Clinical trial NCT02620150
Conditions: Depression HIV AIDS
Keywords: HIV AIDS Depression SSRI Escitalopram Immunity
Sponsor: University of Pennsylvania
Start date: 2017-02-16; Completion date: 2022-03-31
Enrollment: 108 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 10 week, double-blind, placebo controlled trial to evaluate SSRI (Selective Serotonin Reuptake Inhibitor) effects for treatment of depression in HIV/AIDS with a focus on innate immunity and inflammation. Depressed population is HIV + on cART (Combination Antiretroviral Therapy), not currently on pharmacotherapy for depression. Subjects will complete computerized cognitive behavior therapy, CCBT for their depression. Blood samples collected for virologic, neuroendocrine, and immunologic evaluation. Our overarching hypothesis is that SSRI treatment of depression and improvement of depressive symptoms leads to increased innate immunity and decreased inflammation, resulting in better control of HIV disease and decreased morbidity.

Detailed description:
To pursue our long-term objective of successfully treating co-morbid mental and medical disorders in HIV/AIDS, this study aims to determine whether: 1) SSRI treatment significantly increases innate immunity and decreases chronic inflammation and immune activation, and 2) changes in depressive symptoms correlate with changes in immunity in HIV/AIDS.

HIV-seropositive, depressed subjects will be randomized to 10 weeks of double blind therapy with either escitalopram or placebo. All participants will concurrently begin CCBT (Computerized Cognitive Behavioral Therapy) using the program Good Days Ahead.

Subject visits will occur weekly for the first 6 weeks and then at weeks 8 and 10. The treating clinician will assess side effects, review symptomatic progress, and adjust the study medication as clinically appropriate. An independent clinical evaluator will assess patients at baseline, and weeks 1-6, 8 and 10. Blood samples collected at baseline and weeks 2, 4, and 10 will be used to assay markers of innate immune suppression (lytic units of NK cells, LUNK, and intracellular IFN gamma in NK cells) and markers of inflammation (IL-6 and C-Reactive Protein). At the end of the 10-week treatment phase, all participants will be referred for appropriate clinical treatment of their depression.

Arms: arm 1: CCBT plus Escitalopram, oral, for 10 weeks, once daily, starting at 10mg/day. Tapered up or down, based on tolerability and clinical response, to 20mg/day max. arm 2: CCBT plus Placebo, oral, for 10 weeks, once daily, starting at 10mg/day. Tapered up or down, based on tolerability and clinical response, to 20mg/day max.
Interventions: intervention 1: Escitalopram intervention 2: Placebo
Intervention descriptions: intervention 1: 10 week trial intervention 2: 10 week trial

Protocol documents:
Prot_002.pdf: 
Page 1 of 15
Protocol Title:
SSRI Effects on Depression and Immunity in HIV/AIDS
Protocol 
Description:
This a 10 week, double-blind, placebo controlled trial to evaluate SSRI effects 
for treatment of depression in HIV/AIDS with a focus on innate immunity and 
inﬂammation. Depressed population is HIV + on cART, not currently on 
pharmacotherapy for depression. Subjects will complete cognitive behavior 
therapy for their depression. Subjects seen weekly to monitor clinical response 
and possible side effects. Blood samples collected for virologic, neuroendocrine, 
and immunologic evaluation.
Protocol
Abstract
Our prior work established links between depression, immune dysregulation, and HIV disease 
progression, as well as immune regulating and antiviral effects of SSRI treatment. We found depression 
was associated with decreased natural killer (NK) cytolytic activity in both medically healthy individuals 
and in HIV- infected patients, and we showed that depression was associated with accelerated HIV 
disease progression. We also observed that resolution of depression was associated with increased NK 
cytotoxicity and we demonstrated that ex vivo SSRI treatment of immune cells enhances NK cytolytic 
activity. Further, we discovered that an SSRI inhibited HIV infectivity of immune cells ex vivo, and that 
SSRI treatment signiﬁcantly down-regulated the expression of HIV receptors and co-receptors (CD4, 
CXCR4, CXCR5) on macrophages and T-cells. Our studies thus indicate that SSRIs may have a direct 
action on peripheral immune cells. This work suggests that SSRI treatment could reduce psychiatric 
morbidity and help reverse immune dysregulation in depressed, People Living with HIV/AIDS. To 
pursue our long-term objective of successfully treating co-morbid mental and medical disorders in HIV/
AIDS, this study aims to determine whether: 1) SSRI treatment signiﬁcantly increases innate immunity 
and decreases chronic inﬂammation and immune activation, and 2) changes in depressive symptoms 
correlate with changes in immune regulation in HIV/AIDS. This study will be the ﬁrst double-blind, 
placebo controlled trial of a SSRI for treating depression in HIV/AIDS with a focus on innate immunity 
and inﬂammation.
Objectives
Overall objectives
The overall objectives of this study are to evaluate if SSRI's and improvement of depression lead to
Date:
February 9, 2021


Page 2 of 15
restoration of immune function in aviremic individuals. We will study the effects of SSRI treatment on 
biomarkers of immune suppression and immune activation that are common in both depression and 
HIV/AIDS. Our overarching hypothesis is that SSRI treatment of depression and improvement of 
depressive symptoms leads to increased innate immunity and decreased inﬂammation, resulting in 
better control of HIV disease and decreased morbidity.
Primary outcome variable(s)
We are comparing the effects of SSRI Vs Placebo in depressed, HIV+ individuals. We are measuring 
Lytic Units of Natural Killer cell activity (LUNK) and intracellular IFNgamma to evaluate direct SSRI 
effects on innate immunity. We are measuring IL-6 and C Reactive Protein (CRP), to evaluate direct 
SSRI effects on systematic inﬂammation.
Secondary outcome variable(s)
We are measuring Lytic Units of Natural Killer cell activity (LUNK) and intracellular IFNgamma to 
evaluate improvement of depressive symptom effects on innate immunity. We are measuring IL-6 and C 
Reactive Protein (CRP), to evaluate improvement of depressive symptom effects on systematic 
inﬂammation.
Background
Depression is highly comorbid with HIV/AIDS, occurring at nearly double the rate of the general 
population (1) and is commonly not recognized and not treated (2, 3). Both depression and HIV/AIDS 
are characterized by immune dysregulation, including suppressed innate immunity and heightened 
immune activation/inﬂammation. As described in this section, it may be possible to target shared 
pathophysiologic immune mechanisms using a SSRI, which could signiﬁcantly advance the treatment 
of HIV and comorbid mental disorders involving serotonergic neurotransmission and immune 
regulation. Biomarkers of impaired innate immunity (decreased NK cell cytotoxicity) and inﬂammation 
(elevated IL-6, TNF-, and CRP) have been associated with depression (4-8). There is recent evidence 
that treatment of depression with SSRIs leads to both decreased immune suppression and decreased 
immune activation (8-10). Stress and depression are implicated as risk factors in the morbidity and 
mortality of a wide range of human diseases (11). Stress and depression may impair key components of 
cell-mediated immunity (12-16) and heighten susceptibility to infectious diseases (17-19), including 
HIV infection (11, 20-29) both before and after the advent of HAART (27). Although the speciﬁc 
immune mechanisms by which depression may inﬂuence immunity and HIV disease progression and 
mortality remain to be understood, increasing evidence suggests that killer lymphocytes play a key role. 
Clinical studies of depression in subjects without other medical illnesses (30-32) have demonstrated 
functional impairment and changes in populations of cells which mediate innate immunity. NK cells as 
well as CD8 cells, are two immune cell populations that play key roles in regulating HIV infection. NK 
and CD8 T lymphocytes are involved in the natural resistance against HIV infection through both 
cytolytic and noncytolytic activity. NK and CD8 cells lyse HIV-1 infected cells and also produce HIV 
suppressive factors that include chemokines MIP-1 (CCL3), MIP-1 (CCL4), and RANTES (CCL5) and 
cytokines (IFN, TNF and GMCSF) that inhibit HIV-1 by suppressing viral entry and replication 
(33-41). With HIV infection, however, there is a notable decrease in NK cell function early post 
infection that persists and becomes more pronounced upon progression to acquired immunodeﬁciency 
syndrome (AIDS). Numerous experimental and clinical studies have documented this ﬁnding (42-44). 
The negative effects of HIV on NK cells are pervasive, involving both the quantity and functions of NK 
cells and their subpopulations. These impairments in NK cell number and function have been proposed 
to result in susceptibility to opportunistic infection and tumorigenesis, as well as decreased control of 
HIV replication. In general, highly active antiretroviral treatment (HAART) does not fully reverse and 
correct the NK deﬁciencies in HIV-infected patients, and NK defects persist. Abnormal NK cytolytic 
function and production of NK mediators (e.g. gamma interferon) contributes to HIV disease (45).  
Since the advent of HAART, morbidity and mortality of HIV have been signiﬁcantly reduced. 
Nevertheless, immune dysregulation persists with impairment of the innate immune system (43, 46-48) 
as well as chronic immune activation which has been associated with increased morbidity and mortality 
(49-54). Numerous pharmacological agents have been studied to reduce chronic immune activation in 
HIV and the available data are largely from small trials (51, 55-59). Recent studies suggest that the 
peripheral markers that have promise as biomarkers of activation which may be responsive to 
therapeutic intervention include IL-6, CRP, sCD14, sCD163, and PD1 (51, 60-62). Immunologic 
activation may be the consequence of residual HIV in reservoirs and sanctuaries or the result of initial 
HIV infection and consequential cell, tissue and organ damage (62, 63). Furthermore, the immune 
system is important in controlling the latent HIV pool (64).  Serotonin (5-hydroxytryptophan, or 5-HT) 


