Ketamine Tolerated Dose for Postpartum Depression and Pain After Cesarean Delivery (PREPARE1)
Phase: PHASE1
Conditions: Pain, Postoperative, Depression, Postpartum
Sponsor: Grace Lim, MD, MS

v.7.0    05/29/2024 
Ketamine Tolerated Dose to Prevent  
Postpartum Depression and Pain after Cesarean 
Delivery (PREPARE 1) 
 
Protocol Number: 
 
 STUDY22100018 
 
Version Date:   
 
05/29/2024 
 
Version Number:  
 
7.0  
 
IND Sponsor:   
 
University of Pittsburgh 
 
Principal Investigator:  
Grace Lim, MD, MSc 
 
IND Number:  
 
IND 142105 
 
NCT Number:  
 
NCT05907213  
 
Source of Funding: 
 
National Institute of Mental Health: R01MH134538 
 

 
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05/29/2024    v 7.0 
History of Protocol Versions: 
Version  
Date 
Sections Changed 
Rationale for the Change 
1.0 
April 26, 2023 
N/A 
N/A 
2.0 
May 30, 2023 
5.2 inclusion criteria 
5.4 payment plan 
6.4 storage in lockbox 
7.4 patient safety 
IRB comment response 
3.0 
June 6, 2023 
5.4 payment plan 
 
4.0 
September 12, 2023 
Various 
Update consistency with MOP 
DSMB edits 
5.0 
September 22, 2023 
1 
5.2 
Study population clarification 
Updated inclusion wording 
6.0 
December 7, 2023 
Protocol Overview 
 
Section 4 
 
 
Section 5.2 
 
 
 
 
 
Section 5.3 
 
 
 
 
 
 
 
 
 
 
Updated wording for clarity 
 
Revised wording to make timing 
of assessments clearer 
 
Revised inclusion criteria to 
clarify only cesarean delivery, 
removal of neuraxial morphine 
restriction as it is not germane to 
the primary study objectives, 
specified term delivery definition 
 
Revised exclusion criteria to 
clarify patient undergoing 
general anesthesia to match 
wording in other documents; 
other wording modification to 
match wording in institutional 
protocol; removed 
contraindication to NSAID as it is 
not germane to primary study 
objective 
 

 
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05/29/2024    v 7.0 
Section 7.1 
 
 
Section 7.6 
 
Section 8.2 
 
 
 
 
Section 9.2 
 
 
Updated screening procedures to 
reflect workflow optimization 
 
Corrected a spelling error 
 
Deleted "risks of withholding 
breastfeeding for 60 hours" as we 
are not asking women to 
withhold breastfeeding  
 
Spelling error 
7.0 
May 16, 2024 
Appendix 3 
 
 
 
Appendix 2 
 
 
 
 
 
 
Figure 1 
 
 
 
 
Section 3.4.1, 6.3, Table 1 
of Section 6.2 
 
 
 
 
 
Corrected to include protocol-
listed assessments at postpartum 
week 12, which is Day 84, Visit 13  
 
Corrected RASS and vital signs to 
line up with protocol text 
LSD >8 cutoff for PI notification 
and bedside check to enhance 
safety and facilitate direct event 
attributions 
 
 
Corrected to line up with 
protocol text for RASS, side effect 
assessments and postpartum 
assessments 
 
DLT event definition revised to 
include complete infusion 
cessation due to intolerable side 
effect acceptability ratings by 
patient. Table now specifies 
events that qualify as DLT in 
accordance with revised DLT 
definition 

 
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05/29/2024    v 7.0 
 
Section 6.2 
 
 
 
Sections 3.4.1, 6.3, 9.1, 
12.3, Table 1 of Section 
6.2 
 
 
 
 
 
Section 6.6 
 
Added grace period range +15 
minutes for maintenance infusion 
dose adjustment times 
 
Reduced systolic blood pressure 
cutoff from 190mmHg to 
160mmHg in accordance with 
DSMB recommendations and to 
be more aligned with systolic 
blood pressure cutoffs in the 
pregnant and postpartum 
population 
 
Clarified rescue medication 
protocol for nausea/vomiting 
 
 
 
 

 
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Contents 
 
1 
Protocol Overview ............................................................................................................. 1 
1.1 
Study Schema ................................................................................................................. 2 
2 
Background and Rationale ................................................................................................ 3 
2.1 
Background .................................................................................................................... 3 
2.2 
Rationale ......................................................................................................................... 4 
3 
Hypotheses, Objectives and Endpoints ............................................................................ 4 
3.1 
Hypotheses ..................................................................................................................... 4 
3.2 
Primary Hypothesis .................................................................................................. 4 
3.3 
Objectives........................................................................................................................ 4 
3.3.1 
Primary Objective: ................................................................................................. 4 
3.3.2 
Secondary Objective .............................................................................................. 4 
3.3.3 
Exploratory Objectives .......................................................................................... 5 
3.4 
Endpoints ........................................................................................................................ 5 
3.4.1 
Primary Endpoint .................................................................................................. 5 
3.4.2 
Secondary Endpoints ............................................................................................. 5 
4 
Research Design ................................................................................................................ 6 
5 
Human Subjects ................................................................................................................ 7 
5.1 
Subject Population ......................................................................................................... 7 
5.2 
Inclusion Criteria ........................................................................................................... 7 
5.3 
Exclusion Criteria .......................................................................................................... 7 
5.4 
Recruitment Methods ................................................................................................... 8 
5.5 
Screen Failures ............................................................................................................... 9 
6 
Study Drug ........................................................................................................................ 9 
6.1 
Dose Selection .............................................................................................................. 10 
6.2 
Study Drug Preparation and Dispensing ................................................................ 11 
6.3 
Dose Delays and Modifications ................................................................................. 11 
6.4 
Study Drug Storage and Accountability .................................................................. 14 
6.5 
Prohibited Medications .............................................................................................. 15 
6.6 
Rescue Medications ..................................................................................................... 15 
7 
Research Activities .......................................................................................................... 15 
7.1 
Screening Procedures .................................................................................................. 19 

 
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7.2 
Study Entry Procedures .............................................................................................. 19 
7.3 
Study Drug Administration ....................................................................................... 19 
7.4 
Safety Assessments/Procedures During Treatment ............................................... 20 
7.5 
Safety Assessments/Procedures During Follow-up ............................................... 20 
7.6 
End of Study Safety and Efficacy Assessments/Procedures ................................. 20 
8 
Potential Risks and Benefits ........................................................................................... 20 
8.1 
Reasonably Foreseeable Risks Related to Study Drug ........................................... 21 
8.2 
Reasonably Foreseeable Risks Related to Research Interventions ....................... 21 
8.3 
Potential Benefits ......................................................................................................... 22 
9 
Protection Against Risks ................................................................................................. 22 
9.1 
Management of drug related toxicity ....................................................................... 22 
9.2 
Management of research related risks...................................................................... 22 
10 
Adverse Events and Serious Adverse Events .................................................................. 23 
10.1 Severity ......................................................................................................................... 24 
10.2 Relatedness ................................................................................................................... 25 
10.3 Expectedness ................................................................................................................ 25 
10.4 Reporting Serious Adverse Events ........................................................................... 26 
11 
Withdrawal of Subjects and Stopping Rules .................................................................. 26 
11.1 Adverse Events Requiring Discontinuation ............................................................ 26 
11.2 Other Criteria Requiring Discontinuation ............................................................... 27 
11.3 Clinical Trial Stopping Rules ..................................................................................... 28 
12 
Statistical Analysis .......................................................................................................... 28 
12.1 General Approach ....................................................................................................... 28 
12.2 Sample Size Determination ........................................................................................ 29 
12.3 Analysis of Primary Endpoint ................................................................................... 29 
12.4 Analysis of Secondary Endpoints ............................................................................. 29 
13 
Data and Safety Monitoring ............................................................................................ 29 
13.1 Data Safety Monitoring Plan ..................................................................................... 30 
13.2 Parameters to be Monitored ...................................................................................... 30 
13.3 Frequency of Monitoring ........................................................................................... 31 
13.4 Clinical Monitoring ..................................................................................................... 31 
13.5 Data and Safety Monitoring Board ........................................................................... 31 

 
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14 
Regulatory, Ethical, and Study Oversight ....................................................................... 32 
14.1 IRB Approval ............................................................................................................... 32 
14.2 Informed Consent Procedures ................................................................................... 32 
14.3 Protocol Deviations ..................................................................................................... 33 
15 
References ....................................................................................................................... 35 
Appendix 1 – Surveys Measures .............................................................................................. 48 
Appendix 2 – Schedule of Perinatal, Surgical, and Infusion-Specific Research Activities ..... 49 
Appendix 3 – Schedule of Postpartum Research Activities ..................................................... 50 
 
 
 

 
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ABBREVIATIONS AND ACRONYMS 
 
AE 
Adverse Event 
ADL 
Activities of Daily Living 
ASA PS 
American Society of Anesthesiologist Physical Status 
AUC 
Area Under Curve 
CD 
Cesarean Delivery 
CFR 
Code of Federal Regulations 
Cmax 
Peak concentration of “drug” 
CRF 
Case Report Form 
Css 
Concentration of “drug” at Steady State 
DHHS 
Department of Health and Human Services 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
EPDS 
Edinburgh Postnatal Depression Scale 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization  
IDE 
Investigational Device Exemption 
IDS 
Investigational Drug Service 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
IV 
Intravenous 
MDD 
Major Depressive Disorder 
MTD 
Maximum Tolerate Dose 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NMDA 
N-Methyl-D-Aspartate Receptor 
PCP 
Phencyclidine 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PPD 
Postpartum Depression 
PSS 
Perceived Stress Scale 
RASS 
Richmond Agitation Sedation Scale 
REDCap 
HIPAA compliant data management software 
RID 
Relative Infant Dose 
SAE 
Serious Adverse Event 
SSRI 
Selective Serotonin Reuptake Inhibitor 
UPMC 
University of Pittsburgh Medical Center 
 

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v.7.0   05/29/2024 
1 
Protocol Overview 
 
 
Study Description  
The purpose of this study is to identify a tolerable dose for 
postpartum ketamine infusion using a maximum tolerated dose 
(MTD) 3+3 design. A loading dose over 1 hour will be the MTD 
variable to be tested, as our data suggest that ketamine side 
effects occur with the loading dose. 
Study Population: 
Patients having  cesarean delivery (CD) who are either: 1) 
planning not to breastfeed; or 2) are receiving ketamine as part of 
clinical care, will be enrolled. Ketamine will be started in 
postpartum patients, after cord clamping. 
Planned Sample Size:  
The projected sample size will be a maximum of 12 patients with 
complete primary outcome data within the MTD 3+3 design.  
 
