Clinical trial NCT03113968
Conditions: Treatment Resistant Depression Electroconvulsive Therapy ECT Ketamine Psychiatric Disorder Depression Major Depressive Disorder Major Depressive Episode Unipolar Depression
Sponsor: Bo Hu
Start date: 2017-04-07; Completion date: 2022-11-17
Enrollment: 403 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of the study is to conduct a comparative randomized trial of electroconvulsive therapy (ECT) vs. ketamine for patients with treatment resistant depression (TRD) in a real world setting with patient reported outcomes as primary and secondary outcome measures.

Detailed description:
Patients with treatment resistant depression who meet all inclusion criteria and do not meet any exclusion criteria will be randomized to either electroconvulsive therapy (ECT) three times per week or ketamine infusion two times per week. Patients will answer questionnaires about their symptoms prior to treatments. The acute treatment phase of the study will last three to five weeks. Depending on response to treatment, some patients will be followed for an additional six months.

Arms: arm 1: Treatments will be given 3 times a week up to a total of 9 treatments over 3 - 5 weeks. Initial ECT treatment is Right Unilateral (RUL) ultra-brief pulse at 6X seizure threshold. Seizure threshold and dose can be increased per investigator and patient discretion. arm 2: Treatments will be given 2 times a week up to a total of 6 treatment over 3 - 5 weeks. Initial standard dose will be 0.5 mg/kg infusion over 40 min. The dose can be modified if clinically warranted per investigator and patient discretion.
Interventions: intervention 1: electroconvulsive therapy (ECT) intervention 2: Ketamine
Intervention descriptions: intervention 1: ECT is a procedure done under general anesthesia where small electric currents are passed through the brain, intentionally triggering a brief seizure. Patients who have not responded to antidepressant medications may be candidates for ECT. ECT is FDA approved for treatment resistant depression. intervention 2: Ketamine is a medication that is used as a short acting anesthetic in pediatric and adult medicine. Subanesthetic (low) doses will be given to patients via infusion in order to assess whether it helps with depression symptoms in patients who have not responded to antidepressant therapy. Ketamine is not FDA approved for this indication and its effectiveness in treatment resistant depression has not been proven. Prior studies have indicated that subanesthetic doses of ketamine may be helpful for treatment resistant depression.

Protocol documents:
SAP_002.pdf: 
 
1 
 
 
ELEKT–D: Electroconvulsive therapy (ECT) vs. ketamine in patients 
with treatment resistant depression (TRD)  
 
 
 
 
 
Statistical Analysis Plan 
 
Version 2.0  
07/01/2022 
 
 
 


 
2 
 
ELEKT-D is an open label, multi-center clinical trial to compare electroconvulsive therapy (ECT) 
with ketamine (KET) in patients with treatment resistant depression (TRD). The specific study 
aims include: 
• 
Aim 1: to investigate the comparative effectiveness of ECT and ketamine on measures of 
depression. 
• 
Aim 2: To investigate the relative impact of ECT and ketamine on measures of memory 
and cognitive function. 
• 
Aim 3: To investigate the relative impact of ECT and ketamine on patient reported QoL 
measures after acute treatment and at follow-up over six months. 
Table 1 below lists the primary, secondary and safety endpoints measured from the study 
participants. More details and the measurement schedules of these endpoints are described in 
the study protocol.  
 
Analysis of baseline characteristics. The analysis will be based on the randomized population 
(i.e., all participants randomized). Participant characteristics at baseline will be summarized as 
descriptive statistics (mean, standard deviation [SD], median, inter-quartile range, or range for 
continuous data, and count and percentage for categorical data). The baseline characteristics will 
be compared between the two study groups using the t-test, the Wilcoxon rank sum test, or the 
chi-squared test as appropriate.  
 
Analysis of primary endpoint. The primary endpoint of the trial is treatment response, which is 
defined as a ≥ 50% decrease in QIDS-SR-16 scores from the baseline visit/visit 1 to the end of 
treatment visit in the acute phase. The study hypothesis is that the response rate of ketamine is 
non-inferior to ECT with a margin of -10%, that is,  
H0: Pk - Pe ≤ -10% vs.  H1: Pk - Pe > -10% 
where Pk represents the response rates in the ketamine group, and Pe represents the response 
rate in the ECT grou; H0 and H1 denote the null and alternative hypotheses, respectively. The 
primary endpoint of treatment response will be summarized as proportions, along with 95% 
confidence intervals, for each treatment group. The Farrington-Manning score test will be then 
used to compare the response rates between ECT and KET at an inferiority margin of -10% 
(ketamine minus ECT) and a one-sided type I error of 0.025. The difference of the two response 
rates will be also reported with the 95% confidence interval.  


 
3 
 
 
The principal analysis of the primary outcome will be based on the modified intention to 
treatment (mITT) population, which include the participants who receive at least one treatment 
and have at least one QIDS-SR-16 measurement during the acute phase. Multiple sensitivity 
analyses will be performed by imputing the missing primary endpoints. (1) Multiple imputations 
based on the chained-equation approach will be applied to the dataset, including baseline 
demographic and illness characteristics, the QIDS-SR-16 and MADRS scores at baseline, and 
their percent changes at the EOT visit. The imputed percent changes of QIDS-SR16 are then 
dichotomized to derive the imputed response outcomes. The Farrington-Manning score test will 
be applied to each of the five imputed datasets, and the results need to be summarized using 
Rubin’s rule. (2) The worst-best and best-worst imputation methods will be used to examine the 
results in the extreme cases of the missing data. The former method will impute all missing 
outcomes in ECT as responders and all missing outcomes in KET as non-responders, and the 
latter imputes the missing outcomes in ECT as non-responders and all missing outcomes in KET 
as responders. The results from these two methods can be considered as the range of uncertainty 
due to the missing data.  
 
Analysis of secondary endpoints. The secondary outcome of MADRS response will be tested 
for noninferiority of KET using the same approach as the primary outcome. MADRS response is 
defined as 50% or greater decline in the MADRS total score from baseline to the EOT visit. 
Similar as the primary outcomes, the MADRS response rates will be compared between the two 
groups to test the non-inferiority of KET at a margin of -10% and one-sided alpha of 0.025.  
The other dichotomous secondary outcomes such as remission will be summarized as 
percentages by group and compared using the chi-squared test.  
 
Since the QIDS-SR16 score itself is repeatedly measured over time, a linear mixed-effects 
model will be applied to estimate its trajectories of the two groups during the acute treatment 
phase. The model will include measurement time, treatment group, their interaction, and site as 
fixed effects, and a Gaussian random intercept at the patient level. Baseline patient characteristics 
with statistically significant differences between the two groups may be also included as fixed 
effects if deemed necessary. The covariance matrix of the repeated measurements within each 
patient will be selected from the candidates of compound symmetric, first-order autoregressive 
(AR1), Toeplitz, and unstructured structures using the information criterion. Least-square 
estimates will be derived to estimate the QIDS-SR16 mean at each visit by group, and 
corresponding linear contrasts can be used for group comparison at each visit. Since the 
responders will be further followed at months 1, 3 and 6 after the acute phase, another linear 


 
4 
 
mixed-effects model with the same formation will be applied to the subgroup of responders for 
their longitudinal QIDS-SR-16 data until the end of the follow up phase. The model for the change 
of QIDS-SR-16 score will include the score changes as the dependent variable and further 
include the baseline QIDS-SR-16 score as a covariate. For the other continuous secondary 
endpoints measured longitudinally, their analyses will follow the analysis of the QIDS-SR-16 
score. These endpoints include various patient and clinician rated scales for depression, 
suicidality, and cognitive function (e.g., MADRS and YMRS).  
For the cross-sectional endpoints such as the MoCA rating assessed at the end of 
treatment visit, linear regression will be used to analyze and compare the data between the two 
groups. Generalized linear regression (e.g., logistic regression or ordinal logistic regression) will 
be applied to binary or multi-categorical outcomes, depending on the variable type of the outcome.   
 
 
Analysis of safety endpoints. Mortality will be summarized as percentage by group, and the 
chi-squared test will be used to compare the mortality rates between the two groups. If the 
expected number of deaths is small, the Fisher’s exact test will be used instead. The other 
dichotomous safety outcomes such as the unexpected adverse events, adverse events causing 
treatment discontinuation and serious adverse events will be analyzed in the same manner.  
For the vital signs including BMI, blood pressure and heart rate, the linear mixed-effect 
models will be applied to estimate their least-square means over time by group.  
 
Subgroup analyses. Multiple subgroup analyses will be performed in order to determine whether 
there is heterogeneity of treatment effect due to demographic and clinical risk factors. The 
predefined subgroups include: psychiatric comorbidity, depression subtype, gender, race, age, 
treatment resistance (Stage IV-V vs other) and prior history of ECT treatment.  For each subgroup 
analysis, we will test the interaction using the Breslow-Day test. Recognizing that the power to 
detect significant interactions will be low, all subgroup analyses are thus considered to be 
hypothesis generating.  
 
Missing data. The missing primary endpoints will be imputed as described in the section of 
analysis of primary endpoint. Regarding the missing data in the secondary endpoints, the mixed-
effects models or the generalization regression models implicitly assume data missing at random. 
We will also perform sensitivity analyses if needed. The first sensitivity analysis will be imputation. 


 
5 
 
If the endpoints are longitudinal and have mixed variable types, the set of longitudinal data will be 
arranged chronologically. The results are then summarized using Rubin’s rule. Another sensitivity 
analysis will be using the pattern mixed modeling if the missingness is considered non-ignorable 
(i.e., missing not at random).   
 
Sample size justification. For the outcome measure of QIDS-SR16 in TRD patients in standard 
anti-depressant analyses, an overall response rate of 47% was reported in the STAR*D study [1]. 
Zarate et al. showed that a 71% response rate of ketamine on HAMD-21 was associated with 
patients with major depression [2]. Murrough et al. reported a 64% response rate of ketamine on 
MADRS in patients with TRD [3]. Other studies revealed response rates of ketamine ranging from 
50% to 90% in patients with TRD [4-14]. Janicak et al. reported a 56% response rate of ECT on 
HAMD-24 in patients of major depression [15]. Our preliminary internal data showed 45.8% 
patients as responders in the ketamine group, and 45.1% patients as responders in the ECT 
group, using clinician rated MADRS scales. The patients in the ketamine group were resistant to 
ECT treatment and still had a comparable response rate as ECT. For the ELEKT-D study, patients 
do not have to be ECT resistant, and hence the ketamine response rate is expected to be even 
higher. Based on the above data from the previous studies and our pilot study, we assume a 50% 
response rate for ECT patients. At a non-inferiority margin of 10% (i.e. response rate of ketamine 
is at most 10% lower than ECT) and a one-sided alpha value of 0.025, a total sample of 346 is 
needed to provide 80% power using the Farrington-Manning score test of risk difference if the 
actual difference is +5% (i.e. response rate of ketamine is 5% higher than ECT). If the actual 
difference is +10%, the statistical power would increase to 96.4% with the same sample size; if 
the non-inferiority margin is reduced to 5%, then the power will be 80.3%. Assuming an attrition 
rate of 15%, a total number of 400 subjects (200 per treatment group) are then required. 
 
