Clinical trial NCT03390933
Conditions: Depression Hemodialysis-Induced Symptom
Sponsor: MetroHealth Medical Center
Start date: 2018-03-01; Completion date: 2023-02-28
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Depression is present in about 20-30% of hemodialysis patients and is associated with morbidity and mortality. However, depression is inadequately diagnosed and treated among dialysis patients. This is due in part to the overlap between depressive symptoms (e.g. appetite change, trouble sleeping, feeling tired) and symptoms related to persistent metabolic derangements in hemodialysis patients (e.g. nausea, nocturnal cramps, feeling washed out after treatment). The overlap between depressive symptoms and dialysis-related complications makes it difficult to diagnose and therefore to treat depression. In addition, prescription of antidepressant medication may increase an already high pill burden and result in poor adherence. Moreover, the evidence base to guide depression treatment among hemodialysis patients is limited. In the investigators' previous work, they developed methods to use latent variables and structural equation modeling to isolate depressive symptoms. Other investigators have demonstrated that directly observed treatment enhances the effectiveness of tuberculosis and HIV treatment.

Investigators now propose a cross-sectional study (Phase 1) followed by a single-arm clinical trial (Phase 2) at 17 dialysis facilities. The cross-sectional study will involve assessments of depressive symptoms (using the PHQ-9 screening instrument) as well as dialysis-related complications, anxiety, and quality of life (Quality of Life Questionnaire) in about 1083 patients. Investigators will then use structural equation modeling to develop and validate a hemodialysis-specific PHQ-9 (hdPHQ-9) that will isolate depressive symptoms. The trial will involve 96 patients with confirmed depression who will be assigned to directly observed weekly antidepressant treatment with fluoxetine. The primary outcome of the trial will be remission of depression at 12 weeks. The trial results will also be used to compare the responsiveness of the PHQ-9 and the hdPHQ-9. Investigators anticipate that the hdPHQ-9 will be a valid and responsive instrument that will isolate depressive symptoms in hemodialysis patients and ultimately improve the screening and diagnosis of depression. Investigators also expect that directly observed weekly fluoxetine treatment will be an effective way to manage depression among hemodialysis patients.

Detailed description:
Depression is present in about 20-30% of hemodialysis patients and is associated with morbidity and mortality. However, depression is inadequately diagnosed and treated among dialysis patients. This is due in part to the overlap between depressive symptoms (e.g. appetite change, trouble sleeping, feeling tired) and symptoms related to persistent metabolic derangements in hemodialysis patients (e.g. nausea, nocturnal cramps, feeling washed out after treatment). The overlap between depressive symptoms and dialysis complications makes it difficult to diagnose and therefore to treat depression. In addition, prescription of antidepressant medication may increase an already high pill burden and result in poor adherence. Moreover, the evidence base to guide depression treatment among hemodialysis patients is limited. In the investigators' previous work, they developed methods to use latent variables and structural equation modeling to isolate depressive symptoms. Other investigators have demonstrated that directly observed treatment enhances the effectiveness of tuberculosis and HIV treatment.

Investigators now propose a cross-sectional study (Phase 1) followed by a single-arm clinical trial (Phase 2) at 17 dialysis facilities. The cross-sectional study will involve assessments of depressive symptoms (using the PHQ-9 screening instrument) as well as dialysis-related complications, anxiety, and quality of life (Quality of Life Questionnaire) in about 1083 patients. The investigators will then use structural equation modeling to develop and validate a hemodialysis-specific PHQ-9 (hdPHQ-9) that will isolate depressive symptoms. The trial will involve 96 patients with confirmed depression who will be assigned to directly observed weekly antidepressant treatment with fluoxetine. The primary outcome of the trial will be remission of depression at 12 weeks. The trial results will also be used to compare the responsiveness of the PHQ-9 and the hdPHQ-9.

The investigators anticipate that the hdPHQ-9 will be a valid and responsive instrument that will isolate depressive symptoms from dialysis complications and ultimately improve the screening and diagnosis of depression. They also expect that directly observed weekly fluoxetine treatment will be an effective way to manage depression among hemodialysis patients.

Innovative features of the proposed project include the use of latent variables to address overlap, administration of a long acting weekly antidepressant, and directly observed treatment. The project has the potential not only to improve the diagnosis and management of depression among hemodialysis patients but also to improve their morbidity and mortality. Furthermore, it may serve as a model for future studies to isolate symptoms among overlapping medical conditions.

Aim A. To develop and validate a self-reported depression screening instrument that isolates depressive symptoms from hemodialysis-related complications.

Hypothesis: A hemodialysis-specific PHQ-9 (hdPHQ-9) will isolate depressive symptoms from dialysis complications.

Aim B. To determine the impact of directly observed weekly fluoxetine treatment on remission of depression among hemodialysis patients.

Hypothesis: About half of patients who have directly observed fluoxetine treatment will have remission of depression.

Aim C. To examine the responsiveness of the new depression screening instrument to depression treatment.

Hypothesis: Fluoxetine treatment will be associated with larger improvements in hdPHQ-9 scores than in PHQ-9 scores.

Arms: arm 1: Approximately 96 patients will be enrolled into the intervention (Phase II) over the duration of the entire study.
Interventions: intervention 1: Fluoxetine
Intervention descriptions: intervention 1: Patients enrolled into Phase II will be prescribed 2 weeks of short-acting fluoxetine 20 mg and will be instructed to take the prescription daily for 2 weeks. Then patients will be prescribed 10 additional weeks of 90 mg (weekly) fluoxetine and will be observed taking it once weekly at the dialysis unit. At the end of the 12 week study period, participants will be provided 4 additional weeks of 90 mg fluoxetine in order to provide sufficient time to follow up with their primary care physician or nephrologist.

Protocol documents:
ICF_002.pdf: 
 
METROHEALTH MEDICAL CENTER 
 
Human Investigation Consent Form  
 
 
 
 
 
Treating Depression among Hemodialysis 
Patients – Consent Form 
 
Page 1 of 10 
 
November 20, 2017 
 
 
  
HUMAN INVESTIGATION CONSENT FORM 
 
HUMAN INVESTIGATION CONSENT FORM 
 
TITLE: TREATING DEPRESSION AMONG HEMODIALYSIS PATIENTS 
 
 
 
 
 
Introduction 
 
You are being asked to participate in a research study. Before you can decide whether or not to 
volunteer for this study, you must be given information about the purpose of the research study, how 
this study may help you, any risks to you, and what is expected of you.  This process is called 
informed consent. 
 
You were chosen as a possible participant for this study because you are on hemodialysis and you 
have been diagnosed with depression. The goal of the study is to compare two strategies for treating 
depression among hemodialysis patients. 
 
You do not have to participate in this study.  You may stop your participation in this study at any time 
without changing your current or future relations with MetroHealth Medical Center, the Centers for 
Dialysis Care (CDC), or its medical providers.  
 
If you decide to participate in this study you will be told about any new information learned during the 
course of the study that might cause you to change your mind about staying in the study. If you decide 
to withdraw, we will still provide you with information regarding possible impacts to your health status or 
future health care decisions. 
 
 
Why is this study being done? 
 
Depression can be difficult to diagnose and treat among dialysis patients.  This is due in part to overlap 
between symptoms of depression (such as poor appetite, trouble sleeping, feeling tired) and symptoms 
related to kidney failure or dialysis treatment (such as nausea, nighttime cramps, feeling washed out 
after treatment).  This overlap makes it difficult to diagnose and therefore to treat depression.  In 
addition, most dialysis patients already take a number of different medications, and adding another 
medication for depression will further increase the number of medications they have to take.  Moreover, 
treatments for depression have been less well studied among dialysis patients than among the general 
population.  
 
The purpose of this study is to compare two strategies for treating depression among hemodialysis 
patients. One strategy is referring patients to a mental health provider for treatment.  The other strategy 
is taking the antidepressant medication fluoxetine on a weekly basis during dialysis treatment.  
Fluoxetine is approved by the U. S. Food and Drug Administration (FDA) and has been used for many 
years in the treatment of depression. 


 
METROHEALTH MEDICAL CENTER 
 
Human Investigation Consent Form  
 
 
 
 
 
Treating Depression among Hemodialysis 
Patients – Consent Form 
 
Page 2 of 10 
 
November 20, 2017 
 
 
  
HUMAN INVESTIGATION CONSENT FORM 
 
HUMAN INVESTIGATION CONSENT FORM 
 
 
How many people will take part in the study? 
This study will take place at up to 17 Centers for Dialysis Care (CDC) dialysis facilities in Northeast 
Ohio.  A total of about 216 hemodialysis patients will be asked to participate in this study.  Participants 
will not necessarily be MetroHealth Medical Center patients, but rather come from a wide range of other 
practices and institutions in Northeast Ohio.   
 
What is involved in the study? 
 
