consent ...................................................................................................66 
12.4 
Potential Benefits ....................................................................................................67 
12.5 
Potential Risks .......................................................................................................67 
12.6 
Reimbursement/Compensation...................................................................................69 
12.7 
Privacy and Confidentiality ........................................................................................69 
12.8 
Communicable Disease Reporting...............................................................................70 
12.9 
Management of Incidental Findings .............................................................................70 
12.10 
Management of New Information Pertinent to Study Participation ........................................70 
13 
ADMINISTRATIVE PROCEDURES ................................................................... 70 
13.1 
Regulatory Oversight ...............................................................................................70 
13.2 
Protocol Registration................................................................................................70 
13.3 
Study Implementation ..............................................................................................71 
13.4 
Protocol Deviation Reporting ......................................................................................71 
13.5 
Critical Events Reporting ...........................................................................................71 
13.6 
 ClinicalTrials.gov ....................................................................................................72 
14 
PUBLICATIONS ................................................................................................. 72 
15 
REFERENCES ................................................................................................... 73 
16 
Appendix I: Schedule of Evaluations for All Participants ............................. 77 

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Appendix II: Sample Informed Assent ............................................................ 79 
 
Appendix III: Sample Informed Consent ......................................................... 82 
 
Appendix IV: Sample Participant Informed Consent ..................................... 89 
 
 
 
 
 
 

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IMPAACT 2002 
Combined Cognitive Behavioral Therapy and a Medication Management 
Algorithm for Treatment of Depression among Youth Living with HIV in the United 
States 
 
ABBREVIATIONS AND ACRONYMS    
 
AACAP 
American Academy of Child and Adolescent Psychiatry 
ACASI  
Audio Computer-Assisted Self Interview 
AE 
 
Adverse event  
AIDS  
Acquired Immunodeficiency Syndrome 
APA 
 
American Psychological Association 
ARV 
 
Antiretroviral 
ATN 
 
Adolescent Trials Network  
CAP/CLIA 
College of American Pathologists/Clinical Laboratory Improvement Amendments 
CBT 
 
Cognitive Behavioral Therapy 
CDC 
 
Centers for Disease Control  
CFR 
 
Code of Federal Regulations 
COMB-R 
Combined CBT and medication - revised 
CRF  
 
Case report form 
CSQ-8  
Client Satisfaction Questionnaire 
DAIDS  
Division of AIDS  
DAIDS PRO 
Division of AIDS Protocol Registration Office 
DAERS 
DAIDS Adverse Event Reporting System 
DE 
 
Design effect 
DIC 
 
Diffuse intravascular coagulation 
DMC  
Data Management Center 
DSM-IV/V 
Diagnostic and Statistical Manual of Mental Disorders  
EAE 
 
Expedited Adverse Event 
EC 
 
Ethics committee 
EIA  
 
Enzyme-linked immuno assay 
ESC 
 
Enhanced Standard Care 
FDA 
 
(U.S.) Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FSTRF  
Frontier Science and Technology Research Foundation 
FTFI 
 
Face-to-Face Interviews 
GCP 
 
Good Clinical Practices 
H&W CBT 
Health and Wellness Cognitive Behavioral Therapy 
HCG 
 
Human chorionic gonadotropin 
HIV 
 
Human Immunodeficiency Virus 
IATA  
International Air Transport Association 
ICC 
 
Intra-cluster correlation coefficient 
ICH 
 
International Conference on Harmonization 
ICU 
 
Intensive Care Unit 
IMPAACT  
International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
IRB  
 
Institutional review board 
IoR 
 
Investigator of Record 
LAR   
Legally authorized representative 
LC 
 
Laboratory Center  
LDMS  
Laboratory Data Management System  

IMPAACT 2002, Version 1.0 
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19 August 2016 
LPC 
 
Laboratory Processing Chart 
MAOI  
Monoamine oxidase inhibitors  
MI 
 
Motivational Interviewing 
MM 
 
Medication Management 
MOH  
Ministry of Health 
MOP   
Manual of Procedures 
NIAID  
National Institute of Allergy and Infectious Diseases 
NICHD  
National Institute of Child Health and Human Development 
NIH 
 
National Institutes of Health 
NMS 
 
Neuroleptic malignant syndrome 
OCSO  
Office of Clinical Oversight  
OHRP   
Office for Human Research Protection  
PEPFAR 
President’s Emergency Plan for AIDS Relief  
PID 
 
Participant Identification Number 
QIDS  
Quick Inventory of Depression Symptomatology  
QIDS-C 
Quick Inventory of Depression Symptomatology - Clinician 
QIDS-SR 
Quick Inventory of Depression Symptomatology - Self report 
RNA 
 
Ribonucleic acid  
RSC 
 
Regulatory Support Center 
SAE 
 
Serious Adverse Event 
SD 
 
Standard Deviation 
SDMC  
Statistical Data Management Center 
SES 
 
Subject Enrollment System 
SID 
 
Study Identification Number 
SIP 
 
Site Implementation Plan 
SMC 
 
Study Monitoring Committee 
SMFQ  
Short Moods and Feelings Questionnaire 
SNRI  
Serotonin and norepinephrine reuptake inhibitors 
SSRI 
 
Serotonin reuptake inhibitor  
SOP 
 
Standard Operating Procedure 
SoE 
 
Schedule of Evaluations 
SR  
 
Self-report 
SS  
 
Serotonin syndrome 
STI 
 
Sexually transmitted infection  
TAU 
 
Treatment as usual 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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IMPAACT 2002 
Combined Cognitive Behavioral Therapy and a Medication Management 
Algorithm for Treatment of Depression among Youth Living with HIV in the United 
States 
 
PROTOCOL TEAM ROSTER 
 
Protocol Chair 
Larry K. Brown, MD  
Director of Child, Adolescent, and Young 
Adult Psychiatry Research 
Department of Psychiatry, Rhode Island 
Hospital  
Professor, Alpert Medical School of Brown 
University   
167 Point St., Suite 161 
Providence, R.I. 02903  
Phone: (401) 793-8808  
Email: larry_brown@brown.edu 
 
Protocol Vice-Chairs 
Patricia Emmanuel, MD 
Lewis A. Barness Endowed Chair 
Professor and Chair of Pediatrics 
USF Health; Morsani College of Medicine 
2 Tampa General Circle, 5th Floor, Rm 5016 
Tampa, FL  33606 
Phone: (813) 259-8867 
Email: pemmanue@health.usf.edu 
 
Beth D. Kennard, Psy.D 
University of Texas  
Southwestern Medical Center  
5323 Harry Hines Boulevard 
Dallas, TX 75390-8589  
Phone: (214) 456-4244 
E-mail: beth.kennard@utsouthwestern.edu 
 
NIAID Medical Officers 
Ellen Townley, MSN, FNP 
International Maternal Adolescent Pediatric 
Branch, DAIDS/NIAID/NIH 
5601 Fishers Lane, Rm 8B37 
Rockville, MD 20852-9831 
Phone: (240) 292-4784 
Fax: (240) 627-3465 
Email: ellen.townley@nih.gov 
 
 
 
Adeola Adeyeye, MD, MPA  
Prevention Science Program, DAIDS, NIAID, 
NIH Room 8B36 MSC 9831, 5601 Fishers Lane 
Rockville, MD 20852-9831 
Phone: (240) 669- 5005 
BB: (240) 421-8446 
Email: adeola.adeyeye@nih.gov 
 
NICHD Medical Officer 
Sonia Lee, PhD 
Maternal and Pediatric Infectious Disease 
Branch  
6100 Executive Blvd, Rm 4B11K 
Bethesda, MD 20892 
Phone: (301) 594-4783 
Email: sonia.lee@nih.gov 
 
NIMH Medical Officer  
Susannah Allison, PhD 
Scientific Program Officer 
Infant, Child, & Adolescent Research Programs 
NIMH Division of AIDS Research 
5601 Fishers Lane, 9E26, MSC 9831 
Rockville, MD 20582-9831 
Phone: (240) 627-3861 
Email: Susannah.Allison@nih.gov 
 
Clinical Trials Specialists 
Kathryn Lypen, MPH 
IMPAACT Operations FHI 360  
359 Blackwell St 
Durham, NC 27701 
Phone: (919) 544-7040, Ext. 11684 
Email: klypen@fhi360.org  
 
JL Ariansen, MS 
IMPAACT Operations Center, FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: (919) 544-7040 x11185 
Email: jariansen@fhi360.org 
 
 

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Protocol Statisticians 
Miriam Chernoff, PhD 
Center for Biostatistics in AIDS Research  
Harvard T.H. Chan School of Public Health 
651 Huntington Avenue 
Boston, MA 02115 
Phone: (617) 432-0358 
Email: mchernoff@sdac.harvard.edu 
 
David Shapiro, PhD 
Center for Biostatistics in AIDS Research 
Harvard T.H. Chan School of Public Health 
651 Huntington Avenue 
Boston, MA 02115 
Phone: (617) 432-2426 
Email: shapiro@sdac.harvard.edu 
 
Statistical Programmer 
Shirley Traite, MSW 
Center for Biostatistics in AIDS Research 
Harvard T.H. Chan School of Public Health 
651 Huntington Avenue 
Boston, MA 02115-6017 
Phone: (617) 432-0073 
Email: traite@sdac.harvard.edu 
 
Protocol Data Managers 
Michael Basar, BA  
Frontier Science & Technology Research 
Foundation  
4033 Maple Road  
Amherst NY  14226-1056  
Phone: (716) 834-0900 x7271 
E-mail: basar.michael@fstrf.org 
 
Jenna Kearly, MPH 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: (716) 834-0900 x7249 
E-mail: kearly.jenna@fstrf.org 
 
Laboratory Data Managers 
Kaitley Wozer, BS 
Frontier Science & Technology  
Research Foundation  
4033 Maple Road  
Amherst, NY 14226 
Phone: (716) 834-0900 x7224 
Email: wozer@fstrf.org 
Laura J. Hovind, MS 
Frontier Science & Technology  
Research Foundation 
4033 Maple Road  
Amherst, NY 14226 
Phone: (716) 834-0900 x7468 
Email: hovind@fstrf.org 
 
Central Laboratory Specialist 
Diane Costello 
Children’s Hospital of Los Angeles 
4546 Sunset Blvd. 
Smith Research Tower, Room 902Los Angeles, 
CA 90027 
Phone: (703) 862-0820Email: 
dcostello@impaactlabcenter.org  
 
Laboratory Technologist 
Bill Kabat 
Infectious Disease Laboratory, Ann & Robert H. 
Lurie Children’s Hospital of Chicago 
225 East Chicago Avenue, Box 82 
Chicago, Illinois 60611 
Phone: (312) 227-6291 
Email: bkabat@luriechildrens.org  
 
Protocol Immunologist  
Adriana Weinberg, MD 
Professor of Pediatrics, Medicine and Pathology 
Medical Director of the Molecular and Virology 
Clinical Laboratories 
University of Colorado Denver Anschutz 
Medical Center 
Mail Stop: 8604 
12700 East 19th Ave. Room 11126 
Aurora, CO  80045 
Phone: (303) 724-4480 
E-mail: adriana.weinberg@ucdenver.edu 
 
Westat Clinical Research Associate  
Rita Patel, MS 
Westat, Inc. 
1441 W. Montgomery Ave. 
Rockville, MD 20850 
Phone: (240) 453-2693 
Email: ritapatel@westat.com 
 
 
 
 
 

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19 August 2016 
Investigators 
Graham Emslie, MD  
University of Texas  
Southwestern Medical Center  
5323 Harry Hines Boulevard 
Dallas, TX 75390-8589  
Phone: (214) 456-5921  
E-mail: graham.emslie@utsouthwestern.edu  
 
Laura Whiteley, MD 
Clinical Director of Young Adult Behavioral 
Health 
Department of Psychiatry, Rhode Island 
Hospital  
Assistant Professor, Alpert Medical School of 
Brown University   
167 Point St., Suite 161 
Providence, R.I. 02903  
Phone: (401) 793-8808  
Email: lbwhiteley@gmail.com 
 
Community Program Manager  
Cheryl D. Cokley, BS 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 22701, USA 
Phone: (919) 544-7040 x11359 
Email: ccokley@fhi360.org 
 
Community Advisory Board Member 
Leslie Raneri  
Texas Children’s Hospital  
6621 Fannin St 
Houston, TX 77071  
Phone: (832)689-4845 
Email: lraneri@hotmail.com, 
lgraneri@texaschildrens.org 
 

 
IMPAACT 2002, Version 1.0                   Page 10 of 95                                   19 August 2016 
STUDY SITE ROSTER 
 
Site 5114, Bronx-Lebanon Hospital Center 
Murli Purswani, MD 
Principal Investigator 
Bronx Care Center for Comprehensive Care 
1650 Selwyn Avenue 
9th Floor 
Bronx, NY 10457  
Phone: (718) 579-5337 
Email: mpurswan@bronxleb.org 
 
Martha Cavallo, PNP 
Study Coordinator 
722 W 168th St 
Suite 820 
New York, NY 10032-3727  
Phone: (866) 463-2778 
Email: mcavallo@bronxleb.org 
 
Site 5055, Children’s Diagnostic and Treatment 
Center 
Patricia A. Garvie, PhD 
Psychologist 
Children’s Diagnostic & Treatment Center 
1401 S. Federal Highway 
Fort Lauderdale, FL 33316 
Phone: 954-728-1032 
Email: pgarvie@browardhealth.org 
 
Ana M. Puga, MD, FAAP 
CFAP Medical Director  
Children’s Diagnostic & Treatment Center 
1401 S Federal Highway 
Fort Lauderdale, Florida 33316 
Phone: 954-728-1017 
Email: apuga@browardhealth.org 
 
Site 5030, Emory University School of Medicine 
Andres Camacho-Gonzalez, MD 
Principal Investigator 
Family & Youth Clinic at Ponce, Room 201 
341 Ponce de Leon Avenue NE 
Atlanta, GA 30308 
Phone: (404) 616-9786 
Email: ACAMAC2@emory.edu 
 
 
 
 
Bridget Wynn, MPH 
Study Coordinator 
Family & Youth Clinic at Ponce, Room 201 
341 Ponce de Leon Avenue NE 
Atlanta, GA 30308 
Phone: (404) 966-1487 
Email: Bridget.wynn@emory.edu 
 
Site 5052, The Regents of the University of 
Colorado 
Carrie Chambers, RN 
Study Coordinator 
B055 
Department of Pediatric Infectious Disease 
Children’s Hospital of Colorado 
13123 East 16th Ave 
Aurora, CO 80045 
Phone: (720) 777-4424 
Email:carrie.chambers@childrenscolorado.org 
 
Kimberly Pierce, DNP, RN, CPNP 
Site Clinician, Medication Management 
B055 
Department of Pediatric Infectious Disease 
Children’s Hospital of Colorado 
13123 East 16th Ave 
Aurora, CO 80045 
Phone: (720) 777-2870 
Email: kimberly.pierce@childrenscolorado.org 
 
Site 6501, St Jude Children’s Research Hospital 
Sandra Boyd, RN, MSN, CPNP 
Study Coordinator 
262 Danny Thomas Place, MS 600 
Memphis, TN 38105 
Phone: (901) 595-5059 
Email: sandra.boyd@stjude.org 
 
Megan Wilkins, PhD 
Investigator of Record 
262 Danny Thomas Place, MS 600 
Memphis, TN 38105 
Phone: (901) 595-5965 
Email: megan.wilkins@stjude.org 
 
 
 

IMPAACT 2002, Version 1.0 
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19 August 2016 
Site 5040, The Research Foundation of SUNY- 
Stony Brook University Medical Center 
Michele Kelly, CPNP, NPP 
Study Coordinator 
Department of Pediatrics 
Stony Brook University School of Medicine 
Stony Brook, NY 11794-8225 
Phone: (631) 444-8832 
Email: Michele.kelly@stonybrookmedicine.edu 
 
Site 5013, Jacobi Medical Center 
Andrew Wiznia, MD 
Principal Investigator 
Jacobi Medical Center 
1400 Pelham Parkway South 
Building #1, Suite 1W5 
Bronx, NY 10461 
Phone: (718) 918-4664 
Email: Andrew.wiznia@einstein.yu.edu 
 
Marlene Burey, PNP 
Site Coordinator 
Jacobi Medical Center 
1400 Pelham Parkway South 
Building #1, Suite 1W5 
Bronx, NY 10461 
Phone: (718) 918-4783 
Email: marlene.burey@nbhn.net 
 
Jacobo Abadi, MD 
Pediatrician 
Jacobi Medical Center 
1400 Pelham Parkway South 
Building #1, Suite 1W5 
Bronx, NY 10461 
Phone: (718) 918-4108 
Email: Jacob.abadi@nbhn.net 
 
Ray Shaw, PhD 
Psychologist 
Jacobi Medical Center 
1400 Pelham Parkway South 
Building #1, Suite 1W5 
Bronx, NY 10461 
Phone: (718) 918-4589 
Email: ray.shaw@nbhn.net 
 
 
 
 
Site 5048, The University of Southern 
California- MCA Center 
Mikhaela Cielo, MD 
Investigator of Record 
1000 S. Freemont Avenue 
Unit 62, Bldg. A 
10N Suite 200 
Alhambra, CA 91803 
Phone: (323) 226-4619 
Email: mikhaela.cielo@usc-mca.org 
 
Yvonne Morales, LVN 
Study Coordinator 
1000 S. Freemont Avenue 
Unit 62, Bldg. A 
10N Suite 200 
Alhambra, CA 91803 
Phone: (626) 457-5861 
Email: ytr@usc.edu 
 
Site 3801, Texas Children’s/Baylor 
Chivon McMullen-Jackson, RN, BSN, CCRP 
Study Coordinator 
Texas Children's Hospital/Baylor College of 
Medicine 
Department of Immunology, Allergy & 
Rheumatology  
1102 Bates Ave., Suite 330 
Houston, TX 77030  
Phone: (832) 824-1339 
Email: cdmcmull@texaschildrens.org 
 
Site 4001, Chicago Children’s 
Melanie Koch, LPC 
Health and Wellness CBT 
Lurie Children's Memorial Hospital 
225 East Chicago Ave Box 155 
Chicago IL 60611-2605 
Phone: (312) 227-8269 
Email: mkoch@luriechildrens.org 
 
Site 5092, Johns Hopkins University School of 
Medicine 
Allison Agwu, MD, ScM, FAAP, FIDSA 
PI, JHU IMPAACT and ATN 
Johns Hopkins University School of Medicine 
200 North Wolfe Street, Rm 3145 
Baltimore, MD  21287 
Phone: (410) 614-3917 
Email: ageorg10@jhmi.edu 
 

IMPAACT 2002, Version 1.0 
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19 August 2016 
Thuy Anderson, RN, BSN 
Research Nurse Manager 
Johns Hopkins University 
200 N Wolfe St 
Suite 3147 
Baltimore, MD 21287 
Phone: (443) 287-8942 
Email: tander34@jhmi.edu 
 
Aleisha Collinson-Streng, RN, ACRN 
IMPAACT Nurse Study Coordinator 
Johns Hopkins University 
200 N Wolfe St. 
Suite 3096 
Baltimore, MD 21287 
Phone: (443) 287-8888 
Email: Acolli14@jhmi.edu 
 
Site 5083, Rush University Medical Center 
Mariam Aziz, MD 
Principal Investigator 
2020 W. Harrison 
Chicago, IL 60612 
Phone: (312) 942-4265 
Email: mariam-aziz@rush.edu 
 
Maureen McNichols, RN, MSN 
Study Coordinator 
2020 W. Harrison 
Chicago, IL 60612 
Phone: (312) 572-4541 
Email: Maureen_mcnicols@rush.edu 
 
Katie Howe, MSW 
Therapist 
2020 W. Harrison 
Chicago, IL 60612 
Phone: (312) 572-4541 
Email: khowe@cookcountyhhs.org 
 
Site 5112, David Geffen School of Medicine at 
UCLA 
Jaime Deville, MD 
Principal Investigator 
UCLA Department of Pediatrics 
Division of Infectious Diseases 
10833 Le Conte Ave, MDCC 22-442 
Los Angeles, CA 90095 
Phone: (310) 206-6369 
Email: jdeville@mednet.ucla.edu 
 
Michele Carter, RN 
Study Coordinator 
UCLA Department of Pediatrics 
Division of Infectious Diseases 
10833 Le Conte Ave, MDCC 22-442 
Los Angeles, CA 90095 
Phone: (310) 206-6369 
Email: mfcarter@mednet.ucla.edu 
 
Shellye Jones, LCSW 
Mental Health Clinician 
UCLA Department of Pediatrics 
Division of Infectious Diseases 
10833 Le Conte Ave, MDCC 22-442 
Los Angeles, CA 90095 
Phone: (310) 206-6369 
Email: sdjones@mednet.ucla.edu 
 
Site 4601, UCSD 
Stephen A. Spector, MD 
Investigator of Record 
Director, Mother-Child-Adolescent HIV 
Program 
University of California, San Diego 
La Jolla, CA 92093-0672 
Phone: (858) 534-7055 
Email: saspector@ucsd.edu 
 
Daniel Szpak, RN, CCRC 
Study Coordinator 
UCSD Mother-Child-Adolescent HIV Program 
4076 Third Avenue, Suite 301 
San Diego, CA  92103 
Phone: (858) 534-9216 
Email: dszpak@ucsd.edu 
 
 
 
 

 
IMPAACT 2002, Version 1.0                   Page 13 of 95                                   19 August 2016 
IMPAACT 2002 
Combined Cognitive Behavioral Therapy and a Medication Management 
Algorithm for Treatment of Depression among Youth Living with HIV in the United 
States 
 
SCHEMA 
 
Purpose: 
 
 
To examine if a Health and Wellness Cognitive Behavioral Therapy and 
Medication Management (COMB-R) intervention for depression 
demonstrates improved outcomes for HIV-infected youth in the United 
States 
 
Design:  
 
 
Multi-site, two-arm, cluster-randomized study 
 
Study Population: 
 
HIV-infected youth, ages 12 to 24 years, diagnosed with nonpsychotic 
depression 
 
Sample Size: 
 
 
Approximately 14 sites will be randomized. A total of 156 participants 
will be enrolled to achieve at least 140 evaluable for primary study 
outcomes. The sample size may be increased to achieve a sufficient 
number of evaluable participants, if the percentage of non-evaluable 
participants or the intracluster correlation coefficient turn out to be 
higher than assumed for the sample size calculations 
 
Study Intervention: 
 
Sites will be assigned to provide either COMB-R or Enhanced Standard 
of Care (ESC) to enrolled participants for 24 weeks  
 
Study Duration:  
 
Approximately 36 months total; accrual is expected to require 
approximately 24 months and each enrolled participant is expected to 
complete approximately 48 weeks of follow-up 
 
Primary Objectives 
 
To evaluate whether the Health and Wellness Cognitive Behavioral Therapy and Medication 
Management Algorithm (COMB-R) treatment for depression is associated with improved depression 
outcomes at 24 weeks, compared to Enhanced Standard Care (ESC) 
 
To evaluate whether COMB-R is associated with improved biological measures of health over 24 
weeks, including CD4 cell numbers and copies of HIV RNA in plasma compared to ESC   
 
Secondary Objectives 
 
To assess whether COMB-R is associated with improved adherence for HIV and depression treatment 
compared ESC for the first 24 weeks and whether any differences are maintained at 48 weeks  
 
To assess whether differences in depression treatment outcomes are maintained at 48 weeks 
 
To assess whether demographic, behavioral, and biological factors could moderate the efficacy of 
COMB-R compared to ESC arms  
 
To assess whether COMB-R is associated with improved behavioral risk outcomes (alcohol/drug use; 
sex-risk behaviors) compared to those on ESC at Week 24 and Week 48 
 
To describe the implementation fidelity at COMB-R sites and the counseling strategies and 
medication patterns at ESC sites 
 
To describe and compare the number of interim visits, the frequency of medication use, and 
acceptability of COMB-R and ESC among participants and clinicians 

IMPAACT 2002, Version 1.0 
Page 14 of 95 
19 August 2016 
 
To compare the frequency and types of Grade 3 or higher Adverse Events, psychological 
hospitalizations and suicide attempts between COMB-R and ESC arms 
1 
INTRODUCTION 
 
1.1 
Background  
 
Depression is common in patients with Human Immunodeficiency Virus (HIV). The majority of 
studies suggest that rates of psychiatric disorders, particularly mood disorders, are higher in 
patients with HIV than in the general population. In a study of 2,032 youth aged 14 to 24 living 
with HIV and in medical care, 21% had depression (1). In a study examining psychiatric care 
among 2,864 adults with HIV, 26% had sought individual or family treatment, 27% had regularly 
taken medication for depression, anxiety, or other emotional problems, and over 40% had 
discussed emotional problems with their medical provider (2, 3). Vitiello (3) further reported that 
among those taking antidepressants, 63% were taking at least one other psychotropic medication, 
suggesting that patients with HIV have significant difficulties with emotional disturbance, often 
requiring treatment beyond a single antidepressant. In the study by Bing, participants younger 
than 35 years old had a higher chance of having major depression, dysthymia, generalized anxiety 
disorder, or panic attacks (4), suggesting that younger age may be associated with increased risk 
of depression and other psychiatric disorders.  
 
A full understanding of the mechanisms leading to depression in HIV-infected individuals is 
currently lacking. HIV infects glial cells of the central nervous system promoting local 
inflammation and cell destruction (5, 6). However, the systemic inflammatory component of HIV 
infection may play an additional role in its neurologic complications, just as it is a major 
determinant of other end-organ disorders. Animal models and studies of HIV-infected and 
uninfected individuals support the notion that systemic inflammatory factors may contribute to 
depression and other mood disorders (7-10) (11, 12). Conversely, depression also interferes with 
the treatment of HIV infection creating the potential of a vicious cycle in which individuals may 
fail to adhere to treatment regimens.  
 
