Clinical trial NCT04979910
Conditions: Major Depressive Disorder
Keywords: depression investigational medication treatment resistant depression inflammation ixekizumab major depressive disorder
Sponsor: Icahn School of Medicine at Mount Sinai
Start date: 2021-08-27; Completion date: 2024-04-12
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The proposed study aims to test ixekizumab, a monoclonal antibody (mAb) against interleukin 17A (IL-17A), in patients with treatment-resistant depression (TRD).

Detailed description:
In the proposed study n=20 adult individuals with TRD will be treated with ixekizumab for 4 weeks. Participants will complete screening procedures, body fluid analyses and brain imaging before and after treatment with ixekizumab.

Arms: arm 1: Ixekizumab 160 mg (two 80 mg injections) at Week 0, followed by 80 mg at Weeks 2 and 4 via subcutaneous route.
Interventions: intervention 1: Ixekizumab
Intervention descriptions: intervention 1: a monoclonal antibody (mAb) against interleukin 17A (IL-17A)

Protocol documents:
Prot_SAP_000.pdf: 
An Experimental Therapeutics Study of a Monoclonal Antibody Against
Interleukin 17A in Patients With Treatment-Resistant Depression
PI: James Murrough, MD, PhD
NCT04979910
Document Date: 6/3/2024


  
 
1 
 
An Experimental Therapeutics Study of Ixekizumab, a Monoclonal 
Antibody Against Interleukin 17A, on Anhedonia, Reward Circuit 
Function, and Blood Brain Barrier Physiology in Patients with 
Treatment- Resistant Depression 
 
 
 
Protocol Number: 21-00325  
Principal Investigator: James Murrough, M.D., Ph.D. 
Sponsor: Hope for Depression Research Foundation 
Funded by: Hope for Depression Research Foundation 
Version Number: V2 
03 June 2024


  
 
2 
 
Table of Contents 
 
 
STATEMENT OF COMPLIANCE 
1 
1 
2 
1.1 
2 
1.2 
4 
1.3 
5 
2 
6 
2.1 
6 
2.2 
6 
2.3 
8 
2.3.1 
8 
2.3.2 
9 
2.3.3 
10 
3 
10 
4 
12 
4.1 
12 
4.2 
12 
4.3 
12 
4.4 
13 
5 
13 
5.1 
13 
5.2 
13 
5.3 
14 
5.4 
14 
5.5 
15 
6 
16 
6.1 
16 
6.1.1 
16 
6.1.2 
17 
6.2 
17 
6.2.1 
17 
6.2.2 
17 
6.2.3 
17 
6.2.4 
18 
6.3 
18 
6.4 
18 
6.5 
18 
6.5.1 
18 
7 
18 
7.1 
18 
7.2 
19 
7.3 
19 
8 
19 
8.1 
19 
8.2 
Evaluations 22 


  
 
3 
 
8.3 
25 
8.3.1 
25 
8.3.2 
26 
8.3.3 
26 
8.3.4 
27 
8.3.5 
28 
8.3.6 
29 
8.3.7 
29 
8.3.8 
29 
8.3.9 
29 
8.4 
29 
8.4.1 
29 
8.4.2 
30 
8.4.3 
30 
9 
30 
9.1 
30 
9.2 
31 
9.3 
31 
9.4 
31 
9.4.1 
31 
9.4.2 
32 
9.4.3 
32 
9.4.4 
33 
9.4.5 
33 
9.4.6 
33 
9.4.7 
33 
9.4.8 
33 
9.4.9 
33 
10 
34 
10.1 
34 
10.1.1 
34 
10.1.2 
34 
10.1.3 
35 
10.1.4 
36 
10.1.5 
36 
10.1.6 
36 
10.1.7 
36 
10.1.8 
37 
10.1.9 
37 
10.1.10 
38 
10.1.11 
38 
10.1.12 
39 
10.2 
40 
11 
41 
 


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STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the Hope for 
Depression Research Foundation Terms and Conditions of Award. The Principal Investigator will assure 
that no deviation from, or changes to the protocol will take place without prior agreement from the 
Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor, funding agency and 
documented approval from the Institutional Review Board (IRB), except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  All changes to the consent form 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
 
 


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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
An Experimental Therapeutics Study of Ixekizumab, a Monoclonal 
Antibody Against Interleukin 17A, on Anhedonia, Reward Circuit Function, 
and Blood Brain Barrier Physiology in Patients with Treatment- Resistant 
Depression 
 
Study Description: 
The proposed study aims to establish the feasibility and safety of 
ixekizumab, a monoclonal antibody (mAb) against interleukin 17A (IL-17A), 
for patients with treatment-resistant depression (TRD). IL-17A is a pro-
inflammatory cytokine that is elevated in subgroup of patients with TRD 
and we hypothesize that blocking IL-17A immune signaling with 
ixekizumab will improve depressive symptoms in adults with TRD. We also 
hypothesize that use of ixekizumab will be associated with changes in 
other symptom and functional domains (such as anhedonia), functional 
neuro-circuitry of brain’s reward system, permeability of blood-brain 
barrier, and circulating immune factors. These hypotheses will be tested in 
the context of an open-label trial where up to n=20 patients with TRD will 
be treated with ixekizumab for 4 weeks and will undergo brain scans 
before and after the treatment period. 
 
 
 
Objectives: 
 
 
Primary Objective 
The primary objective of the current study is to test the safety and 
feasibility of treatment with ixekizumab in patients with TRD. Open-label 
ixekizumab will be given at a dose of 160 mg (two 80 mg injections) at 
Week 0, followed by 80 mg at Weeks 2 and 4. Treatment-related adverse 
effects will be assessed, and drop-out rates will be calculated. 
 
Secondary Objectives 
The study will also test the effect of ixekizumab on (1) Changes in 
depression severity, as assessed by the Montgomery-Asberg Depression 
Rating Scale (MADRS) scores from baseline to the end of treatment (EOT) 
visit (6-week post-treatment); (2) response and remission rates with 
ixekizumab treatment; (3) change in measures of clinical symptoms, 
including anhedonia, anxiety, and functioning, and (4) change in blood-
based inflammatory markers, including CRP and other immune markers. 
Exploratory Objectives 


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The study will also test the effect of ixekizumab on changes in resting state 
functional connectivity (RSFC) of brain’s reward circuit and change in blood 
brain barrier (BBB) permeability. 
Endpoints: 
Primary Endpoint: Completion of treatment measured as the receipt of all 
3 ixekizumab injections (160 mg at week 0, and 80 mg at weeks 2 and 4. 
 
Secondary Endpoints: 1) Baseline-to-week-6 changes in depression 
severity as assessed by MADRS score; 2) Response and remission rates at 
week 6 (defined by ≥50% MADRS total score improvement and MADRS 
total score of ≤10, respectively); 3) Measures of global illness [Clinical 
Global Impression Severity (CGI-S) and Improvement (CGI-I) scale], overall 
depression [the Quick Inventory of Depressive Symptomatology Self-
Report (QIDS-SR)], anxiety [Hamilton Anxiety Rating Scale (HAM-A)], 
suicidal ideation and  attempt [the Columbia Suicide Severity Rating Scale 
(C-SSRS)], anhedonia [the Snaith Hamilton Pleasure Scale (SHAPS) and the 
Temporal Experience of Pleasure Scale (TEPS)], and symptoms associated 
with depression such as fatigue, sleep/wakefulness disturbances, anxiety, 
and irritability; 4) Baseline-to-week-6 changes in blood-based immune 
markers, like CRP and other immune markers 
 
Exploratory Endpoints: Baseline-to-week-6 changes in RSFC will be 
evaluated with resting-state functional magnetic resonance imaging (MRI) 
scans. Baseline-to-week-6 changes in BBB permeability will be evaluated 
with dynamic contrast enhanced MRI.  
 
Safety endpoints: 1) treatment-related adverse events; 2) Columbia-
Suicide Severity Rating Scale at each time point 
 
 
Study Population: 
Up to n=20 adults (Aged 18-70 years; male and female) with a primary 
diagnosis of MDD who have failed two adequate trials of medication in the 
current depressive episode. Demographics reflective of the greater NYC 
population.   
 
Phase: 
 Phase 2 study 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
The human research will be conducted at the Icahn School of Medicine at 
Mount Sinai (ISMMS). Research will be conducted at the Depression and 
Anxiety Center for Discovery and Treatment, the Clinical Research Unit 
(CRU), the Infusion Suite of the Psychiatry Department of ISMMS. 
Functional MRI scans will be completed at the BioMedical Engineering and 
Imaging Institute (BMEII) in the Hess Center for Science and Medicine.   
 
Description of Study 
Intervention: 
One treatment condition in an open-label study design: ixekizumab 160 
mg (two 80 mg subcutaneous injections) at Week 0, followed by 80 mg at 
Weeks 2 and 4. 
 


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Study Duration: 
The proposed study is to be completed in 24 months.  
 
Participant Duration: 
The duration of an individual subject’s participation in the study will be a 
maximum of 12 weeks including the screening (up to 4 weeks), study 
treatment visits (weeks 0, 2, and 4), post-treatment primary outcome visit 
(week 6), and study exit visit (week 8). 
 
 
 
 
 
1.2 
SCHEMA 
 
 
 
 
 


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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
Study Phase 
Screening Open-label Treatment Period 
(Bi-Weekly Study Visits) 
Primary 
Outcome 
Study 
Exit 
Study Visit 
V0 
V1 
V2 
V3 
V4 
V5 
Week 
-4 - 0 
0 
2 
4 
6 
8 
Screening 
Informed Consent 
x 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
Family Psychiatric History 
x 
 
 
 
 
 
ATRQ  
x 
 
 
 
 
 
SCID-5-RV 
x 
 
 
 
 
 
QIDS-C 
x 
 
 
 
 
 
CGI-S 
x 
 
 
 
 
 
Study drug administration 
Ixekizumab Treatment 
 
x 
x 
x 
 
 
Safety assessments, concomitant medication and compliance monitoring 
Physical Exam 
x 
 
 
 
x 
 
Vital Signs 
x 
x 
x 
x 
x 
 
Laboratory Tests  
x 
 
 
 
x 
 
U-Toxicology 
x 
x 
 
 
x 
 
Pregnancy Test 
x 
x 
x 
x 
x 
 
Adverse Events Monitoring 
x 
x 
x 
x 
x 
x 
C-SSRS Past Month 
x 
 
 
 
 
 
C-SSRS Since Last Visit 
 
x 
x 
x 
x 
x 
Clinical efficacy assessments 
MADRS  
 
x 
x 
x 
x 
x 
CGI-S 
x 
x 
x 
x 
x 
x 
CGI-I 
 
x 
x 
x 
x 
x 
SHAPS 
 
x 
x 
x 
x 
x 
TEPS 
 
x 
x 
x 
x 
x 
QIDS-SR 
 
x 
x 
x 
x 
x 
HAM-A 
 
x 
x 
x 
x 
x 
Blood Markers 
Immune Markers 
 
x 
 
 
x 
 
Neuroimaging 
fMRI (RSFC)/DCE-MRI 
 
x 
 
 
x 
 
 
* Study visits 1-5 may occur 3 days before or after the scheduled visit.  


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2 
INTRODUCTION 
2.1 
STUDY RATIONALE 
This study aims to establish the safety and feasibility of ixekizumab, a monoclonal antibody 
(mAb) against interleukin 17A (IL-17A), for patients with treatment-resistant depression (TRD) and 
evaluate its open-label effects on depression severity, other clinical symptoms, blood-based immune 
markers, BBB permeability, and functional brain reward circuitry. It is now clear that targeting the 
immune system holds enormous potential to identify novel therapeutic agents for severe and resistant 
forms of depression. Despite the growing evidence that immune dysregulation and depression are 
associated with one another, the promise of immune-modulating therapies for TRD has not been 
realized. In order to address this gap in knowledge, we propose to test an anti-IL-17A therapy for TRD. 
Based on the available clinical and preclinical work, IL-17A represents the most promising immune 
target for TRD that has yet to be tested in humans. If the goals of the project are achieved, the 
knowledge gained can be used to inform larger, placebo-controlled, well-powered trials to determine 
efficacy and the mechanism of action of ixekizumab for TRD. Ultimately, this can be transferred to 
clinical practice because marketed monoclonal antibodies, like ixekizumab, can be repurposed. The 
knowledge gained from this project will also stimulate new avenues in immune-based treatment 
discovery for depression. 
2.2 
BACKGROUND 
2.2. A Need to develop novel antidepressant treatments. 
There is a need for antidepressant medications with novel mechanisms of action, as currently 
available medications that target monoamine neurotransmission, are ineffective in about a third of 
patients with MDD.1  There are few effective options for the subset of patients–those with treatment 
resistant depression (TRD)–who have failed multiple pharmacotherapy trials. The public health need of 
MDD in the United States is compounded by its high prevalence (1 in 5 adults during their lifetime), cost 
(over $200 billion per year), and burden (second highest cause of disability-adjusted life years).2-4  
2.2. B Role of systemic inflammation in treatment-resistant depression (TRD) 
* Clinical laboratory tests include chemistry, complete blood count, liver function tests, TB test, and
thyroid-stimulating hormone levels (see protocol for details). 
Abbreviations: ATRQ, Antidepressant Treatment Response Questionnaire; C-SSRS, Columbia-Suicide 
Severity Rating Scale; CGI-I, Clinical Global Impression-Improvement; CGI-S, Clinical Global Impression-
Severity; fMRI, functional Magnetic Resonance Imaging; MADRS, Montgomery-Asberg Depression 
Rating Scale; QIDS-SR, Quick Inventory of Depressive Symptomatology-Self-Report; QIDS-C, Quick 
Inventory of Depressive Symptomatology-Clinician Rated; SHAPS, Snaith-Hamilton Pleasure Scale; 
TEPS, Temporal Experience of Pleasure Scale; HAM-A, Hamilton Anxiety Rating Scale  


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Converging lines of evidence suggest that major depressive disorder (MDD) – and TRD in particular 
– is associated with immune dysregulation, which is thought to drive symptoms of anhedonia via 
dysfunction within the brain reward circuit.5,6 Increased signaling of peripheral pro-inflammatory 
cytokines lead to anhedonia-like behavior in animals, and patients with depression (TRD in particular) are 
characterized by elevated levels of circulating cytokines, while systemic administration of pro-
inflammatory cytokines triggers depressive symptoms and changes in brain responses to reward in 
humans.5,7 
2.2. C Role of blood brain barrier (BBB) permeability in depression 
Recent preclinical work from our team show that high levels of circulating immune factors gain 
access to the brain reward circuit to promote pro-depressive behaviors via increased permeability of the 
BBB.8 Use of gadolinium-based contrast agents in dynamic contrast enhance magnetic resonance imaging 
(DCE-MRI) have facilitated quantification of BBB permeability in human for conditions ranging from 
multiple sclerosis and dementia.9,10 A recent study of patients with bipolar disorder and healthy controls 
found that higher BBB leakage on DCE-MRI was associated with more severe depression and more chronic 
course of illness.11   
2.2. D Role of interleukin 17 (IL-17) mediated immune signaling in depression 
IL-17A is a highly pro-inflammatory cytokine produced by T helper 17 (Th17) cells that induces the 
production of numerous other inflammatory cytokines such as IL-6, IL-1β and TNF-α. Preclinical studies 
show that a) stress-induced pro-depressive behaviors are associated with increased levels of IL-17A or 
Th17cells in brain, b) peripheral infusion of IL-17A causes depression-like behaviors, and c) peripheral 
blockade of IL-17A with MABs directed against IL-17A is sufficient to reverse the pro-depressive 
phenotype.12 Extending this work to humans, we and others have found that IL-17A levels are elevated in 
patients with depression versus healthy controls (HC), and higher levels of circulating IL-17A are 
associated with more severe depression and anhedonia.13,14 Data from our group show that IL-17A is 
elevated specifically in patients with TRD (F=5.66; df=2,68; p=0.005), compared to HC or non-TRD forms 
of MDD. Critically, data show that IL-17A increases BBB permeability in preclinical models, providing a 
mechanism whereby peripheral IL-17A promotes depression in part by increasing BBB permeability and 
allowing circulating pro-inflammatory factors to gain access to mood-relevant brain circuits such as the 
VTA-NAc system.5,15 
2.2. E Antidepressant effects of anti-IL-17A MABs. 
The Food and Drug Administration (FDA) has approved three monoclonal antibodies (mAbs) 
targeting either IL-17A directly (ixekizumab and secukinumab) or its receptor (brodalumab). In phase 3 
studies of psoriasis, both ixekizumab and brodalumab were associated with marked improvement in 
depressive symptoms which was not fully accounted for by improvement in psoriatic lesions. The evidence 
for antidepressant efficacy from clinical trial data for our study drug ixekizumab is particularly strong, 
wherein administration of ixekizumab every 2 weeks resulted in markedly higher improvement in overall 
depression versus placebo with a large effect size (Cohen’s d = 0.81).16  