You will be asked to read and sign this consent form after all your questions have been answered.  A 
copy of the consent will be provided to you for your records. Your participation in this study is expected 
to last about 12 weeks.   All study tasks will take place during regularly scheduled dialysis treatments. If 
you choose to participate, you will be randomly selected to be placed into one of two groups. 
Randomization is like flipping a coin to decide which group you will be in. Neither you nor your doctor(s) 
can choose the group you will be in. You have an equal chance of being in one or the other group.  
 
All study participants will do the following: 
 
• 
You will be asked to complete one questionnaire on day 3 and during weeks 1, 2, 4, 6, 8 10 
and 12. The questions will be read to you by a study team member. The name of the 
questionnaire is: 
 
o Patient Health Questionnaire (PHQ-9): there are 9 questions that ask about 
symptoms related to mood and depression.  This takes about 5 minutes to complete.  
 
• 
You will be asked to complete two additional questionnaires during week 12. The questions will 
be read to you by a study team member. The names of the questionnaires are: 
 
o Kidney Disease and Quality of Life (KDQOL-36): there are 47 questions that ask 
about your health and quality of life. This takes about 15 minutes to complete. 
 
o Mini International Neuropsychiatric Interview (MINI): the MINI is a semi-structured 
interview that asks about mental health symptoms that are going on now or in the past. 
This takes about 1 hour to complete.  
 
 
 


 
METROHEALTH MEDICAL CENTER 
 
Human Investigation Consent Form  
 
 
 
 
 
Treating Depression among Hemodialysis 
Patients – Consent Form 
 
Page 3 of 10 
 
November 20, 2017 
 
 
  
HUMAN INVESTIGATION CONSENT FORM 
 
HUMAN INVESTIGATION CONSENT FORM 
If you are randomly selected to be in the referral group: 
 
• 
You will be given a list of local mental health providers who specialize in treating depression 
and will be encouraged to seek treatment from one of them. 
 
• 
If you prefer, you can also ask your nephrologist or primary care physician for treatment or 
advice.   
 
• 
We will let your nephrologist or primary care doctor know about your depression diagnosis. 
 
If you are randomly selected to be in the fluoxetine group: 
 
• 
You will be given a prescription of daily 20 milligram (mg) fluoxetine by a psychiatric nurse 
practitioner.  You will be instructed to take one 20 mg pill once a day for two weeks.  A study 
team member will periodically ask you questions about your adherence to the medication.  
Your nephrologist or primary care doctor will continue to make decisions about other 
medications that you are taking. 
 
You will be asked to keep your fluoxetine pills in a pill box. If you don’t have a pill box, we will 
provide one for you. You will be asked to bring the pill box with you each time you go the 
dialysis unit. A member of the study team will call you periodically to remind you to take your 
daily fluoxetine and to bring your pill box to the dialysis unit.  
 
• 
During week 3, the psychiatric nurse practitioner will instruct you to stop taking the daily 20 mg 
pills and switch to weekly 90 mg fluoxetine.  You will be given a prescription of weekly 90 mg 
fluoxetine by the psychiatric nurse practitioner.   
 
• 
You will take each dose of weekly 90 mg fluoxetine at the dialysis unit while a study team 
member watches you once a week for 10 weeks. 
 
• 
The psychiatric nurse practitioner will meet with you to monitor side effects and make 
medication adjustments, if needed, throughout the duration of the study. 
 
• 
All the fluoxetine pills that you are asked to take during the study will be provided to you at no 
cost.  
 
o We will ask you to follow some safety precautions.  Fluoxetine must be taken only by 
you.  Keep the fluoxetine in a safe place out of reach of children and other people who 
cannot read well or understand that they should not take it. 
 


 
METROHEALTH MEDICAL CENTER 
 
Human Investigation Consent Form  
 
 
 
 
 
Treating Depression among Hemodialysis 
Patients – Consent Form 
 
Page 4 of 10 
 
November 20, 2017 
 
 
  
HUMAN INVESTIGATION CONSENT FORM 
 
HUMAN INVESTIGATION CONSENT FORM 
• 
At the end of the 12 week study, you will receive a filled 4 week prescription for weekly 
fluoxetine 90 mg and instructions on how to communicate with your nephrologist and/or 
primary care physician about how long to continue taking it. 
 
• 
The psychiatric nurse practitioner will also communicate with your nephrologist and/or primary 
care physician about the need for further treatment. 
 
 
What happens if I stop or withdraw from the study? 
You are free to withdraw from the study at any time. If you withdraw from the study before its 
completion, you will not be asked for any further information.  Your care at the Centers for Dialysis Care 
(CDC) or MetroHealth Medical Center will not be affected. 
If you are randomly selected to be in the fluoxetine group, you may decide to discontinue fluoxetine.      
Discontinuation of fluoxetine is usually mild and more tolerable for patients than discontinuation of 
some other antidepressants.  The most common discontinuation symptoms tend to be flu-like 
symptoms and headache.  The onset of discontinuation symptoms can be within a few days of stopping 
any antidepressant and may take 1 to 2 weeks to resolve.  If you are unable to tolerate the 
discontinuation symptoms of fluoxetine, you will be instructed to contact the study psychiatric nurse 
practitioner, Kelley Kauffman, by study cell phone (216-339-9244).  The nurse practitioner will assess 
the symptoms with you, and then will consult with the study psychiatrist, Dr. Sajatovic, regarding the 
appropriate course of action.  
 
What are the risks of this study? 
 
As you complete the questionnaires, some of the questions we ask may be upsetting, or you may feel 
uncomfortable answering them.  If you do not wish to answer a question, you may skip it and go to the 
next question. If, during the process of being assessed, research staff feel that you are an immediate 
risk of harm to yourself or others, staff will make efforts to make sure that you are safe. This may 
include recommending that you go to the emergency room or consulting with our study psychiatrist (Dr. 
Martha Sajatovic) or your regular doctor or clinician as appropriate. 
 
All antidepressant medications, including fluoxetine, may have side effects.  If you are randomly 
selected to be in the fluoxetine group, the psychiatric nurse practitioner will meet with you to ask 
questions about any possible side effects of fluoxetine (listed below). If you appear to be having trouble 
with side effects, the psychiatric nurse practitioner may adjust the dose of your study medication, or in 
some cases, may instruct you to stop taking fluoxetine. You should call her if you experience serious 
side effects (listed below) between visits. You are also free to stop participating in the study at any time.  


 
METROHEALTH MEDICAL CENTER 
 
Human Investigation Consent Form  
 
 
 
 
 
Treating Depression among Hemodialysis 
Patients – Consent Form 
 
Page 5 of 10 
 
November 20, 2017 
 
 
  
HUMAN INVESTIGATION CONSENT FORM 
 
HUMAN INVESTIGATION CONSENT FORM 
 
Common (greater than 10%) possible side effects of fluoxetine: 
• 
Problems falling and staying asleep 
• 
Headache 
• 
Drowsiness 
• 
Anxiety 
• 
Nervousness 
• 
Yawning 
• 
Nausea 
• 
Diarrhea 
• 
Anorexia 
• 
Dryness of mouth  
• 
Tiredness or weakness  
• 
Tremor or shaking  
• 
Sore throat  
• 
Hot flashes  
 
Uncommon (between 1-10%) possible side effects of fluoxetine: 
• 
Chest pain 
• 
High blood pressure  
• 
Dizziness 
• 
Unusual dreams 
• 
Problems concentrating or thinking  
• 
Loss of memory  
• 
Confusion 
• 
Increased sweating 
• 
Skin rash  
• 
Itching 
• 
Weight loss or weight gain 
• 
Stomach pain or discomfort 
• 
Constipation 
• 
Gas 
• 
Vomiting 
• 
Increased or loss of appetite 
• 
Erectile dysfunction (ED) 
• 
Decreased libido 
• 
Vision problems 
• 
Ear pain 


 
METROHEALTH MEDICAL CENTER 
 
Human Investigation Consent Form  
 
 
 
 
 
Treating Depression among Hemodialysis 
Patients – Consent Form 
 
Page 6 of 10 
 
November 20, 2017 
 
 
  
HUMAN INVESTIGATION CONSENT FORM 
 
HUMAN INVESTIGATION CONSENT FORM 
• 
Ringing in the ears 
• 
Flu-like symptoms 
• 
Sinus infection 
 
Rare (1% or less) but Serious possible side effects of fluoxetine (tell the psychiatric nurse practitioner 
immediately if you experience them): 
 
• 
Feeling agitated, restless, angry or irritable  
• 
Talking more or faster than what is normal for you 
• 
Hallucinations (seeing something that is not really there) 
• 
Coordination problems or muscle twitching  
• 
Very stiff (rigid) muscles 
• 
High fever 
• 
Fast heartbeat 
• 
Tremors 
• 
Seizure 
• 
Severe allergic reaction: trouble breathing, sore throat, rash, blisters, swelling in your face, 
tongue, eyes or mouth 
• 
Severe trouble sleeping 
• 
Racing thoughts  
• 
Reckless behavior  
• 
Unusually grand ideas  
• 
Excessive happiness 
• 
Increased bleeding or bruising 
• 
Thoughts about suicide or dying  
• 
Attempts to commit suicide  
• 
Acting on dangerous impulses (urges)  
• 
Acting aggressive or violent  
• 
Worsening of depression  
• 
New or worse anxiety or panic attacks  
 
 
 
Confidentiality breach 
 
In any instance where protected health information is collected, there is a risk for a breach of 
confidentiality.  Every effort by study staff will be made to keep your information confidential, including 
storing documents in locked file cabinets, encrypted laptop computers, and de-identifying information 
whenever possible.  The risk of a confidentiality breach is rare. 