Children and youth infected with HIV at birth have additional factors, both biologic and 
environmental which may contribute to psychopathology. IMPAACT P1055, a prospective, 
longitudinal cohort study performed at 29 U.S. sites, found that 27% reported psychiatric 
symptoms that interfered with functioning. Although rates were comparable to a peer comparison 
group which included youth uninfected with HIV who were either perinatally exposed to HIV or 
were living in a household with an HIV-infected member (including some who were siblings of 
youth in the HIV-infected cohort), HIV positive youth were more likely to have received 
psychotropic medications and counseling, perhaps due to greater contact with medical care 
facilities (13). 
 

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As in medically healthy individuals, depression leads to decreased functioning and poorer 
outcomes in patients with HIV. Several studies have shown that depression interferes with 
adherence to HIV treatment, increases caregiver burden, increases healthcare costs, and decreases 
quality of life. Thus, addressing depressive disorders is essential for improving both psychiatric 
and medical outcomes for those living with HIV. In a retrospective cohort study over a three-year 
period, it was found that of 3,359 adults receiving HIV care, 42% (n=1398) had a diagnosis of 
depression and 15% (n=508) were receiving selective serotonin reuptake inhibitor (SSRI) 
treatment. In the 12 months after initiation of antiretroviral treatment, the study demonstrated that 
depressed adults had significantly decreased medical adherence and reduced ability to achieve an 
HIV viral load below 500 copies/mL than non-depressed patients (p=0.02). Depressed patients 
who were being treated with an antidepressant showed similar medical outcomes (adherence and 
viral load) to non-depressed patients, and significantly better outcomes than depressed patients 
not receiving antidepressant medication (14). Controlled trials and reviews indicate that treatment 
with SSRI medications can also lead to improved CD4 T-cell counts (14). Research into whether 
treating the depressive disorder leads to similar results in younger age groups is needed, 
particularly given that this age group has such a high rate of non-adherence to ARV treatment.  
 
Current APA Practice Guidelines recommend treatment interventions for depression in persons 
living with HIV similar to those for non-medically ill patients with depression, albeit with 
increased attention to the potential drug-drug interactions with antidepressants (15). In those who 
are HIV-uninfected a combination of psychiatric medication and psychotherapy is recommended. 
The use of both a medication algorithm and cognitive behavioral therapy (CBT) has been shown 
to be most effective for the treatment of moderate and severe depression in a number of clinical 
trials and is considered the gold standard for treatment (16, 17). Studies in the U.S. and abroad 
suggest that collaborative care using measurement-based evidenced-based clinical decisions are 
effective for the treatment of chronic diseases, including depression (18, 19). Unfortunately, this 
standard of care (CBT and a medication algorithm in a collaborative care model) is often not 
practiced. Psychopharmacologic treatment algorithms for depression in non-infected individuals 
are often not followed in treatment settings because of the concern of clinicians about drug-drug 
interactions or idiosyncratic opinions about the efficacy of specific medications. Medication 
guidelines and CBT tailored for youth living with HIV do not exist for the treatment of 
depression. In addition, CBT is often unavailable for patients (16, 20) and CBT tailored for youth 
living with HIV (e.g. focusing on adherence, coping with medical illness, stigma) is not 
uniformly available or tested. For example, in the IMPAACT Network, only three of the 33 U.S. 
sites that were polled during the development of the study indicated that they are currently using a 
structured CBT manual, and the same number indicated that a medication management algorithm 
was used for treatment of depression. Only two sites indicated that both practices were used 
simultaneously. Finally, no IMPAACT site queried reported utilizing CBT or a medication 
algorithm that was adapted or tailored to the unique needs of HIV-infected patients. 
 
1.2 
Prior Research 
 
The Adolescent Medicine Trials Network (ATN) 080, which concluded in October 2013, is the 
one other intervention study combining a medication algorithm and cognitive behavioral therapy 
in a stepped-care framework for the treatment of depression in youth living with HIV. This study 
will build on results from ATN 080. As shown in Table 1 below, the mean age of the 42 
participants in ATN 080 was 21 years, and most were behaviorally-infected males. The four sites 
were randomly assigned to either the combination treatment condition (COMB) or to treatment as 
usual (TAU). 
 

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ATN 080 participants: 
 
Mean age: 21.5 (range 18-24) 
 
Male: 69% (COMB 95%, TAU 40%) statistically significant difference between conditions 
 
Black: 83% 
 
Hispanic: 21% 
 
Behaviorally-acquired HIV: 90% 
 
CD4 < 500: 52% 
 
Viral load < 400: 50% 
 
At baseline, participants were judged by clinicians and by self-report to have moderate to severe 
depression as measured by validated scales. Outcomes on the major endpoints are shown below. 
 
Table 1 
Depressive Symptom Outcomes 
 
 
Baseline 
Week 12 
Week 24 
Week 48 
 
COMB 
TAU 
COMB 
TAU 
COMB 
TAU 
COMB 
TAU 
Measure 
N=22 
N=20 
N=19 
N=19 
N=20 
N=20 
N=17 
N=15 
QIDS* – 
Clinician (S.D.) 
15.4 
(4.4) 
14.1 
(4.1) 
6.9 
(4.3) 
N/A 
 
2.1 
(2.6) 
10.4 
(5.5) 
N/A 
(1.8) 
N/A 
 
QIDS* – Self-
report (S.D.) 
15.5 
(4.9) 
15.4 
(4.0) 
7.4 
(4.4) 
11.0 
(5.6) 
4.3 
(2.9) 
11.1 
(4.6) 
4.1 
(3.5) 
10.2 
(5.5) 
Response rate  
(QIDS*↓≥50%) 
__ 
__ 
52.6% 
21.1% 
85.0% 
20.0% 
88.2% 
33.3% 
Beck 
Hopelessness 
Scale (S.D.) 
10.3 
(4.1) 
8.3 
(3.8) 
5.9 
(4.5) 
7.5 
(5.7) 
4.8 
(3.6) 
6.1 
(3.3) 
3.6 
(1.8) 
6.0 
(3.7) 
*QIDS = Quick Inventory of Depression Symptomatology 
 
Analyses examined the effect of condition on the outcomes over time, adjusting for baseline 
values and gender. Overall, the analyses indicated that participants in the COMB intervention 
reported significantly fewer symptoms of depression at all follow-up points (all p < .0001), and 
exhibited a response to treatment three to four times of that reported by those in the TAU 
condition. The effects were maintained at Week 48, which was 24 weeks after the intervention 
concluded. Similar changes were seen in the clinician scores for depression at Week 24, which 
was the primary endpoint of the study (clinician data was not collected beyond 24 weeks). 
Participants in the COMB intervention also reported significantly less hopelessness over time 
than did those in the TAU condition. There were no differences between conditions in the scores 
on Life Satisfaction Scale or CD4 but scores changed in the expected direction. Among those 
with a detectable HIV viral load at baseline, reduction in viral load was associated with reduction 
in depressive symptoms, although there was no difference based on condition. 
 
This study builds on the demonstration of efficacy of COMB found in ATN 080 by: (1) testing a 
“core component” version of COMB that retains all of the essential elements of the collaborative, 
stepped care intervention but is adapted for easy implementation and dissemination (COMB-R), 
(2) examining the impact of COMB-R on biological and medical adherence outcomes with a 
larger sample with greater power to detect differences than was available in the ATN trial, and (3) 
examining potential moderators of the intervention’s impact, which could not be examined in the 
ATN study. Specifically, this trial will be able to examine the impact of gender, transmission 
category, and initial level of depression because it will enroll more females, younger ages (and 

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therefore more youth who are perinatally infected) and those with milder depressive symptoms 
than did ATN 080. In addition, the project will collect data on the number of interim visits to 
judge the impact of mental health treatment sessions. Data on these factors need to be collected in 
U.S. IMPAACT sites prior to the development of guidelines for the treatment of depression in 
youth living with HIV and prior to the translation and cultural adaptation that will be needed for 
interventions internationally.  
 
1.3 
Rationale 
 
Depression is prevalent among youth living with HIV. While approximately 8% of the general 
adolescent population develops depression, prevalence among adolescents and young adults 
living with HIV has been reported as high as 50% (14, 21-23). HIV-infected individuals who 
have depression have poorer outcomes, not only with regard to functioning and life satisfaction, 
but also with medical outcomes. Studies indicate that depression leads to reduced adherence to 
HIV treatment and in turn HIV illness progression. Treatment of depression leads to improved 
life satisfaction, improved treatment adherence, and reduced illness progression (24). Although 
depression among youth living with HIV is prevalent and detrimental to treatment outcomes, little 
research has been conducted on the treatment of depression among HIV-infected adolescents and 
young adults. 
 
In non-HIV infected populations there is significant evidence supporting the use of depression 
treatment strategies that combine psychiatric medication and therapy. Specifically, the utilization 
of both medication algorithms and cognitive behavioral therapy has been shown to be most 
effective for the treatment of moderate and severe depression in a number of clinical trials (25). 
However, simply extrapolating from depression trials in non-infected individuals is insufficient 
when providing treatment for HIV-infected youth. Individuals living with both HIV and 
depression are a unique population and present distinct diagnostic difficulties (e.g. symptoms 
common to both depression and HIV-related illnesses), as well as medical treatment issues (e.g. 
drug-drug interactions). Furthermore, adolescents with HIV present with additional and unique 
hurdles during treatment for depression compared to adults. This age group responds differently 
than adults to antidepressant treatments (e.g. lower response rates) (26) and adherence to mental 
health treatment (problematic in medically healthy youth) is further complicated and magnified 
by frequent treatment non-adherence associated with youth living with HIV. In addition, studies 
consistently indicate that CBT should be tailored for important developmental, cultural and 
contextual factors (27-29). 
 
CD4 cell numbers and HIV plasma RNA burden are key measures of HIV disease progression. 
AIDS and non-AIDS adverse events, including neurocognitive disorders, are more common in 
HIV-infected individuals with low CD4 cell counts and high HIV plasma RNA burden. In this 
study we will determine the association of depression with CD4 cell numbers at entry and at 
nadir, HIV plasma RNA burden at entry and CDC category. However, depression is associated 
with low adherence to antiretroviral medication contributing to HIV disease progression. Thus, 
CD4 cell counts and HIV plasma RNA burden at the end of this study will be used as outcome 
measures, to test the hypothesis that an effective treatment of depression will improve adherence 
and consequently decrease HIV replication and increase CD4 cell counts. 
 

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The role of inflammation in neurocognitive disorders, including depression, is becoming 
increasingly recognized. Both in HIV-infected and uninfected individuals, high levels of C 
reactive protein, IFN alpha, fibrinogen, sP-selectin and IL6 have been associated with the 
development of depression and other neurocognitive disorders. Furthermore, in HIV-infected 
individuals, inflammation as measured by sCD14, IL1 beta, IL 6, di-dimers, TNF alpha, CCL10 
and VCAM1 in the blood compartment and at mucosal sites has been shown to be a major 
component of HIV pathogenesis (30-33). Thus, inflammation and depression may synergize in 
HIV-infected individuals, further increasing morbidity. Inflammation may respond to 
interventions that improve adherence to and effectiveness of antiretroviral treatments.  
 
Recent studies of HIV-infected individuals on ART uniformly show that the majority of adverse 
clinical outcomes with high morbidity and mortality are currently non-AIDS related (34-37). In 
the current treatment era, increased plasma inflammatory biomarkers are the best predictors of 
non-AIDS serious adverse events, morbidity and mortality of HIV-infected individuals (38-40). 
Thus, decreasing inflammatory biomarkers is extremely important in association with any 
intervention that aims at improving the long-term prognosis of HIV-infected individuals. 
Therefore, we will study the effect of the neuro-behavioral interventions planned in this protocol 
on plasma inflammatory biomarkers.  
 
The intervention to be evaluated in this study is a treatment for depression that includes 
manualized Health and Wellness Cognitive Behavioral Therapy (H&W CBT) for youth living 
with HIV and Medication Management using an algorithm (MM). The H&W CBT addresses the 
unique challenges faced by this population. The intervention, utilizing collaborative care, 
evidence-based strategies (H&W CBT and MM) for youth living with HIV, will be compared to 
Enhanced Standard Care (ESC) for depression at selected IMPAACT sites. The study will 
examine whether participants receiving a tailored, evidenced-based and stepped-care treatment 
for depression (H&W CBT and MM) demonstrate improved depression and medical outcomes 
compared to participants receiving ESC. 
 
1.4 
Hypotheses 
 
1) Participants receiving COMB-R will demonstrate improved depression outcomes (e.g., 
decreased depressive symptoms, and greater remission and response rates) compared to 
participants receiving ESC. 
 
2) Participants receiving COMB-R will demonstrate improved medical outcomes (e.g., 
increased CD4 T-cell count, decreased HIV RNA level) compared to participants receiving 
ESC.  
 
2 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
The primary objectives of this study are to:  
 
2.1.1 
To evaluate whether the Health and Wellness Cognitive Behavioral Therapy and 
Medication Management Algorithm (COMB-R) treatment for depression is associated 
with improved depression outcomes at 24 weeks, compared to Enhanced Standard Care 
(ESC).  

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2.1.2 
To evaluate whether the COMB-R is associated with improved biological measures of 
health over 24 weeks, including CD4 cell numbers and copies of HIV RNA in plasma 
compared to ESC.  
 
2.2 
Secondary Objectives 
 
The secondary objectives of this study are to:  
 
2.2.1 
To assess whether COMB-R is associated with improved adherence for HIV and 
depression treatment compared to ESC for the first 24 weeks and whether any differences 
are maintained at 48 weeks. 
 
2.2.2  To assess whether differences in depression treatment outcomes are maintained at 48 
weeks. 
 
2.2.3 
To assess whether demographic, behavioral, and biological factors could moderate the 
efficacy of COMB-R compared to ESC arms  
 
2.2.4  To assess whether COMB-R is associated with improved behavioral risk outcomes 
(alcohol/drug use; sex-risk behaviors) compared to those on ESC at Week 24 and Week 
48 
 
2.2.5 
To describe the implementation fidelity at COMB-R sites and the counseling strategies 
and medication patterns at ESC sites.  
 
2.2.6  To describe and compare the number of interim visits, the frequency of medication use, 
and acceptability of COMB-R and ESC among participants and clinicians 
 
2.2.7 
To compare the frequency and types of Grade 3 or higher Adverse Events, psychological 
hospitalizations and suicide attempts between COMB-R and ESC arms 
 
2.3 
Exploratory Objectives 
 
The exploratory objectives of this study are to:  
 
2.3.1  To examine whether COMB-R is associated with a larger decrease in plasma 
inflammatory biomarkers from entry to Weeks 24 and 48 compared to ESC 
 
2.3.2  To evaluate the moderating effect of inflammatory markers on the efficacy of COMB-R 
compared to ESC. 
 
 
 
 
 
 

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3 
STUDY DESIGN 
 
IMPAACT 2002 study is a prospective, multi-site, two-arm cluster-randomized study of the 
efficacy of a cognitive-behavioral intervention (COMB-R) for depression in youth with HIV 
compared to enhanced standard care (ESC). Youth enrolled in the study will attend a 
Screening/Entry Visit and study visits at Weeks 1, 6, 12, and 24. They will have two additional 
follow-up visits at Weeks 36 and 48 for the study team to evaluate if observed effects of the 
intervention are maintained.  
 
Approximately 14 U.S. IMPAACT sites will be randomly assigned to either the COMB-R group 
or the ESC group. Randomization of sites was chosen due to the potential contamination that 
could occur if same site clinicians were delivering both ESC and COMB-R. A pre-study survey 
will ascertain various characteristics, such as number of youth served, gender, age (12-18 versus 
19-24 years of age), viral suppression status (below versus not below the level of detection as 
defined by the laboratory), transmission routes (perinatal versus behavioral HIV acquisition), 
initial levels of depression (moderate vs. severe), and whether site IRBs will allow a parental 
waiver of consent. A restricted randomization procedure will be used to assign sites to the two 
study arms in a way that balances these characteristics across arms (based on the pre-study 
survey). The protocol team will also monitor the balance of these characteristics in the two study 
arms (blinded to which arm is which) on a quarterly basis, or as needed, and may impose limits 
on enrollment of participants with one or more of the specific characteristics noted above, if it is 
determined that any of these characteristics of the study arms are becoming unbalanced. Further 
details on the randomization procedure and criteria for adjusting enrollment at sites are provided 
in Section 9.0. The protocol includes several design features to minimize selection bias, including 
defining eligibility criteria that apply equally to both study arms; requiring sites to obtain 
screening numbers for all potentially eligible participants and randomizing the order in which the 
site will approach potential participants for enrollment; and collecting limited data on patients 
who do not enroll so that their characteristics can be compared to those of participants who did 
enroll (to assess the potential extent of selection bias). New randomized lists will be created for 
sites as needed. 
 
Selected sites will have the capacity to enroll at least eight participants over the two years of 
enrollment and to perform assessments listed in Section 6.0 of the protocol. They will also have a 
mental health clinician, who will be trained in H&W CBT, treat youth between the ages of 12 and 
24 and their families, attend a monthly phone supervision call, and treat approximately three 
participants in weekly H&W CBT. The sites also have access to a licensed prescriber (MD or 
LNP, etc.) who will be trained in the MM algorithm, attend monthly conference calls, and follow 
the MM guidelines. A clinician will be available to verify the diagnosis of depression and clinical 
eligibility criteria at time of enrollment. COMB-R sites will have the capacity to obtain the QIDS-
SR from the patient and provide the score to the clinician at the time of the medication 
management visit.  
 
4 
STUDY POPULATION 
 
The study population will be HIV-infected youth with depression, who meet criteria outlined in 
Sections 4.1 and 4.2.  
 
 
 

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4.1 
Inclusion Criteria 
 
Potential participants must meet all of the following criteria in order to be included in this study: 
 
 
4.1.1 
Age 12 through 24 years (inclusive)  
 
4.1.2  Receiving mental health or HIV-related care at participating U.S. IMPAACT sites  
 
4.1.3  Confirmation of HIV-1 Infection 
 
Has confirmed HIV-1 infection based on testing of two samples (whole blood, serum, or 
plasma) collected at different time points: 
 
Sample #1 may be tested using any of the following:  
 
Two rapid antibody tests from different manufacturers or based on different 
principles and epitopes  
 
One EIA or Western blot OR immunofluorescence assay OR chemiluminescence 
assay 
 
One HIV DNA PCR  
 
One quantitative HIV RNA PCR (above the limit of detection of the assay)  
 
One qualitative HIV RNA PCR 
 
One total HIV nucleic acid test  
 
Sample #2 may be tested using any of the following:  
 
One rapid antibody test. If this option is used in combination with two rapid tests for 
Sample #1, at least one of the three rapid tests must be FDA-approved and the third 
rapid test must be from a third manufacturer or based on a third principle or epitope.  
 
One EIA OR Western blot OR immunofluorescence assay OR chemiluminescence 
assay 
 
One HIV DNA PCR  
 
One quantitative HIV RNA PCR (above the limit of detection of the assay)  
 
One qualitative HIV RNA PCR  
 
One total HIV nucleic acid test  
 
If both samples are tested using antibody tests, at least one of the samples must be tested 
in a laboratory that operates according to Good Clinical Laboratory Practice (GCLP) 
guidelines and participates in an appropriate external quality assurance program. If 
nucleic acid testing is used, at least one test must be performed in a CLIA certified or 
equivalent laboratory. For tests performed in other settings, adequate source 
documentation including the date of specimen collection, date of testing, test performed, 
and test result must be available.  
 
4.1.4  Participant aware of his or her HIV infection, as determined by site staff   
 
4.1.5  Per clinician assessment, primary diagnosis of nonpsychotic depression, including Major 
Depressive Disorder, Depression NOS, or Dysthymia, as defined by DSM-IV or DSM-V 
criteria 
 

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4.1.6  Current depressive symptoms that warrant intervention as determined by a score of ≥ 11 
on the Quick Inventory of Depressive Symptomatology – Clinician (QIDS-C) 
 
4.1.7  Able to communicate in spoken and written English 
 
4.1.8  Able and willing to provide written informed assent/consent and able to obtain written 
parental or guardian permission (if required, as specified in site SOP, by State law, and/or 
IRB policy) to be screened for and to enroll in IMPAACT 2002  
 
4.2 
Exclusion Criteria 
 
Potential participants who meet any of the following criteria will be excluded from this study: 
 
4.2.1 
Known or self-reported by participant to have a history of any psychotic disorder and/or 
bipolar I or II disorder 
 
4.2.2  Severe disorders (more than 6 symptoms) based on DSM-V criteria) related to alcohol, 
cannabis or other substances; or those with moderate symptoms (4 or 5 symptoms) who 
are also currently experiencing withdrawal or dependence symptoms; within the past 
month prior to enrollment 
 
4.2.3  Per clinician assessment at screening, depression and/or suicidal ideation requiring more 
intensive treatment than the study provides or at immediate risk of being a danger to 
themselves or others 
 
4.2.4 
Per participant report at screening, intends to relocate away from the study site during 
study participation 
 
4.2.5 
Participant currently in therapy with a non-study provider, unless willing to switch to a 
study-trained provider 
 
4.2.6  Has any other condition that, in the opinion of the Investigator of Record (IoR)/designee, 
would preclude informed assent/consent, make study participation unsafe, complicate 
interpretation of study outcome data, or otherwise interfere with achieving the study 
objectives 
 
4.3 
Co-Enrollment Considerations 
 
Co-enrollment in other studies is not precluded, although careful consideration must be given to 
issues such as eligibility criteria, visit burden, and interpretation of outcome data across studies. 
Given these considerations, requests for co-enrollment must be approved in advance by the 
Protocol Teams of both studies. 
 
4.4 
Recruitment, Screening, and Enrollment Process 
 
After the sites are randomized to COMB-R or ESC (see Section 9.3), participants will be 
recruited in a systematic manner from among the potentially eligible HIV-infected youth patient 
population at each site. Sites should consider youth with or without a history of depression, those 
with or without a history of mental health treatment, and those currently in mental health 
treatment; providing they are thought to meet study eligibility criteria. 

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As noted in Sections 3.0 and 9.1, selection bias is a concern. The protocol includes several design 
features to minimize selection bias, including requiring sites to obtain screening numbers for all 
potentially eligible participants and randomizing the order in which the site will approach 
potential participants for enrollment; and collecting limited data on patients who do not enroll so 
that their characteristics can be compared to those of participants who did enroll (to assess the 
potential extent of selection bias). New randomized lists will be created for sites as needed 
 
It is expected that site staff will approach all potentially eligible youth for possible study 
participation. Patients will be recruited, and proceed with the screening process as follows: 
 
1. Sites create a list of all potentially eligible youth at their site and complete a Screening Log in 
the Subject Enrollment System (SES) for each patient from their list. Completion of the 
Screening Log will generate a screening number. 
2. Prior to site initiation of formal screening and enrollment into the study, the Statistical Data 
Management Center (SDMC) will retrieve the lists of potential participants entered, and 
randomly order all of the screening numbers within each site into blocks. The DMC 
randomization department will load these blocks into the randomization system and send the 
blocks to the sites; the team will then notify sites that this process has been completed and 
that they can begin screening and enrollment.  
3. Sites may start screening and enrolling anyone from their first block of screening numbers. 
Patients from the subsequent blocks may not be approached until all patients from the 
previous block are enrolled or have been approached but will not enroll into the study (for 
any reason).  
4. If a patient is interested in the study, they will undergo the informed assent/consent process 
and be assigned a PID. If a patient is approached but not interested in enrolling in the study, 
the site will submit a Screening Failure Result Form using the screening number. This form 
will collect the reason(s) for not enrolling (i.e., ineligibility, refusal, and associated reasons 
for ineligibility or refusal), in addition to the patient’s gender, race, age, viral suppression 
status, depression severity estimate, and mode of transmission. This record will not include 
patient-identifying data because they have not yet provided informed assent/consent for the 
study. 
5. When a patient is enrolled into IMPAACT 2002, the screening number, in addition to the 
eligibility criteria, will be entered into the data base. The DMC randomization system will 
verify that the screening number is on the list. Enrollment will occur upon successful entry of 
required eligibility data into the SES. Successful entry into the SES will generate a study 
identification number (SID). 
 
Ideally, screening and enrollment into the study will be conducted on one day, if the participant is 
willing and found to be eligible.  
 
Ineligible participants may rescreen for study participation provided their initial reason for 
ineligibility has changed. In addition, those participants listed on the pre-screening list who do not 
screen for the study or do not enroll for any reason may be subsequently assigned new screening 
numbers, and new potential participants will be assigned screening numbers as they are 
identified. The SDMC will regularly retrieve the lists of potential participants and steps 2 through 
5 above will be repeated as needed to achieve the target study enrollment.  
  
The protocol team will provide site staff with standardized training on pre-screening and 
screening potential participants, such that patient characteristics are balanced across study arms. 
Refer to Section 9.5 for more information on monitoring participant accrual in this study. 
 

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Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol informed consent form(s) approved, as appropriate, by 
their local institutional review board (IRB)/ethics committee (EC) and any other applicable 
regulatory entity. Upon receiving final approval, sites will submit all required protocol 
registration documents to the DAIDS Protocol Registration Office (DAIDS PRO) at the 
Regulatory Support Center (RSC). 
 
4.5 
Participant Retention 
 
Once a participant is enrolled in IMPAACT 2002, the study site will make every effort to retain 
them in follow-up through their study end date. Optimally, participant retention procedures will 
be established such that loss rates do not exceed 15% of enrolled participants over the 48 weeks 
of follow-up, and do not exceed 10% during the first 24 weeks of follow-up. Study site staff are 
responsible for developing and implementing local standard operating procedures to target this 
goal. Refer to Section 9.5 for more information on monitoring participant retention in this study. 
 