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Thus, anti-IL-17 mAbs may address the urgent need of developing novel antidepressants. This 
proposal will investigate ixekizumab for TRD during an 8 week open-label study. We are interested in 
evaluating ixekizumab and its effects on 1) depression severity; 2) other clinical symptoms; 3) the effect 
of IL-17A on brain function; 4) blood-based immune markers, like CRP and other immune markers; and 
changes in RSFC using functional magnetic resonance imaging (MRI) scans and changes in BBB 
permeability using dynamic contrast enhanced MRI . 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 
KNOWN POTENTIAL RISKS 
 
2.3.1. A Risks of MRI Procedures 
The functional MRI procedure is very safe and exposes subjects to minimal risk or discomfort. The MRI 
scanning involves the subject placing his/her head in a tube and some subjects may experience a feeling 
of claustrophobia while in the scanner. The subjects are always in voice contact with a researcher or 
technician and the scanning session can be terminated quickly if the subject so requests. Subjects with 
metal objects including surgical clips or metallic prostheses (such as an artificial hip or knee), or shrapnel 
(metal fragments) will be excluded. The risk to the subject in the event that there is susceptible metal in 
or on his or her body is significant and may include death. Every subject will be carefully screened using 
existing standard operating procedures of the Biomedical Engineering and Imaging Institute (BMEII) for 
the presence of susceptible metal.  
 
MRI with Contrast: Gadolinium (MRI dye) is routinely used in medical imaging. As described in the MRI 
safety literature, it is a substance that is not normally absorbed into the tissues of the body. Once it is 
injected, it will stay in the blood stream and will be eliminated a few hours later in the urine. Some 
patients may have a reaction to this dye, which may be itching, nausea, breathing problems, vomiting, 
or a metallic taste. These reactions are very rare and usually occur in people who already have severe 
lung disease. There is a slight chance of an allergic reaction from the contrast which has a less than 1 in 
300,000 chance that this will be severe. 
 
A recent FDA warning has been issued that states subjects with kidney problems must not be given 
contrast because it may lead to debilitating and potential fatal disease that involves the skin, muscles, 
and internal organs. Patients with kidney disease can develop skin thickening that may prevent bending 
and extending joints, resulting in decreased mobility of joints. The chance of developing nephrogenic 
systemic fibrosis (NSF) is extremely low in individuals with normal kidney function. In addition, patients 
may experience scarring that has spread to other parts of the body such as the diaphragm, muscles in 
the thigh and lower abdomen, and the interior areas of lung.  
 
 
2.3.1. B Risks of ixekizumab  
The risks of ixekizumab are summarized below from the package insert provided by Ely Lilly (available at: 
https://uspl.lilly.com/taltz/taltz.html#pi) and are based on bi-weekly treatment in three placebo-
controlled studies for adult patients with plaque psoriasis (n = 1167).  Similar side effect profiles were 
observed in other studies that dosed ixekizumab once a month.   
 


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Most common (≥1%) adverse reactions associated with ixekizumab treatment are injection site 
reactions, upper respiratory tract infections, nausea, and tinea infections. Adverse reactions that 
occurred at rates less than 1% in the ixekizumab group and more frequently than in the placebo group 
during the 12-week induction period included rhinitis, oral candidiasis, urticaria, influenza, conjunctivitis, 
inflammatory bowel disease, angioedema, and abnormal laboratory values (complete blood count). 
Treatment with ixekizumab may worsen symptoms of active tuberculosis (TB) infection. Patients will be 
evaluated for TB infection prior to initiating treatment with ixekizumab.  
 
In the pooled data, infections occurred in 27% of subjects treated with ixekizumab compared to 23% of 
subjects treated with placebo. Serious infections occurred in 0.4% of subjects treated with ixekizumab 
and in 0.4% of subjects treated with placebo. 
 
There are no available data on ixekizumab use in pregnant women to inform any drug associated risks. 
Human IgG is known to cross the placental barrier; therefore, ixekizumab may be transmitted from the 
mother to the developing fetus. There are no data on the presence of ixekizumab in human milk, the 
effects on the breastfed infant, or the effects on milk production. 
 
2.3.1. C Psychological Screening Risks  
Answering questions related to mental health and past experiences may be stressful. Research 
interviews will be interrupted if subjects become distressed or object to answering questions. If in the 
judgment of the PI or study-affiliated psychiatrist, the patient has worsened to such a degree that 
further participation would put the patient at risk, then the subject will be discontinued from the study 
and provided appropriate clinical care. Also, at any point during the study any subject meeting DSM-5 
criteria for a manic episode or psychosis based on clinical interview by the Study PI or study-affiliated 
psychiatrist will be discontinued and provided appropriate clinical care.  
 
2.3.1. D Medical Screening Risks 
 
Subjects might feel pain during blood draw or when IV is inserted, and can develop bruising, and rarely, 
infection. The sight of blood or insertion of IV cannula may also cause dizziness or brief loss of 
consciousness due to vasovagal response. Therefore, all blood draws will be conducted by trained 
personnel, using aseptic precautions, and in a setting where the subject is resting comfortably and the 
risk of fall is minimized. 
 
2.3.1. E Privacy and Confidentiality Risks  
As the research study involves collection of protected and sensitive health information, there is a 
potential risk of loss of confidentiality. This risk will be conveyed to subjects as part of informed consent 
and will be minimized by using SOPs at our Center which comply with Health Insurance Portability and 
Accountability Act rules. 
 
2.3.1. F Financial risks 
Subjects will not be charged for any study procedures. However, in case they experience an adverse 
effect and seek care, they or their insurance provider will be responsible for this clinical care. This risk 
will be informed to the subject as part of informed consent process. 
 
 
2.3.2 
KNOWN POTENTIAL BENEFITS  
 


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All study subjects will be informed that there may not be any potential benefit to them individually as a 
result of taking part in the study. All study subjects will receive without cost an extensive psychiatric and 
medical evaluation which may be of potential benefit for the subjects. Furthermore, subjects may 
experience improvement in symptoms, including anhedonia, with the study drug. Participating subjects 
may gain knowledge about the biological and psychological processes of depression, which they may 
find interesting and helpful in dealing with illness. No other direct benefits result from study 
participation. 
 
 
2.3.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Data from clinical trials reveal that ixekizumab is well tolerated with minimal side effects during the first 
12 weeks of biweekly dosing. The majority of side effects compared to placebo are injection site 
reactions. Ixekizumab may minimally increase the risk of infection, as the drug group had a higher rate 
of injections than placebo (27% vs. 23%). Overall, the cumulative risks stemming from ixekizumab 
treatment, psychological screening, medical screening, privacy and confidentiality, financial exposure 
are manageable, and the benefit of acquiring data on a novel medication for TRD outweighs the risks.  
 
 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
 
The primary objective of the 
current study is to test the safety 
and feasibility of using ixekizumab 
in patients with TRD. 
 
 
Completion of treatment measured as 
the receipt of all three Ixekizumab 
injections (160 mg at week 0, 80 mg 
at weeks 2 and 4). Drop-out rates will 
be calculated. The incidence and 
frequency of all anticipated and 
unanticipated serious and non-serious 
adverse events that occur between 
baseline and study exit visit will be 
determined. 
 
The effect of Ixekizumab will be 
assessed by changes in depression 
Drop-out rates and 
treatment-related 
adverse events indicate 
the safety and 
tolerability of the study 
medication. 
 
 
The MADRS assessment 
is used as a gold-
standard for assessing 
changes in depression 


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severity as assessed with the 
Montgomery Asberg Depression 
Rating Scale (MADRS) scores from 
baseline to the end of treatment 
(EOT) visit (6-week post-treatment). 
 
 
severity in clinical trials. 
The MADRS will be the 
primary endpoint of the 
study as we will use it 
to test the 
antidepressant effects 
of ixekizumab, our 
primary objective in the 
study.   
Secondary 
 
 
 
The study will also test the effect of 
ixekizumab on  
 
(1) Changes in depression severity 
(as assessed by the MADRS from 
baseline to week 6 post-ixekizumab 
treatment); 2) response and 
remission rates with ixekizumab 
treatment; 3) change in measures 
of clinical symptoms, including 
anhedonia, anxiety, and 
functioning, and 4) change in blood-
based inflammatory markers 
including CRP and other immune 
markers. 
 
1) Baseline to week-6 changes in 
depression severity; 2) Response and 
remission rates at week 6 (defined as 
≥50% MADRS total score 
improvement and MADRS total score 
of ≤10, respectively); 3) Measures of 
global illness [Clinical Global 
Impression Severity (CGI-S) and 
Improvement (CGI-I) scale], overall 
depression [the Quick Inventory of 
Depressive Symptomatology, Self-
Report (QIDS-SR)], suicidal ideation 
and attempt [the Columbia Suicide 
Severity Rating Scale (C-SSRS)], 
anxiety [HAM-A], anhedonia [the 
Snaith Hamilton Pleasure Scale 
(SHAPS) and the Temporal Experience 
of Pleasure Scale (TEPS)], and 
symptoms associated with depression 
such as fatigue, sleep/wakefulness 
disturbances, anxiety, and irritability; 
4) Baseline to week-6 changes in 
blood-based immune markers, 
including CRP and other immune 
markers 
To collect pilot data on 
the potential 
antidepressant effects 
of ixekizumab and its 
effects on the 
measures taken in this 
study.  


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Exploratory 
 
 
The study will also test the effect of 
ixekizumab on changes in resting 
state functional connectivity (RSFC) 
of brain’s reward circuit and change 
in blood brain barrier (BBB) 
permeability. 
Baseline-to-week-6 changes in RSFC 
will be evaluated with resting-state 
functional magnetic resonance 
imaging (MRI) scans. Baseline-to-
week-6 changes in BBB permeability 
will be evaluated with dynamic 
contrast enhanced MRI. \ 
 
BBB permeability and  
RSFC will also be 
assessed to determine 
the effects of 
ixekizumab on these 
measures.  
 
 
 
 
4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
We will enroll up to N=20 adults (aged 18-70 years) with TRD, defined as inadequate 
improvement with two or more antidepressants in the current episode. If patients are on antidepressant 
medications, they must be on a stable dose for >4 weeks prior to treatment. Patients will not be on any 
medication or nutritional supplement known to affect inflammatory status. Primary inflammatory 
disorder or an unstable medical condition will also be exclusionary. Subjects will receive 3 doses (160 mg 
at week 0, 80 mg at week 2, 80 mg at week 4) in total of ixekizumab injection, with dosing to occur every 
2 weeks over a 6-week period. The primary clinical outcome will be safety and feasibility of ixekizumab 
as treatment for patients with TRD. The secondary clinical outcome will be change in MADRS from 
baseline to week 6, additional clinical outcomes, and changes in immune markers in the blood. 
Participants will undergo neuroimaging with DCE-MRI and rs-fMRI at baseline and at the primary 
outcome visit to measure the effect of treatment and change in depression severity on BBB permeability 
and reward circuit function. 
 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
We have selected to use an open-label study design for this study to determine the impact of 
ixekizumab in adults with TRD and no history of primary immune disorders. If successful, data from this 
study will be used to inform the design of larger randomized controlled clinical trials to further test the 
stated hypotheses.  
 
4.3 
JUSTIFICATION FOR DOSE 
The use of ixekizumab via subcutaneous route is consistent with the FDA-approved usage for other 
indications (psoriasis). The dosing regimen is based on the report by Griffiths et al.16 which evaluated the 
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patients with psoriasis and moderate-to-severe depression, ixekizumab was started at 160 mg. Over the 
next 12 weeks, patients either received 80 mg of ixekizumab every 2 weeks (Q2W), 80 mg of ixekizumab 
every 4 weeks (Q4W), or placebo. Remission from depressive symptoms was more common in those 
who received ixekizumab Q2W (45.2%) as compared to ixekizumab Q4W (33.6%) or placebo (17.8%). 
Therefore, our planned use of ixekizumab with dose of 160 mg at baseline, and 80 mg at weeks 2 and 4 
at a Q2W dosing interval is consistent with the dosing regimen found to be most effective in attaining 
remission of depressive symptoms in the Phase 3 clinical trials of patients with psoriasis and moderate-
to-severe depression. 
 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. Alternatively, a participant may be considered exited from the study due to early 
withdrawal, drop-out, or screen failure. See Section 7 for more details. 
 
5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
1. Written informed consent (and assent when applicable) obtained from subject; 
2. Ability for subject to comply with the requirements of the study as determined by the PI; 
3. Men and women, age 18-70 years; 
4. Participants must meet DSM-5 criteria for Major Depressive Disorder [MDD]) in a current 
major depressive episode (MDE) as determined by a study psychiatrist and confirmed using 
the Structured Clinical Interview for DSM-5 Research Version (SCID-5-RV); 
5. Participants have had ≥ 2 adequate trials of antidepressants/augmentation strategies during 
current episode. (Refer to ATRQ Guidelines for Completion for guidelines on dose/duration 
required for a trial to be considered adequate.); 
6. If patient is on antidepressant medication, they must be on a stable dose for >4 weeks prior 
to treatment; 
7. Quick Inventory of Depressive Symptoms – Clinician Administered (QIDS-C) score ≥ 14 
8. If female of childbearing potential, must agree to use of a medically accepted form of 
contraception, or else agree to abstinence until 6 months after the last dose of study drug. 
9. Male patients, if heterosexually active with a partner who is female of childbearing 
potential, pregnant, or breastfeeding, must agree to barrier contraception for the treatment 
period and for at least 6 months after the last dose of study drug. Female partners of male 
participants must use at least one form of highly effective contraception starting at least 
one cycle prior to male patient study drug initiation until 6 months after the last dose of 
study drug. 
 
5.2 
EXCLUSION CRITERIA 


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1.  A primary psychiatric diagnosis other than MDD as defined by DSM-5; [comorbid anxiety 
disorders (including agoraphobia, generalized anxiety disorder, social anxiety disorder and panic disorder) 
and posttraumatic stress disorder (PTSD) are allowed]; 
2.  Has a history of schizophrenia or other psychotic disorder, major depressive disorder with 
psychotic features, or bipolar I or II disorder; 
3.  Diagnosis of a major neurocognitive disorder; 
4. Meets criteria for a moderate or severe substance use disorder within the past 6 months, 
with the exception of nicotine use disorder; 
5. The patient is pregnant or breastfeeding; 
6.  Any contraindication to MRI or gadolinium including claustrophobia, any trauma or surgery 
which may have left magnetic material in the body, magnetic implants or pacemakers, inability to lie still 
for 1 hour or more, any known allergy to gadolinium;* 
7.  Positive urine toxicology screen for illicit drugs at the time of screening; 
8.  Serious and imminent risk of self-harm or violence as determined by the PI; 
9.  History of suicide attempt in the past 2 years or screening CSSRS Ideation Score >2 in the past 
month; 
10.  Clinically significant abnormalities of laboratory tests or physical examination; 
11. Any unstable medical illnesses including hepatic, renal, gastroenterological, respiratory, 
cardiovascular (including ischemic heart disease); endocrinologic, neurologic (including history of severe 
head injury), immunologic, or hematologic disease; 
12. Presence of TB as assessed by Quantiferon Gold test at screening; 
13. Concomitant treatments with other biologics or other immune-suppressant agents; PRN use 
of NSAIDs is permissible; 
14. Female participants who are pregnant, breastfeeding, or may become pregnant, or unwilling 
to practice birth control during participation in the study or the 6 months following; 
15. Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the patient or the quality of the data. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Not applicable. 
 