 
METROHEALTH MEDICAL CENTER 
 
Human Investigation Consent Form  
 
 
 
 
 
Treating Depression among Hemodialysis 
Patients – Consent Form 
 
Page 7 of 10 
 
November 20, 2017 
 
 
  
HUMAN INVESTIGATION CONSENT FORM 
 
HUMAN INVESTIGATION CONSENT FORM 
 
 
Are there benefits to taking part in the study? 
 
It is possible that participating in this study and receiving treatment from a local mental health provider 
or the study psychiatric nurse practitioner will result in a decrease in your depressive symptoms and 
improvement in your mood and quality of life.  However, you may not respond to treatment and there 
may be no direct benefit to you in participating in this study. Your participation in this study will help us 
better understand the best treatments for depression among hemodialysis patients.  
 
 
What other options are there? 
Participation in this research study is voluntary. You do not have to take part in this study to be treated 
for depression. You can follow-up with your nephrologist or primary care doctor to discuss other 
treatment options. Other treatment options include a different antidepressant medication, 
psychotherapy, and electroconvulsive therapy (ECT). 
 
What are the costs? 
 
If you are randomly selected to be in the referral group, the cost of seeing a mental health provider will 
be the responsibility of you and your health insurance plan.   
 
If you are randomly selected to be in the fluoxetine group, fluoxetine will be provided at no cost to you 
during the 12 week study duration.  Any other health care costs during the 12 week study duration will 
be the responsibility of you and your health insurance plan.  If you decide to continue taking fluoxetine 
after the end of the study, you and your health insurance plan will be responsible for the cost of 
fluoxetine. 
 
 
Will I be paid for participating in this study? 
 
You will receive $20 for completing all questionnaires on day 3 and weeks 1, 2, 4, 6, 8, 10, and 12. 
Therefore, you could receive a possible total of $160 for the entire study. You will be paid using a 
ClinCard, which is a re-loadable debit card. You will only be paid for questionnaires that you completed.  
 
 
 
 
 


 
METROHEALTH MEDICAL CENTER 
 
Human Investigation Consent Form  
 
 
 
 
 
Treating Depression among Hemodialysis 
Patients – Consent Form 
 
Page 8 of 10 
 
November 20, 2017 
 
 
  
HUMAN INVESTIGATION CONSENT FORM 
 
HUMAN INVESTIGATION CONSENT FORM 
What happens if I am injured while participating in this study?  
 
All research involves a chance that something bad might happen to you.  This may include the risk of 
personal injury.  If such problems occur during the course of the study, you must contact your study 
coordinator, Ms. Jacqueline Dolata at (216)-778-1792 or your study doctor, Dr. Ash Sehgal at (216)-
778-8484.  Necessary medical care will be provided to you by the provider of your choice. This medical 
care is not free. You and/or your insurance company will be responsible for the costs.  However, you 
can still try to collect compensation for injury related to malpractice, fault, or blame on the part of those 
involved in the research, including the hospital.  
 
 
Health Insurance Portability and Accountability Act (HIPAA) 
 
As part of this study, we are collecting Protected Health Information (PHI) such as: your name, address, 
date of birth, telephone number, and social security number. This information is being collected in order 
to provide you with the ClinCard (debit card). All information will be kept on a password-protected 
secure network, an encrypted laptop computer, or a locked file cabinet in a locked office.  Only the 
primary investigator and study staff will have access to these files.  The following individuals, 
departments or agencies will have access to your PHI: MetroHealth Institutional Review Board or 
United States Department of Health and Human Services.  The investigators will have access to your 
PHI collected until data analysis is complete.  At that time, the PHI will be destroyed.  The study file will 
be kept for 5 years after study completion, at which time it too will be destroyed. You have the right to 
withdraw your permission/authorization for us to access your PHI at any time except to the extent the 
PHI already collected by the investigators before your withdrawal has already been acted upon based 
on your signed Authorization. No new PHI about you will be collected for study purposes unless 
required by law.  
 
 
What about confidentiality? 
 
We will make every effort to keep your research records private, but confidentiality cannot be assured. 
The MetroHealth System has no control over the use of this information once it is released. The 
information about you that is collected in this study will be shared with the study sponsor and may be 
combined with information gathered from public sources or other research studies. This information 
may be used for purposes unrelated to this research and could potentially be used to identify you.  
 
Records that identify you and this consent form may be looked at by a regulatory agency such as: 
United States Department of Health and Human Services  
MetroHealth Institutional Review Board 
National Committee for Quality Assurance 
 


 
METROHEALTH MEDICAL CENTER 
 
Human Investigation Consent Form  
 
 
 
 
 
Treating Depression among Hemodialysis 
Patients – Consent Form 
 
Page 9 of 10 
 
November 20, 2017 
 
 
  
HUMAN INVESTIGATION CONSENT FORM 
 
HUMAN INVESTIGATION CONSENT FORM 
If the results of the study are published or presented in public, your name will not be used. 
 
 
What are my rights as a study participant? 
 
Taking part in this study is voluntary.  You have the right to choose not to take part in this study. If you 
do not take part in the study, your doctor will still take care of you. You will not lose any benefits or 
medical care to which you are entitled.  
 
If you chose to take part, you have the right to stop at any time. You will be told of any new findings 
from this or other studies that may affect your health, welfare, or willingness to stay in this study. 
 
 
Termination of Participation 
 
Your participation in this study may be ended by the investigator without your consent if they feel it is in 
your best interest. 
 
 
Does MetroHealth or any member of the study team have a financial conflict of interest in this 
study? 
 
This study is being sponsored by a grant from the National Institutes of Health.  Portions of Dr. Ash 
Sehgal’s, Dr. Doug Gunzler’s, and Dr. Martha Sajatovic’s and the study team’s salaries are being paid 
by this grant.  There is no other financial conflict of interest among study staff. 
 
 
Whom do I call if I have questions or problems? 
 
If you have questions about any part of the study now or in the future or if you wish to communicate 
concerns or a complaint you should contact Ms. Jacqueline Dolata at (216)-778-1792 or Dr. Ash Sehgal 
at (216)-778-8484.  If you have any questions about your rights as a research participant, or if you wish 
to express any concerns or complaints please contact the MetroHealth Medical Center’s Institutional 
Review Board (which is a group of people who review the research to protect your rights) at (216)-778-
2021. 
 
 
Patient/Subject acknowledgement: 
 
The procedures, purposes, known discomforts and risks, possible benefits to me and to others, and the 
availability of alternative procedures regarding this research study have been explained to me. I have 


 
METROHEALTH MEDICAL CENTER 
 
Human Investigation Consent Form  
 
 
 
 
 
Treating Depression among Hemodialysis 
Patients – Consent Form 
 
Page 10 of 10 
 
November 20, 2017 
 
 
  
HUMAN INVESTIGATION CONSENT FORM 
 
HUMAN INVESTIGATION CONSENT FORM 
read this consent form or it has been read to me, and I have been given the opportunity to ask 
questions or request clarifications for anything I do not understand. I voluntarily agree to participate in 
this study. I have been given a copy of this consent form. 
 
 
___________________________________  
 
_______    _______  
 
 
Patient/Subject Signature 
 
 
 
 
Date           Time  
 
 
 
_______________________________ 
 
 
_______     _______  
 
 
Signature of Person Obtaining Informed Consent 
            Date            Time 
 

SAP_004.pdf: 
USING LATENT VARIABLES AND DIRECTLY OBSERVED TREATMENT TO IMPROVE THE 
DIAGNOSIS AND MANAGEMENT OF DEPRESSION AMONG HEMODIALYSIS PATIENTS 
Date: October 3, 2017 
NCT Number: NCT03390933 
 
Statistical analyses 
 
Develop and validate hemodialysis-specific depression screening instrument. We will 
begin by using graphs and descriptive statistics to summarize demographic and medical 
characteristics as well as scores on our measures of depression (PHQ-9) and dialysis 
complications. Next, we will perform exploratory factor analysis of the nine PHQ-9 items to 
determine how many latent factors represent aspects of depression. It has been hypothesized 
that the PHQ-9 has a two factor structure representing somatic and affective domains of 
depression. However, our previous work on depression and multiple sclerosis suggested a 
single factor structure. We will use an oblique (geomin) rotation and will examine the 
eigenvalues, which represent the variance accounted for by each underlying factor, in a scree 
plot. The number of eigenvalues >1 represent unique latent factors. We will also use parallel 
analysis to calibrate our decisions regarding meaningful eigenvalues. This approach computes 
eigenvalues from a random dataset via Monte Carlo simulation with the same number of 
observations and variables as used in the factor analytics model. Further, we will use model fit 
criteria such as chi-square, comparative fit index (CFI), Tucker Lewis fit index (TLI), root mean 
square error of approximation (RMSEA), and standardized root mean square residual (SRMR) 
statistical test values to help determine the measurement properties of our latent constructs. 
 