Participating 
Institutions (if a multi-
center clinical trial) 
N/A 
 
 
 
 

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v.7.0   05/29/2024 
 
1.1 Study Schema 
 
Figure 1. Assessment timeline for MTD study and follow-up assessments 
 
 
Figure 2. MTD dosing schematic for PREPARE 1. 
 

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2 
Background and Rationale 
 
2.1 
Background 
 
A lack of data on new pain treatments in pregnancy and lactation puts 1.2 million US women having 
cesarean delivery (CD) every year at risk for poor pain control, depressed mood, and poor recovery7,8. 
Despite high individual variability in pain after CD6,9, current CD treatments ignore the 
multidimensionality of pain, including the influence of mood on pain. NMDA receptor antagonists like 
ketamine significantly reduce postoperative pain and opioid use by up to 40%10.  In addition to its 
analgesic effects, a single dose of IV ketamine has been shown to rapidly reduce depressive symptoms 
by 50% and remission rates 43-77%86 in non-obstetric populations. Evidence of successful post-surgical 
pain management and rapid reduction of depressive symptoms render ketamine a great candidate for 
post-CD pain management and potential reduction of PPD symptomology.   
 
Ketamine at sub-anesthetic doses is effective in post-surgical acute pain management, with long-
lasting analgesia. Many trials (non-obstetric) have shown ketamine effectiveness for post-operative 
analgesia94-96. Available postpartum ketamine studies have focused on various doses (ranging 0.1-0.5 
mg/kg, single doses, infusions) for efficacy16-18,66, but have not emphasized side effects. Although high 
doses of ketamine induce psychomimetic effects, low doses, such as in the current proposal, can reduce 
pain without side effects10,78 and potentially reduce pain intensity for 1 year after a single dose (effect 
size 0.61, 95% CI 0.40 – 0.80)97.  
 
In addition to its analgesic effects, ketamine use for depression treatment promotes fast, effective 
depression symptom reductions, a robust effect occurs from 4-72 hours post-infusion (0.5 mg/kg over 
40 min) in patients with MDD; this dose is commonly used for depression87. The antidepressant effect 
lasts beyond psychotomimetic symptoms, which peak during the infusion and return to baseline 
within 1-2 hours86. These findings contrast traditional antidepressants whereby only 1/3 of patients 
become symptom-free after 7 weeks of treatment with SSRI.85 A widely cited trial of 205 ketamine 
doses (0.5mg/kg, 40 min) for depression concluded ketamine was, “safe and well- tolerated” but did 
not probe patient acceptability of side effects33. Dose-dependent side effects are common, with a high 
incidence of vertigo, nausea, sedation, and dissociation in intranasal dosing to plasma levels similar to 
an IV dose of 0.5 mg/kg over 40min88. These dose-dependent side effects preclude widespread use in 
the peripartum population. Identifying ketamine dose tolerability in a post-CD population has the 
potential to improve treatment of postoperative pain as well as mood-related outcomes of chronic pain 
such as comorbid onset of PPD. This work will  
 
Defining postpartum ketamine PK is critical to understanding the potential role of ketamine for PPD 
prevention, and to understanding the plasma ketamine concentration time profile with its maximum 
tolerated dose. There are no PK/PD models for ketamine-induced side effects or analgesia, although 
there are isolated reports of ketamine side effects with plasma concentrations. Available trials that 
conclude ketamine is “well tolerated” did not query patient perspectives in acceptability33. The 
duration of ketamine exposure may be important as well, given that subcutaneous administration may 
have greater antidepressant duration than intravenous administration of the same dose, despite lower 

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v.7.0   05/29/2024 
peak plasma concentrations in subcutaneous administration19. These knowledge gaps are significant 
because they limit patient-centered acceptability of ketamine and a finer understanding of its potential 
effective utility for PPD prevention. Because ketamine is metabolized by CYP3A and CYP2B6 
(increased activity in pregnancy and immediately after delivery)34, and because pregnancy induces 
sensitivity to anesthetics, it is critical in this project to identify a tolerable dose of postpartum ketamine 
and the perioperative factors impacting its PK. 
 
2.2 
Rationale 
 
Defining postpartum ketamine tolerable doses and ketamine PK is critical to understanding the 
potential role of ketamine for PPD prevention, and to understanding the plasma ketamine 
concentration time profile with its maximum tolerated dose. There are no PK/PD models for ketamine-
induced side effects or analgesia, although there are isolated reports of ketamine side effects with 
plasma concentrations. Available trials that conclude ketamine is “well tolerated” did not query 
patient perspectives in side effect acceptability33. The duration of ketamine exposure may be important 
as well, given that subcutaneous administration may have greater antidepressant duration than 
intravenous administration of the same dose, despite lower peak plasma concentrations in 
subcutaneous administration19. These knowledge gaps are significant because they limit patient-
centered acceptability of ketamine and a finer understanding of its potential effective utility for PPD 
prevention. Because ketamine is metabolized by CYP3A and CYP2B6 (increased activity in pregnancy 
and immediately after delivery)34, and because pregnancy induces sensitivity to anesthetics, it is 
critical in this project to identify a tolerable dose of postpartum ketamine and the perioperative factors 
impacting its PK. 
 
3 
Hypotheses, Objectives and Endpoints 
 
3.1 
Hypotheses 
3.2 
Primary Hypothesis 
The purpose of this study is to identify a tolerable dose for postpartum ketamine infusion using a 
maximum tolerated dose (MTD) 3+3 design. A loading dose over 1 hour will be the MTD variable 
to be tested, as our data suggest that ketamine side effects occur with the loading dose. 
 
Our working hypothesis, based on our preliminary PK and safety data and that of Loo et al [19], is 
that a 12-hr IV ketamine infusion of 0.05 mg/kg/hour is the MTD. 
 
3.3 
Objectives 
3.3.1 
Primary Objective: 
Quantify maximum tolerable dose of postpartum ketamine infusion post-cesarean delivery. 
 
3.3.2 
Secondary Objective 
Quantify side effect acceptability of low-dose ketamine infusion in peripartum people. 

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3.3.3 
Exploratory Objectives 
Measure maternal pain and depression in this cohort before and after cesarean delivery until 
12weeks postpartum. 
 
3.4 
Endpoints 
 
3.4.1 
Primary Endpoint 
Maximum Tolerated Dose (MTD).   The MTD will be defined as the dose at which fewer than 
33% of patients experience a DLT defined by intolerability.  
 
Tolerability (dichotomous Yes/No) 
Tolerability (YES) will be defined as: lack of adverse events (adverse event defined 
as: severe unresolved hemodynamic effect: systolic blood pressure <80 or >160, heart 
rate <40 or >120).33 
Lack of Tolerability will be defined as presence of any adverse event (i.e., 
severe unresolved hemodynamic effect: systolic blood pressure <80 or >160, 
heart rate <40 or >120).33 
 
A DLT event is defined by complete infusion cessation due to intolerable side effect 
acceptability ratings by patient, OR the experience of an intolerable event as defined above. The 
escalation of dosing will be as noted in Figure 2 and is based on a modified Fibonacci 
sequence101,102 with smaller proportional increases in dose in the escalation scheme. Escalations 
occur until 2 in a cohort of 3 to 6 experiences DLT (i.e., until ≥33% of patients experience DLT at 
that dose). The dose below this level estimates the MTD. 
 
Participants will be classified as having had a DLT if any of the following conditions are met: 
• 
Persisting (i.e., unresolved after 3 consecutive measurements within a 15-minute interval) 
hemodynamic side effects defined as below and despite treatments or minimizing 
infusion rates as specified.   
o Systolic blood pressure <80 or >160  
o Heart rate <40 or >120   
• 
Complete infusion cessation due to intolerable side effect acceptability ratings by patient 
 
Primary Outcomes will be measured at a minimum of every 4-hours from the start of the 
ketamine infusion (t = 0) for 24-hours (12-hours post infusion cessation). Additional assessments 
will be administered between the 4-hour measurements if any adverse event or side effect is 
noted by the patient.   
 
