Clinical trial NCT02017535
Conditions: Adolescent Depression
Sponsor: University of Minnesota
Start date: 2012-06-01; Completion date: 2018-10-01
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Aim 1: Assess the feasibility and acceptability of the personalized continuation treatment strategy.

Aim 2: Estimate variances of primary and secondary outcomes with the continuation treatment.

Aim 3: Conduct exploratory hypothesis-generating analyses to inform further development of the personalized continuation treatment strategy to be tested in a subsequent R01 proposal.

Detailed description:
Male and female adolescents (ages 12-18) will be eligible for the study if they completed acute phase treatment and showed at least a partial response to treatment (CGI-I of minimally improved or better (CGI-I \< 3)). Adolescents will enter continuation treatment having either received 12 sessions of IPT-A, 16 sessions of IPT-A, or 12 sessions of IPT-A plus fluoxetine.This is a continuation of the study "An Adaptive Treatment Strategy for Adolescent Depression (PTAD)" NCT01802437

Arms: arm 1: Participants in this group will receive interpersonal psychotherapy for adolescents (IPT-A) only.

During the Continuation IPT-A sessions, the therapist will continue to emphasize the interpersonal strategies that were learned and practiced during the acute phase, and address any current interpersonal problems before they result in a recurrence of depressive symptoms. Adolescents who have responded to acute phase treatment (CGI-I = much improved or very much improved) will attend 4 biweekly IPT-A sessions followed by 2 monthly sessions. arm 2: Participants in this group will receive interpersonal psychotherapy for adolescents (IPT-A) and fluoxetine treatment.

Adolescents who have responded to acute phase treatment (CGI-I = much improved or very much improved) will attend 4 biweekly IPT-A sessions followed by 2 monthly sessions and will continue their acute phase fluoxetine dosing regimen and will meet with the psychiatrist on a monthly basis. arm 3: Participants in this group will receive interpersonal psychotherapy for adolescents (IPT-A) and fluoxetine treatment.

Adolescents who received only IPT-A during acute phase and who showed a partial response (CGI-I = minimally improved) will attend 8 weekly IPT-A sessions followed by 2 monthly sessions and will begin treatment with fluoxetine during the continuation phase.The dosage schedule will be 10mg per day for the first week and 20mg per day for the following 5 weeks. If no treatment response is observed by the 6th week, the dosage can be increased to 40mg per day. Pharmacotherapy sessions will be scheduled weekly for the first 4 weeks and biweekly thereafter. Pharmacotherapy sessions will include assessment of vital signs, adverse effects, safety, and symptomatic response. arm 4: Participants in this group will receive interpersonal psychotherapy for adolescents (IPT-A) and fluoxetine treatment.

Adolescents who received IPT-A and fluoxetine during the acute phase and were partial responders (CGI-I = minimally improved) will attend 8 weekly IPT-A sessions followed by 2 monthly sessions and will have their fluoxetine dose increased to 60mg. Partial responders will meet with the psychiatrist biweekly for the first 2 months and monthly for the second 2 months.
Interventions: intervention 1: Fluoxetine intervention 2: Interpersonal Psychotherapy
Intervention descriptions: intervention 1: Prozac (fluoxetine capsules, USP) is a selective serotonin reuptake inhibitor for oral administration. intervention 2: Type of talk therapy that focuses on an adolescents relationship and communication skills in the context of of their depression.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
University of Minnesota  
 
 
 
 
 
 A PERSONALIZED APPROACH TO ACHIEVING A 
SUSTAINED RESPONSE TO TREATMENT FOR 
ADOLESCENT DEPRESSION 
Phase II, pilot study, open trial 
 
 
 
Regulatory Sponsor: 
Meredith Gunlicks-Stoessel 
Department of Psychiatry 
University of Minnesota 
Funding Sponsor: 
Minnesota Medical Foundation (MMF), University of 
Minnesota Office of the Vice President for Research 
Study Product: 
Interpersonal Psychotherapy for Depressed 
Adolescents (IPT-A) and Prozac (Fluoxetine) 
Protocol Number: 
N/A 
UMN IRB code: 
1206M15365 
 
 
 
 
 
Date updated: 7-6-15 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of the University of Minnesota.  
No part of it may be transmitted, reproduced, published, or used by other persons 
without prior written authorization from the study sponsor. 


 
 
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CONFIDENTIAL 
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Table of Contents 
INFORMATION RESOURCES ................................................................................................................................. 1 
STUDY SUMMARY .................................................................................................................................................... 2 
1 
INTRODUCTION ............................................................................................................................................... 4 
1.1 
BACKGROUND ............................................................................................................................................. 4 
1.2 
INVESTIGATIONAL AGENT ........................................................................................................................... 5 
1.3 
CLINICAL DATA TO DATE ............................................................................................................................ 9 
1.4 
DOSE RATIONALE AND RISK/BENEFITS ..................................................................................................... 9 
2 
STUDY OBJECTIVES .................................................................................................................................... 10 
3 
STUDY DESIGN .............................................................................................................................................. 10 
3.1 
GENERAL DESIGN .................................................................................................................................... 10 
3.2 
PRIMARY STUDY ENDPOINTS ................................................................................................................... 13 
3.3 
SECONDARY STUDY ENDPOINTS ............................................................................................................. 13 
3.4 
PRIMARY SAFETY ENDPOINTS ................................................................................................................. 13 
4 
SUBJECT SELECTION AND WITHDRAWAL........................................................................................... 13 
4.1 
INCLUSION CRITERIA ................................................................................................................................ 13 
4.2 
EXCLUSION CRITERIA ............................................................................................................................... 13 
4.3 
SUBJECT RECRUITMENT AND SCREENING .............................................................................................. 13 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ........................................................................................................ 13 
4.4.1 
When and How to Withdraw Subjects ............................................................................................ 13 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .............................................................. 14 
5 
STUDY DRUG ................................................................................................................................................. 14 
5.1 
DESCRIPTION ............................................................................................................................................ 14 
5.2 
TREATMENT REGIMEN .............................................................................................................................. 14 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ............................................................ 145 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG .......................................................................... 15 
5.5 
SUBJECT COMPLIANCE MONITORING ...................................................................................................... 15 
5.6 
PRIOR AND CONCOMITANT THERAPY ...................................................................................................... 15 
5.7 
DRUG SUPPLY .......................................................................................................................................... 15 
6 
STUDY PROCEDURES ................................................................................................................................. 16 
7 
STATISTICAL PLAN ...................................................................................................................................... 16 
7.1 
SAMPLE SIZE DETERMINATION ................................................................................................................ 16 
7.2 
STATISTICAL METHODS ............................................................................................................................ 16 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS .............................................................................................. 167 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................................. 18 
8.1 
DEFINITIONS ............................................................................................................................................. 18 
8.2 
RECORDING OF ADVERSE EVENTS .......................................................................................................... 19 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS ........................................................................................... 20 
8.3.1 
Study Sponsor Notification by Investigator ................................................................................... 20 
8.3.2 
IRB Notification by Investigator ....................................................................................................... 21 
8.3.3 
FDA Notification by Sponsor ........................................................................................................... 21 
8.4 
STOPPING RULES ..................................................................................................................................... 21 
8.5 
MEDICAL MONITORING ............................................................................................................................. 22 
8.5.1 
Internal Data and Safety Monitoring Board ................................................................................... 22 
9 
DATA HANDLING AND RECORD KEEPING ........................................................................................... 23 
9.1 
CONFIDENTIALITY ..................................................................................................................................... 23 
9.2 
SOURCE DOCUMENTS .............................................................................................................................. 24 
9.3 
RECORDS RETENTION .............................................................................................................................. 25 


 
 
