Clinical trial NCT04504175
Conditions: Treatment Resistant Depression Refractory Depression Therapy-Resistant Depression Late Life Depression Geriatric Depression
Keywords: ketamine
Sponsor: Washington University School of Medicine
Start date: 2020-10-22; Completion date: 2022-03-15
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot study will assess the safety and feasibility of intravenous (IV) ketamine in older adults with Treatment-Resistant Depression (TRD). In addition, this study will develop and utilize innovative methodological approaches to demonstrate the feasibility of precision medicine and mobile health approaches in depression treatment.

Detailed description:
Participants in this study will receive ketamine infusions twice a week for 4 weeks (acute phase). Participants who respond or remit will continue with an additional 4 weeks of weekly ketamine infusions (continuation phase). Participants will be assessed at baseline, end of acute phase, and end of continuation phase for effectiveness, safety, and executive functioning. Participants will be asked to complete daily surveys of their depression symptoms during their participation.

Arms: arm 1: Acute phase: ketamine infusions twice a week for 4 weeks
Interventions: intervention 1: Ketamine
Intervention descriptions: intervention 1: ketamine will be infused using an IV infusion pump at a rate of 0.5 mg/kg of body weight over 40 minutes

Protocol documents:
Prot_000.pdf: 
Protocol Version: 4 
 
1 
Protocol Date: 10/12/21 
Precision medicine with ketamine for older adults 
with treatment-resistant depression: Pilot Study 
 
PI: Eric Lenze 
WUSTL IRB ID#: 202007085 
ClinicalTrials.Gov Identifier: NCT04504175 
 
 
 


Protocol Version: 4 
 
2 
Protocol Date: 10/12/21 
I. 
STUDY OVERVIEW 
This pilot study will assess the safety and feasibility of intravenous (IV) ketamine in older adults with 
Treatment-Resistant Depression (TRD). In addition, this study will develop and utilize innovative 
methodological approaches to demonstrate the feasibility of precision medicine and mHealth approaches 
in depression treatment.  
II. 
METHODS 
A. 
Design Overview 
Participants will receive ketamine infusions twice a week for 4 weeks (acute phase). Participants who 
respond or remit will continue with an additional 4 weeks of weekly ketamine infusions (continuation 
phase). Participants will be assessed at baseline, end of acute phase, and end of continuation phase for 
effectiveness, safety, and executive functioning. Participants will be asked to complete daily surveys of 
their depression symptoms during their participation.   
B. 
Participant Recruitment 
The study will enroll up to 15 participants. Participants will be enrolled from existing studies (WU 
IRB#201609085, 201202157, and 201811036). In addition we will elicit referrals from our established 
referral networks of PCPs and specialty mental health practices. Potential participants will undergo pre-
screens by phone and then an in-person visit that includes a psychiatric and medical history, blood 
chemistries, and an ECG. 
1. 
Inclusion Criteria 
(1)  
Community-living men and women age 60 years and older;  
(2) 
Treatment-resistant depression: defined as unipolar major depressive disorder, non-delusional 
(diagnosed by SCID-5) that persists despite ≥ 2 adequate antidepressant trials of different classes in the 
current episode; including at least one evidence-based second-line treatment in the current episode 
(including serotonin norepinephrine reuptake inhibitors, bupropion, tricyclics, monoamine oxidase 
inhibitors, or augmentation with an atypical antipsychotic, stimulant, bupropion, lithium, or 
Triiodothyroinine 
(3) 
Persistent moderate to severe depressive symptoms determined by Patient Health Questionnaire 
9-item (PHQ-9)26 score ≥15 at baseline  
(4)  
Able to provide informed consent. 
2. 
Exclusion Criteria 
(1) 
Dementia per history, score ≥10  on the Short Blessed Test, or determined by clinical interview 
with geriatric psychiatrist to have high likelihood of dementia;  
(2)  
Psychotic spectrum or bipolar disorder or severe personality disorder that at the PIs discretion 
would interfere with safe participation.  Anxiety disorders are not an exclusion.  
(3)  
Unstable medical conditions such that IV ketamine is not safe or tolerated or that would interfere 
with participation in a long-term study (i.e., poorly controlled hypertension, life expectancy < 1 year 
because of terminal illness, unstable angina).  


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Protocol Date: 10/12/21 
(4)  
Baseline systolic BP > 150 systolic or 90 diastolic at evaluation. Participants who initially present 
with elevated blood pressure may be re-assessed; and if needed, referred to their healthcare provider for 
hypertension management. Clonidine is preferred as the agent to control blood pressure, as it will also 
improve tolerability of ketamine infusion.  However, patients' providers are not required to use this drug 
(vs. other strategies such as optimizing doses of existing medication). Once blood pressure is adequately 
managed, they can be reconsidered for study participation.  
(5) 
Current alcohol or substance use disorder or lifetime recreational ketamine use or other 
dissociative agent (e.g., PCP).  
(6)  
Use of naltrexone, memantine, or any medication that could be considered contraindicated with 
ketamine. 
(7) 
Taking more than 2 adequately-dosed oral antidepressants. 
(8) 
High acute risk for suicide and unable to be managed safely in the clinical trial. 
 