3.4.2 
Secondary Endpoints 
Patient-reported side effect acceptability ratings, defined below 
Peripartum pain scores, defined in Appendix 1 

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Peripartum depression scores, defined by Edinburgh Postnatal Depression Score (EPDS) 
 
Side Effect Acceptability Ratings 
Any reported side effects are rated by patients. Patient reported side effects (i.e., dizziness, 
lightheadedness, bad dreams, nausea, vomiting, itchiness, and hallucinations: all dichotomous 
outcomes) will be evaluated based on patient-specific reports of how “acceptable” or 
“unacceptable” the side effects are for continued or future use of the study medication. Patient-
reported acceptability is defined based on theoretical framework of acceptability103 and focused 
on constructs of Burden (“Would experiencing side effects keep you from participating in this 
intervention (ketamine) again?” yes/no) and Affective Attitude (“Based on your experience 
with this medication, would you be willing to participate in this intervention (ketamine) 
again?” yes/no).  
1. Acceptability is the absence of patient-centered unacceptable side effects. Patients with 
side effects who report that the side effects were “acceptable” on digital diary will be 
counted as having confirmed side effect acceptability ratings, regardless of the presence 
of any side effects to the ketamine dose. Patient-reported acceptability is defined as a 
“yes” to Affective Attitude with a “no” to Burden. 
2. Unacceptability is any patient report of unacceptable side effects, defined as any 
positive response on the digital side effect diary rated unacceptable by the patient. 
Either a negative response to Attitude, or a positive response to Burden, will define 
patient unacceptability. 
4 
Research Design  
This is an open-label maximum tolerated dose (MTD) 3+3 design.101,102 
 
Protocol Overview.  
Patients will respond to surveys prior to and following cesarean delivery regarding their current pain 
and mood. Patients will begin study procedures in the third trimester of pregnancy, within 
approximately one week of scheduled cesarean delivery, until 12-weeks postpartum. 
 
Preoperative weight and vital signs will be measured, and baseline inventories completed (Figure 1; 
refer to section 1.1). After delivery, cord clamping and declaration of clinical stability by the 
anesthesiologist (typically~5-15 min after delivery; ±30 minutes), a loading infusion of ketamine 0.05 
mg/kg/hour will begin for the first 3-patients in the study. Vital signs and side effect symptomology will 
be measured 15, 30, and 60 minutes (±5 minutes) after infusion start, and at 4, 8, 10, 12, 16, and 24 hours 
(±30 minutes) after infusion start. Plasma samples will be collected at 1, 6, 10, and 12 hours (±30 minutes) 
after infusion. Any report of adverse events or side effects will trigger a blood draw for analysis and 
correlation of these symptoms to plasma levels of ketamine within the 12-hour infusion. All assessments 
have been timed to coincide with timing intervals of typical post-CD clinical care interventions. Patients 
dosing after the first three patients will proceed based on the MTD protocol in Figure 2; refer to section 
1.1. 
 
MTD dosing protocol.  

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A loading dose and maintenance infusion strategy will be used (Figure 2; in section 1.1). MTD to be 
tested will focus on the initial loading dose used to achieve a higher plasma concentration in a brief 
period. Ketamine dose will not exceed sub-anesthetic ranges (≤0.2mg/kg/hr78). The maintenance rate of 
0.05mg/kg/hr is based on our preliminary data suggesting tolerability, and on data suggesting that this 
rate might yield adequate plasma concentrations necessary for the treatment of depression. The first 
set of 3 patients will receive a loading infusion of ketamine 0.05 mg/kg/hr for the first data. The 
decision to escalate the loading infusion dose, enter 3 more at the same level, or stop, will not occur 
until 3 patients complete the 0.05 mg/kg/hr protocol. A DLT event is defined in section 3.4.1. 
 
5 
Human Subjects 
 
5.1 
Subject Population 
 
The maximum tolerated dose (MTD) 3+3 design encompasses blocks of 3 patients allocated to dosing 
schematics. In this study, we have 4 dosing schematics to be tested. Therefore, a minimum number of 6 
and maximum number of 12 patients will participate in this trial.  
 
5.2 
Inclusion Criteria 
• 
Cesarean delivery 
• 
Adults 18 years and older 
• 
Term delivery ≥ 37 weeks gestation anticipated at time of delivery 
• 
ASA PS 2 or 3   
• 
 
• 
 
• 
One of the following must be met for inclusion: 
o Not planning to breastfeed  
o Ketamine use indicated for pain management plan.   
 
5.3 
Exclusion Criteria 
• 
Patient going under general anesthesia for cesarean delivery 
• 
Allergy to study medication (ketamine) 
• 
ASA PS 4 +  
• 
Contraindications to neuraxial anesthesia  
• 
Preterm delivery (<37 weeks gestation) 
• 
Anticipated fetal-neonatal complex care plan as indicated in the patient’s chart 
• 
Patient history of ketamine or PCP abuse 
• 
Patient history of schizophrenia or psychosis 
• 
Patient history of liver or renal insufficiency 
• 
Patient history of uncontrolled hypertension, chest pain, arrhythmia, head trauma, or 
intracranial hypertension, uncontrolled thyroid disease, or other contraindications to 
ketamine 
• 
Participating in another pain intervention trial   

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• 
Pre-eclampsia with severe features 
• 
Hemodynamic instability 
• 
Contraindicated medications use:   
o Oral antihypertensive medications (exclusion: hypertensive disorders of pregnancy)   
o Intravenous magnesium (exclusion: pre-eclampsia with severe features)   
o Ketamine, phencyclidine, psilocybins, or any other psychedelics (exclusion: ketamine 
or PCP abuse)   
o Lithium, valproate, carbamazepine, lamotrigine, haloperidol, chlorpromazine, 
fluphenazine, aripiprazole, clozapine, or other typical or atypical   
o antipsychotic medications (exclusion: schizophrenia or psychosis)   
 
 
5.4 
Recruitment Methods 
 
The current process for research recruitment is that the research anesthesia team will review charts for 
all patients presenting for cesarean delivery or who are likely to present for a cesarean delivery in the 
labor and delivery rooms. Prenatal records will indicate patients planning not to breastfeed. During 
prenatal anesthesiology evaluations, the anesthesiology team will identify patients who are including 
ketamine infusion as part of their pain management care. Research staff will contact patients to explain 
the availability of the study to the patient meeting eligibility criteria.  
 
Additional methods of recruitment include directly approaching potential subjects (in-person), the use 
of Email/Listserv/Electronic Mailing List, use of Flyers/Posters or Brochures in provider offices and 
clinics, use of Pitt+Me university research registry portal, and patient/participant referrals. 
 
Patients will be eligible if they are receiving ketamine as part of their clinical care, and these typically 
include patients with a history of complex pain, history of chronic pain with or without treatment, 
current everyday smokers, patients with opioid or substance use disorder, and patients who have a 
documented history of treated or untreated anxiety, depression, or trauma.  
 
Eligible patients will be notified of their eligibility to participate in the study by clinical and research 
staff. Should the patient wish to hear more, the study coordinator will discuss study participation. 
Questions will be answered, and time will be afforded to patients per the Informed Consent Procedures 
outlined, to minimize risks of coercion or undue influence. 
 
Upon completion of the baseline inventories and the ketamine infusion and blood collection, 
patients will receive a payment of $750 (see Appendix 4 for payment details). Upon completion of 
the postpartum weekly surveys, payments of up to $150 will be made at both 6- and 12-weeks 
postpartum.  
 
In-Hospital Encounter  
 
  
 
Baseline inventories  
 
 
 
 

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Complete infusion and all blood draws 
 
 
         $ 750.00   
 
Postpartum Encounters 
Complete all weekly surveys @ $25.00/week  
Complete weekly surveys for 6 weeks  
 
 
    up to $150.00 
Complete weekly surveys for weeks 7-12 
 
 
    up to $150.00 
Grand Total  
 
 
 
         
 
 
          $ 1,050.00 
 
5.5 
Screen Failures 
 
Participants who are consented to participate in the third trimester of pregnancy, may be withdrawn 
from the study protocol before, during, or following the cesarean surgery if events arise such as to 
preclude them from participating in the remainder of the study. These participants will be considered 
“Screening Failures”. The following list is non-comprehensive, but represents the most likely scenarios: 
• 
Vaginal or non-cesarean delivery 
• 
Development of exclusion-based criteria prior to cesarean surgery (i.e., severe preeclampsia, 
preterm delivery, NICU assessment likely, etc.) 
• 
Severe complications during labor and/or delivery whereby the PI and/or patient’s surgeon 
recommend a change in therapeutic response. 
 
Withdrawn participants will be replaced at a proportion of 1:1. Procedures are as follows:  
• 
Study personnel and investigators will be notified. 
• 
Written documentation of withdrawal and reason for withdrawal will be noted per IRB protocol. 
• 
Study personnel, investigators, and pharmacy will be informed of the need for replacement of 
pharmaceuticals due to participant withdrawal.  
• 
Subsequent data to be collected from the withdrawn participant will be restricted to the 
minimum amount necessary to continue to monitor safety, i.e., side effect diary including 
questions of sedation, LSD short form, dizziness, lightheadedness, bad dreams, nausea, 
vomiting, pruritus, hallucinations.  
 
6 
Study Drug 
 
Ketalar (Ketamine) (C13H16ClNO, 2-(2-chlorophenyl)-2-(methylamino) cyclohexan-1-one) is a 
cyclohexanone derivative with known analgesic and anesthetic properties. It inhibits biogenic amine 
uptake, binds opioid receptors, and inhibits N-methyl D-aspartate (NMDA) receptors. 
 
Ketamine will be used for post-cesarean delivery analgesia. Specifically, it will be evaluated for its role 
in pain reduction, opioid reduction, and improved pain outcomes. In the non-obstetric surgical 
population, modalities such as intravenous ketamine are well-recognized as effective adjuncts in opioid-
reduction strategies for postoperative pain. Ketamine is used off-label as standard clinical care in 
perioperative pain management for patients with a history of complex pain such as people with chronic 

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pain (treated or untreated), a history of or current symptoms of depression and anxiety, current 
smokers, and women with opioid or substance use disorders. 
 