 
References  
[1] Warden D, Rush AJ, Trivedi MH, et al. The STAR*D project results: a comprehensive review 
of finding. Current Psychiatry Reports. 2007;9(6):449-459. 
[2] Zarate CA Jr., Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate 
antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006; 63(8):856–864. 
[3] Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-
resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 
2013;170(10):1134-1142. 


 
6 
 
[4] Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-
Daspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010; 
67(8):793–802. 
[5] Valentine GW, Mason GF, Gomez R, et al. The antidepressant effect of ketamine is not 
associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-
MRS. Psychiatry Res. 2011; 191(2):122–127.  
[6] aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose 
intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010; 67(2):139–145.  
[7] DiazGranados N, Ibrahim LA, Brutsche NE, et al. Rapid resolution of suicidal ideation after a 
single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major 
depressive disorder. J Clin Psychiatry. 2010; 71(12):1605–1611. 
[8] Ibrahim L, Diazgranados N, Luckenbaugh DA, et al. Rapid decrease in depressive symptoms 
with 
an 
N-methyl-d-aspartate 
antagonist 
in 
ECT-resistant 
major 
depression. 
Prog 
Neuropsychopharmacol Biol Psychiatry. 2011; 35(4):1155–1159.  
[9] Machado-Vieira R, Yuan P, Brutsche N, et al. Brain-derived neurotrophic factor and initial 
antidepressant response to an N-methyl-D-aspartate antagonist. J Clin Psychiatry. 2009; 
70(12):1662–1666.  
[10] Mathew SJ, Murrough JW, aan het Rot M, et al. Riluzole for relapse prevention following 
intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled 
continuation trial. Int J Neuropsychopharmacol. 2010; 13(1):71–82. 
[11] Phelps LE, Brutsche N, Moral JR, et al. Family history of alcohol dependence and initial 
antidepressant 
response 
to 
an 
N-methyl-D-aspartate 
antagonist. 
Biol 
Psychiatry. 
2009;65(2):181–184.  
[12] Price RB, Nock MK, Charney DS, et al. Effects of intravenous ketamine on explicit and implicit 
measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009; 66(5):522–526. 
[13] Salvadore G, Cornwell BR, Colon-Rosario V, et al. Increased anterior cingulate cortical 
activity in response to fearful faces: a neurophysiological biomarker that predicts rapid 
antidepressant response to ketamine. Biol Psychiatry. 2009; 65(4):289–295. 
[14] Salvadore G, Cornwell BR, Sambataro F, et al. Anterior cingulate desynchronization and 
functional connectivity with the amygdala during a working memory task predict rapid 
antidepressant response to ketamine. Neuropsychopharmacology. 2010; 35(7):1415–1422. 
[15] Janicak PG, Dowd SM, Martis B, et al. Repetitive transcranial magnetic stimulation versus 
electroconvulsive therapy for major depression: preliminary results of a randomized trial. Biol 
Psychiatry. 2002;51(8):659–667 
 
 
 
 


 
7 
 
Table 1. Primary, secondary and safety endpoints in ELEKT-D 
Study Endpoint 
Definition 
Measure Type 
Primary 
Response (≥50% reduction in 
QIDS-SR16 scores from the 
Baseline/Visit 1 to End of 
Treatment visit) 
Patient rated scale 
Secondary 
Remission (QIDS-SR16<5 at 
two consecutive visits)  
Patient rated scale 
 
Summary score of MINI 7.0.2 
questions 
Diagnostic interview 
 
Summary score of QIDS-SR-16 
Patient rated scale 
 
Summary score of GSE-My 
Patient rated scale 
 
Summary score of SMCQ 
Patient rated scale 
 
Summary score of PGI-S and 
PGI-I 
Patient rated scale 
 
Summary score of QOLS 
Patient rated scale 
 
Summary score of PRISE 
Patient rated scale 
 
Summary score of Treatment 
Preference 
Patient rated scale 
 
Summary score of MADRS 
Clinician rated scale 
 
Summary score of CSSRS 
Clinician rated scale 
 
Summary score of CADSS 
Clinician rated scale 
 
Summary score of YMRS 
Clinician rated scale 
 
Summary score of BPRS 
Clinician rated scale 
 
Summary score of CGI-S and 
CGI-I 
Clinician rated scale 
 
Summary score of MoCA 
Cognitive testing 
 
Summary score of COWAT 
Cognitive testing 
 
Summary score of HVLT-R 
Cognitive testing 
 
Summary score of Stroop 
Cognitive testing 
 
Summary score of NAART 
Cognitive testing 
 
Summary score of CPFQ 
Cognitive testing 
Safety 
Mortality 
 
 
Unexpected adverse event 
 
 
Study treatment discontinuation 
adverse event 
 
 
Serious adverse event 
 
 
Vital signs (BMI, BP, heart rate) 
 
 


Summary of the Changes in the Statistical Analysis Plan (SAP) 
 
The two SAPs generally have the same content. The first version of the SAP was drafted for the 
original grant application, and the second version was drafted at the end of the study. The 
differences between the two versions are summarized below.  
1. Section 3.2 in version 1, the analysis plan for the secondary measures of cognitive 
assessment, was revised in version 2. In version 2, since these measures were 
longitudinal data, their analyses were proposed to follow the analyses of the 
longitudinal QIDS-SR-16 or MADRS scores (“Analysis of secondary endpoints” in version 
2).  
2. Section 4 in version 1, data analysis for follow-up period, was revised in version 2.  In 
version 2, separate linear mixed models were proposed for responders and non-
responders for the follow-up data since these two groups had different follow-up 
schedules after the acute phase.  
 
 

Prot_001.pdf: 
ELEKT-D Clinical Protocol 
Amendment V7.0 16Feb2022 
Confidential                                                             Page 1 of 40                                 Protocol V7.0 16Feb2022 
 
 
 
 
 
 
 
 
 
 
 
 
ELEKT–D: Electroconvulsive therapy (ECT) vs. ketamine in patients 
with treatment resistant depression (TRD) 
 
 
 
 
Sponsor: Cleveland Clinic Foundation 
 
Funding Agency: PCORI (Patient Centered Outcomes Research Institute)  
 
Principal Investigator: Amit Anand, MD 
 
ClinicalTrials.gov Identifier: NCT03113968 
 
 
 
Protocol V 3.0  
02 Feb 2017 
Protocol V4.0   
06 Apr 2017 
Protocol V5.0  
20 Jul 2018 
  
Protocol V6.0  
28 Jun 2019 
 
Protocol V7.0  
16 Feb 2022 
 
 
 
 
 
 
 
 
 
 
 
 
This investigational protocol contains confidential information for use by the principal 
investigators and their designated representatives participating in this clinical investigation. It 
should be held confidential and maintained in a secure location. It should not be copied or 
made available for review by any unauthorized person or firm. 
 
 


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Signature Page 
 
 
Study Title: 
 
ELEKT-D: Electroconvulsive therapy (ECT) vs. ketamine in patients with treatment resistant 
depression (TRD) 
 
Version date: 16Feb2022 
 
Protocol Version: 7.0 
 
 
 
I, the undersigned, have read and approve this protocol and agree on its contents. It is 
confirmed that the information and guidance given in this protocol complies with scientific 
principles, the guidelines of Good Clinical Practice, the Declaration of Helsinki in the latest 
relevant version, and the applicable legal and regulatory requirements. 
 
 
 
 
 
Principal Investigator 
Signature 
 
 
 
 
 
 
 
Amit Anand, MD 
 
 
 
 
                  
        
 
Date 
 
 
2.18.2022


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  List of Abbreviations 
 
 
 
AE 
Adverse Event 
ATHF 
Antidepressant Treatment History Form 
BCM 
Baylor College of Medicine 
BPRS 
Brief Psychiatric Rating Scale 
GCI-S/CGI-I 
Clinical Global Impression Scale for Severity and Improvement 
CCBH 
Cleveland Clinic Center for Behavioral Health 
CNRU 
Clinical Neuroscience Research Unit (Yale) 
COWAT 
Controlled Oral Word Association Test 
CSSRS 
Columbia Suicide Severity Rating Scale 
C5R 
C5Research (Cleveland Clinic) 
CADSS 
Clinician Administered Dissociative Symptoms Scale 
CPFQ 
Cognitive and Physical Functioning Questionnaire 
DALY 
Disability-Adjusted Life Years 
DSMB 
Data Safety Monitoring Board 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders (5th Ed.) 
ECT 
Electroconvulsive Therapy 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
EC 
Executive Committee 
GSE-My 
Global Self Evaluation of Memory 
HIPAA 
Health Insurance Portability and Accountability Act 
HVLT-R 
Hopkins Verbal Learning Test 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
LTFU 
Lost To Follow Up 
MADRS 
Montgomery Asberg Depression Rating Scale 
MAOI 
Monoamine Oxidase Inhibitor 
MAP 
Mt. Sinai Mood and Anxiety Disorders Program 
MINI 7.0.2 
Mini Neuropsychiatric Interview 
MoCA 
Montreal Cognitive Assessment 
MOP 
Manual of Operations 
MDD 
Major Depressive Disorder 
MSSM 
Mount Sinai Medical Center 
NAART 
North American Adult Reading Test 
NMDA 
N-methyl-d-aspartate 
PGI-S/PGI-I 
Patient Global Impression Scale 
PRISE 
Patient Rated Inventory of Side Effects 


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QIDS-SR-16 
Quick Inventory of Depressive Symptoms 
QOLS 
Quality of Life Scale 
RUL 
Right Unilateral 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Stakeholder Committee 
SOC 
Standard of Care 
SMCQ 
Squire Memory Complaint Questionnaire 
SSRI 
Selective Serotonin Reuptake Inhibitor  
TRD 
Treatment Resistant Depression  
YMRS 
Young Mania Rating Scale  
 
 
 
 
 
 
 
 
Table of Contents 
Study Synopsis ................................................................................................................................................ 7 
1.   Introduction ............................................................................................................................................ 12 
2.   Background and Rationale ...................................................................................................................... 12 
3.   Study Design ........................................................................................................................................... 13 
4.   Outcome Measures ................................................................................................................................ 14 
4.1 Primary Outcome ................................................................................................................................ 14 
4.2 Secondary Outcomes .......................................................................................................................... 15 
5.   Subject Selection .................................................................................................................................... 15 
5.1 Recruitment of Trial Participants ........................................................................................................ 15 
5.2 Inclusion Criteria ................................................................................................................................. 16 
5.3 Exclusion Criteria ................................................................................................................................. 16 
5.4 Randomization of Patients .................................................................................................................. 17 
6. Study Treatments ..................................................................................................................................... 17 
6.1 Acute Treatment Phase (To occur over 3 to 5 weeks) ......................................................................... 17 
6.1.1 ECT Arm ....................................................................................................................................... 17 
6.1.2 Ketamine Arm .............................................................................................................................. 17 
6.2 Assessment for Response during Acute Treatment Phase .................................................................. 18 
6.2.1 Responders .................................................................................................................................. 18 