Page 3 of 15
neurotransmission is involved in the regulation of mood and is a pharmacologic target in the treatment 
of depression (65, 66). Several studies have documented the widespread distribution of 5-HT receptors 
and the 5-HT transporter on monocytes, macrophages, T cells, and possibly NK cells (67-77). Serotonin 
may have a direct modulating effect on both NK cell function and T-lymphocyte function. Serotonin 
enhances the cytolytic activity of NK cells, possibly through 5-HT1A receptors on monocytes (69, 78), 
and may protect the function of NK cells (78). Serotonin also activates 5-HT receptors on T cells (79). 
In addition, inhibitors of serotonin synthesis and antagonists of 5-HT1A receptors inhibit T-cell 
function in vitro and cell-mediated immunity in vivo in human and murine T cells; this inhibition is 
reversed by serotonin and by a 5-HT1A receptor agonist (79). Findings from our ex vivo studies extend 
these data and suggest that a SSRI may increase NK cytolytic activity and may enhance killer 
lymphocyte noncytolytic HIV suppression of HIV infectivity (80, 81).  Several clinical studies (70, 
82-84) have demonstrated a positive effect of SSRIs on NK cytolytic activity in depression. We found a
similar increase in NK cytolytic activity associated with the resolution of depression in a naturalistic
study of HIV-seropositive women (85). Additional studies (86-88) have also suggested similar serotonin
up-regulation of T-cell function in HIV infection. Thus, serotonin and drugs affecting serotonin
transmission, including SSRIs, may play important regulatory roles in immune system dysregulation
suggesting potential clinical beneﬁts in HIV infection (89, 90). Furthermore, there is clinical evidence
of antiviral activity of SSRIs in the central nervous system. Letendre et al. (91) reported that individuals
taking SSRIs (citalopram, sertraline or trazodone) were more likely to have lower HIV viral loads in
cerebrospinal ﬂuid and better neuropsychological performance. Recent studies have also demonstrated
anti-inﬂammatory effects of SSRIs in microglia (92, 93). Thus, serotonin and drugs affecting serotonin
transmission, including SSRIs may play important regulatory roles in central and peripheral immune
system dysregulation suggesting potential clinical beneﬁts in HIV infections (89, 90). Further
supporting these clinical ﬁndings on the effects of serotonin on HIV-related immunity are ﬁndings from
in vitro experiments indicating that 5-HT decreases acute HIV replication by down-regulating the
CCR5 receptor as well as by increasing the secretion of the HIV suppressive chemokine MIP-1 (94).
These ﬁndings on the direct effects of serotonin are consistent with our ﬁnding of the direct effects of
the SSRI citalopram on decreasing HIV viral infectivity of human macrophages in an acute ex vivo
model as well as a chronic model of both a T cell line and a macrophage cell line (81). Recently, we
have found that in additional ex vivo studies, citalopram downregulates CCR5, CXCR4, and CD4
receptors on T cells and macrophages and inhibits infection of macrophages in depressed and
nondepressed seronegative individuals. Several clinical studies have demonstrated a beneﬁcial effect of
SSRIs on inﬂammation in depression (95-103). A meta analysis of four studies found that SSRIs were
associated with a decrease in IL-6 and a meta analysis of ﬁve studies found that SSRIs were associated
with a decrease in TNF-alpha. Even though other antidepressants were effective in reducing depression,
they were not effective in decreasing cytokine levels (9). A recent meta analysis also reported similar
ﬁndings for IL-6 as well as CRP (10). Therefore, SSRIs may have dual immune beneﬁts in HIV/AIDS
enhancing innate immunity and decreasing chronic immune activation - both of which are implicated in
viral control and HIV disease progression. Despite the fact that depression is very prevalent in HIV/
AIDS, is associated with immune suppression and immune activation, and is a risk factor for morbidity
and mortality in HIV/AIDS, there is a paucity of double-blind, randomized and placebo controlled trials
of antidepressant medication among depressed HIV seropositive individuals (104-108). These available
trials demonstrated mixed antidepressant effectiveness on depressive symptoms and none examined
biomarkers of immune suppression or immune activation. Thus, a randomized controlled trial is highly
warranted and essential in order to determine the effects of a SSRI and improvement of depression on
biomarkers of immune dysregulation in depression and HIV/AIDS.
Study Design
Phase*
Not applicable
Design
This is a 10 week randomized, parallel-group, placebo controlled trial.
Study duration
The study is planned to last for 5 years. Each subjects participation is planned to be 11 weeks (10 week 
trial with one week baseline screening prior to randominization). We anticipate beginning the project in 
December 2015.


Page 4 of 15
Resources necessary for human research protection
Describe research staff and justify that the staff are adequate in number and qualiﬁcations to conduct 
the research. Describe how you will ensure that all staff assisting with the research are adequately 
informed about the protocol and their research related duties. Please allow adequate time for the 
researchers to conduct and complete the research. Please conﬁrm that there are adequate facilities for 
the research.
All research staff working on this project will be thoroughly conversant with details of the study before 
it begins. The PI will lead weekly meeting prior to the start of the project to review all study procedures. 
Researchers will be given adequate time to conduct and complete the research. There are adequate 
facilities here at UPENN to conduct this research.
Characteristics of the Study Population
Target population
Men and Women, 18-70 years old, any race and ethnicity, HIV positive, on cART, depressed but not 
receiving pharmacotherapy for treatment of depression.
Subjects enrolled by Penn Researchers
180
Subjects enrolled by Collaborating Researchers
0
Accrual
Recruitment Procedures  The enrollment of 180 depressed HIV positive, cART suppressed individuals 
will be accomplished through the implementation of a series of structured and well-coordinated 
recruitment and screening activities. These activities include: 1) the use of the Penn CFAR HIV clinical 
registry; 2) traditional advertising via ﬂiers and print media; 3) networking with MH and HIV 
clinicians, clinic staff, case managers and patients; and 4) regular presence at clinic staff meetings to 
provide project visibility and feedback on project enrollment. We will post the IRB approved ﬂyers in 
key locations and on the PMHARC HIV Research Bulletin Board, a web site that provides a central 
location for posting IRB recruitment ﬂyers. We will begin recruitment by targeting the ﬁve adult HIV 
clinics that operate under the umbrella of the University of Pennsylvania Health System (UPHS). The 
UPHS clinics serve approximately 2,000 patients each year and are linked administratively, share a 
common database and electronic medical record system. We will also recruit participants from the 
Drexel Partnership Clinic, the Temple HIV Clinic and the Lax Clinic of Philadelphia Fight. Thus, 
collectively the clinics from which we will be recruiting see approximately 7,500 patients each year. 
Recruitment will be initiated upon notice of grant award and enrollment will begin in the fourth month 
of the study and continue for 53 months.  Power Analysis and Sample Size Calculation for Primary 
Aims We used two-sided hypothesis tests, and assumed 10% loss to attrition over the 10 weeks. We set 
an overall alpha level of 5% within the innate immunity and inﬂammation hypotheses, so each 
Hypothesis is tested at alpha=0.025. We used the methods of Hedeker et al. (152): assuming a within 
person correlation of 0.6 between visits, we have 80% power to detect a linear group by time effect 
(from week 0 through week 10) of Cohens d=0.42 or higher, and 80% power to detect a main effect 
(from week 2 through week 10) of d=0.41 or higher.  Biostatistical Consideration and Analysis Plan for 
Primary Aims For Primary Aims 1A and 1B, participants will provide measures of innate immunity and 
inﬂammation at baseline, and at weeks 2, 4, and 10. The measures will be continuously distributed, and 
we will use linear mixed effects models, probably after log transformation of a response, to estimate the 
effects of medication group and time on the distribution of the responses across the 10 week period. The 
explanatory variables in these models will be a binary indicator of medication group, variables 
representing time effects, together with possible group by time interaction terms. Time will be modeled 
as a discrete factor. For the covariance structure, we expect that a random intercept model will provide a 
good ﬁt to the data, and will also compare other possible speciﬁcations using BIC comparisons.  
Biostatistical Consideration and Analysis Plan for Secondary Aim First, we will examine whether 
participants showing improvement in depression measures are also those showing improvement in 
primary biological measures. Here, we will calculate change from baseline scores for the HAM-D and 
for the four immunity measures. For each immunity measure and HAM-D, we will use bivariate mixed 