We will then use structural equation modeling to examine overlap between depressive 
symptoms and dialysis complications. Conducting these analyses involves four steps: 1) 
specifying the conceptual model, 2) estimating model parameters and assessing goodness of 
fit, 3) making any model modifications, and 4) testing hypotheses of interest. In particular, we 
will apply a measurement model with covariates which permits detection and adjustment for 
differential item functioning (DIF), i.e. when subgroups with the same latent trait have a different 
likelihood of responding to specific questions.79 The initial model will include the factors 
representing aspects of depression, depressive symptoms, dialysis complications, and all the 
potential paths (referred to as DIF paths) connecting them. We will then make model 
comparisons and modifications to our initial model using multiple indices and statistics (e.g. chi- 
square, CFI, TLI, RMSEA, SRMR, modification indices) along with clinical input to establish the 
best fitting model, i.e. the most parsimonious model with all clinically relevant DIF paths of at 
least a small standardized path coefficient.30 The results of these analyses will be standardized 
path coefficients which indicate the magnitude of the effect of one variable on another such as 
the impact of nocturnal cramps on sleep disturbance after adjustment for all other relationships 
in the model.29 Both factor analysis and structural equation modeling will be performed with 
MPlus software.80 
 
For clinical use, we will develop a hemodialysis-specific PHQ-9 (hdPHQ-9) free of overlapping 
symptoms to isolate the underlying dimension of depression. We will extract factor scores from 
the latent construct (or constructs) representing depression in the final best fitting model to form 
this adjusted scale.  A factor score is an individualized score on a latent  construct representing 
a scale of interest. These factor scores will be linearly transformed to fit the range of the original 
PHQ-9 (i.e. 0–27) using a probability integral transformation to maintain the interpretation and 
thresholds of the PHQ-9. This one-to-one transformation will result in similar distributions of 
PHQ-9 and hdPHQ-9 scores in the sample. However, certain individuals will have sizeable 
differences between the two scores. We will also develop a web app that will allow users to 
enter information for a patient and will automatically calculate the hdPHQ-9 score. 
 
Finally, we will use bootstrapping in order to validate our hdPHQ-9. After developing our model 


based on the entire sample, we will fit the model on a series of bootstrap datasets (each by 
resampling with replacement the same number of observations as the entire sample). From this 


procedure we will: 1) obtain the average (as well as the 95% confidence interval) for each of the 
model parameters and fit indices across the bootstrap samples and 2) observe how the 
extracted hdPHQ-9 factor scores for each individual in the original data set vary across the 
models derived from each bootstrapped sample. Thus, bootstrapping validation can be used to 
understand if there is any bias and sampling variation in the model parameters and associated 
hdPHQ-9 scores due to overfitting in the final model. 

Prot_003.pdf: 
PROTOCOL 
 
TITLE: USING LATENT VARIABLES AND DIRECTLY OBSERVED TREATMENT TO 
IMPROVE THE DIAGNOSIS AND MANAGEMENT OF DEPRESSION AMONG 
HEMODIALYSIS PATIENTS 
 
Date: October 3, 2017 
 
NCT Number: NCT03390933 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ABSTRACT 
 
Depression is present in about 20-30% of hemodialysis patients and is associated with 
morbidity and mortality.  However, depression is inadequately diagnosed and treated among 
dialysis patients.  This is due in part to the overlap between depressive symptoms (e.g. appetite 
change, trouble sleeping, feeling tired) and symptoms related to persistent metabolic 
derangements in hemodialysis patients (e.g. nausea, nocturnal cramps, feeling washed out after 
treatment).  The overlap between depressive symptoms and dialysis-related complications 
makes it difficult to diagnose and therefore to treat depression.  In addition, prescription of 
antidepressant medication may increase an already high pill burden and result in poor 
adherence.  Moreover, the evidence base to guide depression treatment among hemodialysis 
patients is limited.  In our previous work, we developed methods to use latent variables and 
structural equation modeling to isolate depressive symptoms.  Other investigators have 
demonstrated that directly observed treatment enhances the effectiveness of tuberculosis and 
HIV treatment. 
 
We now propose a cross-sectional study (Phase 1) followed by a randomized controlled trial 
(Phase 2) at 17 dialysis facilities.  The cross-sectional study will involve assessments of 
depressive symptoms (using the PHQ-9 screening instrument) as well as dialysis-related 
complications (KDQOL) in about 1083 patients.  We will then use structural equation modeling 
to develop and validate a hemodialysis-specific PHQ-9 (hdPHQ-9) that will isolate depressive 
symptoms.  The trial will involve 216 patients with confirmed depression who will be randomly 
assigned to (a) directly observed weekly antidepressant treatment with fluoxetine or (b) referral 
to their nephrologists, their primary care physicians, or nearby mental health providers.  The 
primary outcome of the trial will be remission of depression at 12 weeks.  The trial results will 
also be used to compare the responsiveness of the PHQ-9 and the hdPHQ-9.  We anticipate 
that the hdPHQ-9 will be a valid and responsive instrument that will isolate depressive 
symptoms in hemodialysis patients and ultimately improve the screening and diagnosis of 
depression.  We also expect that directly observed weekly fluoxetine treatment will be an 
effective way to manage depression among hemodialysis patients. 
 
Innovative features of the proposed project include the use of latent variables to address 
overlap, administration of a long acting weekly antidepressant, directly observed treatment, and 
a rigorous randomized controlled trial design.  The project has the potential not only to improve 
the diagnosis and management of depression among hemodialysis patients but also to improve 
their morbidity and mortality.  Furthermore, it may serve as a model for future studies to isolate 
symptoms among overlapping medical conditions. 
 
 
Participating dialysis facilities 
 
FACILITY NAME 
FREE-
STANDING? 
FOR 
PROFIT? 
NUMBER OF 
PATIENTS 
% FEMALE 
% AFRICAN-
AMERICAN 
CDC Eliza Bryant 
No 
Yes 
117 
48 
86 
CDC East 
Yes 
No 
343 
39 
92 
CDC Euclid 
Yes 
Yes 
240 
46 
64 
CDC Mentor 
Yes 
No 
175 
42 
7 
CDC Shaker 
Yes 
Yes 
196 
52 
85 
CDC Warrensville 
Yes 
Yes 
186 
46 
80 
CDC West 
Yes 
No 
113 
34 
47 
CDC Canfield 
Yes 
No 
88 
43 
38 
CDC Heather Hill 
No 
No 
72 
40 
5 
CDC Jefferson 
Yes 
No 
17 
60 
7 


CDC Beachwood 
No 
Yes 
62 
38 
32 
CDC Garfield 
Yes 
Yes 
96 
54 
66 
CDC Painesville 
Yes 
Yes 
42 
45 
37 
CDC Oakwood 
Yes 
Yes 
92 
46 
55 
CDC Park East 
No 
Yes 
39 
60 
69 
CDC Warren 
Yes 
Yes 
55 
46 
30 
CDC Youngstown 
Yes 
Yes 
31 
57 
25 
 
We propose to conduct our trial at the 17 facilities affiliated with the Centers for Dialysis Care 
(CDC), a greater Cleveland dialysis chain.  The median facility size is 92, 47% of patients are 
female, 48% are African-American, and 3% are Hispanic.  These facility and patient 
characteristics are roughly comparable to national figures, except that there are more African 
American and fewer Hispanic dialysis patients in the Cleveland area compared to the United 
States as a whole.  We have previously conducted several NIH-funded randomized 
controlled trials at these facilities.43-46 
 
Study design overview and timetable 
 
  BASELINE  
 
 
 
 
 
 
 
 
 
 
FINAL 
  EVALUATION  
 
 
 
 
 
 
 
 
 
 
 
 
        If high 
 
 
if depression 
 
 
         PHQ-9 
 
 
diagnosis 
 
 
 
 
Aim A  
 
 
 
 
 
    Aim B 
 
 
Aim C 
 
After a development and training period, we propose a cross-sectional study followed by a 
randomized controlled trial.  The cross-sectional study will involve assessments of depressive 
symptoms (PHQ-9) and quality of life for 1083 patients.  These data will be used to address 
Aim A (diagram above).  The trial will involve 216 patients with DSM5-confirmed depression 
who will be assigned to 2 groups using envelopes for randomization.   
• 
Approximately 108 patients will be randomized into the intervention/fluoxetine group over 
the duration of the entire study.  Patients randomized to fluoxetine will be prescribed 2 
weeks of short-acting fluoxetine 20 mg and will be instructed to take the prescription 
daily for 2 weeks.  After the approximately 2 weeks of daily fluoxetine is completed, 
patients will receive a filled prescription of long-acting fluoxetine 90 mg to be taken 
weekly (observed during dialysis) for 10 additional weeks. The first dose of fluoxetine 
90mg will be 5-8 days after the last dose of daily 20mg fluoxetine based on FDA 
guidelines. During each week, the nurse practitioner or research assistant will review 
possible adverse effects and response to treatment.  At the end of the 12-week study 
period, participants will be provided 4 additional weeks of 90 mg fluoxetine in order to 
provide sufficient time to follow up with their primary care physician or nephrologist.   
 