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6.2.2 Non-Responders .......................................................................................................................... 18 
6.3 Concomitant Medication .................................................................................................................... 18 
6.3.1 Medications Allowed During Study .............................................................................................. 18 
6.3.2 Prohibited Medications ................................................................................................................ 19 
7.   Study Procedures .................................................................................................................................... 19 
7.1 Screening Period (Maximum of 28 days)  ........................................................................................... 19 
7.1.1 Screen Failures ............................................................................................................................. 20 
7.2 Baseline /Visit 1 (Randomization to occur as soon as possible, but within 1 week after  eligibility is 
confirmed) ................................................................................................................................................ 20 
7.3 Treatment Visits (To occur over 3 to 5 weeks) .................................................................................... 21 
7.3.1 ECT Arm ....................................................................................................................................... 21 
7.3.2 Ketamine Arm .............................................................................................................................. 22 
7.3.3 Completion and/or Early Termination of Treatment Phase ........................................................ 22 
7.4 End of Treatment (EOT) Visit .............................................................................................................. 23 
7.5 Follow-Up Visits ................................................................................................................................... 24 
7.5.1 Follow-Up Visits for Responders .................................................................................................. 24 
7.5.1.1 Month 1 Follow-Up Visit (+/- 2 weeks) ................................................................................. 24 
7.5.1.2 Month 3 Follow-Up Visit (+/- 2 weeks) ................................................................................. 25 
7.5.1.3 Month 6 Follow-Up Visit (+/- 2 weeks) .................................................................................. 25 
7.5.2 Follow-Up Phone Call for Non-Responders ....................................................................................... 26 
7.5.2.1 Month 1 Follow-Up Phone Call (+/- 2 weeks) ....................................................................... 26 
7.5.3 End of Study participation for the subject ........................................................................................ 26 
7.6 Non-Compliance ................................................................................................................................. 27 
7.7 Subject Withdrawal ............................................................................................................................ 27 
7.8 Lost to Follow-Up ................................................................................................................................ 27 
7.9 Study Termination .............................................................................................................................. 27 
8.   Safety Monitoring and Reporting ............................................................................................................ 28 
8.1 Unexpected Adverse Events ............................................................................................................... 28 
8.2 Study Treatment Discontinuation Adverse Events .............................................................................. 29 
8.3 Serious Adverse Events ....................................................................................................................... 29 
8.4 Documentation and Reporting of Serious Adverse Events ................................................................. 29 
8.5 Pregnancy ........................................................................................................................................... 29 
9.   Statistical Plan ......................................................................................................................................... 30 


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10. Study Committees ................................................................................................................................... 30 
10.1 Executive Committee ........................................................................................................................ 31 
10.2 Data and Safety Monitoring Board .................................................................................................... 31 
10.3 Stakeholder Committee .................................................................................................................... 31 
10.4 Reporting Plan .................................................................................................................................. 31 
11. Data Handling and Record Keeping ......................................................................................................... 31 
11.1 Data Collection ................................................................................................................................. 31 
11.2 Retention of Records ........................................................................................................................ 32 
12. Study Monitoring .................................................................................................................................... 32 
13. Ethical Considerations ............................................................................................................................ 32 
14. Publication and Disclosure ...................................................................................................................... 33 
15. References .............................................................................................................................................. 34 
16. Appendix ............................................................................................................................................... 35 
 


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Study Synopsis 
 
Title 
ELEKT-D: Electroconvulsive therapy (ECT) vs. ketamine in patients with 
treatment resistant depression (TRD) 
Sponsor 
Cleveland Clinic Foundation 
Funding Source PCORI (Patient Centered Outcomes Research Institute) 
Study Centers 
There will be 4-6 study sites located throughout the U.S. 
Patient 
Population 
Outpatients or inpatients with TRD referred by their clinical providers and eligible 
for ECT treatment. 
Study 
Objectives 
The aim of the study is to conduct a comparative randomized trial of 
ECT versus ketamine for TRD in a real world setting with patient 
reported outcomes as primary and secondary outcome measures. 
Specific Aim 1: To investigate the comparative effectiveness of ECT and 
ketamine on measures of depression. 
Specific Aim 2: To investigate the relative impact of ECT and ketamine on measures 
of memory and cognitive function. 
Specific Aim 3: To investigate the relative impact of ECT and ketamine on patient 
reported quality of life measures after acute treatment and at follow-up over six 
months. 
Study Design 
This is an unblinded prospective randomized open-label clinical trial. 
Patients will be randomized 1:1 to receive either ECT three times per week or 
ketamine two times per week over three weeks (additional two week window 
allowed for flexibility). 
Responders (patients who achieve a ≥ 50% decrease on their QIDS-SR-16 score 
from Baseline/Visit 1 to the End of Treatment visit) may return for three follow-
up visits over a six month period following the end of treatment visit, depending 
on the date of enrollment relative to the end of study. Non-responders will 
receive a phone call one month after the End of Treatment visit. 
Number of 
Patients 
Approximately 400 eligible subjects will be enrolled, 200 in the ECT arm and 200 in 
the ketamine arm. It is estimated that 60% or 240 patients (approximately 120 in 
each arm) will be classified as responders. Due to the expected high level of 
attrition, 192 patients classified as responders (approximately 96 in each arm) are 
expected to complete the follow-up visits, depending on when the study 
 ends. 


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Duration of 
Patient 
Participation 
and Duration of 
the Study  
The screening period will be a maximum of 28 days. Randomization should occur 
within one week after eligibility is confirmed. 
 
After patients are enrolled they will be randomized to either ECT or     ketamine 
therapy. Patients in the ECT arm will receive up to nine treatments over three 
weeks (+ two weeks). Patients in the ketamine arm will receive up to six treatments
over three weeks (+ two weeks). 
Patients in both arms classified as responders may have three additional visits, at 
Month 1, Month 3, and Month 6 after the End of Treatment visit, depending on the 
date of enrollment relative to the end of study. 
Patients in both arms classified as Non-responders will receive a phone call one 
month after the End of Treatment visit. 


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Key Selection 
Criteria 
INCLUSION CRITERIA 
1.   Written informed consent before any study related procedures are 
performed 
2.   Inpatients or outpatients referred by their providers for ECT 
treatment and eligible for ECT treatment 
3.   Males/females at least 21 years of age but no older than 75 years 
of age 
4.   Meet DSM-5 criteria for a Major Depressive Episode as 
determined by both: 
A. a clinician’s diagnostic evaluation and 
B. confirmed with the MINI International Neuropsychiatric 
Interview (MINI 7.0.2) 
5.   A current depressive episode that has lasted a minimum of 4 weeks 
6.   Meet all of the following criteria on symptom rating scales at 
screening: 
A. Montgomery Asberg Depression Rating Scale (MADRS) score >20 
B. Young Mania Rating Scale (YMRS) of ≤ 5 
C. Montreal Cognitive Assessment (MoCA) of ≥18 
7.   Have had ≥ 2 adequate trials of antidepressants or augmentation 
strategies during their lifetime.  An adequate trial is defined as 4 
weeks of medication at the minimum FDA approved dose.  This 
will be equal to a trial rating of 3 or more.  
8.   In the opinion of the investigator, the patient is willing and able to 
comply with scheduled visits, treatment plan, and other trial 
procedures for the duration of the study 
EXCLUSION CRITERIA 
1.   Meet DSM-5 criteria for bipolar disorder, schizophrenia, 
schizophreniform disorder, schizoaffective disorder, mental 
retardation, or pervasive developmental disorder 
2. Meets any exclusion criteria for ECT or ketamine treatment as 
described in the clinical guidelines or according to investigator 
judgment 
3.   The patient is pregnant or breast feeding 
4.   The patient has a severe medical illness or severe neurological 
disorder 
5.   The patient has a known ketamine allergy or is taking a medication 
that may interact with ketamine 
6.   Diagnosis of major depressive disorder with psychotic features 
during the current depressive episode 
7.   Unable to give informed consent 
8.   Was previously enrolled/randomized into the trial 
 


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 Test Product, 
 Dose, and 
Mode of 
Administration 
 ECT: 
Patients randomized to the ECT arm will receive standardized ECT treatment as   
determined by each study site. The starting ECT treatment will be Right Unilateral 
(RUL) ultra-brief pulse at 6X seizure threshold determined during titration at the first 
visit. If there is not satisfactory improvement after RUL for three to five treatments, 
there will be a switch to Bilateral (BL) utilizing brief pulse using 0.5 modified half-age 
method to determine stimulus intensity. Investigators may adjust treatments at any 
time if clinically warranted. 
Anesthesia will be administered according to standard of care at each site, but 
ketamine will not be allowed. Patients will receive up to nine treatments over three 
weeks (additional two week window allowed for flexibility). 
Ketamine: 
The standard dose of ketamine (0.5mg/kg infusion over 40 minute period) will be 
administered two times per week over three weeks (additional two week window 
allowed for flexibility). The investigator will be able to adjust the dose if clinically 
warranted. 
For both treatments, flexibility will be allowed for the clinician to adjust the 
treatment as clinically necessary. 
Concomitant 
Medications 
All patients will continue their existing antidepressant treatment while on the study 
protocol. Patients will also continue existing non-psychotropic medications 
initiated prior to the Baseline/Visit 1, unless the investigator determines that they 
are contraindicated for ECT or ketamine treatment. Each site will follow their 
standard clinical protocol for this. 
 
Investigators will follow their site’s standard safety evaluation process for 
anesthesia administration and ECT. 
Prohibited 
Medications 
Any medication that is judged by the investigator to have significant clinical 
interaction with ECT or ketamine. 
Outcome 
Measures 
The primary outcome measure is response rate, defined as ≥50% reduction in QIDS-
SR16 scores from Baseline/Visit 1 to the End of Treatment Visit. 
Secondary 
Outcome 
Measures 
Secondary outcome measures will include clinician and patient rated scales for 
depression, suicidality, cognition, and associated psychiatric symptoms. 
 


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AE/ SAE 
Collection 
SAEs will be reported to the sponsor and the respective site IRB within 24 
hours of notification of the event. 
 
SAEs 
• Death 
• Life threatening AEs (including suicide attempt) 
• A new inpatient hospitalization or prolongation of existing 
hospitalization. 
• A disability/incapacity 
• A congenital anomaly/birth defect in the offspring of a patient who 
received drug 
• Other Serious Event (Important Medical Event) - an important 
medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
Medical and scientific judgment should be exercised in deciding 
whether other situations should be considered serious adverse 
event. 
Statistical 
Methodology 
We will conduct an intention to treat (ITT) analysis. A sensitivity analysis will 
be performed on the modified intention-to-treat (mITT) population defined 
as a randomized patient having at least one treatment and one QIDS-SR16 
measurement during the acute treatment phase.  
 
The primary outcome measure of response rate will be compared between 
ketamine and ECT using a chi-square test, to test the comparative efficacy of 
ketamine and ECT for reduction in depressive symptoms. A multivariable 
logistic regression model will be constructed for the analysis, to account for 
potential heterogeneity of treatment effect caused by confounding variables. 
A similar analytic strategy will be applied to evaluate cognitive function and 
quality of life. 
 
 
 
 
 


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  1.   Introduction 
 
Major depressive disorder (MDD) accounts for 65.5 million disability-adjusted life years 
(DALYs) and ranks third among illnesses of global disease burden (1). Identifying 
treatments that are more effective for MDD is required to meet this large and growing 
public health challenge. However, recent data suggest that antidepressant therapies are 
less efficacious than previously thought (2, 3). The real-world effectiveness of 
antidepressants is sub-optimal in approximately two of three patients (4, 5). Treatment 
Resistant Depression (TRD) has been defined as depression resistant to one or more 
adequate trials of antidepressants for which the patient reports minimal or no 
significant improvement in mood (6, 7). TRD has been noted to be present in 20-50% of 
depression patients. TRD patients have significantly higher outpatient costs and a higher 
cost of hospitalization (8). Chronic, inadequately treated depression is associated with 
loss of social and workplace functioning, increased medical illnesses and healthcare use, 
and an increased risk for suicide(6). In the United States, the total economic cost of 
depression in 2012 was estimated at $188 billion (6). Hence, there is an urgent need to 
identify treatments that can be effective for TRD. 
 