C. 
Screening Procedures 
After providing informed consent, participants will be assessed for eligibility as follows: 
1) SCID-5: Meet criteria for unipolar Major Depressive Disorder, non-delusional, current. Rule out 
psychotic and bipolar disorder.  
2) AUDIT: Rule out current alcohol use disorder (past 3 months) 
3) DAST: Rule out current substance use disorder (past 3 months) 
4) PHQ-9: Score must be 15 or higher at baseline. 
5) Short Blessed Test: Score must 0-9 (excluded if score is 10 or higher).  
6) ATHF:  Must have 2 or more adequate antidepressant trials of different classes in the current 
episode 
7) Review of current medications: Must not be taking naltrexone memantine, or any medication that 
could be considered contraindicated with ketamine. Must not be taking more than two 
adequately-dosed oral antidepressant. Must be stable on antidepressant regimen for at least two 
weeks.  
8) Review of medical conditions: Must not have any medical conditions affecting IV ketamine safety 
or tolerability or that would interfere with participation in a long-term study. (i.e., life expectancy 
< 1 year because of terminal illness, unstable angina). Must not have inadequately controlled 
hypertension.  
D. 
Schedule of Measures 
 
SCHEDULE OF MEASURES 
FOLLOW – UP +++ 
 
BASELINE 
ACUTE END 
(WK 4)* 
CONTINUATION 
END (WK 8)** 
1 
MONTH 
2 
MONTH 
3 
MONTH 
Screening 
 
 
 
 
 
 
SCID-5+ 
X 
 
 
 
 
 
PHQ-9 
X 
 
 
X 
X 
X 
ATHF 
X 
 
 
 
 
 


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Protocol Date: 10/12/21 
Short 
Blessed 
Test 
X 
 
 
 
 
 
Blood Pressure 
X 
 
 
 
 
 
AUDIT 
X 
 
 
 
 
 
DAST 
X 
 
 
 
 
 
CIRS-G 
X 
 
 
 
 
 
Outcomes 
 
 
 
 
 
 
MADRS 
X 
X 
X 
X 
X 
X 
Scale for Suicidal 
Ideation (SSI) 
X 
X 
X 
 
 
 
Psychological 
well-being (NIH 
Toolbox) 
X 
X 
X 
 
 
 
Cognitive Battery 
(NIH Toolbox) 
X 
X 
X 
 
 
 
Miro Health 
Cognitive Battery 
X 
X 
X 
 
 
 
Pittsburgh Sleep 
Quality Index 
(PSQI)++ 
X 
X 
X 
 
 
 
Safety 
 
 
 
 
 
 
AE Monitoring 
X 
X 
X 
 
 
 
Medication List 
X 
X 
X 
 
 
 
Medical History 
X 
 
 
 
 
 
Height/Weight 
X 
 
weight 
 
 
 
ECG 
X 
 
X 
 
 
 
Blood 
Chemistries*** 
X 
 
X 
 
 
 
Craving Scale 
X 
X 
X 
 
 
 
Depression daily 
self-reports 
THROUGHOUT 
 
 
 
*Acute End assessments will take place after at least 4 weeks of treatment or upon early termination from 
Acute phase. There may be some delays between baseline assessments and the start of treatment.  
**Continuation End assessments will take place after the 8th week of treatment or upon early termination 
from Continuation phase.  
*** Blood chemistries may include CBC, BMP (including LFTs); and TSH at baseline if not obtained within 
the last 6 months.  
+Subset of SCID-5 will be administered to assess Bipolar And Related Disorders, Depressive Disorders, 
Schizophrenia And Other Psychotic Disorders 
++Item 6 of PSQI will be administered.  
+++ Follow-Up assessments (typically phone) will be conducted for participants who begin Continuation 
Phase at 1, 2, and 3 months after their last study visit (Wk 8, or their last study visit if the participant ends 
early) 


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Protocol Date: 10/12/21 
E. 
Determination of Remission  
1. 
Acute Phase End 
Participants who complete the acute phase and reach a MADRS score indicating remission (<10) or  
response (30% reduction) will continue IV ketamine for  4 weeks. This continuation phase is needed to 
establish the stability of remission/response. 
Participants without a 30% reduction in  MADRS score at the end of the acute phase will not proceed to 
the Continuation Phase of the study; their participation will end. 
If needed, a 9th infusion can take place if there is an interruption of infusions during the final week of 
acute, give one additional so that in the final week prior to assessing response there have been 2 infusions. 
2. 
Continuation Phase End 
Participants who complete the Continuation phase will be assessed for remission and response using the 
MADRS. A second confirmatory MADRS will be obtained at the end of the Continuation Phase to 
determine final remission status.  
F. 
Intervention: Ketamine Infusions 
1. 
Details of Infusion 
To ensure dose accuracy, participants will have weight confirmed prior to each infusion. After safety 
ratings (see table below) are performed, an IV line will be inserted into upper extremity by research 
personnel. The ketamine will be infused using an IV infusion pump at a rate of 0.5 mg/kg of body weight 
over 40 minutes. Heartrate, blood pressure, and pulse-oximetry will be routinely monitored throughout 
the infusion and for approximately up to two hours after the end of the infusion. Safety ratings will be 
repeated prior to discharge. After normalization of any psychotomimetic symptoms or blood pressure 
elevation and IV removal, participants will be discharged. Participants will be provided with 
transportation to and from infusion visits. 
If a participant is unable to receive IV ketamine (e.g., because of lack of IV access), he or she can receive 
IM ketamine as a bolus. The dosage will be the same (0.5 mg/kg) because its bioavailability is 93% and 
its plasma half-life is similar to IV. 
2. 
Clonidine co-administration 
The two most concerning problems observed during infusions are sympathomimetic (blood pressure 
changes) and psychotomimetic/dissociation. These are a tolerability issue (patients may not tolerate 
ketamine secondary to these problems), safety issue (transient hypertension or psychosis require 
additional monitoring and could cause cardiac or psychiatric risks, although to date these have not been 
seen in our or others’ research), and an access issue (hypertension is common in older adults with 
depression and could prevent many patients from receiving an otherwise effective treatment).  Our 
group showed that co-administered clonidine, an alpha-2 agonist, safely and effectively mitigates both 
of these concerning side effects of ketamine. Thus, pre-dosing of clonidine can improve the tolerability 
of ketamine and maximize its potential treatment benefits. Clonidine has not been widely used in 
ketamine treatment of depression, but it is routinely co-administered with ketamine in chronic pain 
management to reduce these side effects, and perioperatively as well. Clonidine co-administration does 
not alter the antidepressant activity of ketamine in either preclinical or clinical studies. If indicated (see 
human subjects section) participants may receive a 0.1 mg oral clonidine test dose to ensure tolerability, 
and those who tolerate and accept it will receive pre-dosing with clonidine prior to infusions during the 


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Protocol Date: 10/12/21 
acute phase.  Higher doses of clonidine (up to 0.3 mg) can be used if needed in certain cases to provide 
greater blood pressure control or prevent distressing neuropsychiatric symptoms (eg, dissociation).  The 
co-administration of clonidine does not introduce excess polypharmacy for older adults because it is 
used only on days of ketamine infusions, as needed. It may not be needed long-term for most patients, 
as ketamine’s neuropsychiatric side effects decline in most patients with repeat infusions.   
 