5 
STUDY INTERVENTIONS 
 
This study will not directly supply or distribute any ARVs or psychiatric medications to study 
participants. Details on the study intervention are included below for COMB-R (Section 5.1) and 
ESC (Section 5.2). Specific measures and assessments used across both arms are further 
explained in Section 5.3. Descriptive data on provider characteristics will be collected at all sites 
and may include the provider’s position at the site, degree and specialty, years since degrees, 
years of HIV experience, years working with adolescents, and/or other similar characteristics. 
 
5.1 
COMB-R Study Sites 
 
Therapists at COMB-R sites will provide behavioral therapy to participants as per the Cognitive 
Behavioral Manual. Health and Wellness (H&W) Cognitive Behavioral Therapy (CBT) and 
medication management treatment strategies have been developed specifically for youth living 
with both HIV and depression. H&W CBT is based on a relapse prevention CBT manual for 
treating youth with depression who are uninfected (41) and upon research on adults with HIV 
(42). H&W CBT uses problem-solving, motivational interviewing, and cognitive-behavioral 
strategies to decrease adherence obstacles and increase wellness. Further details on these manuals 
are provided in Sections 5.1.1 and 5.1.2 below. Participants will also complete behavior 
questionnaires and receive laboratory testing to monitor HIV disease progression. 
 
 
 
 
 
 
 
 
 
 
 

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5.1.1 
Medication Management (MM) Manual 
 
The MM manual includes guidance for clinicians on strategies and tactics to treat depression in 
this population, including factors to consider when deciding on treatments (i.e., drug-drug 
interactions, side effects). An algorithm will be used that specifies the order of the antidepressant 
medications to be used (with several options at each stage), length of time, and doses for 
antidepressant treatment, taking into consideration current and previous medications used for 
depression and their reported response. The algorithm was developed based on current practice 
guidelines for treating adolescent and young adult depression, as well as recommendations from 
the American Psychological Association (APA) guidelines for treating depression in participants 
with HIV. In addition, due to frequent side effects associated with HIV illness and treatments, it 
is likely many of these participants will have other symptoms associated with depression, such as 
anxiety, aggression/irritability, and severe sleep disturbance. Most medication treatment 
guidelines fail to address these symptoms. However, the MM manual includes components from 
algorithms used in completed trials with depressed and suicidal adolescents, which provide 
treatment options for associated symptoms such as these (43-45). 
 
The algorithm provides a guideline for clinicians, which includes several treatment options; 
clinicians then have freedom to choose in which direction to take the participant. The algorithm is 
not intended to restrict the clinician; rather, it provides a framework by which to treat depressed 
adolescents and young adults based on the scientific data available. Clinicians will be expected to 
follow the algorithm, and if deviations from the algorithm are made, justification and 
documentation as to the reason for the deviation will be recorded on the Medication Management 
Checklist. Decisions concerning medication changes will be discussed on the monthly COMB-R 
medication management calls. 
 
Clinicians often continue individuals on suboptimal doses or ineffective medications for too long 
or make medication changes too quickly without adequate opportunity for the initial medication 
to work. The algorithm will provide decision points throughout treatment intended to guide the 
clinician to evaluate whether treatment is sufficiently improving depressive symptoms and 
provides guidelines for alternative strategies if there is inadequate improvement.  
 
Despite using treatments from general adolescent and adult depression populations, modifications 
have been made to address issues specific to adolescents and young adults living with HIV. 
Specifically, the manual includes:  
 
1) A medication staged approach: The first stage of treatment in the MM manual is a non-
medication stage (Stage 0) in which participants are monitored. If participants, their 
parent/guardian (if parental consent required), and clinician agree that their depressive symptom 
presentation does not warrant medication treatment, they may continue in this stage until a 
decision is made to initiate antidepressant treatment. The visit schedule will remain the same for 
participants who do not begin antidepressants so they can continue to be closely monitored for 
potential worsening of depression. It is possible that some participants will not require any 
medication for depression. Subsequent stages of the algorithm are based on using medications 
with the greatest efficacy and fewest side effects first, followed by medications with less 
empirical evidence and potential increased risk. Generally, Stage 1 includes SSRI medications, as 
these appear most efficacious with the fewest side effects. Subsequent stages will include an 
alternative SSRI, followed by other novel antidepressants (e.g., bupropion, venlafaxine). At each 
stage, participants with a partial response to the antidepressant may be prescribed augmenting 
agents (e.g., lithium, bupropion, and atypical antipsychotics) to enhance the treatment response. 
Additional stages will be provided, although there is less empirical evidence for these later stages. 

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Medications such as atypical antipsychotics and sleep aids may also be used to address associated 
symptoms, and recommended methods for implementing these medications are included in the 
manual. See Table 2 for an outline of the medication stages. 
 
2) Psychoeducation about adherence: Adherence to medications in general is often a problem for 
adolescents and young adults with HIV. This population is required to take multiple medications, 
many of which cause significant side effects, and are expected to be taken indefinitely. 
Furthermore, depression often leads to reduced compliance with medication for medical 
conditions, which in turn causes worsening of medical symptoms, which can also lead to further 
depression. Compounding this issue, some youth will not want to take additional medications to 
treat depression on top of their HIV regimen. One component of the MM in this study will be 
education about the importance of compliance, both with the antidepressant treatment as well as 
ARV treatments. The H&W CBT therapist will provide more in depth education and motivational 
interviewing (MI) to improve adherence, while the site prescribing clinician will focus more on 
the medical impact of adherence and non-adherence.  
 
3) Issues related to side effects associated with antidepressants and/or HIV medications: Another 
modification specific to HIV-infected adolescents and young adults is the role of potential 
antidepressant side effects. While the side effect profile of medications is always a consideration 
for individuals, regardless of medical status, it is a particularly guiding factor for those with 
serious medical conditions and/or chronic medication interventions. For example, weight loss is a 
common side effect associated with ARVs and their treatments. Some antidepressants are more 
known for causing weight gain (e.g., mirtazapine), and may serve not only as an antidepressant, 
but also to reduce weight loss. Other common side effects of ARVs and associated treatments that 
may be improved by different antidepressants include fatigue, insomnia, and nausea. The manual 
has been modified to include specific side effects associated with each of the antidepressants, a 
list of common side effects associated with ARVs and ARV treatments, and recommendations for 
specific antidepressants that may improve those symptoms.  
 
4) Drug-drug interactions associated with the medication options: Drug-drug interactions among 
antidepressants and ARV treatments will need to be considered. The manual has been modified to 
include potential drug-drug interactions so physicians can avoid these combinations. A recent 
review by Yanofski and Croarkin (46) addresses safety and side effect issues related to treating 
depression concurrently with antiviral medications. Thus, study investigators have collaborated 
with Dr. Croarkin, as well as other experts and clinicians in the ATN, to address these issues in 
the manual. It is beyond the scope of this exploratory study to conduct formal pharmacokinetic 
analyses of relevant antidepressants and ARV treatments, so this study will rely on existing data 
and expert opinion to address the issues of drug-drug interaction.  
 

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Table 2 
Stages of the Medication Algorithm for Depression 
 
Stage 
Treatment 
Medication Options 
Stage 0 
No medication 
N/A 
Stage 1 
Monotherapy with SSRI 
Fluoxetine, citalopram, sertraline, escitalopram, 
paroxetine 
Partial responders after six weeks may receive 
augmentation with lithium, bupropion, or an atypical 
antipsychotic 
Stage 2 
Monotherapy with 2nd SSRI  
Fluoxetine, citalopram, sertraline, escitalopram, 
paroxetine 
Partial responders after six weeks may receive 
augmentation with lithium, bupropion, or an atypical 
antipsychotic 
Stage 3 
Monotherapy with non-SSRI 
Venlafaxine, bupropion, mirtazapine, duloxetine 
Partial responders after six weeks may receive 
augmentation with lithium, bupropion, or an atypical 
antipsychotic 
Stage 4 
Combination treatment 
Two antidepressants or antidepressant plus lithium 
 
5.1.2 
Health and Wellness Cognitive Behavioral Therapy (H&W CBT) Manual 
 
The H&W CBT manual may be flexibly used to address the individual needs of the participant. 
Thus, while the typical stages of treatment for a given participant are presented in Table 3 below, 
therapists will have the ability to adjust the sequence of the treatment as needed, as well as the 
ability to bring in treatment modules specific to other relevant clinical issues (e.g., anxiety, 
emotional regulation difficulties, and social skills deficits). These modules will be known as 
“Sequence Adjustment procedures.” The three primary components presented in sequenced 
stages below include: (1) psychoeducation and motivation for treatment; (2) reducing depressive 
symptoms; and (3) achieving and maintaining wellness.  
 

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Table 3 
 H&W CBT Session Content 
 
Treatment 
Stage 
Stage Objectives 
Week 
Session Content 
Stage 1 
Psychoeducation 
and Motivation 
for Treatment 
 Build rapport 
 Educate about depression 
and HIV and the H&W CBT 
model 
 Increase adherence  
1-2 
 Psychoeducation (participant and 
 family, if appropriate) 
 Mood monitoring 
 Motivational interviewing 
component for increased adherence  
Stage 2 
Reducing 
Depressive 
Symptoms 
 Reduce residual symptoms 
 through core skills 
 Assess and identify core 
 beliefs 
 Identify and increase areas of 
 strength and wellness 
3-8 
 
 
 
 Psychoeducation about relapse risk 
 Begin timeline  
 Mood monitoring 
 Behavioral coping skills  
 Family module on negative emotion 
 (as needed) 
 Cognitive restructuring  
 Core beliefs and positive self-schema  
 Problem solving 
 Individualized skill modules as 
needed 
 Begin wellness assessment  
Stage 3 
Achieving and 
Maintaining 
Wellness  
 Consolidation and further 
 practice of core skills and 
 wellness skills to 
 manage mood 
 Relapse prevention 
10, 12, 
14, 16 
 
 Introduce concept of wellness 
 Identify current strengths and areas 
of wellness needing improvement 
 Practice and apply core and wellness 
skills for relapse prevention 
 Relapse Prevention and Wellness 
 Plan 
Continuation 
 Consolidation of treatment 
 gains 
 Evaluate/revise relapse 
prevention and wellness 
plans as needed 
20, 24 
 Content varies depending on 
 participant’s needs 
 
 
1) Stage 1: Psychoeducation and Motivation for Treatment:  
 
The H&W CBT treatment addresses the numerous psychosocial stresses of HIV infection and 
chronic medical care, as well as treatment of ongoing symptoms of depression. As noted above, 
there are several issues specific to HIV-infected adolescents and young adults that go beyond 
strict depression treatment. Specifically, these participants may be less committed to treatment for 
depression because the seriousness of their medical condition far outweighs that of depressive 
symptoms. Adolescents and young adults with HIV already are required to attend multiple 
medical appointments, and may be less likely to want to add additional visits with a therapist for 
depression treatment. In addition, adherence to antidepressant medication also may be 
problematic. Also, stressors such as poverty, stigma, and alienation from families may feel more 
pressing than the need for treatment. Therefore, the first portion of the H&W CBT is non-
confrontational and includes Motivational Interviewing (MI) techniques to engage the adolescents 

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and young adults in psychotherapeutic care. The first two sessions will be devoted to 
psychoeducation and adherence promotion, both with regard to HIV and depression. Participants 
will be educated on the link between depression and medical conditions (i.e., the impact of 
depression on their condition and vice versa), relationship of depression and general functioning, 
and importance of reducing depression to improve daily functioning. In addition, because 
adherence to treatment is often a concern with chronic medical conditions, MI techniques will be 
used to improve compliance with both medical treatments and depression treatments (47-49). 
 
Additionally, these initial sessions will serve as a period of establishing an alliance between the 
participant and the H&W CBT therapist and establishing specific areas of concern for the 
participant and therapist to focus on during the remaining stages. The manual also has flexibility 
in the session schedule, so that participants who would benefit from additional intervention to 
improve adherence can have more sessions devoted to these areas. In addition, during the course 
of treatment (six months), the therapist may return to these topics if the need arises (e.g., the 
participant has been noncompliant with medications). 
 
2) Stage 2: Reducing Depressive Symptoms:  
 
This module will include six sessions focused on reducing current symptoms (primarily 
depressive symptoms, although modules can be added for other comorbid symptoms such as 
anxiety as described above). The content of these sessions will focus on teaching the participant 
skills that reduce depressive symptoms. These core skills include mood monitoring, behavioral 
activation, reducing negative thinking, and problem-solving. As mentioned earlier, the participant 
may need more or less of these sessions depending on the level of symptomatology present. The 
manual is flexible, such that a participant with fewer symptoms may move more quickly to the 
wellness modules (Stage 3 below). On the other hand, participants with more clinical issues may 
have “Sequence Adjustment procedure” modules added to address these issues prior to moving to 
Stage 3.  
 
3) Stage 3: Achieving and Maintaining Wellness: 
  
Once depressive symptoms have significantly improved, the therapist and participant work 
together on identifying factors associated with enhancing wellness and preventing relapse. This 
module will continue through the final four sessions. Wellness enhancement will be an important 
area for HIV-infected adolescents and young adults, as they are likely to have become entrenched 
in the “patient” mode, particularly given their young age. Identifying and enforcing the areas in 
which they are “well” and “thriving” will allow them to build on personal strengths and adaptive 
behaviors. The focus of the sessions is on identifying the participant’s current areas of strength, as 
well as targeting areas/behaviors for improving and enhancing wellness. During this stage, the 
participant and therapist will also work to identify factors that may lead to worsening of mood, 
and methods to prevent depression from returning. Again, these sessions will incorporate topics 
to address concerns associated with HIV and chronic illness.  
 
5.2 
ESC Study Sites 
 
Participants at ESC sites will receive enhanced standard of care counseling. They will also 
complete behavior questionnaires and receive laboratory testing to monitor HIV disease 
progression. This study will assess the care provided at participating ESC sites by documenting 
the number of sessions of psychotherapy and medication management provided, the medications 
used by participants, provider characteristics, and mental health care accessed outside the 
research site. 

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5.2.1 
ESC counseling 
 
Patients will be screened and assented/consented as described above. In order for the study to 
have greater generalizability and external validity, psychopharmacological and psychosocial 
interventions will not be standardized but rather will reflect on-going treatment for depression at 
HIV clinical treatment centers. Participants may receive any depression treatment recommended 
by the site clinicians. Sites will use the clinicians who usually provide these services. The project 
will assess clinician degrees and length of HIV-related experience. Clinical coordinators will 
record attendance at medical and mental health visits and HIV illness outcomes. 
 
Enhancement of standard of care counseling with up-to-date training on treatment of depression 
The standard care arm is considered “enhanced” due to clinicians at ESC sites receiving updated 
didactic information from the study team, on the current principles for the use of medication and 
psychotherapy in the treatment of depression. This brief training will be relevant for clinicians 
and will include clinician rated instruments, but will not provide details on the medication 
management algorithm or tailored H&W CBT treatment used in COMB-R.  
 
Training in clinical management for both groups will include how to assess current symptoms, 
and the impact of symptoms on level of function. In addition, training on the provision of 
supportive care—specifically involving those nonspecific elements of psychotherapy that are not 
considered CBT components (reflective listening, validation, supportive problem-solving) will be 
provided. Training will also be provided in the medication management of depressed youth. 
Specifically, trainers will review standard care practices, including the American Academy of 
Child and Adolescent Psychiatry (AACAP) Practice Parameters for the treatment of depression in 
youth. In addition, trainers will discuss how symptoms will be assessed at each treatment visit, 
and how to assess clinical outcomes using evidenced based measures.  
 
5.3 
Study Evaluations and Measures 
 
Evaluations will include self-reported assessments collected via Audio Computer-Assisted Self 
Interview (ACASI) and/or interview administered forms, to document depressive symptoms, 
ARV medication adherence, risk behaviors, and consumer perspectives (i.e., satisfaction with 
intervention). ACASI is used in research studies to collect sensitive data, as studies have shown 
that participants may provide more accurate responses when questions are asked in a computer-
assisted format. (50-53). ACASI allows for complex skip patterns so that participants only answer 
items that are relevant based on their earlier responses. Additional outcome measures will be 
collected via medical record abstraction, and face-to-face interviews (FTFI) to assess areas of 
functioning and symptoms (i.e., cognitions, conduct, satisfaction) and service utilization (i.e., 
treatments and adherence). Table 4 outlines the various measures used for each intervention arm. 
Assessments for participants in both arms will be conducted on entry and at 6, 12, 24, 36 and 48 
weeks.  
 
 
 
 
 
 
 
 

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Table 4 
Study Measures and Assessments by Study Arm 
 
Measure 
COMB-R 
Arm 
ESC Arm 
 
Quick Inventory Depressive Symptomatology – Clinician 
(QIDS-C)   
X 
X 
Quick Inventory Depressive Symptomatology – Self Report 
(QIDS-SR) 
X 
X 
Behavioral assessment; includes sexual behavior, alcohol 
and drug use, and adherence modules 
X 
X 
ESC Therapist Checklist 
 
X 
H&W CBT Adherence Checklist 
X 
 
Medication Management Checklist  
X 
 
Client Satisfaction Questionnaire-8 (CSQ-8) 
X 
X 
Clinician Satisfaction Scales 
X 
X 
 
5.3.1 
Quick Inventory Depressive Symptomatology – Clinician (QIDS-C)   
 
A licensed mental health clinician will complete the QIDS-C, a scale assessing the symptoms of 
depression in the past seven days, via a FTFI at screening. The purpose of the QIDS-C at 
screening is to serve as a depression severity rating for eligibility. At subsequent study visits, the 
COMB-R clinicians will use the QIDS-SR to assess symptom change, which will be used to 
guide treatment decisions.  
5.3.2 
Quick Inventory Depressive Symptomatology – Self Report (QIDS-SR) 
 
Participants will complete the Quick Inventory of Depressive Symptomatology – Self-Report 
(QIDS-SR), a 17-item scale assessing nine depressive symptoms, at baseline and follow-up visits 
as described in Section 6.0. QIDS-SR is a reliable and valid measure of depression in adults and 
adolescents (54, 55). Total scores range from 0-27, whereby scores of 6-10 reflect mild 
symptoms, 11-15 moderate, and >16 severe. Score range and symptom severity categories are the 
same for the QIDS-C. QIDS-SR scores over time are used in two binary outcomes. Response to 
treatment is defined as a >50% decrease from baseline, and remission from depression is defined 
as a QIDS-SR score <5. Only the participant will complete the survey, and not the participant’s 
parent or guardian. The QIDS-SR will be conducted via either ACASI or paper form as follows: 
 
Study Visit 
COMB-R Arm 
ESC Arm 
Baseline/Enrollment 
ACASI 
ACASI 
Weeks 1, 6 and 12 
Paper form 
ACASI 
Weeks 24, 36, and 48 
ACASI 
ACASI 
Interim Visits 
Paper form 
NA 
 
Notes:  
1. When participants complete the QIDS-SR on paper, those data will be provided to the 
COMB-R clinicians in real-time. Data from ACASI will not be provided in real-time; 
however, clinicians at all sites will continue to assess for any changes in the participant’s 
depression status during therapy sessions.  

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2. COMB-R sites that will complete QIDS-SR on paper, as indicated above, will enter the 
data from the paper QIDS-SR into the study database. 
5.3.3 
Behavioral Assessment  
 
Risk behaviors will be assessed based on modules developed by the Adolescent Trials Network 
(ATN) Secondary Prevention and Adherence Workgroups. These items assess sexual risk 
behaviors, and drug and alcohol use. The adherence assessment will assess frequency and 
consistency of use of ARV and depression medications and attendance at therapy sessions. This 
scale will be administered via the ACASI at baseline and follow-up, per Section 6.0. 
 
Substance use will be assessed with an abbreviated 24 item ASSIST, which was developed by the 
World Health Organization for use in medical care settings (56). Items used will assess lifetime 
history and frequency of past three-month use of nine classes of substances: tobacco, alcohol, 
cannabis, cocaine, stimulants, inhalants, sedatives, hallucinogens, and opioids on a five-point 
scale (“never” to “daily or almost daily”). In addition, quantity of alcohol and cannabis is 
assessed in the past three months. The ASSIST is a frequently used measure of substance use and 
has been found to be reliable and valid (57).  
 
Sexual behavior will be assessed with 16 items from a more detailed assessment developed by the 
ATN Secondary Prevention Working Group. Items assess any lifetime history and past three-
month frequency of occurrence of oral, vaginal and anal sex. Skip patterns allow for more 
detailed assessment of relevant behaviors such as number of sexual partners, frequency of 
condom use (vaginal and anal) and condom use with main and “other” partners, and condom use 
at the time substance use. Sexual orientation and gender of sexual partners is also assessed. The 
items assess behaviors most commonly measured in sexual risk reduction interventions and have 
been found to be associated with mental health symptoms and reflect the impact of behavioral 
interventions (58, 59).  
 
Adherence to HIV and mental health treatment medications  
Medication adherence assessment, to both depression medications and ARV, and counseling will 
occur during MM and ESC follow up visits to determine if changes in medication and dosing are 
needed based on improvement or lack of improvement of depressive symptom severity.  
 
Clinicians providing treatment counseling during MM visits will utilize the MM algorithm as a 
framework to treat patients. Results from the participant self-report depressive symptoms survey, 
conducted at H&W CBT visits, will be shared with clinicians during MM visits. 
 
Adherence to HIV and mental health treatment medications will also be measured via ACASI by 
three items. One item assesses the number of days in the past month when at least one dose was 
missed, and two assess the patient’s perception of their frequency of adherence and their 
effectiveness at adherence on Likert-type scales (“very poor” to “excellent”). These items were 
found to have an internal consistency of 0.89 in a cognitive and field test to determine clarity, 
comprehension, and reliability characteristics among taking antiretroviral medications (60). 
In addition to adherence questions asked via ACASI (described above), staff will review clinic 
records at baseline, 12, 24, 36 and 48 weeks to determine the number of kept and missed visits for 
medical and mental health (therapy or psychiatric medication evaluation or management) care in 
the IMPAACT clinic site in the past 12 weeks. The number of unscheduled visits for medical and 
mental health care during the 12 weeks will also be recorded. Visits scheduled and attended 

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during the 12 weeks, even if the visits were rescheduled, will be recorded as “kept”. Participants 
self-report of adherence will also be assessed at the same time points. 
5.3.4 
ESC Therapy Checklist  
 
ESC therapists will complete a checklist at the end of each session that documents the strategy 
used for that session, using a list of common categories of psychotherapy. 
5.3.5 
COMB-R Therapy Adherence Checklist 
 
COMB-R therapists will complete a checklist at the end of each H&W CBT visit to document 
which elements of the intervention were delivered, and to record unique issues that arise.  
5.3.6 
Medication Management Checklist  
 
 
At the end of MM visits, COMB-R site clinicians will list the participant’s algorithm stage, 
clinical depression status, any changes to medication status, and deviations to the algorithm of 
participants participating in the intervention. ESC site clinicians will list the participant’s current 
medication and any changes.  
5.3.7 
Client Satisfaction Questionnaire-8 (CSQ-8) 
 
The CSQ-8 will be used at the completion of the intervention to assess the participant’s 
satisfaction with the intervention, including the procedures, quality and quantity of service, 
outcome, and general satisfaction. These domains are assessed on a four-point response scale 
with individually specified anchors. In addition, three open-ended questions are included that 
solicit comments about what respondents liked most and least about the intervention. This scale 
will be administered via the ACASI. 
5.3.8 
Clinician Satisfaction Scales 
 
Clinician satisfaction measures for clinicians at all sites will be completed via paper 
questionnaire. 
 
At the COMB-R sites, the prescribing clinician will complete a short survey, at the completion of 
the intervention, about their experience with the algorithm treatment for each participant. The 
first section contains three questions, which are rated on a scale from “Strongly agree” to 
“Strongly disagree”: 1) Following the algorithm was difficult with this participant; 2) Using the 
algorithm assisted me in making treatment decisions for this participant; and 3) The participant’s 
symptoms have improved since starting the algorithm. The second section contains one question 
about the overall quality of the treatment using the algorithm (responses: Excellent, Very good, 
Good, Substandard, Unacceptable).  
 
At the ESC sites, the prescribing clinician conducting medication management will complete a 
short survey, at the completion of the intervention, about their experience of treatment for each 
participant. The survey contains two questions, which are rated on a scale from “Strongly agree” 
to “Strongly disagree”: 1) Following my medication treatment plan was difficult for this 
participant; 2) The participant’s symptoms have improved since starting the medication treatment.  
 

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At the COMB-R sites, the clinician conducting the H&W CBT sessions will complete a seven 
item survey to assess the appropriateness, effectiveness, flexibility, ease of use, and “fit” of the 
H&W CBT treatment approach for the patient and the clinic (responses: Excellent, Good, Fair, 
Poor).  
 
At the ESC sites, the clinician conducting the counseling sessions will complete a seven item 
survey to assess the appropriateness, effectiveness, flexibility, ease of use, and “fit” of their 
treatment strategies for the patient and the clinic (responses: Excellent, Good, Fair, Poor).  
5.3.9 
Other Assessment Considerations 
 
This study will not assess for minor cognitive limitations, and as such, no measure of cognitive 
limitations will be utilized during screening or study follow-up. Based on ATN 080, there will 
unlikely be a moderating impact of minor cognitive impairment on the study’s objectives. 
Furthermore, currently available measures were designed to assess cognitive limitations 
associated with aging and pre-Alzheimer’s pathology, and have not been validated for children. 
 