 
2.   Background and Rationale 
 
ECT Use in TRD 
Electroconvulsive therapy (ECT) has been in use for nearly 75 years for severe TRD and 
is considered to be one of the most effective treatments (9). However it is associated 
with a number of side effects and social stigma. 
 
Cognitive impairment and significant memory loss has been observed in unilateral and 
bilateral as well as higher dose ECT immediately after treatment (10). Additional 
adverse events associated with ECT include anterograde amnesia (i.e. memory 
disturbance of events after ECT treatment) in the short-term and retrograde amnesia 
(memory disturbance of events before ECT treatment) in the long-term. Retrograde 
amnesia can persist for years after ECT treatment particularly for events near the time 
of treatment (11). 
 
Other side effects of ECT include risks of receiving general anesthesia and muscle 
relaxants, delirium in the post- ECT period, headaches and muscle aches, nausea and 
fatigue and rarely, prolonged seizures. 
 
 
Ketamine as an Alternative Treatment for TRD 
Ketamine shows promise as a treatment for TRD, but there is an evidence gap in its use 
as an alternative to ECT. Ketamine is a sedative/analgesic and general anesthetic 
approved by the FDA for human and veterinary use. It is an antagonist of the N-
methyl-d-aspartate (NMDA) receptors in the brain and decreases the 
neurotransmission of glutamate (the main excitatory neurotransmitter) via the NMDA 


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receptor. 
 
Single infusion of a sub-anesthetic dose of ketamine has shown rapid but transient 
reversal of TRD symptoms. A number of open label studies done so far indicate that 
repeated ketamine infusion treatment results in responses similar to that of ECT (40). 
Ketamine can lead to symptoms of dissociation, perceptual disturbances, or even 
psychotic like symptoms (33) although these are seen infrequently at sub-anesthetic 
doses used in the treatment of TRD and are rapidly reversed after stopping the 
infusion. 
 
Currently, there are no formal randomized trials with detailed clinical and demographic 
data to provide direct comparative efficacy evidence between ECT and ketamine 
treatment. This study will provide such data and help to fill the evidence gap for 
efficacy of ECT and ketamine treatment for TRD. 
3.   Study Design 
This is a prospective randomized open-label 2-arm (1:1) clinical trial of TRD with either 
ECT or ketamine treatment. Given the nature of ketamine and ECT treatments 
randomization and treatment arms cannot be blinded at the clinician or patient level. 
 
After screening and evaluation of inclusion/exclusion criteria, patients will be 
randomized to either ECT three times per week or ketamine two times per week. This 
acute treatment phase will last between three to five weeks. This timeframe allows for 
changes in the treatment schedule due to clinician discretion or the patient’s schedule. 
Patients may respond or remit to ECT or ketamine before they have completed all 
treatment visits and therefore may not undergo the full nine visits (for ECT) or six visits 
(for ketamine). Investigators will closely monitor patients and may adjust treatments 
during the acute treatment phase at any time. All patients, regardless of how many 
treatment visits have been completed, should complete an End of Treatment Visit 
(EOT). 
 
All patients will complete self-reported cognitive assessments, depression 
questionnaires, and quality of life scales at the Baseline Visit/Visit 1 and throughout 
the acute treatment phase of the study (see Schedule of Events). Diagnostic interviews 
and clinician rated scales will also be performed at regular intervals throughout the 
acute treatment phase. 
 
After the acute treatment phase, all patients will complete an EOT visit within 3 days of 
their last study treatment and will be classified as either a responder or a non-
responder. Patients may continue to receive ECT or ketamine clinically after the EOT 
visit, but this will mark the end of the acute treatment phase of the study. If the 
patient is a responder, any ECT or ketamine treatments administered after the EOT 
visit will be recorded in the follow-up phase. If the patient is not a responder they will 
receive a phone call one month after the End of Treatment Visit for completion of PGI-
I, PGI-S, QIDS and MADRS, and record any ECT or ketamine treatments administered 
after the EOT visit. This will conclude their participation in the study and they will be 


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treated clinically. 
 
Responder: a patient who achieves a ≥ 50% decrease in their QIDS-SR-16 score from 
Baseline/Visit 1 to the End of Treatment visits. Responders may continue in the study 
for three follow-up visits at one month, three months, and six months after the EOT 
Visit, depending on the date of enrollment relative to the end of study.  They will 
continue naturalistic treatment with a clinician of their choice. 
 
Non-Responder: a patient who achieves <50% decrease in their QIDS-SR-16 score from 
Baseline/Visit 1 to the End of Treatment Visit. Non-responders will receive a phone call 
at one month after the EOT Visit. They will be exited from the study after the one 
month phone follow-up visit and will not be contacted or seen for the three and six 
month follow-up visits. They will continue treatment with the clinician of their choice. 
 
Early Completion of Acute Treatment Phase 
The investigator or patient can choose to stop treatment at any time. Investigators will 
monitor patients closely for signs of improvement, remission, or decline. The 
investigator will use his or her discretion and clinical judgment to determine if a 
patient should stop treatment and be scheduled for an End of Treatment Visit. 
 
Investigators may decide to stop treatment for patients who show improvement after 
less than nine ECT treatments or six ketamine treatments. These patients should be 
scheduled for an End of Treatment Visit and if they are found to be responders will 
participate in the follow-up visits. 
 
Investigators may also decide to stop treatment for patients who decline or have 
worsening depression or suicidality during the acute treatment phase. These patients 
should be scheduled for an End of Treatment Visit and be evaluated for response. 
(These patients are unlikely to be classified as responders. 
 
If an outpatient has worsening depression that requires psychiatric hospitalization, the 
patient may continue in the study at investigator discretion. These patients can receive 
study ECT or ketamine treatments as an inpatient. 
 
4.   Outcome Measures 
To avoid potential bias, the patient assessments and the clinician assessments should 
be completed independently and without reference to one another. The research 
coordinator or clinician administering the questionnaires should not view the patient’s 
responses on patient rated scales. (They should, however, remind the patient to 
answer all questions and not leave any questions blank.) 
 
4.1 Primary Outcome 
 
The primary outcome measure is the percent of responders.  Treatment response is 
defined as a ≥ 50% decrease in QIDS-SR-16 scores from the Baseline Visit to the EOT 


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visit.  The QIDS-SR-16 will be administered prior to treatment according to the 
following schedules.  
 
ECT Arm 
The QIDS-SR-16 will be administered at certain time points during the acute treatment phase 
(Baseline/Visit 1, Visit 2, Visit 4, Visit 6, Visit 7, Visit 9, and EOT visit). Patients in the ECT arm who 
are classified as responders will complete the QIDS-SR-16 at all follow-up visits. Non-responders 
will follow-up at one month to complete the PGI-I, PGI-S, QIDS and MADRS, and record any ECT 
or ketamine treatments administered after the EOT visit. 
Ketamine Arm 
The QIDS-SR-16 will be administered at all visits during the acute treatment phase 
(Baseline/Visit 1, Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, EOT visit).  Patients in the 
ketamine arm who are classified as responders will complete the QIDS-SR-16 at all 
follow-up visits. Non-responders will follow-up at one month to complete the PGI-I, 
PGI-S, QIDS and MADRS, and record any ECT or ketamine treatments administered 
after the EOT visit. 
This scale should be the first assessment administered and should be checked for 
completeness by the study nurse or research coordinator. All attempts should be made 
to have a consistent and neutral atmosphere for the patient to complete the QIDS and 
all patient rated scales to minimize outside influence. 
 
4.2 Secondary Outcomes 
 
Other patient and clinician rated scales will be used as secondary outcome 
measurements. (See Table 1.) 
 
All scales (except CADSS and BPRS) will be administered prior to treatment. CADSS and 
BPRS will be administered by the research nurse or a clinician post treatment. 
Questionnaires will be administered according to the schedule of events. 
 
During the follow-up visits, data analysis for the Month 1, Month 3, and Month 6 visits 
will be conducted using the End of Treatment Visit as baseline. 
 
5.   Subject Selection 
5.1 Recruitment of Trial Participants 
 
Inpatients or Outpatients with TRD without psychotic features referred by their clinical 
providers for ECT, and found to be eligible for ECT treatment, will be pre-screened for 
the study.  Potential patients will be approached after a psychiatrist has evaluated them 
and recommended them for clinical ECT treatment. At this time, the patient will be 
informed about the study and given a thorough explanation of risks, benefits, study 
procedures, and expectations. 
Patients interested in participation will be scheduled for a screening visit as soon as 
possible, but no later than 28 days from the clinical consult. Typically patients should be 


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scheduled for screening within two weeks from the consult.  
 
5.2 Inclusion Criteria 
 
Patients are eligible for the study if they meet the following inclusion criteria: 
 
1)   Written informed consent before any study related procedures are performed 
2)  Inpatients or outpatients referred by their providers for ECT treatment and eligible for ECT 
treatment 
3)  Males or females at least 21 years of age, but no older than 75 years of age 
4)  Meet DSM-5 criteria for a Major Depressive Episode as determined by both: 
• a clinician’s diagnostic evaluation and  
• confirmed by interview using the Mini International Neuropsychiatric 
Interview (MINI 7.0.2) 
5)  A current depressive episode that has lasted a minimum of two weeks 
6) Meet all of the following criteria on symptom rating scales at screening: 
• Montgomery Asberg Depression Rating Scale (MADRS) score >20 
• Young Mania Rating Scale (YMRS) ≤ 5 
• Montreal Cognitive Assessment (MoCA) of ≥ 18 
7)   Have had ≥ 2 adequate trials of antidepressants/augmentation strategies during their 
lifetime.  An adequate trial is defined as 4 weeks of a medication at minimum FDA approved 
dose.  This will be equal to a trial rating of 3 or greater.   
8)  In the opinion of the investigator, the patient is willing and able to comply with scheduled 
visits, treatment plan, and other trial procedures for the duration of the study 
 
5.3 Exclusion Criteria 
 
Patients must NOT meet any of the following exclusion criteria: 
 
1)   Meets DSM-5 criteria for bipolar disorder, schizophrenia, schizophreniform 
disorder, schizoaffective disorder, mental retardation, or pervasive 
development disorder 
2)  Meet any exclusion criteria for ECT or ketamine treatment as described in the 
clinical guidelines or according to investigator judgment 
3)   The patient is pregnant or breast feeding 
4)  The patient has a severe medical illness or severe neurological disorder 
5)   The patient has a known ketamine allergy or is taking any medication that may 
interact with ketamine 
6) Diagnosis of major depressive disorder with psychotic features during the 
current depressive episode 
7)   Unable to give informed consent 
8)  Was previously enrolled/randomized into the trial 
 
 
 


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5.4 Randomization of Patients 
All patients who are eligible for the trial will be randomized in a 1:1 fashion to either 
ECT or ketamine treatment. Given the nature of these treatments, treatment arms 
cannot be blinded at the patient or clinician level. Randomization will be conducted 
centrally through a secure electronic data management system. Detailed instructions 
can be found in the Manual of Operations (MOP). Collect patient status as inpatient or 
outpatient at randomization.  
 