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10 
STUDY MONITORING, AUDITING, AND INSPECTING.......................................................................... 25 
10.1 
STUDY MONITORING PLAN ....................................................................................................................... 25 
10.2 
AUDITING AND INSPECTING ...................................................................................................................... 26 
11 
ETHICAL CONSIDERATIONS ..................................................................................................................... 26 
12 
STUDY FINANCES ......................................................................................................................................... 27 
12.1 
FUNDING SOURCE .................................................................................................................................... 27 
12.2 
CONFLICT OF INTEREST ........................................................................................................................... 27 
12.3 
SUBJECT STIPENDS OR PAYMENTS ......................................................................................................... 27 
13 
PUBLICATION PLAN .................................................................................................................................... 27 
14 
REFERENCES ................................................................................................................................................ 28 
 


 
 
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List of Abbreviations 
 
 
AE 
 
Adverse Event 
CC 
 
Cubic Centimeters 
CDRS  
Children’s Depression Rating Scale 
CFR  
Code of Federal Regulations 
CGI 
 
Clinical Global Impressions 
CMRR 
Center for Magnetic Resonance Research 
CRF  
Case Report Form 
CTSI  
Clinical and Translational Science Institute 
 
DSMB  
Data and Safety Monitoring Board 
DSMP  
Data and Safety Monitoring Plan 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
IDS 
 
Investigational Drug Services 
IRB 
 
Institutional Review Board 
KG 
 
Kilogram 
K-SADS-PL Kiddie-Sads-Present and Lifetime 
MDD  
Major-Depressive Disorder 
MEG  
Magnetoencephalography 
MG 
 
Milligram 
ML 
 
Milliliter 
MMC  
Mayo Mail Code 
MRI 
 
Magnetic Resonance Imaging 
MRS  
Magnetic Resonance Spectroscopy 
NOS  
Not Otherwise Specified 
PET  
Positron Emission Tomography 
PHA  
Phytohemagglutinin 
PHI 
 
Protected Health Information 
PI 
 
Principal Investigator 
SAE  
Serious Adverse Event 
TRD  
Treatment-Resistant Depression 
VA 
 
Veterans’ Affairs 


Clinical Research Protocol Template 
 
Page 1 
Version 18SEP08 
Information Resources 
 
 
 
 
 
 
        Name / Address 
  Phone / Fax / E-mail 
Principal Investigator  
 
Meredith Gunlicks-Stoessel        612-273-9844 
 
 
 
 
 
      2450 Riverside Ave 
     mgunlick@umn.edu 
 
 
 
 
 
  Minneapolis, MN 55454 
 
 
Questions concerning eligibility            Ana Westervelt  
 
612-626-7065 
 
 
 
 
              2450 Riverside Ave             Bortn005@umn.edu 
                                                      Minneapolis, MN 55454 
 
For patient enrollment                          Ana Westervelt 
 
 
Questions concerning drug ordering,      Ana Westervelt 
Shipment, transfer or returns 
 
 
Lab shipping or requests                       Ana Westervelt 
 
 
Submission of data forms /                    Ana Westervelt 
Questions on data management 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Study Summary 
Title 
A Personalized Approach to Achieving a Sustained Response to 
Treatment for Adolescent Depression 
Short Title 
PTAD GIA 
Protocol Number 
1206M15365 
Phase 
2 
Methodology 
open label pilot 
Study Duration 
3 years 
Study Center(s) 
Single-center 
Objectives 
To develop and assess the feasibility, acceptability, and 
preliminary efficacy of a personalized approach to delivering 
continuation treatment 
Number of 
Subjects 
30 
Diagnosis and 
Main Inclusion 
Criteria 
Male and female adolescents (ages 12-18) will be eligible for the 
study if they completed acute phase treatment and showed at 
least a partial response to treatment (CGI-I of minimally improved 
or better (CGI-I < 3)). Adolescents will enter continuation 
treatment having either received 12 sessions of IPT-A, 16 
sessions of IPT-A, or 12 sessions of IPT-A plus fluoxetine. 
Study Product, 
Dose, Route, 
Regimen 
Adolescents who received fluoxetine during the acute phase and 
were responders (CGI-I = much improved or very much improved 
(CGI-I = 1 or 2)) will continue their acute phase dosing regimen 
and will meet with the psychiatrist on a monthly basis. 
Adolescents who received fluoxetine during the acute phase and 
were partial responders (CGI-I = minimally improved (CGI-I = 3)) 
will enter the continuation phase on 40mg fluoxetine, and will 
have their dose increased to 60mg. Adolescents who received 
only IPT-A during acute phase and were partial responders (CGI-
I = minimally improved (CGI-I = 3)) will begin treatment with 
fluoxetine, in addition to continuing their IPT-A treatment. The 
dosage schedule will be 10mg per day for the first week and 
20mg per day for the following 5 weeks. If no treatment response 
is observed by the 6th week, the dosage can be increased to 
40mg per day.15 
Duration of 
administration 
16 weeks  
Reference therapy 
Interpersonal Psychotherapy for Depressed Adolescents (IPT-A) 


 
 
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Statistical 
Methodology 
1. Mean [95% confidence interval] treatment satisfaction for each 
adaptive treatment strategy (ATS) 
 
2. Mean therapy session attendance and dropout rates for each 
ATS. 
 
3. Within-subject change scores in CDRS-R, SAS-SR, and CGAS 
scores for the early and late decision point groups from pre- to 
post-treatment using repeated measures ANOVA. 
 


 
 
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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 
312 or 812 and International Conference on Harmonization guidelines), applicable 
government regulations and Institutional research policies and procedures.  
1.1 Background 
 Adolescent depression is a prevalent and debilitating disorder that places youth at risk 
for suicidality, other psychiatric diagnoses, and significant psychosocial impairment both 
during adolescence and into adulthood.1,2 Research on the treatment of adolescent 
depression has dramatically increased over the past two decades. Two psychotherapies 
meet the American Psychological Association’s criteria for “well-established” treatments 
(interpersonal psychotherapy and cognitive behavioral therapy).3 Fluoxetine, paroxetine, 
sertraline, and escitalopram also have demonstrated efficacy as pharmacological 
treatments.4-8 While the progress in this area has been substantial, the overwhelming 
majority of treatment studies have focused on the acute phase of treatment, that is, the 
phase of treatment focused on initial clinical response and remission of symptoms.9 
However, among the acute treatment studies that have reported long-term follow-up 
data, 25-50% of the adolescents in these studies experienced a depressive relapse 
following the completion of treatment.10-13  
 
The American Academy of Child and Adolescent Psychiatry Practice Parameter for the 
treatment of depression recommends providing continuation treatment following the 
symptom remission achieved during the acute phase of treatment.14 The goals of 
continuation treatment are to consolidate the acute phase treatment response and avoid 
relapse. Research on continuation phase treatment for adolescent depression is 
extremely limited, and as a consequence, this Practice Parameter was based primarily 
on adult treatment studies and clinical consensus.14 The handful of studies with 
adolescents that have examined postacute treatment have found that continuation 
treatment is associated with a decreased risk of relapse,11,15,16 and can facilitate further 
symptom reduction in adolescents who were partial responders to acute phase 
treatment.11,17  
 
One of the primary risk factors for relapse in youth is interpersonal conflict, particularly 
within the adolescent’s family.10,18 As a consequence, it has been recommended that 
continuation treatments for adolescent depression focus not only on the depressive 
symptoms, but on the family conflict and relationship problems that may trigger a 
relapse.19 Interpersonal Psychotherapy for Depressed Adolescents (IPT-A)20 is a 
natural treatment modality for targeting both depressive symptoms and interpersonal 
risk factors. IPT-A is an evidence-based psychotherapy that aims to reduce 
adolescents’ depressive symptoms by helping them improve their relationships and 
interpersonal interactions.21-23 Of note, our group found that the benefits of IPT-A are 
particularly strong for adolescents who report high levels of conflict with their mothers.24 
This finding is significant in light of previous studies that have found that perceived 
parent–adolescent conflict predicted a poorer treatment response.10,25 A continuation 


 
 
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version of IPT-A has not yet been studied in a clinical trial. However, IPT as a 
continuation treatment for adult depression has been investigated, and the results 
indicated that patients had significantly lower relapse rates.26,27 In addition, continuation 
IPT has been found to decrease the impact of negative life events in provoking 
relapse.28 This suggests that continuation versions of IPT-A may be useful for 
preventing the relapse of adolescent depression, as well. 
 