 
 
INFUSION SCHEDULE  
To accommodate delays in the infusion schedule for various reasons (e.g. participant 
travel, illness, or COVID-19 safety guidelines), each phase may be extended by an 
additional 4 weeks. 
Acute Phase 
Infusion Schedule 
Two infusions per week X 4 weeks (at least two days apart) 
Continuation Phase 
Infusion Schedule 
One infusion per week X 4 weeks 
 
Safety Monitoring for Infusions  
 
Before 
Infusion 
40 
Minutes 
After 
60 
Minutes 
After 
90 
Minutes 
After 
Weight 
X 
X 
X 
X 
Vital Signs: Blood Pressure, Pulse rate, oxygen 
saturation, body temperature 
X 
X 
X 
X 
Brief Psychiatric Rating Scale - positive (psychotic) 
symptom subscale (BPRS+) 
X 
X 
- 
X 
Clinician Administered Dissociative States Scale 
(CADSS) 
X 
X 
- 
X 
 
G. 
Potential Risks & Risk Mitigation 
Interviews/Questionnaires/Surveys: 
Participants may experience emotional discomfort with the neuropsychological testing and medical and 
psychological questionnaires. If any particular question makes the participant uncomfortable, the 
participant may discuss its importance and the need to answer it with the specially-trained interviewer. 
These assessments will be administered in private settings.  Participants have the right to refuse to answer 
any question for any reason.   
 
Infusion Procedure/Blood Draws/ Injections:  
While rare, participants may experience pain, bruising, and/or bleeding at the site of needle insertion for 
blood draws, injections and the intravenous catheter. There is a rare risk of infection from a needle 
insertion.  Phlebotomy, IM injection, and IV insertion will be performed by certified and trained staff. 
 
Ketamine: 


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Common side effects: Feeling light-headed, “high,” exhilarated, having perceptual changes or 
hallucinations, floating sensations, and/or difficulty concentrating, paying attention, or remembering as 
many items as usual from a list (like items on a grocery list)   Mild and temporary increases in blood 
pressure. 
Less likely: Feeling dizzy, sleepy, anxious, suspicious, nauseated.  
Rare side effects: Feeling sad, scared, confused, disoriented, moderate and temporary increases in blood 
pressure, future abuse of ketamine, prolonged psychosis in individuals with a pre-existing psychiatric 
condition. It is possible that the use of ketamine could increase interest in the illicit use or abuse of this 
substance although the fact that individuals with any past or current substance abuse will be excluded 
makes this highly unlikely.   
 
We will minimize these risks by adhering to all entry criteria, not enrolling participants with uncontrolled 
hypertension or other unstable medication conditions, having same-room observation of all participants 
during the infusion and for 2 hours post-infusion that includes blood pressure monitoring, oxygen 
saturation monitoring, and management of psychotomimetic adverse effects by highly trained and 
psychologically-informed nursing and medical support staff.  We will also use clonidine as needed the day 
of infusion (if determined to not increase risk of hypotension or orthostasis; see below). 
 
Plans to ensure cardiovascular safety during the ketamine infusions: The most frequent cardiovascular 
effect of ketamine infusion is increase in blood pressure. A study of 66 patients, mean age 57, 38% with 
controlled hypertension and excluding patients with either a systolic BP >160 mmHg or diastolic BP > 100 
mmHg at baseline, reported blood pressure effects of 684 IV ketamine infusions (Riva-Posse et al, Blood 
pressure safety of subanesthetic ketamine for depression: a report on 684 infusions. J Affect Disord 2018). 
In 9% of infusions a blood pressure measurement that was greater than 30 mmHg systolic or 15mmHg 
diastolic was recorded although there was no measurement that was greater than 45mmHg systolic of 
30mmHG diastolic over baseline.  The blood pressure increases were transitory. No patient required an 
intervention to treat blood pressure. 
In this study the mean age of the patient group is anticipated to be 10-13 years older than the patient 
group in the Riva-Posse study and it is also anticipated that the rate of controlled hypertension will be 
higher. There are several procedures to increase safety in this study. 
1. Participants with uncontrolled hypertension, defined as baseline systolic BP > 150 systolic or 90 
diastolic, will be excluded. 
2. Participants will be routinely pre-treated with clonidine 0.1mg the night before treatment and 
the morning of treatment, unless otherwise indicated (e.g., baseline BP is below 110 systolic of 
70 diastolic).  
3. Prior to each infusion BP will be measured after the patient has been lying quietly for 5 minutes. 
This recording will be the baseline BP. If baseline BP is elevated (Systolic > 160 or Diastolic >95), 
oral clonidine 0.1 mg will be administered and BP will be re-checked 20-30 minutes later. The 
dose of clonidine may be increased up to 0.2-0.3 mg depending upon participant benefit and 
tolerability. If BP continues to be elevated (Systolic > 160 or Diastolic >95), ketamine infusion 
will not be administered that day.  
4. During the IV ketamine infusion BP is recorded every 10 minutes. A measurement that shows a 
BP increase over 25% from systolic or diastolic baseline and reaches a level of 175 systolic or 105 
diastolic will trigger a repeat measurement in two minutes. If the same increase is recorded, 
then oral clonidine 0.1 mg will be given. If increased blood pressure measurements persist 
(above 175 systolic or 105 diastolic) the infusion will be discontinued. 