5.4 
SCREEN FAILURES 
 
If the patient fails to qualify for the study after signing the informed consent form, they will be 
considered a screen failure. Screen failures should be recorded on the electronic screening log along 
with the reason for disqualification. Patients who screen fail and are not randomized will be eligible to 
rescreen later. Patients should only be enrolled into the study once, therefore patients who have been 
randomized will not be eligible for future screening. 
 


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5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
5.5.A  Planned Recruitment Activities 
 
The research strategy for the present study calls for the enrollment of up to N=20 adults (aged 18-70 
years) with treatment-resistant depression over the two-year project period. Our total enrollment target 
of up to N=20 reflects individuals who are screened, eligible, and treated in the protocol. Anticipating 
screen fails, dropouts after enrollment and lost to follow-ups post-treatment, we plan to screen a total 
of N=40 individuals over the proposed 24-month recruitment period. This enrollment period provides 
for a highly feasible ~2 subjects screened and ~1 subject who complete baseline visits per month, 
allowing for 2-month follow-up after the enrollment of last subject. 
 
DAC has implemented a robust workflow for identifying and screening candidates for clinical research 
and employs direct-to-patient advertising through radio, newspaper, internet-based and other media 
outlets. A centralized programmatic intake process (under protocol STUDY-10-00606; A Screening 
Protocol for Adult Patients with Mood and Anxiety Disorders, Chronic Medical Conditions, and 
Healthy Volunteers.) is employed that includes a central phone line, a program-specific email, and a 
website featuring a web-based survey that patients can take to see if they qualify for studies. Individuals 
who contact DAC by completing the pre-screener online survey are automatically entered into a secure 
web-based database in order to be contacted by a member of the research staff for additional 
screening. 
  
In addition to recruiting individuals through the DAC centralized programmatic intake process, 
recruitment is also anticipated from the following additional sources: (1) patients with MDD who are 
currently receiving clinical care from providers (psychiatrists and psychologists) in DAC; (2) the Mount 
Sinai Hospital Adult Outpatient Psychiatry Clinic; (3) self-referrals from patients who have completed 
other research protocols through DAC; (4) clinicians within and outside of the Mount Sinai Health 
System, including large departments of psychiatry at Mount Sinai Beth Israel, Mount Sinai West, Mount 
Sinai Morningside, and Mount Sinai South Nassau; and (5) self-referrals from individuals attending 
community outreach programs in the New York State and tristate area and from media advertisements.  
The PI will review subject enrollment at weekly project meetings with the study coordinator and team 
members, so that any deviation from the anticipated enrollment schedule will be detected quickly.  All 
outreach and advertising activities will also be reviewed on a weekly basis. 
 
5.5.B Engagement Strategies for Retention 
 
The PI will hold weekly project meeting with the study coordinator in order to monitor enrollment and 
ensure that enrolled subjects are completing all study procedures as intended.  
 
In terms of infrastructure, the data coordinating facilities at ISMMS provides a secure, validated, 
centralized electronic data management facility that is HIPAA and FDA-compliant (Research Electronic 
Data Capture, or REDCap). The REDCap system employed in this study includes several components, 
including a Screening Database and a Subject Tracking Database, in addition to the Study Database 
proper. As subjects complete visits, the date of the visit will be entered into the database. Missed visits 
will be coded for reason (such as ill, scheduling problem, inability to contact, etc.). If subjects terminate 
early, the date and reason will be coded in the Subject Tracking Database.  On a weekly basis, the study 
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and completion status for review by the PI and the team. On an ongoing basis, the study data manager, 
the PI, and other team members will review the status of patient accrual and retention, as well as form 
completion, to identify and resolve any bottlenecks or problem areas that arise during the course of the 
study. 
 
At DAC, the study coordinator will be the subject’s point of contact during the study. Subjects will be 
provided with phone and email contact information for their coordinator, in addition to the contact 
information for the study PI.  
 
5.5.C Strategies that will be used to ensure a diverse, representative study sample 
 
The ISMMS is part of a large urban medical center, and benefits from a large and diverse catchment 
area. Located in the Manhattan borough of New York City, the racial and ethnic distribution of Mount 
Sinai’s catchment area is 49% Hispanic, 38% African American, and 13% white non-Hispanics. The 
catchment area of the Mount Sinai’s affiliated hospitals in Queens and the Bronx includes 22% 
Hispanics, 23% white non-Hispanics, 26% Asians and 24% African Americans. For the proposed clinical 
trial there are no special restrictions with regard to ethnicity or race. It is expected that the study sample 
will closely approximate the racial and ethnic composition of the greater catchment area of the Mount 
Sinai Health System. 
 
5.5.D Potential recruitment/enrollment challenges and strategies that can be implemented in the 
event of enrollment shortfalls  
 
Anticipated study related barriers may involve issues including staff workload and scheduling windows. 
This will be addressed by including coordinators who serve as back-up for the primary study coordinator 
responsible for the proposed project. These back-up staff members will allow the study team to screen 
and enroll subjects and complete study visits within subject’s availability. All study staff will be trained 
by the PI and study procedures will be reviewed at weekly project meetings to ensure consistency of 
study procedures across both primary and back-up study personnel. 
 
Some participant related barriers include appointment scheduling, transportation issues, and 
maintaining contact between study visits. To ensure that subjects can attend appointments, whenever 
possible, the visit schedule will include flexibility. To help address transportation issues, the study team 
will offer patients metro cards and other transportation resources available through DAC. The research 
staff will check voicemail and email daily to be able to respond to any patient contact and will reach out 
before each scheduled appointment to ensure that subjects are still available and able to complete the 
visit as scheduled.   
 
6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION  
 
6.1.1 
STUDY INTERVENTION DESCRIPTION 
 
Ixekizumab is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (mAb) with 
neutralizing activity against IL-17A. Ixekizumab is produced by recombinant DNA technology in a 
recombinant mammalian cell line and purified using standard technology for bioprocessing. Ixekizumab 
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chain polypeptides of 445 amino acids each, and has a molecular weight of 146,158 Daltons for the 
protein backbone of the molecule.  
 
Ixekizumab injection is a sterile, preservative free, clear and colorless to slightly yellow solution, for 
subcutaneous use available as 80 mg of ixekizumab in a 1 mL single-dose prefilled auto injector or a 
single-dose prefilled syringe. The prefilled auto injector and prefilled syringe each contain a 1 mL glass 
syringe with a fixed 27 gauge ½ inch needle. The ixekizumab 80 mg prefilled auto injector and prefilled 
syringe are manufactured to deliver 80 mg of ixekizumab. Each mL is composed of ixekizumab (80 mg); 
Citric Acid Anhydrous, USP (0.51 mg); Polysorbate 80, USP (0.3 mg); Sodium Chloride, USP (11.69 mg); 
Sodium Citrate Dihydrate, USP (5.11 mg); and Water for Injection, USP. Ixekizumab solution has a pH of 
5.3 – 6.1. 
 
Ixekizumab is a humanized IgG4 monoclonal antibody that selectively binds with the interleukin 17A (IL-
17A) cytokine and inhibits its interaction with the IL-17 receptor. IL-17A is a naturally occurring cytokine 
that is involved in normal inflammatory and immune responses. Ixekizumab inhibits the release of 
proinflammatory cytokines and chemokines.  
 
6.1.2 
DOSING AND ADMINISTRATION 
 
Ixekizumab will be administered by subcutaneous injection. The dose is 160g (two 80 mg injections) at 
Week 0, followed by 80 mg at Weeks 2, and 4. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
 
6.2.1 
ACQUISITION AND ACCOUNTABILITY 
 
Ixekizumab will be obtained from commercial supplies by the Investigational Drug Service (IDS) at 
ISMMS.  
 
6.2.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Ixekizumab injection for subcutaneous use manufactured by Eli Lilly.  
 
Ixekizumab injection is a sterile, preservative free, clear and colorless to slightly yellow solution, for 
subcutaneous use available as 80 mg of ixekizumab in a 1 mL single-dose prefilled auto injector or a 
single-dose prefilled syringe. The prefilled auto injector and prefilled syringe each contain a 1 mL glass 
syringe with a fixed 27 gauge ½ inch needle. The ixekizumab 80 mg prefilled syringe are manufactured to 
deliver 80 mg of ixekizumab. Each mL is composed of ixekizumab (80 mg); Citric Acid Anhydrous, USP 
(0.51 mg); Polysorbate 80, USP (0.3 mg); Sodium Chloride, USP (11.69 mg); Sodium Citrate Dihydrate, 
USP (5.11 mg); and Water for Injection, USP. The ixekizumab solution has a pH of 5.3 – 6.1. 
 
6.2.3 
PRODUCT STORAGE AND STABILITY 
 


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Ixekizumab injection is a sterile, preservative free, clear and colorless to slightly yellow solution available 
in a single-dose prefilled syringe to deliver 80 mg ixekizumab. 
 
Ixekizumab is sterile and preservative-free. Discard any unused portion. Ixekizumab must be protected 
from light until use. Store refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Do not use Ixekizumab 
if it has been frozen. Do not shake. Discard the Ixekizumab single-dose syringe after use in a puncture-
resistant container. Not made with natural rubber latex. 
 
 
6.2.4 
PREPARATION 
Ixekizumab will be provided in a single dose prefilled syringe.  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
6.3.1 RANDOMIZATION AND BLINDING 
This study will be open-label with one treatment condition. Given that this study is open label with one 
treatment condition, participants cannot be blinded. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
An accurate and current accounting of the dispensing of study drug for each subject will be maintained 
on an ongoing basis by a member of the study site staff. The investigational site must keep an accurate 
inventory of study drug shipments received and the amount of study drug dispensed per patient on the 
Investigational Drug Accountability Record. At the end of the study, a full reconciliation of drug inventory 
will be performed. After a full reconciliation, any unused study drug will be destroyed by study personnel 
(if the site has the capability to do so, in accordance with applicable regulations) or sent to a designee for 
subsequent destruction. If no study drug remains, this will be indicated in the drug accountability log. 
 
 
6.5 
CONCOMITANT THERAPY 
 
Participants will be permitted to remain on a stable dose of their psychotropic medications, per 
eligibility criteria. Concomitant treatments with other biologics or other immune-suppressant agents will 
be exclusionary. PRN use of NSAIDs is permissible. 
 
6.5.1 
RESCUE MEDICINE 
  Not applicable. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
A subject may be discontinued from study treatment at any time if the subject, the investigator, or the 
Sponsor feels that it is not in the subject’s best interest to continue. The following is a list of possible 
reasons for study treatment discontinuation: 
● Subject withdrawal of consent 
● Subject is not compliant with study procedures 


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● Adverse event that in the opinion of the investigator would be in the best interest of the subject 
to discontinue study treatment 
● Protocol violation requiring discontinuation of study treatment 
● Lost to follow-up 
● Sponsor request for early termination of study 
● Positive pregnancy test (females) 
  
Subjects who discontinue study treatment should come in for an early discontinuation visit as soon as 
possible. For patients who are lost to follow up, it may not be possible to complete early discontinuation 
procedures. For subjects who wish to withdraw consent, they will be asked to do so in writing following 
the completing of an early discontinuation visit. Some subjects may not agree and wish to withdraw 
consent immediately in which case these early discontinuation procedures may not occur. Reasonable 
attempts will be made by the investigator to provide a reason for subject discontinuation from study 
treatment. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
A subject may be withdrawn from the study at any time if the subject or the investigator-sponsor feels 
that it is not in the subject’s best interest to continue. All subjects are free to withdraw from participation 
at any time, for any reason, specified or unspecified, and without prejudice. 
  
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals. The 
reason for the subject’s withdrawal from the study will be specified in the subject’s source documents. 
As noted above, subjects who discontinue study treatment early (i.e., they withdraw prior to Visit 6) 
should have an early discontinuation visit. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for any of the scheduled 
visits and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
● The site will attempt to contact the participant and reschedule the missed visit as well as 
counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
● Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
● Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
CLINICAL OUTCOMES AND SAFETY MEASURES 
Clinical Assessments 
 


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Demographics: Demographic information (date of birth, gender, race/ethnicity) will be recorded at 
screening. 
 
Medical History: Relevant medical history, including history of current disease, other pertinent history, 
and information regarding underlying diseases will be recorded at screening.  
 
Physical Examination: A complete physical examination will be performed by qualified staff (MD, NP, RN, 
or PA) at screening and primary outcome (week 6). New abnormal physical exam findings must be 
documented and will be followed by a physician or other qualified staff at the next scheduled visit. If a 
novel adverse event is found at study exit, subjects will be followed for up to 30 days or until resolved. 
 
Vital Signs: Body temperature, blood pressure, pulse and respirations will be performed after resting for 
5 minutes at screening, each of the three treatment visits, and at Visit 4, the primary outcome visit.  
Structured Clinical Interview for DSM-5 (SCID-5). The Structured Clinical Interview for DSM-5 (First et al. 
2015) is a semi-structured interview guide for making DSM-5 diagnoses. It includes an overview to obtain 
information about demographics, work history, chief complaint, and history of present illness, past 
history, treatment history, and current functioning. The main body of SCID-5 includes 9 modules that are 
designed to diagnose 51 mental illnesses in all. During the study screening period, the SCID-5 will be 
administered by a trained study team member who has completed SCID-5-RV training and who is familiar 
with the DSM-5 classification and diagnostic criteria. The current study will utilize the most comprehensive 
version of the SCID-5, the SCID-5-Research Version (RV), which contains more disorders than the Clinician 
Version and includes all of the relevant subtypes, severity, and course specifiers. An important feature of 
the SCID-5-RV is its customizability, allowing the instrument to be tailored to meet the requirements of a 
particular study. The SCID-5-RV comes in a standard "core" configuration that includes the disorders most 
researchers are likely to assess routinely for most studies, as well as in an “enhanced” configuration that 
includes a number of optional disorders, in addition to the disorders from the "core" configuration. 
  
Antidepressant Treatment History Questionnaire (ATRQ): The ATRQ17 is a self-rated scale used to 
determine treatment resistance in major depressive disorder (MDD) during the current episode. The ATRQ 
defines 6 weeks as an adequate duration of treatment and provides specific operational criteria for 
adequate dosage for each of the most commonly used antidepressant medications. 
  
Montgomery-Asberg Depression Rating Scale (MADRS):18 this is a 10 
-item instrument used for the evaluation of depressive symptoms in adults and for the assessment of any 
changes to those symptoms.  Each of the 10 items is rated on a scale of 0 to 6, with differing descriptors 
for each item. These individual item scores are added together to form a total score, which can range 
between 0 and 60 points. The MADRS provides a measure of the overall level of depression. 
  
Snaith-Hamilton Pleasure Scale (SHAPS): The SHAPS19 is a well-validated 14-item self-report questionnaire 
commonly used to assess anhedonia. Each item on the SHAPS is worded so that higher scores indicate 
greater pleasure capacity. A total score can be derived by summing the responses to each item. Items 
answered with “strongly agree” are coded as “1”, while a “strongly disagree” response was assigned a 
score of “4.” Total scores on the SHAPS can range from 14 to 56, with higher scores corresponding to 
higher levels of anhedonia. 
 