6. Study Treatments  
6.1 Acute Treatment Phase (To occur over 3 to 5 weeks) 
 
6.1.1 ECT Arm 
Patients will undergo anesthesia evaluation according to each site’s standard clinical 
procedure. Anesthesia will be administered according to standard of care at each site, 
but ketamine will not be allowed. 
 
The initial ECT treatment will be Right Unilateral (RUL) ultra-brief pulse at 6X seizure 
threshold determined during titration at first visit. If there is not satisfactory 
improvement with RUL the investigator may change to Bilateral (BL) utilizing brief 
pulse using 0.5 modified half-age method to determine stimulus intensity. The seizure 
threshold may increase during the course of treatment and the dose of the electric 
stimulus may need to be increased incrementally (16). It is suggested to change to 
bilateral after three to five RUL treatments (17). 
 
Treatments will be given three times a week and after nine treatments the acute arm 
of the study would be complete. Flexibility will be allowed for the ECT clinician to 
adjust the treatments as clinically necessary. 
 
Patients will receive up to nine treatments over three to five weeks. Ideally patients 
will receive treatments at regular intervals of three times per week for three weeks. 
The window allows for modifications based on clinician discretion and the patient’s 
schedule. 
 
Patients will be assessed by clinical providers prior to each visit to evaluate treatment 
response and appropriateness for continued treatment. Patients will be assessed for 
any adverse events and treated per investigator discretion. 
 
Patients will receive both patient rated and clinician rated behavioral scales at 
Baseline/Visit 1, Visit 2, Visit 4, Visit 6, Visit 7, Visit 9, and EOT Visit. 
 
6.1.2 Ketamine Arm 
Patients will receive up to six treatments over three to five weeks. Ideally patients will 
receive treatments at regular intervals of two times per week for three weeks. The 
window allows for modifications based on clinician discretion and patient schedules. 


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Ketamine will be administered according to the standard dose of 0.5mg/kg infusion 
over a 40 min period. The investigator will be able to modify the dose if clinically 
warranted. Treatments will be given two times a week for a maximum of six 
treatments after which the acute arm of the study will be complete. 
 
Patients will be clinically assessed prior to each treatment to evaluate response and 
appropriateness for continued treatment. Patients will be assessed for any adverse 
events and treated per investigator discretion. 
 
Patients will receive both patient rated and clinician rated behavioral scales at all 
treatment visits (Baseline/Visit 1, Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, and EOT Visit). 
 
6.2 Assessment for Response during Acute Treatment Phase 
 
6.2.1 Responders 
Patients who have a decrease of ≥ 50% on the QIDS-SR-16 from Baseline/Visit 1 to the 
EOT Visit will be classified as a responder. These patients may be included in the six 
month follow-up phase, depending on the date of enrollment relative to the end of 
study. The clinician may decide to stop treatment before the maximum number of 
visits and schedule the patient for an EOT Visit. 
 
6.2.2 Non-Responders 
Patients who have less than a 50% decrease in QIDS-SR-16 score from the 
Baseline/Visit 1 to the EOT Visit will be classified as non-responders. These patients will 
not be seen for follow-up visits. However, these patients will receive a follow-up phone 
call one month after the End of Treatment Visit to ask about AEs/SAEs, treatment with 
ECT, ketamine, psychotropic medications, and complete the PGI-S and PGI-I, QIDS and 
MADRS assessments. Patients will be referred to their clinical provider for ongoing 
treatment of depression. Continuity of care between study staff and clinical providers 
will be carefully managed in order to provide optimal ongoing psychiatric care for the 
patient. 
 
6.3 Concomitant Medication 
 
6.3.1 Medications Allowed During Study 
Patients will be allowed to continue their existing psychotropic medications. Changes 
in psychotropic medications throughout the trial are best avoided but are permitted 
according to investigator discretion. These medications must be recorded on the 
Psychiatric Medication Log. 
 
Subjects should continue medications for other conditions and be reminded to tell 
study staff of any changes to medical history or concomitant medications. This will be 
assessed at each visit prior to treatment. All subjects should receive optimal care for any 
side effects occurring during the study (nausea, headache, etc.) according to local 


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standards of care or evidence based guidelines, and at the discretion of the investigator. 
 
6.3.2 Prohibited Medications 
Patients should not be enrolled in the study if they are taking any medication that is 
contraindicated for ECT or ketamine treatment. 
 
Changes in medical history and concomitant medications will be assessed at each visit 
and patients may be withdrawn from the study at any point if they are taking 
prohibited medication. 
 
7.   Study Procedures 
 
7.1 Screening Period (Maximum of 28 days)  
 
• Informed Consent: An investigator and/or other delegated study team 
member will discuss all risks and benefits of participation and review the 
study visit schedule with the patient. The patient will sign the informed 
consent form prior to any study procedures being performed. 
• Assessment of Inclusion/Exclusion Criteria 
• Demographics 
• Medical History, including psychiatric history and history of neurological conditions 
• Psychiatric Medication Log  
• Somatic Therapies Log 
• Clinical Psychiatric Evaluation 
• Diagnostic evaluation by investigator 
o Meets DSM-5 criteria for MDD, but does not meet DSM-5 criteria for Bipolar 
Disorder, Schizophrenia, Schizophreniform disorder, schizoaffective disorder, 
mental retardation, Pervasive Development Disorder 
o No psychotic features during the current depressive episode 
o Verify current depressive episode has lasted at least 4 weeks 
o Verify that patient has had at least two adequate  trials of antidepressant therapy 
• Urine pregnancy test for females of child bearing potential 
 
• Diagnostic Interview 
o MINI 7.0.2 
 
• Clinician Rated Scales 
o MADRS 
o YMRS 
 
• Cognitive Assessments 
o MoCA 
 
 


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If patients meet eligibility criteria, they will be randomized into either the ECT or 
ketamine arm via a secure electronic data management system. Randomization can be 
done by study staff after the screening visit. Depending on which arm the patient is 
randomized to, the study nurse will schedule them for their Baseline/Visit 1 according to 
the site’s clinical or research schedule. 
 
7.1.1 Screen Failures 
If the patient fails to qualify for the study after signing the informed consent form, they 
will be considered a screen failure.  Patients who screen fail and are not randomized 
will be eligible to rescreen at a later date. Patients should only be enrolled into the 
study once, therefore patients who have been randomized will not be eligible for future 
screening. 
 
7.2 Baseline /Visit 1 (Randomization to occur as soon as possible, but within 1 week after 
eligibility is confirmed) 
• Update Medical History 
• Update Psychiatric Medication Log 
• Update Somatic Therapies Log  
• Clinical Psychiatric Evaluation 
• Vitals (BP, heart rate, height, weight) 
• Evaluation for AEs and SAEs 
 
Questionnaires to be Completed Prior to Treatment 
• Patient Rated Behavioral Scales 
o QIDS-SR-16 (to be completed first) 
o SMCQ 
o PGI-S 
o QOLS 
o PRISE 
o CPFQ 
 
• Clinician Rate Behavioral Scales 
o MADRS 
o CSSRS  
o YMRS 
o CGI-S  
 
• Cognitive Assessments 
o COWAT 
o HVLT-R 
o Stroop 
o NAART 
 
ECT Procedure or Ketamine Infusion 


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Questionnaires to be Completed Post Treatment* 
o CADSS 
o BPRS 
 
*Patients in the ECT arm will need to have a recovery period prior to completing the 
post treatment questionnaires. 
 
 
7.3 Treatment Visits (To occur over 3 to 5 weeks) 
 
7.3.1 ECT Arm 
Prior to each treatment, patients will be assessed if clinically appropriate for the 
treatment. Components of the evaluation for ECT will vary on a case-by-case basis. Each 
site will perform the following minimal set of assessments: 
 
• Update Medical History 
• Update Psychiatric Medication Log 
• Update somatic therapies log 
• Vitals (BP, heart rate, weight) 
• Evaluation for Adverse Events or Serious Adverse Events 
• Clinical Psychiatric Evaluation 
• Patient and Clinician Rated Behavioral Scales (to be completed at 
Baseline/Visit 1, Visit 2, Visit 4, Visit 6, Visit 7, and Visit 9) 
 
   Prior to Treatment: 
• Patient Rated Behavioral Scales  
o QIDS-SR-16 (To be completed first) 
o GSE-MY (Not completed at Baseline/Visit 1)  
o SMCQ 
o PGI-S & PGI-I (PGI-I not completed at Baseline/Visit 1) 
o QOLS 
o PRISE 
o CPFQ 
 
• Clinician Rated Behavioral Scales 
o MADRS 
o CSSRS 
o YMRS 
o CGI-S & CGI-I (CGI-I not completed at Baseline/Visit 1)  
 
• Post Treatment (clinician rated) 
o CADSS 
o BPRS 
 


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7.3.2 Ketamine Arm 
Prior to each treatment, patients will be assessed if clinically appropriate for the 
treatment. Each site will follow their standard of care for evaluating patients for 
ketamine treatment. Each site will perform the following minimal set of assessments: 
 
• Update Medical History 
• Update Psychiatric Medication Log 
• Update Somatic Therapies Log   
• Vitals (BP, heart rate, weight) 
• Evaluation for Adverse Events or Serious Adverse Events 
• Clinical Psychiatric Evaluation 
• Patient and Clinician Rated Behavioral Scales (to be completed at every visit) 
 
   Prior to Treatment: 
• Patient Rated Behavioral Scales (to be completed at every visit) 
o QIDS-SR-16 (To be completed first) 
o GSE-MY (Not completed at Baseline/Visit 1) 
o SMCQ 
o PGI-S & PGI-I (PGI-I not completed at Baseline/Visit 1) 
o QOLS 
o PRISE 
o CPFQ 
 
• Clinician Rated Behavioral Scales (to be completed at every visit) 
o MADRS 
o CSSRS 
o YMRS 
o CGI-S & CGI-I (CGI-I not completed at Baseline/Visit 1) 
 
Post Treatment (clinician rated): 
o CADSS 
o BPRS 
 
7.3.3 Completion and/or Early Termination of Treatment Phase 
Investigators can end the treatment phase early, before the maximum number of 
treatments are completed, if: 
 
• The clinician feels the patient has achieved a sustained remission (QIDS-SR-
16 score <5 on two consecutive assessments) or the clinician determines 
additional treatments are not clinically warranted 
• The patient has worsening depression, severe psychotic symptoms, or 
becomes suicidal 
 
If these situations occur the patient should be scheduled for an End of Treatment Visit. 
The patient can decide not to continue treatment for any reason. They should be 
encouraged to complete an End of Treatment Visit. 


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7.4 End of Treatment (EOT) Visit 
 
Patients should complete an EOT visit within three (3) days of their last study 
treatment. If patients do not stop treatment early, this will occur after the 9th ECT 
treatment or the 6th ketamine treatment. If patients stop earlier, the EOT visit should 
occur within three (3) days of this final treatment. Patients may continue to receive 
ECT or ketamine clinically, but the EOT visit marks the end of the acute treatment 
phase for the study. 
 