Page 5 of 15
effects models to simultaneously model the pattern of depression change scores and immunity change 
scores across weeks 2 through 10. Here, for each of the four immunity measures, we are modeling the 
three HAM-D change scores and the three immunity change scores as a six-dimensional response, with 
explanatory variables of week, medication, and type of response (depression versus immunity). Our 
hypotheses, that decreases in HAM-D will be associated with increases in innate immunity, and with 
decreases in inﬂammation, will be tested by modeling the covariance structure, and testing individual  
covariances for signiﬁcant differences from zero. We will perform these analyses separately for the four 
immunity responses. Second, we will test whether escitalopram has direct and indirect effects on the 
immune responses. The primary analyses (for Aims 1A and 1B) have addressed the total effect of 
escitalopram on the four immunity measures. One set of analyses will use the conﬁdence limit approach 
of MacKinnon et al. (153, 154), to test whether changes in HAM-D score at week 2 (and, separately, at 
week 4 and 8) mediate the change in immunity measures at week 10. To obtain a complete picture of 
the possible mediation effects of depression, we will also perform these analyses using 50% reduction 
in HAM-D, and HAM-D less than or equal to 7, as the measures of the direct effect of escitalopram on 
depression. We will perform these analyses on the four innate immunity and inﬂammation responses 
separately. These mediation analyses focus on the end of treatment time point. To obtain information on 
longitudinal mediation across the full period, we will use latent growth curve mediation models (154). 
These models are similar to the bivariate mixed effects models describe above, but here we include 
additional regression terms to isolate effects of depression on immunity across time, and random 
intercepts and slopes for the repeated depression scores and the repeated immunity scores, with the 
intercept and slope of the immunity response regressed on the intercept and slope of the depression 
response. MacKinnon (154) describes how the estimated coefﬁcients of these models can be used to 
provide estimates and conﬁdence intervals for the indirect and direct effects of escitalopram on 
immunity. Note: Subjects that are withdrawn from the study will be replaced.
Key inclusion criteria
1) Men and women aged 18-70 years, of any race and ethnicity, 2) HIV-seropositive by ELISA and
Western Blot assays, infected by behavioral transmission (perinatal HIV excluded), 3) Willing and able
to comply with antidepressant medication regimen and scheduled follow-up visits, 4) Currently on a
regimen of cART and Viral load less than 200 RNA copies/ml, 5) Current depressive symptoms
(HAMD- 17 score greater than or equal to 13 and a SCID diagnosis of either Major Depressive
Disorder, Persistent Depressive Disorder (Dysthymia), Unspeciﬁed Depressive Disorder, or Other
Speciﬁed Depressive Disorder, 6) Able to understand and provide informed consent.
Key exclusion criteria
1) Acute suicidal ideation, gestures, or attempts (e.g., HAM-D suicide item score of 3 "Ideas or gestures
of suicide" or 4 "Attempts at suicide" at intake or HAM-D suicide item score of 4 "Attempts at suicide"
during study), 2) Signiﬁcant cognitive impairment or dementia (including HIV Associated Dementia
(HAD)), 3) Use of a medication known to alter immune function within 4 weeks prior to randomization
(the following are not excluded: a. acyclovir and related antiviral medications, b. topical corticosteroids,
c. corticosteroid nasal sprays or inhalers, d) statin medications,), 4) Immunization with HIV vaccine, 5)
Presence of psychotic symptoms or known diagnosis of a primary psychotic disorder, 6) Currently
taking an anti- psychotic medication, 7) Pregnant or within nine months post-delivery, lactation, 8)
Current or chronic medical condition that would likely preclude adherence to protocol or completion of
the trial (per investigator judgment), 9) bipolar disorder (I or II) or schizophrenia, 10) Current
pharmacotherapy for treatment of depression, 11) A history of intolerance or nonresponse to an
adequate trial of escitalopram (or other SSRIs),12) Renal failure, including those who require dialysis,
13) History of epilepsy or seizure disorder, 14) Taken MAOIs within 14 days of randomization, 15) On
the antibiotic Linezolid and taking IV methylene blue, 16) On a regular regime of medication known to
have anticoagulant properties such as NSAID, aspirin or warfarin, 17) A history of acute narrow/closed
angle glaucoma, 18) Currently taking CNS drugs (the following are not excluded: gabapentin,
pregabalin, varenicline, antihistamines, and hypnotics (e.g. zolpidem, zaleplon, eszopiclone), 19) On
any triptan medications, 20) Undergoing ECT.


Page 6 of 15
Vulnerable Populations
Children Form
Pregnant women (if the study procedures may affect the condition of the pregnant woman or 
fetus) Form
Fetuses and/or Neonates Form
Prisoners Form
Other
x None of the above populations are included in the research study
The following documents are currently attached to this item:
There are no documents attached for this item.
Populations vulnerable to undue inﬂuence or coercion
The compensation offered is commensurate with travel and time-related expenses and is not coercive to 
participation. Study populations will be informed that their decision to participate or not participate will 
in no way prejudice their care. Patients who are not capable of giving informed consent will be 
excluded from this study. Employees and students at Penn will be informed that their decision to 
participate or not participate will in no way be indicated on their record or shared with their department.
Subject recruitment
As described above in the Accrual section, the enrollment of 180 depressed HIV positive, cART 
suppressed individuals will be accomplished through the implementation of a series of structured and 
well-coordinated recruitment and screening activities. These activities include: 1) the use of the Penn 
CFAR HIV clinical registry; 2) traditional advertising via ﬂyers and print media; 3) networking with 
MH and HIV clinicians, clinic staff, case managers and patients; and 4) regular presence at clinic staff 
meetings to provide project visibility and feedback on project enrollment .We will post the IRB 
approved ﬂyers in key locations and on the PMHARC HIV Research Bulletin Board, a web site that 
provides a central location for posting IRB recruitment ﬂyers. We will begin recruitment by targeting 
the ﬁve adult HIV clinics that operate under the umbrella of the University of Pennsylvania Health 
System (UPHS). The UPHS clinics serve approximately 2,000 patients each year and are linked 
administratively, share a common database and electronic medical record system. We will also recruit 
participants from the Drexel Partnership Clinic, the Temple HIV Clinic and the Lax Clinic of 
Philadelphia Fight. Thus, collectively the clinics from which we will be recruiting see approximately 
7,500 patients each year. Recruitment will be initiated upon notice of grant award and enrollment will 
begin in the fourth month of the study and continue for 53 months.  We will screen an average of 20 
potential participants each month, 4 of whom we expect to be eligible, willing and enrolled. Thus, the 
screening to enrollment ratio for this study is projected to be 5:1. These recruitment projections are 
based on our extensive experience in recruiting HIV-positive individuals and our access to an existing 
clinic-based recruitment infrastructure supported by the Penn Mental Health AIDS Research Center and 
the Penn CFAR and our teams afﬁliation with the Philadelphia Integrated Behavioral Health Initiative, a 
network of behavioral health specialists who are embedded within six HIV provider agencies and last 
year identiﬁed 2,065 patients who met criteria for depression.  The project will include an experienced 
recruitment staff with knowledge of the HIV treatment community in Philadelphia. Screening 
appointments will be scheduled by the recruitment staff and conducted at the subject's convenience at 
our research ofﬁces located in close proximity to bus, trolley, and subway stops. Enrollment numbers 
and participant characteristics will be closely monitored by investigators at weekly project meetings 
using screening and enrollment data reports produced by Participant File. This is a research study 
tracking software that retains relevant data and produces custom reports clearly showing the number of 
participants screened, their recruitment source, the number eligible, reasons for ineligibility, and the 
enrollment status of those who were eligible. The database is housed on a UPHS protected server and 
meets all NIH and University requirements for protection of conﬁdentiality of personal health 
information (PHI).
Will the recruitment plan propose to use any Penn media services (communications, marketing, etc.) for 
outreach via social media avenues (examples include: Facebook, Twitter, blogging, texting, etc.) or does 