Temporal Experience of Pleasure Scale (TEPS): The TEPS is an 18-item self-report measurement of 
anhedonia which consists of a series of statements that must be rated according to how accurate they are 


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for the individual.20  The scale produces two sub-scores that differentiate the role of anticipatory pleasure 
(‘wanting’) from consummatory pleasure (‘liking’). The anticipatory sub-score (TEPS-ant) is derived of 10 
items while the consummatory sub-score (TEPS-cons) is derived from 8 items. 
 
The Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR): The QIDS-SR21 is a 16-item 
self-rated instrument designed to assess the severity of depressive symptoms. The 16 items cover the 
nine symptom domains of major depression and are rated on a scale of 0-3. Total score ranges from 0 to 
27, with ranges of 0-5 (normal), 6-10 (mild), 11-15 (moderate), 16-20 (moderate to severe), and 21+ 
(severe). 
 
The Quick Inventory of Depressive Symptomatology, Clinician Rated (QIDS-C): The QIDS-C21 is a 16-item 
instrument designed to assess the severity of depressive symptoms. The 16 items cover the nine symptom 
domains of major depression and are rated on a scale of 0-3. Total score ranges from 0 to 27, with ranges 
of 0-5 (normal), 6-10 (mild), 11-15 (moderate), 16-20 (moderate to severe), and 21+ (severe). This 
instrument will be used at the screening visit. 
 
Clinical Global Impression - Severity (CGI-S): this is a widely administered clinician rated global measure 
of subject overall illness severity. Subjects are rated on a 1-7 scale where 1 corresponds to “Normal, Not 
at All Ill”, 2 is “Borderline Mentally Ill”, the anchor for 3 is “Mildly Ill”, the anchor for 4 is “Moderately Ill”, 
5 is “Markedly Ill”, 6 is “Severely Ill”, and 7 is “Among the Most Extremely Ill Patients”. 
 
Clinical Global Impression - Improvement (CGI-I): this is a widely administered clinician rated global 
measure of the degree of improvement from the initial assessment in subject overall illness severity. 
Subjects are rated on a 1-7 scale where 1 corresponds to “Very Much Improved”, 2 is “Much Improved”, 
the anchor for 3 is “Minimally Improved”, the anchor for 4 is “No Change”, 5 is “Minimally Worse”, 6 is 
“Much Worse”, and 7 is “Very Much Worse”. 
  
Columbia-Suicide Severity Rating Scale (C-SSRS): The Columbia-Suicide Severity Rating Scale (C-SSRS)22 is 
a comprehensive, semi-structured interview that uniquely measures the full spectrum of suicidality 
including passive and active suicidal ideation, suicidal intent as well as suicidal behaviors. Subjects will be 
assessed at every visit with the CSSRS by a qualified rater. Study participants will meet with a study 
physician at each study visit, which will include a review of the C-SSRS. Any subject with an increase in 
suicidality and all those subjects found to have a plan or intent will undergo thorough assessment by the 
study psychiatrist. If, at any point during the clinical trial, a participants will be assessed by the study 
physician with a suicidal ideation with any intent or plan, as measured by a C-SSRS score of greater than 
2 during the past week and with either a CGI-S score ≥6 (indicating extreme illness severity) or a CGI-I 
score ≥ 6 (indicating an extreme worseness of the symptoms), the site PI, or his designee, will conduct a 
safety review to determine the appropriate course of action including whether acute intervention is 
needed and whether it is in the best interests of the subject to continue in the study. 
 
Hamilton Anxiety Rating Scale (HAM-A): The Hamilton Anxiety Rating Scale (HAM-A) is a scale of 
assessments of anxiety states. The scale consists of 14 items, each defined by a series of symptoms, and 
measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical 
complaints related to anxiety). Each item is scored on a scale of 0 (not present) to 4 (severe), with a total 
score range of 0–56, where <17 indicates mild severity, 18–24 mild to moderate severity and 25–30 
moderate to severe. 
  
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Resting State fMRI (R-fMRI): Approximately 10 minutes worth of resting state fMRI data will be collected 
both pre- and post-treatment. Participants will be instructed to rest, eyes open and fixed on a central 
fixation cross, and to try to remain as still as possible. R-fMRI data will be examined primarily as an 
exploratory aim and additionally contributes to the common data element initiative. As there are a 
number of serious, potential confounds to the analysis of R-fMRI, advanced processing and analytic 
methods will be employed, including the use of robust artifact detection and removal.23 We will conduct 
targeted analysis to explore whether treatment alters connectivity and network patterns with known 
abnormalities and that are specifically impacted by our treatment (e.g., fronto-striatal connectivity 
implicated in reward; see Heller et al., 201324).  
 
Clinical Laboratory Measurements 
 
Hematology and Blood Chemistry Profile: Blood will be obtained at screening and primary outcome (week 
6) and sent to each site’s clinical hematology lab for a Hemoglobin, Hematocrit, Electrolytes, Metabolic 
Panel, Thyroid Function Tests, Hepatic and Renal Function Tests. At screening, blood will also be obtained 
to assess for existing TB infection. 
 
Pregnancy Test: A urine pregnancy test will be obtained from female subjects who are of childbearing age 
prior to their participation in the study (screening visit), at Visit 1 (Week 0), Visit 2 (Week 2), Visit 3 (Week 
4), and primary outcome Visit 4 (Week 6). 
 
Urinalysis and Urine Toxicology: Urine will be obtained at the site’s clinical laboratory for determination 
of color, urine specific gravity, osmolality, cellules, proteins and bacteria prior to their participation in the 
study (screening visit) and at study primary outcome (week 6). A urine toxicology screen for drugs of abuse 
will be performed at screening and on the day of both the pre-treatment and post-treatment scans (Visit 
1 and 4).  
 
Blood Immunological Measures: Blood will be obtained at baseline and primary outcome to be analyzed 
for inflammatory biomarkers and neurotrophic biomarkers. In brief, inflammatory biomarkers and 
neurotrophic factors will be measured using commercially available enzyme-linked immunosorbent 
assays or multiplex panels to analyze several biomarkers at once. Serum cytokine levels were chosen as 
biomarkers of inflammation because prior studies revealed a link between these biomarkers and 
depression.  
 
8.2 
EVALUATIONS BY VISIT 
 
SCREENING VISIT (V0, WEEK -4 – 0) 
1. Review the study with the subject and obtain written informed consent and HIPAA authorization. 
2. Review inclusion and exclusion criteria. 
3. Assign the subject a unique screening number. 
4. Record demographics data. 
5. Record medical, psychiatric, family, medication and treatment history, diagnosis date, and prior 
treatments. 
6. Record concomitant medications. 
7. Perform self and clinician administered ratings scale: 


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 
SCID-5-RV 
 
CGI-S 
 
CSSR-S – Past month 
 
QIDS-C 
8. Perform a complete physical examination. 
9. Perform and record vital signs. 
10. Urine for urinalysis, urine toxicology and pregnancy test (female subjects who are of childbearing 
age). 
11. Collect blood for clinical laboratory tests. 
12. Schedule subject for Baseline (Visit 1) within 4 weeks of Screening. 
 
Note: The screening visit may occur on up to three separate days. The whole procedures will be 
completed before the treatment day and within four weeks of the first screening visit. Screening 
measures may be completed under a separate screening protocol at each site. As long as the 
assessments are completed within four weeks of the signing of consent for this protocol, the screening 
measures will not be repeated. Subjects who are deemed screen fails may be re-screened at a later date, 
based on PI discretion. If re-screened, subjects will repeat all screening procedures.  
A portion of this visit, including clinician administered rating scales, may be completed remotely via a 
HIPAA-compliant virtual platform. 
 
BASELINE (V1, WEEK 0) 
1. Obtain interval medical history. 
2. Record any AEs. 
3. Record changes to concomitant medications. 
4. Collect urine for urine toxicology and pregnancy test (female subjects who are of childbearing age). 
5. Record vital signs  
6. Perform self and clinician administered ratings scale: 
 
MADRS 
 
CSSRS-Since Last Visit 
 
HAM-A 
 
CGI-S 
 
CGI-I 
 
SHAPS 
 
TEPS 
 
QIDS-SR 
7. Neuroimaging procedures. 
8. Collect blood immunological measures. 
9. Dispense study medication.  
 
Note: The Baseline Visit should take place within four-weeks of the date that the subject signed consent 
for this study. The Baseline Visit may occur on up to two separate days within 5 business days of each 
other. The neuroimaging procedures must be completed before the subject is randomized and receives 


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the study drug.   
 
VISIT 2 (WEEK 2) 
1. Obtain interval medical history. 
2. Record vital signs 
3. Record any AEs. 
4. Record changes to concomitant medications. 
5. Collect urine for a pregnancy test, (female subjects who are of childbearing age) 
6. Perform self and clinician administered ratings scale: 
 
MADRS 
 
CSSRS-Since Last Visit 
 
HAM-A 
 
CGI-S 
 
CGI-I 
 
SHAPS 
 
TEPS 
 
QIDS-SR 
7. Dispense study medication.  
 
VISIT 3 (WEEK 4) 
1. Obtain interval medical history. 
2. Record any AEs. 
3. Record changes to concomitant medications. 
4. Record vital signs  
5. Collect urine for a pregnancy test, (female subjects who are of childbearing age) 
6. Perform self and clinician administered ratings scale: 
 
MADRS 
 
CSSRS-Since Last Visit 
 
HAM-A 
 
CGI-S 
 
CGI-I 
 
SHAPS 
 
TEPS 
 
QIDS-SR 
7. Dispense study medication. 
 
VISIT 4 (WEEK 6) 
1. Obtain interval medical history. 
2. Record any AEs. 
3. Record changes to concomitant medications. 
4. Perform self and clinician administered ratings scale: 
 
MADRS 
 
CSSRS-Since Last Visit  
 
HAM-A 


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 
CGI-S 
 
CGI-I 
 
SHAPS 
 
TEPS 
 
QIDS-SR 
5. Perform a complete physical examination. 
6. Perform and record vital signs. 
7. Urine for urinalysis, urine toxicology, and pregnancy test (female subjects who are of childbearing 
age). 
8. Collect blood for clinical laboratory tests and immunological measures. 
9. Neuroimaging Procedures. 
 
STUDY EXIT - VISIT 5 (WEEK 8) 
10. Obtain interval medical history. 
11. Record any AEs. 
12. Record changes to concomitant medications. 
13. Perform self and clinician administered ratings scale: 
 
MADRS 
 
CSSRS-Since Last Visit  
 
HAM-A 
 
CGI-S 
 
CGI-I 
 
SHAPS 
 
TEPS 
 
QIDS-SR 
 
Note: This visit, including clinician administered rating scales, may be completed remotely via a HIPAA-
compliant virtual platform. 
Note: Study Visits 2, 3, and 4 are due to take place 2, 4, and 6 weeks after the baseline visit 1 (week 0) 
respectively. To allow for scheduling feasibility, Visits 1-5 can take place within 5 days before or after the 
scheduled visit.  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 
DEFINITION OF ADVERSE EVENTS (AE) 
An Adverse Event (AE) is any untoward medical occurrence in a study subject administered as an 
investigational product and that does not necessarily have a causal relationship with this treatment. 
  
An AE therefore can be any unfavorable and unintended sign (including laboratory finding), symptom or 
disease temporally associated with participation in an investigational study, whether or not considered 
drug-related.  In addition to new events, any increase in the severity or frequency of a pre-existing 
condition that occurs after the subject signs a consent form for participation is considered an AE.  This 
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Any condition, laboratory abnormality, or physical finding with an onset date prior to the subject signing 
consent for study participation is considered to be pre-existing in nature and part of the subject’s medical 
history and will not be recorded as AEs. 
 
8.3.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
· Death 
· Life threatening experience defined as any adverse experience that places the subject, in the view of 
the treating physician, at immediate risk of death at the time of occurrence; i.e, it does not include a 
reaction that, had it occurred in a more severe form, might have caused death. 
· Requires inpatient hospitalization or prolongation of an existing hospitalization (except scheduled 
hospitalizations for non-acute, unrelated cause such as an elective surgery) 
· Results in persistent or significant disability/incapacity 
· Is a congenital anomaly/birth defect in the offspring of an exposed subject 
· Important medical events that may not result in death, be life threatening, or require hospitalization, 
may be considered an SAE when, based upon appropriate medical judgment, it jeopardizes the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
· Any death occurring within 30 days of the subject receiving study drug, regardless of the subject 
having discontinued from the protocol, must be reported as an SAE. 
 
 
8.3.3 
CLASSIFICATION OF AN ADVERSE EVENT 
SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”.] 
 
 
RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 


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• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.] 
 
EXPECTEDNESS  
 
The Principal Investigator (PI)  will be responsible for determining whether an adverse event (AE) is 
expected or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the risk information previously described for the study intervention.] 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 


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Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The Principal Investigator will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 
study participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs 
since the last visit.  Events will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
To IRB, PI, Sponsor, and DSMB 
  
Any AE must be recorded on the appropriate CRF/eCRF. All AE/SAEs that are considered related to study 
drugs must be followed to resolution or stabilization if improvement is not expected. AE/SAEs that 
completely resolve and then recur should be recorded as a new AE/SAE. AE/SAEs that are considered 
related to study drug and continuing at 30 days post-last dose should have a comment in the source 
documents by the site PI that the event has stabilized or is not expected to improve. 
  
Any SAE occurring during the study period (beginning with informed consent and lasting until 30 days 
after the last dose of study drug) must be immediately reported no later than 3 business days after 
learning of an SAE to the Study PI. 
  
All AE/SAEs with an onset date after the subject signs consent for study participation must be reported to 
the IRB at the time of annual renewal. Details of the event must include seriousness, severity, 
expectedness, relationship to study drug, duration, action taken, and outcome.   
  
All AE/SAEs that are drug-related and unexpected (not listed as treatment-related in the current 
Investigator’s Brochure) must be reported to the PI and IRB as detailed below in Section 11.5 
“Unanticipated Problem Reporting”. 
 
To FDA 
A report on the MedWatch 3500A form must be sent to the FDA when the event is: 
 
(1) serious unexpected suspected reaction (the investigator judges there is evidence to suggest a causal 
relationship); 
(2) findings from other clinical, animal, or in-vitro studies that suggest significant human risk and 
(3) a clinically important increase in the rate of a serious suspected adverse reaction no later than 15 days 
after determining that the information qualifies for reporting. 
  
The relevant health authorities will be notified of any unexpected serious adverse reactions (SUSARs) 
within the required reporting timelines (within 7 calendar days for fatal and life-threatening SUSARs, or 
15 calendar days for all other SUSARs). 


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8.3.6 SERIOUS ADVERSE EVENT REPORTING  
The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or package insert and must 
include an assessment of whether there is a reasonable possibility that the study intervention caused 
the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported 
in accordance with the protocol unless there is evidence suggesting a causal relationship between the 
study intervention and the event (e.g., death from anaphylaxis). In that case, the investigator must 
immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable.  
 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information.  In addition, the sponsor must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting. 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Participants will be notified of any abnormal clinical lab findings and directed to appropriate medical 
care. In the event that a participant’s pregnancy test returns positive, the participant will be notified 
immediately and exited from the study.  
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
Not applicable. 
 
8.3.9 REPORTING OF PREGNANCY  
Subjects will be asked to immediately inform the study team and their doctor if any of the following occur: 
· They become pregnant while taking the study drug 
· They miss their menstrual period, or experiences unusual menstrual bleeding 
· They stop using birth control 
· They think, FOR ANY REASON, that they may be pregnant 
  
Pregnancies occurring while the subject is participating in the study or within 30 days after the subject’s 
administration of study drug are considered expedited reportable events. The pregnancy will be 
considered an immediately reportable event and will be reported to the study PI within 5 business days 
of the site PI becoming aware of the event.  
 