Ketamine is an approved drug or biologic being evaluated for a new indication, population, route of 
administration, or dosage level not specified in the FDA approved labeling.  
 
6.1 
Dose Selection 
 
Safety and Efficacy: Preclinical studies, including studies on animals, and clinical studies, including 
studies on non-pregnant women, have been conducted and provide reassuring data on minimal 
potential risks to postpartum women. [45 CFR 46.204 (a)]. The selected reference list below demonstrates 
experience with this drug in dosing regimens matching or exceeding the currently proposed dosing, in 
both pregnant and postpartum people. The data support low risks to this population. In the dosing 
regimen that we describe which is "sub-anesthetic" (i.e., ≤0.2 mg/kg/hr, lower than the anesthetic dosing 
regimens), we expect that the risks are sufficiently low to justify studying it in this fashion.   
  
Selected Relevant References  
• 
Suppa E, Valente A, Catarci S, Zanfini BA, Draisci G. A study of low-dose S-ketamine 
infusion as "preventive" pain treatment for cesarean section with spinal anesthesia: benefits 
and side effects. Minerva Anestesiol. 2012 Jul;78(7):774-81.   
• 
Joel S, Joselyn A, Cherian VT, Nandhakumar A, Raju N, Kaliaperumal I. Low-dose ketamine 
infusion for labor analgesia: A double-blind, randomized, placebo controlled clinical trial. 
Saudi J Anaesth. 2014 Jan;8(1):6-10.  
• 
Sen S, Ozmert G, Aydin ON, Baran N, Caliskan E. The persisting analgesic effect of low-dose 
intravenous ketamine after spinal anaesthesia for caesarean section. Eur J Anaesthesiol. 2005 
Jul;22(7):518-23.  
• 
Menkiti ID, Desalu I, Kushimo OT. Low-dose intravenous ketamine improves postoperative 
analgesia after caesarean delivery with spinal bupivacaine in African parturients. Int J Obstet 
Anesth. 2012 Jul;21(3):217-21.  
• 
Bilgen S, Köner O, Türe H, Menda F, Fiçicioğlu C, Aykaç B. Effect of three different doses of 
ketamine prior to general anaesthesia on postoperative pain following Caesarean delivery: a 
prospective randomized study. Minerva Anestesiol. 2012 Apr;78(4):442-9.   
• 
Heesen M, Böhmer J, Brinck EC, Kontinen VK, Klöhr S, Rossaint R, Straube S. Intravenous 
ketamine during spinal and general anaesthesia for caesarean section: systematic review and 
meta-analysis. Acta Anaesthesiol Scand. 2015 Apr;59(4):414-26.   
• 
Bauchat JR, Higgins N, Wojciechowski KG, McCarthy RJ, Toledo P, Wong CA. Low-dose 
ketamine with multimodal postcesarean delivery analgesia: a randomized controlled trial. Int 
J Obstet Anesth. 2011 Jan;20(1):3-9.  
• 
Reza FM, Zahra F, Esmaeel F, Hossein A. Preemptive analgesic effect of ketamine in patients 
undergoing elective cesarean section. Clin J Pain. 2010 Mar-Apr;26(3):223-6.  
 
 

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6.2 
Study Drug Preparation and Dispensing  
 
The study drug, ketamine, will be sourced by investigational (IDS) Pharmacy at UPMC Magee Women’s 
Hospital. The infusions will be packaged and labeled for use in the clinical research study per pharmacy 
protocols and guidelines. Ketamine will be prepared by pharmacy with dosing instructions. There will 
be no blinding. 
 
For on-site preparation and dispensing of the study drugs, the following procedures will be followed. 
The pharmacist of record will: maintain adequate records confirming receipt, expiration dates, or other 
disposition information on the investigational drug; they will record the name of the individual to 
whom the drug is shipped, date, quantity, and batch number. They will secure the drug in a locked 
storage area and monitor to ensure proper storage conditions; they will also complete regular inventory 
to assure accurate indication of stock on hand, as well as proper recording of stock received, dispensed, 
and returned. For the patients enrolled for open label pharmacokinetic studies, the pharmacist will 
generate a label prior to dispensing the study drug, including the date dispensed, quantity and 
expiration information, drug strength and dose; they will affix the label to the dispensed drug. For 
dispensing and drug disposition recording, they will record the date dispensed, patient initials or other 
identifiers, drug treatments, quantity dispensed, initials of dispenser, date and amount of patient 
returns documented in study records (i.e., returned drug that cannot be re-dispensed). Filing and all 
drug documentation will occur within study records, medical records, and logs. 
 
Following the cesarean delivery, the initial drug administration (via IV infusion) will begin 15 minutes 
(± 30 minutes) after cord clamping and declaration of clinical/ hemodynamic stability by the case 
anesthesiologist after delivery. The maintenance dose will start 60 min (range: +15min) after the initial 
loading dose. The infusion will be completely stopped 12 hours after the start of infusion. The same 
infusion pump will follow the patient throughout the postoperative period for 12 hours until 
completion of the study drug. No manipulation of the infusion pump will occur by the patient. 
Adjustments to the rate will be at the discretion of the study team and can be physically made by study 
personnel qualified and trained in these procedures, or by clinical care providers under direct orders 
from the study team. 
 
6.3 
Dose Delays and Modifications 
 
All subjects will be monitored for adverse events throughout participation in this trial. Events requiring 
a dose delay or adjustment are described below. 
 
Adverse Event, Dose Delays or Adjustments Procedures. 
Contingency for lowest dose not tolerated. Our preliminary data suggests that only 1/8 (12.5%) of 
individuals received an infusion rate lower than 0.05mg/kg/hr due to side effects. However, these data 
are not representative of our study population, so it is conceivable that PK or PD for side effects may 
differ in the immediate postpartum setting, and that the lowest loading dose may not be tolerated. If 
loading dose of 0.05mg/kg/hr is not tolerated, we will follow the dose adjustments in Table 1 and Figure 
3 below. 

12 
v.7.0   05/29/2024 
 
Events that Trigger Dose Adjustment Procedures: 
• 
Persisting unresolved hemodynamic side effects defined as Systolic blood pressure <80 or >160, 
Heart rate <40 or >12033     
o Unresolved after 3 consecutive measurements within a 15-minute interval 
• 
Persisting (i.e., unresolved within 1 hour of onset) side effects sedation, dizziness, 
lightheadedness, persistent itchiness, bad dreams, hallucinations, or other side effects that are 
reported as not acceptable to patients or clinicians, despite minimizing infusion rate. 
• 
Table 1 includes procedures for dose adjustments. 
 
Patient Reported Side Effects Dose Delays or Adjustments  
• 
Side Effect Acceptability ratings are defined in section 3.4.2. Patient reported side effects (i.e., 
dizziness, lightheadedness, bad dreams, nausea, vomiting, itchiness, and hallucinations: all are 
dichotomous outcomes). These side effects will be evaluated based on patient-specific reports of 
how “acceptable” or “unacceptable.” Patients reporting side effects and rating them as 
“unacceptable” will follow the dose delay or adjustment described in the Table 1. If side effects 
are rated “acceptable” then no dose delays or adjustments will occur.  
• 
Figure 3 Decision Chart for Acceptability Based dose revisions. 
 
Table 1. Loading and Maintenance Dose Adjustment Procedures: 
 
Event 
1st Action 
2nd Action 
3rd Action 
If event does 
not resolve 
If event does 
not resolve 
If the event 
resolves 
If event does 
not resolve  
 
If the event 
resolves 
Systolic blood 
pressure <80 or >160, 
Heart rate <40 or >120 
Treat with 
labetalol or 
hydralazine per 
managing 
anesthesiologist 
 
Monitor for 5 
minutes for 
symptom 
resolution 
Hold infusion 
for 5 minutes - 
symptom 
recheck at 5 
minutes 
 
↓ dose by 50% 
(e.g., 
0.05mg/kg/hr 
reduced to 0.025 
mg/kg/hr) and 
continue 
infusion. 
Hold infusion 
for 5 minutes - 
symptom 
recheck at 5 
minutes:  
 
May D/C 
infusion based 
on investigator 
discretion and 
monitor subject 
for safety as 
described in 
Section 7.4 and 
7.5 
↓ dose by 50% 
(e.g., 
0.025mg/kg/hr 
reduced to 0.013 
mg/kg/hr) and 
continue 
infusion. 
Total of 15 
minutes of 
unresolved 
hemodynamic 
effect: 
 
D/C infusion 
and monitor 
subject for 
safety as 
described in 
Section 7.4 and 
7.5 
 
Event qualifies 
as DLT 

13 
v.7.0   05/29/2024 
Event 
1st Action 
2nd Action 
3rd Action 
If event does 
not resolve 
If event does 
not resolve 
If the event 
resolves 
If event does 
not resolve  
 
If the event 
resolves 
If RASS -2 or below, 
OR Respiratory Rate 
is < 8 
Hold infusion 
for 10 minutes - 
symptom 
recheck every 
10 min until 
resolution  
If no resolution 
within 1 hour:  
 
D/C infusion 
based on 
investigator 
discretion and 
monitor subject 
for safety as 
described in 
Section 7.4 and 
7.5 
↓ dose by 50% 
(e.g., 
0.05mg/kg/hr 
reduced to 0.025 
mg/kg/hr) and 
continue 
infusion. 
If no resolution 
within 1 hour:  
 
D/C infusion 
based on 
investigator 
discretion and 
monitor subject 
for safety as 
described in 
Section 7.4 and 
7.5 
↓ dose by 50% 
(e.g., 
0.025mg/kg/hr 
reduced to 0.013 
mg/kg/hr) and 
continue 
infusion. 
D/C infusion 
and monitor 
subject for 
safety as 
described in 
Section 7.4 and 
7.5 
  