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Protocol Date: 10/12/21 
5. If BP increases to levels described in #3 or participants experience psychotomimetic/dissociative 
effects, prior to the subsequent ketamine infusion, oral clonidine 0.1 mg will be taken by 
participants the night before the infusion and at least 30 minutes prior to the infusion.  The dose 
of clonidine may be increased up to 0.2-0.3 mg, depending upon participant benefit and 
tolerability, for a maximum total daily dose of 0.6 mg when clonidine is used by the team for 
pre-treatment (night before/morning of). (Lenze et al, Ninety-six hour ketamine infusion with 
co-administered clonidine for treatment-resistant depression; World J Biol Psychiatry 2016). 
6. An ECG will be done at baseline, at the end of continuation and at the end of the maintenance 
or at time of reoccurrence of depression 
 
Plans to monitor and minimize psychotomimetic/dissociative effects:   
We will measure transient neuropsychiatric changes with the Brief Psychiatric Rating Scale - positive 
(psychotic) symptom subscale (BPRS+) and the Clinician Administered Dissociative States Scale (CADSS) at 
baseline, 40 minutes, and 1.5 hours after infusion.  Patient participants must be asymptomatic according 
to these measures and to clinical assessment prior to discharge from the infusion center.  To prevent 
distressing symptoms, clonidine will be prescribed (see above) to take orally the night before and the 
morning of the subsequent infusion (dose starting at 0.1 mg, increased up to 0.3 mg as needed and 
tolerated).  Nursing and medical support staff will all be trained in the care of patient participants 
experiencing psychological symptoms in response to a medical treatment, and we will follow best practice 
nursing approaches to calm and comfort participants by re-orienting them, preventing wandering and 
falls, assuring them they are safe and their feelings are normal and transient, and by having a psychiatrist 
on call at all times.   
 
Clonidine: 
Common side effects: Dry mouth, constipation, nausea, vomiting, mild abnormalities in liver function 
blood tests; salivary gland pain, leg cramps pain or musculoskeletal pain or joint pain, and feeling weak. 
Less likely side effects: Dry throat, low blood pressure, dizziness, tremor; feeling nervous or irritable, 
having trouble sleeping or feeling drowsy, tired, or sedated; dry or blurred eyes or feeling tearful. 
Rare side effects: Lack of appetite, transient elevation of blood glucose or blood serum creatinine tests, 
fluid retention, sexual dysfunction, genitourinary effects, headache, abdominal pain, change in taste, 
unpleasant dreams, ECG abnormalities, and palpitations have also been reported. We will only use 
clonidine in participants who experience infusion-related blood pressure elevations or psychotomimetic 
effects (e.g., dissociation).  Prior to using low-dose clonidine, frequently prescribed for older adults with 
hypertension, and which we observed to be well-tolerated when administered prior to ketamine infusions 
to minimize these adverse effects, we will assure there are no pharmacodynamic interactions which would 
preclude its safe use, and as needed, consult with the participant’s primary care physician or the study’s 
PCP consultant, Dr. Bruce Rollman. 
 
Suicide:  
Patients who are identified as acutely suicidal will be excluded from the study and referred for acute 
psychiatric evaluation and care. Nevertheless, since the rate of completed suicide in the USA remains high 
(i.e., about twice the rate of homicide) and most Americans who commit suicide suffer from depression, 
all participants eligible to participate in this study are statistically at a relatively higher risk for suicide than 
the general population. However, the participants’ absolute risk for completing suicide during this study 
remains very low (i.e., about 1 in 3,000 to 10,000) and participation in the study does not create or 
increase the risk of completed suicide. Actually, most experts believe that one of the most efficient ways 
to decrease suicidal risk in older depressed individuals is to treat their depression. Furthermore, all 


Protocol Version: 4 
 
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Protocol Date: 10/12/21 
participants will be formally assessed at least every two weeks for the duration of the study, and we will 
make efforts to engage family caregivers and obtain an emergency phone number for all participants. All 
sites have a 24/7/365 on-call system with geriatric psychiatry back-up. If the study personnel identify that 
a participant has become acutely suicidal, the local study team will take all necessary efforts to assure the 
participant is safe (i.e., escort them to the emergency room for evaluation, activate emergency medical 
services, speak with PCP or family members). This may lead to a clinical intervention that is lifesaving and 
may not have occurred had the participant not been participating in the study.  We have published about 
our suicide safety risk management protocol (Herbeck Belnap et al, Electronic protocol for suicide risk 
management in research participants, J Psychosom Res 2015) and will follow this algorithm at every 
clinical assessment if it is triggered. This protocol has already been used successfully by this team to 
manage acutely suicidal patients in the ongoing OPTIMUM study. Briefly, the protocol entails a specific 
determination of the suicidal risk and prescribes a set of actions.  For instance, when a participant is 
determined to be at high and immediate risk, the rater is instructed to stay with the participant until he 
or she has contacted a clinician to discuss the situation and to devise a plan. For this reason, raters will 
have cell phones and a study clinician will be reachable via cell phone.  In case of extreme emergency, 
raters are instructed to call their hospital security team or 911 for immediate help and in order to have 
the participant escorted to the emergency department for further safety evaluation.   
Breach of Confidentiality: 
One risk of participating in this study is that confidential information may be accidentally disclosed.  We 
will follow our established best-practice procedures to keep the information about participants secure.  
All private information is stored in secured areas and on encrypted and password-protected servers. 
 
Other risks: 
Participants may experience all or some of the risks listed above.  There may also be unknown risks.  We 
will adjust the informed consent process if new risks are identified.  We will monitor adverse events and 
serious adverse events to determine if an emerging pattern suggests a re-evaluation of the risk/benefit 
ratio. 
 