• Vitals (BP, Heart rate)  
• Update Medical History 
• Update Psychiatric Medication Log 
• Update Somatic Therapies Log 
• Evaluation for AEs or SAEs 
• Clinical Psychiatric Evaluation 
 
• Patient Rated Behavioral Scales 
o QIDS-SR-16 (to be completed first) 
o GSE-MY 
o SMCQ 
o PGI-S & PGI-I 
o QOLS 
o PRISE 
o CPFQ 
o Treatment Preference Questionnaire 
 
• Clinician Rated Behavioral Scales 
o MADRS 
o CSSRS 
o YMRS 
o BPRS 
o CGI-S & CGI-I 
o CADSS 
 
• Cognitive Assessments 
o MoCA 
o COWAT 
o HVLT-R 
o Stroop 
 
Patients will be classified as responders or non-responders after the EOT Visit.  
 
Responders will be patients who had a ≥ 50% decrease in their QIDS-SR-16 score from 
Baseline/Visit 1 to the EOT Visit. Responders will be asked to participate in the follow-up 


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phase of the study. Follow-up visits may occur one month, three months, and six 
months after the EOT Visit, depending on the date of enrollment relative to the end of 
study. 
 
Non-responders will have had < 50% decrease in their QIDS-SR-16 score from 
Baseline/Visit 1 to the EOT Visit. Non-responders will not be seen for follow-up visits. 
However, these patients will receive a follow-up phone call one month after the End of 
Treatment Visit.  
 
Inpatient / Outpatient Status - If the patient was an inpatient at randomization, record 
if they were discharged during treatment and the date of discharge, at the End of 
Treatment Visit.  
 
7.5 Follow-Up Visits  
 
7.5.1 Follow-Up Visits for Responders (These visits may be completed depending on the date of 
enrollment relative to the end of study.) 
 
7.5.1.1 Month 1 Follow-Up Visit (+/- 2 weeks) 
 
• Update Medical History 
• Update Psychiatric Medication Log 
• Update Somatic Therapies Log 
• Vitals (BP, heart rate, weight) 
• Evaluation for Adverse Events or Serious Adverse Events 
• Psychiatric Evaluation 
 
• Patient Rated Behavioral Scales 
o QIDS-SR-16 (to be completed first) 
o GSE-MY 
o SMCQ 
o PGI-S & PGI-I 
o QOLS 
o PRISE 
o CPFQ 
 
• Clinician Rated Behavioral Scales 
o MADRS 
o CSSRS 
o YMRS 
o BPRS 
o CGI-S & CGI-I 
o CADSS 
 
• Cognitive Assessments 


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o MoCA 
o COWAT 
o HVLT-R 
o Stroop 
 
 
7.5.1.2 Month 3 Follow-Up Visit (+/- 2 weeks) 
 
• Update Medical History 
• Update Psychiatric Medication Log 
• Update Somatic Therapies Log 
• Vitals (BP, heart rate, weight) 
• Evaluation for Adverse Events or Serious Adverse Events 
• Psychiatric Evaluation 
• Patient Rated Behavioral Scales 
o QIDS-SR-16 (to be completed first) 
o GSE-MY 
o SMCQ 
o PGI-S & PGI-I 
o QOLS 
o PRISE 
o CPFQ 
 
• Clinician Rated Behavioral Scales 
o MADRS 
o CSSRS 
o YMRS 
o BPRS 
o CGI-S & CGI-I 
o CADSS 
 
• Cognitive Assessments 
o MoCA 
o COWAT 
o HVLT-R 
o Stroop 
 
7.5.1.3 Month 6 Follow-Up Visit (+/- 2 weeks) 
 
• Update Medical History 
• Update Psychiatric Medication Log 
• Update Somatic Therapies Log 
• Vitals (BP, heart rate, weight) 
• Evaluation for Adverse Events or Serious Adverse Events 
• Psychiatric Evaluation 


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• Patient Rated Behavioral Scales 
o QIDS-SR-16 (to be completed first) 
o GSE-My 
o SMCQ 
o PGI-S& PGI-I 
o QOLS 
o PRISE 
o CPFQ 
 
• Clinician Rated Behavioral Scales 
o MADRS 
o CSSRS 
o YMRS 
o BPRS 
o CGI-S & CGI-I 
o CADSS 
 
• Cognitive Assessments 
o MoCA 
o COWAT 
o HVLT-R 
o Stroop 
 
7.5.2 Follow-Up Phone Call for Non-Responders 
7.5.2.1 Month 1 Follow-Up Phone Call (+/- 2 weeks) 
• 
 Evaluation for Adverse Events or Serious Adverse Events 
• Evaluation for additional ECT, ketamine, psychotropic treatment(s) performed 
o Update Somatic Therapies Log 
o Update Psychiatric Medications Log 
•  Patient Rated Behavioral Scale 
• PGI-S & PGI-I 
• Completion of QIDS  
• Completion of MADRS  
 
7.5.3 End of Study participation for the subject 
A subject will be considered as achieving End of Study when: 
• 
Subject completes all treatment visits and follow-up visits, according to Responder/Non-
Responder classification  
• 
Subject withdraws full consent  
• 
Subject is Lost to Follow Up 
• 
Subject Expires 
• 
Clinician discretion 
An End of Study eCRF will be completed for each subject randomized to treatment.  


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7.6 Non-Compliance 
A patient can be withdrawn from the study for non-compliance, per investigator 
discretion, if they miss two or more consecutive treatments during the acute 
treatment phase of the study. 
 
7.7 Subject Withdrawal 
Subjects may withdraw from study participation or from the study treatment at any time at their 
own request, or they may be withdrawn at any time at the discretion of the investigator for safety 
or behavioral reasons, or the inability of the subject to comply with the protocol required 
schedule of study visits or procedures at a given study site. If the subject elects to discontinue 
participation in the study or to discontinue study treatment, the investigator should: 
• Inquire about the reason for withdrawal 
• Request the subject to return for an EOT Visit to assess AEs/SAEs, 
safety endpoints, outcome events, vital status 
• Follow-up with the subject regarding any unresolved adverse events. 
 
If the subject withdraws from the trial and also withdraws consent for disclosure of 
future information, no further evaluations should be performed and no additional data 
should be collected. Adequate documentation of this request should be obtained and 
retained in the subject’s source file. True withdrawal of consent should be subject 
initiated and in writing. The sponsor may retain and continue to use any data collected 
before withdrawal of consent. 
 
7.8 Lost to Follow-Up 
Contact information from the patient, including an emergency contact will be obtained 
at the time of screening. This information will be reviewed and verified at each clinic 
visit and telephone contact. 
 
Patients will be considered lost to follow-up (LTFU) after the End of Treatment phase, 
when one of the following is met: 
• For Non-Responders in the one month Follow-Up Phase - patients will be 
considered LTFU after 3 attempts to contact the patient.  
• For Responders in the Follow-Up Phase - patients will be considered LTFU 
only after the Month 6 Visit, or at the end of study, whichever comes first.  
 
For each missed visit, study staff should make three attempts to contact the patient as 
soon as possible at various intervals.  The site should access medical records, other 
health care professionals, institutional databases and any other means to contact the 
patient as allowed by their IRB. All attempts to contact the patient should be 
documented in the research chart and medical records.  
 
7.9 Study Termination 
This study may be terminated or suspended at any time. If the study is terminated or 
suspended, the sponsor will promptly inform the investigators / institutions and PCORI. 


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The IRB should be promptly informed and provided the reasons(s) for the termination 
or suspension by the sponsor and by the investigator / institution, as specified by the 
applicable regulatory requirement(s). 
 
8.   Safety Monitoring and Reporting 
 
Patients will be closely monitored for adverse events (AEs) or serious adverse events 
(SAEs), including worsening of depression symptoms. Study investigators will be able to 
modify treatment or remove patients from the trial based on their clinical discretion and 
specific patient outcomes. 
 
An adverse event is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product. An 
undesirable medical condition can be symptoms (e.g., nausea, headache, fatigue, blurry 
vision) or signs (e.g., rapid or irregular heart rate, hypertension). In clinical studies, an AE 
can include an undesirable medical condition occurring at any time after the informed 
consent is signed even if no study treatment has been administered. 
 
Assessment of adverse events, including grading of severity and attribution to research 
will start at the time of consent. AEs will be evaluated at each visit. 
 
For adverse events (AEs), the following guidelines will be used to describe severity.  
 
• Mild – Events or symptoms that are easily tolerated and do not interfere with the 
participant’s daily activities.  
• Moderate – Events or symptoms that result in a low to moderate level of 
inconvenience or concern with normal daily activities.  Moderate events may 
cause some interference with functioning. 
• Severe – Events or symptoms that interrupt a participant’s usual daily activity and 
may require 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” 
 
Note:  As of 1/1/2018, AEs that are classified as mild, do not need to be reported in the 
patients chart or the eCRF, per Investigator discretion. AEs classified as moderate or severe, 
as assessed by an Investigator, need to be reported in the patients chart and the eCRF.  
 
8.1 Unexpected Adverse Events 
The following adverse events will be collected from the time of randomization for the 
study: 
Adverse events that are not listed in the current labeling for ketamine (Ketalar Product 
Information) or ECT. This includes events that are similar to those on the labeling but 
differ from the event because of greater severity or specificity. 
 
 


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The following AEs should be captured and recorded on the AE form: 
• Prolonged seizure 
• Tardive seizure (late occurring) 
• Delirium (prolonged) 
• Psychosis (prolonged) 
• Suicide Attempt 
• Severe hypertension (prolonged) 
• Dissociation (prolonged) 
• Substance abuse (new onset/reoccurrence) 
• Clinically significant arrhythmia 
• Pregnancy 
• Other AEs per Investigator discretion 
8.2 Study Treatment Discontinuation Adverse Events 
Events that lead to the discontinuation of either treatment (ECT or ketamine) during the 
treatment phase, before completion of the final dose, will be collected for the study. 
These events will be recorded on either an AE or an SAE form. 
 
8.3 Serious Adverse Events 
All SAEs that meet the following definition will be collected from the time of consent 
until completion of either the One Month Follow-Up Call (for non-responders) or 
throughout the applicable follow-up visit (for responders). 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above 
 
8.4 Documentation and Reporting of Serious Adverse Events 
SAEs will be reported to C5Research within 24 hours of learning of the event. The 
causality of the SAE (the relationship to the study treatment/procedures) will be 
assessed by the investigator. The SAE will also be documented on the appropriate eCRF. 
 
Since the use of Ketamine in the ELEKT-D study is exempted from IND reporting, the 
Investigator does not have the responsibility to report any AEs/SAEs to the FDA. 
 
 8.5 Pregnancy 
All pregnancies should be reported to C5Research within 24 hours of becoming aware 
of the pregnancy. 
• Maternal exposure – If a patient becomes pregnant during the course of the 
study, study treatment will be continued or discontinued per investigator 
discretion. If any pregnancy occurs in the course of the study, the investigator 


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must inform C5Research within 24 hours of awareness of the pregnancy. 
• Paternal exposure – There are no known risks regarding fathering a child while 
receiving either ECT or ketamine treatment. But, since there is limited data on 
ketamine in pregnancy it is advised that patients practice adequate birth control 
while in the study. 
 
9.   Statistical Plan 
 
The key exposures of this study are alternate day ECT treatment and twice a week 
ketamine infusion. We will conduct an intention to treat (ITT) analysis. A sensitivity 
analysis will be performed on the modified intention-to-treat (mITT) population defined 
as a randomized patient having at least one treatment and one valid QIDS- SR16 
measurement during the acute treatment phase. Percent of responders is the primary 
outcome in this study. A responder is defined as a subject with a ≥50% decrease from 
baseline in the primary endpoint (QIDS-SR-16). 
 