5.4 
Intervention Monitoring/Quality Control 
 
Study fidelity for both COMB-R and ESC sites will be accomplished through online or remote 
training on the assessment of depressive symptoms using the QIDS-C and SR ratings.  
5.4.1 
Quality Control for Medication Management Intervention Visits 
 
The MM portion of the intervention will be monitored for quality control in the following ways: 
On-line Training: Site prescribing clinicians will be trained by members of the study team, on the 
MM manual, algorithm, assessment of depression treatment history, assessment of depressive 
symptoms (QIDS-C and QIDS-SR ratings), and the use of these rating scales to optimize 
treatment (e.g., when to change dose or medication based on ongoing lack of response). Several 
vignettes will be used to develop a common culture for identifying treatment staging within the 
algorithm, which will be particularly important for participants entering the study already on an 
antidepressant medication (See Section 5.5). 
 
Monthly Monitoring Calls with COMB-R Site Prescribers: The Protocol Chairs, and others as 
needed, will provide monthly MM supervision for all COMB-R site prescribers through a group 
conference call, and each participant entering the study will be reviewed on the call for deviations 
from algorithm staging. Any deviations will be documented on the Medication Management 
Checklist by prescribers. The Algorithm is not prescriptive. It provides a framework for decision-
making. Site clinicians will make the final decisions as to the medication and doses prescribed. 
Ongoing cases with treatment concerns will also be reviewed on the call, and all clinicians will 
provide input as to the best treatment plans, thereby developing a common culture across sites. 
Sites may also contact the protocol team with any questions or comments that may arise in 
between conference calls. 
 
MM Report: A report will be generated that contains the QIDS-SR scores, algorithm stage, 
antidepressant medications, augmenting medications, number of weeks on medication, clinical 
status, any side effects to antidepressants reported and additional psychotropics 
prescribed/indicated. The IMPAACT Statistical and Data Management Center will generate the 
report monthly initially, or as needed, for the protocol investigators to review participants’ 
depression and medication status to ensure that the clinicians are following the algorithm.  

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5.4.2 
Quality Control for Cognitive Behavioral Therapy Intervention Visits 
 
The H&W CBT portion of the intervention will be monitored for quality control in the following 
ways: 
 
On-line Training: H&W CBT therapists will be trained on the H&W CBT manual through 
didactic instruction, role plays, and/or vignettes. All sessions and assessments will be practiced to 
ensure consistency prior to intervention delivery (See Section 5.5). 
 
Monthly Monitoring Calls with H&W CBT Therapists: The Protocol Chairs, and others as 
needed, will provide monthly supervision (or more frequent at study initiation) for H&W CBT 
therapists via H&W CBT group conference calls to discuss ongoing cases. Sites may also contact 
the protocol team with any questions or comments that may arise in between conference calls. 
 
H&W CBT Adherence Checklist: The H&W CBT Adherence Checklist contains all the required 
items that must be covered in each H&W CBT visit. Site therapists will complete the adherence 
checklist after each H&W CBT visit. The DMC will provide all newly completed forms to the 
protocol chairs to review on the monthly calls with the clinicians. The Checklist will identify 
items in sessions that were difficult to address or were omitted so that these issues can be 
discussed on the calls.  
5.4.3 
Quality Control for ESC Visits 
 
ESC therapists will complete a checklist at the end of each session that documents the strategy 
used for that session, using a list of common categories of psychotherapy. This measure will 
document procedures at the ESC sites, in order to be able to compare and contrast the treatment 
strategies of ESC with COMB-R. 
 
5.5 
Research Staff Training 
 
Site prescribing clinicians, licensed mental health clinicians, therapists, study coordinators, and 
other research staff will engage in an online training. Site prescribing clinicians and therapists 
will have separate training sessions specific to their responsibilities, as outlined in Table 5 below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 5 
Training Session Responsibilities 
 
Provider 
Training Component 
Training Method(s) 
COMB-R 
Sites 
ESC Sites 
Site prescribing 
clinicians/licensed 
mental health 
clinicians 
QIDS ratings 
 
Didactic review; rating 
tapes; case vignettes 
X 
X 
Site prescribing 
clinicians/licensed 
mental health 
clinicians 
Medication manual 
(algorithm) 
  
Didactic review; rating 
tapes; case vignettes 
X  
 
Therapists 
H&W CBT manual 
Didactic review; watch 
videos; case vignettes for 
case conceptualization; 
review of core treatment 
strategies 
X 
 
Therapists 
Supportive Care, not 
considered CBT 
components 
Didactic review 
X 
X 
Therapists 
Standard care practices, 
including the American 
Academy of Child and 
Adolescent Psychiatry 
(AACAP) Practice 
Parameters 
Didactic review of 
practice parameters 
X 
X 
 
 
5.6 
Concomitant Medications  
 
Enrolled study participants may use concomitant medications during study participation. All 
concomitant medications reported throughout the course of the study will be recorded on case 
report forms designated for that purpose. All prescription medications, over-the-counter 
preparations, vitamins, nutritional supplements, and herbal preparations will be recorded on forms 
for concomitant medications. If a female participant initiates use of antidepressants during the 
study, counseling will be provided on the risks of pregnancy while using these medications, as 
per standard clinical care.  
 
6 
STUDY VISITS AND PROCEDURES 
 
An overview of study visits and evaluations is provided in Appendix I; blood draw volumes for 
each visit are also detailed in Appendix I. Presented in this section is additional information on 
visit-specific study procedures. All visit procedures must be conducted at the clinical research 
site, or associated facilities, identified in each site’s approved site implementation plan (SIP) 
and must be documented in accordance with DAIDS policies for source documentation; refer to 
Section 10.0 for more information on documentation requirements. Refer to Section 7.0 for 
information on expedited adverse event reporting, which may be required at any time during 
follow-up. All procedures specified to be performed at scheduled visits should ideally be 

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performed on the same day. However, if this is not possible (e.g., if a participant must leave the 
clinical research site before all procedures can be performed), visits may be split, with procedures 
performed on more than one day within the allowable visit window.  
 
In addition to the protocol-specified procedures listed in this section, study staff may complete 
other tasks consistent with site SOPs, including but not limited to collecting, reviewing, and 
updating demographic and locator 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 site SOPs.  
 
Participants at every COMB-R and ESC assigned site will attend a Screening/Entry Visit, and 
follow-up clinic visits at Weeks 1, 6, 12, 24, 36, and 48. In addition, participants in the COMB-R 
sites will be encouraged to return to the clinic for weekly therapy visits through Week 8, every 
other week through Week 16, and then monthly until Week 24. These visits are not mandatory, 
and will be considered and documented as interim visits. At these interim visits, study staff will 
conduct therapy utilizing the CBT manual, and provide medication management, utilizing the 
MM manual, as indicated. Participants in the ESC sites will likewise return to the clinic for 
interim visits, based on the clinical indication of the participant.  
 
Further details and form instructions for these interim visits are provided in the IMPAACT 2002 
study MOP. Requiring assessment visits at Weeks 1, 6, 12, 24, 36, and 48, while also allowing 
for flexibility in scheduling clinical interim visits, will demonstrate COMB-R management in 
realistic clinical settings. This will furthermore allow participants, approached to participate in the 
study at both COMB-R and ESC sites, to perceive a similar study burden and visit schedule. 
Following completion of the study, researchers will analyze the number of interim visits 
conducted at COMB-R and ESC sites, based on clinician and participant clinical needs, to better 
understand the amount of clinical visits needed to improve depression outcomes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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6.1 
Screening and Entry Visit 
 
Screening and enrollment procedures may be performed on the same day. Multiple visits may be 
conducted to complete all required screening procedures if necessary, and within 30 days of 
enrollment. Written informed assent/consent must be obtained before any screening procedures 
are performed. For potential participants who do not meet the eligibility criteria, screening may 
be discontinued once ineligibility is determined.  
 
Screening and Entry Visit Procedures (Day 0) 
Administrative 
and Regulatory 
 Obtain written informed consent; or written informed assent 
and parental or guardian consent, for Screening and 
Enrollment  
 Assign participant identification number (PID) 
 Collect demographic and locator information 
 Determination of eligibility  
 Complete paper-based eligibility checklist*, enter checklist 
data into SES to enroll the participant, print and file a copy of 
the confirmation file 
Behavioral  
and Counseling 
 Provide HIV pre-/post-test counseling* 
 Administer behavioral questionnaire 
 Administer QIDS-SR 
Clinical 
 Obtain medical and medications history; including 
assessments for suicidality  
 Assess CDC HIV disease category 
 Complete QIDS-C 
 Obtain CD4 nadir based on medical chart review 
Laboratory 
 
Blood 
Collect blood for: 
 CD4+ T-Cell Count^  
 HIV-1 RNA^ 
 Plasma storage, for inflammatory markers  
 HIV-1 test (confirmatory tests as needed)* 
* If indicated; ^Documented laboratory results from an external provider that is CLIA-certified may be 
utilized for IMPAACT 2002, if the sample(s) was collected within 14 days of study entry 
 
Note: if the screening and entry visit is split, sites must complete the following procedures at the entry visit: confirm 
eligibility, obtain an updated medical and medication history, collect laboratory specimens, and administer the baseline 
behavioral questionnaire, QIDS-SR and QIDS-C forms. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.2 
1 Week Visit 
 
The 1-Week Visit is targeted to take place on Day 7, counted from the date of enrollment as Day 
0, with an allowable window of -7 and +14 days. Sites may conduct the 1-Week visit procedures 
on the same day as the Screen/Entry visit, if the participant and site staff have adequate time. If 
the 1-Week Visit is conducted on the same day as the Screen/Entry visit, then sites should not 
repeat procedures, such as the QIDS-SR and collecting medical and medication history. The 
primary purpose in this case, would be to provide therapy and medication management as 
indicated below. If the 1-Week Visit is not conducted on the same day as Screen/Entry, then all 
the procedures listed below must be performed. 
 
1 Week Visit Procedures  
Study Days 7 (-7/+14 days) 
Behavioral  
and Counseling 
 Administer QIDS-SR 
Clinical 
 Collect/update medical and medications history; including 
assessments for suicidality and number of kept and missed 
medical and mental health visits 
 Identify/review/update adverse events (signs, symptoms, 
diagnoses) 
 COMB-R Sites Only: 
 Administer CBT Session and complete the CBT 
Adherence Checklist 
 Administer the MM Session and complete the MM 
Checklist 
 ESC Sites Only: 
 Psychotherapy as indicated by symptoms 
 Medication management as indicated by symptoms 
 Complete the ESC therapy Checklist 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.3 
6 and 12 Week Visits  
 
The 6-Week Visit is targeted to take place on Day 42 with an allowable window of ± 14 days. 
The 12-Week Visit is targeted to take place on Day 84 with an allowable window of ± 14 days.  
 
6 and 12 Week Visit Procedures  
Study Days 42 (+/- 14 days), 84 (+/- 14 days) 
Behavioral  
and Counseling 
 Administer QIDS-SR 
 Administer behavioral questionnaire  
Clinical 
 Collect/update medical and medications history; including 
assessments for suicidality and number of kept and missed 
medical and mental health visits 
 Identify/review/update adverse events (signs, symptoms, 
diagnoses) 
 COMB-R Sites Only: 
 Administer CBT Session and complete the CBT 
Adherence Checklist 
 Administer the MM Session and complete the MM 
Checklist 
 ESC Sites Only: 
 Psychotherapy as indicated by symptoms 
 Medication management as indicated by symptoms 
 Complete the ESC therapy Checklist 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.4 
24 Week Follow-up Visit 
The 24-Week Visit is targeted to take place on Day 168 with an allowable window of ± 14 days.  
 
24 Week Visit Procedures  
Study Day 168 (+/- 14 days) 
Behavioral  
and Counseling 
 Administer QIDS-SR 
 Administer behavioral questionnaire  
 Administer Client Satisfaction Questionnaire 
 Administer Physician Satisfaction Questionnaire (COMB-
R Sites Only) 
Clinical 
 Collect/update medical and medications history; including 
assessments for suicidality and number of kept and missed 
medical and mental health visits 
 Assess CDC HIV disease category 
 Identify/review/update adverse events (signs, symptoms, 
diagnoses) 
 COMB-R Sites Only: 
 Administer CBT Session and complete the CBT 
Adherence Checklist 
 Administer the MM Session and complete the MM 
Checklist 
 ESC Sites Only: 
 Psychotherapy as indicated by symptoms 
 Medication management as indicated by symptoms 
 Complete the ESC therapy Checklist 
Laboratory 
 
Blood 
Collect blood for: 
 CD4+ T-Cell Count^  
 HIV-1 RNA^ 
 Plasma storage, for inflammatory markers  
^ Documented laboratory results from an external provider may be utilized for IMPAACT 2002, if the 
sample(s) was collected in the visit window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.5 
36 and 48 Week Follow-up Visits 
 
Following the Week 24 visits, participants in both COMB-R and ESC groups may receive 
counseling and psychiatric medication per individual clinician/patient decisions. Participants at 
all sites will have two follow-up visits, at Week 36 and Week 48, to monitor if the effects of the 
intervention were maintained. The Week 48 Visit will serve as the final clinic. 
 
36 and 48 Week Follow-up Visit Procedures  
Study Days 252 and 336 (+/- 14 days) 
Behavioral  
and Counseling 
 Administer QIDS-SR 
 Administer behavioral questionnaire 
Clinical 
 Collect/update medical and medications history; including 
assessments for suicidality and number of kept and missed 
medical and mental health visits 
 Assess CDC HIV disease category 
 Identify/review/update adverse events (signs, symptoms, 
diagnoses) 
Laboratory 
 
Blood 
Week 48 ONLY: Collect blood for: 
 CD4+ T-Cell Count^  
 HIV-1 RNA^ 
 Plasma storage, for inflammatory markers  
^ Documented laboratory results from an external provider may be utilized for IMPAACT 2002, if the 
sample(s) was collected in the visit window 
 
Sites should inform study participants that they will not continue to receive study-provided 
therapy through the study after their 24 Week Visit, but will continue with their therapist or be 
referred for care if needed. They will continue to return to the study site for study follow-up visits 
however to assess whether effects of the intervention are maintained. Sites should also arrange 
with participants to provide any laboratory test results obtained at the 48 Week Visit, as well as 
results of the study when available.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.6 
Interim Follow-up Visits 
 
Participants in the COMB-R sites will be encouraged to return to the clinic for weekly interim 
therapy visits through Week 8, every other week through Week 16, and then monthly until Week 
24. ESC sites will conduct interim visits, based on the clinical indication of the participant. 
Interim visits are not mandatory and will not be considered missed, if a participant is unable to 
attend the visit. 
 
Interim Follow-up Visit Procedures  
Behavioral  
and Counseling 
 Administer QIDS-SR (COMB-R Sites only)* 
Clinical 
 Collect/update medical and medications history; including 
assessments for suicidality* 
 Identify/review/update adverse events (signs, symptoms, 
diagnoses) 
 COMB-R Sites Only: 
 Administer CBT Session and complete the CBT 
Adherence Checklist* 
 Administer the MM Session and complete the MM 
Checklist* 
 ESC Sites Only: 
 Psychotherapy as indicated by symptoms* 
 Medication management as indicated by 
symptoms*Complete the ESC therapy Checklist* 
*if indicated 
 
6.7 
Premature Discontinuation of Study Participation Visit 
 
Any participant that terminates from the study early will be requested to return to the clinic to 
complete the final evaluations as specified for the Week 48 visit.  
 
6.8 
Procedures for Participants Who Become Pregnant 
 
Pregnant participants may remain in the study and will continue all protocol-specific procedures, 
but will be counseled on discontinuing use of antidepressants in accordance with clinical 
judgment of site investigator and standard care practices. Additionally, if site staff suspect a 
female participant is at high risk for pregnancy, and she is currently using antidepressants, 
counseling will be provided on safety risks in accordance with the clinical judgment of the site 
investigator and standard of care practices. 
 
Study sites will refer pregnant participants to providers of obstetric and gynecologic care for 
counseling and further related care. Every effort will be made to facilitate access to prevention of 
mother-to-child transmission regimens if the participant is not yet accessing ART. Study staff, 
with permission from the participant and, if required, the participant’s parent and/or guardian, 
may contact the medical care provider to inform him/her of the participant’s involvement in 
IMPAACT 2002.  
 
HIV-1 infected women who are pregnant should be treated according to the Public Health Service 
Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-Infected Women 
for Maternal Health and Interventions to Reduce Peri-natal HIV Transmission in the United 

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States: June 7, 2016 (https://aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0# ). Study 
sites will also be encouraged to prospectively register the participant’s pregnancy in the 
Antiretroviral Pregnancy Registry. http://www.apregistry.com/ (In U.S.: 1-800-258-4263).  
 
6.9 
Additional Considerations for Laboratory Procedures 
 
Each study site and laboratory involved in this study will comply with the DAIDS policy on 
Requirements for DAIDS Funded and/or Sponsored Laboratories in Clinical Trials Policy, which 
is available at: 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/Pages/Laboratories.aspx 
6.9.1 
Specimen Collection  
 
Specimens will be collected for this study as indicated in the Schedule of Evaluations and per 
detailed guidance provided in the Laboratory Processing Chart (LPC), which will be available on 
the IMPAACT website: www.impaactnetwork.org.  
 
In accordance with U.S. National Institutes of Health (NIH) recommendations, for pediatric 
patients, no more than 5 mL/kg may be drawn for research purposes in a single day, and no more 
than 9.5 mL/kg may be drawn over any eight-week period. The amount of blood that may be 
drawn from adult participants (i.e., those persons 18 years of age or older) for research purposes 
shall not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight-week period. In the 
event that blood collection must be limited, available specimens should be prioritized for use in 
the following order: (1) CD4+ T-Cell Count and HIV-1 RNA, (2) plasma storage for 
inflammatory markers.  
 
Each study site will adhere to the standards of good clinical laboratory practice in accordance 
with current DAIDS Laboratory Requirements, and site Standard Operating Procedures (SOPs) 
for proper collection at the local laboratory. In cases where laboratory results are not available 
due to administrative or laboratory error, sites are permitted to re-draw specimens. 
6.9.2 
Specimen Preparation, Testing, Storage, and Shipping 
 
All specimens collected for this study will be labeled, transported, processed, tested, stored and/or 
shipped in accordance with the DAIDS policy referenced in Section 6.9, site and local laboratory 
SOPs, and the LPC. The Laboratory Data Management System (LDMS) will be used to document 
specimen collection, testing, storage, and shipping as specified in LPC. 
 
CD4 and HIV RNA will be performed locally at CLIA certified or equivalent laboratories. 
Plasma in EDTA will be collected for inflammatory biomarkers and stored at -70ºC at the local 
laboratory. At the end of the study, samples will be shipped to a designated central laboratory for 
testing. Analytes will include hsCRP, d-dimer, IL1, IL6, IP10, sCD14 and TNF. 
 
After all protocol-specified laboratory testing has been performed, residual specimens may be of 
interest for future research use. Participants (and authorized guardians if applicable) will be asked 
to provide written informed consent for future research use of these specimens, if permitted by 
site IRBs/ECs and other applicable review bodies. Participants and/or their guardians may choose 
to provide or to decline informed consent for future research use of residual specimens with no 
impact on their participation in the study. 

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6.9.3 
Biohazard Containment 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study as recommended by the CDC and NIH. All biological specimens will be 
transported using packaging mandated by Code of Federal Regulations (CFR) 42 Part 72. All 
dangerous goods materials, including diagnostic specimens and infectious substances, must be 
transported according to instructions detailed in the International Air Transport Association 
(IATA) Dangerous Goods Regulations. Biohazardous waste will be contained according to 
institutional, transportation/carrier, and all other applicable regulations. 
 
7 
SAFETY ASSESSMENT AND REPORTING 
 
An overview of the protocol-required safety assessment and reporting requirements for site 
investigators is provided below. Safety monitoring by the protocol team and the Study 
Monitoring Committee (SMC) is described in Section 9.5. 
 
7.1 
Safety-Related Roles and Responsibilities for Site Investigators 
 
Site investigators are responsible for continuous monitoring of all study participants and for 
alerting the protocol team if unexpected concerns arise. Medical history, occurring within 30 days 
prior to enrollment, will be considered past medical history. These data will be graded to compare 
with worsening conditions during study follow-up, and to determine whether or not an AE has 
occurred, as indicated in Section 7.2. Site investigators will record safety-related events during 
follow-up on case report forms (CRFs) as indicated in Section 7.3 and complete expedited 
adverse event (EAE) reporting as indicated in Section 7.4. Site investigators are also responsible 
for prompt reporting to their IRBs/ECs and other applicable review bodies of any unanticipated 
problems involving risks to participants or others. 
 
7.2 
Recording of Pre-Existing Conditions 
 
All pre-existing conditions, occurring within 30 days prior to enrollment and regardless of grade, 
will be recorded on case report forms as signs, symptoms, and diagnoses. 
 
7.3 
Safety Data on Case Report Forms  
 
Grade 3 or higher adverse events, regardless of presumed relationship to study intervention, will 
be recorded on case report forms as signs, symptoms, and diagnoses as specified below. 
Additionally, all psychological hospitalizations, and suicide attempts will likewise be documented 
on CRFs. Sites will determine relationship status by considering whether the AE resulted from 
the COMB-R or ESC counseling procedures. 
 
Signs and Symptoms: Grade 3 or higher signs and symptoms occurring after enrollment through 
study exit visit, which may or may not be related to the study counseling procedures, will be 
recorded on the relevant CRF. The site investigator will determine relationship status of each sign 
or symptom. In addition, Grade 4 signs and symptoms that occur after enrollment will be further 
evaluated, with additional data recorded on the relevant event evaluation CRF. 
 

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Diagnoses: Grade 3 diagnoses occurring after enrollment (through the study exit visit) will be 
recorded on the relevant CRF. The site investigator will determine relationship status of each 
diagnosis. Grade 4 or higher diagnoses that occur after enrollment will be further evaluated, with 
additional data recorded on the relevant event evaluation CRF. All diagnoses will be recorded on 
case report forms consistent with the specifications of the relevant diagnosis appendix, which is 
available at www.fstrf.org. 
 
CRFs used to record the above-listed safety outcomes must be completed and entered into the 
study database within 21 calendar days from the date of the visit.  
 
7.4 
Expedited Adverse Event (EAE) Reporting 
 
Requirements, definitions and methods for expedited reporting of Adverse Events (AEs) are 
outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the RSC website at 
http://rsc.tech-res.com/safetyandpharmacovigilance/.  
 
The study team will monitor and track unanticipated problems related to study counseling 
procedures until participants’ time of termination from the study. Study staff will provide 
clinically appropriate treatment and/or referrals should any such problems occur. 
7.4.1 
Adverse Event Reporting to DAIDS 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting 
system, must be used for expedited AE reporting to DAIDS. In the event of system outages or 
technical difficulties, expedited AEs may be submitted via the DAIDS EAE Form. For questions 
about DAERS, please contact DAIDS-ES at CRMSsupport@niaid.nih.gov. Site queries may also 
be sent from within the DAERS application itself. 
 
For Expedited Adverse Event (EAE) Reporting/Questions: Contact DAIDS through the RSC 
Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 1-800-537-9979 or 301-897-
1709; or fax 1-800-275-7619 or 301-897-1710. 
7.4.2 
Reporting Requirements for this Study 
 
The intervention for which expedited reporting is required is: the study counseling 
procedures.  
 
The following types of events will be reported on an expedited basis for this study:  
  
1. Suicide attempts 
2. Psychological hospitalization  
 
Note: Any event that occurs in a participant that is not necessarily a suicide attempt or 
psychological hospitalization, but in the opinion of the site investigator could cause harm to the 
participant or harm to others is also important for the study team to monitor. While these 
instances do not need to be recorded as an EAE using DAERS, sites should inform the Protocol 
Chairs and DAIDS Medical Officers, via email, as soon as the site is aware of the event. 

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7.4.3 
Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(DAIDS AE Grading Table), Version 2.0, dated November 2014 will be used for this study. This 
table is available on the RSC website at http://rsc.tech-res.com/safetyandpharmacovigilance/.  
 
Grading severity for adverse events will follow Table 6 below.  
 
Table 6 
Severity Grading of Events 
 
Severity Grading of Events  
Grade 1 
Mild 
 
Grade 2 
Moderate 
 
Grade 3 
Severe 
 
Grade 4 
Potentially Life-
Threatening 
 
 
 
 
Symptoms causing no 
or minimal 
interference with 
usual social and 
functional activities 
 
Symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities 
 
Symptoms causing 
inability to perform 
usual social and 
functional activities 
OR resulting in 
hospitalization 
 
Symptoms causing 
inability to perform 
basic self-care 
functions OR Medical 
or operative 
intervention indicated 
to prevent permanent 
impairment, persistent 
disability or death 
 
7.4.4 
Expedited AE Reporting Period 
 
The EAE reporting period begins at the time of enrollment and continues through the Week 48 
Visit. 
 
After the protocol-defined AE reporting period, unless otherwise noted, only suspected 
unexpected serious adverse reactions, as defined in Version 2.0 of the EAE Manual and assessed 
as related to the study counseling procedures, will be reported to DAIDS if the study staff become 
aware of the events on a passive basis (from publicly available information). 
 
8 
PARTICIPANT SAFETY MANAGEMENT 
 
8.1 
Management of Adverse Events 
 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the counseling procedures, whether or not related to the counseling procedures.  
 

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All reportable adverse events identified in this study will be source documented consistent with 
the policies and procedures referenced in Section 10. Among other details, source documentation 
will include the severity of each event (graded as described in Section 7.4.3) and its relationship 
to study counseling procedures, assessed by the site investigator according to the following 
categories and definitions: 
 
Related 
There is a reasonable possibility that the adverse event may be related to 
the study counseling procedures 
 
Not related 
There is not a reasonable possibility that the adverse event may be 
related to the study counseling procedures 
 
 
Acute management of any AE will be according to best clinical practices and the judgment of the 
site investigator in consultation with the psychiatrist involved with the participant’s care. The 
relationship between the AE and the study counseling procedures will be presumed unless a 
clearly recognized etiology is identified.  
 