The primary aim of this study is to develop and assess the feasibility and acceptability of 
a personalized approach to delivering continuation treatment for adolescent depression. 
The development of evidence-based guidelines for personalizing treatments has been 
identified as a public health priority29 (NIMH Strategic Plan, 2008, Strategy 3.2: Expand 
and deepen the focus to personalize intervention research). Personalized interventions, 
also known as adaptive treatment strategies, provide empirically-derived guidelines or 
decision rules that recommend when, how, and for whom treatment should be changed 
to meet the needs of individual patients.30,31 Adaptive treatment strategies can, for 
example, operationalize for patients who are responding to a given treatment, what kind 
of treatment plan to follow for the continuation phase of treatment. These decision rules 
are based on patient characteristics and outcomes collected during the treatment 
process, such as patient response and adherence.  
 
We are currently conducting a pilot study of a personalized approach to acute phase 
treatment for adolescent depression (Gunlicks-Stoessel, PI, K23MH090216). 
Adolescents begin treatment with IPT-A and may have their treatment augmented either 
with an increased number of therapy sessions or the addition of fluoxetine if they are 
showing an insufficient response to treatment. The proposed study would examine the 
feasibility and acceptability of extending the adaptive treatment strategy into the 
continuation phase of treatment. There is a clear need for the development and 
empirical examination of continuation treatments for depression in youth. Given the 
significant impact that adolescent depression has on both adolescent and adult 
development and functioning, a continuation treatment that achieves a sustained 
remission and prevents relapse could have considerable public health significance. 
1.2 Investigational Agent 
PROZAC® (fluoxetine capsules, USP) is a selective serotonin reuptake inhibitor for oral 
administration. It is also marketed for the treatment of premenstrual dysphoric disorder 
(Sarafem®, fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α-
trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of 
C17H18F3NO•HCl. Its molecular weight is 345.79.  
 
Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 
mg/mL in water. Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg 
(32.3 μmol), 20 mg (64.7 μmol), or 40 mg (129.3 μmol) of fluoxetine. The Pulvules also 
contain starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive 
ingredients. The 10 and 20 mg Pulvules also contain FD&C Blue No. 1, and the 40 mg 
Pulvule also contains FD&C Blue No. 1 and FD&C Yellow No. 6.  
 


 
 
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PROZAC Weekly™ capsules, a delayed-release formulation, contain enteric-coated 
pellets of fluoxetine hydrochloride equivalent to 90 mg (291 μmol) of fluoxetine. The 
capsules also contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, 
hypromellose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, 
titanium dioxide, triethyl citrate, and other inactive ingredients.  
 
Although the exact mechanism of PROZAC is unknown, it is presumed to be linked to 
its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in 
man have demonstrated that fluoxetine blocks the uptake of serotonin into human 
platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake 
inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, 
and α1-adrenergic receptors has been hypothesized to be associated with various 
anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant 
(TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue 
much less potently in vitro than do the tricyclic drugs.  
 
Systemic Bioavailability — In man, following a single oral 40 mg dose, peak plasma 
concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The 
Pulvule and PROZAC Weekly capsule dosage forms of fluoxetine are bioequivalent. 
Food does not appear to affect the systemic bioavailability of fluoxetine, although it may 
delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, 
fluoxetine may be administered with or without food. PROZAC Weekly capsules, a 
delayed-release formulation, contain enteric-coated pellets that resist dissolution until 
reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. The enteric 
coating delays the onset of absorption of fluoxetine 1 to 2 hours relative to the 
immediate-release formulations. OCHCH2CH2NHCH3• HClF3C21  
 
Weekly Dosing — Administration of PROZAC Weekly once weekly results in increased 
fluctuation between peak and trough concentrations of fluoxetine and norfluoxetine 
compared with once-daily dosing [for fluoxetine: 24% (daily) to 164% (weekly) and for 
norfluoxetine: 17% (daily) to 43% (weekly)]. Plasma concentrations may not necessarily 
be predictive of clinical response. Peak concentrations from once-weekly doses of 
PROZAC Weekly capsules of fluoxetine are in the range of the average concentration 
for 20 mg once-daily dosing. Average trough concentrations are 76% lower for 
fluoxetine and 47% lower for norfluoxetine than the concentrations maintained by 20 mg 
once-daily dosing. Average steady-state concentrations of either once-daily or once-
weekly dosing are in relative proportion to the total dose administered. Average steady-
state fluoxetine concentrations are approximately 50% lower following the once-weekly 
regimen compared with the once-daily regimen. Cmax for fluoxetine following the 90 mg 
dose was approximately 1.7-fold higher than the Cmax value for the established 20 mg 
once-daily regimen following transition the next day to the once-weekly regimen. In 
contrast, when the first 90 mg once-weekly dose and the last 20 mg once-daily dose 
were separated by 1 week, Cmax values were similar. Also, there was a transient 
increase in the average steady-state concentrations of fluoxetine observed following 
transition the next day to the once-weekly regimen. From a pharmacokinetic 


 
 
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perspective, it may be better to separate the first 90 mg weekly dose and the last 20 mg 
once-daily dose by 1 week [see Dosage and Administration (2.1)]. 
 
Daily Dosing -- Adult — The efficacy of PROZAC was studied in 5- and 6-week placebo-
controlled trials with depressed adult and geriatric outpatients (≥18 years of age) whose 
diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of 
Major Depressive Disorder. PROZAC was shown to be significantly more effective than 
placebo as measured by the Hamilton Depression Rating Scale (HAM-D). PROZAC 
was also significantly more effective than placebo on the HAM-D subscores for 
depressed mood, sleep disturbance, and the anxiety subfactor.  
 
Two 6-week controlled studies (N=671, randomized) comparing PROZAC 20 mg and 
placebo have shown PROZAC 20 mg daily to be effective in the treatment of elderly 
patients (≥60 years of age) with Major Depressive Disorder. In these studies, PROZAC 
produced a significantly higher rate of response and remission as defined, respectively, 
by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤8. 
PROZAC was well tolerated and the rate of treatment discontinuations due to adverse 
reactions did not differ between PROZAC (12%) and placebo (9%).  
 
A study was conducted involving depressed outpatients who had responded (modified 
HAMD-17 score of ≤7 during each of the last 3 weeks of open-label treatment and 
absence of Major Depressive Disorder by DSM-III-R criteria) by the end of an initial 12-
week open-treatment phase on PROZAC 20 mg/day. These patients (N=298) were 
randomized to continuation on double-blind 23 PROZAC 20 mg/day or placebo. At 38 
weeks (50 weeks total), a statistically significantly lower relapse rate (defined as 
symptoms sufficient to meet a diagnosis of Major Depressive Disorder for 2 weeks or a 
modified HAMD-17 score of ≥14 for 3 weeks) was observed for patients taking 
PROZAC compared with those on placebo.  
 
Pediatric (children and adolescents) — The efficacy of PROZAC 20 mg/day in children 
and adolescents (N=315 randomized; 170 children ages 8 to <13, 145 adolescents 
ages 13 to ≤18) was studied in two 8- to 9-week placebo-controlled clinical trials in 
depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or 
DSM-IV category of Major Depressive Disorder.  
 
In both studies independently, PROZAC produced a statistically significantly greater 
mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score 
from baseline to endpoint than did placebo. Subgroup analyses on the CDRS-R total 
score did not suggest any differential responsiveness on the basis of age or gender.  
 