Multiple imputations may be implemented to achieve completeness of the data. In an 
unlikely case that missing data are non-ignorable, pattern-mixture modeling will be 
applied. 
 
As a general principle, the statistical analysis will follow the pre-specified statistical 
analysis plan (SAP). The SAP will be finalized prior to the end of the study. The SAP will 
address how missing data will be handled. 
 
The primary outcome measure of response rate will be compared between ketamine 
and ECT using a chi-square test. A multivariable logistic regression model will be 
constructed, to account for potential heterogeneity of treatment effect caused by 
confounding variables. A similar analytic strategy will be applied to evaluate cognitive 
function and quality of life. 
 
Sample size 
The sample size justification will be for the primary outcome measure of response rate. 
Historical data reveal that the overall response rate as well as the respective response 
rate of ketamine and of ECT is around 50% – 60% on various scale measurements in 
patients with treatment-resistant depression. Assuming an observed difference of 10% 
and an acceptable difference margin of 5% with a 1-sided alpha=0.025, a sample of 400 
patients (200 per group) provides 81.8% power to detect a treatment response, based 
on the Farrington-Manning score test of risk difference. The total sample also considers 
a 10% attrition rate. 
 
10. Study Committees 
 
The following committees will be responsible for the management of the study and the 
monitoring of the safety of the study patients. 
 


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10.1 Executive Committee 
The Executive Committee (EC) will have scientific responsibility for the study. They will 
review study conduct and progress, consider recommendations from the Data and 
Safety Monitoring Board (DSMB), and resolve any other study related issues. The EC will 
serve as the publishing committee for the study. The EC Charter document will guide the 
conduct of the EC. 
 
10.2 Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will be appointed to monitor the key 
safety and efficacy outcomes at regular intervals, to safeguard the safety and interests 
of the study participants, and maintain/uphold the scientific merit of the study. 
Members of the DSMB will not be investigators of the study. The DSMB Charter 
document will guide the conduct of the DSMB, and will include the procedures and 
stopping rules for the study. 
 
10.3 Stakeholder Committee 
A Stakeholder Advisory Committee will be formed with investigators, patient partners, 
patient advocacy groups (i.e. Ketamine Advocacy group, NAMI), third-party payer 
representatives (i.e. Medical Mutual, Blue Cross). The committee will meet during the 
study to review study conduct and provide input on the progress of the study. The 
Stakeholder Committee will be involved in disseminating the final study results, 
information and other materials in lay language to patients/non-scientists. 
 
10.4 Reporting Plan 
Study progress reports will be presented at regular intervals to the Executive 
Committee, the Stakeholders Committee, the Data and Safety Monitoring Board 
(DSMB) and to the Cleveland Clinic and site Institutional Review Boards (IRBs). Since 
this is an un-blinded study, the total number of subjects enrolled in each treatment 
arm will be reported. The reports may include information on demographics, AEs/SAEs, 
significant protocol deviations, retention/withdrawals. 
 
 
Table 5: Reporting Timeline 
Committee 
Participants 
Suggested Frequency 
Executive Committee 
Lead PI, site-PIs 
Quarterly 
Data Safety Monitoring Board 
DSMB Members, Lead  P.I. 
Twice/year 
Stakeholders Committee 
All Investigators, Consultants, patient advocates 
Twice/year 
Investigational Review Board 
Cleveland Clinic and individual site IRBs 
Annually or more as needed. 
 
11. Data Handling and Record Keeping 
 
11.1 Data Collection 
Data will be collected by the study personnel at the site. Data sources include patient 
reports, questionnaires and available medical records. An eCRF must be completed for 
each randomized patient. It is the responsibility of the Investigator to ensure that the 


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eCRF is completed accurately and in a timely manner. Screen failures should be recorded 
on the eCRF with the reason for ineligibility recorded on the screening logs. 
 
11.2 Retention of Records 
The Investigators must maintain all confidential study documentation and take 
measures to prevent accidental or premature destruction of these documents. 
Documents should be retained for a minimum of six years after the completion or 
discontinuation of the clinical trial. However, applicable regulatory and institutional 
requirements will be taken into account in the event that a longer period is required. 
 
 
12. Study Monitoring 
 
Study Monitoring Plan 
C5Research is responsible for monitoring the conduct of this study. The study will be 
monitored according to the Monitoring Plan, and per the applicable C5Research 
Standard Operation Procedures for clinical monitoring. It is the responsibility of the 
Investigator to allocate adequate time for monitoring, to allow the monitor to access the 
medical records of the patients and to provide for adequate space to conduct the 
monitoring visit. 
 
13. Ethical Considerations 
 
The study protocol, consent forms, data collection forms, and recruitment materials, if 
applicable, will be submitted to each site’s IRB. All study personnel will have completed 
training in the Protection of Human Subjects according to Institutional guidelines. 
 
Institutional Review Board (IRB) 
It is the investigator’s responsibility to ensure that the study protocol and informed 
consent documents are reviewed and approved by the appropriate IRB. Each clinical 
site will obtain a letter of approval from the IRB before approaching participants. Sites 
will provide C5Research with copies of the initial IRB approval notice prior to enrolling 
the first patient, and subsequent renewals, as well as copies of the IRB approved 
consent and other IRB approved forms. 
 
If, during the study, it is necessary to amend either the protocol or informed consent 
document, the investigator will be responsible for ensuring that the IRB reviews and 
approves the amended documents. IRB approval of any procedures must be obtained 
before implementing new processes or procedures. 
  
Informed Consent Document and Process 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision. The 


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informed consent document will inform patients of their right to refuse any release of 
their protected health information.  Each clinical site, according to local IRB 
requirements, is allowed to modify this informed consent document and make any 
necessary editorial changes, as long as neither the meaning nor intent of any section is 
changed. 
 
The investigator or his/her designee (i.e., research coordinator or study nurse) will 
inform the patient of all aspects of the study pertaining to the patient’s participation in 
it. The process for obtaining informed consent will be in accordance with all applicable 
regulatory requirements. The informed consent form (ICF) must be signed and dated by 
the patient and the investigator or his/her designee BEFORE the patient can participate 
in the study. The participant will receive a copy of all signed and dated documents, and 
the originals will be retained in the patient’s study file or medical record. 
 
Subject Information and Consent 
Each clinical site is responsible for the confidentiality of the data associated with 
participants enrolled in this study, in the same manner that it is responsible for the 
confidentiality of any patient information within its sphere of responsibility. All forms 
used for the study data will be identified by coded identification number, which will be 
generated at the clinical center, to maintain subject confidentiality. All records will be 
kept in locked file cabinets at the clinical centers with access limited to study staff, and 
all study staff will identify participants via their unique identifier. Clinical information 
will not be released without written permission of the participant, except as necessary 
for monitoring by the IRB or DSMB. The participant grants permission to share research 
data with these entities in the consent document. Federal regulations govern the 
protection of patient’s rights relative to data confidentiality and use of research data. 
 
Consent procedures and forms, and the communication, transmission and stoppage of patient 
data will comply with individual-site IRB requirements for compliance with The Health Insurance 
Portability and Accountability Act (HIPAA). The Privacy Rule of HIPAA governs the protection of 
an individual’s identifiable health information. C5Research will ensure that clinical centers 
associated with the project comply with HIPAA regulations by requiring documentation from the 
IRBs with the appropriate authorization or consent form. C5Research will maintain copies of all 
relevant documents from each clinical center. If IRB approvals are not current, data will not be 
accepted by C5Research. A secure, electronic data management system will be used to ensure 
the confidentiality of electronic protected health information. All questionnaires and study 
related materials will be labeled with each participant’s coded identification number; there will 
be no protected health information indicated on the forms. 
14. Publication and Disclosure 
The study findings will be disseminated to the public through manuscripts, scientific and 
patient organization led conferences, press releases and through a dedicated website. 
The PIs may also publicize the study findings through talks and public symposia with 
their local mental health advocacy organizations (NAMI, DBSA, etc.). 
 
This study will be registered on ClinicalTrials.gov. 


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15. References 
 
1.   Global Burden of Disease; 2004. Geneva, Switzerland: World Health Organization, 2008. 
2.   Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression 
severity: A patient-level meta-analysis. JAMA. 2010;303(1); 47-53 
3.   Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective Publication of 
Antidepressant Trials and Its Influence on Apparent Efficacy. New England Journal of 
Medicine. 2008;358(3):252-60. 
4.   Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute 
and longer-term outcomes in depressed outpatients requiring one or several treatment 
steps: a STAR*D report. American Journal of Psychiatry. 2006;163(11):1905-17. 
5.   Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation 
of outcomes with citalopram for depression using measurement-based care in STAR*D: 
implications for clinical practice. American Journal of Psychiatry. 2006;163(1):28-40. 
6.   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. 
2014;65(8):977-87. 
7.   Nemeroff CB. Prevalence and management of treatment-resistant depression. J Clin 
Psychiatry. 2007;68 Suppl8:17-25. 
8.   Crown WH, Finkelstein S, Berndt ER, Ling D, Poret AW, Rush AJ, et al. The impact of 
treatment-resistant depression on health care utilization and costs. The Journal of 
Clinical Psychiatry. 2002;63(11);963-71. 
9.   Kellner CH, Greenberg RM, Murrough JW, Bryson EO, Briggs MC, Pasculli RM. ECT in 
Treatment-Resistant Depression. American Journal of Psychiatry. 2012;169(12):1238-44. 
10. The UKECTRG. Efficacy and safety of electroconvulsive therapy in depressive disorders: a 
systematic review and meta-analysis. The Lancet. 2003;361(9360):799-808. 
11. Lisanby SH. Electroconvulsive Therapy for Depression. New England Journal of Medicine. 
2007;357(19):1939-45. 
12. Golden, C. J., & Freshwater, S. M. (1978). Stroop color and word test. 
13. Blair, J. R., & Spreen, O. (1989). Predicting premorbid IQ: a revision of the National Adult 
Reading Test. The Clinical Neuropsychologist, 3(2), 129-136. 
14. aan het Rot M, Collins KA, Murrough JA, Perez AM, Reich DL, Charney DS, et al. Safety 
and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. 
Biological psychiatry. 2010;67(2):139-45. 
15. Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB. Ketamine 
and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in 
Depression. The American journal of psychiatry. 2015;172(10):950-66. 
16. van Waarde JA, van Oudheusden LJ, Verway B, Giltay EJ, van der Mast RC. European 
archives of psychiatry and clinical neuroscience. 2013 Mar;263(2):167-75. Doi: 
10.1007/s00406-012-0342-7. 
17. Lapidus KA, Kellner CH. Journal of ECT. 2011 Sep;27(3):244-6. Doi: 
10.1097/YCT.0b013e31820059e1. 
 