Page 7 of 15
the study team plan to directly use social media to recruit for the research?
Yes
Please identify which method(s) of social media you will utilize, the content of the text to be used, and 
the method(s) for posting this information (i.e., using Penn supported communication services). When 
proposing the text to utilize, please be aware of any social media limitations (i.e., number of characters 
allowed in a tweet) and any appropriate conﬁdentiality practices necessary to be compliant with posting 
research recruitment text.*
We will post ads which have the same images and text as previously approved recruitment ﬂyers; we 
would just be posting this in different locations, such as Craigslist, Facebook, etc. In addition, if we 
wish to post a new advertisement, we will submit these to the IRB for approval before posting them.
The following documents are currently attached to this item:
There are no documents attached for this item.
Subject compensation*
Will subjects be ﬁnancially compensated for their participation?
Yes
The following documents are currently attached to this item:
There are no documents attached for this item.
If there is subject compensation, provide the schedule for compensation per study visit or session 
and total amount for entire participation, either as text or separate document
Subjects will receive $100 for completing the baseline assessment. This may be done is a single visit or 
divided into two shorter visits. If done in two shorter visits they will receive $50 for each. For each 
weekly assessment study visit at weeks 1,3 ,5 ,6 ,and 8, the subject will receive $30 for each visit. For 
weeks 2 and 4, which include a blood draw, the subject will receive $40 for each visit, and for the ﬁnal 
visit at week 10, which also includes a blood draw and longer visit, subjects will receive $50. Thus, If 
the subject completes the baseline visit(s) and all weekly assessment visits (8) they would receive $380 
total. Research participants may be compensated via the Greenphire Clincard for their study 
participation. In addition, if a participant is required to travel to the research site to complete any missed 
parts of a study visit, and the participant is traveling from a location within Philadelphia, we may add 
up to $5 to their payment as needed to cover the costs of this additional transportation. Also if a 
participant is traveling from a location outside Philadelphia for their study visit, we may add up to $10 
to their payment as needed to cover the costs of additional transportation. In some cases, the study may 
provide a ride to the research location by a ride share service. In such situations, this additional 
compensation to cover transportation will not be provided to the participant.
Study Procedures
Suicidal Ideation and Behavior
Does this research qualify as a clinical investigation that will utilize a test article (ie- drug or biological) 
which may carry a potential for central nervous system (CNS) effect(s)?
Yes
Procedures
Screening and Baseline Assessments Prospective subjects will be screened for eligibility via a phone 
interview. Eligible subjects will be invited to complete further screening and baseline assessments, 
which will be conducted either remotely or in person. Visit locations may include our Mobile Clinical 
Trials Unit. Trained clinicians with on-going monitoring and feedback to ensure reliability will perform 
assessments. Following study review, consenting subjects will complete the following: 1) SCID-RV to 
verify inclusion and exclusion criteria, as well as for diagnostic purposes; 2) HAM-D, to determine 
depression severity; 3) HAM-D Anxiety Subscale to determine the severity of anxiety symptoms; 4) 


Page 8 of 15
BDI II for subjective ratings of depressive symptoms; 5) C-SSRSC to assess suicidal ideation; 6) 
Medical history and vital signs; 7) Neuroropsychological assessment to exclude HAD; 8) HIV plasma 
RNA viral load test; 9) Biological assessment: comprehensive immune, virologic and neuroendocrine 
measures, a complete blood count (CBC), and a comprehensive metabolic panel (CMP); and 10) 
Pregnancy test. These procedures may happen at our research ofﬁces, remotely via private video or 
telephone call, or on our Mobile Clinical Trials Unit (MCTU). The SCID-RV, HAM-D, and C-SSRS 
will be audio recorded for training purposes on a digital audio recorder or on Bluejeans. Subjects will 
also sign a release of information to allow us to communicate with their HIV primary care provider. The 
baseline assessment may be completed in one longer visit (8-10 hours) or two shorter visits (each 4-5 
hours).  Randomization The 180 HIV-seropositive eligible and consenting depressed subjects will be 
randomized to 10 weeks of double blind therapy with either escitalopram or placebo. Study medication 
may be sent to participants via mail. All participants will concurrently begin CCBT. Stratiﬁcation based 
on race, sex, and baseline depression symptom severity, will be incorporated to ensure an even 
distribution of more severely depressed subjects (i.e., those with HAM-D scores greater than or equal to 
20) in each treatment condition. Neither the research nurse nor the study clinicians will be aware of the
assigned treatment condition for each subject nor will any research staff having any clinical contact
with the study participants be aware of the treatment assignment during each subjects participation in
the study. Only the research pharmacist will be unblinded to the treatment condition during each
subjects participation Treatment To address ethical concerns about withholding active treatment, all
study subjects will receive CCBT in combination with pharmacotherapy. We have selected a computer-
assisted model of cognitive behavior therapy because it is less resource intensive and has been
recommended for depression in primary care (119, 120). We have chosen the Good Days Ahead (121)
model of CCBT because our mood disorders group has extensive experience with this approach (122)
and we have recently completed a two-center study of outpatients with Major Depressive Disorder that
demonstrated noninferiority to conventional Cognitive Behavioral Therapy (CBT) conducted by
therapists trained at our Center for Cognitive Therapy (R01-MH082794; ME Thase, PI). Escitalopram,
which is the active isomer of citalopram, was selected for its efﬁcacy and pharmacologic properties. A
meta analysis conducted by the Cochrane Collaboration concluded that escitalopram was one of only 2
(along with sertraline) newer generation antidepressants that was superior in terms of both efﬁcacy and
tolerability (123). Furthermore, it is well-suited for a study of medically complex patients because it has
relatively simple dosing and few drug-drug interactions. Escitalopram and placebo will be prepared in
the form of identical capsules by the Investigational Drug Service (IDS) research pharmacy at
University of Pennsylvania School of be Medicine. The active capsules will contain 5mg, 10mg, or
20mg of escitalopram. Patients will be started at 10mg daily (or placebo equivalent) for the ﬁrst week.
Upward titration will be permitted after one week based on tolerability and clinical response, (maximun
dose is 20mg/day). Downward titration to will be permitted if side effects are severe. We anticipate that
about 3/4th of the patients will be taking 20mg/day (or placebo equivalent) by week 10. In the case of a
medical emergency or serious adverse event, the blind will be broken by the research pharmacist and
the information provided to an independent study psychiatrist. Subjects that do not tolerate the study
drug will be withdrawn and replaced and referred for treatment of their depression. Treatment(s) they
receive after being withdrawn are their ﬁnancial responsibility. Also, at the end of ten weeks or if the
study needs to be stopped for some reason that we do not currently anticipate, or if the subject needs to
be withdrawn for any reason, we may need to wean the subject off the medicine as opposed to stopping
it abruptly. We have stated this in the Informed Consent. Over a maximum two week period we will
gradually decrease the amount of study medicine a subject is taking, and by phone we will monitor the
subject for any discontinuation or worsening of depression symptoms. We will speak with the subject
about options for continued care and will provide appropriate referrals. This may include treatment by
staff and faculty of the Penn Department of Psychiatry, Mood and Anxiety Disorders Treatment and
Research Program or by the subject's primary care provider, or by an alternate care provider the subject
chooses. We will encourage subjects to speak with their physician about continued care. If we need to
taper the subject off the study medicine we will continue to supply and pay for the study medicine. In
addition to the possibility of tapering, in some circumstances we might also provide at no cost to the
subject two weeks of escitalopram to participants who had been receiving active medication at the ﬁnal
week 10 visit, when subjects are unblinded to their treatment assignment, to maximize patient care.
After the two week period, if the subject has not been able to receive a prescription from their provider
or referral physician, our study psychiatrist will prescribe an additional two weeks of escitalopram
which will be the ﬁnancial responsibility of the subject. Any treatments, including medication, that the
subject receives elsewhere after they leave or are withdrawn from the study are their ﬁnancial
responsibility and will not be paid for by the study.  At the ﬁrst visit following randomization, a
certiﬁed cognitive therapist will meet with the participant for 60 minutes in person or remotely to


Page 9 of 15
provide an overview about cognitive therapy and to demonstrate how to log in to the Good Days Ahead 
program. This therapist will serve as the patients coach and will meet either in person or via private 
video or telephone call to review progress or trouble shoot for thirty minute sessions every other week. 
More frequent sessions, either in person or by phone, can be scheduled if problems arise. Good Days 
Ahead consists of 8 distinct modules and it is recommended that participants work at a pace of one 
module per week. Computer-assisted sessions can be done at home or, if no computer or internet access 
is available, at the clinic. We anticipate that the average participant will have about 3 hours of therapist 
contact during the 10 week protocol. Pharmacotherapy visits will occur either in person or via private 
video or telephone call weekly for the ﬁrst 6 weeks and then at weeks 8 and 10. The treating clinician 
will assess side effects, review symptomatic progress, and adjust the study medication as clinically 
appropriate. These visits typically last 15-30 minutes. An independent clinical evaluator or clinician 
will assess patients with the HAM-D and C-SSRS at baseline, and weeks 1-6, 8 and 10 during double 
blind therapy. During each assessment visit, adherence to research medication will be assessed. At the 
end of the 10-week treatment phase, all participants will be referred for appropriate clinical treatment of 
their depression.
The following documents are currently attached to this item:
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Deception
Does your project use deception?
No
International Research
Are you conducting research outside of the United States?
No
Analysis Plan
We have included this in the accrual section of the detailed protocol and in the attached grant.
The following documents are currently attached to this item:
There are no documents attached for this item.
Data conﬁdentiality
x Paper-based records will be kept in a secure location and only be accessible to personnel involved 
in the study.
x Computer-based ﬁles will only be made available to personnel involved in the study through the 
use of access privileges and passwords.
x Prior to access to any study-related information, personnel will be required to sign statements 
agreeing to protect the security and conﬁdentiality of identiﬁable information.
x Wherever feasible, identiﬁers will be removed from study-related information.
x A Certiﬁcate of Conﬁdentiality will be obtained, because the research could place the subject at 
risk of criminal or civil liability or cause damage to the subject's ﬁnancial standing, 
employability, or liability.
A waiver of documentation of consent is being requested, because the only link between the 
subject and the study would be the consent document and the primary risk is a breach of 
conﬁdentiality. (This is not an option for FDA-regulated research.)
x Precautions are in place to ensure the data is secure by using passwords and encryption, because 
the research involves web-based surveys.
Audio and/or video recordings will be transcribed and then destroyed to eliminate audible 
identiﬁcation of subjects.
Subject Conﬁdentiality
Conﬁdentiality Risks:  There is a small risk of breach of conﬁdentiality related to collection of sensitive 
health and psychological information. We recognize the serious adverse effects that can occur with a 