Weekly dosing for Maintenance/Continuation Treatment--A longer-term study was 
conducted involving adult outpatients meeting DSM-IV criteria for Major Depressive 
Disorder who had responded (defined as having a modified HAMD-17 score of ≤9, a 
CGI-Severity rating of ≤2, and no longer meeting criteria for Major Depressive Disorder) 
for 3 consecutive weeks at the end of 13 weeks of open-label treatment with PROZAC 
20 mg once daily. These patients were randomized to double-blind, once-weekly 
continuation treatment with PROZAC Weekly, PROZAC 20 mg once daily, or placebo. 


 
 
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PROZAC Weekly once weekly and PROZAC 20 mg once daily demonstrated superior 
efficacy (having a significantly longer time to relapse of depressive symptoms) 
compared with placebo for a period of 25 weeks. However, the equivalence of these 2 
treatments during continuation therapy has not been established. 
 
 ------------------------ INDICATIONS AND USAGE ---------------------------  
PROZAC® (fluoxetine hydrochloride) is a selective serotonin reuptake inhibitor 
indicated for:  
• Acute and maintenance treatment of Major Depressive Disorder (MDD) in adult 
and pediatric patients aged 8 to 18 years  
• Acute and maintenance treatment of Obsessive Compulsive Disorder (OCD) in 
adult and pediatric patients aged 7 to 17 years  
• Acute and maintenance treatment of Bulimia Nervosa in adult patients  
• Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients  
  
----------------------- 
DOSAGE AND 
ADMINISTRATION 
---------------------- 
Indication  
Adult  
Pediatric  
MDD (2.1)  
20 mg/day in 
am (initial 
dose)  
10 to 20 
mg/day (initial 
dose)  
Depressive 
Episodes 
Associated with 
Bipolar I Disorder 
(2.5)  
Oral in 
combination 
with 
olanzapine: 5 
mg of oral 
olanzapine 
and 20 mg of 
fluoxetine 
once daily 
(initial dose)  
-  
Treatment 
Resistant 
Depression (2.6)  
Oral in 
combination 
with 
olanzapine: 5 
mg of oral 
olanzapine 
and 20 mg of 
fluoxetine 
once daily 
(initial dose)  
-  
 ---------------------- DOSAGE FORMS AND STRENGTHS ---------------------  


 
 
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• Pulvules: 10 mg, 20 mg, 40 mg (3)  
• Weekly capsules: 90 mg (3) 
1.3 Clinical Data to Date 
Psychotherapy. According to the American Psychological Association’s criteria for 
evaluating the extent to which a particular psychosocial intervention model has 
evidence of treatment efficacy to warrant its dissemination,32,33 interpersonal 
psychotherapy (IPT-A) has been categorized as a “well-established” intervention for 
adolescent depression.3 In clinical trials, depressed adolescents treated with IPT-A 
demonstrated fewer depressive symptoms, better social functioning, and better global 
functioning at the completion of treatment than adolescents in control conditions. 21-23 
 
Pharmacotherapy. Fluoxetine has a treatment response rate of approximately 60% 
4,13,34,35. It is one of two antidepressant medications that has FDA approval for use with 
children and adolescents. 
 
Combined Treatment. Five recent studies have examined the efficacy of a combination 
of psychotherapy and medication in comparison to psychotherapy alone and/or 
medication alone, with response rates ranging from 50-70%.35-39  Three studies found 
that the combined treatment approach was significantly more efficacious in reducing 
depressive symptoms than medication or psychotherapy alone,35-37 whereas the other 
two did not.38,39   
1.4 Dose Rationale and Risk/Benefits 
Adolescents who received fluoxetine during the acute phase and were responders (CGI-
I = much improved or very much improved) will continue their acute phase dosing 
regimen and will meet with the psychiatrist on a monthly basis. Adolescents who 
received fluoxetine during the acute phase and were partial responders (CGI-I = 
minimally improved) will enter the continuation phase on 40mg fluoxetine, and will have 
their dose increased to 60mg.40 Partial responders will meet with the psychiatrist 
biweekly for the first 2 months and monthly for the second 2 months.  Adolescents who 
received only IPT-A during acute phase and were partial responders (CGI-I = minimally 
improved) will begin treatment with fluoxetine during the continuation phase, in addition 
to continuing their IPT-A treatment. The dosage schedule will be 10mg per day for the 
first week and 20mg per day for the following 5 weeks. If no treatment response is 
observed by the 6th week, the dosage can be increased to 40mg per day.41 
Pharmacotherapy sessions will be scheduled weekly for the first 4 weeks and biweekly 
thereafter.  Pharmacotherapy sessions will include assessment of vital signs, adverse 
effects, safety, and symptomatic response. 
 
The major risks of this study are deterioration with study treatment or the experience of 
side effects with fluoxetine, if prescribed. The benefits to the subjects are having 
extensive psychiatric assessments and a possible reduction in depressive symptoms 
and improvement in social and family functioning with study treatment. The treatments 
provided in this study are empirically-supported treatments for adolescent depression. 
Many community clinicians are not trained in evidence-based treatments, and so it is 


 
 
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possible that adolescents seeking treatment from a community clinic might be at a 
greater risk for clinical deterioration and might be less likely to demonstrate a clinical 
improvement than if they received the treatments provided in this study. What is 
experimental in this study is the criteria for initiating a change in the treatment plan, the 
timing of a potential change in the treatment plan, and the type of change to the 
treatment plan. Currently, there are virtually no empirically-derived guidelines to direct 
clinicians in deciding whether, when, or how to alter a treatment plan for adolescent 
depression. Consequently, we expect the relation of the anticipated benefits to the risks 
to be at least as favorable to the subjects as that presented by available non-study 
treatment. 
 
2 Study Objectives 
Aim 1: Assess the feasibility and acceptability of the personalized continuation 
treatment strategy. 
 Hypothesis 1: Adolescents who responded to the acute phase treatment 
provided in the K23 study and their parents will consent to participate in 
continuation treatment. 
 Hypothesis 2: Adolescents will be adherent to continuation treatment and will 
complete the continuation treatment protocol. 
 Hypothesis 3: Adolescents and parents will report satisfaction with continuation 
treatment. 
 Hypothesis 4: Treating clinicians will report satisfaction with continuation 
treatment. 
Aim 2: Estimate variances of primary and secondary outcomes with the continuation 
treatment. 
 Hypothesis 5: Adolescents who were responders to acute treatment will show 
sustained response to continuation treatment. 
 Hypothesis 6: Adolescents who were partial responders to acute treatment will 
show significant improvement in depressive symptoms and social and global 
functioning. 
Aim 3: Conduct exploratory hypothesis-generating analyses to inform further 
development of the personalized continuation treatment strategy to be tested in a 
subsequent R01 proposal. 
3 Study Design 
3.1 General Design 
Adolescents will receive 16 weeks of continuation treatment. They will be treated by the 
same clinicians who provided their acute phase treatment. The personalized 
continuation treatment plan is illustrated below. 
 
Continuation IPT-A. The goal of IPT-A20 is to decrease depressive symptoms by 
focusing on current interpersonal difficulties and helping the individual improve his or her 
relationships and interpersonal interactions. This is accomplished through review of the 


 
 
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adolescent’s significant relationships which leads to the identification of the interpersonal 
problem areas on which to focus the treatment, development of communication and 
interpersonal problem solving skills, and role-playing. During the Continuation IPT-A 
sessions, the therapist will continue to emphasize the interpersonal strategies that were 
learned and practiced during the acute phase, and address any current interpersonal 
problems before they result in a recurrence of depressive symptoms.  Adolescents who 
have responded to acute phase treatment (CGI-I = much improved or very much 
improved) will attend 4 biweekly IPT-A sessions followed by 2 monthly sessions. 
Adolescents who showed a partial response to acute phase treatment (CGI-I = 
minimally improved) will attend 8 weekly IPT-A sessions followed by 2 monthly 
sessions. 
 