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 
DEFINITION OF UNANTICIPATED PROBLEMS (UP) 


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The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
•
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the
participant population being studied;
•
Related or possibly related to participation in the research (“possibly related” means there is a
reasonable possibility that the incident, experience, or outcome may have been caused by the
procedures involved in the research); and
•
Suggests that the research places participants or others at a greater risk of harm (including
physical, psychological, economic, or social harm) than was previously known or recognized.
8.4.2 
 UNANTICIPATED PROBLEM REPORTING 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will 
include the following information: 
•
Protocol identifying information: protocol title and number, PI’s name, and the IRB project
number;
•
A detailed description of the event, incident, experience, or outcome;
•
An explanation of the basis for determining that the event, incident, experience, or outcome
represents an UP;
•
A description of any changes to the protocol or other corrective actions that have been taken or
are proposed in response to the UP.
8.4.3 
REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
Not applicable. 
9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
●
Primary Efficacy Endpoint(s):
The primary efficacy endpoint is the completion of treatment measured as the receipt of all three 
Ixekizumab (160 mg at week 0, 80 mg at weeks 2 and 4) to assess the safety and feasibility of ixekizumab 
in patients with TRD. The analysis of the primary endpoint for this study will be descriptive and no 
formal hypothesis testing with be conducted. 
●
Secondary Efficacy Endpoint(s):
Secondary efficacy endpoints include 1) Baseline-to-week-6 changes in depression severity, as measured 
by MADRS; 2) Response and remission rates at week 6; 3) changes in other clinical symptoms ;4) 


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Baseline-to-week-6 changes in RSFC as evaluated by fMRI scans and changes in BBB permeability; 5) 
Baseline-to-week-6 changes in blood-based immune markers, including CRP and other immune markers; 
6) the relationship between baseline-to-week-6 changes in blood-based immune markers and RSFC with 
changes in depression severity scores. Analyses of secondary efficacy endpoints will be considered 
exploratory and hypothesis-generating. Therefore, no formal hypothesis testing will be conducted. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
In this study, up to 20 patients will be enrolled. We anticipate 80% of more of the sample will complete 
treatment (<20% early drop out) and the treatment will be well-tolerated with no treatment-related 
adverse effects. A sample size of 20 patients will produce a two-sided 95% confidence interval around 
the proportion who completed treatment with a width equal to 0.35 when the sample proportion is 0.8. 
Precision was estimated using PASS 2019 (26). 
 
9.3 
POPULATIONS FOR ANALYSES 
 
Intent-to-Treat (ITT) Population 
The ITT population will consist of all enrolled subjects regardless of whether or not they actually 
received ixekizumab. This sample will be used for summaries and analyses of the primary endpoint and 
the secondary endpoints.  
 
 
Safety Analysis set 
The safety analysis set will include all enrolled participants who were given at least one dose of 
ixekizumab, and on whom any post-dose data are available and are classified according to the treatment 
actually received. The safety analysis set will be used to assess safety and tolerability variables.  
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 
GENERAL APPROACH 
 
Continuous variables will be summarized using the following descriptive statistics: number of non-missing 
values, means, standard deviations, medians, interquartile range, maximum, and minimum.  Categorical 
variables will be summarized using number of non-missing values, counts and percentages.  
 
Rates of events will be calculated as the ratio of the total number of events recorded divided by the total 
patient-time. Total patient-time will be calculated by summing the time (in study time units, e.g., days or  
months) that patients were at risk for a specific event from the reference time point until either study exit or 
the end of the time period of interest. Rates and their 95% confidence intervals will be reported.   
 
Time-to-event variables will be summarized using the Kaplan-Meier method. 
 
For any variable measured at multiple points in time, change from baseline will be calculated as the 
difference between the value of the variable at a specific point in time (e.g. 6 weeks) minus the baseline 
value.  Relative change from baseline will be calculated as the value of a parameter at a specific point in 


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time minus the baseline value of the parameter divided by the baseline value of the parameter.  Percent 
change will be calculated as the relative change multiplied by 100. 
All hypothesis testing will be conducted at the 0.05 two-sided significance level unless otherwise specified.   
P-values will be rounded to three decimal places. P-values less than 0.001 will be reported as <0.001 in tables. 
P-values greater than 0.999 will be reported as >0.999. 
Should any of the statistical methods proposed prove unsuitable during data analysis, more appropriate 
methods will be used. These include data transformation (for example to a logarithmic scale) to satisfy model 
assumptions such as normally distributed residuals with constant variance, the application of non-parametric 
techniques or the use of a different link function or modeling technique. The SAP will be updated with the 
methods used and the justification for the change prior to data set and database lock. 
 
9.4.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary efficacy endpoint is the completion of treatment measured by the receipt of all three 
ixekizumab injections (160 mg at week 0, 80 mg at weeks 2 and 4) to assess the safety and feasibility of 
ixekizumab in patients with TRD. The analysis of the primary endpoint for this study will be descriptive. 
The proportion of enrolled patients that complete treatment and the corresponding 95% confidence 
interval will be reported. 
9.4.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) 
1) Baseline-to-week-6 changes in depression severity, measured by MADRS scores 
MADRS scores will be reported descriptively at each time point using the number observed, mean, 
standard deviation, median, and interquartile range. Individual patient trajectories will be plotted over 
time to explore patterns in treatment response. Mean change in MADRS scores from baseline and 
corresponding 95% confidence intervals will also be reported at each time point. 
2) Response and remission rates at week 6 
The number and proportion of patients who respond ot treatment and who remain in remission will be 
reported at each time point. 
3) Baseline-to-week 6 changes in other clinical symptoms as measured by CGI-S, CGI-I, QIDS-SR, C-SSRS, 
SHAPS, TEPS, and HAM-A. 
 
4) Baseline-to-week-6 changes in RSFC as evaluated by fMRI scans and changes in BBB permeability 
RSFC and BBB permeability will be analyzed in the same manner described above for MADRS scores. 
5) Baseline-to-week-6 changes in blood-based immune markers, including CRP and other immune markers 
Biomarkers will be analyzed in the same manner described for MADRS scores above. 


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6) the relationship between baseline-to-week-6 changes in blood-based immune markers and RSFC and 
BBB permeability with changes in depression severity scores.  
We will explore whether improving depressive symptoms correlate with changes in blood-based 
immune markers and RSFC and BBB permeability. MADRS scores will be plotted with biomarkers, RSFC, 
and BBB over time to evaluate trends descriptively. Fixed and mixed effects regression models may also 
be explored to estimate associations and 95% confidence intervals. 
 
9.4.4 
SAFETY ANALYSES 
 
All safety analyses will be conducted in the safety population. 
 
Safety and tolerability data will also be summarized descriptively. Adverse events will be categorized 
using the Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred terms. 
For each group, number and rates of events and number and percent of patients will be tabulated by 
preferred term and system organ class.  
 
All laboratory test results, vital signs, weight, and BMI will be summarized using descriptive statistics at 
each visit for raw numbers and change from baseline. Suicidality measures based on the C-SSRS will be 
summarized for each treatment group using descriptive statistics at each assessment.  
 
9.4.5 
BASELINE DESCRIPTIVE STATISTICS 
 
Baseline characteristics will be reported descriptively.  Continuous variables will be summarized using the 
number of non-missing values, means, standard deviations, medians, interquartile range, maximum, and 
minimum.  Categorical variables will be summarized using number of non-missing values, counts and 
percentages.  
 
9.4.6 
PLANNED INTERIM ANALYSES  
No interim analyses are planned. 
 
9.4.7 
SUB-GROUP ANALYSES 
 
No sub-group analyses are planned.  
 
9.4.8 
TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Per NIMH policy, we will submit a final deidentified data set, listed by measure and time point, as part of 
the data sharing plan.  
 
9.4.9 
EXPLORATORY ANALYSES 
 


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Treatment effects on R-fMRI data will be explored. It is hypothesized that Ixekizumab will result in 
neuroimaging changes in resting state functional connectivity, and blood brain barrier permeability, 
evaluated with magnetic resonance imaging (MRI) scans. As there are a number of serious, potential 
confounders to the analysis of R-fMRI, advanced processing and analytic methods will be employed, 
including the use of robust artifact detection and removal (Pruim et al., 2015). We will conduct targeted 
analysis to explore whether treatment alters connectivity and network patterns with known 
abnormalities and that are specifically impacted by our treatment (e.g., fronto-striatal connectivity 
implicated in reward; see Heller et al., 2013).  
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The consent materials are submitted with this protocol. 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US Code of 
Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, and CFR Part 56, 
Subpart A), the Health Insurance Portability and Accountability Act (HIPAA), and local regulations. 
The Investigator-sponsor will prepare the informed consent form, assent and HIPAA authorization. The 
consent form generated by the Investigator must be approved by the IRB. The written consent document 
will embody the elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations.  
A properly executed, written, informed consent will be obtained from each subject prior to entering the 
subject into the trial. Information should be given in both oral and written form and subjects must be 
given ample opportunity to inquire about details of the study. If appropriate and required by the local IRB, 
assent from the subject will also be obtained. If a subject is unable to sign the informed consent form (ICF) 
and the HIPAA authorization, a legal representative may sign for the subject. A copy of the signed consent 
form (and assent) will be given to the subject and the original will be maintained with the subject’s 
records. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 


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provided by the suspending or terminating party to study participants, investigator, funding agency, the 
Investigational New Drug (IND) sponsor and regulatory authorities.  If the study is prematurely 
terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, the 
Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination or 
suspension.  Study participants will be contacted, as applicable, and be informed of changes to study 
visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
●
Determination of unexpected, significant, or unacceptable risk to participants
●
Demonstration of efficacy that would warrant stopping
●
Insufficient compliance to protocol requirements
●
Data that are not sufficiently complete and/or evaluable
●
Determination that the primary endpoint has been met
●
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
10.1.3 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
Certificate of Confidentiality 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
National Institutes of Health (NIH).  This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, legislative, 


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or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored on site.  
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regards to 
biosample storage may not be possible after the study is completed.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
The Principal Investigator, Dr. James Murrough, will serve as the medical monitor for this single-site 
study. 
Principal Investigator 
Medical Monitor 
James Murrough, MD, PhD 
James Murrough, MD, PhD 
Icahn School of Medicine  
Icahn School of Medicine 
1399 Park Avenue 
1399 Park Avenue 
212-585-4640 
212-585-4640 
james.murrough@mssm.edu 
James.murrough@mssm.edu 
 
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of an Independent Safety Monitor, Dr. Sanjay Matthews. 
Members of the study team will meet with the ISM at least semiannually to assess safety and efficacy 
data on each arm of the study.  
 
10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 


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the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
The site PI, Dr. James Murrough, and the study team will conduct clinical monitoring on-site for 
the duration of the study. 
• 
Study coordinators will comprehensive patient binder checks and review study participant’s 
databases for accurate data entry, signatures, and accuracy of all information, on a weekly basis 
until the study exit of a participant. 
• 
The study team will meet at least weekly to review participant progress, clinical safety, and data 
monitoring throughout the duration of the study. 
 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Study personnel at the site will perform internal quality management of study conduct, data and 
biological specimen collection, documentation and completion.   
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
The ISM will verify that the clinical trial is conducted and data are generated and biological specimens 
are collected, documented (recorded), and reported in compliance with the protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  


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Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into Redcap. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source 
documents. 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
10.1.10 PROTOCOL DEVIATIONS 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH GCP: 
•
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3
•
5.1 Quality Assurance and Quality Control, section 5.1.1
•
5.20 Noncompliance, sections 5.20.1, and 5.20.2.
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 7 working days of identification of the protocol deviation, or within 7 working days of 
the scheduled protocol-required activity.  All deviations must be addressed in study source documents. 
Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their policies. The 
site investigator is responsible for knowing and adhering to the reviewing IRB requirements. Further 
details about the handling of protocol deviations will be included in the MOP. 
10.1.11 PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
This study will comply with the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.   


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10.1.12 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.   
 
 
 
 


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10.2 ABBREVIATIONS 
The list below includes abbreviations utilized in this template.  However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
AE 
Adverse Event 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CRF 
Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIPAA 
Health Insurance Portability and Accountability Act  
ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOA 
Schedule of Activities 
UP 
Unanticipated Problem 
 
 
 


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11 REFERENCES  
1. 
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients 
requiring one or several treatment steps: a STAR*D report. The American journal of psychiatry. 
2006;163(11):1905-1917. 
2. 
Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and 
injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. 
Lancet (London, England). 2017;390(10100):1211-1259. 
3. 
Hasin DS, Sarvet AL, Meyers JL, et al. Epidemiology of Adult DSM-5 Major Depressive Disorder and Its 
Specifiers in the United States. JAMA psychiatry. 2018;75(4):336-346. 
4. 
Mrazek DA, Hornberger JC, Altar CA, Degtiar I. A review of the clinical, economic, and societal burden of 
treatment-resistant depression: 1996-2013. Psychiatric services (Washington, DC). 2014;65(8):977-987. 
5. 
Hodes GE, Kana V, Menard C, Merad M, Russo SJ. Neuroimmune mechanisms of depression. Nature 
neuroscience. 2015;18(10):1386-1393. 
6. 
Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern 
treatment target. Nature reviews Immunology. 2016;16(1):22-34. 
7. 
Hodes GE, Pfau ML, Leboeuf M, et al. Individual differences in the peripheral immune system promote 
resilience versus susceptibility to social stress. Proceedings of the National Academy of Sciences of the 
United States of America. 2014;111(45):16136-16141. 
8. 
Menard C, Pfau ML, Hodes GE, et al. Social stress induces neurovascular pathology promoting depression. 
Nature neuroscience. 2017;20(12):1752-1760. 
9. 
Ingrisch M, Sourbron S, Morhard D, et al. Quantification of perfusion and permeability in multiple 
sclerosis: dynamic contrast-enhanced MRI in 3D at 3T. Investigative radiology. 2012;47(4):252-258. 
10. 
Raja R, Rosenberg GA, Caprihan A. MRI measurements of Blood-Brain Barrier function in dementia: A 
review of recent studies. Neuropharmacology. 2018;134(Pt B):259-271. 
11. 
Kamintsky L, Cairns KA, Veksler R, et al. Blood-brain barrier imaging as a potential biomarker for bipolar 
disorder progression. NeuroImage: Clinical. 2020;26:102049. 
12. 
Beurel E, Harrington LE, Jope RS. Inflammatory T helper 17 cells promote depression-like behavior in mice. 
Biological psychiatry. 2013;73(7):622-630. 
13. 
Jha MK, Miller AH, Minhajuddin A, Trivedi MH. Association of T and non-T cell cytokines with anhedonia: 
Role of gender differences. Psychoneuroendocrinology. 2018;95:1-7. 
14. 
Syed SA, Beurel E, Loewenstein DA, et al. Defective Inflammatory Pathways in Never-Treated Depressed 
Patients Are Associated with Poor Treatment Response. Neuron. 2018;99(5):914-924.e913. 
15. 
Kebir H, Kreymborg K, Ifergan I, et al. Human TH17 lymphocytes promote blood-brain barrier disruption 
and central nervous system inflammation. Nature medicine. 2007;13(10):1173-1175. 
16. 
Griffiths CEM, Fava M, Miller AH, et al. Impact of Ixekizumab Treatment on Depressive Symptoms and 
Systemic Inflammation in Patients with Moderate-to-Severe Psoriasis: An Integrated Analysis of Three 
Phase 3 Clinical Studies. Psychotherapy and psychosomatics. 2017;86(5):260-267. 