III. 
SAFETY AND ADVERSE EVENTS  
A. 
Safety Monitoring 
Safety will be systematically monitored during infusions according to the Safety Monitoring for Infusions 
schedule.  
In addition, we will ask each participant to notify us of new symptoms, illnesses, or other problems.  
B. 
Definitions of Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a subject or clinical investigation subject 
administered a drug under study.  An AE does not necessarily have a causal relationship with the study 
drug.   
The criteria for identifying AEs are: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a drug under study, whether or not considered 
related to the drug under study 
 
Any new disease or exacerbation of an existing disease 


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Protocol Date: 10/12/21 
 
Any deterioration in nonprotocol required measurements of a laboratory value or other clinical 
test (e.g., ECG or x ray) that results in symptoms, a change in treatment, or discontinuation of 
study drug 
 
Recurrence of an intermittent medical condition (e.g., headache) not present pretreatment (i.e., 
baseline) 
 
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, whether prescribed in the protocol or not. 
 
A laboratory result should be considered by the investigator to be an AE if it: 
o Results in the withdrawal of study drug 
o Results in withholding of study drug pending some investigational outcome 
o Results in an intervention, based on medical evaluation (e.g., potassium supplement for 
hypokalemia) 
o Results in any out of range laboratory value that in the investigator’s judgment fulfills 
the definitions of an AE with regard to the subject’s medical profile. 
 
All AEs observed during the study will be reported on the Redcap AE form.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the subject signs the 
study ICF through the last visit.   
Abnormal laboratory values should not be listed as separate AEs if they are considered to be part of the 
clinical syndrome that is being reported as an AE.  Any laboratory abnormality considered to constitute 
an AE should be reported as an AE on the E-CRF. 
It is the responsibility of the investigator to review all laboratory findings in all subjects and determine if 
they constitute an AE.  Medical and scientific judgment should be exercised in deciding whether an 
isolated laboratory abnormality should be classified as an AE. 
C. 
Classification of Events 
Every effort must be made by the investigator to categorize each AE according to its severity and its 
relationship to the study treatment. 
1. 
Assessing Severity of Adverse Events  
AEs will be graded on a 3 point scale (i.e., mild, moderate, and severe) and reported in the detail indicated 
on the CRF.  The definitions are as follows: 
 
Mild: 
 
Discomfort noticed, but no disruption of normal daily activity 
 
Moderate: 
Discomfort sufficient to reduce or affect normal daily activity 
 
Severe:  
Incapacitating, with inability to work or to perform normal daily activity 
2. 
Assessing Relationship of Adverse Events 
The causal relationship of the study drug to an AE will be assessed as related or unrelated, as follows: 
 
Probably Related: 
There is a reasonable causal relationship between the study drug and 
the AE.  The event responds to dechallenge.  Seeing a recurrence of the AE with study 
medication rechallenge is not required. 
o Example: patient receives a ketamine infusion.  They report vertigo that starts during 
their infusion and persists for 2 days afterwards, interfering with their day-time 
functioning (moderate AE).  At the next infusion, the vertigo occurs again. 


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Protocol Date: 10/12/21 
 
Possibly Related: 
There is a reasonable causal relationship between the study drug and 
the AE.   Dechallenge is lacking or unclear. 
o Example: patient reports new-onset insomnia the night after their first infusion but does 
not disrupt their daily activity (mild AE).  They continue with the infusions and insomnia 
does not reliably occur after subsequent infusions. 
Unrelated: 
 
Not Likely Related: 
There is a temporal relationship to study drug administration, but there 
is not a reasonable causal relationship between the study drug and the event. 
o Example: patient is started on ketamine infusions.  One day after the first infusion, they 
are driving and are hit by another car, necessitating hospitalization (severe and serious 
AE).  The accident is the fault of the other driver. 
3. 
Assessing Expectedness of Adverse Events  
An Unexpected Adverse Event is an adverse reaction, the nature or severity of which is not consistent 
with the applicable product information. 
4. 
Assessing Seriousness of Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (i.e., the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form or was 
allowed to continue, might have caused death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect in the child of a subject who was exposed to the 
study drug 
Other important medical events that may not be immediately life threatening or result in death or 
hospitalization but, when based on appropriate medical judgment, may jeopardize the subject or may 
require intervention to prevent one of the outcomes in the definition of SAE listed above should also be 
considered SAEs.  Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in such situations. 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” (i.e., 
there is no untoward medical occurrence) associated with the hospitalization: 
• 
Hospitalizations for respite care 
• 
Hospitalization planned before informed consent where the condition requiring the 
hospitalization has not changed post study drug administration 
• 
Hospitalization for routine maintenance of a device (e.g., battery replacement) that was 
in place before study entry 


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D. 
Data Collection Procedures for Adverse Events 
Participating sites are responsible for gathering and documenting data pertinent to Adverse Events 
occurring at their sites and for collecting Adverse Event information from each treating physician, 
including but not limited to:  
 
Description of the event, including onset and duration 
 
Treatment assignment, dose recommendation, and adherence 
 
Relevant medical and laboratory findings and reports 
 
Correspondence regarding the event 
 
Action taken in response to the event 
 
Classification of the Adverse Event (Severity, Relationship, Expectedness, Seriousness) 
 
All Adverse Events observed during the study will be recorded on the Redcap AE form.  All Adverse Events 
will be collected from the time of informed consent through the last assessment.  
1.a 
Reporting Procedures for Adverse Events 
 
Serious Adverse Events: Must be reported to local site IRB as per each institutional policy.  
 
All Adverse Events: Document promptly via Redcap AE form, within 5 working days of the 
occurrence of the event or notification to the investigator or research team of the event.  
 
Other Reporting Requirements: Adverse Events will be reported per relevant reporting criteria 
and timeframes to IRB and FDA as required by each institutional policy.  
 