• 
Approximately 108 patients will be randomized into the control/referral group over the 
duration of the study.  Patients randomized to referral will be informed about their 
diagnosis and asked to follow-up with their nephrologists or primary care physicians and 
will also be given a list of nearby mental health providers.  Details about their study 
PHQ-9 
KDQOL 
DSM5 
Structured 
Interview 
Fluoxetine 
vs. 
Referral 
PHQ-9 
KDQOL 
DSM5 Interview 


evaluation will be shared with their nephrologists, primary care physicians, and any 
mental health providers.  
 
• 
After 12 weeks, patients in both groups will undergo repeat assessments of the PHQ-9, 
KDQOL, and DSM5 structured diagnostic interview.  These data will be used to address 
Aims B and C.   
 
We anticipate beginning the project at 2-3 dialysis facilities and estimate it will take about 4-5 
months to complete the cross-sectional study and randomized controlled trial at these facilities.  
We will then involve another 2-3 facilities in the project.  This process will continue until we 
reach our target sample size.  Based on our previous work, we anticipate that it will take 
approximately 45 months to complete the trial.  We considered involving more study personnel 
to shorten the time necessary to complete the trial but felt that this would impair our ability to 
maintain study quality and intervention fidelity.  Intervention fidelity will be maintained through 
initial training, in-person meetings, monitoring of study notes, and direct observation.  Trial 
results will be reported in accordance with CONSORT recommendations.51 
 
Note that we will use the PHQ-9 and the DSM5 structured interview to screen for depression, 
confirm the diagnosis, and determine response to treatment.  While the overlap between 
dialysis complications and depressive symptoms may affect the accuracy of these methods, 
they are currently standard practice in depression intervention trials.  Until we have assessed 
the validity and responsiveness of the hemodialysis-specific PHQ-9 (hdPHQ-9), it would 
be premature to use this new instrument for screening or for determining response to 
treatment. 
 
Year 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 4 5 5 5 5 
Quarter 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 
DEVELOPMENT & TRAINING 
  Finalize study protocol, instruments 
  Train study personnel 
  Refine conceptual model 
 
x 
x 
x 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RANDOMIZED CONTROLLED TRIAL 
  Recruit eligible patients 
  Baseline evaluation 
 
 
 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
 
 
  Fluoxetine vs. referral trial 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
  Final evaluation 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
ANALYSIS & MANUSCRIPTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Develop, validate new screening instrument 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
 
  Impact of directly observed weekly fluoxetine 
  Responsiveness of new instrument 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
 
x 
 
 
 
 
 
Screening & Study sample 
 
Patients will be screened from the previously mentioned CDC dialysis units.  Appropriate 
approval including credentialing, electronic medical record (Clarity) training and access, as well 
as the appropriate letter of support from the CDC medical director have all been secured.  Study 
team staff will access the Clarity system remotely at MetroHealth.  Staff will use the chart 


abstraction form to look for eligible participants (see study sample above). A note will be made 
in the patient’s Clarity chart deeming them “eligible” or “ineligible” based on screening.  For Aim 
A, we will restrict the study to patients age > 18 who have been on dialysis for > 3 months, 
speak English, are not cognitively impaired, and are not currently being treated for depression.  
We will exclude children age < 18 because the performance of the PHQ-9 and the DSM5 
criteria for depression are slightly different among children compared to adults.24,52  We will 
exclude new patients because the first 3 months of dialysis treatment is often a time of multiple 
adjustments in dialysis prescriptions which may in turn affect dialysis complications. We will also 
exclude patients with the following comorbid conditions: Alzheimer’s, Dementia, Bipolar 
Disorder, Psychotic Disorder, Substance Use Dependence.  This will be assessed by cross 
referencing diagnosis in Clarity as well as the patient’s medication list.   Eligible participants will 
be assigned a study ID.   A screening interview form will be partially completed to note the study 
ID and dialysis shift.  In this way, no Protected Health Information (PHI) will leave MetroHealth.  
The research assistant will take the coded screening form to the dialysis facility and log onto 
Clarity to confirm patient identity and initial eligibility.  The research assistant will then approach 
the patient and ask if they would be willing to answer a few brief screening questions to see if 
they qualify for a research study.  Interested participants will be asked the questions in the 
screening interview.  The screening interview will exclude non-English speaking patients 
because we are not budgeted to have study documents in both English and Spanish.  It will also 
exclude cognitively impaired patients because they will be unable to reliably report on 
depressive symptoms and dialysis complications.53  Patients who meet eligibility criteria will be 
invited to participate in the first Phase of the study and to provide written informed consent. The 
informed consent process will take place and participants will be given a chance to ask any 
questions they have regarding the study.  A copy of the signed informed consent will be given to 
them.  After consenting, the research assistant will administer the PHQ-9 followed by the 
KDQOL.  Patients scoring under a 10 on the PHQ-9 will have completed their part in the study 
and will receive a $20 clincard.  Only de-identified data (utilizing the subject ID) will be 
transported back to MetroHealth for data entry. 
  
 
Patients with a PHQ-9 score >10 will be told that the psychiatric nurse practitioner will first 
perform a DSM5 structured diagnostic interview.  Patients with a diagnosis of depression based 
on the DSM5 structured interview will then be further evaluated by the nurse practitioner to 
confirm the diagnosis prior to randomization to fluoxetine or referral.  This will involve an 
approximately hour-long standard clinical mental health assessment and will exclude individuals 
with bipolar or psychotic disorders, individuals who are at immediate risk of harm to themselves 
or others, individuals who have a history of intolerance or failure to respond to fluoxetine, 
individuals with substance use dependence, and individuals who have any comorbid conditions 
that would make them unable to comply with study procedures.  Patients diagnosed as 
depressed based on the MINI assessment will then be asked to participate in Phase 2 of the 
study (the randomized controlled trial).  Willing participants will be consented and subsequently 
randomized into one of the 2 following groups: 
 
 
Fluoxetine (Intervention) group 
 
The study psychiatric nurse practitioner will write a prescription for 2 weeks (14 days) of short-
acting fluoxetine 20 mg and order the prescription from the MetroHealth Research Pharmacy.  
The short-acting fluoxetine prescription will be picked up from the MH Research Pharmacy the 
following day by either the study coordinator or the nurse practitioner.  The prescription will be 
transported by the nurse practitioner or other study team member to the dialysis facility and 


given to the participant by the nurse practitioner.  The nurse practitioner will instruct them to 
take one capsule daily for the next 14 days.  The nurse practitioner will meet with patients at day 
3, end of week 1, and end of week 2 to assess adverse effects (such as insomnia, headache, 
nausea, weakness), adherence, and response to treatment based on interviewing the patient 
and re-administering the PHQ-9.  After consultation with Drs. Sehgal and Sajatovic, the nurse 
practitioner may encourage adherence (if patient has missed fluoxetine doses at home), or 
discontinue fluoxetine (if moderate-severe adverse effects).  After the successful completion of 
the 2 weeks of daily fluoxetine, a prescription of weekly (90 mg) fluoxetine will be ordered by the 
nurse practitioner from the MetroHealth Research Pharmacy.  The weekly fluoxetine will be 
filled and transported to the participant’s upcoming dialysis visit by the nurse practitioner or 
other study team member.  The participant will be instructed by the nurse practitioner to take the 
weekly/long-acting once weekly at the dialysis facility while observed by the nurse practitioner or 
other study team member starting 5-8 days after the last dose of daily 20mg fluoxetine.  If a 
patient misses the dialysis treatment that fluoxetine should be taken at, the nurse practitioner or 
other study team member will remind him/her by telephone to take the medication.  The nurse 
practitioner will then meet with patients every two weeks for the next 10 weeks and make 
necessary medication adjustments.   
 
Beginning with daily short acting fluoxetine and then transitioning to weekly long-acting 
fluoxetine is the recommended approach for using long acting fluoxetine.34,36  A recent 
systematic review concluded that 12 weeks is an appropriate period of time to determine if 
depression treatment is effective in kidney disease patients.28  If a patient is suicidal at any time 
during the trial (e.g. based on response to the last question in the PHQ-9 or as ascertained from 
other interactions with the patient), we will immediately administer the MINI suicidality module.  
If the participant is determined to have low risk, we will notify the dialysis facility social worker or 
charge nurse and document in the progress note.  If the participant is determined to have 
moderate to high risk, we will call the study nurse practitioner on study cell (216-339-9244) or 
Dr. Sajatovic (if needed) then notify the dialysis facility social worker and/or charge nurse so 
they can arrange for urgent evaluation and treatment.  This will also be documented in the 
progress note. 
 