Event qualifies 
as DLT 
Dizziness, 
lightheadedness, bad 
dreams, persistent 
itchiness, 
hallucinations, 
nausea, vomiting, or 
other side effects 
rated by patient as 
Not Acceptable 
Hold infusion 
for 10 minutes - 
symptom 
recheck every 
10 min until 
resolution  
 
Supportive care 
medications in 
9.1 
If no resolution 
within 1 hour:  
 
D/C infusion 
based on 
investigator 
discretion and 
monitor subject 
for safety as 
described in 
Section 7.4 and 
7.5 
↓ dose by 50% 
(e.g., 
0.05mg/kg/hr 
reduced to 0.025 
mg/kg/hr) and 
continue 
infusion. 
If no resolution 
within 1 hour:  
 
D/C infusion 
based on 
investigator 
discretion and 
monitor subject 
for safety as 
described in 
Section 7.4 and 
7.5 
↓ dose by 50% 
(e.g., 
0.025mg/kg/hr 
reduced to 0.013 
mg/kg/hr) and 
continue 
infusion. 
D/C infusion 
and monitor 
subject for 
safety as 
described in 
Section 7.4 and 
7.5 
  
Event qualifies 
as DLT 
Nausea or Vomiting 
Rescue 
medications as 
indicated in 6.6 
 
Re-evaluate for 
symptom 
resolution  10 
min after 
rescue 
medication 
 
Hold infusion 
for 10 minutes - 
symptom 
recheck every 
10 min until 
resolution 
If no resolution 
within 1 hour:  
 
D/C infusion 
based on 
investigator 
discretion and 
monitor subject 
for safety as 
described in 
Section 7.4 and 
7.5 
↓ dose by 50% 
(e.g., 
0.05mg/kg/hr 
reduced to 0.025 
mg/kg/hr) and 
continue 
infusion. 
If no resolution 
within 1 hour:  
 
D/C infusion 
based on 
investigator 
discretion and 
monitor subject 
for safety as 
described in 
Section 7.4 and 
7.5 
↓ dose by 50% 
(e.g., 
0.025mg/kg/hr 
reduced to 0.013 
mg/kg/hr) and 
continue 
infusion. 
D/C infusion 
and monitor 
subject for 
safety as 
described in 
Section 7.4 and 
7.5 
  
Event qualifies 
as DLT 
 
 
 
 
 
 
 
 
 

14 
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Figure 3. Dose adjustments based on patient-reported acceptability 
 
6.4 
Study Drug Storage and Accountability 
 
For on-site preparation and dispensing of the study drugs, the following procedures will be followed. 
The investigational drug (IDS) pharmacist of record will: maintain adequate records confirming receipt, 
expiration dates, or other disposition information on the investigational drug; they will record the name 
of the individual to whom the drug is shipped, date, quantity, and batch number. They will secure the 
drug in a locked storage area and monitor to ensure proper storage conditions; they will also complete 
regular inventory to assure accurate indication of stock on hand, as well as proper recording of stock 
received, dispensed, and returned. For the 24 patients enrolled for open label pharmacokinetic studies, 
the pharmacist will generate a label prior to dispensing the study drug, including the date dispensed, 
quantity and expiration information, drug strength and dose; they will affix the label to the dispensed 
drug. Pharmacist will generate a label prior to dispensing the study drug, including the date dispensed, 
quantity and expiration information; they will affix the label to the dispensed drug; they will record but 
not disclose on the label the drug strength and dose. For dispensing and drug disposition recording, 

15 
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they will record the date dispensed, patient initials or other identifiers, drug treatments, quantity 
dispensed, initials of dispenser, date and amount of patient returns documented in study records (i.e., 
returned drug that cannot be re-dispensed). Filing and all drug documentation will occur within study 
records and IDS logs. During the infusion, the ketamine will be stored in a lockbox and all Magee 
standard of care procedures for the safety of controlled substances will be in place for the use of 
ketamine from the start of infusion through the end of the infusion in the postpartum unit. 
 
6.5 
Prohibited Medications 
 
Medications that will not be permitted prior to or during subject participation in the study are as 
follows: 
• 
Oral antihypertensive medications (exclusion: hypertensive disorders of pregnancy) 
• 
Intravenous magnesium (exclusion: pre-eclampsia with severe features) 
• 
Ketamine, phencyclidine, psilocybins, or any other psychedelics (exclusion: ketamine or PCP 
abuse) 
• 
Lithium, valproate, carbamazepine, lamotrigine, haloperidol, chlorpromazine, fluphenazine, 
aripiprazole, clozapine, or other typical or atypical antipsychotic medications (exclusion: 
schizophrenia or psychosis) 
 
6.6 
Rescue Medications 
 
Rescue antiemetics will be provided for patients reporting nausea or vomiting. The following 
medications will be used to treat nausea or vomiting at the time of patient reporting these symptoms: 
• 
Ondansetron 4mg IVP p.r.n. nausea or vomiting   or  
• 
Dexamethasone 4-6mg IVP p.r.n. nausea or vomiting  
• 
After a total of two doses of ondansetron or dexamethasone, additional rescue antiemetics will 
be given at the full discretion of anesthesiologist 
7 
Research Activities 
 
Figure 1 (section 1.1) illustrates all encounters for measurements at the preoperative baseline, during the 
intraoperative period, ketamine infusion period, in the postpartum hospital stay (or until patient 
discharge), and the 1- to 12-week assessments of pain and depression. Study procedures will begin at 
enrollment pre-operatively, continue during the ketamine infusion, and hospital post-operative stay, 
continue weekly in the postpartum period, and end at 12-weeks postpartum.  
 
Information collected at baseline includes maternal demographic information, prenatal pain and 
depressive symptomology, concurrent acute pain, and covariables such as demographic characteristics, 
and perceived stress. EPDS is completed twice, at least 1 week apart, prior to delivery. The baseline 
measures are repeated weekly in the postpartum period until 12-weeks postpartum.   
 

16 
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During the ketamine infusion, blood samples will be taken at 1-, 6-, 10-, & 12-hours post-infusion start, 
as well as at the time of any adverse side effect report to assess ketamine/metabolite levels at the time of 
event.  
 
Baseline (Preoperative) Procedures.  
a. Demographic Data and Medical History. Demographic data will be collected through self-
reported questions through the RedCap interface.  Data from the medical record will be 
extracted and recorded by trained research associates to be entered into the RedCap interface. 
Individual surveys are transposed into RedCap for ease of patient use either on a tablet or paper 
when patients are in person, and via text or email-linked surveys for remote responses. Survey 
measure timepoints are described in the Appendix. 
b. Surveys.   Patient-reported measures will occur by validated instruments delivered by paper, 
tablet (in hospital), or via Mosio text-based interface with data integration via REDCap. Texting 
and email will be used via patient-preferred cellular phone numbers and email addresses for 12-
weekly postpartum assessments. Each weekly assessment will occur within ±3 days of the 
weekly postpartum date.  Each set of patient-reported REDCap surveys, in total, is expected to 
last between 15- and 20-minutes, except for the postoperative timepoints which are expected to 
take less than 15-minutes to complete. Specific surveys and timeline of surveys will be as follows 
and as indicated in Table 1 and Figure 1.  
 
Intraoperative Procedures: Day of Surgery  
 
Standardized Surgical, Anesthesia and Analgesia Protocols  
Surgical personnel role will be recorded (e.g., titles such as private vs faculty obstetricians, 
resident, or physician assistant). Standardized spinal anesthesia and intraoperative medications 
will be as follows. Intraoperative medications include current clinical standards of prophylactic 
phenylephrine infusion to reduce hypotension and related intraoperative nausea/vomiting; 
ondansetron at the time of delivery for postpartum nausea/vomiting prophylaxis; and ketorolac 
15-30 mg at the time of facial closure. Rescue analgesia and antiemetics will follow our existing 
clinical protocols.  
 
Spinal anesthesia medications: bupivacaine 0.75% 1.6mL with fentanyl 10-15mcg and morphine 
100-150mcg.  
 
Co-medications:  
• 
Per clinical routine, prophylactic phenylephrine infusion at 0.5 mcg/kg/min (37.5mL/hr 
at standard concentrations) will be started at the beginning of spinal anesthesia 
induction and discontinued at the time of delivery. 
• 
Supplemental vasopressor boluses are delivered at the full discretion of the managing 
anesthesiology team. 
• 
Ondansetron 4mg IVP for PONV prophylaxis 
• 
Dexamethasone 4mg IVP for PONV prophylaxis unless contraindications 
• 
Acetaminophen 1000mg either orally pre-operatively or IVPB at facial closure 

17 
v.7.0   05/29/2024 
• 
Ketorolac 15-30mg IVP at facial closure 
 
Rescue intraoperative antiemetic: Ondansetron 4mg IVP as a rescue dose as needed x1 dose; 
dexamethasone 4-6mg IVP as needed x1 dose; after this, additional rescue antiemetic can be 
given at the full discretion of the managing anesthesia team. 
 
Postpartum Analgesia Protocol 
Postpartum analgesia protocols will be aligned with routine clinical practice at UPMC Magee-
Womens Hospital. Specifically, ketorolac 30 mg IV q6h x24 hours (total of 4 doses) will be 
administered. After all doses of ketorolac have been given, ibuprofen 600mg q6h x24 hours will 
be delivered, not to be given within 6 hours of ketorolac. Acetaminophen 500-650mg q4h no 
more than 4000mg q24hr will be given with the first dose given on postoperative day 0. For 
severe breakthrough pain rated 7-10 on VAS, the Investigator will be called to assess the need 
to order oxycodone 5-10mg if necessary, as needed for severe breakthrough pain. The 
Investigator may also assess the need for parenteral rescue agents, namely hydromorphone. 
 