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16. Appendix 
 
Table 1 Outcome Measures and Scales 
MEASURE 
NAME 
DESCRIPTION 
DIAGNOSTIC INTERVIEW 
MINI 7.0.2 
Mini Neuropsychiatric Interview 
Diagnostic interview used to determine DSM-5 
diagnosis (30 mins) 
PATIENT RATED SCALES 
QIDS-SR-16 
(Primary Outcome Measure) 
Quick Inventory of Depressive 
Symptoms 
Self-report of depressive symptoms based on DSM 
diagnostic criteria (10 mins) 
GSE-My 
Global Self Evaluation of Memory 
Self-reported scale of global memory (2 mins) 
SMCQ 
Squire Memory Complaint 
Questionnaire 
Self-report of memory issues before and after ECT (5 
mins) 
PGI-Sand PGI-I 
Patient Global Impression Scale for 
Severity and Improvement for 
Depression 
7 point scales assessing improvement and severity of 
depression (2 mins) 
QOLS 
Quality of Life Scale 
Self-reported questionnaire that measures quality of 
life in 8 domains (5 mins) 
PRISE 
Patient Rated Inventory of Side 
Effects 
Self-report of adverse events specific to nine organ or 
function systems (<5 mins) 
Treatment Preference 
Treatment Preference 
7 point scale assessing preference for either study 
treatments  
CLINICIAN RATED SCALES 
MADRS 
Montgomery Asberg Depression 
Rating Scale 
Measures severity of depression symptoms 
including sadness, concentration, sleep, and 
disruptive thoughts (10-20 mins) 
CSSRS 
Columbia Suicide Severity Rating 
Scale 
Assessment of suicidal ideation (10 mins) 
CADSS* 
Clinician Administered Dissociative 
Symptoms Scale 
Dissociative symptom scale to be administered post- 
treatment (10 mins) 
YMRS 
Young Mania Rating Scale 
Measures symptoms of mania (10 mins) 
BPRS* 
Brief Psychiatric Rating Scale 
Measures positive symptoms of psychosis (5 mins) 
CGI-S and CGI-I 
Clinical Global Impression Scale for 
Severity and Improvement 
Scales to record global clinical impression by a 
clinician regarding improvement and severity of 
patients mental condition (5 mins) 
COGNITIVE TESTING 
MoCA 
Montreal Cognitive Assessment 
Tests cognitive function covering 8 cognitive domains 
including visuospatial assessment, short-term 
memory and working memory (10 mins) 
COWAT 
Controlled Oral Word 
Association Test 
Verbal fluency test that measures spontaneous 
production of words belonging to the same category or 
beginning with the same letter (5- 10 mins) 
HVLT-R 
Hopkins verbal Learning Test - 
Revised 
Verbal learning and memory test with six alternate forms 
(10 mins) 
Stroop 
Stroop Color Word Test 
Measures processing speed and selective inhibition (5 
mins) 
NAART 
North American Adult Reading Test 
Estimate of premorbid intellectual ability (3 mins) 
CPFQ 
Cognitive and Physical 
Functioning 
Assessment of motivation, energy level, & mental acuity (5 
mins) 
*To be administered post treatment 


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   Schedule of Events (ECT Arm)  
 
 
Visit 
Screening 
(Maximum   
of 28 days)  
 
Randomization 
(within 1 week after 
eligibility is confirmed) 
 
Treatment Phase 
(Up to 9 treatments over 3- 5 weeks) 
 
EOT 
(within  3 
days after 
last 
treatment) 
 
 
 
 
Baseline
/ V1 
 
V2 
 
V3 
 
V4 
 
V5 
 
V6 
 
V7 
 
V8 
V9 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine 
pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
Vitals (BP, 
heart rate, 
weight) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BP, HR 
Randomization  
X 
 
 
 
 
 
 
 
 
 
Psychiatric 
Evaluation 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECT 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Psychiatric 
Medication Log 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Somatic 
Therapies Log 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Evaluate for 
AEs/SAEs 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diagnostic 
Interview 
 
 
 
 
 
 
 
 
 
 
 
MINI 7.0.2 
X 
 
 
 
 
 
 
 
 
 
 
Patient 
Rated Scales  
 
 
 
 
 
 
 
 
 
 
QIDS-SR-16 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 


ELEKT-D Clinical Protocol 
Amendment V7.0 16Feb2022 
Confidential                                                             Page 37 of 40                                 Protocol V7.0 16Feb2022 
Schedule of Events (ECT Arm) 
  
 
Visit 
Screening 
(Maximum    
of 28 days)  
 
Randomization 
(within 1 week after 
eligibility is 
confirmed) 
 
Treatment Phase 
(Up to 9 treatments over 3- 5 weeks) 
 
EOT 
(within   3 
days after 
last 
treatment) 
 
 
 
Baseline/
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
 
GSE-MY 
 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
SMCQ 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
PGI-S  
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
PGI-I 
 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
QOLS 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
PRISE 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
CPFQ 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
Treatment 
Preference 
 
 
 
 
 
 
 
 
 
 
X 
Clinician 
Rated Scales  
 
 
 
 
 
 
 
 
 
 
MADRS 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
CSSRS 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
YMRS 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
BPRS* 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
CGI-S** 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
CGI-I** 
 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
CADSS* 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
Cognitive 
Assessments  
 
 
 
 
 
 
 
 
 
 
MoCA 
X 
 
 
 
 
 
 
 
 
 
X 
COWAT 
 
 
X 
 
 
 
 
 
 
 
X 
HVLT-R 
 
 
X 
 
 
 
 
 
 
 
X 
Stroop 
 
 
X 
 
 
 
 
 
 
 
X 
NAART 
 
 
X 
 
 
 
 
 
 
 
 
 
*CADSS and BPRS to be administered post treatment. 
**CGI-S and CGI-I to be performed by psychiatrist. 
 


ELEKT-D Clinical Protocol 
Amendment V7.0 16Feb2022 
Confidential                                                             Page 38 of 40                                 Protocol V7.0 16Feb2022 
  Schedule of Events (Ketamine Arm) 
 
 
Visit 
Screening 
(Maximum    
of 28 days)  
 
Randomization 
(within 1 week of 
confirmed eligibility) 
 
Treatment Phase 
(Up to 6 treatments over 3- 5 weeks) 
EOT (within 
3 days after 
last 
treatment) 
 
 
 
 
Baseline/V1 
 
V2 
 
V3 
 
V4 
V5 
V6 
 
Informed 
consent 
X 
 
 
 
 
 
Eligibility 
Criteria 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urine 
pregnancy test 
X 
 
 
 
 
 
Vitals (BP, 
heart rate, , 
weight) 
 
 
X 
X 
X 
X 
X 
X 
BP, HR 
Randomization  
X 
 
 
 
 
Psychiatric 
Evaluation 
X 
 
X 
X 
X 
X 
X 
X 
X 
Ketamine 
Infusion 
 
 
X 
X 
X 
X 
X 
X 
Psychiatric 
Medication 
Log 
X 
 
X 
X 
X 
X 
X 
X 
X 
Somatic 
Therapies 
Log 
X 
 
X 
X 
X 
X 
X 
X 
X 
Evaluate for AEs 
/SAEs 
 
 
X 
X 
X 
X 
X 
X 
X 
Diagnostic 
Interview 
 
 
 
 
 
 
MINI 7.0.2 
X 
 
 
 
 
 
Patient 
Rated Scales  
 
 
 
 
 
QIDS-SR-16 
 
 
X 
X 
X 
X 
X 
X 
X 
 


ELEKT-D Clinical Protocol 
Amendment V7.0 16Feb2022 
Confidential                                                             Page 39 of 40                                 Protocol V7.0 16Feb2022 
 Schedule of Events (Ketamine Arm) 
 
 
Visit 
Screening 
(Maximum   
of 28 days)  
 
Randomization 
(within 1 week of 
confirmed eligibility) 
 
Treatment Phase 
(Up to 6 treatments over 3- 5 weeks) 
 
EOT (within 
3 days after 
last 
treatment) 
 
 
 
Baseline/V1 
V2 
V3 
V4 
V5 
V6 
 
GSE-MY 
 
 
 
X 
X 
X 
X 
X 
X 
SMCQ 
 
 
X 
X 
X 
X 
X 
X 
X 
PGI-S 
 
 
X 
X 
X 
X 
X 
X 
X 
PGI-I 
 
 
 
X 
X 
X 
X 
X 
X 
QOLS 
 
 
X 
X 
X 
X 
X 
X 
X 
PRISE 
 
 
X 
X 
X 
X 
X 
X 
X 
CPFQ 
 
 
X 
X 
X 
X 
X 
X 
X 
Treatment 
Preference 
 
 
 
 
 
 
 
 
X 
Clinician 
Rated Scales  
 
 
 
 
 
 
 
 
MADRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
CSSRS 
 
 
X 
X 
X 
X 
X 
X 
X 
YMRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
BPRS* 
 
 
X 
X 
X 
X 
X 
X 
X 
CGI-S** 
 
 
X 
X 
X 
X 
X 
X 
X 
CGI-I** 
 
 
 
X 
X 
X 
X 
X 
X 
CADSS* 
 
 
X 
X 
X 
X 
X 
X 
X 
Cognitive 
Assessments  
 
 
 
 
 
 
 
 
MoCA 
X 
 
 
 
 
 
 
 
X 
COWAT 
 
 
X 
 
 
 
 
 
X 
HVLT-R 
 
 
X 
 
 
 
 
 
X 
Stroop 
 
 
X 
 
 
 
 
 
X 
NAART 
 
 
X 
 
 
 
 
 
 
 
*CADSS and BPRS to be administered post treatment. 
**CGI-S and CGI-I to be performed by psychiatrist. 
 
 
 


ELEKT-D Clinical Protocol 
Amendment V7.0 16Feb2022 
Confidential                                                             Page 40 of 40                                 Protocol V7.0 16Feb2022 
 Schedule of Events (Follow-Up Phone Call – Non-Responders) 
Visit 
Month 1 (+/- 2 weeks) 
Evaluate for AEs/SAEs 
X 
Evaluate  for additional ECT,  ketamine,  psychotropic treatment(s) 
X 
Patient Rated Scales:  PGI-S  & PGI-I 
X 
Complete QIDS Form 
X 
Complete MADRS Form 
X 
 
Schedule of Events (Follow-Up Visits – Responders will occur through Month 1 Follow-Up at a minimum)  
 
Visit 
Month 1 
(+/- 2 weeks) 
Month 3 
(+/- 2 weeks) 
Month 6 
(+/- 2 weeks) 
Update Medical History 
X 
X 
X 
Vitals (BP, heart rate, weight) 
X 
X 
X 
Psychiatric Evaluation 
X 
X 
X 
Psychiatric Medication Log 
X 
X 
X 
Somatic Therapies Log 
X 
X 
X 
Evaluate for AEs/SAEs 
X 
X 
X 
Patient Rated Scales 
 
 
 
QIDS-SR-16 
X 
X 
X 
GSE-MY 
X 
X 
X 
SMCQ 
X 
X 
X 
PGI-S  & PGI-I 
X 
X 
X 
QOLS 
X 
X 
X 
PRISE 
X 
X 
X 
CPFQ 
X 
X 
X 
Clinician Rated Scales 
 
 
 
MADRS 
X 
X 
X 
CSSRS 
X 
X 
X 
YMRS 
X 
X 
X 
BPRS 
X 
X 
X 
CGI-S & CGI-I* 
X 
X 
X 
CADSS 
X 
X 
X 
Cognitive Assessments 
MoCA 
X 
X 
X 
COWAT 
X 
X 
X 
HVLT-R 
X 
X 
X 
Stroop 
X 
X 
X 
 
*To be performed by psychiatrist.