E. 
Data Management & Analysis 
The study is a pilot, feasibility study in that sample size is determined by feasibility, not a power 
calculation. If the study demonstrates feasibility of methods and a positive signal, then pilot data would 
be used to construct a larger, adequately-powered clinical trial with federal funding. 
Study data are collected and managed using REDCap electronic data capture tools hosted in the 
Washington University School of Medicine Institute for Informatics (I2), Informatics Core Services (ICS).  
REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data 
capture for research studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails 
for tracking data manipulation and export procedures; 3) automated export procedures for seamless 
data downloads to common statistical packages; and 4) procedures for importing data from external 
sources. 
Study data will also be collected using NIH Toolbox and Miro Health ipad applications which use 
recognized security features. Study devices will be kept secured and passcode-protected.  
  
IV. 
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2018;34(13):i438-i446. 
 

SAP_001.pdf: 
Precision medicine with ketamine for older adults with treatment-resistant depression: Pilot Study 
Statistical Analysis Plan 
 
1. Administrative information 
1.1. Title and Trial Registration 
Full study title: Precision medicine with ketamine for older adults with treatment-resistant depression: 
Pilot Study  
Acronym:  
ClinicalTrials.gov identifier: NCT04504175 
Washington University in St. Louis IRB ID number: 202007085 
PCORI Contract number:  
SAP version: 1.1 (May 28, 2021) 
Study protocol version: 2.3 (May 6, 2021) 
SAP version history: Version 1.0 dated May 20, 2021 
SAP version justification: - Review by investigators on May 21, 2021 recommended clarification to 
section 4.2.2 and 3.4.1.  
SAP Revision timing: Revision will be conducted after reviewing by PI and biostatistician. This version 
is the primary draft of the detailed SAPs for each outcome. 
1.2. Roles and Responsibility 
Author: Lei Yang, Statistical Data Analyst 
Biostatistician: J. Philip Miller 
Principal investigator: Eric Lenze, MD 
SAP contributors and roles: Michael Yingling, Data Manager  
 
 
 
      Vy Pham, Statistical Data Analyst 
 
 
 
      Emily Lenard, Study Coordinator 
Affiliations: 1. Washington University in St. Louis, Missouri, USA 
 
       2. University of California Los Angeles, California, USA 
 
       3. University of Pittsburgh, Pennsylvania, USA 
 
       4. Columbia University, New York, USA  
 
       5. University of Toronto, Ontario, Canada 
 
 


Precision medicine with ketamine for older adults with treatment-resistant depression: Pilot Study 
Table of Contents 
1. Administrative information ................................................................................................................... 1 
1.1. Title and Trial Registration ............................................................................................................ 1 
1.2. Roles and Responsibility .................................................................................................................. 1 
Table of Contents ........................................................................................................................................ 2 
Abbreviation ................................................................................................................................................ 4 
2. Introduction ............................................................................................................................................. 5 
2.1. Overview ........................................................................................................................................... 5 
2.2. Objectives.......................................................................................................................................... 5 
2.2.1. Objectives and study aims ........................................................................................................ 5 
2.2.2. Hypothesis .................................................................................................................................. 5 
2.2.3. Scope ........................................................................................................................................... 5 
3. Study Methods ......................................................................................................................................... 5 
3.1. Study Design and Plan: ................................................................................................................... 5 
3.2. Screening data .................................................................................................................................. 6 
3.3. Eligibility ........................................................................................................................................... 6 
3.3.1. 
Inclusion Criteria ................................................................................................................ 6 
3.3.2. 
Exclusion Criteria ............................................................................................................... 6 
3.4. Intervention ...................................................................................................................................... 7 
3.4.1. 
Ketamine Infusion ............................................................................................................... 7 
3.4.2. 
Clonidine Co-administration ............................................................................................. 7 
4. Statistical principles ................................................................................................................................ 7 
4.1. Confidence intervals and p values .................................................................................................. 7 
4.2. Adherence and protocol deviations ................................................................................................ 7 
4.2.1. Definitions of protocol deviations ............................................................................................ 7 
4.2.2. Adherence and protocol deviations to be summarized .......................................................... 8 
4.2.3. Electronic Data Capture ........................................................................................................... 8 
4.3. Analysis populations ........................................................................................................................ 8 
5.  Analysis ................................................................................................................................................... 8 
5.1. Outcome definitions ......................................................................................................................... 8 
5.1.1. Primary outcomes ..................................................................................................................... 8 
5.1.2. Outcome measurements ........................................................................................................... 8 
5.2. Analysis methods .............................................................................................................................. 8 
5.3. Missing data ...................................................................................................................................... 8 
5.4. Interim analyses and stopping rules ............................................................................................... 9 


Precision medicine with ketamine for older adults with treatment-resistant depression: Pilot Study 
5.5. Safety and Adverse Events .............................................................................................................. 9 
5.5.1. Safety Monitoring ..................................................................................................................... 9 
5.5.2. Recording Adverse Events ....................................................................................................... 9 
5.6. Statistical software ........................................................................................................................... 9 
 
 
 


Precision medicine with ketamine for older adults with treatment-resistant depression: Pilot Study 
Abbreviation 
 
AE 
 
 
Adverse Event 
ATHF   
 
Antidepressant Treatment History Form 
AUDIT  
 
Alcohol Use Disorders Identification Test 
DAST  
 
Drug Abuse Screening Test 
FDA 
 
 
Food and Drug Administration 
IV 
 
 
Intravenous 
MADRS 
 
Montgomery-Asberg Depression Rating Scale 
PCP 
 
 
Primary Care Physician 
PHQ-9  
 
Patient Healthcare Questionnaire 9-items 
SAE 
 
 
Serious Adverse Event 
SCID-5  
 
Structured Clinical Interview for DSM-5 
TRD 
 
 
Treatment-Resistant Depression 
 
 