Continuation Pharmacotherapy.  Adolescents who received fluoxetine during the acute 
phase and were responders (CGI-I = much improved or very much improved) will 
continue their acute phase dosing regimen and will meet with the psychiatrist on a 
monthly basis. Adolescents who received fluoxetine during the acute phase and were 
partial responders (CGI-I = minimally improved) will enter the continuation phase on 
40mg fluoxetine, and will have their dose increased to 60mg.40 Partial responders will 
meet with the psychiatrist biweekly for the first 2 months and monthly for the second 2 
months.  Adolescents who received only IPT-A during acute phase and were partial 
responders (CGI-I = minimally improved) will begin treatment with fluoxetine during 
the continuation phase, in addition to continuing their IPT-A treatment. The dosage 
schedule will be 10mg per day for the first week and 20mg per day for the following 5 
weeks. If no treatment response is observed by the 6th week, the dosage can be 
increased to 40mg per day.41   Pharmacotherapy sessions will be scheduled weekly 
for the first 4 weeks and biweekly thereafter.  Pharmacotherapy sessions will include 
assessment of vital signs, adverse effects, safety, and symptomatic response. 
 
Assessments.  Assessments will be administered by independent evaluators who are 
blind to treatment condition.  Adolescents will enter continuation treatment at week 16.  
Assessments will be conducted at week 24 and 32. The week 32 evaluation is already 
funded through the K23 study. Assessment measures include the Schedule for 
Affective Disorders and Schizophrenia for School-aged Children-Present and Lifetime 
Version (K-SADS-PL),42 Children’s Depression Rating Scale-Revised (CDRS-R),43 
Columbia Suicide Severity Rating Scale (CSSRS),44 Global Assessment Scale for 
Children (C-GAS),45 Beck Depression Inventory-II (BDI-II),46 Social Adjustment Scale-
Self-report (SAS-SR),47 Conflict Behavior Questionnaire (CBQ),48 and Client 
Satisfaction Questionnaire (CSQ-8).49 
 
 
 
 
 
 
 
 
 


 
 
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R 
R 
PR 
PR 
NR 
NR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IPT-A 
IPT-A plus 
FLX 
Referred out of study 
2 monthly IPT-A sessions 
2 monthly IPT-A sessions 
Continue FLX 
2 monthly IPT-A sessions 
Continue FLX 
2 monthly IPT-A sessions 
Continue FLX 
4 biweekly IPT-A sessions 
8 weekly IPT-A sessions 
Add FLX 
4 biweekly IPT-A sessions 
Continue FLX 
8 weekly IPT-A sessions 
Increase dose FLX 
Referred out of study 
R = Responder (CGI-I = much improved or very much improved), PR = Partial Responder (CGI-I = minimally improved),  
NR = Nonresponder (CGI-I = no change or worsening) 
Treatment Phase 
Assessment 
Acute 
Week 16 
Continuation 
Week 24 
Week 32 


 
 
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3.2 Primary Study Endpoints 
The primary outcome measure is feasibility/acceptability (treatment satisfaction, session 
attendance, drop-out rates) 
3.3 Secondary Study Endpoints 
The secondary outcome measures include depressive symptoms Children’s Depression 
Rating Scale (CDRS), Children’s Global Assessment Scale (C-GAS), Social Adjustment 
Scale (SAS-SR), and response status as defined by Clinical Global Impressions Scale 
(CGI).50 Responders will be defined as having a 1 or 2 (much or very much improved), 
partial responders will be defined as having a 3 (minimally improved) whereas non-
responders will be defined as having a 4-7 on the CGI (minimally improved to very 
much worse). 
3.4 Primary Safety Endpoints 
Primary safety endpoints include suicidality (Columbia Suicide Severity Rating Scale), 
side effects (Side Effects Measure), and vital signs (blood pressure, pulse, weight). 
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
 Male and female adolescents ages 12-18 
 Completed acute phase treatment and showed at least a partial response to 
treatment (CGI-I of minimally improved or better (CGI-I < 3)).50  
4.2 Exclusion Criteria 
 Completed acute phase treatment and were are non-responder to treatment 
(CGI-I of no change or worsening (CGI-I > 4)).  
4.3 Subject Recruitment and Screening 
We will only enroll adolescents who completed acute phase treatment in our linked 
study (Gunlicks-Stoessel, PI, K23MH090216) and showed at least a partial response to 
treatment (CGI-I of minimally improved or better (CGI-I < 3)). Adolescents will enter 
continuation treatment having either received 12 sessions of IPT-A, 16 sessions of IPT-
A, or 12 sessions of IPT-A plus fluoxetine. 
 
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
A subject may be withdrawn from the study prior to expected completion for the 
following reasons:  
 Participant or participant’s parent(s) withdraw consent 
 Participant fails to adhere to protocol requirements (no show to 3 appointments) 


 
 
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 Participant experiences adverse side effects to the fluoxetine that are intolerable 
to the adolescent or the parent.  
 Participant experiences a significant worsening in symptoms: the participant will 
be evaluated by an independent safety monitor if at any time any of the following 
occur: 1) a suicide attempt, 2) serious suicidal ideation (with a plan and/or intent) 
and refusal to contract for safety, 3) psychiatric hospitalization, 4) possible need 
for psychiatric hospitalization, or 5) significant worsening of depressive or other 
clinical symptoms (CDRS-R> 76 or CGI improvement score> 5). Adolescents will 
be removed from the study immediately following review if the independent 
safety monitor deems that the patient requires treatment outside of study 
protocols or if the treatment provided in the study is contraindicated. 
 
If a subject exits the study for any reason, the participant will be provided with referrals 
to receive treatment out of the protocol. 
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
In the event of subject withdrawal from the treatment, we will ask permission to contact 
the family to continue to complete the study evaluations. Subjects will be determined 
lost to follow-up if they do not respond to 3 phone calls to their primary number.   
 
5 Study Drug  
5.1 Description 
The study drug will come as a tablet that the participant will be advised to take once a 
day, preferably in the morning with a meal.  
5.2 Treatment Regimen 
Adolescents who received fluoxetine during the acute phase and were responders (CGI-
I = much improved or very much improved (CGI-I = 1 or 2)) will continue their acute 
phase dosing regimen and will meet with the psychiatrist on a monthly basis. 
Adolescents who received fluoxetine during the acute phase and were partial 
responders (CGI-I = minimally improved (CGI-I = 3)) will enter the continuation phase 
on 40mg fluoxetine, and will have their dose increased to 60mg.   Partial responders will 
meet with the psychiatrist biweekly for the first 2 months and monthly for the second 2 
months.  Adolescents who received only IPT-A during acute phase and were partial 
responders (CGI-I = minimally improved (CGI-I = 3)) will begin treatment with fluoxetine 
during the continuation phase, in addition to continuing their IPT-A treatment. The 
dosage schedule will be 10mg per day for the first week and 20mg per day for the 
following 5 weeks. If no treatment response is observed by the 6th week, the dosage 
can be increased to 40mg per day.  Pharmacotherapy sessions will be scheduled 
weekly for the first 4 weeks and biweekly thereafter.  Pharmacotherapy sessions will 
include assessment of vital signs, adverse effects, safety, and symptomatic response. 