This protocol studies depression treatment strategies in participants who have been prescribed 
certain medications by their primary physician or a consulting site prescribing clinician. Note that 
no drugs are supplied as part of this study. All drugs, including those being studied at non-
standard doses, must be provided by participants’ clinical care providers by prescription. Any 
abnormal laboratory results must be communicated promptly to the treating physician and site 
investigator. While these medications are not given as study drugs, they are concomitant 
medications, and they need to be managed per the Medical Management Algorithm on the 
COMB-R arm, or per standard of care in the ESC arm of the study. 
 
Toxicities have been associated with medications used in the treatment of depression. In the 
COMB-R sites, toxicities will be managed by the site prescriber in conjunction with the 
Medication Management Manual (MM), package insert, clinical judgment, and consultation with 
the protocol investigators as needed. Similarly, ESC sites will manage toxicity as per standard of 
care, package insert, and best medical judgment. The protocol chairs will provide guidance on 
clinical management of any toxicities as needed. 
8.2 
Criteria for Premature Discontinuation of Study Participation 
 
Participants must be discontinued from the study if: 
 
The site investigator, NIAID, IMPAACT, the Office for Human Research Protection 
(OHRP), other governmental agencies or the site’s IRB discontinues this study; 
 
The participant/legal guardian refuses further participation in the study; 
 
The investigator determines further participation would be detrimental to the participant’s 
health or well-being; 
 
The participant fails to comply with the study requirements, so as to cause harm to self or 
seriously interfere with the validity of the study results 
 

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9 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues 
 
This is a multisite, two-arm cluster (site)-randomized trial of a Health and Wellness Cognitive 
Behavioral Therapy (H&W CBT) and Medication Management (MM; COMB-R) intervention for 
depression. Prior to the start of enrollment, all the selected sites will be randomized to either the 
COMB-R group or the Enhanced Standard of Care (ESC) group, and then each site will enroll 
participants and provide the intervention to which that site was randomized. The study population 
will be HIV-infected youth in the U.S., who are between 12 and 24 years old (inclusive), and who 
have been diagnosed with depression and have a QIDS-C score of > 11. The primary objectives 
are to compare the two study arms with respect to depression outcomes, and biological measures 
of health after 24 weeks. The secondary objectives are to compare the two study arms with 
respect to adherence to HIV and depression treatment; examine whether differences in depression 
outcomes are maintained at 48 weeks; assess whether demographic, behavioral and biological 
factors could moderate the efficacy of COMB-R compared to ESC; assess whether COMB-R is 
associated with improved behavioral risk outcomes; describe the implementation fidelity at 
COMB-R sites and counseling strategies at ESC sites; compare the  number of interim visits, the 
frequency of medication use, and acceptability of COMB-R and ESC among participants and 
clinicians; and compare the frequency and types of Grade 3 or higher adverse events, 
psychological hospitalizations and suicide attempts. The exploratory objectives will assess 
inflammatory biomarkers and their moderating effect on intervention outcomes. 
 
It is anticipated that 14 sites will be randomized to either the COMB-R arm or the ESC arm. The 
target sample size will be to enroll 156 participants (to achieve 140 evaluable, allowing for up to 
10% loss to follow-up; a participant is evaluable if QIDS-SR data at both baseline and week 24 
were obtained). The sample size may be increased if the percentage of non-evaluable participants 
or the observed intracluster correlation coefficient is higher than assumed for sample size 
calculations (see Section 9.5.1 for details). Each site is expected to enroll a minimum of eight 
participants. Accrual is expected to require approximately two years. The expected study duration 
for each participant will be approximately 48 weeks.  
 
Randomization of sites instead of individual participants was chosen because it would be difficult 
for the same provider to deliver ESC to some patients and COMB-R to other patients in the same 
clinic without any loss in fidelity of ESC or COMB-R or cross-talk between patients in the two 
study arms. It would be ideal to screen and enroll all participants in the study before the sites are 
randomized to ESC or COMB-R, to avoid selection bias (discussed below). However, this design 
was deemed not feasible, because it would not be possible to enroll a sufficient number of 
participants in a short enough period of time; based on the site implementation plans, the number 
of anticipated enrollments in the first six months of enrollment was three-five participants for 
nine sites, and more than seven participants for only two sites. Consequently, participants will be 
enrolled after the sites have been randomized.  
 

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One potential source of bias with this design is selection bias, which can occur if not all 
potentially eligible participants are approached for enrollment (e.g., if the COMB-R sites are 
more stringent in selecting potential participants to be approached). Selection bias is of much 
greater concern with this site-randomized design than in an individually randomized trial, because 
enrollment of participants after the site has been randomized means that the site randomization 
cannot protect against imbalance in participant characteristics between study arms. The sites will 
be randomized using a restricted randomization procedure designed to balance key characteristics 
of the site populations. In addition, the protocol includes several design features to minimize 
selection bias, including defining eligibility criteria that apply equally to both study arms; 
requiring sites to obtain screening numbers for all potentially eligible participants and 
randomizing the order in which the site can approach potential participants for enrollment; and 
collecting limited data on patients who do not enroll so that their characteristics can be compared 
to those of participants who did enroll, to assess the potential extent of selection bias.  
 
9.2 
Outcome Measures 
9.2.1 
Primary Outcome Measures  
 
Depression Outcomes:  
 
 
QIDS-SR score at Week 24 (primary efficacy outcome) 
 
 
Response to Treatment, defined as a decrease in QIDS-SR score by >50% from entry to 
week 24 
 
 
Remission, defined as a QIDS-SR score < 5 at week 24  
 
Biological Measures:  
 
 
CD4 cell count at Week 24 
 
 
Plasma HIV RNA level at Week 24   
9.2.2 
Secondary Outcome Measures 
 
 
Adherence to anti-HIV medications and psychiatric medications at each assessment for 
the first 24 weeks (during active treatment) and at 48 weeks, as measured by self-report; 
and adherence to study visits and psychotherapy sessions  
 
 
Depression outcomes (QIDS-SR score, Response to Treatment, and Remission) over 48 
weeks. Note: The following factors will be assessed as potential effect-modifiers 
(moderators): Demographic: age, gender. Behavioral: HIV acquisition category, initial 
level of depression. Biological: baseline CD4, nadir CD4, plasma HIV RNA, CDC 
category.  
 
 
Behavioral risk outcomes: alcohol/drug use, sex-risk behaviors at week 24 and week 48 
 
 
Implementation fidelity (COMB-R sites); counseling strategies and medication patterns 
(ESC sites) (see Section 5 for measures).  

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 
Number of interim visits; frequency of medication use; acceptability among participants 
and clinicians (see Section 5 for measures).   
 
 
Grade 3 or higher adverse events, psychological hospitalizations, and suicide attempts 
9.2.3 
Exploratory Outcome Measures 
 
 
Plasma inflammatory biomarkers at 24 and 48 weeks  
 
9.3 
Randomization  
 
Prior to the start of enrollment, all of the selected sites will be randomized to either the COMB-R 
group or the ESC group, and then each site will enroll participants and provide the intervention to 
which that site was randomized. The sites will be randomized using a restricted randomization 
procedure (61) to avoid imbalances in participant characteristics. A pre-study survey of the sites 
collected information on site characteristics, including number of youth served, route of HIV 
infection (perinatal versus behavioral), age (12-18 versus 19-24 years of age), and gender. Among 
the 14 sites selected to do IMPAACT 2002, four sites see primarily behaviorally HIV-infected 
youth, four other sites see large numbers of patients, and the other six sites appear to be 
approximately balanced with respect to route of infection and numbers of patients seen. Within 
the above groupings, the sites are well-balanced across gender and age. If two of the four 
primarily behavioral infection sites and two of the four large sites are randomly assigned to each 
study group, and three of the remaining six sites are randomly assigned to each study group, then 
the two groups would be expected to be approximately balanced with respect to number of youth 
served, route of HIV infection, age, and gender.  
 
A computer program will be written to generate all possible allocations of the 14 sites that have 
two primarily behavioral sites in each study group and two large sites in each study group. To 
further protect against imbalance in gender, age, mode of transmission, severity of depression and 
viral load suppression status, the program will discard any allocations that exceed a maximum 
acceptable imbalance in any of these characteristics, and then will choose one allocation 
randomly from all of the allocations with acceptable balance. Specifically, before the 
randomization is performed, the sites will determine potentially eligible participants. Sites should 
consider youth, with or without a history of depression, with or without a history of mental health 
treatment, and those currently in mental health treatment; providing they are thought to meet 
study eligibility criteria. Sites will then be required to submit the following summary information 
for their potentially eligible patients: % <18 years vs. > 18 years, % male vs. female, % perinatal 
vs. behavioral HIV acquisition, % with moderate vs. severe depression based on clinician 
judgment, and % virally suppressed vs. not suppressed (below or not below the level of detection 
as defined by the laboratory). A maximum acceptable difference between the means of the site-
specific proportions in the COMB-R and ESC arms will be specified (e.g., allowing the means to 
differ by no more than 0.25 standard deviations (SD) or no more than 10% (i.e. their ratio should 
be between 0.9 and 1.1)). The computer program will randomly choose one allocation from 
among all allocations of sites to arms that have less than or equal to the maximum difference for 
each of the five characteristics of interest. Imbalance criteria may be adjusted (for example, 
allowing the means to differ by no more than 20% instead of 10%) if they result in too few 
possible allocations. 
 

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Initially, there will not be any limits on enrollment according to the above characteristics. During 
enrollment, the core protocol team will monitor the balance of the above characteristics between 
arms quarterly or as needed (blinded to which arm is which), and if an imbalance greater than the 
maximum allowable imbalance is identified, will impose enrollment limits in the DMC 
enrollment system for all sites in one arm or the other to force subsequent enrollments to be from 
a specific category of age (<18 years or > 18 years) or, gender (male or female) or HIV 
acquisition route (perinatal or behavioral) or  depression level (moderate or severe) or viral 
suppression (suppressed or not suppressed), as needed, to achieve approximate  balance of these 
characteristics in the two study arms.  
 
Potentially eligible patients will be screened as described in Section 4.4. All participants at ESC 
sites will be directly assigned to ESC and all participants at COMB-R sites will be directly 
assigned to COMB-R.  
 
9.4 
Sample Size and Accrual 
9.4.1 
Sample Size 
 
The proposed sample size for IMPAACT 2002 is approximately 140 evaluable participants (an 
average of 10 evaluable participants per site) to be enrolled at 14 clinical research sites. A total of 
156 participants will be enrolled to allow for up to 10% loss to follow-up by week 24 (note: the 
team anticipates that there may be higher loss to follow up after week 24, but no more than 15% 
total through week 48). Should the percentage of participants who are non-evaluable at Week 24 
exceed 10%, the sample size may be increased to achieve 140 evaluable (see Section 9.5.1 for 
details). This sample size was chosen to provide high power to detect a clinically important 
difference in the primary efficacy outcome measure, the QIDS-SR score between study arms at 
24 weeks. The QIDS-SR is a 16-item scale assessing nine depressive symptoms. Total QIDS-SR 
scores range from 0-27. QIDS-SR scores of six-ten reflect mild symptoms, 11-15 reflect 
moderate symptoms, and >16 reflect severe symptoms. The study team indicated that the smallest 
clinically important difference to detect would be a difference in the QIDS-SR score of 0.8 
standard deviation (SD) units, which corresponds to a difference of about three to four points on 
the QIDS-SR scale based on the observed standard deviations at baseline in the ATN 080 study. 
Note that an effect size of 0.8 SD is plausible and conservative in that the effect size observed at 
Week 24 in the ATN 080 study of this intervention was almost two times larger.  
 
IMPAACT 2002 is a cluster-randomized trial where each cluster is a clinical research site. The 
statistical power to detect a difference between arms depends on the number of clusters (sites) per 
arm (n), the average number of participants per site (m), and the intra-cluster correlation 
coefficient (ICC) (61). The ICC is a measure of within-cluster (within-site) correlation and is 
defined as ICC= (between-cluster variation)/(between-cluster variation + within-cluster 
variation). An ICC of zero indicates that the within- cluster variation outweighs the between-
cluster variation to the extreme, so that essentially there is no within-cluster correlation. In 
contrast, an ICC of 1 indicates perfect within-cluster correlation (0 within-cluster variation). In 
this case, the sample devolves into the number of clusters. 
 
For cluster-randomized trials with relatively small numbers of clusters (fewer than 15-20 clusters 
per treatment arm), the recommended analysis approach (61) is a cluster-level analysis, in which 
a summary outcome measure is calculated for each cluster (e.g., the mean score or response 
proportion across participants in that cluster) and the cluster-specific outcome measures are 
compared between treatment arms using an appropriate two-sample test such as a t-test.  

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Cluster-randomized trials typically require larger sample sizes than individual-randomized trials, 
because cluster randomization provides less precise (more variable) estimates of treatment effects 
due to the between-cluster variation. The design effect (DE) is the multiplier that indicates the 
increase in sample size needed to achieve a given power compared to the sample size that would 
be required if there were no cluster randomization (SampleSizeRT): 
 
DE= 1 + (m-1)*ICC 
 
 
The final sample size for the cluster randomized trial (SampleSizeCRT) is: 
 
SampleSizeCRT = SampleSizeRT * DE = SampleSizeRT * (1 + (m-1)*ICC) 
 
An estimate of the ICC is needed for sample size calculations. The ATN 080 study was too small 
to provide ICC estimates (only four sites were randomized) and a literature search did not identify 
any ICC estimates for the QIDS-SR. The University of Aberdeen Health Services Research Unit 
has compiled a database of ICCs calculated from a number of different interventions and settings 
in cluster randomized studies of interventions to change physician practices (62). In this database, 
the pre-intervention ICCs for the SF36 Mental Health Component score in cluster-randomized 
trials which randomized at the practice level ranged between 0.02 and 0.05 in patients with 
different diseases (benign prostatic hyperplasia, microscopic haematuria, asthma, angina, and 
epilepsy). Also, in a cluster randomized trial of class-room cognitive–behavioral therapy to 
reduce depression symptoms in high-risk adolescents, the estimated ICC for the Short Mood and 
Feelings Questionnaire (SMFQ) was 0.025 in the pilot phase and the ICCs (upper 95% 
confidence limit) were as follows in the main trial: baseline < 0.001 (0.006); 6 months 0.007 
(0.026); 12 months 0.012 (0.039). Based on the above ICC estimates, the ICC is anticipated to be 
in the range 0.02-0.05, but to be conservative, a range of 0.02-0.16 was used for sample size 
calculations. As described in Section 9.5.1, an interim analysis will be performed to estimate the 
ICC using the baseline data, to assess whether the sample size should be increased to increase 
power.  
 
Sample size calculations were performed using the cluster randomization modules in the PASS 
11 software. The sample size was chosen to provide high power to detect a clinically important 
difference in the primary efficacy outcome measure, the QIDS-SR score between study arms at 
24 weeks. For the secondary efficacy outcome measures (treatment response, remission, CD4, 
and viral suppression), the effect size that would be detectable with 80% power with the chosen 
sample size was calculated. No adjustment for multiple comparisons was made in the sample size 
because the week 24 QIDS-SR score has been designated as the primary efficacy outcome; 
however, the interpretation of the results will comment on whether a multiple comparisons 
adjustment would change the conclusions of the analyses for the efficacy outcomes. Sample size 
calculations for comparison of means used the t-test and for comparisons of proportions used the 
two-sided Z test (unpooled). 
 
Figure 1 shows the power to detect a difference in means of 0.8 SD units in QIDS-SR score (e.g., 
a difference of four points if the standard deviation is 5) with seven sites per arm and a range of 
ICCs (R) and average number of evaluable participants per site (N), using a two-sided 0.05 
significance level. With an average of ten evaluable participants per site (N=10), the study will 
have at least 90% power if the ICC is less than 0.09 and at least 80% power if the ICC is between 
0.09 and 0.15.  
 
 

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Figure 1: Power to detect 0.8 SD difference in means (D) in QIDS-SR score at 24 weeks with 
seven sites per arm and a range of ICCs (R) and average number of evaluable participants per site 
(N), using a two-sided 0.05 significance level. 
 
 
 
In ATN 080, the treatment response proportion in the control group was 20% and the remission 
rate was 10%, which are unusually low. The study team anticipates that the rates in the ESC 
group will be 50% better than in the ATN 080 control group, namely 30% and 15%, respectively. 
Figure 2 shows the response probability in the COMB-R group (P1.1) that would be detectable 
with 80% power if the response probability in the ESC group is 30%, for a range of ICC values 
and average numbers of evaluable participants per site (M1), using a two-sided 0.05 significance 
level. With an average of 10 evaluable participants per site, the study would be able to detect an 
increase in treatment response from 30% to 55-60% (a 25-30% absolute increase) if the ICC is in 
the range 0.02-.08, and an increase from 30% to 60-65% (a 30-35% absolute increase) if the ICC 
is in the range 0.08-0.15. Figure 3 shows the remission probability in the COMB-R group (P1.1) 
that would be detectable with 80% power if the remission probability in the ESC group is 15%, 
for a range of ICC values and average numbers of evaluable participants per site (M1), using a 
two-sided 0.05 significance level. With an average of 10 evaluable participants per site, the study 
would be able to detect an increase in remission from 15% to 37-42% (a 22-27% absolute 

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increase) if the ICC is in the range 0.02-.08, and an increase from 15% to 42-47% (a 27-32% 
absolute increase) if the ICC is in the range 0.08-0.15. 
 
 
Figure 2: Response probability in the COMB-R group (P1.1) that would be detectable with 80% 
power if the response probability in the ESC group (P2) is 30% for a range of ICC values and 
average numbers of evaluable participants per site (M1), using a two-sided 0.05 significance level  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Figure 3: Remission probability in the COMB-R group (P1.1) that would be detectable with 80% 
power if the remission probability in the ESC group (P2) is 15%, for a range of ICC values and 
average numbers of evaluable participants per site (M1), using a two-sided 0.05 significance 
level. 
 
 
 
In ATN 080, 50% of participants had baseline viral load <400 copies/mL. Figure 4 shows the 
viral suppression probability in the COMB-R group (P1.1) that would be detectable with 80% 
power if the viral suppression probability in the ESC group is 50%, for a range of ICC values and 
average numbers of evaluable participants per site (M1), using a two-sided 0.05 significance 
level. With an average of 10 evaluable participants per site, the study would be able to detect an 
increase in viral suppression from 50% to 74%-78% (a 24-28% absolute increase) if the ICC is in 
the range 0.02-.08, and an increase from 50% to 78%-82% (a 28-32% absolute increase) if the 
ICC is in the range 0.08-0.15. 
 
 
 
 
 
 

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Figure 4: Viral suppression probability in the COMB-R group (P1.1) that would be detectable 
with 80% power if the viral suppression probability in the ESC group (P2) is 50%, for a range of 
ICC values and average numbers of evaluable participants per site (M1), using a two-sided 0.05 
significance level.  
 
 
In ATN 080, the mean CD4+ cell count was approximately 500 cells/mm3 and the standard 
deviation was approximately 300 cells/mm3. Figure 5 shows the difference in mean CD4+ cell 
counts (D) that would be detectable with 80% power if the ESC group had the same mean and SD 
as in ATN 080, for a range of ICC values and average numbers of evaluable participants per site 
(N), using a two-sided 0.05 significance level. With an average of 10 evaluable participants per 
site, the study would be able to detect a difference of 165-205 cells/mm3 if the ICC is in the range 
0.02-.08, and a difference of 205-235 cells/mm3 if the ICC is in the range 0.08-0.15. 
 
 
 
 
 
 
 
 

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Figure 5: Difference in Mean CD4+ Cell Count Detectible (D) with 80% Power if the ESC group 
has mean 500 cells/ mm3 and SD 300 cells/mm3, for a range of ICC values (R) and average 
numbers of evaluable participants per site (N), using a two-sided 0.05 significance level. 
 
 
9.4.2 
Accrual 
 
Accrual of the target sample size of approximately 156 participants (140 evaluable) is expected to 
be completed within 24 months of when accrual opens at each site. There will be a cap of at most 
ten participants enrolled at any single site in the first year of accrual, and the study team will re-
evaluate whether to have a cap for the second year of accrual.  
 
9.5 
Monitoring 
 
This study will be monitored at multiple levels, consistent with standard IMPAACT procedures. 
A study monitoring plan that details monitoring roles and responsibilities and data to be reviewed 

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at each level will be prepared before the study opens to accrual. The core protocol team (which 
consists of the protocol chair, vice-chairs, medical officers, statisticians, data managers, and 
clinical trial specialists) is responsible for closely monitoring study progress, including timely 
achievement of key milestones, the quality of study conduct, and safety. IMPAACT leadership 
will also monitor study progress and quality. The IMPAACT Study Monitoring Committee 
(SMC) will also conduct formal reviews of study conduct and safety. Unless otherwise specified, 
monitoring reports distributed to the protocol team will be pooled across the COMB-R and ESC 
arms. Monitoring reports distributed to the SMC may be broken out by blinded study arm. In 
addition, an interim analysis to confirm assumptions made in the power analysis will be 
performed as noted in Section 9.5.1 
 
Please refer to Section 7.0 for more information on safety assessment and reporting and Sections 
10.0 and 11.0 for more information on on-site monitoring and quality management at the site 
level. Further information on monitoring of study progress, quality of study conduct, and 
participant safety across sites is provided below. 
9.5.1 
Monitoring of Study Accrual and Retention  
 
The study team anticipates that accrual of the target sample size of 156 participants (140 
evaluable) will require approximately 24 months and expects a minimum of eight participants to 
enroll in each site, with a minimum of three enrollments in the first six months. The protocol 
team will monitor the timing of site-specific study activation, which will determine when each 
site will begin accruing participants, and accrual performance following activation. The protocol 
team will closely monitor participant screening, accrual and retention based on reports that will 
be generated by the SDMC monthly during accrual and every three months once accrual is 
complete. The protocol team may decide to revise this schedule as needed. Using these reports, 
the protocol team will monitor accrual closely, relative to the study-specific accrual plan that has 
been established in collaboration with the study sites. Additionally, the protocol team will 
monitor pre-screening and recruitment activities across all sites during study implementation. The 
team will specifically monitor the enrollment of eligible participants at each site (including 
reasons for lack of enrollment). To monitor for selection bias, the characteristics (gender, age, 
mode of transmission, severity of depression and viral load suppression status) of those 
participants screening but not enrolling will be compared between study arms. The same 
characteristics will be compared overall and within treatment arms for those participants enrolling 
vs. not enrolling into the study. In the event that accrual or retention rates fall below target team 
members will work with study sites to identify operational issues or problems, and take 
appropriate action to address those issues. Monitoring of imbalance in baseline characteristics 
between the COMB-R and ESC arms is described in Section 9.3. 
 
The core protocol team will also monitor the percentage of evaluable participants, namely those 
with both baseline and Week 24 QIDS-SR data, as participants reach the Week 24 visit. Should 
the percentage of participants who are non-evaluable at Week 24 exceed 10%, the sample size 
may be increased to achieve 140 evaluable. Additionally, the numbers and characteristics 
(gender, age, mode of transmission, severity of depression and viral load suppression status) of 
non-evaluable participants will be compared between study arms. Characteristics of those 
evaluable vs. non-evaluable will also be compared overall and within treatment arms. 
 
To check the validity of the assumptions used for sample size calculations, an interim analysis 
will use the baseline QIDS-SR data to estimate the ICC. This interim analysis will be performed 
either (a) once at least 5 participants at each site have completed Week 0 or (b) 18 months from 

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the start of study accrual, whichever occurs first. If the estimated ICC is larger than 0.15 (the 
largest value for which the selected sample size provides 80% power), the protocol team will 
assess whether to increase the number of participants to be enrolled, to ensure adequate statistical 
power for the primary study objective. 
 
 
IMPAACT leadership will also monitor accrual relative to the study accrual plan and retention, 
based on standard IMPAACT study accrual and retention reports that they receive on a monthly 
basis. The SMC may be asked to evaluate accrual as part of a review, and, if so, it will report its 
findings and recommendations to the study team and IMPAACT leadership. IMPAACT 
leadership, including the SMC, may request action plans from the team to address accrual delays 
and/or shortfalls and will monitor the implementation and outcomes of such plans as part of an 
overall assessment of the feasibility of the study to achieve its objectives. 
9.5.2 
Monitoring of Study Conduct 
 
Core protocol team members will review key indicators of the quality of study conduct based on 
reports generated periodically by the SDMC and take action with study sites as needed to ensure 
high quality study conduct throughout the period of study implementation. These reports will 
include information on the quality and completeness of data collection, visit completeness, and 
the fidelity of implementation of the study intervention (medication management report and CBT 
adherence checklist – see Section 5.4).  
9.5.3 
Monitoring of Participant Safety 
 
Participant safety will be closely monitored by the core protocol team through periodic reviews of 
adverse event reports (pooled across the COMB-R and ESC arms) generated by the SDMC. 
These reports will provide summaries of ≥ Grade 3 adverse events, psychological 
hospitalizations, and suicide attempts. At the time of each review, the DAIDS Medical Officer 
will also review any EAEs (defined in Section 7.3) reported to the DAIDS Safety Office that are 
not yet reflected in the data reports. Core team members will continually evaluate the pattern and 
frequency of reported adverse events and assess for any individual occurrences or trends of 
concern. Relationship status of adverse events to COMB-R or ESC counseling will also be 
summarized. 
9.5.4 
Study Monitoring Committee 
 
An independent IMPAACT SMC will also review this study regularly with respect to study 
progress, quality of study implementation, and conduct (including retention and data 
completeness), and safety. No interim efficacy analyses are planned because the entire sample 
size will be required to assess the efficacy of the intervention. Reviews will be scheduled at least 
annually. The SMC will review the same type of data reports as the core protocol team; however, 
data may be provided to the SMC by blinded study group. Based on any of its reviews, 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 that may be identified during their reviews.  