Precision medicine with ketamine for older adults with treatment-resistant depression: Pilot Study 
2. Introduction 
2.1. Overview  
Ketamine is approved by the U.S. Food and Drug Administration (FDA) for anesthesia and pain relief. 
Ketamine is known to cause side effects such as confusion and hallucinations.  While these are temporary, 
they can be quite uncomfortable.  Therefore, along with ketamine, we will administer clonidine to prevent 
or reduce the uncomfortable side effects of ketamine during the infusion and follow-up injections. 
Clonidine is approved by the U.S. Food and Drug Administration for treatment of high blood pressure, 
attention deficit disorder, neuropathic pain, seizure disorder, mood disorder and migraine headaches. The 
use of ketamine and clonidine are considered investigational in this study. 
The Precision medicine with ketamine for older adults with treatment-resistant depression: Pilot Study 
will assess the safety and feasibility of intravenous (IV) ketamine in older adults with Treatment-Resistant 
Depression (TRD).  
2.2. Objectives 
2.2.1. Objectives and study aims 
The study aims to learn whether it is feasible to conduct a larger, longer trial in the future to learn about 
the long-term effects of ketamine infusions. In addition, this study will develop and utilize innovative 
methodological approaches to demonstrate the feasibility of precision medicine and mHealth approaches 
in depression treatment.  
The study will also provide preliminary data on response and remission rates, adverse events, and 
cognitive changes with ketamine during a 4-week acute phase, 4-week continuation phase, and 3-month 
post-infusion follow-up phase. 
2.2.2. Hypothesis 
Ketamine infusions will show preliminary evidence of acute and continuation efficacy, as assessed by 
response and remission rates, and changes in MADRS score. 
Ketamine infusions will be safe and well-tolerated as measured by adverse events (AEs) and severe 
adverse events (SAEs). 
Ketamine infusions will produce increases in cognitive function as measured by NIH Toolbox and Miro 
measures. 
2.2.3. Scope 
This Statistical Analysis Plan will be the guiding document for the quantitative analyses that will be 
conducted in the Ketamine pilot study.  
3. Study Methods 
3.1. Study Design and Plan: 
The study will enroll approximately 25 participants across 5 sites in the US and Canada.  
Participants will receive ketamine infusions twice a week for 4 weeks (acute phase). At the end of the 
acute phase, those who have a MADRS score <10 or have a MADRS ≥ 30% reduction from baseline 
will continue with an additional 4 weeks of weekly ketamine infusions (continuation phase). Participants 
whose MADRS score was not reduced at least 30% from baseline will not proceed to the Continuation 
Phase of the study; their participation will end. At the end of continuation phase, those who complete the 
Continuation phase will be assessed for remission and response using the MADRS.  
Participants will be assessed at baseline, end of acute phase, and end of continuation phase for 
effectiveness, safety, and executive functioning. Participants will be asked to complete daily surveys of 


Precision medicine with ketamine for older adults with treatment-resistant depression: Pilot Study 
their depression symptoms during their participation. Participants who choose to withdraw from the study 
early (during acute phase) will be treated as did not respond or remit. Final visit prior to withdrawing 
early from the study is not required. 
3.2. Screening data 
Potential participants identified from existing studies will be screened for eligibility. After providing 
informed consent, the following assessments must be conducted prior to randomization to ensure 
eligibility (see also Section 3.3.1 and 3.3.2 for Inclusion and Exclusion Criteria):  
 
SCID-5: Meet criteria for unipolar Major Depressive Disorder, non-delusional, current. Rule out 
psychotic and bipolar disorder.  
 
AUDIT: Rule out current alcohol use disorder (past 3 months) 
 
DAST: Rule out current substance use disorder (past 3 months) 
 
PHQ-9: Score must be 15 or higher at baseline. 
 
Short Blessed Test: Score must 0-9 (excluded if score is 10 or higher).  
 
ATHF:  Must have 2 or more adequate antidepressant trials of different classes in the current episode. 
 
Review of current medications: Must not be taking naltrexone memantine, or any medication that 
could be considered contraindicated with ketamine. Must not be taking more than two adequately-
dosed oral antidepressant. Must be stable on antidepressant regimen for at least two weeks.  
 
Review of medical conditions: Must not have any medical conditions affecting IV ketamine safety or 
tolerability or that would interfere with participation in a long-term study. (i.e., life expectancy < 1 
year because of terminal illness, unstable angina). Must not have inadequately controlled 
hypertension. 
3.3. Eligibility 
All participants will meet the following eligibility criteria:  
3.3.1. Inclusion Criteria 
a) Community-living men and women age 60 years and older. 
b) Treatment-resistant depression: defined as unipolar major depressive disorder, non-delusional 
(diagnosed by SCID-5) that persists despite ≥ 2 adequate antidepressant trials of different classes in the 
current episode, including at least one evidence-based second-line treatment in the current episode 
(including serotonin norepinephrine reuptake inhibitors, bupropion, tricyclics, monoamine oxidase 
inhibitors, or augmentation with an atypical antipsychotic, stimulant, bupropion, lithium, or 
Triiodothyronine). 
c) Moderate to severe depressive symptoms determined by Patient Health Questionnaire 9-item (PHQ-9) 
score ≥15 at baseline. 
d) Able to provide informed consent. 
3.3.2. Exclusion Criteria 
a) Dementia per history, score ≥10 on the Short Blessed Test, or determined by clinical interview with 
geriatric psychiatrist to have high likelihood of dementia. 
b) Psychotic spectrum or bipolar disorder or severe personality disorder that at the PIs discretion would 
interfere with safe participation.  Anxiety disorders are not an exclusion. 
c) Baseline systolic BP > 150 systolic or 90 diastolic at evaluation. Participants who initially present with 
elevated blood pressure may be re-assessed; and if needed, referred to their healthcare provider for 
hypertension management. Clonidine is preferred as the agent to control blood pressure, as it will also 
improve tolerability of ketamine infusion.  However, patients' providers are not required to use this drug 