 
 
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5.3 Method for Assigning Subjects to Treatment Groups 
There is no randomization in this study. Assignment to treatment groups is described 
above (based on CGI-I score). 
5.4 Preparation and Administration of Study Drug 
The study psychiatrist will give the adolescent a prescription for the study medication 
that they will then fill with a licensed pharmacy.  
5.5 Subject Compliance Monitoring 
Adolescents will be given enough pills to last until their next scheduled appointment and 
will be asked to bring back the bottle of pills to each appointment. The study coordinator 
or the psychiatrist will count the number of pills remaining to assess treatment 
adherence. Families will be provided with the study pager number with instructions for 
emergencies during after hours. Families will be advised to call 911 in case of life 
threatening emergencies.  
5.6 Prior and Concomitant Therapy 
Adolescents will not be permitted to take any medications for a psychiatric diagnosis 
other than ADHD. Depressed adolescents with a comorbid diagnosis of ADHD who are 
on a stable dose of stimulant medication (> 3 months) will be eligible to participate in the 
studies. Adolescents will not be permitted to participate in alternative forms of 
psychotherapy (e.g. family therapy, group therapy, additional individual therapy). 
5.7 Drug Supply 
The psychiatrist will give the adolescent a prescription for the study medication that they 
will then fill with a licensed pharmacy. If the families’ insurance company does will not 
cover the cost of the medication, the family will need to pay for the medication out of 
pocket.  
 
The following products are manufactured by Eli Lilly and Company for Dista Products 
Company: Pulvule are available in 10mg, 20mg and 40mg capsule strengths and 
packages as follows:  
Pulvule Strength  
 
10 mg1  
                             20 mg1                     40 
mg1                 
Pulvule No.2  
PU3104  
PU3105  
PU3107  
Cap Color  
Opaque green  
Opaque green  
Opaque 
green  
Body Color  
Opaque green  
Opaque yellow  
Opaque 
orange  
Identification  
DISTA 3104  
Prozac 10 mg 
DISTA 3105  
                    Prozac 20 mg 
DISTA 3107  
Prozac 40 
mg  
 


 
 
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6 Study Procedures 
Continuation IPT-A. Adolescents who have responded to acute phase treatment (CGI-I 
= much improved or very much improved)  will attend 4 biweekly IPT-A sessions 
followed by 2 monthly sessions. Adolescents who showed a partial response to acute 
phase treatment (CGI-I = minimally improved) will attend 8 weekly IPT-A sessions 
followed by 2 monthly sessions. 
 
Continuation Pharmacotherapy.  Adolescents who received fluoxetine during the acute 
phase and were responders (CGI-I = much improved or very much improved) will 
continue their acute phase dosing regimen and will meet with the psychiatrist on a 
monthly basis. Adolescents who received fluoxetine during the acute phase and were 
partial responders (CGI-I = minimally improved) will enter the continuation phase on 
40mg fluoxetine, and will have their dose increased to 60mg. Partial responders will 
meet with the psychiatrist biweekly for the first 2 months and monthly for the second 2 
months.  Adolescents who received only IPT-A during acute phase and were partial 
responders (CGI-I = minimally improved) will begin treatment with fluoxetine during 
the continuation phase, in addition to continuing their IPT-A treatment. The dosage 
schedule will be 10mg per day for the first week and 20mg per day for the following 5 
weeks. If no treatment response is observed by the 6th week, the dosage can be 
increased to 40mg per day. Pharmacotherapy sessions will be scheduled weekly for 
the first 4 weeks and biweekly thereafter.   
 
Assessments.  Adolescents will enter continuation treatment at week 16.  Assessments 
will be conducted at week 24 and 32. The week 32 evaluation is already funded 
through the K23 study.  
 
7 Statistical Plan 
7.1 Sample Size Determination 
Statistical experts warn against over-interpreting pilot data for estimating power and 
effect sizes for larger clinical trials.51 Consequently, the proposed research study does 
not aim to evaluate the efficacy of the adaptive treatment strategies. Rather, the sample 
size was determined by the study aims which are to demonstrate the feasibility and 
acceptability of implementing the adaptive treatment strategies. With these aims in 
mind, an intent-to-treat sample size of 30 was selected. A sample size of 30 will help 
ensure there are enough depressed adolescents in each adaptive treatment strategy to 
assess feasibility and acceptability. 
 
7.2 Statistical Methods 
All statistical analyses will be conducted on the intent-to-treat sample. 
 Hypothesis 1: Among families in the acute phase study who are eligible to 
participate in continuation treatment, the percentage of adolescents and parents 


 
 
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who consent to participate in the continuation treatment, and associated 95% 
confidence intervals will be calculated. 
 Hypothesis 2: The mean/median (depending on the distribution) number and 
proportion of sessions attended by adolescents, as well as the associated 95% 
confidence intervals, will be calculated. The proportion of adolescents dropping 
out of treatment prematurely, and the associated 95% confidence interval, will 
be calculated. 
 Hypothesis 3: An overall mean treatment satisfaction rating, and associated 95% 
confidence interval, will be calculated based on adolescents’ and parents’ 
responses on the CSQ-8. 
 Hypothesis 4: An overall mean treatment satisfaction rating and the associated 
95% confidence interval will be calculated based on clinicians’ response on the 
clinician satisfaction measure. 
 Hypotheses 5 & 6: (1) Primary analyses will examine within-subject change 
scores in CDRS, C- SSRS and CGAS over the course of acute and continuation 
treatment using repeated measures analysis of variance (ANOVA). Linear 
regression and analysis of covariance (ANCOVA) adjusting for pre-treatment 
scores will also be used to analyze changes in adolescents’ outcomes. The 
magnitudes of changes in outcomes variables over time will be assessed using 
the paired t-test or Wilcoxon signed-rank test for continuous variables.  Mixed-
effects regression models will also be employed to compare CDRS, C-SSRS, 
and CGAS scores over multiple time points in order to obtain information on 
specific patterns of change over time. (2) Secondary analyses comparing within-
subjects change scores across treatment groups on self-report measures of 
depression (BDI-II) and functioning (CBQ, SAS-SR) will be conducted using two- 
sample t-test, Wilcoxon rank sum test, and linear regression analysis. 
Hierarchical linear modeling (HLM) will also be conducted to compare scores 
over multiple time points within each treatment group. (3) Recovery will be 
defined as an absence of depression symptoms on the KSADS-PL for at least 8 
weeks. Relapse will be defined as the reemergence of 5 or more symptoms of 
depression on the KSADS-PL. The percentage of adolescents who meet 
recovery criteria, and associated 95% confidence interval will be calculated. 
The percentage of adolescents who meet relapse criteria, and associated 95% 
confidence interval will be calculated. For those with a relapse, the mean (SD) 
time from recovery to relapse will be calculated. 
 
Exploratory Analyses: Exploratory analyses will be conducted to determine whether 
comorbid psychiatric disorders, baseline severity of depression, and different forms of 
functioning (CBQ, SAS-SR, CGAS) predict or moderate positive or negative treatment 
outcomes. Potential predictors and moderators will be used to refine the personalized 
treatment strategy that will be tested in the subsequent R01. 
7.3 Subject Population(s) for Analysis 
All populations. 
 


 
 
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8 Safety and Adverse Events 
8.1 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops 
or worsens in severity during the course of the study.  Intercurrent illnesses or 
injuries will be regarded as adverse events.  Abnormal results of diagnostic 
procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse 
event (SAE ) is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, 
but are clearly of major clinical significance.   They may jeopardize the subject, and 
may require intervention to prevent one of the other serious outcomes noted 
above.  For example, drug overdose or abuse, a seizure that did not result in in-
patient hospitalization, or intensive treatment of bronchospasm in an emergency 
department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be 
regarded as non-serious adverse events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally 
defined as the period from the initiation of any study procedures to the end of the 
study treatment follow-up.  For this study, the study treatment follow-up is defined 
as 30 days following the last administration of study treatment.  
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition will be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
General Physical Examination Findings 


 
 
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At screening, any clinically significant abnormality will be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events 
are resolved, the subject is lost to follow-up, or the adverse event is otherwise 
explained.  At the last scheduled visit, the investigator will instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in this study.   
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any 
one of the following conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to 
confirm the abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management; e.g. 
change of dose, discontinuation of the drug, more frequent follow-up 
assessments, further diagnostic investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization lasting >24 hours or prolonged 
hospitalization should be documented and reported as a serious adverse event 
unless specifically instructed otherwise in this protocol.  Any condition responsible 
for surgery will be documented as an adverse event if the condition meets the 
criteria for and adverse event.    
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for a preexisting condition.  Surgery should not be 
reported as an outcome of an adverse event if the purpose of the surgery 
was elective or diagnostic and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease 
of the study, unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator. 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on all 