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9.6 
Analyses 
 
This section provides a brief overview of the data analyses to address the objectives of the study. 
A comprehensive statistical analysis plan with full details of the planned analyses will be 
developed at least six months prior to the first SMC review of safety data.  
 
9.6.1  Primary Objectives  
 
The primary analyses to address the primary objectives will be cluster-level analyses, where the 
unit of analysis is the site; although this method does not use all the information in the data, this 
method is recommended when there are fewer than 15-20 clusters per group, because individual-
level analyses do not appear to perform robustly with small numbers of clusters (61). The cluster-
level analyses will involve a two-stage procedure. The first stage will calculate a summary 
measure for each site – the mean for continuous outcome measures (QIDS-SR, CD4 count) and 
the proportion for dichotomous outcomes (response to treatment, remission, undetectable plasma 
HIV RNA). The second stage will perform a two-sample t-test (with two-sided alpha =0.05) on 
the site-specific summary measures. Note that the alpha level will not be adjusted for multiple 
comparisons, because the Week 24 QIDS-SR score has been designated as the primary efficacy 
outcome and the response, remission, CD4, and RNA outcomes are considered secondary 
efficacy outcomes; however, the interpretation of the results will comment on whether a multiple 
comparisons adjustment would change the conclusions. If the summary measures have a skewed 
distribution, a log transformation will be performed before doing the t-test. Methods based on the 
t-test have been shown to be highly robust to departures from the underlying assumptions. 
However, with small numbers of clusters per arm, the cluster-level t-test will be less robust to 
non-normality of the underlying distribution of cluster summaries, and it will be difficult to make 
a reliable assessment of non-normality. A non-parametric test that does not rely on a normality 
assumption, but which may be less powerful than the t-test, such as the Wilcoxon rank sum test or 
a permutation test (based on all the permissible allocations that were generated for the site 
randomization) will be performed to supplement the primary analysis. 
 
The primary analysis will focus on the primary outcome measures at Week 24 that are listed in 
Section 9.2.1, because the protocol team believes that it is important that the intervention 
demonstrate a lasting effect; a shorter term effect may not be as clinically meaningful. Secondary 
analyses that use information from earlier time points will also be conducted to supplement the 
results of the primary analyses, including analyses of the change in outcome measures over time 
(such as cross-sectional summaries at each time point, with the non-parametric Wei-Johnson test 
for change over time between groups). As noted above, cluster-level analyses are robust to 
departures from assumptions, but do not use all the information in the data, since the outcomes 
are measured at the individual participant level. Secondary analyses of the primary outcome 
measures will be conducted using individual-level regression methods, including mixed-effects 
linear regression models for continuous outcomes and generalized estimating equations (GEE) 
models for dichotomous outcomes, to supplement the primary cluster-level analyses. For 
example, linear mixed models will be used to evaluate the influence of the COMB-R condition on 
QIDS-SR trajectories over the four assessment points. 
 
Descriptive analyses of participant characteristics at study entry and Week 24 (gender, age, mode 
of transmission, severity of depression, CD4 and RNA levels and viral suppression status) will be 
performed using appropriate statistical tests for categorical and continuous measures of clustered 
data as noted above. To assess the potential for selection bias, the numbers and characteristics 

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(gender, age, mode of transmission, severity of depression, and viral suppression status) of 
participants screening but not enrolling in the study will also be compared between treatment 
groups, and the characteristics of participants enrolling vs. not enrolling will be compared overall 
and within treatment arms as well. We will also compare patient characteristics according to 
treatment arm and whether or not sites allowed parental waivers of consents. 
 
High rates of loss to follow-up before Week 24, particularly if differential between randomized 
arms might affect the ability of the study to answer its primary objective, i.e. power may be 
reduced and the interpretation of any difference between randomized arms may be complicated 
by potential differences between participants who do versus do not remain in follow-up, 
particularly if this also differs between randomized arms. Allowance for a loss to follow-up rate 
of up to 10% prior to Week 24 has been built into the sample size/power considerations for the 
study, and the protocol (Schema and Section 9.5.1) specifies that the sample size may be 
increased if the loss-to-follow-up rate exceeds 10%.  
 
If more than 10% of participants are lost to follow-up before Week 24, or if a larger proportion of 
participants are lost to follow up in one arm (especially  if the loss is due to serious adverse 
events, or suicide attempts), several analyses will be undertaken to explore the potential effects of 
missing data on the conclusions of the study, The characteristics at study entry (gender, age, 
mode of transmission, severity of depression and viral load suppression status) for participants 
who discontinued from the study before Week 24 will be compared between treatment arms. 
Characteristics of participants discontinuing vs. not discontinuing before Week 24 will also be 
compared overall and within treatment arms. In addition, the reasons for losses to follow-up will 
be assessed and compared between treatment arms, with special attention paid to reasons related 
to Grade 3 or higher adverse events, psychological hospitalizations and suicide attempts. 
Descriptive comparisons by site will be performed for sites with sufficient numbers of 
participants. In addition, the probability and timing of loss to follow-up will be summarized and 
compared using Kaplan-Meier plots and the log-rank test. 
 
Sensitivity analyses will be conducted to explore the potential impact of missing data on the 
conclusions of the primary efficacy analyses. Of primary concern are missing QIDS-SR scores at 
Week 24 for participants who had low or decreasing QIDS-SR scores at time points before Week 
24. The sensitivity analyses will be done in two ways: (a) as an extreme, by imputing missing 
QIDS-SR scores at Week 24 so as to minimize the difference between randomized groups (e.g., if 
the primary efficacy analysis among participants with available Week 24 QIDS-SR score 
suggests that COMB-R is better than ESC, impute a high Week 24 QIDS-SR score for COMB-R 
participants who do not have a Week 24 QIDS-SR score, and impute a low Week 24 QIDS-SR 
score for ESC participants who do not have a Week 24 QIDS-SR score, and (b) more plausibly, 
by imputing missing QIDS-SR scores at Week 24 as the mean of the Week 24 QIDS-SR scores 
for participants who had that evaluation and also had similar QIDS-SR scores at earlier time 
points. Use of multiple imputation procedures will be considered if the attrition rate is high. The 
interpretation will need to be more cautious if the results of these analyses suggest different 
conclusions. 
 
9.6.2   Secondary and Exploratory Objectives  
 
Adherence to both HIV and depression medication and depression counseling sessions will be 
assessed as continuous and categorical measures. For example, adherence to HIV medications 
will be dichotomized based on the data distribution of the number of days when doses were 
missed. Likert scales for self-reports of adherence frequency (how often did you take your 
medications the way you were supposed to?) and efficacy (how good a job did you do at taking 

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your medications?) will be dichotomized or analyzed as an ordinal measure, based on the 
observed data distribution. The proportions of expected counseling sessions attended will 
likewise be summarized and analyzed as a continuous or categorical measure based on the 
distribution observed. For each dichotomized adherence assessment, the proportions of 
participants with good versus poor adherence will be compared using the cluster-randomized 
methods described above. Similarly, if it is decided that the proportions of expected sessions can 
be analyzed as a continuous variable, methods noted above will be used to compare the COMB-R 
group to the ESC group at Week 24 and Week 48. A limitation of the depression medication 
adherence analyses is that adherence data will only be available for participants who are taking 
depression medications, so this will be a non-randomized comparison. 
  
Week 48 depression treatment outcomes will be analyzed similarly to the Week 24 outcomes in 
order to ascertain whether any reported effects are maintained.  
 
Analyses to adjust for imbalance and potential confounding, and assess effect modification will 
be performed using cluster-level methods and also using individual level regression methods 
(because cluster-level methods do not use all the information in the data). Each approach is 
described in turn below. 
 
In the cluster-level analyses, adjustment for baseline covariates (e.g., the QIDS-SR score at entry) 
will be done by modifying the first stage of analysis and then completing the second stage. In the 
first stage, an individual-level regression of the individual outcome measures (e.g., QIDS-SR 
scores at Week 24) on the baseline covariates will be performed, ignoring the clustering of the 
data, and then the residuals between observed and predicted values from this model will be used 
as the summary measures in the second stage.  
 
Specifically, in the first stage of the cluster-level analyses, all variables of interest except for the 
study group (ESC or COMB-R) will be entered into the regression model, and the summary 
statistic for each cluster will be the residual based on comparison of the summary measure 
calculated from the observed values of the outcome measure in that cluster and the summary 
outcome measure calculated from the predicted values of the outcome measures from the model 
in the absence of an intervention effect. For example, the site-specific residual for the QIDS-SR 
score at Week 24 will be the difference between the observed site-specific mean QIDS-SR score 
and the predicted site-specific mean QIDS-SR score (mean of the predicted QIDS-SR scores for 
that site from a linear regression model of Week 24 QIDS-SR score on baseline QIDS-SR score); 
the site-specific residual for the response proportion will be the difference between the observed 
site-specific response proportion and the predicted site-specific response proportion (predicted 
response proportion for that site from a logistic regression model). Then, in the second stage, 
these site-specific residuals will be compared using the two-sample t-test or other test as 
described above. Analyses of effect modification for cluster-level covariates and individual level 
covariates will be performed using methods described by Hayes and Moulton (56).  
 
As noted above, cluster-level analyses are robust to departures from assumptions, but do not use 
all the information in the data, since the outcomes are measured at the individual participant level. 
Additional analyses will be conducted using individual-level regression methods, including 
mixed-effects linear regression models for continuous outcomes and generalized estimating 
equations (GEE) models for dichotomous outcomes, to supplement the primary cluster-level 
analyses. These individual level analyses will facilitate adjustment for baseline covariates, 
longitudinal analyses of the outcome measures over the 48-week study period, and assessment of 
effect modification by individual-level covariates. For example, linear mixed models will be used 

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to evaluate the influence of the COMB-R condition on QIDS-SR trajectories over the five 
assessment points.  
 
If depression decreases over the course of treatment, we would expect the level of high risk sex 
and alcohol/drug behaviors to decline. We will assess whether COMB-R treatment for depression 
is associated with reduced alcohol/drug and sex risk behaviors using similar methods as described 
for the primary study objectives. Dichotomized measures for levels of high risk behaviors at 
weeks 24 and 48 will be compared between the COMB-R and ESC arms.  
 
The implementation fidelity at COMB-R sites and the counseling strategies and medication 
patterns at ESC sites will be summarized using descriptive statistics. The use of medication, the 
number of therapy visits, and treatment acceptability, for both clinicians and participants will be 
described and compared for both COMB-R and ESC using standard descriptive statistics such as 
Chi square tests for categorical variables (such as clinician satisfaction rating items) and t-tests or 
non-parametric Wilcoxon rank sum tests for continuous measures (e.g., number of therapy 
sessions; client satisfaction score). CBT adherence checklist and ESC therapy checklist results as 
well as the COMB-R MM checklist will also be summarized. 
 
The frequency and pattern of Grade 3 or higher adverse events, psychological hospitalizations 
and suicide attempts will be described for both treatment arms and the proportion of participants 
with each of these outcomes will be compared between arms using methods described for the 
primary study outcomes. Presumed relationship of adverse events to COMB-R and ESC 
counseling will be summarized and compared. 
 
Similar methods to those described for the primary and secondary study objectives will be used to 
assess whether inflammatory markers decrease with the COMB-R intervention compared to ESC 
and whether the inflammatory markers could moderate the treatment effects on the primary 
outcome measures. 
 
10 
DATA HANDLING AND RECORD KEEPING 
 
10.1 
Data Management Responsibilities 
 
As described in Section 4.4, data on screening and enrollment in this study will be collected using 
the DMC 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 CRFs and supporting 
source data. In maintaining these records, sites must comply with the standards of source 
documentation specified in the DAIDS policy on Requirements for Source Documentation in 
DAIDS Funded and/or Sponsored Clinical Trials (available on the web site referenced in Section 
10.2). 
 
CRFs are completed by site staff and, following quality control and quality assurance reviews, are 
keyed using a remote data entry system designated by the DMC, and transferred electronically to 
the DMC. Selected laboratory data are transferred electronically to the DMC through the 
Laboratory Data Management System (LDMS).  
 

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At the DMC, computerized checks are applied to the transferred data and, when required, data 
queries are issued for resolution by site staff. All data must be transferred to the DMC within 
timeframes specified in the forms instructions; queries must also be resolved in a timely manner.  
 
Further information on the study CRFs and IMPAACT data management procedures, including a 
Forms Manual: Policies and Procedures for Forms Completion for DAIDS-Sponsored Clinical 
Trials, a comprehensive Computing Manual, and a User Manual for the Subject Enrollment 
System, is available on the DMC portal at www.fstrf.org.  
 
10.2  Essential and Source Documents and Access to Source Data 
 
All DAIDS policies referenced in this section are available at: 
www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/Pages/ClinicalSite.aspx 
 
Study sites must comply with the DAIDS policies on Requirements for Essential Documents at 
Clinical Research Sites Conducting DAIDS Funded and/or Sponsored Clinical Trials and 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials. In 
its policy on Requirements for Manual of Operational Procedures, DAIDS requires sites to 
establish SOPs for maintaining essential and source documents in compliance with these policies. 
Site SOPs should be updated and/or supplemented as needed to describe roles, responsibilities, 
and procedures for this study, and site SOPs should be followed throughout the conduct of the 
study.  
 
Per the DAIDS policy on Storage and Retention of Clinical Research Records, study records must 
be stored in a manner that ensures privacy, confidentiality, security, and accessibility during the 
conduct of the study and after the study is completed. Records must be retained for a minimum of 
three years after the completion of the study.  
 
All study records must be accessible for inspection, monitoring, and/or auditing during and after 
the conduct of the study by authorized representatives of the study sponsors and their contracted 
monitors, IMPAACT, site IRBs/ECs, OHRP, and other applicable regulatory entities. Records 
must be kept on-site throughout the period of study implementation; thereafter, instructions for 
off-site storage may be provided by NIAID or NICHD. No study records may be removed to an 
off-site location or destroyed prior to receiving approval from NIAID or NICHD.  
 
10.3  Quality Control and Quality Assurance 
 
All study sites will conduct quality control and quality assurance procedures in accordance with 
current NIAID policies. 
(http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/qmppolicy.pdf) 
 
11 
CLINICAL SITE MONITORING 
 
Site monitors under contract to NIAID or NICHD will visit study sites to inspect study facilities 
and review participant study records including consent forms, CRFs, medical records, and 
laboratory records, to ensure protection of study participants, compliance with the IRB/EC 
approved protocol, and accuracy and completeness of records. The monitors will also review site 
essential document files to ensure compliance with all applicable regulatory requirements. Site 

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investigators and their designees will make study facilities and documents available for inspection 
by the monitors.  
 
12  
HUMAN SUBJECTS PROTECTIONS 
 
12.1  Institutional Review Board/Ethics Committee Review and Approval  
 
Each participating institution is responsible for assuring that this protocol, the associated site-
specific informed consent forms, and study-related documents (such as participation education 
materials) are reviewed by an IRB/EC responsible for oversight of research conducted at the 
study site. Any amendments to the protocol must be approved by the responsible IRBs/ECs prior 
to implementation. 
 
Subsequent to the initial review and approval, in accordance with 45 CFR 46.109(e), the 
responsible IRBs/ECs must review the study at least annually. Sites will submit documentation of 
continuing review to the DAIDS Protocol Registration Office in accordance with the DAIDS 
Protocol Registration Policy and Procedures Manual. 
 
12.2 
Vulnerable Participants 
 
Study sites must comply with the requirements of the DAIDS policy on Enrolling Children 
(including Adolescents) in Clinical Research, which is available at: 
www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/Pages/ClinicalSite.aspx 
 
The children enrolled in this study are considered vulnerable participants per 45 CFR 46 Subpart 
D. Site IRBs/ECs must consider the potential benefits, risks, and discomforts of the study to 
children and assess the justification for their inclusion in the study. As part of this assessment, 
IRBs/ECs must determine the level of risk to children in the categories specified in 45 CFR 
46.404-407. Documentation of this determination is required to complete the DAIDS protocol 
registration process described in Section 13.2.  
 
The risk category assigned by the IRB/EC determines whether parental/guardian permission is 
required, and if so, the informed consent requirements for the study at each site. Per 45 CFR 
46.408 (b), the IRB/EC may find that the permission of one parent is sufficient for research to be 
conducted under 46.404 or 46.405. Where research is covered by 46.406 or 46.407, both parents 
must give their permission unless one parent is deceased, unknown, incompetent, or not 
reasonably available, or when only one parent has legal responsibility for the care and custody of 
the child (as determined locally). Alternatively, IRBs/ECs may allow sites to obtain a waiver for 
parental permission per 45 CFR 46.408 (c), given the perceived minimal risk and potential benefit 
to participants. IRBs/ECs must document their risk determination and study sites should adapt the 
signature pages of their site-specific informed consent forms as needed to accommodate the 
parental consent requirements, if needed, associated with the IRB/EC determination.  
 
12.3  Informed Consent 
 
Written informed assent/consent must be obtained from a participant prior to performance of 
screening and enrollment procedures. If required per site IRB/EC, written permission may also be 
required from the participant’s parent or legal guardian. A participant at a site that requires 
parental/guardian permission may enroll in the study as a minor, but reach the legal age of 

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consent during study follow-up. In this case, they will sign the assent form upon screening and 
will later sign the consent form once they reach legal age, at their next scheduled visit. A 
participant at a site that obtained a waiver for parental permission, may enroll in the study as a 
minor and sign the participant informed consent form without a separate parental consent. 
 
The informed consent will describe the purpose of the study, the procedures to be followed, and 
the risks and benefits of participation. Informed consent for specimen storage and future testing 
will be documented in the consent form; however, a participant (or parent/guardian if applicable) 
may still enroll in the study without agreeing to the storage and future testing of laboratory 
specimens. A copy of the consent form will be given to the participant (or parent or legal 
guardian).  
 
Should the parent(s) of an enrolled participant, at a site where parental permission is required, die 
or no longer be reasonably available for any reason, no further study-specific visits or procedures 
may be performed until informed consent for continued study participation is obtained from a 
locally authorized guardian. In accordance with the DAIDS policy on Enrolling Children 
(including Adolescents) in Clinical Research (available at the website referenced in Section 12.2), 
all study sites must establish and maintain written procedures describing the standards that will be 
followed to identify who may serve as guardian for an enrolled participant, reflective of 
applicable IRB/EC guidance for conduct of human subjects research within the context of 
available local law, regulation, or government policy.  
 
12.4  Potential Benefits 
 
Participants in this study may experience no direct benefit. The study may help participants gain 
skills to assess and monitor their depression symptoms and improve their levels of functioning 
through the use of medication and therapy. Participants and others may benefit in the future from 
information learned from this study. Specifically, information learned in this study may lead to 
the development of medication guidelines and H&W CBT tailored for youth living with HIV. 
Participants also may appreciate the opportunity to contribute to the field of HIV and depression 
research. Participants will receive laboratory testing and treatment counseling. For other medical 
conditions identified as part of the study screening and/or follow-up procedures, participants will 
be referred to other sources of care available in their community. Some participants may have the 
opportunity to access expedient treatment and decreased morbidity due to early diagnosis and 
treatment of abnormalities identified during tests, examinations and referrals. 
 
12.5  Potential Risks  
12.5.1 General 
 
It is not expected that this trial will expose participants to unreasonable risk. Phlebotomy may 
lead to discomfort, feelings of dizziness or faintness, and/or bruising, swelling and/or infection. 
Participants may experience discomfort when answering questions of a personal nature, such as 
questions dealing with sexual behaviors. 
 
Although study sites make every effort to protect participant privacy and confidentiality, it is 
possible that participants' involvement in the study could become known to others, and that social 
harms may result (i.e., because participants could become known as HIV-positive). For example, 
participants could be treated unfairly or discriminated against, or could have problems being 
accepted by their families and/or communities. 

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12.5.2 Unimproved depression or clinical deterioration  
 
Continued depression or worsening of depressive symptoms is always a risk of depression 
regardless of use of medication and/or counseling. In addition, as suicidal ideation is a symptom 
of depression, suicide or suicide attempt is a risk. Clinical deterioration due to the underlying 
psychiatric condition(s), or the study interventions themselves (CBT therapy, MM algorithm; 
ESC), is also a risk. These risks will be assessed during MM visits with the site prescribing 
clinician who will be monitoring the participant’s depression symptoms using the QIDS-SR 
regardless of the use of medication. The H&W CBT therapist will also be monitoring depression 
symptoms during H&W CBT visits. ESC therapists and clinicians will likewise be monitoring 
depression symptoms as per their usual standard of care. 
12.5.3 Medication side effects 
  
Although this protocol is not providing medications directly to participants; participants may be 
using antiretroviral and/or anti-depressive medication during the course of the study. Common and 
rare side effects of antidepressants and any other adjunctive medications that are prescribed will be 
discussed with the participant by the site prescribing clinician. 
 
Participants will be informed that they are free to decline starting medications or stop taking 
medications at any time without penalty. Participants who start new medications while on study 
may have more frequent study visits as determined by the site prescribing clinician. Site prescribing 
clinicians will request any clinically indicated laboratory tests including hematology, chemistry 
panel (including: Ca, PO4, Cr, Liver tests (AST, ALT, Albumin, Bilirubin, Alkaline Phosphatase) 
and electrolytes (Na, K, Cl, HCO3)), lithium levels and an electrocardiogram) per standard of care 
for the antidepressant prescribed. All grade 3 or higher adverse effects relating to medications will 
be reported to the protocol team, using the Adverse Event form. 
12.5.4 Drug-drug interaction 
 
Drug-drug interactions among antidepressants and ARV treatments will be considered and 
clinically monitored. While there are no antidepressants specifically contra-indicated with ARV 
treatments, the pharmacological characteristics of antidepressants are important to consider as such 
interactions can result in significant consequences (e.g. lowering of ARV blood levels leading to 
reduced efficacy, increasing serotonin levels with the potential for serotonin syndrome, etc).  
12.5.5 Complications with pregnancy 
  
There is a risk that antidepressant medications may cause birth defects including fetal growth 
changes, shorter gestations, neonatal irritability, neurobehavioral changes and problems with fetal 
breathing in female participants who become pregnant while participating in the study. Although 
there is some concern regarding the use of SSRIs during pregnancy and their effects on the 
growing fetus, research results are not conclusive. There is also a risk that antidepressant 
medications may cause changes in sperm in males. All participants, who are sexually active, will 
be recommended to use condoms because of the risk in pregnancy and STI transmission.  
 
Female participants who become pregnant during the study, or who are at high risk of becoming 
pregnant, may continue in the study, and site investigators will counsel them on continued use of 
antidepressants in accordance with best clinical judgment and standard care practices. 

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Furthermore, study staff will refer pregnant participants, or treat them, according to the Public 
Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-
Infected Women for Maternal Health and Interventions to Reduce Peri-natal HIV Transmission in 
the United States: dated June 7, 2016 (https://aidsinfo.nih.gov/guidelines/html/3/perinatal-
guidelines/0# ); and register them in the Antiretroviral Pregnancy Registry as per Section 6.8.  
 
Regardless of action taken with medications, all participants will continue to be followed in the 
study and remain in their assigned groups for the purposes of analysis.  
 
12.6  Reimbursement/Compensation 
 
Pending IRB/EC approval, participants will be compensated for time and effort in this study, 
and/or be reimbursed for travel to study visits. Site specific reimbursement amounts will be 
specified in the study informed consent forms of each individual site. 
 
12.7  Privacy and Confidentiality 
 
All study procedures will be conducted in private, and every effort will be made to protect 
participant privacy and confidentiality to the extent possible. The information a participant 
provides during study visits will not be shared routinely with their parent/guardian, unless the 
participant and site staff agree that this is important for their well-being. Sites should follow their 
SOPs and standard of care to involve parents/guardians when appropriate. Sites will inform 
potential participants about any limits to confidentiality, including state laws that require 
reporting of abuse or harm to the participant or others.  
 
Each study site will implement confidentiality representatives to identify potential confidentiality 
issues and strategies to address them. In addition to local considerations, the protections described 
below will be implemented at all sites. 
 
All study-related information will be stored securely. All participant information will be stored in 
locked areas with access limited to study staff. All laboratory specimens, study data collection, 
and administrative forms will be identified by coded (PID) number only to maintain participant 
confidentiality. Study sites are encouraged but not required by DAIDS policies to store study 
records that bear participant names or other personal identifiers separately from records identified 
by PID. Forms, lists, logbooks, appointment books, and any other listings that link participants’ 
ID numbers to identifying information will be stored in a separate, locked file in an area with 
limited access. After receiving appropriate approval, all study documents/data will be properly 
disposed of, including the proper destruction and/or deletion of paper files, electronic study data, 
and electronic documents. Participants’ study information will not be released without their 
written permission, except as necessary for review, monitoring, and/or auditing by the following: 
 
• 
Representatives of the U.S. Federal Government, including OHRP, NIH, and/or contractors 
of the NIH 
• 
Representatives of the IMPAACT Operations Center, SDMC, and/or Laboratory Center (LC) 
• 
Study staff 
• 
Site IRBs 
 

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In addition to the above, a Certificate of Confidentiality has been obtained for this study from the 
U.S. Department of Health and Human Services. This certificate protects study staff from being 
compelled to disclose study-related information by any U.S. Federal, state, or local civil, 
criminal, administrative, legislative, or other proceedings. It thus serves to protect the identity and 
privacy of study participants. 
 
12.8  Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases, including HIV-
1, identified among study participants to health authorities. Participants will be made aware of 
reporting requirements during the informed consent process. 
 
12.9  Management of Incidental Findings 
 
Site staff will inform participants of all exam findings and clinically meaningful laboratory test 
results. When applicable, site staff will provide referral to non-study sources of medical care for 
further evaluation and/or treatment of these findings.  
 
12.10  Management of New Information Pertinent to Study Participation 
 
Participants enrolled in the study will receive new information learned during the course of the 
study that is pertinent and might affect their willingness to remain in the study. 
 