Discharge Analgesia Regimen 
Consistent with current routine clinical practice at UPMC Magee, subjects will be discharged 
with a prescription for oxycodone 5-10mg q6h #12-20 p.r.n. severe pain. Adjustments to this 
regimen will be made on an individual basis based on prescriber and institutional practice 
changes that may arise. 
 
Surgical case reports.  
Surgical elements will be collected from surgeons as well as data abstraction from the medical 
record (Table 3). Surgeons will complete the Surgeon Operative Survey (Table 2) described 
below: 
 
Table 2. Surgical Operative Survey 
Surgeon/Obstetrician Operative Survey 
1. 
Reason for Cesarean Delivery 
2. 
Type of Skin Incision 
3. 
Type of Uterine Incision 
4. 
Dissection type and inclusion of rectus 
5. 
Uterine exteriorization 
6. 
Bladder Flap 
7. 
Any unanticipated surgical challenges? 
8. 
Please rate difficulty of delivery  
(0-10 numeric rating scale, 0 is no difficulty, 10 is the most difficult imaginable) 
9. 
Please rate difficulty of overall surgery  
(0-10 numeric rating scale, 0 is no difficulty, 10 is the most difficult imaginable) 
10. Please rate degree of adhesive disease  
(0-10 numeric rating scale, 0 is no adhesive disease, 10 is the most adhesive disease imaginable) 
11. Please rate degree of difficulty of fetal extraction.  
(0-10 numeric rating scale, 0 is no adhesive disease, 10 is the most adhesive disease imaginable) 
12. Were there any unanticipated surgical challenges encountered? (yes/no) 
13. Did you make any intraoperative consultations to other surgeons? (yes/no) 
14. What materials were used for Facial and Skin closure. 

18 
v.7.0   05/29/2024 
 
Table 3. Surgical data abstraction from the medical record  
Element  
Where to find in EHR  
Duration of surgery (min)  
Cerner Surginet Operative Report  
Surgical assist role (resident, physician assistant)  Cerner Surginet Operative Report  
Surgical attending role (private vs faculty)  
Cerner Surginet Operative Report  
Infant weight (grams)  
Cerner Surginet Operative Report  
Apgar score 1 minute (integer 0-9)  
Cerner Surginet Operative Report  
Apgar score 5 minutes (integer 0-9)  
Cerner Surginet Operative Report  
Estimated blood loss (mL) 
Cerner Surginet Operative Report 
Cerner SA Anesthesia Record 
Total intravenous fluids administered (mL) 
Cerner SA Anesthesia Record 
Total urine output (mL) 
Cerner SA Anesthesia Record 
MME Opioid use in postpartum days 1-3 
Cerner SA Anesthesia Record 
  
Ketamine Infusion, Side Effect Measures, and Plasma Sampling Procedures. 
Preoperative weight and vital signs will be measured, and baseline inventories completed 
(Figure 1). After delivery, cord clamping and declaration of clinical stability by the 
anesthesiologist (approximately 5-15 minutes after delivery, ± 30 minutes), a loading infusion of 
ketamine 0.05 mg/kg/hr will begin for the first 3-patients in the study. Vital signs and Richmond 
Agitation Sedation Scale (RASS), and self-reports of side effects will be measured 15, 30, and 60 
minutes (±10 minutes) after infusion start, and at 4- 8- 10- 12- 16- 24- hours (±30 minutes) after 
infusion start. Plasma samples will be collected at 1- 6-, 10- and 12- hours (±30 minutes) after 
infusion start via an indwelling IV catheter to facilitate ease of access. Plasma samples at 1- 6-, 10- 
and 12- hours after infusion start will be used to calculate Cmax, AUC, and Css and to correlate 
DLTs with these PK parameters. Any report of adverse events or side effects will trigger a blood 
draw for analysis and correlation of these symptoms to plasma levels of ketamine. All 
assessments have been timed to coincide with timing intervals of typical post-CD clinical care 
interventions. Patient dosing after the first three patients will proceed based on the MTD protocol 
in Section 1.1. 
 
MTD Dose Adjustment Procedures.  
Figure 2 (section 1.1) outlines the dosing approach. Dose adjustment procedures are outlined in 
section 6.3. 
 
 
Side Effect Acceptability Ratings.  
Our existing and previously tested digital diary will automate alerts for questions about side 
effects after infusion start at 15-, 30-, 60- minutes, and every 4 hours in the first 24 hours after 
infusion start (Figure 1, section 1.1). The diary has been tested and used by our group in 
previous work; alerts coincide with RASS assessments and similar timing of clinical 
assessments for routine CD nursing care and monitoring (i.e., is not more burdensome or 
intrusive to patients than routine clinical post-CD care). The digital diary will assess side effects 

19 
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(i.e., dizziness, lightheadedness, bad dreams, nausea, vomiting, itchiness, and hallucinations: 
all dichotomous outcomes). Any positive response to any item will trigger the subject to rate 
their acceptability of side effects in the following way. Patient-reported acceptability is defined 
based on theoretical framework of acceptability103 and focused on constructs of Burden (“Would 
experiencing side effects keep you from participating in this intervention (ketamine) again?” 
yes/no) and Affective Attitude (“Based on your experience with this medication, would you be 
willing to participate in this intervention (ketamine) again?” yes/no). Either a negative response 
to Attitude, or a positive response to Burden, will define patient unacceptability. 
 
Side Effects.  
Monitoring during the infusion will follow our clinical standards of perioperative ketamine 
monitoring. A maternal side effect digital diary will also be used. The digital diary has been 
previously developed and tested in our preliminary lactation volunteer study. The diary alerts 
questions to patients include the Richmond agitation-sedation scale (RASS)104, dysphoria (LSD 
short form105), and side effects. Automated alerts for abnormal responses go to clinical and 
research staff for immediate action. Any report of side effects will trigger a blood draw for 
analysis and correlation to measured plasma levels.  
 
Postpartum 12-week Follow-up Procedures. 
Figure 1 (section 1.1) outlines weekly follow-up procedures. Participants will receive weekly 
surveys containing the questionnaires that are specified in Appendix 1. Surveys focus on pain 
and depression symptoms throughout the postpartum period. 
 
7.1 
Screening Procedures 
Per our existing research procedures, patients will be screened from the Magee-Womens Hospital OB 
surgery schedule by dedicated trained research associates. Screening will be completed using the “Core 
Surgical PowerChart” and “Epic” Electronic Health Record (EHR) systems. All procedures will follow 
existing processes with clinicians for patient enrollment in research. Patients scheduled for CD are 
contacted prior to surgery by phone or in person to assess eligibility, explain the study protocol, and 
provide consent. Patients who are eligible within the prenatal  clinics will be contacted prior to surgery 
in person, via a MyUPMC message or using videoconferencing to explain the study and obtain consent.  
 
7.2 
Study Entry Procedures 
Participants will be screened for eligibility prior to consent. Inclusion criteria and exclusion criteria are 
described in Sections 5.2 and 5.3.  
 
7.3 
Study Drug Administration 
 
Following the cesarean delivery, the initial drug administration will be made after cord clamping and 
once anesthesiologist has declared hemodynamic stability (i.e., infusion starts approximately 5-15 
minutes after delivery, ± 30 minutes). The infusion will be completely stopped at 12 hours after the start 
of infusion. The same infusion pump will follow the patient throughout the postoperative period for 12 
hours until completion of the study drug. No manipulation of the infusion pump will occur by the 

20 
v.7.0   05/29/2024 
patient. Adjustments to the rate will be at the discretion of the study team and can be physically made 
by study personnel qualified and trained in these procedures, or by clinical care providers under direct 
orders from the study team. 
 
7.4 
Safety Assessments/Procedures During Treatment 
Maternal monitoring during the infusion will follow our clinical standards perioperative ketamine 
monitoring and the standard Magee system safety precautions for administration of a controlled 
substance will be in place to protect from any misuse. A licensed and qualified anesthesia provider 
(resident, fellow, nurse anesthetists, or anesthesiologist) will be present during the first 30 minutes of 
the infusion and will have the option to treat blood pressures >180/100 mm Hg or heart rate >110 bpm. 
The study infusion will be discontinued if 3 consecutive measurements within a 15-minute interval 
remain above protocol-defined limits despite intervention (section 6.3). Maternal side effect 
symptomology monitoring will occur throughout the ketamine infusion. Automated alerts for 
maternal side effect responses go to clinical and research staff for immediate action. Any report of side 
effects will trigger a blood draw for analysis and correlation to measured plasma levels.  
 
An independent DSMB will define frequency of monitoring of tolerability and DLT data. The severity 
of adverse events are classified in section 10.1  
 
7.5 
Safety Assessments/Procedures After Ketamine Infusion Stop 
Maternal side effect monitoring following the infusion will continue at 4-hour intervals for 12-
hours after the cessation of ketamine infusion. Monitoring will occur via clinical staff monitoring 
and via patient self-report indices of side effect symptomology (Figure 1; section 1.1).  
After the study drug infusion is complete, safety and efficacy assessments consist of the following. 
Digital diaries will assess self-reported side effects according to the study schematic Figure 1; 1.1, until 
12 hours after infusion discontinuation. Vital signs will be monitored during that same period.  
 