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17.
Chandler GM, Iosifescu DV, Pollack MH, Targum SD, Fava M. RESEARCH: Validation of the Massachusetts
General Hospital Antidepressant Treatment History Questionnaire (ATRQ). CNS neuroscience &
therapeutics. 2010;16(5):322-325.
18.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. The British journal
of psychiatry : the journal of mental science. 1979;134:382-389.
19.
Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of
hedonic tone the Snaith-Hamilton Pleasure Scale. The British journal of psychiatry : the journal of mental
science. 1995;167(1):99-103.
20.
Ho PM, Cooper AJ, Hall PJ, Smillie LD. Factor structure and construct validity of the temporal experience of
pleasure scales. Journal of personality assessment. 2015;97(2):200-208.
21.
Rush AJ, Trivedi MH, Ibrahim HM, et al. The 16-Item Quick Inventory of Depressive Symptomatology
(QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with
chronic major depression. Biological psychiatry. 2003;54(5):573-583.
22.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide
Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of
antidepressants. The American journal of psychiatry. 2007;164(7):1035-1043.
23.
Pruim RHR, Mennes M, van Rooij D, Llera A, Buitelaar JK, Beckmann CF. ICA-AROMA: A robust ICA-based
strategy for removing motion artifacts from fMRI data. NeuroImage. 2015;112:267-277.
24.
Heller AS, Johnstone T, Light SN, et al. Relationships between changes in sustained fronto-striatal
connectivity and positive affect in major depression resulting from antidepressant treatment. The
American journal of psychiatry. 2013;170(2):197-206.
25.
Grieder TE, Besson M, Maal-Bared G, Pons S, Maskos U, van der Kooy D. β2* nAChRs on VTA dopamine
and GABA neurons separately mediate nicotine aversion and reward. Proceedings of the National
Academy of Sciences of the United States of America. 2019;116(51):25968-25973.
26.
NCSS. Power Analysis and Sample Size Software (2019). ncss.com/software/pass. . Kaysville, Utah, USA:
NCSS, LLC. 2019.

ICF_001.pdf: 
An Experimental Therapeutics Study of a Monoclonal Antibody Against 
Interleukin 17A in Patients With Treatment-Resistant Depression
PI: James Murrough, MD, PhD 
NCT04979910
Document Date: 6/3/2024


THE MOUNT SINAI HEALTH SYSTEM 
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STUDY ID: STUDY-21-00325     
Form Version Date: 03June2024 
---------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------- 
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____________________________ 
STUDY INFORMATION: 
Study Title: An Experimental Therapeutics Study of Ixekizumab, a Monoclonal Antibody Against 
Interleukin 17A, on Anhedonia, Reward Circuit Function, and Blood Brain Barrier Physiology in Patients 
with Treatment-Resistant Depression 
Study site(s): School of Medicine at Mount Sinai, Mount Sinai Hospital 
Principal Investigator (Head Researcher): James Murrough, M.D., Ph.D. 
Physical Address: 1399 Park Avenue, Second Floor, New York, NY 10029 
Mailing Address: One Gustave L Levy Place Box 1230, New York, NY 10029 
Phone: 212-585-4640 
____________________________ 
SUMMARY OF THIS RESEARCH STUDY: 
This document explains a research study you might be interested in joining. Participation in the study 
is voluntary. You can agree to join or not. Your decision will not limit your ability to receive care at Mount 
Sinai. You should only agree to take part if you understand the study and if all of your questions about 
the research study are answered. If you do join the study, the research team must share any new 
information with you that may change your mind about taking part. 
The purpose of this research study is to determine whether researchers can develop new therapies 
for the treatment of depression by acting on the immune system. 
Recent scientific research has suggested that the immune system, which usually fights diseases, is 
disturbed in depression. This study is looking at the effects of the medication ixekizumab in patients 
with depression whose current depression symptoms have not improved following two prior 
treatments. Ixekizumab is a commercially available medication that is approved by the FDA (The 
United States Food and Drug Administration) to treat autoimmune diseases like plaque psoriasis and 
some forms of arthritis The drug works by binding to a protein called interleukin 17a and reducing 
inflammation. This drug is not approved by the FDA for depression. 
If you choose to take part, you will be asked to complete six study visits for up to 12 weeks and take 
three doses of the study drug. 
We also want to know whether people with depression have problems with their brain activity. To do 
this, we will ask you to undergo a brain scan to take high-resolution images of your brain both before 
and after receiving treatment with the study drug ixekizumab. 
During the study visits, we will: 

Assess your physical health,


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 
Assess your depression symptoms,  
 
Collect blood to measure immune proteins, and 
 
Complete a brain scan to measure brain activity.  
 
If you choose to take part, the main risks to you are (1) discomfort or pain during or after the blood draw, 
including bruising, infection, and dizziness or feeling faint after your blood has been taken; (2) having 
claustrophobic reactions in the MRI scanner, which means that you may experience feelings of being 
trapped, feel as if the walls are closing in, or feel discomfort because of being in a small place for a 
period of time. If you do have metal objects of any kind in your body, you will not be able to participate 
for matters of your own safety: metal objects cannot be in an MRI scanner because the scanner acts 
as a magnet, and this can cause you danger; (3) reaction to Gadolinium (MRI dye), which may be 
itching, nausea, breathing problems, vomiting, or a metallic taste. These reactions are very rare and 
usually occur in people who already have severe lung disease. 
 
Other risks that may occur on the study drug ixekizumab are potential side effects such as headaches 
or upset stomach, allergic reactions, increased chance of minor infections or Inflammatory Bowel 
Disease (IBD) or worsen existing tuberculous infections. The study drug may also potentially harm a 
pregnancy or fetus in ways that are unknown. 
 
You may benefit from taking part in this research. Some potential benefits are improvement in your 
symptoms of depression. However, participating in the study may not benefit you and no benefit is in 
any way guaranteed as a result of your participation.  
 
Instead of taking part in this research, you may consider treatments such as medications (approved 
medications include fluoxetine, sertraline, etc.) or cognitive behavioral therapy that have been shown 
to be effective as treatment for depression. 
 
If you are interested in learning more about this study, please continue to read below. 
____________________________ 
STUDY PARTICIPATION: 
This research study will be fully explained to you by a member of the study team. Feel free to ask all 
the questions you want before you make a decision about whether or not to participate. Any new 
information that develops during this research study that might make you change your mind about 
participating will be given to you promptly. 
 
You may qualify to take part in this research study because you are a medically healthy individual with 
a diagnosis of Major Depressive Disorder and your symptoms have not improved after two prior 
treatments during your current episode.  
 
Your participation in this research study is expected to last up to 12 weeks. 
 


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There are up to 20 people expected to take part in this research study at the Depression and Anxiety 
Center at the Icahn School of Medicine at Mount Sinai.  
 
Funds for conducting this research are provided by the Hope for Depression Research Foundation.   
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include 
a summary of the results. You can search this Web site at any time. 
____________________________ 
DESCRIPTION OF WHAT IS INVOLVED: 
If you agree to participate in this research study, here is what may be involved: 
 
After receiving complete disclosure about the research and being given the opportunity to fully review 
the consent form, you will also be given the opportunity to ask questions. If you choose to take part in 
the study, you will be asked to sign this written consent form. 
 
 
Screening Visit (3-5hrs, can occur over multiple days) 
 
A study team member will ask questions about your health and complete tests to see if you are 
eligible for this study. This is called the “screening visit” and the following examinations will be 
completed during this visit, with the expectation of this taking about 3 to 5 hours: 
 
o Medical, Psychiatric, and Personal History: Research personnel will ask you questions 
about your medical and psychiatric history, medications you have taken, and your 
family psychiatric history. You will also be asked if you have any planned surgeries or 
other medical procedures. 
 
o Clinical Interviews: Research personnel will conduct assessments to determine the 
presence of any current or past psychiatric symptoms. 
 
o Questionnaires: The research staff will ask that you complete self-report questionnaires 
to evaluate any symptoms of depression, anxiety, and stress. 
 
o Physical examination: A study doctor or nurse will check you for general signs of 
disease. 
 
o Vital signs: Your heart rate, blood pressure, respiratory rate, height, and weight will be 
recorded. 
 
o Blood draw: A blood sample (13ml, approximately 1 tablespoon) will be drawn from a 
vein in your arm. This blood sample will be used for routine clinical laboratory test 
(blood count, electrolytes, thyroid function, liver function, etc.).  


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o Urine sample: You will be asked to pee into a cup. This urine sample will be used for 
routine analysis, testing if you are pregnant, and to test for illegal drugs. If you test 
positive for pregnancy or illegal drugs, you may be unable to participate in the study. 
Results from your urine drug test will be filed in your research record and will not be 
entered into your medical record. 
 
If you are already participating in and/or have already completed screening assessments under the 
screening protocol “A Screening Protocol for Adult Patients with Mood and Anxiety Disorders, Chronic 
Medical Conditions, and Healthy Volunteers” (GCO: 06-0945; PI Dr. Murrough), and these assessments 
have been completed within 1 month of signing the consent for this protocol, you do not need to repeat 
these assessments. 
 
Some of the study screening procedures may be conducted remotely over a HIPAA-compliant virtual 
platform. The screening period may last from 1 day up to 4 weeks. If you meet all eligibility criteria you 
can go on to the next phase. 
 
 
Visit 1 (Week 0, 3-5 hours, can occur over two days up to 5 days apart) 
 
o Clinical Interviews: Research personnel will conduct assessments to determine the 
presence of psychiatric symptoms and any changes in your medical history. 
 
o Questionnaires: The research staff will ask that you complete self-report questionnaires 
to evaluate any symptoms of depression, anxiety, and stress. 
 
o Vital signs: Your heart rate, blood pressure, respiratory rate, height, and weight will be 
recorded. 
 
o Urine sample: You will be asked to pee into a cup. This urine sample will be used to test 
if you are pregnant and to test for illegal drugs. Results from your urine drug test will be 
filed in your research record and will not be entered into your medical record. 
 
o MRI scan: You will be asked to participate in a brain scan and a behavioral task. The 
details of the MRI procedures are outlined in the next section. 
 
o Blood draw: A blood sample (36 ml, approximately 2.5 tablespoons) will be drawn from 
a vein in your arm. This blood sample will be used for immunological analysis. 
 
o You will receive the first injection of the study drug. 
 
You may elect to participate in the MRI scan portion of the visit first up to 5 days earlier than the 
remainder of this visit. Due to scheduling restrictions, we may also ask you to come in on two separate 
days to complete all of the visit procedures. 


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Magnetic Resonance Imaging (MRI) with Contrast 
All of the described procedures are for research purposes. To study the brain, you will undergo a 60-
minute MRI scan with a 3 Tesla (3T) MRI scanner machine (Biograph mMR) present at the Icahn School 
of Medicine at Mount Sinai in the Hess Building. The 3T MRI scanner uses a strong magnet to collect 
images of the brain. 
 
Prior to the scan, you will be asked a series of questions to confirm MRI eligibility. These questions 
assess your prior history in order to minimize risks associated with contra-indications to MRI and include 
questions regarding metal objects, pregnancy, etc. If you are pregnant or have an electrical or metal 
device inside of you, you will not be eligible to participate in the study. Prior to beginning any of the MRI 
procedures, you will be asked to urinate into a cup. This urine sample will be used to test for illegal 
drugs. If you test positive for any illegal drugs, you will be unable to participate in the MRI scan and 
exited from the study. Results from your urine drug test will be filed in your research record and will not 
be entered into your medical record. Your urine will also be tested for pregnancy. 
 
To study the Blood Brain Barrier (BBB), a protective cell barrier around the brain, the study doctor 
would like to request your consent to use a dye called gadolinium, which will be injected into your 
blood during the scan. This is often called “contrast”. The dye is given through a small tube in a blood 
vessel (vein) in the back of the hand or forearm. This tube will be inserted by one of the nurses or a 
certified technologist. Inserting the tube into your vein may cause minimal discomfort. Gadolinium is 
considered a safe, FDA-approved contrast agent used routinely in MRI scanning to make certain brain 
tissue brighter in the MRI images. The FDA has recently issued a warning about contrast agents 
which contain gadolinium paying particular attention to some participant(s) who have acute or chronic 
kidney disease. Any participant(s) who is considering having a MRI with contrast will be provided with 
a blood test at screening to measure their serum creatinine and calculate the GFR (a measure of 
kidney function) to determine that it is safe to have the MRI contrast agent. The creatinine is a waste 
product in your blood that comes from muscle activity. It is normally removed from your blood by your 
kidneys, but when kidney function slows down, the creatinine level rises. We will use the results of 
your serum (from either a finger-stick or blood draw) creatinine test to calculate your glomerular 
filtration rate (GFR). The GFR tells us your kidney function. If your test shows that your GFR level is 
too low, one of the study personnel or the nurse present will tell you of your kidney test result. You 
may then wish to consult with your own doctor. If you meet the required criteria, you will be given a 
standard clinical dose, approximately 20 to 40 mL (or between 1-3 tablespoons) of contrast and then 
scanned at your baseline visit 1. At the end of the scan, the tube in your vein will be removed. 
 
Once eligibility is confirmed, preparation for the MRI study will involve removing all metallic objects 
(such as watches, keys, chains, hair pins, glasses, jewelry, coins, etc.), items with magnetic data 
(credit cards), and other valuables. You will change out of any street clothing that is incompatible with 
the MRI study and into scrubs or hospital gowns that will be available during your visit. You will be 
given the opportunity to use the bathroom. You will then be escorted to the MRI room and positioned 
on the MRI bed. You will be asked to lie still on the MRI bed for up to one hour while the MRI machine 
gathers data. This will be a single scan session. During the scan, a researcher in Dr. Murrough’s team 


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or a trained technician will be present to talk with you throughout the scan and to oversee the scan. 
During this time, you will not be exposed to x-rays, but will be exposed to a strong magnetic field and 
radiofrequency magnetic fields. You will hear repetitive tapping noises that arise from the MRI 
scanner. We will provide earplugs or headphones that you will be able to wear during the scan. The 
space within the large magnet in which you lie is narrow. While lying in the scanner you will be asked 
to hold completely still, and padding such as a cushion may be used to stabilize your head. If you feel 
uncomfortable for any reason, you may choose to stop the scanning procedure at any time. 
 
Because this project involves the use of a medical device, it is necessary that we make a note of your 
participation in the electronic medical record. That way anyone treating you will be aware of your 
participation and may be able to avoid any unfortunate outcomes that could arise if your research 
participation were unknown. All MRI scans will be reviewed by a licensed radiologist. In the event that 
an abnormality is detected, Dr. Murrough will communicate this to you, in consultation with a 
radiologist. Medical referral will be offered if it is considered necessary. 
 
 
 
Visit 2 (Week 2, approximately 2 hours) 
 
o Clinical Interviews: Research personnel will conduct assessments to determine any 
changes in your psychiatric symptoms or medical history. 
 
o Questionnaires: The research staff will ask that you complete self-report questionnaires 
to evaluate any symptoms of depression, anxiety, and stress. 
 
o Vital signs: Your heart rate, blood pressure, respiratory rate, height, and weight will be 
recorded. 
 
o Urine sample: If you are of childbearing potential, you will be asked to pee into a cup. 
This urine sample will be used to test if you are pregnant. If you test positive for 
pregnancy, you may be unable to participate in the study. 
 
o You will receive the second injection of the study drug. 
 
 
 
Visit 3 (Week 4, approximately 2 hours) 
 
o Clinical Interviews: Research personnel will conduct assessments to determine any 
changes in your psychiatric symptoms or medical history. 
 
o Questionnaires: The research staff will ask that you complete self-report questionnaires 
to evaluate any symptoms of depression, anxiety, and stress. 
 


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o Vital signs: Your heart rate, blood pressure, respiratory rate, height, and weight will be 
recorded. 
 
o Urine sample: If you are of childbearing potential, you will be asked to pee into a cup. 
This urine sample will be used to test if you are pregnant. If you test positive for 
pregnancy, you may be unable to participate in the study. 
 
o You will receive the third injection of the study drug. 
 