Page 10 of 15
breach of conﬁdentiality. Our research team is trained and experienced in the ethics of medical research 
and operating procedures will be enforced to insure that all subject interactions are treated 
conﬁdentially and all data are protected by use of only a unique study ID number to identify the subject. 
Furthermore, the University of Pennsylvania has developed policies and guidelines to ensure HIPPAA 
compliance in the collection of research data. Compliance for research data will be reviewed by the IRB 
as part of the human subjects approval process. The investigators will assure that the data collection 
instruments and consent forms are in compliance with Penn policies in this area.  We are particularly 
sensitive to the issues of subject conﬁdentiality with respect to HIV and depression . Consequently, we 
have adapted extensive procedures for our HIV and depression studies and will adapt similar 
procedures for the proposed study. We are committed to a system that maximally protects the 
conﬁdentiality of our subjects. All subjects who consent to participation in this study receive a research 
identiﬁcation number. Only this number, not subject name, will identify the subject in all research 
records. In no case will names or other personal identiﬁers such as social security numbers be used. The 
majority of data collected in this study will be entered in real time directly into the studys REDCap 
(Research Electronic Data Capture) database, a password-protected on-line database. Only authorized 
staff working on the study will have access to this database. All hard copy data will be stored separately 
from documents with identifying information, such as signed informed consent forms, in locked ﬁle 
cabinets. The security and conﬁdentiality of the data in paper and hard copy form will be the 
responsibility of the P.I. Access to these locked ﬁle cabinets will be limited to the research staff under 
the supervision of Dr. Evans or the study coordinator.
Sensitive Research Information*
Does this research involve collection of sensitive information about the subjects that should be excluded 
from the electronic medical record?
No
Subject Privacy
Privacy refers to the person's desire to control access of others to themselves. Privacy concerns people, 
whereas conﬁdentiality concerns data. Describe the strategies to protect privacy giving consideration to 
the following: The degree to which privacy can be expected in the proposed research and the safeguards 
that will be put into place to respect those boundaries. The methods used to identify and contact 
potential participants. The settings in which an individual will be interacting with an investigator. The 
privacy guidelines developed by relevant professions, professional associations and scholarly 
disciplines (e.g., psychiatry, genetic counseling, oral history, anthropology, psychology). 
The research team has considerable experience relating to depressed and HIV infected subjects and 
understands and respects the need for patient privacy. We anticipate being able to maintain a high 
degree of privacy in this research project and will do everything we can to protect the privacy of 
individuals participating in this research. The consenting process will take place in a closed private 
setting or via a remote method per IRB guidance issued on 5/22/2020, such as REDCap and/or 
telephone or video call. All assessment visits will be kept as private as possible and generally will 
happen in a closed private ofﬁce or via a private telephone or video call.  If and when the study 
coordinator or study recruiter calls a subject they will only leave their name and a phone number. They 
will not leave anything in a message that could identify the study, or department, or status of the 
subject. Study procedures conducted remotely (such as informed consent, psychiatric evaluations, 
cognitive therapy sessions, etc.) will be conducted via either a private video or phone call. Procedures 
conducted through REDCap (such as informed consent or completing survey questionnaires) will be 
private because the study team will generate a secure survey to be sent to and completed by the 
participant.
Data Disclosure
Will the data be disclosed to anyone who is not listed under Personnel?
No, unless we are required by law to disclose speciﬁc data.


Page 11 of 15
Data Protection*
x Name
x Street address, city, county, precinct, zip code, and equivalent geocodes
x All elements of dates (except year) for dates directly related to an individual and all ages over 89
x Telephone and fax number
x Electronic mail addresses
x Social security numbers
x Medical record numbers
Health plan ID numbers
Account numbers
Certiﬁcate/license numbers
Vehicle identiﬁers and serial numbers, including license plate numbers
Device identiﬁers/serial numbers
Web addresses (URLs)
Internet IP addresses
Biometric identiﬁers, incl. ﬁnger and voice prints
Full face photographic images and any comparable images
Any other unique identifying number, characteristic, or code
None
Does your research request both a waiver of HIPAA authorization for collection of patient information 
and involve providing Protected Health Information ("PHI") that is classiﬁed as a "limited data set" 
(city/town/state/zip code, dates except year, ages less than 90 or aggregate report for over 90) to a 
recipient outside of the University of Pennsylvania covered entity?
No
Tissue Specimens Obtained as Part of Research*
Are Tissue Specimens being obtained for research?
Yes
Tissue Specimens - Collected during regular care*
Will tissue specimens be collected during regulator clinical care (for treatment or diagnosis)?
No
Tissue Specimens - otherwise discarded*
Would specimens otherwise be discarded?
No
Tissue Specimens - publicly available*
Will tissue specimens be publicly available?
No
Tissue Specimens - Collected as part of research protocol*
Will tissue specimens be collected as part of the research protocol?
Yes
Tissue Specimens - Banking of blood, tissue etc. for future use*
Does research involve banking of blood, tissue, etc. for future use?
Yes
Genetic testing
If genetic testing is involved, describe the nature of the tests, including if the testing is predicative or 
exploratory in nature. If predictive, please describe plan for disclosing results to subjects and provision 


Page 12 of 15
of genetic counseling. Describe how subject conﬁdentiality will be protected Note: If no genetic testing 
is to be obtained, write: "Not applicable."
Not Applicable
Consent
1. Consent Process
Overview
The PI or his designee will review all study procedures and answer all questions that a potential study 
subject has. Only after the study has been explained thoroughly will the study staff offer the subject to 
sign the Informed consent. This will take place in one of the research ofﬁces used by this study on the 
UPENN campus (TBD), on our Mobile Clinical Trials Unit, via a private telephone or video call and/or 
via REDCap.  The PI/ or designee will explain the study using lay language. If a subject is not capable 
of providing consent they will not be consented into this study. Under no circumstance will study staff 
try to unduely inﬂuence a subject to consent.
Children and Adolescents
Not Applicable
Adult Subjects Not Competent to Give Consent
Adult subjects not competent to give consent will not be eligible to participate in the study.
2. Waiver of Consent
Waiver or Alteration of Informed Consent*
No Waiver Requested
Minimal Risk*
Impact on Subject Rights and Welfare*
Waiver Essential to Research*
Additional Information to Subjects
Written Statement of Research*
No
If no written statement will be provided, please provide justiﬁciation
The following documents are currently attached to this item:
There are no documents attached for this item.
Risk / Beneﬁt
Potential Study Risks
All potential risks that might occur as a result of the participation in this study are detailed in the 
Informed Consent form and will be fully discussed with each subject by the research staff. General: It 
will be explained to each subject that in the event of physical injury directly resulting from the research 
procedures, every effort will be made to make available the facilities and professional skills of the 
University of Pennsylvania Health System. It will be further explained that while some risks are not 
predictable, every precaution consistent with the best medical practice to protect the health and safety of 
the subjects will be taken. We will explain to each subject that participation in the research study is 
completely voluntary. The subject has the right to refuse participation or withdraw at any point in the 