Patients who discontinue fluoxetine due to severe adverse effects will be referred to their 
nephrologists or primary care physicians for consideration of alternative depression treatments.  
Based on studies in the general population, we estimate that about 65% of patients will respond 
to daily fluoxetine and that 80-90%% of responders will continue to do well with weekly 
fluoxetine (at 90 mg or, if necessary, 180 mg).34-36,40  We further estimate that about 5% of all 
fluoxetine group patients will need to discontinue fluoxetine because of adverse effects.34-36,40  
Because of the short duration of the trial, we will not simultaneously provide other 
pharmacologic or non-pharmacologic treatments for depression.  Moreover, long-acting 
fluoxetine is the only treatment that allows for weekly directly observed administration.  At the 
end of 12 weeks, participants will be given a filled prescription of 90 mg fluoxetine for 4 
additional weeks.  They will also be given a set of instructions to follow up with their 
nephrologists or primary care physicians for decisions about ongoing depression treatment. 
 
Referral (Control) group 
 
Patients will be informed about their diagnosis and asked to follow-up with their nephrologists or 
primary care physicians and will also be given a list of nearby mental health providers.  A written 
summary of their study evaluation will be shared with their nephrologists and primary care 
physicians.  A research assistant will see referral group patients at the same frequency that the 
nurse practitioner will see fluoxetine group patients (i.e. day 3 and weeks 1, 2, 4, 6, 8, 10).  At 


these visits, the research assistant will administer the PHQ-9 and inquire about any depression 
treatment that the patients’ providers have initiated (such as specific antidepressant medications 
or cognitive behavioral therapy).  If a patient is suicidal at any time during the trial (e.g. based on 
response to the last question in the PHQ-9 or as ascertained from other interactions with 
patient), we will immediately administer the MINI suicidality module.  If the participant is 
determined to have low risk, we will notify the dialysis facility social worker or charge nurse and 
document in the progress note.  If the participant is determined to have moderate to high risk, 
we will call the study nurse practitioner on study cell (216-339-9244) or Dr. Sajatovic (if needed) 
then notify the dialysis facility social worker and/or charge nurse so they can arrange for urgent 
evaluation and treatment.  This will also be documented in the progress note. 
   
 
 
 
Data elements 
 
Baseline (week 0) and final (week 12) data on patient characteristics, PHQ-9 and KDQOL will 
be obtained by a research assistant.  Patients will be interviewed during dialysis to obtain the 
data elements listed below.  In previous trials, we found that many patients are unable to 
complete self-administered questionnaires such as the PHQ-9 because of visual problems or 
low health literacy.  Other patients are not allowed to move their dominant arm during dialysis 
treatment because tubing from the dialysis machine is connected to blood vessels in the arm.  
The combination of sitting next to the patient and the ambient noise in the dialysis facility allows 
for a relatively private interview.  If patients prefer, they may be interviewed in a separate room 
following completion of dialysis treatment.  It is not possible to blind study personnel to 
assessments of depression treatment, adherence, response, and adverse effects during the trial 
(day 3, weeks 1, 2, 4, 6, 8, 10).  Patients will be given a $20 clincard at the end of each 
interview to thank them for participation.  The nurse practitioner and other study team members 
will have a lock box for transporting consent and clincard receipts.  Other study documents will 
be devoid of PHI.  Patients will be assigned a study ID that is linked only by a secure RedCap 
database.  A study ID system utilizing patient initials and codes for dialysis facility will be 
employed to keep track of patients.  Below is a chart outlining the various instruments that have 
been either developed or utilized for the purposes of this study: 
 
 
 
 
Form Name 
Summary 
Study 
Group 
Type 
When to Be 
Administered 
Chart 
Abstraction 
Eligibility Form 
Chart review to 
gather demographic 
info and determine 
initial eligibility for 
study 
Both 
Data entry Form 
Screening (via 
CDC medical 
record) 
Screening 
Interview 
Interview with 
patient to determine 
final eligibility for 
Phase 1 of the study 
Both 
Data entry Form 
Screening  


Phase 1 
consent form  
To consent patients 
to first phase of the 
study if eligible 
(1083 patients) 
Both 
Consent 
After eligibility for 
study confirmed 
Enrollment 
Checklist 
Checklist to ensure 
completion of all 
baseline tasks 
Both 
Administrative 
Document 
After baseline 
surveys are 
complete 
Phase 2 
consent form  
To consent patients 
to second phase of 
the study if eligible 
(216 patients) 
Both 
Consent 
After Mini 
reviewed and 
diagnosis of 
depression 
assessed 
Patient 
Instructions for 
Daily Fluoxetine 
To direct 
intervention patients 
in first part of filling 
prescription and 
taking fluoxetine 
daily 
Interventio
n 
Patient 
Information 
After 
randomization 
into intervention 
group 
Daily Adherence 
Form 
To use to assess 
adherence to daily 
fluoxetine 
Interventio
n 
Administrative 
Document 
Visits 1, 2, 3 & 4 
(Fluoxetine) 
Patient 
Instructions for 
Weekly 
Fluoxetine 
To direct 
intervention patients 
in 2nd part of filling 
their prescription 
and taking fluoxetine 
(weekly) 
Interventio
n 
Administrative- 
Patient Info 
After daily 
fluoxetine is 
completed (Visit 
4) 
Advanced 
Practice Nurse 
Study Note 
To track the 
patient's response to 
fluoxetine treatment; 
to record any 
adverse events 
Interventio
n 
Source 
Document 
Visits 1,2, 3, 4, 5, 
7,9,11,13 
Patient 
Instructions for 
Control Group 
To let patients know 
that they may be 
depressed and to 
seek outside help 
Control 
Patient 
Information 
After 
randomization 
into control group 
(Visit 1) 
List of Mental 
Health 
Providers for 
Control Group 
To be used in 
tangent with Patient 
Instructions for 
Control Group 
Control 
Patient 
Information 
After 
randomization 
into control group 
(Visit 1) 
Referral Group 
Follow Up 
Checklist 
To record ongoing 
PHQ-9 scores and 
monitor for adverse 
events 
Control 
Source 
Document 
Visits 1-9 


Fluoxetine 
Group 
Adherence 
Checklist 
To record ongoing 
PHQ-9 scores and 
observations of 
fluoxetine 
administration 
Interventio
n 
Source 
Document 
Visit 1-13 
Patient Letter 
for End of Study 
(Intervention 
Group) 
To be used after 
study is over to 
direct patients to 
speak with their 
physician to 
continue treatment 
Interventio
n 
Patient 
Information 
Visit 13: after all 
follow up surveys 
have been 
completed 
Close-out 
Checklist 
To capture 
administration of all 
follow up surveys, 
instructions & 
payment 
Both 
Data Entry Form 
Visit 13  
PHQ-9 
9-item questionnaire 
that asks about 
depressive 
symptoms 
Both 
Questionnaire 
Baseline, Visits 
2,3,4,5,7,9,11,13 
Dialysis 
Symptoms 
Index 
Addresses 
complications in 
dialysis 
Both 
Questionnaire 
Baseline and 
Final (Week 12) 
Kidney Disease 
Quality of Life 
Addresses quality of 
life and 
complications in 
dialysis 
Both 
Questionnaire 
Baseline and 
Final (Week 12) 
MINI (Mini 
International 
Neuropsychiatri
c Interview) 
Gold standard for 
depression 
diagnosis 
Both 
Structured 
Interview 
Baseline and 
Final (Week 12) 
 
 
 
 
Patient characteristics.  Captured by “Chart Abstraction Eligibility.” Included on these 
forms are demographic variables to be obtained by chart abstraction include age, gender, 
race/ethnicity. Medical variables will be cause of renal failure, number of years on dialysis, and 
possible depressive treatment and/or medications.18,59 Also, a “Screening interview” will be done 
to ensure cognitive ability and confirm no current depression treatment.  
 