13  
ADMINISTRATIVE PROCEDURES 
 
13.1  Regulatory Oversight 
 
This study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), 
National Institute of Child Health and Human Development (NICHD), and National Institute of 
Mental Health (NIMH), which are part of the United States National Institutes of Health (NIH). 
The Division of AIDS (DAIDS) within the NIAID is responsible for regulatory oversight of this 
study. NIAID and NICHD provide funding support to the clinical research sites at which this 
study will be conducted. Each institute contracts with clinical site monitors who will perform on-
site monitoring visits as described in Section 11.0. As part of these visits, monitors will inspect 
site files to ensure compliance with both US and local regulatory requirements. 
 
13.2  Protocol Registration 
 
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol informed consent form(s) approved, as appropriate, by 
their local institutional review board (IRB)/ethics committee (EC) and any other applicable 
regulatory entity (RE). Upon receiving final approval, sites will submit all required protocol 
registration documents to the DAIDS Protocol Registration Office (DAIDS PRO) at the 
Regulatory Support Center (RSC). The DAIDS PRO will review the submitted protocol 
registration packet to ensure that all of the required documents have been received. 
 

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Site-specific informed consent forms (ICFs) WILL be reviewed and approved by the DAIDS 
PRO and sites will receive an Initial Registration Notification from the DAIDS PRO that 
indicates successful completion of the protocol registration process. A copy of the Initial 
Registration Notification should be retained in the site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an amendment, sites 
should implement the amendment immediately. Sites are required to submit an amendment 
registration packet to the DAIDS PRO at the RSC. The DAIDS PRO will review the submitted 
protocol registration packet to ensure that all the required documents have been received. Site-
specific ICF(s) WILL NOT be reviewed and approved by the DAIDS PRO and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a complete registration 
packet. A copy of the Amendment Registration Notification should be retained in the site's 
regulatory files. 
 
For additional information on the protocol registration process and specific documents required 
for initial and amendment registrations, refer to the current version of the DAIDS Protocol 
Registration Manual. 
 
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 MOP, Laboratory Processing Chart (LPC), and 
other study implementation materials, which will be available on the IMPAACT web site: 
www.impaactnetwork.org. 
 
Study implementation at each site will also be guided site-specific standard operating procedures 
(SOPs). The DAIDS policy on Requirements for Manual of Operational specifies the minimum 
set of SOPs that must be established at sites conducting DAIDS funded and/or sponsored clinical 
trials (available on the website referenced in Section 10.2). These SOPs should be updated and/or 
supplemented as needed to describe roles, responsibilities, and procedures for this study. 
 
13.4  Protocol Deviation Reporting 
 
Per the policy for Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials (available at the website referenced in Section 10.2), all protocol deviations must 
be documented in participant research records. Reasons for the deviations and corrective and 
preventive actions taken in response to the deviations should also be documented.  
 
Deviations should be reported to site IRBs/ECs and other applicable regulatory entities in 
accordance with the policies and procedures of these review bodies. Serious deviations that are 
associated with increased risk to one or more study participants and/or significant impacts on the 
integrity of study data must also be reported within IMPAACT, following procedures specified in 
the IMPAACT Manual of Procedures (which is available on the IMPAACT website: 
www.impaactnetwork.org). 
 
13.5 Critical Events Reporting 
 
DAIDS has developed a critical event reporting system. Per the policy, critical events include the 
following:  

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 
Unanticipated Problems  
 
Serious or Continuing Noncompliance  
 
Suspension or Termination of IRB/EC Approval  
 
Suspected Research Misconduct 
 
Additional details on site responsibilities for identification and classification of critical events, the 
critical events manual, and associated appendices can be found at: 
 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/Pages/Safety.aspx 
 
All critical event reporting questions should be directed to the site’s OCSO representative. 
 
13.6  ClinicalTrials.gov 
 
This protocol is not subject to the Food and Drug Administration Amendments Act of 2007 
(FDAAA). However, it will be registered in https://clinicaltrials.gov/ to meet International 
Committee of Medical Journal Editors (ICMJE) requirements. 
14  
PUBLICATIONS 
 
 
       DAIDS/NIAID and IMPAACT policies will govern publication of the results of this study. 
 
 

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Sauter FM, Heyne D, Michiel Westenberg P. Cognitive Behavior Therapy for Anxious 
Adolescents: Developmental Influences on Treatment Design and Delivery. Clinical Child and 
Family Psychology Review. 2009;12(4):310-35. 
30. 
Fischer-Smith T, Tedaldi EM, Rappaport J. CD163/CD16 co-expression by circulating 
monocytes/macrophages in HIV: potential biomarkers for HIV infection and AIDS progression. 
AIDS research and human retroviruses. 2008;24(3):417-21. 
31. 
Castley A, Berry C, French M, Fernandez S, Krueger R, Nolan D. Elevated plasma soluble CD14 
and skewed CD16+ monocyte distribution persist despite normalisation of soluble CD163 and 
CXCL10 by effective HIV therapy: a changing paradigm for routine HIV laboratory monitoring? 
PloS one. 2014;9(12):e115226. 
32. 
Borges AH, Weitz JI, Collins G, Baker JV, Levy Y, Davey RT, Jr., et al. Markers of 
inflammation and activation of coagulation are associated with anaemia in antiretroviral-treated 
HIV disease. Aids. 2014;28(12):1791-6. 
33. 
Boulware DR, Hullsiek KH, Puronen CE, Rupert A, Baker JV, French MA, et al. Higher levels of 
CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are 
associated with increased risk of AIDS or death. The Journal of infectious diseases. 
2011;203(11):1637-46. 

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34. 
Group TISS. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. New 
England Journal of Medicine. 2015;373(9):795-807. 
35. 
Emery S, Neuhaus JA, Phillips AN, Babiker A, Cohen CJ, Gatell JM, et al. Major clinical 
outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at 
baseline in the SMART study. J InfectDis. 2008;197(8):1133-44. 
36. 
Severe P, Jean Juste MA, Ambroise A, Eliacin L, Marchand C, Apollon S, et al. Early versus 
Standard Antiretroviral Therapy for HIV-Infected Adults in Haiti. New England Journal of 
Medicine. 2010;363(3):257-65. 
37. 
Grinsztejn B, Hosseinipour MC, Ribaudo HJ, Swindells S, Eron J, Chen YQ, et al. Effects of 
early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: 
results from the phase 3 HPTN 052 randomised controlled trial. The Lancet Infectious diseases. 
2014;14(4):281-90. 
38. 
Baker JV, Neuhaus J, Duprez D, Kuller LH, Tracy R, Belloso WH, et al. Changes in 
inflammatory and coagulation biomarkers: a randomized comparison of immediate versus 
deferred antiretroviral therapy in patients with HIV infection. J Acquir Immune Defic Syndr. 
2011;56(1):36-43. 
39. 
Baker JV, Lundgren JD. Cardiovascular implications from untreated human immunodeficiency 
virus infection. European heart journal. 2011;32(8):945-51. 
40. 
Baker JV, Engen NW, Huppler Hullsiek K, Stephan C, Jain MK, Munderi P, et al. Assessment of 
arterial elasticity among HIV-positive participants with high CD4 cell counts: a substudy of the 
INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. HIV Medicine. 
2015;16:109-18. 
41. 
Kennard BD, Emslie GJ, Mayes TL, Nightingale-Teresi J, Nakonezny PA, Hughes JL, et al. 
Cognitive-Behavioral Therapy to Prevent Relapse in Pediatric Responders to Pharmacotherapy 
for Major Depressive Disorder. Journal of the American Academy of Child and Adolescent 
Psychiatry. 2008;47(12):1395-404. 
42. 
Safren SA, Hendriksen ES, Mayer KH, Mimiaga MJ, Pickard R, Otto MW. Cognitive-behavioral 
therapy for HIV medication adherence and depression. Cognitive and behavioral practice. 
2004;11(4):415-24. 
43. 
Emslie GJ, Mayes T, Porta G, Vitiello B, Clarke G, Wagner KD, et al. Treatment of Resistant 
Depression in Adolescents (TORDIA): week 24 outcomes. The American journal of psychiatry. 
2010;167(7):782-91. 
44. 
Hughes CW, Emslie GJ, Crismon ML, Posner K, Birmaher B, Ryan N, et al. Texas Children's 
Medication Algorithm Project: update from Texas Consensus Conference Panel on Medication 
Treatment of Childhood Major Depressive Disorder. Journal of the American Academy of Child 
and Adolescent Psychiatry. 2007;46(6):667-86. 
45. 
Brent D, Greenhill L, Compton S, Emslie G, Wells K, Walkup J, et al. The Treatment of 
Adolescent Suicide Attempters (TASA) Study: Predictors of Suicidal Events in an Open 
Treatment Trial. Journal of the American Academy of Child and Adolescent Psychiatry. 
2009;48(10):987-96. 
46. 
Yanofski J, Croarkin P. Choosing Antidepressants for HIV and AIDS Patients: Insights on Safety 
and Side Effects. Psychiatry (Edgmont). 2008;5(5):61-6. 
47. 
Erickson JL, Velasco JM, Hieken TJ. Compliance with melanoma treatment guidelines in a 
community teaching hospital: time trends and other variables. Annals of surgical oncology. 
2008;15(4):1211-7. 
48. 
Golin CE, Earp J, Tien HC, Stewart P, Porter C, Howie L. A 2-arm, randomized, controlled trial 
of a motivational interviewing-based intervention to improve adherence to antiretroviral therapy 
(ART) among patients failing or initiating ART. Journal of acquired immune deficiency 
syndromes (1999). 2006;42(1):42-51. 

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Parsons JT, Golub SA, Rosof E, Holder C. Motivational Interviewing and Cognitive-Behavioral 
Intervention to Improve HIV Medication Adherence Among Hazardous Drinkers: A Randomized 
Controlled Trial. Journal of acquired immune deficiency syndromes (1999). 2007;46(4):443-50. 
50. 
Minnis AM, Muchini A, Shiboski S, Mwale M, Morrison C, Chipato T, et al. Audio computer-
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51. 
Hewett PC, Mensch BS, Erulkar AS. Consistency in the reporting of sexual behaviour by 
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52. 
Langhaug LF CY, Pascoe SJS et al. . Comparing 4 questionnaire delivery methods for collection 
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World Congress.(Seattle, Washington, USA. July 29-Aug 1, 2007.). 
53. 
Mensch BS, Hewett PC, Gregory R, Helleringer S. Sexual behavior and STI/HIV status among 
adolescents in rural Malawi: an evaluation of the effect of interview mode on reporting. Studies in 
family planning. 2008;39(4):321-34. 
54. 
Bernstein IH, Rush AJ, Trivedi MH, Hughes CW, Macleod L, Witte BP, et al. Psychometric 
properties of the Quick Inventory of Depressive Symptomatology in adolescents. International 
journal of methods in psychiatric research. 2010;19(4):185-94. 
55. 
Moore HK, Hughes CW, Mundt JC, Rush AJ, Macleod L, Emslie GJ, et al. A pilot study of an 
electronic, adolescent version of the quick inventory of depressive symptomatology. The Journal 
of clinical psychiatry. 2007;68(9):1436-40. 
56. 
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development, reliability and feasibility. Addiction (Abingdon, England). 2002;97(9):1183-94. 
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Humeniuk R, Ali R, Babor TF, Farrell M, Formigoni ML, Jittiwutikarn J, et al. Validation of the 
Alcohol, Smoking And Substance Involvement Screening Test (ASSIST). Addiction (Abingdon, 
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58. 
Naar-King S, Parsons JT, Murphy DA, Chen X, Harris DR, Belzer ME. Improving health 
outcomes for youth living with the human immunodeficiency virus: a multisite randomized trial 
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59. 
Brown LK, Whiteley L, Harper GW, Nichols S, Nieves A. Psychological symptoms among 2032 
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Wilson IB, Fowler FJ, Jr., Cosenza CA, Michaud J, Bentkover J, Rana A, et al. Cognitive and 
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cluster randomised trials. Comput Biol Med. 2004;34:113-25. 
 
 

 
IMPAACT 2002, Version 1.0                   Page 77 of 95                                   19 August 2016 
16 APPENDICES   
 
 
Appendix I: Schedule of Evaluations for All Participants 
Study Visit 
Screening/ 
Entry Visit 
Week 1 
Week 6 
Week 12 
Week 24 
Week 36  
Week 48/Study 
Exit/Early 
Discontinuation  
Interim 
Visit 
Visit Window 
— 
-7/+14 d 
±14 d 
±14 d 
±14 d 
±14 d 
±14 d 
— 
Administrative and Regulatory 
 
Obtain written informed assent and/or consent 
X 
 
 
 
 
 
 
 
Assign PID number  
X 
 
 
 
 
 
 
 
Collect demographic information 
X 
 
 
 
 
 
 
 
Collect/review locator information 
X 
X 
X 
X 
X 
X 
X 
X 
Assess eligibility  
X 
 
 
 
 
 
 
 
Complete Subject Enrollment System  
X 
 
 
 
 
 
 
 
Behavioral and Counseling 
 
HIV pre-/post-test counseling 
* 
 
 
 
 
 
 
 
Behavioral questionnaire+ 
X 
 
X 
X 
X 
X 
X 
 
QIDS-SR 
X 
X~ 
X~ 
X~ 
X 
X 
X 
^~ 
Client Satisfaction Questionnaire 
 
 
 
 
X 
 
 
 
Physician Satisfaction Questionnaire (COMB-R Sites Only) 
 
 
 
 
X 
 
 
 
Clinical 
 
Obtain/update medical and medications history 
X 
X 
X 
X 
X 
X 
X 
* 
Assess CDC HIV disease category 
X 
 
 
 
X 
X 
X 
 
Obtain CD4 nadir from medical history 
X 
 
 
 
 
 
 
 
QIDS-C 
X 
 
 
 
 
 
 
 
Provide available findings/test results 
X 
X 
X 
X 
X 
X 
X 
X 
Record/update AEs 
 
X 
X 
X 
X 
X 
X 
X 
COMB-R Sites ONLY: 
 
Review treatment options using MM  
 
X 
X 
X 
X 
 
 
* 
MM Checklist 
 
X 
X 
X 
X 
 
 
* 
CBT Session using CBT Manual 
 
X 
X 
X 
X 
 
 
* 
CBT Adherence Checklist 
 
X 
X 
X 
X 
 
 
* 
ESC Sites ONLY: 
 
Medication management, as indicated by symptoms 
 
X 
X 
X 
X 
 
 
* 
Psychotherapy, as indicated by symptoms 
 
X 
X 
X 
X 
 
 
* 
 
ESC therapy Checklist 
 
X 
X 
X 
X 
 
 
* 
Laboratory  
 
CD4+ T-Cell Count (4mL) 
X 
 
 
 
X 
 
X 
 
HIV-1 RNA (4mL) 
X 
 
 
 
X 
 
X 
 
Plasma for inflammatory/biomarkers (5 mL) 
X 
 
 
 
X 
 
X 
 
HIV-1 test (confirmatory tests as needed) (5mL)# 
* 
 
 
 
 
 
 
 
Total blood volumes (may vary depending on local 
laboratory requirements) 
13-18mL 
 
 
 
13mL 
 
13mL 
 

IMPAACT 2002, Version 1.0 
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19 August 2016 
X - required, * - if indicated, ~ administered on paper form only at COMB-R sites, ^ only required at COMB-R sites during interim clinical visits when participants meets with site 
prescriber, + includes sexual, adherence and drug and alcohol use, #If HIV RNA PCR is used to establish HIV status at screening /entry, it may be also used as the viral load 
measure for study entry 
 
Note: Week 1 procedures may be combined with the Screening and Enrollment Visit if convenient for the participant and study staff 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
IMPAACT 2002, Version 1.0                   Page 79 of 95                                   19 August 2016 
Appendix II: Sample Informed Assent 
 
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL TRIALS 
(IMPAACT) NETWORK  
 
SAMPLE INFORMED ASSENT 
 
For protocol: 
 
IMPAACT 2002 
COMBINED COGNITIVE BEHAVIORAL THERAPY AND A MEDICATION MANAGEMENT 
ALGORITHM FOR TREATMENT OF DEPRESSION AMONG YOUTH LIVING WITH HIV IN THE 
UNITED STATES 
Version 1.0, dated 19 August 2016 
 
INTRODUCTION 
You are being asked to take part in this research study because you have Human Immunodeficiency Virus 
(HIV) and may have depression. Before you decide if you want to be a part of this study, we want you to 
know about the study.  
 
This form gives you information about this study. The decision of being in the study is up to you. Please 
ask if you have any questions at all. You may choose to stop being in the study at any time. If you agree 
to take part in this study, you will be asked to sign this form. You will get a copy to keep. 
 
WHY IS THIS STUDY BEING DONE? 
This study will test if certain types of counseling help improve depression for youth living with HIV. The 
study may help you gain skills to help you feel better.  
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
You will be asked to come to the clinic for 6 additional visits. Also, you may be asked to come for 
additional counseling visits. How many more visits will be decided based on your needs. You, your 
parents and your doctor will decide how often you need to come. Also, you may be asked to take 
medication to help improve your mood.  
 
WHAT WILL HAPPEN AT MY VISITS?   
The following things may happen during your study visits: 
 
 
We will ask about your health and medications.  
 
At some visits, you will complete a questionnaire. We will ask you questions about your mood, 
medications, sexual behavior, drug and alcohol use. Some will be done on a computer. When the 
interview is complete, the computer “locks in” your information. No one in the clinic can see how 
you answered the questions. At the end of the study we will ask about what you liked and didn’t like 
about this study.  
 
A staff member will talk with you about giving you medication to treat your depression. Taking 
medication for depression is your decision. If you choose not to take medication, you can still 
participate in the study. Your doctor will also keep taking care of you.  
 
At some visits, we will draw blood samples to test the amount of HIV in your blood. Other tests will 
be sent to see how you are doing. 
 
You will meet with a counselor to learn about treating your depression with counseling. 

IMPAACT 2002, Version 1.0 
Page 80 of 95 
19 August 2016 
 
We will give you the results of any blood tests, when available. 
 
These visits will take about [sites to insert] to complete. 
 
The information you provide during your visits will not be shared with your parent/guardian, unless you 
want. But, if we learn something that would put you or others in danger we will share this information 
with the authorities (hospital, police, or social services). 
 
After you sign this assent form, and we check that you are able to join this study, you will be enrolled, 
and we will schedule your next visit.  
 
It is important for you to come to every study visit. If you cannot come to the visit, please tell the study 
staff as soon as possible so that the visit can be rescheduled.  
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Your depression may not get better, or you may have suicidal thoughts. 
 
Other possible risks include:  
o Having blood drawn may cause discomfort, dizziness or faintness, bruising, swelling and/or 
infection. 
o You may become embarrassed and/or worried; study staff will help you with any feelings or 
questions you have.  
o It is possible that others may learn that you are in this study; we will make every effort to protect 
your privacy. 
 
WILL BEING IN THIS STUDY HELP ME? 
This study might help you and others in the future. It may help you because you: 
 
 
Learn ways on how to manage your depression. 
 
Improve your health and energy level with the use of medication and counseling. 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
Taking part in this study is completely voluntary. You may choose not to take part in this study or drop 
out of the study at any time. You can keep going to your therapist and other doctors for medication 
treatment and counseling. You will be treated the same no matter what you decide. Your decision will not 
have any impact on your participation in other studies and will not result in any loss of medical benefits.  
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
You can ask any questions at any time to the people listed below: 
 
 
[Name of the investigator or other study staff] 
 
[Telephone number of above]  
 
For questions about your rights as a research participant, contact: 
 
 
[Name or title of person on the Institutional Review Board (IRB) or other organization appropriate for 
the site] 
 
[Telephone number of above]   
  
 
 
 

IMPAACT 2002, Version 1.0 
Page 81 of 95 
19 August 2016 
SIGNATURE PAGE   
If you have read this assent form (or had it explained to you), all your questions have been answered and 
you agree to take part in this study, please sign your name below. 
 
ASSENT (For children who are capable of understanding the study procedures and their potential 
discomforts and benefits).  
 
 
 
________________________________       
Minor Participant’s Name (Print)   
 
 
  
 
 
________________________________  ______________  
Minor Participant’s Signature   
Date  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
Study Staff Signature 
 
 
Date 
Assent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness Name  
 
 
Witness Signature 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IMPAACT 2002, Version 1.0 
Page 82 of 95 
19 August 2016 
Appendix III: Sample Informed Consent 
 
DIVISION OF AIDS  
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL TRIALS 
(IMPAACT) NETWORK  
 
SAMPLE SCREENING, ENROLLMENT, and LONG-TERM STORAGE CONSENT 
(Parent/Guardian Form) 
 
For protocol: 
 
IMPAACT 2002 
COMBINED COGNITIVE BEHAVIORAL THERAPY AND A MEDICATION MANAGEMENT 
ALGORITHM FOR TREATMENT OF DEPRESSION AMONG YOUTH LIVING WITH HIV IN THE 
UNITED STATES 
Version 1.0, dated 19 August 2016 
 
INTRODUCTION 
Your child is being asked to take part in this research study because s/he is Human Immunodeficiency 
Virus (HIV)-positive, and may have been diagnosed with depression. This study is sponsored by the 
National Institutes of Health (NIH). The doctor in charge of this study at this site is: (insert name of 
Principal Investigator). Before you decide if you want your child to be a part of this study, we want you 
to know about the study.  
 
This consent form gives you information about this study. In order for your child to be in the study, both 
you and your child must agree to join the study. You are free to ask questions about this study at any time. 
You may choose to have your child stop being in the study at any time. If you agree for your child to take 
part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
WHY IS THIS STUDY BEING DONE? 
This study is being done to find out if a certain type of counseling, called Cognitive Behavioral Therapy, 
and a certain method to review and suggest using medications, called the Medication Management 
Algorithm, helps improve depression for youth living with HIV. This study may provide important 
information about the treatment of depression in HIV-positive youth and young adults. In addition, the 
study may help your child understand their depression symptoms and improve their health through the use 
of medication and counseling.  
 
WHAT DOES MY CHILD HAVE TO DO IN THIS STUDY? 
If your child joins this study, s/he will be in the study for about one year. You will be asked for ways for 
study staff to contact you and your child. This contact information will be used to remind you to bring 
your child to the clinic for study visits. All of the contact information you provide will be stored in a 
secure and locked area at the study clinic. Study staff will not leave phone or text messages unless you 
give them permission to do so.  
 
There are two different groups in this study. One group will have the Cognitive Behavioral Therapy and 
Medication Management sessions (this group is called COMB-R). COMB-R is a specific combination of 
talk therapy and a medication map. The other group will have enhanced standard of care, which may be 
like the counseling sessions you currently have (this group is called ESC). If your child is in the COMB-R 
group, you may be asked to switch to a different study therapist, if their current therapist is not working 
on this study. 

IMPAACT 2002, Version 1.0 
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19 August 2016 
 
Both groups, COMB-R or ESC, will be asked to come for six additional visits (at Weeks 1, 6, 12, 24, 36 
and 48). We may be able to complete the Week 1 procedures today if your child and study staff have 
time.  
 
Screening/Entry Visit  
If you and your child are interested in joining this research study, we will first do some tests to see if your 
child can participate. If needed, some screening tests may be done more than once. 
 
 
We will ask your child about their medical and medication history. This may include questions about 
their health and symptoms, medications, and illness. We will also get information from his/her 
medical record.  
 
We will ask your child to complete questionnaires about their depressive symptoms, use of HIV and 
depression medications, sexual behavior and drug and alcohol use. They will also meet with a staff 
member to complete a separate questionnaire that measures their depression symptoms.  
 
A staff member will talk about giving medication to treat your child’s depression. Taking medication 
for depression is you and your child’s choice. If you choose not to, this will not affect your child’s 
participation in the study or their ability to get medical treatment at the clinic.  
 
We will draw about 18 mL (about three and a half teaspoons) of blood: 
o For HIV testing (if documentation needed for the study is not already available) 
o To test the amount of HIV in their blood  
o To test their CD4+ T-cell count. The CD4+T-cell count is a test that measures the amount of 
damage HIV has done to the immune system.  
o Some of the blood will used to test for inflammation, which is the body’s natural response to an 
infection like HIV.  
 
This visit will take about [sites to insert] two hours to complete. 
 
After you sign this consent form, and we confirm that your child is able to join this study, s/he will be 
enrolled. Multiple visits may be needed to understand if your child can participate in the study. This visit 
will need to be completed in 30 days.  
 
Assessment Visits: Weeks 1, 6, 12, 24, 36 and 48  
Participants will have six visits at the clinic at Weeks 1, 6, 12, 24, 36 and 48. These visits may take up to 
two hours. At these visits the following will be done: 
 
Your child will be asked to update their contact information. 
 
Your child will be asked to complete a questionnaire about their depressive symptoms.  
 
Your child will meet with a site therapist and other doctors, to learn about treating their depression 
with counseling and medication, if needed. 
 
We will review any laboratory test results, and current medications taken for HIV or depression since 
the last study visit. 
 
Your child will be asked to complete a questionnaire about the medications they may be taking (for 
HIV and/or depression), sexual behavior, and drug and alcohol use.  
 
At one visit about halfway through the study, your child will be asked to complete a questionnaire 
about their satisfaction with the therapy, including the procedures, quality and quantity of service, 
outcome, and general satisfaction 
 
At some visits, your child will have about 15 mL (about three teaspoons) of blood drawn: 
o To test the amount of HIV in their blood  
o To test their CD4+ T-cell count 
o To test for markers of inflammation. 
 
We will give your child the results of these tests, when available.  

IMPAACT 2002, Version 1.0 
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19 August 2016 
 
It is important for your child to come to every study visit. If they cannot come to the visit, please tell the 
study staff as soon as possible so that the visit can be rescheduled.  
 