Page 13 of 15
study, without inﬂuencing any aspect of medical treatment that they may require.  Medication and 
Placebo Use: The study clinicians will closely monitor subjects for adverse effects throughout the trial. 
Adverse effects can be treated by lowering the dose, or discontinuing it when necessary. Although there 
are no clinically proven adverse effects associated with escitalopram with regard to pregnancy, as a 
safety precaution we will not study pregnant women. All consenting females of childbearing potential 
will be tested for pregnancy prior to receiving treatment. They will be required to use an effective 
contraceptive method during the trial (such as a condom with spermicide or diaphragms with 
spermicide; oral, injectable, or implantable birth control; intrauterine devices (IUDs); surgical sterility). 
This will be explained in the consent form. There are no reported drug-to-drug interactions between 
escitalopram and antiretrovirals. However there are few clinical trials using the particular combination 
of agents our study participants will be on; therefore, the lack of reported interactions does not ensure 
that previously unknown adverse effects will not arise. Nonetheless, escitalopram is not known to have 
any signiﬁcant effects on the cytochrome p450 isoenzyme system and no drug interaction effects are 
anticipated. Adverse effects will be monitored vigilantly. All serious adverse events will be fully 
documented and reported to the Penn IRB within 24hrs of knowledge of the event. The following safety 
procedures will be maintained in order to identify the presence of worsening depressive symptoms. A 
careful clinical psychiatric assessment, including the HAM-D scale, which is a sensitive symptom 
severity rating instrument, and the C-SSRS, which measures suicidal ideation, will be obtained at each 
assessment study "visit" whether conducted in person or remotely via private video or telephone call. In 
addition, study subjects will be instructed by the study clinicians about the signs and symptoms of 
worsening depression, and will be instructed to call the study in the event that they experience these 
symptoms. Information about depressive symptoms will be provided to all subjects at the beginning of 
the study and throughout the course of the study to enhance patient safety and study compliance. 
Subjects will be provided with a 24-hour emergency phone number in case of untoward events or 
worsening depressive symptoms. The magnitude and frequency of the clinical monitoring schedule 
during all aspects of the study should easily permit the study clinicians to determine the presence of 
symptomatic worsening. Rapid clinical intervention will be instituted in the event of signiﬁcant clinical 
worsening. In this event, the subject will be treated as clinically warranted. Given these safeguards, we 
believe that the use of a placebo condition is safe when applied in accordance with the proposed 
treatment guidelines of our study. Risk of Computer-assisted Cognitive Behavior Therapy (CCBT): 
There are no known or foreseeable risks associated with receiving treatment with computer-assisted 
cognitive behavior therapy. Like other treatments for depression, CCBT is not effective therapy for all 
people and there is a chance depressive symptoms could worsen. The safeguards noted above reduce 
risk associated with symptomatic worsening.  Risk of Phlebotomy: The potential risk of an 
approximately 70cc blood draw are minimal, and include the discomfort of an IV, a bruise, or rarely, an 
infection of the vein. To reduce these risks, blood will be collected by an experienced phlebotomist 
following aseptic procedures. Risk of Psychological Evaluation: Although the potential psychological 
risks are also minimal, participation in psychiatric interviews and psychiatric and psychological 
questionnaires can, for some subjects, be psychologically provocative. We will make every effort to be 
sensitive to the psychological response to the assessments of each individual subject. Speciﬁcally the 
research associates will inquire about each subjects psychological experience during each assessment. 
In rare instances where psychological and psychiatric evaluation evokes distressful feelings we will 
provide support as needed and appropriate. If a subject becomes very seriously or suicidally depressed 
there is a rescue procedure which involves breaking the blind on the study medication and providing or, 
if necessary, referring them for appropriate clinical treatment.
Potential Study Beneﬁts
All subjects may beneﬁt from the comprehensive medical and psychiatric diagnostic assessments in the 
study. Half of the depressed subject in the study will receive CCBT and antidepressant medication for 
their depression and will be monitored weekly (weeks 0-6) or biweekly (weeks 6-10). The other half of 
the depressed subjects will receive CCBT and placebo but will also be monitored weekly (weeks 0-6) or 
biweekly (weeks 6-10). Based on previous studies, we expect that ~ 60% of the depressed subjects 
receiving placebo will see an improvement in their depression. The ~40% that do not see an 
improvement will be referred for treatment after their participation in the study is completed. All 
subjects in the study will be referred for treatment of their depression and will receive follow-up to 
maximize treatment initiation, and or continuation. All subjects will receive free of charge medical, 
neurologic, immunologic and psychiatric assessments. Any subject needing immediate medical 
treatment, including psychiatric treatment will be referred for treatment. Being evaluated weekly/
biweekly, the risks to subjects in this study are minimal and reasonable compared to the beneﬁts gained 
by their participation. Subjects will also make important contributions to others via the further 


Page 14 of 15
development of clinical information on the best treatment approach for HIV+ subjects suffering with 
depression. Subjects may also contribute to a better understanding of the immune mechanisms that 
underlie the relationship between depression and HIV disease progression. The potential immune 
mechanisms by which depression may inﬂuence HIV disease progression and mortality remain to be 
understood. Knowledge gained from this study will advance the ﬁeld of HIV care by clarifying if there 
exists dual beneﬁts of pharmacotherapy for clinical depression among HIV+ patients with well-
controlled viral load. This knowledge, and the good it may lead to, outweighs the minimal risks 
associated with this study. The study will speciﬁcally show if escitalopram given to aviremic, HIV+ 
depressed subjects will result in: (1) immune system homeostasis, marked by less innate immune 
suppression and lower levels of inﬂammation and immune activation; (2) if improvement in depressive 
symptoms are associated with improvements in innate immunity and inﬂammation. The proposed study 
is designed to determine if escitalopram will upregulate innate immunity (LUNK and intracellular 
gamma interferon in NK cells) and downregulate inﬂammation (IL-6 and CRP) in depressed, aviremic 
HIV+ individuals. This proposal also has the potential to produce new knowledge on the depression/
endocrine/immune 
mechanisms 
that 
will 
determine 
whether 
traditional 
pharmacotherapy 
(escitalopram), might beneﬁt HIV+ individuals.
Alternatives to Participation (optional)
The alternative to participating in this study is not to participate.
Data and Safety Monitoring
The study will be monitored by the Principal Investigator and the Data Safety Monitoring Board 
(DSMB). Data and Safety Monitoring Plan In order to ensure the safety of participants and the validity 
and integrity of the data, we will appoint a Data and Safety Monitoring Board (DSMB) whose chief 
function will be to ensure safe and effective conduct of the trial. The DSMB will monitor our project 
and serve as a reporting body to the Penn IRB.  Composition of the DSMB The DSMB will consist of 3 
investigators, who are external to this study, selected from a number of scientiﬁc disciplines (including, 
a psychiatrist, an infectious disease practitioner, and a biostatistician) needed to interpret the data and 
ensure patient safety. None of the board members will be directly associated with the proposed research 
study. Activities of the DSMB: The primary goals of the DSMB will be: - To monitor and advise on 
scientiﬁc and ethical issues related to the study implementation for the protection of human subjects. - 
To review and approve the protocol and subsequently conduct annual reviews to determine whether 
patient safety has been adequately safeguarded - To review procedures and decisions regarding the 
adequate protection of speciﬁc patients when investigators break protocol because of adverse events or 
clinical deterioration. - To review progress to see that enrollment goals have been met. - To monitor and 
advise on ethical issues related to adverse events. - To oversee the conﬁdentiality of data, and quality of 
data collection, management, and analysis - To recommend if necessary, discontinuation, modiﬁcation, 
or termination of the study based upon emerging data (in the study and literature) and evaluation of risk/
beneﬁt ratio. - When possible, to serve as the ﬁnal arbiters of whether individual patients should be 
removed from the protocol.  The DSMB will receive quarterly reports of study progress and of any 
adverse effects or protocol violations.  The DSMB will meet once per year, or more often as needed. In 
event of emergencies, the DSMB may meet via teleconference. For each annual meeting, the DSMB 
will ﬁrst meet in an open session attended by the principal investigator and co-investigators, and the 
project statistician. The group will ﬁrst review the research protocol and plans for data safety 
monitoring. The group will be used to review any problems in implementing the safety plan and for 
suggesting any necessary modiﬁcations to the safety plan. The DSMB will then meet in a closed session 
for the purpose of reviewing emerging trial data. Conﬁdentiality will be maintained by providing data 
without any patient identifying information to the committee. At the conclusion of the meeting, the 
DSMB will make recommendations to the investigators and the IRB. The DSMB will make 
recommendations concerning the continuation or conclusion of the study. Data Monitored by the 
DSMB The DSMB will monitor both safety and outcome data as part of the yearly review. Outcome 
evaluations will include review of data quality and timeliness, participant recruitment, accrual and 
retention, and review of interim masked outcome results on primary and secondary efﬁcacy measures. 
Safety evaluations will include review of adverse events and weekly symptom measures for each 
patient. In addition to serious adverse events, the board members will be presented with all adverse 
event information. The DSMB will further consider external factors such as scientiﬁc and therapeutic 
developments that may impact the safety or the ethics of the study. Procedures for reporting Adverse 
Event All serious adverse events will be reported to the members of the DSMB and the IRB within 24 
hours. A report of all non-serious adverse events will be provided to the board members and the IRB 
yearly. NIH will be informed of all actions taken by the IRB as part of its continuing review. Oversight 


Page 15 of 15
of DSMB The investigators will ensure that the Data and Safety Monitoring Plan is reviewed and 
approved by the IRB before the initiation of the study protocol. The DSMB will then provide a report to 
the IRB following each yearly meeting, including recommendations concerning continuation or 
conclusion of the study.  Data Safety Management Data will be gathered using an internet-based direct-
entry data system in REDCap (Research Electronic Data Capture). REDCap is a secure web-based 
application designed to support data capture for research studies. REDCap provides 1) an intuitive 
interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 
3) automated export procedures for seamless data downloads to common statistical packages; and 4)
procedures for importing data from external sources. Interview data and self-report data are entered
directly onto computers and/or tablets at the research sites by research study staff and study subjects
respectively. When data are entered into REDCap remotely, research study staff enter data directly into
REDCap. When links to self-report surveys are sent to a participant, the participant enters their own
responses and submits from their own device. While their responses cannot be accessed by another
person, if someone else has access to a participants email, they may see that the person is being asked
questions about depression and HIV. In cases where the participant cannot complete the surveys online,
a research staff member will ask them the questions and enter their answers into REDCap. Data are
transmitted over a secure web connection with authentication and data logging. Password protection
allows members of the research team appropriate levels of data access.
The following documents are currently attached to this item:
There are no documents attached for this item.
Risk / Beneﬁt Assessment
The risks of participating in this study are minimal and are outweighed by the potential beneﬁts the 
study has not only to each individual subject but to society at large. Subjects in this study are depressed 
but not receiving treatment for their depression. Whether they receive active drug or placebo they all 
will participate in a cognitive behavioral therapy program for their depression. Additionally, at the 
conclusion of their participation each subject will be referred for appropriate treatment of their 
depression.