Patient Health Questionnaire (PHQ-9).  The PHQ-9 is a 9-item questionnaire that asks 
about depressive symptoms (listed in section 3.01).  In the general population, the PHQ-9 has 
good internal reliability (Cronbach’s α of 0.89) and validity (sensitivity and specificity both 88% 
for major depression diagnosed by structured diagnostic interview).26  A small study of dialysis 
patients found similarly high sensitivity and specificity (both 92%).3  However, it is not 
surprising that PHQ-9 scores correlate strongly with structured interview diagnoses of 
depression because both address the same 9 symptoms.  The main difference between 
them is that the structured interview tries to determine if symptoms may be due to another 


psychiatric condition such as bipolar disorder.  We selected the PHQ-9 (rather than other 
depression screening instruments) because it is brief, is commonly used, and will allow us to 
build on our previous work on symptom overlap in multiple sclerosis.14 
 
Quality of life.  We will also use the KDQOL assess quality of life.  This widely used 
instrument includes both general scales on health-related quality of life as well as scales that 
target specific areas relevant to end stage renal disease.19,60,61 10 additional dialysis 
complication symptoms have been added to the KDQOL-36 
 
 
DSM5 structured diagnostic interview.  The gold standard for depression diagnosis is 
a structured diagnostic interview based on DSM5 criteria.  This semi-structured interview 
involves an introductory overview followed by several modules that represent the major axis I 
psychiatric diagnostic classes.  The output of the interview is the presence or absence of the 
disorders being considered.63,64  As in our previous work, we propose to utilize the Mini 
International Neuropsychiatric Interview (MINI) as opposed to other structured interview 
instruments because the MINI is much shorter but still reliable and valid.47,65  The MINI has 
excellent inter-rater agreement (kappa 0.84) and diagnostic accuracy (sensitivity 0.96 and 
specificity 0.88 compared to much longer diagnostic interviews).66  In addition, the diagnostic 
stability of the MINI is superior to unstructured assessments conducted by clinicians.65  
 
Depression treatment, adherence, response, and adverse effects.  To be captured 
by a combination of: “Enrollment Checklist”; “Daily Adherence Form”; “Fluoxetine Group Follow 
Up Checklist”; “Control Group Follow Up Checklist”; “Progress Note.” The psychiatric nurse 
practitioner will meet with fluoxetine patients at day 3 and at weeks 1, 2, 4, 6, 8, and 10 during 
the trial to assess adherence, response to treatment, and adverse effects (see section 4.05 for 
details).  Adherence will be assessed by pill counts and by using an adherence question from 
the Brief Medication Questionnaire that asks participants how consistently they took their 
medication during the prior week.  This questionnaire has been used to assess adherence to 
antidepressants and is correlated with pharmacy fill records.67,68  Patients who miss two or more 
daily doses will be categorized as nonadherent.69,70  Note that adherence will only be assessed 
in this manner when fluoxetine patients are taking short-acting fluoxetine since administration of 
long-acting fluoxetine will be directly observed by the research assistant.    Adverse effects will 
be assessed by the nurse practitioner.  The nurse practitioner will complete a written study note 
listing the fluoxetine dose, adherence, response, and adverse effects. 
 
In a similar manner, the research assistant will meet with referral patients at day 3 and at weeks 
1, 2, 4, 6, 8, and 10 during the trial.  The research assistant will inquire about any depression 
treatment that has been initiated by each patient’s nephrologist, primary care physician, or other 
provider.  The research assistant will complete a study note listing any depression treatment 
including new medication or cognitive behavioral therapy. 
 
 
For detailed visit flow, please see Attachment A.   
 
 
Training and intervention fidelity 
 
Quality control and fidelity during the trial will be maintained through a combination of initial 
trainings, weekly meetings, monitoring of study notes, and direct observation.  Initial 
training will take place over multiple days addressing specifics related to research ethics, the 


study protocol, psychiatric interviewing and dialysis unit etiquette.  All staff will be CREC 
certified and receive additional training on the importance of confidentiality, specific to research 
in a community setting.  The psychiatric interview training will be cover issues related to inter-
rater reliability, as well as how to handle various situations when dealing with depressed 
patients (specifically the topic of suicidality).  The other training will be an introduction to dialysis 
unit etiquette and safety that will include a site visit to a local unit.   As the study progresses, the 
research assistants and nurse practitioner will meet weekly with other research team members 
to review study progress, adherence to the protocol, and address any challenges in carrying out 
study tasks.  Ms. Dolata will review all study notes to identify any deviations from specified 
tasks.  To further ensure intervention fidelity and consistency across research assistants, she 
will also directly observe a randomly selected 5% of research assistant interactions with 
patients.  She will use a fidelity checklist to verify that specific tasks are carried out properly.  In 
a similar manner, Dr. Sehgal or Sajatovic will observe a randomly selected 5% of nurse 
practitioner interactions with patients.  Any problems noted from review of study notes or from 
direct observation will be addressed at our weekly group meetings.  If a research assistant or 
the nurse practitioner is unable to complete the trial, we will identify and train a replacement. 
 
Data and safety monitoring plan 
 
We propose several methods to ensure safety and to monitor our intervention.  First, our 
intervention is theoretically sound and based on our prior work and that of others.  Second, we 
will refine and pre-test our approach prior to beginning the clinical trial.  Third, Dr. Sehgal will 
meet weekly with other study personnel in order to trouble-shoot any potential areas of concern 
regarding the safety of the study protocol.  Fourth, all study personnel will undergo rigorous 
training.  Fifth, we will closely monitor study personnel through a combination of weekly 
meetings, monitoring of study notes, and direct observation.  Sixth, project data will be reviewed 
quarterly by the entire study team.  Any indications of potential threats to patient safety or a 
pattern of refusal by patients to participate in specific interactions with study personnel will be 
responded to immediately by a careful review conducted by the study team.  When appropriate, 
involvement of the patient’s nephrologist or dialysis facility medical director, reporting to our 
Institutional Review Board, reporting to End Stage Renal Network 9 (a regional Medicare quality 
oversight organization), and adjustment of the project protocol will occur.  Although risk to 
subjects is considered low, any adverse events will be reported to our Institutional Review 
Board and the National Institutes of Health. 
 
Confidentiality 
We will do several things to protect the participant's privacy.  First, we are assigning study IDs to 
all data so that PHI is not being regularly written down or collected throughout the study.  Also, 
we will be utilizing the lock box in order to ensure confidential transport of consent forms and 
clincard receipts.  Third, if a participant wishes to discuss the study in a more private area than 
the dialysis chair, we will offer to wait until their dialysis session is over and move to a private 
room in the unit.  All data at Metro will be stored on a secured drive, will be password protected 
and will have no PHI (other than the Key in RedCap). 
 


ATTACHMENT A: VISIT FLOW SHEET 
VISIT TYPE 
TASKS 
PRE-SCREEN 
• 
Identify CDC unit(s) to begin project at 
• 
Introduce study staff to CDC unit staff 
 
SCREENING  
(Part 1-remote at 
Metro) 
• 
Screening for that unit to take place off site by study staff  
• 
Complete Chart Abstraction Eligibility Form 
• 
Enter note in CDC research tab that patient was “successfully 
screened” or a “screen fail” 
• 
Weekly report of potentially eligible patients will be generated at 
Metro through use of CDC Clarity EMR 
• 
Participant is assigned a study ID to be used in future visits 
 
SCREENING  
(Part 2-at dialysis 
facility) 
• 
Research assistants (RA) will bring coded list of eligible patients and 
blank study documents 
• 
RA will log into CDC Clarity to confirm patient ID (via note in 
research tab) 
• 
RA will begin approaching participants based on screening report 
• 
Screening Interview administered by RA and is filled out at the unit 
via patient interview 
 
ENROLLMENT (Part 1-
at dialysis facility) 
• 
Eligible participants will be asked to be in the “Phase I” of the study  
• 
Obtain Informed consent #1; given a copy of consent, another stays 
at unit; another copy goes back to Metro 
ENROLLMENT (Part 2-
at Metro) 
• 
Consented patients’ name and Study ID entered into REDCAP Key 
• 
Baseline info entered into master tracking spreadsheet 
BASELINE (day 1) 
Baseline surveys via patient interview  
• 
PHQ-9 
• 
KDQOL  
Score PHQ-9 at unit (other survey does not need to be scored at that time) 
• 
If Score is less than 10, patient receives CLINCARD, is thanked for 
participation 
• 
If Score is greater than or equal to 10, participant is told that a 
nurse practitioner will be back on next dialysis day to conduct the 
MINI interview 
• 
If patient is suicidal based on PHQ-9 RA immediately performs the 
MINI suicidality module.  *If participant determined to have low 
risk the RA will notify the social worker at dialysis facility that this 
occurred and that it appears to be low risk; document in progress 
note. **If participant determined to have moderate to high risk, 
call study NP on study cell (216-339-9244) or Dr. Sajatovic (if 
needed); then contact SW or charge nurse; then note in progress 
note 
• 
Surveys, Clincard receipt, and consent are transported back to 
Metro in lock box 
 