 
7.6 
Safety Assessments/Procedures During Postpartum Surveys 
Efficacy assessments, exploratory in nature, will consist of pain and depression symptom screening at 
regular intervals from one week postpartum until 12 weeks after delivery, according to the time 
intervals indicated in the study schematic Figure 1; 1.1. Positive screens for depression will be initiate 
an immediate response to the study team. The protocol for positive depression screens is presented in 
Appendix 4. All patients who screen positive for depression (EPDS total score > 14 or positive answer 
to question #10) will be contacted and receive consultation instructions.  
 
After all study procedures are complete 12 weeks after delivery, there will be no further active 
assessments of safety and efficacy by study staff. Participants will continue to have access to their 
primary care physicians and emergency services.  
 
8 
Potential Risks and Benefits 
 

21 
v.7.0   05/29/2024 
8.1 
Reasonably Foreseeable Risks Related to Study Drug 
 
Common side effects of ketamine are sedation, dizziness, lightheadedness, bad dreams, hallucinations, 
euphoria, dysphoria, nausea, vomiting. These risks are minimized by using doses below the doses that 
we typically see these side effects. Seriousness: mild to moderate. 
 
Uncommon effects of ketamine include hypertension or hypotension, tachycardia, or bradycardia. These 
risks are minimized as much as possible by using doses below the doses that we typically see these 
effects. If these effects are noted, the drug will be stopped until the effects dissipate. Should the effects 
not dissipate, the PI will evaluate and determine whether the patient requires additional care. If these 
uncommon effects are experienced, an SAE log will be completed and the IDSMB and IRB notified. 
Seriousness: mild to moderate  
 
8.2 
Reasonably Foreseeable Risks Related to Research Interventions 
 
Risks to confidentiality. There is a risk of breach of confidentiality with the screening procedures and the 
collection and storage of personal health information. To protect against this risk, all screening 
procedures will be done by study staff who have been completely trained in HIPAA/privacy 
procedures; all data collected will be identifiable only by a unique subject ID number, and no personal 
identifiers will be stored with the data. Linkage files identifying subjects will be stored only in physical 
records that are kept in locked files accessible only by study staff; electronic data will be handled and 
protected whereby any linkages between study ID number and patient identification will be separated, 
password protected, and stored behind the UPMC firewall. There are some cases in which a researcher 
is obligated or authorized by law to report mental health symptoms, such as serious threats to public 
health and safety. For example, if patients indicate that they are in imminent risk of harm (e.g., suicide 
or serious threats toward the wellbeing of others), the researchers will contact the appropriate 
authorities to protect patients or the public. Seriousness: mild 
 
Risks of inconvenience from surveys. To minimize the inconvenience/time burden on participants 
associated with the survey questions, we will use an electronic (email) interface preferentially and will 
minimize the number of questions to strictly only the number necessary to address important aspects of 
our study questions. Seriousness: mild 
 
Risk of survey discomfort. An uncommon risk includes inconvenience and potential emotional discomfort 
are risks associated with answering survey questions. Subjects will be asked to answer questions 
regarding pain and depression before, during, and after having their babies. Answering these questions 
may be viewed as an inconvenience. Seriousness: mild  
 
Risks of IV blood collection. Common risks associated with blood collection include bruising or swelling at 
the collection sight, discomfort during venous blood draw, and infection. Seriousness: mild 
 
Risk of sub-anesthetic ketamine infusion dose titration. Common risks include nausea, euphoria, dizziness, 
or lightheadedness. Seriousness: mild. Uncommon risks include temporary hypertensive event. 

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Seriousness: mild to moderate; uncommon risks include hallucinations or dysphoria. Seriousness: mild 
to moderate. 
 
8.3 
Potential Benefits  
 
The potential direct benefits to subject participation in this study is enhanced pain control, opioid 
reduction, closer follow-up for depression symptoms, and reduced depression risk. There are societal 
benefits in that there will be increased knowledge about the use of ketamine after birth to reduce 
depression, alleviate pain and decrease opioid use. Ultimately, the results of this study, if significant, 
will enable health care providers to improve the health of mothers.  
9 
Protection Against Risks 
 
9.1 
Management of drug related toxicity 
 
The PI is a practicing, board-certified clinical anesthesiologist with extensive experience in the 
administration of this study drug under normal clinical circumstances. The study drug will be started 
during routine anesthesia care where monitoring is the strictest and closest, thereby enabling early 
detection of any safety events. The patients will remain monitored in an appropriate care environment 
throughout the duration of the 12-hour drug infusion, enabling timely detection and treatment of any 
serious events should they occur. Staff will also be trained to be familiar with common and uncommon 
side/adverse events for reporting.  
 
Supportive care drugs that may be used in the event of drug related toxicity: 
• 
Event: Persisting unresolved hemodynamic side effects defined as Systolic blood pressure <80 
or >160, heart rate <40 or >120, unresolved after 3 consecutive measurements within a 15-
minute interval 
o Supportive care medications: 
o Labetalol 10-20mg IVP or Hydralazine 10-25mg IVP p.r.n. hypertension at discretion of 
managing anesthesiologist. 
• 
Event: Persisting side effects sedation, dizziness, lightheadedness, bad dreams, hallucinations, 
or other side effects that are reported as not acceptable to patient or clinicians, despite 
minimizing infusion rate 
o Supportive care medications: 
o Midazolam 1-4mg IVP p.r.n. dysphoria, at discretion of managing anesthesiologist. 
 
Refer to Section 6.8 for Rescue Drugs. 
 
Refer to Section 6.3 of the protocol for instructions on dose delays and modifications.   
 
9.2 
Management of research related risks 
 

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All research interventions/activities will be conducted in private patient care areas. The collection of 
sensitive information about subjects is limited to the amount necessary to achieve the aims of the 
research, so that no unneeded sensitive information is collected.  
  
All demographic and clinical information about the subject will be stored in an electronic password-
guarded study database under the supervision of the Investigator for this protocol. The electronic 
system REDCap has features that can enable its use as certifiably compliant with the DFTA regulations 
at 21 CFR part 11 but due to the limited scope of this clinical research study, the electronic data 
recording system has not been certified as fully compliant. The data will be stripped of individual 
identifiers at the time of analysis and stored anonymously with a subject number. Information linking 
subject identifiers with the coded subject number will be stored under password proection on 
computers in locked areas, with access to the database manager. Access to the database will be limited 
to the data manager and staff under the supervision of the Investigator.  
  
All staff involved in this study are properly credentialed and instructed in the areas of testing, 
confidentiality, and safety. All study team members will be properly trained on protocol requirements, 
trained in HIPAA/privacy procedures, and GCPs. Research procedures performed for study purposes 
will be performed by qualified individuals as evidenced by education, experience, and/or training.  All 
members of the study team will have the required human subjects and confidentiality training, which 
includes information about maintaining data integrity and security. Confidentiality will be guarded 
using established procedures such as storing data in locked cabinets within locked offices or locked data 
rooms, coding CRFs and research specimens by study identification numbers rather than any personal 
identifying information to avoid revealing the identity of subjects, and aggregating data across 
participants. The key linking names and study identification numbers will be kept separately from the 
data sets with limited access by study personnel. Only study personnel will have access to the data sets 
on protected servers. 
 
The Investigator will retain the data for the entire period of this study and will retain the specified 
records and reports for up to seven years after the study’s publication. The Investigator may continue to 
use and disclose subjects’ de-identified information for the purpose of this study for a minimum of 
seven years after final reporting or publication of the study. If the subject and/or legal representative 
decide to withdraw or be withdrawn from study participation, they may request in writing that the 
study data and samples be destroyed. Subject names or other directly identifiable information will not 
appear on any reports, publications, or other disclosures of clinical study outcomes.  
  
Clinical data recorded on the electronic database will include intraoperative obstetrician case report 
forms completed by the obstetrician at the end of surgery, and hospital postpartum morphine 
equivalent dosing.  
 
10 Adverse Events and Serious Adverse Events 
 

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The proposed clinical trial will use the FDA definition of an adverse event (AE). Adverse event means 
any untoward medical occurrence associated with the use of a drug in humans, whether considered 
drug related.   
 
The proposed clinical trial will use the FDA definition of SAE.  A serious adverse event is any untoward 
clinical event that is thought by either the investigator or the sponsor to be unexpected and at least possibly 
related to the study and results in any of the following: 
 
1. Death 
2. A life-threatening adverse event 
3. Inpatient hospitalization or prolongation of an existing hospitalization 
4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
5. A congenital anomaly or birth defect 
6. Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient, or subject, and may require medical, or surgical intervention to 
prevent one of the serious outcomes listed above. 
 
Adverse events will be assessed on each participant at stated intervals in Figure 2 section 1.1, both 
during infusion, and for 12 hours after infusion discontinuation. Duration of monitoring is based on 
known pharmacokinetics of ketamine. 
 
When an adverse event is discovered, the event will be assessed for severity, relatedness, and 
expectedness.  All adverse events will be documented in the research records and followed until 
resolved or back to baseline grade. 
 
10.1 Severity 
 
The severity of adverse changes in physical signs or symptoms will be classified as follows: 
 
• 
Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observation only; 
intervention not indicated. 
o e.g., sedation, dizziness, lightheadedness, bad dreams, hallucinations, euphoria, 
dysphoria, nausea, vomiting 
• 
Grade 2 (Moderate): minimal, local, or noninvasive intervention indicated; limiting age-
appropriate ADL. 
o e.g., dysphoria, vomiting 
• 
Grade 3 (Severe): medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care/ADL. 
o e.g., hypertensive urgency or emergency requiring escalated or inpatient treatment 
• 
Grade 4 (Life-threatening): consequences; urgent intervention indicated. 
o e.g., stroke from uncorrected severe hypertension 

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• 
Grade 5 (Death): event is a direct cause of death.  
 
An independent DSMB will define frequency of monitoring of the tolerability and DLT data. 
 