SAP_001.pdf: 
Protocol Title: SSRI Effects on Depression and Immunity in HIV/AIDS 
NCT Number:  NCT02620150 
Document:  Statistical Analysis Plan 
Document Date: March 10, 2015 


3.10.2015 – 5:00pm 
1 
C.3  Research Design and Methods
Aim 1 Determine the effects of an SSRI on innate immunity and inflammation in depressed HIV seropositive
individuals. 
C.3.1  Summary
This will be the first placebo-controlled RCT to determine the immunomodulatory effects of SSRI therapy
among a contemporary, urban cohort of HIV-seropositive individuals whose viral load is well controlled, yet still
experiences immune dysregulation due to co-morbid depression and HIV infection Comparing the two
depressed groups that are randomly assigned to receive SSRI or placebo will allow us to address novel aims:
can SSRI treatment and improvement of depression reverse the immune dysregulation of depression and HIV.
Comprehensive biomarkers of innate immunity, and inflammation will be assayed via blood draw at baseline
and at 2, 4, and 10 weeks. Additionally, we will monitor adherence to SSRI and antiretroviral medications in all
participants using contemporary methodology (i.e., self-reported doses taken and missed, medication
electronic monitoring system (MEMS) caps, and, for HIV, plasma viral load).
Aim 1A. Determine whether an SSRI upregulates innate immunity in depressed HIV seropositive individuals.
Hypothesis: SSRI is superior to placebo in restoring biomarkers of innate immune suppression (LUNK and
intracellular IFNγ in NK cells).
Previously we demonstrated that major depression is associated with significant reductions in NK cell activity 
and resolution of depression resulted in improvement of LUNK (for details see C1.7, C1.8). SSRI enhances 
LUNK ex vivo (for details see C1.9.a). In addition as a part of our recent project (RO1 MH82670) we 
demonstrated that increase in severity of depression is associated with decrease in absolute numbers of total 
NK cells (p=0.008),  reduction in perforin+ NK cells (p=0.009) and reduced expression of activation receptors 
NKP30+ (p=0.011) and NKP46+ (p=0.049) (unpublished observations). NK cell functions are also affected by 
HIV infection in several ways including decreased cytotoxic activity, changes in receptor expression and 
cytokine production (123-125). Although NK functions are partially restored by cART(44, 123), several studies 
demonstrated that recovery is incomplete. NK cells from HIV positive individuals with sustained viral 
suppression by cART do not completely recover in numbers (44), continue to have increased 
activation/degranulation profiles (46), show decreased receptor expression (NKp46 and NKp30) (126) and 
decreased cytokine production (IFNγ, TNF-α) (127).  
In this aim we will assess NK cell functions in HIV positive individuals on stable cART at baseline and after 2, 
4, and 10 weeks of SSRI therapy. NK cell function will be assessed by the standard chromium release assay, 
established in our laboratory, using K562 target cells and peripheral blood mononuclear cells (PBMC) at 
effector to target cell ratios of 6.25 - 50. Percent lysis values will be normalized for percent NK cells within the 
PBMC preparations and are expressed as lytic units (LU) per 107 NK cells or LUNK as previously described 
(41, 71, 72). In addition intracellular IFNγ will be assessed as described (42) (also see letter from Dr. Luis J. 
Montaner) in stimulated PBMCs. The number of IFNγ+ NK cells will be assessed by flow cytometry gated on 
CD45+/CD3-/ CD16+/CD56+ cells. Nonreactive isotype-matched mAb will be used as control. 
Aim 1B. Determine whether an SSRI downregulates 
inflammation in depressed HIV seropositive 
individuals. Hypothesis: SSRI is superior to placebo in 
decreasing biomarkers of inflammation  
(IL-6, CRP). Both MDD and HIV infection are 
associated with elevated levels of pro-inflammatory 
cytokines (for review see (7, 128-130). Although 
increased levels of many cytokines, inflammatory and 
oxidative stress markers were linked to either of those 
conditions extensive literature review show that IL-6 
and CRP are two markers most consistently 
associated with both MDD and HIV infection. We 
propose to use changes in those two markers as a primary outcome of our study. For example in our recent 
clinical trial with aprepitant, a compound with potential utility as a drug for depression and anti-inflammatory 
properties in HIV infected subjects, in non-depressed subjects we detected a decrease in plasma levels of IL-6 
after 2 weeks of treatment  within subjects (p=0.02) and between aprepitant and placebo (p=0.02) (131) 
(Figure 7). In addition to our primary variables (IL-6 and CRP) associated with inflammation, we will measure 
several other plasma markers of inflammation in HIV positive depressed subjects receiving SSRI or placebo 
(see C.4 Further Analyses). 
Secondary Aim. Determine if improvement in depressive symptoms is associated with improvements in innate 
immunity and inflammation in HIV seropositive individuals. 
Hypothesis:  Reduced symptoms of depression after acute (10-week) treatment will correlate with increased 
Figure 7. Changes in plasma 
levels of IL-6 in patients treated 
with aprepitant. IL-6 levels were 
measured in plasma of 48 
patients HIV positive patients 
enrolled in aprepitant trial.   29 
patients received medication 
(125, 250 or 375 mg per day), 19 
received placebo for 14 days. 
Changes in IL-6 are shown as 
delta [IL-6] between baseline and 
after 2 weeks of treatment with 
aprepitant measured.
Aprepitant
Placebo
-6
-4
-2
0
2
4
plasma IL-6 change (pg/ml)
p=0.02
p=0.02
p=0.3


3.10.2015 – 5:00pm 
2 
levels of innate immunity (LUNK and intra cellular IFNγ in natural killer cells) and decreased levels of 
systemic inflammation (IL-6 and CRP). 
C.3.2  Biostatistical Consideration and Analysis Plan
C.3.2.a  Methods and Approach
Primary Aims: For Primary Aims 1A and 1B, participants will provide measures of innate immunity (LUNK and
intracellular IFN-γ) and inflammation (IL6 and CRP) at baseline, and at weeks 2, 4, and 10. The measures will 
be continuously distributed, and we will use linear mixed effects models, probably after log transformation of a 
response, to estimate the effects of medication group and time on the distribution of the responses across the 
10 week period. The explanatory variables in these models will be a binary indicator of medication group, 
variables representing time effects, together with possible group by time interaction terms. Time will be 
modeled as a discrete factor. For the covariance structure, we expect that a random intercept model will 
provide a good fit to the data, and will also compare other possible specifications using BIC comparisons.   
Secondary Aim: In the Secondary Aim, we will examine relationships between the effects of Escitalopram 
versus Placebo on depressive symptoms and the effects on the primary biological responses. Hamilton scores 
will be obtained at baseline and at weeks 2, 4, and 10.  
First, we will examine whether participants showing improvement in depression measures are also those 
showing improvement in primary biological measures. Here, we will calculate change from baseline scores for 
the Hamilton and for the four immunity measures. For each immunity measure and Hamilton, we will use 
bivariate mixed effects models to simultaneously model the pattern of depression change scores and immunity 
change scores across weeks 2 through 10. Here, for each of the four immunity measures, we are modeling the 
three Hamilton change scores and the three immunity change scores as a six-dimensional response, with 
explanatory variables of week, medication, and type of response (depression versus immunity). Our 
hypotheses, that decreases in Hamilton will be associated with increases in innate immunity, and with 
decreases in inflammation, will be tested by modeling the covariance structure, and testing individual 
covariances for significant differences from zero. We will perform these analyses separately for the four 
immunity responses. 
Second, we will test whether Escitalopram has direct and indirect effects on the immune responses. The 
primary analyses (for Aims 1A and 1B) have addressed the total effect of Escitalopram on the four immunity 
measures. One set of analyses will use the confidence limit approach of MacKinnon et al (135, 136), to test 
whether changes in Hamilton score at week 2 (and, separately, at week 4) mediate the change in immunity 
measures at week 10. To obtain a complete picture of the possible mediation effects of depression, we will 
also perform these analyses using 50% reduction in HAM-D, and HAM-D ≤7, as the measures of the direct 
effect of Escitalopram on depression. We will perform these analyses on the four innate immunity and 
inflammation responses separately.  These mediation analyses focus on the end of treatment time point. To 
obtain information on longitudinal mediation across the full period, we will use latent growth curve mediation 
models (MacKinnon, 2008, 8.10-8.14). These models are similar to the bivariate mixed effects models describe 
above, but here we include additional regression terms to isolate effects of depression on immunity across 
time, and random intercepts and slopes for the repeated depression scores and the repeated immunity scores, 
with the intercept and slope of the immunity response regressed on the intercept and slope of the depression 
response. MacKinnon (2008) describes how the estimated coefficients of these models can be used to provide 
estimates and confidence intervals for the indirect and direct effects of Escitalopram on immunity.  
C.3.2.b  Power Analysis and Sample Size Calculation for Primary Aims
We use two-sided hypothesis tests, and assume 10% loss to attrition over the 10 weeks. We set an overall
alpha level of 5% within the innate immunity and inflammation hypotheses, so each Hypothesis is tested at
alpha=0.025. We use the methods of Hedeker et al (122): assuming a within person correlation of 0.6 between
visits, we have 80% power to detect a linear group by time effect (from week 0 through week 10) of Cohen’s
d=0.40 or higher, and 80% power to detect a main effect (from week 2 through week 10) of d=0.4 or higher.
C.3.3  Expected Outcomes, Potential Problems and Alternative Approaches
If successful, this trial will advance the field of HIV care by demonstrating the benefit of SSRI treatment on
immune system homeostasis, marked by less innate immune suppression and less systemic inflammation,
both of which are implicated in HIV pathogenesis. We expect to detect restoration of NK cell functions and
decreases in levels of pro inflammatory markers as a result of SSRI treatment. Pro-inflammatory cytokines are
thought to play a role in the pathophysiology of depression (4, 7, 86, 132). Although this is not an aim of the
present study, data accumulated during our study will allow us to evaluate this relationship along with other
patient characteristics (see C.4 Further Analyses). Both depression and HIV are associated with increased
plasma levels of IFNγ (133, 134) however based on previous observations (42) we expect to see decreased