Interim Visits  
In addition to the visits listed above, your child may be encouraged to come to additional visits in 
between for counseling and treatment. These are called interim visits. You, your child and the doctor will 
decide how often those visits will happen. They may be as often as every week depending on your child’s 
needs. While these visits are not mandatory, they may help your child improve their depressive 
symptoms.  
 
Computer-Assisted Self-Interviews 
Some of the questionnaires will be done on a computer using a program called Audio Computer-Assisted 
Self-Interview (ACASI). ACASI uses a computer so your child can see (on the screen) each question and 
then answer choices for that question. When the interview is complete, the computer “locks in” the 
information so no one at the clinic can see how you answered.  
 
Your child does not have to answer any question that they don’t want to and can end the computer 
interview at any time if they do not want to continue. No one will be able to look at any of their answers 
once they have answered all questions in each section. Once they have finished all the questions, the 
whole interview will be locked and will be kept confidential. No information that identifies your child is 
collected during the computer session; only their study ID number will be recorded.  
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?  
There will be about 156 participants, ages 12 to 24, in this study. There will be about ten study 
participants at this site.  
 
HOW LONG WILL MY CHILD BE IN THIS STUDY? 
Your child will be in this study for about one year. 
 
WHY WOULD THE DOCTOR TAKE MY CHILD OFF THIS STUDY EARLY? 
The study doctor may need to take your child off the study early without your permission if: 
 
The study is cancelled by the National Institutes of Health (NIH), IMPAACT, and local regulatory 
authorities, the Office for Human Research Protections (OHRP), or the site’s Institutional Review 
Board (IRB) or Ethics Committee (EC). An IRB/EC is a committee that watches over the safety and 
rights of research participants. 
 
Your child is not able to attend the study visits as required by the study. 
 
The study doctor determines that further participation in the study would be harmful to your child’s 
health or well-being. 
 
If your child is taken off this study early for any reason, your child will be asked to return to clinic for 
one last visit if they are available. 
 
WHAT ARE THE RISKS OF THE STUDY? 
Unimproved depression or worsening of symptoms   
Continued depression or worsening of depressive symptoms is always a risk of depression regardless of 
use of medication. In addition, suicide or suicide attempt is a risk of depression. These risks will be 
reviewed during clinic visits with the site doctor who will be monitoring your child’s depression 
symptoms. If your child agrees to take medication, they may have additional lab tests done and 
monitored, as is the usual standard of care.  
 

IMPAACT 2002, Version 1.0 
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19 August 2016 
Medication side effects  
Your child is free to decide not to start, or stop, taking antidepressant medications at any time during this 
study. All medications that may be prescribed while your child is in this study are approved for treatment 
of depression. In general, medications for depression are safe. If your child chooses to start taking a 
medication to treat depression, they may experience side effects. They will discuss these potential side 
effects with their doctor. Common side effects of antidepressants may include nausea, vomiting, feeling 
tired, feeling dizzy, feeling nervous, loss of appetite, increased appetite, trouble sleeping, dry mouth, 
headache, changes in interest in sex, feeling thirsty, upset stomach, or runny nose.  
 
Drug-drug interaction 
If your child is taking antidepressant medications and also HIV medications, it is possible that they could 
mix with each other in a negative way. While this is unlikely to happen, your child’s doctors will look for 
any signs that the medications are not working well together. 
 
Complications with pregnancy  
There is a risk that antidepressant medications cause birth defects. If your child becomes pregnant during 
the study, she may continue in the study, and site staff will discuss use of antidepressants based on the 
doctor’s advice. Your child’s doctor may also report their pregnancy to the Antiretroviral Pregnancy 
Registry. The Antiretroviral Pregnancy Registry assists patients and doctors in gauging potential benefits 
and risks of treatment; however, the registry does not collect any identifying information about your 
child, such as name, initials, contact information, or date of birth. There is a risk that antidepressant 
medications may cause changes in sperm in males. All participants, who are sexually active, will be 
recommended to use condoms because of the risk in pregnancy and of STI transmission.  
Other Possible Risks 
Having blood drawn may cause discomfort, feelings of dizziness or faintness, and/or bruising, swelling 
and/or infection. 
Your child may become embarrassed and/or worried when talking to therapists and other site staff. They 
may be worried while waiting for test results. Trained study staff will help your child with any feelings or 
questions they have.  
 
We will make every effort to protect your child’s privacy. Their visits will take place in private. However, 
it is possible that others may learn that your child is in the study, and because of this, may treat your child 
unfairly. For example, s/he may feel uncomfortable at school, may have problems getting or keeping a 
job, or being accepted by their family, friends, or community. If your child has any problems, site staff 
will talk with them, to try to help resolve them. 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
There is no guarantee that your child will benefit from taking part in the study, but participating in the 
study may help them: 
 
Learn how to monitor their depression symptoms; and 
 
Improve their overall health through the use of medication and counseling. 
 
Also, the results from this study may provide important information about the treatment of depression in 
HIV positive youth.  
 
WHAT ABOUT CONFIDENTIALITY? 
We will make every effort to keep your child’s personal information confidential. We cannot guarantee 
absolute confidentiality. The information your child provides during their visits will not be shared with 

IMPAACT 2002, Version 1.0 
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you, unless your child and doctor want us to. If the study staff learns of possible child abuse and/or 
neglect or a risk of harm to your child or others, they will be required to tell the proper authorities. 
Any publication of this study will not use your child’s name. 
 
Your child’s records may be reviewed by the [insert name of site] IRB/EC, National Institutes of Health 
(NIH), Office for Human Research Protections (OHRP), study staff, and study monitors. 
 
In addition to the efforts of the study staff to help keep personal information private, we have obtained a 
Certificate of Confidentiality from the U.S. Federal Government. This certificate protects study staff from 
being forced to tell people who are not connected with this study, such as the court system, about your 
child’s participation or information given for study purposes. This certificate does not prevent you from 
releasing information about yourself or your child and your child’s participation in the study.  
 
ARE THERE ALTERNATIVES TO THIS STUDY? 
You may choose for your child to not take part in this study. Your child can keep going to their therapist 
and other doctors for medication treatment and counseling. [Sites to insert if applicable]: There may be 
other studies going on here or in the community that your child may be eligible for. If you wish, we will 
tell you about those other studies. 
 
WHAT ARE THE COSTS TO ME? 
You and your child will not be charged for any study visits. Your child may get recommendations for 
medications or medical treatments to help with their depression as part of this study. However, the costs 
for medications, treatments, or laboratory tests will be charged to you or your health insurance company 
as would normally be done for your medical care. It cannot be promised that the risks you were told about 
or other unknown problems will not happen. There will be appropriate clinic staff available for you to 
speak with if you or your child become upset at any time during the study. Any further care or treatment 
after your child is no longer in the study will be charged to you or your health insurance company as 
would be done for routine medical care. 
 
REIMBURSEMENT 
[Sites to insert information about local reimbursement:] Your child will get [Sites to insert amount $xx] 
for their time, effort, and travel to and from the clinic at each scheduled visit. They may receive [Sites to 
insert amount $xx] for any visits which occur in between their normally scheduled visits. 
 
WHAT HAPPENS IF YOUR CHILD IS INJURED? 
We do not expect anyone to get injured by participating in this study. If your child is injured or becomes 
ill from taking part in this study, it is important to tell their study doctor and we will help your child get 
the medical care they need. Treatment may be needed, and the cost of treatment would be charged to you, 
or your insurance company, as would normally be done for your medical care. No monetary 
compensation (payment to you) or other forms of compensation for such injuries will be provided by the 
[Name of Institution] or sponsor (NIH).  
WHAT ARE MY CHILD’S RIGHTS AS A RESEARCH PARTICIPANT? 
Taking part in this study is completely voluntary. You may choose for your child to not take part in this 
study or drop out of the study at any time. You and your child will be treated the same no matter what you 
decide. Your decision will not have any impact on your child’s participation in other studies and will not 
result in any penalty or loss of benefits.  
 
We will tell you about new information from this or other studies that may affect your child’s health, 
welfare or willingness to stay in this study. If you want the results from this study, let the study staff 
know. A description of this clinical trial is available on http://www.ClinicalTrials.gov. This website will 

IMPAACT 2002, Version 1.0 
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19 August 2016 
not include information that can identify you. Once available, the website will include a summary of the 
results. You can search this website at any time. 
 
CONSENT FOR STORAGE AND FUTURE TESTING OF SPECIMENS and RELATED HEALTH 
INFORMATION 
 
There might be a small amount of your child’s blood left over after we have done all of the study related 
testing. We would like to ask your permission to store their leftover blood and related health information 
for use in future studies. If you and your child agree, their samples and related health data will be stored 
safely and securely. Only approved researchers will have access to the samples. There is no time limit on 
how long your samples will be stored. The specific type of testing planned for these specimens is not yet 
known. Any future testing will also have to be approved by an Ethics Committee/ Institutional Review 
Board. No genetic testing (limited or genome-wide) is planned.  
 
Your child can still enroll in this study if you decide not to have blood stored for future studies. You can 
withdraw your consent for the storage and future testing of specimens at any time by providing your 
request in writing to the person in charge of this study, and the leftover samples will be destroyed. If your 
child becomes an adult and decides that they want the specimens withdrawn, then they may follow the 
same procedure of providing a request in writing to the person in charge of the study. However, 
researchers will not be able to destroy samples or information from research that is already underway. 
 
 
PARENT/GUARDIAN INITIALS 
 
  ______________ 
  
 
Initials 
 
______________ 
Date 
I DO agree to allow my child’s biological specimens and health data to be 
stored and used in future research studies. 
 
  ______________ 
  
 
Initials  
 
______________ 
Date 
 
I DO NOT agree to allow my child’s biological specimens and health data to 
be stored and used in future research studies. 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
 
[Name of the investigator or other study staff] 
 
[Telephone number of above]  
 
For questions about your child’s rights as a research participant, contact: 
 
 
[Name or title of person on the Institutional Review Board (IRB) or other organization appropriate for 
the site] 
 
[Telephone number of above]   
 
 

IMPAACT 2002, Version 1.0 
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19 August 2016 
SIGNATURE PAGE   
 
I have read this consent form (or had it explained to me), and all my questions have been answered.  
 
I voluntarily agree to allow my child, to whom I am the legal guardian, to be in this research study.  
 
 
______________________________ 
_______________________________ 
Parent’s or Guardian’s Name (Print)  
Relationship to Participant (Child) 
 
 
 
_____________________________     _________________ 
Parent’s or Guardian’s Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
Study Staff Signature 
 
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness Name  
 
 
Witness Signature 
 
 
Date 
 
 
 

IMPAACT 2002, Version 1.0 
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Appendix IV: Sample Participant Informed Consent 
 
DIVISION OF AIDS  
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL TRIALS 
(IMPAACT) NETWORK  
 
SAMPLE SCREENING, ENROLLMENT, and LONG-TERM STORAGE CONSENT 
(for emancipated minors, participants above legal age of consent, or for participants at study sites that 
have obtained a waiver of parental permission) 
 
For protocol: 
 
IMPAACT 2002 
COMBINED COGNITIVE BEHAVIORAL THERAPY AND A MEDICATION MANAGEMENT 
ALGORITHM FOR TREATMENT OF DEPRESSION AMONG YOUTH LIVING WITH HIV IN THE 
UNITED STATES 
Version 1.0, dated 19 August 2016 
 
INTRODUCTION 
You are being asked to take part in this research study because you have been told that you are Human 
Immunodeficiency Virus (HIV)-positive, and may have been diagnosed with depression. This study is 
sponsored by the National Institutes of Health (NIH). The doctor in charge of this study at this site is: 
(insert name of Principal Investigator). Before you decide if you want to be a part of this study, we want 
you to know about the study.  
 
This consent form gives you information about this study. The study staff will talk with you about this 
information. In order for you to be in the study, you must agree to join the study. You are free to ask 
questions about this study at any time. You may choose to stop being in the study at any time. If you 
agree to take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
WHY IS THIS STUDY BEING DONE? 
This study is being done to find out if a certain type of counseling, called Cognitive Behavioral Therapy, 
and a certain method to review and suggest using medications, called the Medication Management 
Algorithm, helps improve depression for youth living with HIV. This study may provide important 
information about the treatment of depression in HIV-positive youth and young adults. In addition, the 
study may help you understand your depression symptoms and improve your overall health through the 
use of medication and counseling.  
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
If you join this study, you will be in the study for about one year. You will be asked for ways for study 
staff to contact you so that you can be reminded to come to the clinic for your study visits. You will not 
be forced to give any contact information that you don’t want to give. All of the contact information you 
provide will be stored in a secure, locked, area at the study clinic. Study staff will not leave phone or text 
messages unless you give them permission to do so.  
 
There are two different groups in this study. One group will have the Cognitive Behavioral Therapy and 
Medication Management sessions (this group is called COMB-R). The other group will have enhanced 
standard of care, which may be like the counseling sessions you currently have (this group is called ESC). 
If you are in the COMB-R group, you may be asked to switch to a different study therapist, if your current 
therapist is not working on this study. 

IMPAACT 2002, Version 1.0 
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Both groups, COMB-R or ESC will be asked to come for six additional visits (at Weeks 1, 6, 12, 24, 36 
and 48). We may be able to complete the Week 1 procedures today if you and study staff have time.  
 
Screening/Entry Visit  
If you are interested in joining this research study, we will first do some tests to see if you can participate. 
If needed, some screening tests may be done more than once. 
 
 
We will ask about your medical and medication history. This may include questions about your health 
and what symptoms, medications, and illnesses you have had. We will also get information from your 
medical records. 
 
We will ask you to complete questionnaires about your depressive symptoms, use of HIV and 
depression medications, sexual behavior and drug and alcohol use. You will also meet with a staff 
member to complete a separate questionnaire that measures your depression symptoms.  
 
A staff member will talk with you about giving medication to treat your depression. Taking 
medication for depression is your choice. If you choose not to, this will not affect your participation 
in the study or your ability to get medical treatment at the clinic.  
 
We will draw about 18 mL (about three and a half teaspoons) of blood: 
o For HIV testing (if documentation needed for the study is not already available) 
o To test the amount of HIV in your blood (your viral load)  
o To test your CD4+ T-cell count. The CD4+T-cell count is a test that measures the amount of 
damage HIV has done to your immune system. The immune system is the part of the body that 
fights off germs and infections.  
o Some of the blood will used to test for inflammation, which is the body’s natural response to an 
infection like HIV.  
 
We will give you the results of your tests, when available. You will get the results of some laboratory 
tests (e.g., HIV-related tests), but you will not receive results of the research laboratory tests done for 
this study.  
 
This visit will take about [sites to insert] two hours to complete. 
 
After you sign this consent form, and we confirm that you are able to join this study, you will be enrolled. 
Multiple visits may be needed to understand if you can participate in the study. This visit needs to be 
completed in 30 days.  
 
Assessment Visits: Weeks 1, 6, 12, and 24  
Participants will have six visits at the clinic at Weeks 1, 6, 12, 24, 36 and 48. These visits may take up to 
2 hours [sites to insert]. At these visits the following will be done: 
 
You will be asked to update any information on where you live and how we can contact you. 
 
You will be asked to complete a questionnaire about your depressive symptoms. Your doctor will 
review your depressive symptoms and may discuss treating your depression with medication 
(antidepressants) as needed.  
 
You will also meet with a site therapist to learn about treating your depression with counseling and 
medication, if needed.  
 
We will talk with you and review your medical records to find out about any laboratory test results, 
and current medications taken for HIV or depression since your last study visit. 
 
At some visits, you will be asked to complete a questionnaire about the medications you may be 
taking (for your HIV and/or antidepressants), your sexual behavior, and drug and alcohol use.  
 
At one visit about halfway through the study, you will be asked to complete a questionnaire about 
your satisfaction with the therapy, including the procedures, quality and quantity of service, outcome, 
and general satisfaction 

IMPAACT 2002, Version 1.0 
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19 August 2016 
 
At some visits, you will have about 15 mL (about three teaspoons) of blood drawn: 
o To test the amount of HIV in your blood  
o To test your CD4+ T-cell count 
o Some of the blood will used for research purposes, to test markers of inflammation in your blood  
 
We will give you the results of your tests, when available.  
 
It is important for you to come to every study visit. If you cannot come to the visit, please tell the study 
staff as soon as possible so that the visit can be rescheduled.  
 
Interim Visits  
In addition to the visits listed above, you may be encouraged to come to additional visits in between for 
counseling and treatment. These are called interim visits. You and the doctor will decide how often those 
visits will happen. They may be as often as every week depending on your needs. While these visits are 
not mandatory, they may help improve your depressive symptoms.  
 
Computer-Assisted Self-Interviews 
Some of the questionnaires you complete during this study will be done on a computer using a program 
called Audio Computer-Assisted Self-Interview (ACASI). ACASI uses a computer so you can see (on the 
screen) each question and the answer choices for that question. You will enter your answer right into the 
computer. When the interview is complete, the computer “locks in” your information so no one at the 
clinic can see how you answered.  
 
You do not have to answer any question that you don’t want to and you can end the computer interview at 
any time if you do not want to continue. No one will be able to look at any of your answers once you have 
answered all questions in each section. Once you have finished all the questions, the whole interview will 
be locked and will be kept confidential. No information that identifies you is collected during the 
computer session; only your study ID number will be recorded.  
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?  
There will be about 156 participants, ages 12 to 24, in this study. There will be about 10 study 
participants at this site. 
 
HOW LONG WILL I BE IN THIS STUDY? 
You will be in this study for about one year. 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
The study doctor may need to take you off the study early without your permission if: 
 
The study is cancelled by the National Institutes of Health (NIH), IMPAACT, and local regulatory 
authorities, the Office for Human Research Protections (OHRP), or the site’s Institutional Review 
Board (IRB) or Ethics Committee (EC). An IRB/EC is a committee that watches over the safety and 
rights of research participants. 
 
You are not able to attend the study visits as required by the study. 
 
The study doctor determines that further participation in the study would be harmful to your health or 
well-being. 
 
If you are taken off this study early for any reason, you will be asked to return to clinic for one final 
visit, if you are available 
 

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WHAT ARE THE RISKS OF THE STUDY? 
Unimproved depression or worsening of symptoms   
Continued depression or worsening of depressive symptoms is always a risk of depression regardless of 
use of medication. In addition, suicide or suicide attempt is a risk of depression. Your symptoms may also 
get worse due to a psychiatric condition(s). These risks will be reviewed during clinic visits with the site 
doctor who will be monitoring your depression symptoms. If you agree to take medication, you may have 
additional lab tests done and monitored, as is the usual standard of care.  
 
Medication side effects  
You are free to decide not to start, or stop, taking antidepressant medications at any time during this 
study. If you start new medications while on study, you may have more study visits if your study doctor 
thinks it is needed. Your doctors may request that you have laboratory tests depending on the 
antidepressant(s) that were prescribed for you. If you are taking antidepressant medications, your doctor 
will discuss the potential side-effects of your specific medications with you.  
 
Drug-drug interaction 
If you are taking antidepressant medications and also HIV medications, it is possible that they could mix 
with each other in a negative way. While this is unlikely to happen, your doctors will look for any signs 
that your medications are not working well together. 
 
Complications with pregnancy  
There is a risk that antidepressant medications may cause birth defects. If you become pregnant during the 
study, you may continue in the study, and site staff will discuss use of antidepressants based on your 
doctor’s advice. Your doctor may also report your pregnancy to the Antiretroviral Pregnancy Registry. 
The Antiretroviral Pregnancy Registry assists patients and doctors in gauging potential benefits and risks 
of treatment; however, the registry does not collect any identifying information about you, such as name, 
initials, contact information, or date of birth. There is a risk that antidepressant medications may cause 
changes in sperm in males. All participants, who are sexually active, will be recommended to use 
condoms because of the risk in pregnancy and of STI transmission. 
Other Possible Risks 
Having blood drawn may cause you to have discomfort, feelings of dizziness or faintness, and/or bruising, 
swelling and/or infection. 
You may become embarrassed and/or worried when talking to therapists and other site staff. You may be 
worried while waiting for your test results. Trained study counselors will help you with any feelings or 
questions you have.  
 
We will make every effort to protect your privacy. Your visits will take place in private. However, it is 
possible that others may learn that you are in the study, and because of this, may treat you unfairly or 
discriminate against you. For example, you may feel uncomfortable at school, you could have problems 
getting or keeping a job, or being accepted by your family, friends, or community. If you have any 
problems, site staff will talk with you, and your parent if you prefer, to try to help resolve them. 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
There is no guarantee that you will benefit from taking part in the study, but participating in the study 
may help you: 
 
Learn how to monitor your depression symptoms; and 
 
Improve your overall health through the use of medication and counseling. 

IMPAACT 2002, Version 1.0 
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19 August 2016 
 
Also, the results from this study may provide important information about the treatment of depression in 
HIV positive youth.  
 
WHAT ABOUT CONFIDENTIALITY? 
We will make every effort to keep your personal information confidential. We cannot guarantee absolute 
confidentiality. The information you provide during study visits will not be shared with anyone, unless 
you want us to. If the study staff learns of possible child abuse and/or neglect or a risk of harm to you or 
others, they will be required to tell the proper authorities. Any publication of this study will not use your 
name or identify you personally. 
 
Your records may be reviewed by the [insert name of site] IRB/EC, National Institutes of Health (NIH), 
Office for Human Research Protections (OHRP), study staff, and study monitors. 
 
In addition to the efforts of the study staff to help keep your personal information private, we have 
obtained a Certificate of Confidentiality from the U.S. Federal Government. This certificate protects study 
staff from being forced to tell people who are not connected with this study, such as the court system, 
about your participation or information you give for study purposes. This certificate does not prevent you 
from releasing information about yourself and your participation in the study.  
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
You may choose not to take part in this study. You can keep going to your therapist and other doctors for 
medication treatment and counseling. [Sites to insert if applicable]: There may be other studies going on 
here or in the community that you may be eligible for. If you wish, we will tell you about those other 
studies. 
 
WHAT ARE THE COSTS TO ME? 
You will not be charged for any study visits. You may get recommendations for medications or medical 
treatments to help with your depression as part of this study. However, the costs for medications, 
treatments, or laboratory tests will be charged to you or your health insurance company as would 
normally be done for your medical care. It cannot be promised that the risks you were told about or other 
unknown problems will not happen. There will be appropriate clinic staff available for you to speak with 
if you become upset at any time during the study. Any further care or treatment after you are no longer in 
the study will be charged to you or your health insurance company as would be done for your routine 
medical care. 
 
REIMBURSEMENT 
[Sites to insert information about local reimbursement:] You will get [Sites to insert amount $xx] for your 
time, effort, and travel to and from the clinic at each scheduled visit. You may receive [Sites to insert 
amount $xx] for any visits which occur in between your normally scheduled visits. 
 
WHAT HAPPENS IF I AM INJURED? 
We do not expect anyone to get injured by participating in this study. If you become upset by the 
questions you are asked, you may be referred to a counselor to speak with. If you are injured or become ill 
from taking part in this study, it is important to tell your study doctor and we will help you get the 
medical care you need. Treatment may be needed, but the cost of treatment would be charged to you, or 
your insurance company, as would normally be done for your medical care. No monetary compensation 
(payment to you) or other forms of compensation for such injuries will be provided by the [Name of 
Institution] or sponsor (NIH).  
 

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19 August 2016 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
Taking part in this study is completely voluntary. You may choose not to take part in this study or drop 
out of the study at any time. You will be treated the same no matter what you decide. Your decision will 
not have any impact on your participation in other studies and will not result in any penalty or loss of 
benefits.  
 
We will tell you about new information from this or other studies that may affect your health, welfare or 
your willingness to stay in this study. If you want the results from this study, let the study staff know. A 
description of this clinical trial is available on http://www.ClinicalTrials.gov. This website will not 
include information that can identify you. Once available, the website will include a summary of the 
results. You can search this website at any time. 
 
CONSENT FOR STORAGE AND FUTURE TESTING OF SPECIMENS and RELATED HEALTH 
INFORMATION 
 
There might be a small amount of blood left over after we have done all of the study related testing for 
your study visits. We would like to ask your permission to store your leftover blood and related health 
information for use in future studies. If you agree, your samples and related health data will be stored 
safely and securely. Only approved researchers will have access to the samples. There is no time limit on 
how long your samples will be stored. The specific type of testing planned for these specimens is not yet 
known. Any future testing will also have to be approved by an Ethics Committee/ Institutional Review 
Board. No genetic testing (limited or genome-wide) is planned.  
 
You can still enroll in this study if you decide not to have blood stored for future studies. You can 
withdraw your consent for the storage and future testing of specimens at any time by providing your 
request in writing to the person in charge of this study, and the leftover samples will be destroyed. 
However, researchers will not be able to destroy samples or information from research that is already 
underway. 
 
PARTICIPANT INITIALS 
 
  _____________   
 
Initials 
 
_____________ 
Date 
I DO agree to allow my biological specimens and health data to be 
stored and used in future research studies. 
 
  _____________  
  
 
Initials  
 
_____________  
Date 
I DO NOT agree to allow my biological specimens and health data 
to be stored and used in future research studies. 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about this study or a research-related injury, contact: 
 
[Name of the investigator or other study staff] 
 
[Telephone number of above]  
 
For questions about your rights as a research participant, contact: 
 
[Name or title of person on the Institutional Review Board (IRB) or other organization appropriate 
for the site] 
 
[Telephone number of above]   

IMPAACT 2002, Version 1.0 
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19 August 2016 
SIGNATURE PAGE   
If you have read this consent form (or had it explained to you), all your questions have been answered and 
you agree to take part in this study, please sign your name below. 
 
 
__________________________ 
__________________________ 
 
 
 
Participant’s Name (Print)  
 
Participant’s Signature  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
Study Staff Signature 
 
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness Name  
 
 
Witness Signature 
 
 
Date