Precision medicine with ketamine for older adults with treatment-resistant depression: Pilot Study 
(vs. other strategies such as optimizing doses of existing medication). Once blood pressure is adequately 
managed, they can be reconsidered for study participation. 
d) Current alcohol or substance use disorder or lifetime recreational ketamine use or other dissociative 
agent (e.g., PCP). 
e) Use of naltrexone, memantine, or any medication that could be considered contraindicated with 
ketamine. 
f) Taking more than 2 adequately-dosed oral antidepressants. 
g) High acute risk for suicide and unable to be managed safely in the clinical trial. 
No exclusion criteria are based on race, ethnicity, or gender. 
3.4. Intervention 
3.4.1. Ketamine Infusion 
To ensure dose accuracy, participants will have weight confirmed prior to each infusion. After safety 
ratings (see table in the protocol) are performed, an IV line will be inserted into upper extremity by 
research personnel. The ketamine will be infused using an IV infusion pump at a dose of 0.5 mg/kg of 
body weight over 40 minutes. Heartrate, blood pressure, and pulse-oximetry will be routinely monitored 
throughout the infusion and for approximately up to two hours after the end of the infusion. Safety ratings 
will be repeated prior to discharge. After normalization of any psychotomimetic symptoms or blood 
pressure elevation and IV removal, participants will be discharged. Participants will be provided with 
transportation to and from infusion visits. 
If a participant is unable to receive IV ketamine (e.g., because of lack of IV access), he or she can receive 
IM ketamine as a bolus. The dosage will be the same (0.5 mg/kg) because its bioavailability is 93% and 
its plasma half-life is similar to IV. 
3.4.2. Clonidine Co-administration 
In order to prevent or reduce the severity of the psychotomimetic/dissociative and hypertensive effects of 
ketamine, Clonidine(0.1mg) is recommended to be routinely co-administered with ketamine. Clonidine 
co-administration does not alter the antidepressant activity of ketamine in either preclinical or clinical 
studies.  
We will measure doses of clonidine co-administration and, if not used, reasons why it is declined. 
4. Statistical principles 
4.1. Confidence intervals and p values 
The primary focus of all analyses of this pilot study will be descriptive and thus summary estimates will 
be accompanied by 95% confidence intervals. 
4.2. Adherence and protocol deviations 
4.2.1. Definitions of protocol deviations 
Any alteration or modification to the IRB-approved research without prospective IRB approval.  The term 
research encompasses all IRB-approved materials and documents including the detailed protocol, IRB 
application, consent form, recruitment materials, questionnaires/data collection forms, and any other 
information relating to the research study. 


Precision medicine with ketamine for older adults with treatment-resistant depression: Pilot Study 
4.2.2. Adherence and protocol deviations to be summarized 
Actual doses and infusion duration will be captured using the Infusion Visit Log. Reasons for not 
completing infusion per protocol will also be documented using the Infusion Visit Log. Follow-up data 
will be collected regardless of treatment adherence.  
4.2.3. Electronic Data Capture 
This study will utilize MyCap smartphone app as the primary data collection method for daily depression 
surveys. Data collected in MyCap is recorded and stored in REDCap, hosted in the Washington 
University School of Medicine Institute for Informatics (I2), Informatics Core Services (ICS). Study data 
will also be collected using paper CRFs and then entered into REDCap. Study data will also be collected 
using NIH Toolbox and Miro Health iPad applications which use recognized security features. Study 
devices will be kept secured and passcode-protected.  
Source documents, including laboratory values, medical records and physician communications will be 
maintained at each site to verify adherence to protocol, inclusion/exclusion criteria, and data accuracy. 
4.3. Analysis populations 
All participants who receive at least one infusion will be part of the analyzed sample. 
5.  Analysis 
5.1. Outcome definitions 
Remission from depression is defined as MADRS score 0-9 at Week 4(acute phase end). 
Response to treatment is defined as ≥ 30% reduction in depressive symptoms on the MADRS from 
baseline to Week 4.  
5.1.1. Primary outcomes 
Remission from Depression at Week 4.  
5.1.2. Outcome measurements 
Change in Depression Severity as measured by MADRS at Week 4 and 8.  
Change in Psychological Well-Being as measured by NIH Toolbox Psychological Well-Being Surveys, 
Positive Affect and General Life Satisfaction at Week 4 and 8.  
Change in Cognition as measured by NIH Toolbox and Miro Health Cognitive Batteries at Week 4 and 8.  
Change in Executive Function as measured by NIH Toolbox and Miro Health Cognitive Batteries at 
Week 4 and 8.  
Change in Suicidal Ideation as measured by Scale for Suicidal Ideation at Week 4 and 8.  
5.2. Analysis methods 
Data analysis will be mostly descriptive, including rates of response and remission and AEs. 
Continuous changes in depressive symptoms and cognitive changes will also be measured with mixed-
effect model.  
5.3. Missing data 
Reasons for missingness will be collected. 


Precision medicine with ketamine for older adults with treatment-resistant depression: Pilot Study 
5.4. Interim analyses and stopping rules 
No interim analysis is planned due to the nature of the trial. As there is no control arm and all treatments 
are FDA-approved and frequently used in older adults, no contingency plans for early stopping because of 
futility or safety are planned. 
5.5. Safety and Adverse Events 
5.5.1. Safety Monitoring 
Safety will be systematically monitored during infusions according to the Safety Monitoring for Infusions 
schedule. In addition, we will ask each participant to notify us of new symptoms, illnesses, or other 
problems. 
5.5.2. Recording Adverse Events 
During the study, regular assessments for AEs will be conducted and recorded in REDCap. Participating 
sites are responsible for gathering and documenting data pertinent to AEs occurring at their sites and for 
collecting AE information, including but not limited to:  
a) Description of the event, including onset and duration. 
b) Doses of study medications and adherence. 
c) Relevant medical and laboratory findings and reports. 
d) Correspondence regarding the event. 
e) Action taken in response to the event. 
f) Classification of the AE (Severity, Relationship, Expectedness, Seriousness). 
5.6. Statistical software 
Data cleaning and statistical analyses will be performed using SAS (SAS Institute, Cary NC) and R (The 
R Foundation for Statistical Computing; Vienna, Austria).