3.10.2015 – 5:00pm 
3 
IFNγ production by stimulated NK cells from HIV+ subjects on cART. We will monitor if SSRI treatment or/and 
depression improvement will restore IFNγ production. However if we do not detect changes in IFN-γ we will 
analyze other markers of NK activation and degranulation which are associated with both chronic HIV infection 
and depression (126) as noted below in C.4. Further Analyses. 
We expect to see Immune changes prior to depression improvements suggesting direct SSRI effects on 
peripheral immune cells.  Although unlikely, It is possible that a ceiling effect could be observed and both 
groups exhibit similar and maximal immune changes at a given time point. If that is the case the frequency of 
our measures will allow us to study the time course of these immune changes over time and over the time 
course of depression improvement which will further inform us about SSRI direct effects and depression 
improvement effects on immunity. 
If successful, this rigorously designed clinical trial will advance the field of HIV care by demonstrating the 
immune benefits of SSRIs among depressed patients with well-controlled viral load – an increasingly prevalent 
population in the era of modern cART. Many large scale clinical trials encounter challenges with recruitment 
and retention. We will proactively monitor accrual and retention and should we encounter this challenge,  we 
will initiate a response that will include consultation with the PMHARC Community Advisory Board to discuss 
recruitment barriers, additional avenues of recruitment and retention strategies.   We will also maintain close 
communications with the Philadelphia Integrated Behavioral Health Initiative which has staff embedded within 
six of the largest HIV care sites in the city. These staff can help promote recruitment and facilitate retention 
should we need assistance.   
C.4 Further Analyses
Innate Immunity, Inflammation and Virology: We will also assess the effects of SSRI on other important
innate immune cell populations. These responses will be available at baseline and after 2, 4 and 10 weeks of
treatment, so they will be analyzed using the approach described above for the primary outcomes of Aim 1. We
will evaluate NK receptor expression before and after 10 weeks of SSRI treatment using Flow cytometry assay.
Total NK cells will be characterized as CD45+/CD3-/ CD16+/CD56+. In addition, the expression of the following
receptors will be assessed: NKp44, NKp46, NKp30 and CD107 using appropriate antibodies. CD56 bright and
dim cells will be also assessed. CD56bright NK cells are associated with cytokine production while CD56 dim
are linked to higher cytotoxic activity (137).
In addition to IL-6 and CRP we identified several other markers for further analyses based on the literature and 
our own immunologic investigations. Specifically, in the aprepitant trial, in addition to IL-6 we also detected a 
decrease in plasma levels of TNFα and soluble CD163 (sCD163) and decreased expression of Programmed 
Death 1 (PD-1) receptor on CD4+ cells. PD-1 is known to suppress T cell activation (138). The assays will be 
done in conjunction with PMHARC Core E. sCD163 and TNF-α will be measured by standard ELISA 
techniques and PD-1 by flow cytometry.  We will use a PD-1 panel established in our laboratory as a part of 
clinical the trial U01 MH090325 (CD3/CD4/CD8/CD45RO/CD197/CD62L/CD95/PD-1/CD38/HLA-DR). We will 
also use the monocyte activation/polarization panel which we have developed (CD3/CD14/CD19/CD56/CD16/ 
CD163/CD97/CD312/CD38/HLA-DR). Further we will quantitate expression of CD4, CCR5, and CXCR4 
receptors on PBMCs and macrophages to evaluate SSRI effect we observed ex vivo (see C1.9.c). We will 
measure both fluid phase (plasma) and cellular markers of innate immunity and inflammation using multiplex 
and flow cytometry technology. These measures will be performed on stored plasma samples and 
cryopreserved PBMCs. 
We expect to find undetectable levels of virus in plasma (<40 copies/ml) in most subjects because all subjects 
will be on a stable cART regimen. Therefore, data on plasmas viral load will be used primarily for monitoring 
cART adherence. In contrast, we expect to find low but detectable levels of viral DNA in most subjects. 
Restoration of NK functions may lead to decreased viral DNA levels. We will analyze if such a decrease is 
linked to SSRI treatment or improvement of depression in general. We will also establish a repository of 
plasma and frozen PBMC samples from the 180 depressed HIV+ subjects. This repository will allow us to 
evaluate other markers associated with depression and/or chronic HIV infection such as oxidative stress (e.g. 
malondealdedyde), markers of monocyte activation (e.g. neopterin) and any other newly identified molecules 
during the period of the current study. We will evaluate monocyte activation/polarization profile since we expect 
that changes in plasma cytokines may affect monocyte polarization which in turn may influence both 
depression and HIV infection (30-33). 
Effects of patient characteristics: Differences in patient demographics (such as age and gender) and 
characteristics (such as depression severity, levels of life stress, social support, neurocognitive capacity, time 
since HIV diagnosis, endocrine status, and systemic inflammation level) could potentially moderate the effects 
of SSRI treatment on our primary outcomes. Some research has suggested that baseline levels of CRP (139),  
IL-6 and TNF-α (7, 86, 140, 141) and of other biological indicators (7, 86, 132) may influence the effects of 


3.10.2015 – 5:00pm 
4 
SSRI on depression. We will perform a series of moderator analyses (142) to address these questions. The 
potential moderators will be included as main effects and as interactions with group in the analyses described 
above for the primary responses. We will use multivariate analyses analogous to the univariate analyses to 
examine SSRI effects on a wider range of biological responses to include endocrine hormones (cortisol, ACTH, 
DHEA), as well as the flow cytometry panels noted above. 
C.5 Missing Data and Nonadherence  For the primary analyses described above, premature discontinuation
from treatment and occasional missing weekly appointments will lead to incomplete data. The mixed effects
models for Aim 1, Hypothesis 1 described above can make use of all available data provided by subjects, but
the inferences drawn from them will be unaffected by the missing data only if the missing data can be regarded
as ignorable. For the other primary responses, dropouts will not provide any responses, so the basic models
require ignorable dropout. To assess the sensitivity of our analyses to this assumption, we will also use
selection models (143) to examine the effects of missing data: we will explicitly model the probability of
premature discontinuation at a time point as a function of baseline characteristics and responses at previous
time points, using a logistic regression model. For the longitudinal analyses of Aim 1, Hypothesis 1, these
probabilities will provide time varying (inverse) weights for reruns of the primary analysis. For the other primary
hypotheses, the overall probability of dropout will be used as a weight, and incorporated into a weighted
analysis of these hypotheses. We will perform these analyses in a range of assumptions on the dropout
process and assess the sensitivity of results to them. To account for possible non-adherence to assigned
intervention, we will use self-report of pill ingestion and MEMS caps, as well as RNA viral load for cART. We
will use the methods of Nagelkerke et al (144, 145), to obtain estimates of the intervention effect in a
population compliant with treatment i.e. the Complier Average Causal Effect (CACE).
C.6 Data Management  Data will be gathered using an internet-based direct-entry data system developed and
used over the last ten years by the U Penn Center for Studies on Addictions in the Department of Psychiatry.
Interview data and self-report data are entered directly onto computers at the research sites by research
technicians and study subjects respectively. Field validation (e.g., no out-of-range or otherwise invalid
responses will be accepted) and form validation (e.g., logically impossible responses to different questions will
not be accepted) are built into this entry process. Data are transmitted (128-bit encrypted form) over the
Internet to the DMU servers. After online reviews, the data are archived on secure servers located in the U
Penn School of Medicine Data Center. No identifying information is stored on the DMU servers. Certain DMU
staff members have permission to modify the archived data. Audit logs record any modification to the original
entry. Password protection allows members of the research team appropriate levels of data access.


3.10.2015 – 5:00pm 
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