BASELINE 
PC enters all info to date into main tracking database at Metro 
BASELINE (part 2-at 
dialysis facility) 
Nurse practitioner conducts MINI interview (on next dialysis day) 
• 
MINI is scored and assessed by NP  
• 
If NOT diagnosed as depressed, participant is given Clincard and 
thanked for their time 
• 
If diagnosed as depressed, participant is asked to be in Randomized 
Controlled Trial (RCT) 
• 
If patient consents to RCT, they are then randomized by the NP via 
envelopes 
• 
If patient is randomized to Fluoxetine (intervention group), the NP 
orders prescription of daily (20 mg) fluoxetine from the 
MetroHealth Research Pharmacy (2 weeks worth) 
BASELINE (part 2-at 
Metro) 
PC or RA creates participant folder (all de-identified info) 
• 
Enrollment checklist 
• 
Blank PHQ-9 forms 
• 
Daily Adherence Form 
• 
Follow Up Checklists 
• 
Progress Notes 
• 
Participant Calendar 
• 
Close-Out Checklist 
VISIT 1 
FLUOXETINE 
(DAY 1) 
• 
NP or study staff picks up prescription of daily fluoxetine at 
research pharmacy 
• 
NP transports prescription to dialysis unit to meet with participant  
• 
NP fills pill holder with participant  
• 
Participant is given Daily Fluoxetine Instructions 
• 
Participant calendar is generated based off first dose 
VISIT 1  
REFERRAL 
(Day 1) 
• 
Participant given referral group instruction sheet 
• 
Participant given list of nearby mental health providers 
VISIT 2 
FLUOXETINE 
(DAY 3 of Daily)   
• 
NP meets with participant 
• 
Checks for adverse events (Progress Note) 
• 
Administers Daily Adherence Form 
• 
Administers PHQ9 
• 
If patient is suicidal based on PHQ-9, NP immediately performs the 
MINI suicidality module.  *If participant determined to have low 
risk the NP will notify the social worker at dialysis facility that this 
occurred and that it appears to be low risk; document in progress 
note. **If participant determined to have moderate to high risk, 
contact SW or charge nurse; then note in progress note 
• 
Clincard payment  
• 
PHQ9, Daily Adherence Form & study note back to Metro before 
next check in 
• 
Chart relevant info in CDC Clarity EMR 
VISIT 2 
REFERRAL 
(DAY3) 
• 
RA meets with participant  
• 
Administers Control Group Follow Up Checklist and inquires re: any 
depressive treatment (medication or cognitive therapy) 


• 
Administer PHQ9  
• 
If patient is suicidal based on PHQ-9, RA immediately performs the 
MINI suicidality module.  *If participant determined to have low 
risk the RA will notify the social worker at dialysis facility that this 
occurred and that it appears to be low risk; document in progress 
note. **If participant determined to have moderate to high risk, 
call study nurse practitioner on study cell (216-339-9244) or Dr. 
Sajatovic (if needed); then contact SW or charge nurse; then note in 
progress note 
• 
PHQ9 & Study notes back to Metro before next check in 
VISIT 3 
FLUOXETINE 
(End WEEK 1 Daily) 
• 
NP meets with participant; Fluoxetine Group Follow Up Checklist 
• 
Checks for adverse events & response to treatment (Study note) 
• 
Administers Daily Adherence Form 
• 
Administers PHQ9 
• 
If patient is suicidal based on PHQ-9, NP immediately performs the 
MINI suicidality module.  *If participant determined to have low 
risk the NP will notify the social worker at dialysis facility that this 
occurred and that it appears to be low risk; document in progress 
note. **If participant determined to have moderate to high risk, 
contact SW or charge nurse; then note in progress note 
• 
Clincard payment  
• 
PHQ9, Daily Adherence Questionnaire & study note back to Metro 
before next check in 
• 
Chart relevant info in CDC Clarity EMR 
VISIT 3 
REFERRAL 
(End WEEK 1) 
• 
RA meets with participant; Completes Control Group Follow Up 
Checklist 
• 
Inquires re: any depressive treatment   
• 
Administer PHQ9  
• 
If patient is suicidal based on PHQ-9, RA immediately performs the 
MINI suicidality module.  *If participant determined to have low 
risk the RA will notify the social worker at dialysis facility that this 
occurred and that it appears to be low risk; document in progress 
note. **If participant determined to have moderate to high risk, 
call study nurse practitioner on study cell (216-339-9244) or Dr. 
Sajatovic (if needed); then contact SW or charge nurse; then note in 
progress note 
• 
PHQ9 & Study notes back to Metro before next check in 
VISIT 4 
FLUOXETINE 
(End WEEK 2 
Daily/Begin Weekly) 
 
• 
NP meets with participant  
• 
Completes Fluoxetine Group Follow Up Checklist 
• 
Checks for adverse events (Study note) 
• 
Administers Daily Adherence Form 
• 
Administers PHQ9 
• 
If patient is suicidal based on PHQ-9, NP immediately performs the 
MINI suicidality module.  *If participant determined to have low 
risk the NP will notify the social worker at dialysis facility that this 
occurred and that it appears to be low risk; document in progress 


note. **If participant determined to have moderate to high risk, 
contact SW or charge nurse; then note in progress note 
• 
Clincard payment  
• 
PHQ9, Daily Adherence Questionnaire & study note back to Metro 
before next check in 
• 
Chart relevant info in CDC Clarity EMR 
VISIT 4 
REFERRAL  
(WEEK 2) 
• 
RA meets with participant; Completes Control Group Follow Up 
Checklist 
• 
Inquires re: any depressive treatment   
• 
Administer PHQ9  
• 
If patient is suicidal based on PHQ-9, RA immediately performs the 
MINI suicidality module.  *If participant determined to have low 
risk the RA will notify the social worker at dialysis facility that this 
occurred and that it appears to be low risk; document in progress 
note. **If participant determined to have moderate to high risk, 
call study nurse practitioner on study cell (216-339-9244) or Dr. 
Sajatovic (if needed); then contact SW or charge nurse; then note in 
progress note 
• 
PHQ9 & Study notes back to Metro before next check in 
Visit 5 
Fluoxetine 
(week 3) 
• 
NP fills new prescription for 90 mg (weekly Fluoxetine) prior to visit 
• 
NP meets with participant and observes first dose of weekly 
treatment 
• 
Study note back to Metro 
• 
Chart relevant info in CDC Clarity EMR 
VISITS 7, 9, 11, 13 
FLUOXETINE 
(weeks 5, 7, 9, 11) 
 
• 
RA observes ongoing doses of weekly fluoxetine on odd weeks (i.e. 
weeks that participant is not meeting with NP) 
• 
Completes Fluoxetine Group Follow Up Checklist 
VISITS 6, 8, 10, 12 
FLUOXETINE 
(Weeks 4, 6, 8, 10) 
• 
NP observes participant administration of fluoxetine (Fluoxetine 
Group Follow Up Checklist) 
• 
Checks for adverse events & response to treatment (APN Study 
Note) 
• 
Administers PHQ-9  
• 
If patient is suicidal based on PHQ-9, NP immediately performs the 
MINI suicidality module.  *If participant determined to have low 
risk the NP will notify the social worker at dialysis facility that this 
occurred and that it appears to be low risk; document in progress 
note. **If participant determined to have moderate to high risk, 
contact SW or charge nurse; then note in progress note 
• 
Clincard payment 
• 
PHQ9 & study note back to Metro 
• 
Chart relevant info in CDC Clarity EMR 
VISITS 5,7, 9, 11  
REFERRAL 
(Weeks 4, 6, 8, 10) 
• 
RA meets with participant 
• 
Inquires re: any depressive treatment (Completes Control Group 
Follow Up Checklist) 
• 
Administer PHQ9  


• 
If patient is suicidal based on PHQ-9, RA immediately performs the 
MINI suicidality module.  *If participant determined to have low 
risk the RA will notify the social worker at dialysis facility that this 
occurred and that it appears to be low risk; document in progress 
note. **If participant determined to have moderate to high risk, 
call study nurse practitioner on study cell (216-339-9244) or Dr. 
Sajatovic (if needed); then contact SW or charge nurse; then note in 
progress note 
• 
PHQ9 & Study notes back to Metro 
VISIT 14 
FLUOXETINE 
(WEEK 12) 
• 
NP observes participant administration of fluoxetine (completes 
Fluoxetine Group Follow Up Checklist) 
• 
Checks for adverse events & response to treatment (APN Study 
Note) 
• 
NP fills prescription (at MH Research Pharmacy) for 4 more weeks 
of 90 mg fluoxetine and give to patient 
• 
Patient is given participant instructions 
• 
PHQ-9, KDQOL & MINI administered  
• 
Final Clincard payment 
• 
Complete Closeout Checklist 
• 
Chart relevant info in CDC Clarity EMR 
• 
Surveys & study note back to Metro 
 
VISIT 13 
REFERRAL  
(WEEK 12) 
• 
RA meets with participant  
• 
Inquires re: any depressive treatment (Control Group Follow Up 
Checklist) 
• 
PHQ-9, KDQOL & MINI  
• 
If patient is suicidal based on PHQ-9, RA immediately performs the 
MINI suicidality module.  *If participant determined to have low 
risk the RA will notify the social worker at dialysis facility that this 
occurred and that it appears to be low risk; document in progress 
note. **If participant determined to have moderate to high risk, 
call study nurse practitioner on study cell (216-339-9244) or Dr. 
Sajatovic (if needed); then contact SW or charge nurse; then note in 
progress note 
• 
Complete Closeout Checklist 
• 
Surveys & study note back to Metro