 
 
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adverse events will be recorded immediately in the source document, and also in the 
appropriate adverse event module of the case report form (CRF).  All clearly related 
signs, symptoms, and abnormal diagnostic procedures results will recorded in the 
source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical 
course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.   Any serious 
adverse event that occurs after the study period and is considered to be possibly related 
to the study treatment or study participation should be recorded and reported 
immediately. 
8.3 Reporting of Serious Adverse Events  
8.3.1 Study Sponsor Notification by Investigator 
A serious adverse event must be reported by telephone within 24 hours of finding 
out of the event.  A Serious Adverse Event (SAE) form must be completed by the 
investigator and faxed to the study sponsor within 24 hours.  The investigator will 
keep a copy of this SAE form on file at the study site.  Report serious adverse 
events by phone and facsimile to: 
 
University of Minnesota, Office of the Vice President of Research  
 facgrant@umn.edu 
(612) 625-2356 
 
Minnesota Medical Foundation 
giving@umn.edu 
(612) 624-3333 
 
At the time of the initial report, the following information should be provided: 
 Study identifier 
 Study Center 
 Subject number 
 Name of the drug/device 
 A description of the event 
 Date of onset 
 Current status (on-going, 
resolved) 
 Whether study treatment was 
discontinued 
 The reason why the event is 
classified as serious 
 Investigator assessment of the 
association between the event 
and study treatment 
 
Within the following 48 hours, the investigator must provide further information on 
the serious adverse event in the form of a written narrative.  This should include 
a copy of the completed Serious Adverse Event form, and any other diagnostic 
information that will assist the understanding of the event.  Significant new 
information of ongoing serious adverse events should be provided promptly to 
the study sponsor. 


 
 
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8.3.2 IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be 
submitted to the IRB within 10 working days if it falls under the UPIRTSO 
guidelines.  
8.3.3 FDA Notification by Sponsor 
The study sponsor shall notify the FDA by telephone or by facsimile transmission 
of any unexpected fatal or life-threatening experience associated with the use of 
the drug as soon as possible but no later than 7 calendar days from the 
sponsor’s original receipt of the information. 
 
If a previous adverse event that was not initially deemed reportable is later found 
to fit the criteria for reporting, the study sponsor will submit the adverse event in a 
written report to the FDA as soon as possible, but no later than 15 calendar days 
from the time the determination is made. 
8.4 Stopping Rules  
Adolescents will enter continuation treatment at week 16.  Assessments will be 
conducted at week 24 and 32.  The adolescent completes the BDI-II at each therapy 
session, and therapists assess suicidality and change in adolescents' clinical status 
using the CGI-I and CGI-S at each therapy session. The subject will be evaluated by  an 
independent safety monitor if at any time any of the following occur: 1) a suicide 
attempt, 2) serious suicidal ideation (with a plan and/or intent) and refusal to contract for 
safety, 3) psychiatric hospitalization, 4) possible need for psychiatric hospitalization, or 
5) significant worsening of depressive or other clinical symptoms (CDRS-R> 76 or CGI 
improvement score> 5). Adolescents will be removed from the study immediately 
following review if the independent safety monitor deems that the patient requires 
treatment outside of study protocols or if the treatment provided in the study is 
contraindicated. In these cases, the family will be provided with referrals to receive 
treatment out of the protocol. 
 
While fluoxetine is generally well tolerated, side effects can occur.  Adverse events will 
be closely monitored during each psychopharmacological treatment visit using the C-
SSRS and the Side Effects forms. The study psychiatrist will review with families the 
following potential fluoxetine related adverse events: gastrointestinal complaints 
(nausea, pain, diarrhea, and constipation), dizziness, allergic reactions, increased 
anxiety or irritability, increased activation/restlessness, sleep changes (increased or 
decreased), sexual side effects, appetite changes (increase or decrease), unusual 
thoughts, sweating, fatigue, suicidal ideation/attempts/and or behaviors. In addition to 
these issues, the study psychiatrist will make the adolescents and their families aware 
of the Food and Drug Administration advisory that the use of antidepressants like the 
SSRIs may lead to suicidal thinking/attempts in depressed youths and that the FDA has 
placed product warning label with information highlighting the need for close 
observation for worsening of depression and the emergence of suicidality in children 
treated with these medications. This information will be a part of the consent process for 
the study so that families are aware of these issues when considering participation in 


 
 
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the study. The study psychiatrist will review with the adolescents and their legal 
guardians, potential adverse events and the need to carefully monitor for any significant 
changes in mood, thinking, behaviors, and physical symptoms especially early in 
treatment. The adolescents and their families will be instructed to call the study 
psychiatrist with any concerns, and to page the PI with any urgent clinical issues that 
emerge in between treatment sessions. The PI will call the study psychiatrist, who will 
follow up with the family. In the event of minor side effects (e.g., mild headaches), the 
medication may be maintained at the current dose levels or reduced. If any adverse 
medication reactions do occur, the medication will be withdrawn and clinical staff will 
follow the patient closely until the adverse reaction remits. 
 
8.5 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at 
his/her site.  This safety monitoring will include careful assessment and appropriate 
reporting of adverse events as noted above, as well as the construction and 
implementation of a site data and safety-monitoring plan (see section 9 Auditing, 
Monitoring and Inspecting).  Medical monitoring will include a regular assessment of the 
number and type of serious adverse events. 
8.5.1 Internal Data and Safety Monitoring Board 
The PI will maximize the safety and privacy of all study participants and ensure the 
integrity, validity, and confidentiality of data collection procedures through regular 
monitoring of clinical and research activities during weekly project meetings with the 
study staff. At the start of each treatment session, clinicians will be required to ask both 
adolescents and parents whether any adverse events or suicidality have occurred in the 
past week. Clinicians will report to the PI any serious or unexpected adverse events, 
unexpected problems that involve risk to the participants or others, and any breaches of 
confidentiality. The PI will report these to the Quorum within 24 hours of their 
occurrence. The PI will also submit an annual progress report to the IRB summarizing 
the data and safety monitoring activities and outlining 1) whether participants’ safety, 
privacy and confidentiality has been consistently assured, 2) whether research 
instruments have been administered in a uniform manner and in a way that protects 
participants’ privacy, 3) progress towards recruitment goals, quality of data collection 
(e.g., appropriate completion of forms), and participant retention/ attrition rates, and 4) a 
review of new scientific literature pertinent to the safety of participants or the ethics of 
research participation. The study psychiatrists, the independent safety monitor, 
psychologists, research clinicians, and clinical interviewers will take all appropriate 
actions to prevent and treat psychiatric emergencies in participating adolescents and 
family members as outlined in the Procedures to Minimize Potential Risks.  
 
On an annual basis, the PI and Dr. Mufson will monitor the safety, quality and conduct 
of this study and decide whether adequate subject safeguards are in place. They will 
review: 1) the progress of the proposed study, including assessments of data quality 
and participant recruitment, accrual and retention; 2) outcome and adverse event data 
to determine whether there is any change to the anticipated benefit-to-risk ratio of study 


 
 
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participation and whether the study should continue, be changed, or terminated; 3) 
external factors or relevant information (e.g., pertinent scientific literature reports or 
therapeutic developments, results of related studies) that may have an impact on the 
safety of study participants or the ethics of the research study; and 4) study procedures 
designed to protect the privacy of the research subjects and the confidentiality of their 
research data. 
 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:  
 What protected health information (PHI) will be collected from subjects in this 
study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (i.e. 
that the subject is alive) at the end of their scheduled study period. 
 