 
 
Visit 4 (Week 6, 4-6 hours) 
 
o Clinical Interviews: Research personnel will conduct assessments to determine any 
changes in your psychiatric symptoms or medical history. 
 
o Questionnaires: The research staff will ask that you complete self-report questionnaires 
to evaluate any symptoms of depression, anxiety, and stress. 
 
o Vital signs: Your heart rate, blood pressure, respiratory rate, height, and weight will be 
recorded. 
 
o Physical examination: A study doctor or nurse will check you for general signs of 
disease. 
 
o Blood draw: A blood sample (45 ml, approximately 3 tablespoons) will be drawn from a 
vein in your arm. This blood sample will be used for routine laboratory test (blood 
count, electrolytes, thyroid function, liver function, etc.) and analysis of immune 
proteins.  
 
o Urine sample: You will be asked to pee into a cup. This urine sample will be used for 
routine analysis, testing if you are pregnant, and to test for illegal drugs. Results from 
your urine drug test will be filed in your research record and will not be entered into your 
medical record. 
 
o MRI scan: You will be asked to participate in another brain scan, the same as the one 
you would have completed at Visit 1. 
 
 
 
Exit Visit 5 (1-2 hours, Week 8) 
 
o Clinical Interviews: Research personnel will conduct assessments to determine any 
changes in your psychiatric symptoms or medical history. 
 


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o Questionnaires: The research staff will ask that you complete self-report questionnaires 
to evaluate any symptoms of depression, anxiety, and stress. 
 
This study exit visit will be conducted entirely remotely over a HIPAA-compliant virtual platform, two 
weeks following the last in-person visit (Visit 4). 
 
Randomization 
 
This is a single-arm, open-label study. All participants will receive the study drug. 
 
Pregnancy 
 
If you can possibly get pregnant, a urine test for pregnancy will be done before you begin the study and 
the pregnancy test will be repeated at each visit.  
You cannot be included in the study if you are or become pregnant, as the study drug could harm your 
fetus. You also should not be in the study if you are producing milk to feed a child as the study drug 
could harm your baby. 
 
Therefore, practicing effective birth control is important. No individual birth control is 100% effective.  
 
Unless you are at least one year past menopause or have had a successful operation to make 
pregnancy impossible, you should use effective birth control. Unless you are sexually abstinent (not 
having genital sex) the recommended methods of birth control are: 
 
The consistent use of approved hormonal birth control (pill, patches, or rings),  
 
An intrauterine device (IUD),  
 
Contraceptive injection (Depo-Provera),  
 
Double barrier methods (Diaphragm with spermicidal gel or condoms with contraceptive foam),  
 
Sexual abstinence (no sexual activity),  
 
Sterilization (a vasectomy, getting tubes tied, or a hysterectomy).  
 
Birth control methods (other than abstinence and sterilization) are only effective if you use them 
properly, start them at least one month before you begin the research study, and continue using them 
throughout the research study and for six months after the research study ends. If you are unsure 
whether the method of birth control you use is approved to use while you are in this study, you should 
ask the Lead Researcher before you begin the study. If you are less than one-year post-menopausal, 
you could still become pregnant. If you or your partner becomes pregnant, or may be pregnant, at any 
time during the trial, you must tell a person from the research team immediately. The team may stop 
the study drug and refer you/your partner to an obstetrician/gynecologist for follow-up.  
Should you/your partner become pregnant, whether or not you/your partner have the baby, the people 
funding and overseeing the research may ask for information on the pregnancy, even if you are no 


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longer part of the study. You/your partner will be asked for additional written consent to share this 
information if that happens. 
  
Semen/Sperm: 
Drugs can be found in semen and alter sperm. Since you are taking part in a study using experimental 
drugs or treatments, it is recommended that 1) you use a condom, 2) you do not get a partner pregnant 
or expose them to semen, and 3) you do not donate semen.  These recommendations apply both while 
you are taking the study drug, and for 6 months after you stop taking the study drug. This is because 
levels of the study drug may be present in the sperm and/or semen even after you stop taking the study 
drug.  You are encouraged to tell your partner(s) and/or their doctor(s) that you are participating in this 
clinical trial. 
____________________________ 
Future Contact:  
The researchers may wish to use your personal contact information to contact you in the future. Do you 
give the researchers permission to contact you in the future to request the collection of   
additional information about you, discuss how your private information, study data and/or samples might 
be used, or discuss possible participation in another research study?  
 
Please initial your choice: Yes_________ No__________ 
 
If “Yes”, please indicate your preferred method of contact: (initial all that apply) 
           [  ] Email            [  ] Phone          [  ] Letter             [  ] Text 
 
____________________________ 
USE OF YOUR DATA AND/OR SPECIMENS: 
 
The researchers would like your permission to keep your personal information (such as, name, address, 
date of birth, social security number), study data and/or samples (blood, tissue, urine, saliva, or any 
other body matter) to use or share in future studies. You can still be part of the study if you do not allow 
us to use or share them. Please select Yes or No to each of the questions below. To decline all future 
uses/sharing please select ‘No’ each time.. 
  
(1) Will you allow the researchers to store your information and/or specimens to use in future research 
studies? 
 


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Please initial your choice: Yes________ No_________  
 
If you select No, please stop here and move to the next section, 'Your Responsibilities If You Take 
Part in This Research' section below." 
 
If yes, please continue to the next question and tell us how your personal information, study data and/or 
samples may be used in future research studies.  
 
(2) The researchers can store your information and/or specimens in one of two ways: 
a) Anonymously (no one will know who the information and/or specimens came from). If you 
choose this option, you can’t change your mind. So, if you wanted to have your information 
and/or specimens destroyed in the future, the team could not do it as they would not know 
which information and/or specimens were yours. 
b) Linked to your identity (using a code that can show the information came from you personally). 
In this case you could ask for your information and/or specimens to be destroyed in the future 
if you want that to happen.  
 
How would you like your information and/or specimens stored? Please initial ONE choice below: 
 
I would like my information and/or specimens stored anonymously ______________ 
 
I would like my information and/or specimens stored with a link to my identity through the use of a 
code______ 
 
(3) Do you give the researchers permission to keep the information and/or specimens, so they could 
use them in future studies that are directly related to the purpose of the current study? 
 
Please initial your choice: Yes_________ No____________________ 
 
(4) Do you give the researchers permission to keep the information and/or specimens indefinitely, so 
they could use them for future studies that are not related to the purpose of the current study (for 
example a different area of research)?    
 
Please initial your choice: Yes_________ No__________ 
 
(4.1) From time to time, researchers outside of medicine and related sciences would like to use 
information and/or specimens. This might be in the fields such as anthropology, human origins, mapping 
human migration patterns. Do you give permission for researchers outside the field of medicine to 
use your information and/or specimens?  
 
Please initial your choice: Yes_________ No__________ 
 


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a. If the future research in a different area can be done without having to know that the information 
and/or specimens came from you personally, that will be done.   
b. If the future research in a different area requires that it is known specifically who information and/or 
specimens came from, then one of the following will be done: 
I. If you allowed the researchers to contact you in the future, they may be able to contact you to 
explain why your information and/or specimens is needed and what will be done with it. Your 
permission will be asked to use your data and/or samples in that research project. 
II. If you do not give permission to be contacted in the future, or if it is found that contacting you is 
not practical (for example, because you have moved), your information and/or specimens may 
still be used. The Institutional Review Board (IRB) will be asked for permission to use the data 
and/or samples linked to your identity. The IRB can give permission for researchers to use and 
share identifiable health information without contacting you, but only if it determines that sharing 
the data and/or samples will not be more than minimal risk to you or your privacy. The IRB is a 
committee of doctors and scientists and nonscientists, including people not associated with this 
hospital or medical school, whose job it is to protect people who participate in research. 
  
(5) Do you give permission to have your information and/or specimens given to other researchers, 
including those at Mount Sinai, other medical or scientific institutions and for-profit companies, for use 
in research within the limits you have chosen above?  
 
Please initial your choice: Yes_________ No__________ 
 
(6) Do you give permission to have portions of your information and/or specimens deposited in large 
public databases (repositories) for use in research with the limits you may have chosen above? Please 
read the paragraphs below which explains repositories, then initial your choice: 
 
To do more powerful research, it is helpful for researchers to share data and/or samples from the people 
they study. They do this by putting information and/or specimens into a repository. A repository is where 
something is stored safely for a specified period of time. Data and/or samples from one study may be 
stored in a repository along with information and/or specimens from other studies. Sample repositories 
are commonly called biobanks, while data repositories are commonly called databases. Researchers 
can then use the information and/or specimens from multiple studies to learn even more about health 
and disease. If you agree to take part in this study, some of your genetic and health information might 
be placed into one or more scientific databases, but they will not share your direct identifiers (for 
example, name, address, date of birth). These databases are maintained by either Icahn School of 
Medicine at Mount Sinai, another institution, the federal government, or private companies. Any 
researcher who wants to do a study using data and/or samples from the repository must apply for 
permission. There are different ways of reviewing such requests. Researchers with an approved study 
may be able to see and use your data, along with that from many other people. Researchers may use 
your samples for genetic sequencing and other experimental testing. Researchers will always have a 
duty to protect your privacy and to keep your information confidential, but there are always risks 
associated with data and/or sample collection and sharing. They are described in more detail in the 
Risks section.  


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Researchers will use a Global Unique Identifier, a computer-generated ID, which cannot be linked back 
to your identity. This is so any data collected from you is linked to one unique ID, so the database can 
make sure your data is secure and is not accidentally duplicated if you take part in research at multiple 
sites. 
 
Please initial your choice:  Yes ________    No _________ 
 
Whether or not you have allowed us to share your information and/or specimens, the researchers at 
Mount Sinai will keep information and/or specimens collected about you during this research study to 
use in future research studies consistent with the wishes you expressed above.  
 
 
____________________________ 
YOUR RESPONSIBILITIES IF YOU TAKE PART IN THIS RESEARCH: 
If you decide to take part in this research study you will be responsible for the following things:  
 
• Come to all study visit appointments and be available for any telephone appointments 
• Complete questionnaires yourself and participate in interviews several times 
• Do not participate in other medical research studies 
• Take the study drug at the prescribed dose and time. 
• Tell the study doctor about any health problems you have during the study 
• Tell the study doctor about any new medicine you take during the study 
• Do not take any other drugs or remedies unless the study doctor has approved them 
beforehand. This includes prescription drugs and over the counter medicine (including 
vitamins and herbal remedies) that you buy without a prescription. 
• Use effective birth control; examples of effective birth control include barrier contraception 
(for example condoms), oral contraceptive pills or intrauterine devices. 
• Do not get pregnant or cause your partner to become pregnant 
• Do not take illegal drugs; examples of illegal drugs include marijuana, cocaine, heroin or 
other narcotic substances. 
 
 
____________________________ 
COSTS OR PAYMENTS THAT MAY RESULT FROM PARTICIPATION: 
Being in this study will not cost you anything extra. If you agree to take part in this study, you will be 
paid a total of $600 for your time and effort/ You will receive a check for $75 upon completing the 
screening visit. You will receive $150 for Visit 1 upon completing the MRI scan and all visit assessments. 
You will receive a check of $100 for each of the other treatment visits (Visit 2 and Visit 3). You will 
receive an additional $150 for Visit 4 upon completing the second MRI scan and all visit assessments. 
In addition, you will receive a check of $25 for completing the study exit procedures.  


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The study team may cover travel or treatment related costs (i.e. car service, train, ferry) in 
addition to the compensation listed above of up to $150 per study. Please provide the study 
team with all travel receipts so that you may be reimbursed. Reimbursement for travel or 
treatment related costs will be provided in the form of a check. 
 
It can take up to 6 weeks to prepare and give you a check for study participation. If you do not get a 
check by then, you can first contact the research team. If further assistance is needed, please contact 
Mount Sinai’s Program for the Protection of Human Subjects at (212) 824-8200. 
 
Tax law may require the Mount Sinai Finance Department to report the amount of payment you receive 
from Mount Sinai to the Internal Revenue Service (IRS) or other agencies, as applicable. Generally, this 
happens if you receive payments that equal $600 or more from Mount Sinai in a calendar year.  
You would be responsible for the payment of any tax that may be due. 
 
If you are unable to complete the entire study, the payment will be prorated for the part you have 
completed. We will pay you based on your completion of the following visits:  
 
 
Study Visit 
Compensation 
Screening 
$75 
Visit 1 
$150 
Visit 2 
$100 
Visit 3 
$100 
Visit 4 
$150 
Study Exit 
$25 
Total 
$600 
 
 
 
____________________________ 
POSSIBLE BENEFITS: 


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It is important to know that you may not get any benefit from taking part in this research.  Others may 
not benefit either. However, possible benefits may include a potential reduction in depression 
symptoms. Potential benefits to others may include increasing scientific knowledge and understanding 
of depression to further advance research and treatment developments. Note that the study drug 
provided at no cost during a study may not be available for free, or at all, when the research ends. 
____________________________ 
REASONABLY FORESEEABLE RISKS AND DISCOMFORTS: 
 
Risks associated with study drug: 
o May cause headaches or stomach upset 
o May result in an allergic reaction  
o The study drug may increase your chances of minor infections 
o May worsen existing tuberculous infections 
o May, in rare cases, increase the likelihood of developing Inflammatory Bowel 
Disease (IBD) 
o Suicidal ideation and behavior have occurred in patients with a similar drug 
o This study drug may harm a pregnancy or fetus in ways that are unknown. You 
should not become pregnant or impregnate a woman while on this research study. 
Please read the acceptable methods of birth control found under the Description of 
What’s Involved section of this document. 
 
Psychological risks - during the psychiatric interviews and questionnaires, participants will 
possibly be exposed to the discomfort of being asked personal questions they may find 
distressing. You may choose to not answer any questions that make you uncomfortable. 
The risks and discomforts associated with answering questionnaires are minimal. 
 
Risks for the following study procedures: 
o Blood Draw: The risks of a blood draw include pain, bruising, and the slight possibility 
of infection at the place where the needle goes in. Some people feel dizzy or may 
faint during or after a blood draw. 
o fMRI: The risk associated with the fMRI procedure is very small. No short-term risks 
have been reported for fMRI. An fMRI does not involve exposure to radiation. Some 
people have claustrophobic reactions in the fMRI scanner, which means that they 
may experience feelings of being trapped, feel as if the walls are closing in, or feel 
discomfort because of being in a small place for a period of time. A member of the 
study team will be present to reassure you and aid in relaxing, but should you wish 
it, the fMRI scanning can be stopped immediately. If you have any surgical clips or 
metallic prostheses (such as an artificial hip or knee), or shrapnel (metal fragments) 
in your body, you will not be able to participate in this study. Metal objects cannot be 
in an fMRI scanner because the scanner acts as a magnet, and this can cause you 
danger. If you do have metal objects of any kind in your body, you will not be able to 
participate for matters of your own safety. 
o MRI with Contrast: Gadolinium (MRI dye) is routinely used in medical imaging. As 
described in the MRI safety literature, it is a substance that is not normally absorbed 


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into the tissues of the body. Once it is injected, it will stay in the blood stream and 
will be eliminated a few hours later in the urine. Some patients very rarely have a 
reaction to this dye, which may be itching, nausea, breathing problems, vomiting, or 
a metallic taste. These reactions are very rare and usually occur in people who 
already have severe lung disease. A safety questionnaire will be given to you before 
the injection to make sure you are safe to have the dye injection. If you are not a 
candidate for this dye, the MRI scan can be done without it. A recent FDA warning 
has been issued that states participant(s) with kidney problems must not be given 
contrast because it may lead to debilitating and potential fatal disease that involves 
the skin, muscles, and internal organs. Patients with kidney disease can develop skin 
thickening that may prevent bending and extending joints, resulting in decreased 
mobility of joints. The chance of developing nephrogenic systemic fibrosis (NSF) is 
extremely low in individuals with normal kidney function. In addition, patients may 
experience scarring that has spread to other parts of the body such as the 
diaphragm, muscles in the thigh and lower abdomen, and the interior areas of lung. 
There is a slight chance of an allergic reaction from the contrast which has a less 
than 1 in 300,000 chance that this will be severe. 
 