All research forms and audiotapes of the treatment sessions will contain the study 
assigned subject ID number only as identifying information. Research forms and will be 
kept in a locked file cabinet at the University of Minnesota. Clinical records will be kept 
in a separate locked file cabinet at the University of Minnesota. Only research staff and 
the treating clinical staff will have access to the research and clinical files. 
 
Confidentiality will be strictly maintained. In order to safeguard the confidentiality and 
security of data files, computer accounts containing data will be password protected.  
Identifying information, records, and audio/ videotapes of clinical interactions will be 
stored in a locked cabinet in a locked office, only accessible to research staff members; 
a participant identification number will identify all materials. Participant identification 
numbers will be unrelated to participant characteristics (e.g. date of birth, social security 
number), and a list with the pairings of names and identification numbers will be kept in 
a separate password protected document a network drive, separate from the data files 
and tapes. All staff will sign confidentiality statements.  
 


 
 
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All tapes will be coded by subject identification number and date All audio files, none of 
which contain PHI, will be saved on an electronic shared folder to which only research 
staff have access. Audio files are saved for 3 years. During the consent process, 
participants have the ability to request deletion of audio files after three years, or allow 
staff to save the files indefinitely for research purposes. Files will be deleted after 3 
years if the participant chooses the former option.  If the adolescent and the parent 
response differ regarding the retention of audio files for training of future research staff, 
the answer is to retain the audio files is no.  
 
All subjects will be informed during the consent process that their information will be 
kept strictly confidential unless information is revealed suggesting that the subject or 
someone else is in danger (e.g., prostitution, IV drug use, child abuse (see below), 
suicidality, homicidality). Prior to eliciting this information, the child will be fully informed 
that the clinician may need to report such information. Before parents will be made 
aware of this information, our procedure will be to first talk with the child and explain 
what information will be disclosed to parents. Because information relating to abuse will 
be assessed, participants will be informed of the need to report child abuse prior to 
eliciting this information. All staff will follow federal and state child abuse reporting 
requirements. 
 
Participants will be assigned a coded identification number that will be used on all data 
collection measures. To minimize the risk of loss of confidentiality, the data collected in 
this study will be protected by the use of separate data files. The first will include the 
subject consent forms, names, addresses, telephone numbers, date of birth, and 
subject ID. Other databases will include the questionnaire data from the project, and 
participants’ study ID will be the only unique piece of information linking the data files to 
the consent file. Audio files of assessment and treatment sessions will be stored in a 
separate storage area online. Only study IDs will be used to link audio files to 
questionnaire data. These files will all be password protected and accessible to only a 
limited number of project personnel. The collected materials will be used only for 
research purposes; participants’ records with identifying information will not be released 
to anyone without participants’ written permission. The databases will be password 
protected and the database password will be changed on a regular basis. The 
Department’s computing system is protected from outside access. All staff members will 
be required to close password-protected applications or lock their workstations when 
they are away from their desks. All paper forms will be kept in locked file cabinets at the 
University of Minnesota. During data analysis all identifying information, with the 
exception of the participant identification number is removed from the data. No 
information about identities of the study participants will be published or presented at 
conferences. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents   Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 


 
 
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laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial. 
 
Data generated by the methods described in the protocol will be recorded in the 
subjects' medical records and/or study progress notes. Data may be transcribed legibly 
on case report forms supplied for each subject or directly inputted into an electronic 
system or any combination thereof. 
9.3 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 6 
years after the last approval of a marketing application in their country and until there 
are no pending or contemplated marketing applications in their country or at least 6 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  These documents will be retained for a longer period if required 
by an agreement with the sponsor.  In such an instance, it is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer 
need to be retained.  
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be monitored according to FDA/GCP guidelines.  (Explain who will be 
monitoring what sites or self-monitoring according to the U of M plan.  The investigator 
will allocate adequate time for such monitoring activities.  The Investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given 
access to all the above noted study-related documents and study related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the 
monitoring visit. 
 
The PI will maximize the safety and privacy of all study participants and ensure the 
integrity, validity, and confidentiality of data collection procedures through regular 
monitoring of clinical and research activities during weekly project meetings with the 
study staff. At the start of each treatment session, clinicians will be required to ask both 
adolescents and parents whether any adverse events or suicidality have occurred in the 
past week. Clinicians will report to the PI any serious or unexpected adverse events, 
unexpected problems that involve risk to the participants or others, and any breaches of 
confidentiality. The PI will report these to the Internal Review Board (IRB) at the 
University of Minnesota within 24 hours of their occurrence. The PI will also submit an 
annual progress report to the IRB summarizing the data and safety monitoring activities 
and outlining 1) whether participants’ safety, privacy and confidentiality has been 
consistently assured, 2) whether research instruments have been administered in a 


 
 
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uniform manner and in a way that protects participants’ privacy, 3) progress towards 
recruitment goals, quality of data collection (e.g., appropriate completion of forms), and 
participant retention/ attrition rates, and 4) a review of new scientific literature pertinent 
to the safety of participants or the ethics of research participation. The study 
psychiatrists, the independent safety monitor psychologists, research clinicians, and 
clinical interviewers will take all appropriate actions to prevent and treat psychiatric 
emergencies in participating adolescents and family members as outlined in the 
Procedures to Minimize Potential Risks.  
 
On an annual basis, the PI and Dr. Mufson will monitor the safety, quality and conduct 
of this study and decide whether adequate subject safeguards are in place. They will 
review: 1) the progress of the proposed study, including assessments of data quality 
and participant recruitment, accrual and retention; 2) outcome and adverse event data 
to determine whether there is any change to the anticipated benefit-to-risk ratio of study 
participation and whether the study should continue, be changed, or terminated; 3) 
external factors or relevant information (e.g., pertinent scientific literature reports or 
therapeutic developments, results of related studies) that may have an impact on the 
safety of study participants or the ethics of the research study; and 4) study procedures 
designed to protect the privacy of the research subjects and the confidentiality of their 
research data. 
10.2 Auditing and Inspecting 
The investigator will permit study-related audits and inspections by the IRB, the 
sponsor, government regulatory bodies, and University compliance and quality 
assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  The investigator will ensure 
the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable University compliance and quality 
assurance offices. 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the IRB 
concerning the conduct of the study will be made in writing to the investigator and a 
copy of this decision will be provided to the sponsor before commencement of this 
study.  The investigator should provide a list of IRB members and their affiliate to the 
sponsor. 


 
 
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All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  The consent form will be submitted with the protocol for 
review and approval by the IRB for the study.  The formal consent of a subject, using 
the IRB-approved consent form, must be obtained before that subject is submitted to 
any study procedure.  This consent form must be signed by the subject or legally 
acceptable surrogate, and the investigator-designated research professional obtaining 
the consent.  
 
12 Study Finances 
12.1 Funding Source 
This study is financed through grants from the University of Minnesota Foundation and 
University of Minnesota Office of Vice President of Research 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must refer to the Regents Policies on Individual Conflict of Interest Policy or Institutional 
Conflict of Interest Policy. These policies require University Faculty and staff to report 
external professional activities and business and significant financial interests related to 
his or her University activities by submitting a REPA (Report of External Professional 
Activities) at least once per year. Faculty and staff should also file a REPA when 
substantial changes in business or financial interests occur, when an activity that 
presents a potential conflict of interest is anticipated, or when submitting an application 
for research support or technology transfer, submitting research protocols to the IRB, or 
receiving financial contributions. All University of Minnesota investigators will follow the 
University conflict of interest policy. 
12.3 Subject Stipends or Payments 
The adolescent will receive $30 in cash directly after the week 24 evaluation and the 
parent will receive $10 in cash for the week 24 evaluation.  
 
13 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this 
protocol, nor any of the information provided by the sponsor for the purposes of 
performing the study, will be published or passed on to any third party without the 
consent of the study sponsor.  Any investigator involved with this study is obligated to 
provide the sponsor with complete test results and all data derived from the study. 
 


 
 
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14 References 
 
 
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