Group Risks - Although we will not give researchers your name, we will give them basic 
information such as your race, ethnic group, and sex. This information helps researchers 
learn whether the factors that lead to health problems are the same in different groups of 
people. It is possible that such findings could one day help people of the same race, ethnic 
group, or sex as you. However, they could also be used to support harmful stereotypes or 
even promote discrimination. 
 
Privacy Risks - Risk of loss of private information; this risk always exists, but there are 
procedures in place to minimize the risk. If your private information was misused it is possible 
you would also experience other harms, such as stress, anxiety, stigmatization, or 
embarrassment from revealing information about your family relationships, ethnic heritage, 
or health conditions. 
 
Insurance Risks – There is a federal law called the Genetic Information Nondiscrimination 
Act (GINA). In general, this law makes it illegal for health insurance companies, group health 
plans, and most employers of over 15 people to discriminate against you based on your 
genetic information. However, it does not protect you against discrimination by companies 
that sell life insurance, disability insurance, or long-term care insurance. 
 
Financial Risks – Participants will not be charged for any study procedures. If a participant 
is injured or made sick from taking part in this research study, medical care will be provided. 
Generally, this care will be billed to the participant or their insurance in the ordinary manner 
and they will be responsible for all treatment costs not covered by their insurance, including 
deductibles, co-payments and coinsurance. This does not prevent you from seeking 
payment for injury related to malpractice or negligence. You may contact the investigator for 
more information. 
____________________________ 
OTHER POSSIBLE OPTIONS TO CONSIDER: 


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You may decide not to take part in this research study without any penalty.  The choice is totally up to 
you.  
This study is not a substitute for comprehensive treatment for MDD. Instead of being in this research 
study, your choices may include treatments such as medications or cognitive behavioral therapy that 
have been shown to be effective as treatment for MDD. These alternatives are available to you at Mount 
Sinai and elsewhere and will be described to you fully prior to agreeing to participation in this study. 
____________________________ 
IN CASE OF INJURY DURING THIS RESEARCH STUDY: 
If you are injured or made sick from taking part in this research study, medical care will be provided. 
Generally, this care will be billed to the participant or their insurance in the ordinary manner and they 
will be responsible for all treatment costs not covered by their insurance, including deductibles, co-
payments and coinsurance. This does not prevent you from seeking payment for injury related to 
malpractice or negligence. You may contact the investigator for more information. 
____________________________ 
ENDING PARTICIPATION IN THE RESEARCH STUDY: 
 
You may stop taking part in this research study at any time without any penalty. This will not affect your 
ability to receive medical care at any of the Mount Sinai Health System hospitals or to receive any 
benefits to which you are otherwise entitled. 
 
If you decide to stop being in the research study, please contact the Principal Investigator or the 
research staff.   
 
If you stop being in the research study, already collected information may not be removed from the 
research study database and will continue to be used to complete the research analysis. You may be 
asked whether the study doctor can collect information from your routine medical care. If you agree, 
this data will be handled the same as research data.  
  
If you decide you don’t want your samples and/or data to be used for research anymore, you can 
contact the researcher and ask to have your samples and/or data removed from future use. If any 
samples or data have already been shared without your identity, it won’t be possible to retrieve them 
because no one will know who you are. Samples and data that have already been used will not be 
affected by your decision. Any samples and/or data that are still linked to your identity by a code the 
researcher has will be withdrawn so that no future sharing of your samples and/or data will take place. 
If your samples have already been deposited in an external repository, the study team will request 
that your samples be removed. 
 
Withdrawal without your consent: The study doctor, the sponsor or the institution may stop your 
involvement in this research study at any time without your consent. This may be because the 
research study is being stopped, the instructions of the study team have not been followed, the 


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investigator believes it is in your best interest, or for any other reason. If specimens or data have been 
stored as part of the research study, they too can be destroyed without your consent.  
 
____________________________ 
CONTACT INFORMATION: 
If you have any questions, concerns, or complaints at any time about this research, or you think the 
research has harmed you, please contact the office of the research team and/or the Principal 
Investigator at phone number 212-585-4640. 
 
This research has been reviewed and approved by an Institutional Review Board. You may reach a 
representative of the Program for Protection of Human Subjects at the Icahn School of Medicine at 
Mount Sinai at telephone number (212) 824-8200 during standard work hours for any of the reasons 
listed below. This office will direct your call to the right person within the Mount Sinai Health System: 
 
Your questions, concerns, or complaints are not being answered by the research team. 
 
You cannot reach the research team. 
 
You are not comfortable talking to the research team. 
 
You have questions about your rights as a research participant(s). 
 
You want to get information or provide input about this research. 
 
 
 
 
____________________________ 
DISCLOSURE OF FINANCIAL INTERESTS: 
Sometimes, physicians/researchers receive payments for consulting or similar work performed for 
industry.  Effective September 2014 Mount Sinai reviews only payments to an individual totaling more 
than $5,000 a year per entity when determining potential conflicts of interest.  If you have questions 
regarding industry relationships, we encourage you to talk your physician/researcher or visit our website 
at http://icahn.mssm.edu/ where Mount Sinai publicly discloses the industry relationships of our faculty.  
____________________________ 
MAINTAINING CONFIDENTIALITY – HIPAA AUTHORIZATION: 
As you take part in this research project it will be necessary for the research team and others to use 
and share some of your private protected health information. Consistent with the federal Health 
Insurance Portability and Accountability Act (HIPAA), we are asking your permission to receive, use 
and share that information. 
 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai 
 
Page 18 of 22 
 
 
STUDY ID: STUDY-21-00325                
             
 
 
 
 
 
 
 
 
Form Version Date: 03June2024 
 
---------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------- 
Rev 1.19.21 
What protected health information is collected and used in this study, and might also be shared with 
others? 
 
As part of this research project, the research team at the hospital(s) involved in the research will 
collect your name, address, dates directly related to you (birth, admission, discharge, etc.), e-mail 
addresses, social security number, and medical records number. The researchers will also get 
information from your medical record. During the study, the researchers will gather information by: 
 
taking a medical history (includes current and past medications or therapies, illnesses, 
 
conditions or symptoms, family medical history, allergies, etc.) 
 
doing a physical examination that generally also includes blood pressure reading, heart rate, 
breathing rate and temperature 
 
completing the tests, procedures, questionnaires and interviews explained in the description 
section of this consent. 
 
reviewing mental health records 
 
Why is your protected health information being used? 
Your personal contact information is important to be able to contact you during the study. Your health 
information and the results of any tests and procedures being collected as part of this research study 
will be used for the purpose of this study as explained earlier in this consent form. The results of this 
study could be published or presented at scientific meetings, lectures, or other events, but would not 
include any information that would let others know who you are, unless you give separate permission 
to do so. 
 
The Principal Investigator may also use and share the results of these tests and procedures to treat you 
in collaboration with others in the Mount Sinai Health System.  
 
The research team and other authorized members of The Mount Sinai Health System (“Mount Sinai”) 
workforce may use and share your information to ensure that the research meets legal, institutional or 
accreditation requirements. For example, the School’s Program for the Protection of Human Subjects 
is responsible for overseeing research on human participant(s), and may need to see your information. 
If you receive any payments for taking part in this study, the Mount Sinai Finance Department may need 
your name, address, social security number, payment amount, and related information for tax reporting 
purposes.  If the research team uncovers abuse, neglect, or reportable diseases, this information may 
be disclosed to appropriate authorities.  
 
Who, outside Mount Sinai, might receive your protected health information? 
As part of the study, the Principal Investigator, study team and others in the Mount Sinai workforce may 
disclose your protected health information, including the results of the research study tests and 
procedures, to the following people or organizations: (It is possible that there may be changes to the 
list during this research study; you may request an up-to-date list at any time by contacting the Principal 
Investigator.) 
- 
The foundation sponsor and/or their representative (who will use the results for submissions 
to the Food and Drug Administration): The Hope for Depression Research Foundation 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai 
 
Page 19 of 22 
 
 
STUDY ID: STUDY-21-00325                
             
 
 
 
 
 
 
 
 
Form Version Date: 03June2024 
 
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Rev 1.19.21 
- 
A Data Safety Monitoring Board or other committee that will monitor the study on an ongoing 
basis for safety. 
- 
The United States Food and Drug Administration 
- 
The United States Department of Health and Human Services and the Office of Human 
Research Protection.  
 
In almost all disclosures outside of Mount Sinai, you will not be identified by name, social security 
number, address, telephone number, or any other direct personal identifier. Some records and 
information disclosed may be identified with a unique code number. The Principal Investigator will 
ensure that the key to the code will be kept in a locked file, or will be securely stored electronically. The 
code will not be used to link the information back to you without your permission, unless the Institutional 
Review Board allows it after determining that there would be minimal risk to your privacy. The Certificate 
of Confidentiality obtained from the Department of Health and Human Services will not be used to 
prevent disclosure to local authorities of child abuse and neglect, or harm to self or others. It is possible 
that a sponsor or their representatives, a data coordinating office, or a contract research organization, 
will come to inspect your records. Even if those records are identifiable when inspected, the information 
leaving the institution will be stripped of direct identifiers.  Additionally, the Office of Human Subjects 
Protection (OHRP) of the Department of Health and Human Services as well as the Food and Drug 
Administration (FDA) will be granted direct access to your medical records for verification of the 
research procedures and data. They are authorized to remove information with identifiers if necessary 
to complete their task. By signing this document, you are authorizing this access. We may publish the 
results of this research. However, we will keep your name and other identifying information confidential. 
 
For how long will Mount Sinai be able to use or disclose your protected health information? Your 
authorization for use of your protected health information for this specific study does not expire. 
 
Will you be able to access your records? 
During your participation in this study, you will be able to access your medical records. Your information 
will be available should an emergency arise that would require your treating physician to know this 
information to best treat you. 
 
Do you need to give us permission to obtain, use or share your health information? 
NO! If you decide not to let us obtain, use or share your health information you should not sign this form, 
and you will not be allowed to volunteer in the research study. If you do not sign, it will not affect your 
treatment, payment or enrollment in any health plans or affect your eligibility for benefits. 
 
Can you change your mind? 
You may withdraw your permission for the use and disclosure of any of your protected information for 
research, but you must do so in writing to the Principal Investigator at the address on the first page. 
Even if you withdraw your permission, the Principal Investigator for the research study may still use 
your protected information that was already collected if that information is necessary to complete the 
study. Your health information may still be used or shared after you withdraw your authorization if you 
should have an adverse event (a bad effect) from being in the study. If you withdraw your permission 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai 
 
Page 20 of 22 
 
 
STUDY ID: STUDY-21-00325                
             
 
 
 
 
 
 
 
 
Form Version Date: 03June2024 
 
---------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------- 
Rev 1.19.21 
to use your protected health information for research that means you will also be withdrawn from the 
research study, but standard medical care and any other benefits to which you are entitled will not be 
affected. You can also tell us you want to withdraw from the research study at any time without canceling 
the Authorization to use your data. 
 
If you have not already received it, you will also be given The Hospital’s Notice of Privacy Practices that 
contains more information about how The Hospital uses and discloses your protected health 
information. 
 
It is important for you to understand that once information is disclosed to others outside Mount Sinai, 
the information may be re-disclosed and will no longer be covered by the federal privacy protection 
regulations. However, even if your information will no longer be protected by federal regulations, where 
possible, Mount Sinai has entered into agreements with those who will receive your information to 
continue to protect your confidentiality. 
 
If as part of this research project your medical records are being reviewed, or a medical history is being 
taken, it is possible that HIV-related information may be revealed to the researchers.  If that is the case, 
the following information concerns you.  If this research does not involve any review of medical records 
or questions about your medical history or conditions, then the following section may be ignored.   
_________________________________________________________________________________ 
Notice Concerning HIV-Related Information 
If you are authorizing the release of HIV-related information, you should be aware that the recipient(s) is 
(are) prohibited from re-disclosing any HIV-related information without your authorization unless permitted 
to do so under federal or state law.  You also have a right to request a list of people who may receive or use 
your HIV-related information without authorization.  If you experience discrimination because of the release 
or disclosure of HIV-related information, you may contact the New York State Division of Human Rights at 
(888) 392-3644 or the New York City Commission on Human Rights at (212) 306-5070.  These agencies 
are responsible for protecting your rights. 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
 
 
Certificate of Confidentiality:  
To further protect your privacy, the researchers have obtained a Certificate of Confidentiality from the 
Department of Health and Human Services. This is intended to ensure that your identity as a 
participant in this research study will not have to be disclosed as a result from a subpoena, for the 
purpose of identifying you in any federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings other than to the FDA or OHRP as identified above. 
 
The research staff will not share any of your research information or biospecimens with anyone who is 
not a member of the research team, including any family members or friends, other than to those 
identified above. However, you should know that if we learn that you or someone else is threatened 
with serious harm, such as a child or an elderly person being abused, the investigators may notify the 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai 
 
Page 21 of 22 
 
 
STUDY ID: STUDY-21-00325                
             
 
 
 
 
 
 
 
 
Form Version Date: 03June2024 
 
---------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------- 
Rev 1.19.21 
appropriate authorities if necessary to protect you or others.  A Certificate of Confidentiality does not 
prevent you or a member of your family from voluntarily releasing information about yourself or your 
involvement in this research. This means that you and your family must also actively protect your own 
privacy. If an insurer or employer learns about your research participation, and you agree that they 
can have your research information, then the researchers may not use the Certificate of 
Confidentiality to keep this information from them. 
_________________________ 
How the Institutional Review Board (IRB) can help you: 
This research has been reviewed and approved by an Institutional Review Board (IRB). You may reach 
a representative of the Mount Sinai Program for Protection of Human Subjects at telephone number 
(212) 824-8200 during regular work hours (Monday-Friday, 9am-5pm, excluding holidays) for any of the 
reasons listed below. This office will direct your call to the right person within the Mount Sinai Health 
System: 
 
Your questions, concerns, or complaints are not being answered by the research team. 
 
You cannot reach the research team. 
 
You are not comfortable talking to the research team. 
 
You have questions about your rights as a research participant. 
 
You want to get information or provide input about this research. 
 
 
 
 
ADULT PARTICIPANT: 
Your signature below documents your permission to take part in this research and to the use and 
disclosure of your protected health information. A signed and dated copy will be given to you. 
 
 
_________________________ 
_________________________ 
__________ __________ 
 
Signature of participant(s) 
 
 
Printed Name of participant(s) 
 
Date 
 
Time 
 
 
PERSON EXPLAINING STUDY AND OBTAINING CONSENT: 
 
 
_________________________ 
_________________________ 
__________ __________ 
 
Signature of consent delegate 
Printed Name of consent delegate 
Date 
 
Time 
 
 
 
 


THE MOUNT SINAI HEALTH SYSTEM 
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY 
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION 
Icahn School of Medicine at Mount Sinai 
 
Page 22 of 22 
 
 
STUDY ID: STUDY-21-00325                
             
 
 
 
 
 
 
 
 
Form Version Date: 03June2024 
 
---------------------------------------------------------FOR IRB USE ONLY-------------------------------------------------------------- 
Rev 1.19.21 
 
WITNESS SECTION: 
When a witness is required to observe the consent process, it should be documented below (for 
example, when participant(s)is illiterate, visually impaired, or this document accompanies a short form 
consent). 
 
My signature below documents that the information in the consent document and any other written 
information was accurately explained to, and apparently understood by, the participant(s), and that 
consent was freely given by the participant(s). 
 
 
 
_________________________ 
_________________________ 
__________ __________ 
 
Signature of Witness  
 
Printed Name of Witness 
 
Date 
 
Time