10.2 Relatedness 
Adverse Events and Serious Adverse Events will be subject to the following criteria to determine the 
relatedness of the experienced event to the research study, protocol, and/or drug.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event occurs in a plausible time relationship to 
study intervention administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the drug is clinically plausible. The event must be 
pharmacologically or phenomenologically definitive. 
 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event occurs within a reasonable time after administration of the 
study intervention, is unlikely to be attributed to concurrent disease or other drugs or chemicals 
and follows a clinically reasonable response on withdrawal of the study drug.  
 
• 
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the study medication). However, other factors may 
have contributed to the event (e.g., the participant’s clinical condition, other concomitant events). 
Although an AE may rate only as “possibly related” soon after discovery, it can be flagged as 
requiring more information and later be upgraded to “probably related” or “definitely related”, as 
appropriate. 
 
• 
Unlikely to be related – A clinical event whose temporal relationship to study intervention 
administration makes a causal relationship improbable (e.g., the event did not occur within a 
reasonable time after administration of the study intervention) and in which other drugs or 
chemicals or underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is related to another etiology. There will be an alternative, definitive 
etiology documented by the clinician. 
 
10.3 Expectedness 
 
The Principal Investigator will be responsible for determining whether an AE is expected or unexpected.  
An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the information previously described (sections 8.2 and 9.1). Note that the risks listed in Section 8.1 
are considered expected and would not require reporting unless the frequency or severity is greater than 
expected.  Events not listed in Section 8.1 but that are listed in the FDA-approved package insert, should 

26 
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also be considered expected.  In such cases, depending on the nature and severity of the event, an 
amendment may be necessary to add the risk to Section 8.1 and the consent form document. 
 
10.4 Reporting Serious Adverse Events 
 
If there is a suggestion that any research procedures have resulted in an injury to subjects, there will be 
immediate contact with the Principal Investigator who is listed on the first page of the informed consent 
documents. Any SAE, which is determined by the PI to be unexpected and at least possibly related to 
study intervention, will be reported to the IRB as soon as possible.  The PI is responsible for notifying 
the FDA within required timeframes.  The IDSMB will be notified in writing at the soonest possible 
timepoint that the event has been identified. The IRB and FDA and will include all known details 
regarding the nature of the SAE.  Outcomes of SAEs not previously reported will be reported to the PI, 
IRB and FDA via a follow-up report.   
 
Life-threatening or fatal unexpected adverse events associated with the use of the study drug or 
procedures must be reported to the IRB within 24 hours of discovery of the incident with subsequent 
follow-up submission of a detailed written report. The IDSMB and IRB will be notified by telephone or 
facsimile transmission of a human adverse event that is fatal or life-threatening no later than 7 calendar 
days after receiving the respective human adverse event information, followed by the subsequent 
submission of a written IND Safety Report. Serious and unexpected adverse events associated with the 
use of the study drug or procedures will be reported to the IRB with subsequent follow-up submission 
of a detailed written report in accordance with the respective policies and procedures of the IRB. A 
summary report of the findings will be prepared and submitted to the regulatory agencies. A written 
IND Safety Report (i.e., Form FDA 3500A) will be submitted to the FDA as soon as possible and, in no 
event, later than 15 calendar days following the investigator-sponsor’s receipt of the respective adverse 
event information. 
 
A summary of the SAEs that occurred during the previous year will be included in the FDA annual 
progress report as well as in the annual IRB continuing review. 
11 Withdrawal of Subjects and Stopping Rules 
 
This section outlines the criteria that specify when dosing an individual subject, cohort, or trial will be 
suspended.  
 
11.1 Adverse Events Requiring Discontinuation 
 
For this study, a serious adverse event is any untoward clinical event that is thought by either the 
investigator or the sponsor to be related to the study and results in any of the following outcomes:  
 
1. Death  
2. A life-threatening adverse event   
3. Inpatient hospitalization or prolongation of an existing hospitalization    

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4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions.  
5. A congenital anomaly or birth defect  
6. Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient, or subject, and may require medical, or surgical intervention 
to prevent one of the serious outcomes listed above.  
 
If clinically important and unexpected adverse experiences or clinically important study-related adverse 
experiences occur, they will be recorded on the adverse event case report form.     
  
Adverse Events Reporting Timeline is documented in 10.4. 
  
Withdrawal of Subjects due to Adverse Events 
Participants will be withdrawn if they experience a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or other important medical events 
that may not result in death, be life threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the patient, or subject, and may 
require medical, or surgical intervention to prevent one of the serious outcomes listed above. 
 
DSMB will review all events pertaining to participant withdrawals. An independent decision will be 
made regarding trial discontinuation based on risk assessment for current and future trial participants. 
 
Withdrawn participants will be replaced at a proportion of 1:1. Procedures are as follows:  
• 
Study personnel, investigators, and pharmacy will be informed of the need for replacement due 
to participant withdrawal.  
• 
Subsequent data to be collected from the withdrawn participant will be restricted to the 
minimum amount necessary to continue to monitor safety, i.e., side effect diary including 
questions of sedation, LSD short form, dizziness, lightheadedness, bad dreams, nausea, 
vomiting, pruritus, hallucinations.  
  
11.2 Other Criteria Requiring Discontinuation 
 
Withdrawal of Subjects for reasons other than Non-compliance or Adverse Events:  
• 
Protocol non-adherence: incorrect dosing strategy or other non-adherence points at the 
judgement of the PI  
• 
Incomplete side effect diary data, defined as missing 20% or more responses 
  
Withdrawn participants will be replaced at a proportion of 1:1. Procedures are as follows:  
• 
Study personnel, investigators, DSMB will be informed of the need for replacement due to 
participant withdrawal.  

28 
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• 
Subsequent data to be collected from the withdrawn participant will be restricted to the 
minimum amount necessary to continue to monitor safety, i.e., side effect diary including 
questions of sedation, LSD short form, dizziness, lightheadedness, bad dreams, nausea, 
vomiting, pruritus, hallucinations.  
 
11.3 Clinical Trial Stopping Rules 
 
This study may be suspended, or prematurely terminated if there is sufficient reasonable cause. DSMB 
will review all events pertaining to participant withdrawals. An independent decision will be made 
regarding trial discontinuation based on risk assessment for current and future trial participants. 
 
Written notification, documenting the reason for study suspension or termination, will be provided by 
the suspending, or terminating party to study participants, investigators, funding agency, the IND 
sponsor, and regulatory authorities.  If the study is prematurely terminated or suspended, the PI will 
promptly inform study participants, the IRB, and sponsor and will provide the reason(s) for the 
termination or suspension.  Study participants will be contacted, as applicable, and be informed of 
changes to the study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or FDA. 
 
12 Statistical Analysis 
By virtue of its design, the maximum tolerated dose (MTD) 3+3 design encompasses a minimum 
number of 6 and maximum number of 12 patients enrolled in this trial. The results identify the drug 
dose at which ≥33% of patients experience dose limiting toxicity, which we have defined by 
unacceptable side effects or adverse events. The number of subjects at each dose is dictated by 
traditional MTD 3+3 design, balancing the risks associated with the study drug and the assessment of 
adverse event rates. A formal power calculation was not performed.  
 
12.1 General Approach 
The outcome of this design is the determination of the Maximum Tolerable Dose of ketamine infusion 
post-cesarean delivery. As such, the final dosing of the MTD design is the primary outcome determined 
as patient report of tolerated dose and acceptable side effect experiences in greater than 66% of patients. 
  

29 
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12.2 Sample Size Determination 
The number of subjects (minimum of 6; maximum of 12) at each dose is dictated by traditional MTD 3+3 
design, balancing the risks associated with the study drug and the assessment of adverse event rates. A 
formal power calculation was not performed. 
 
12.3 Analysis of Primary Endpoint 
 
Maximum Tolerated (Ketamine) Dose (MTD): The MTD will be defined as the dose at which fewer 
than 33% of patients experience intolerable effects.  
Tolerability (dichotomous Yes/No) 
• 
Tolerability (YES) will be defined as: lack of serious adverse events (serious adverse event 
defined as: severe unresolved hemodynamic effect: systolic blood pressure <80 or >160, heart 
rate <40 or >120).33 
• 
Lack of Tolerability will be defined as presence of any serious adverse event (i.e., severe 
unresolved hemodynamic effect: systolic blood pressure <80 or >160, heart rate <40 or >120).33 
 
For this MTD study, rates of the primary endpoint will be reported as numbers and percentages. Rates 
of blood pressure and heart rate events will be reported as numbers and percentages.  
 
12.4 Analysis of Secondary Endpoints 
 
Side effect acceptability ratings will be reported for each side effect reported as numbers and 
percentages. Examination of patient pain and depression scores in the 12-weeks post cesarean delivery 
will be explored. The limited sample size of the MTD design precludes definitive conclusions regarding 
pain and depression. General linear mixed models will be used to assess trends in pain and depression 
over the peripartum period according to dose exposure. Paired t-tests may be used to assess changes in 
pain or depression scores from the preterm to postpartum 12-week assessments. 
13 Data and Safety Monitoring 
 
Monitoring of safety and data quality in the proposed study will be the responsibility of all personnel on 
the project, with primary responsibility and supervision by the Investigator. An Independent Data and 
Safety Monitoring Board (IDSMB) will be convened prior to initiation of the studies and administrated 
by the University of Pittsburgh CTSI. The study will be reviewed a minimum of quarterly in the first 
year and twice yearly on an annual basis (or more frequently as deemed necessary) by the IDSMB. The 
IDSMB will determine the actual frequency of meetings and monitoring, including convening of 
emergency meetings when necessary.  
  
The Institutional Review Board (IRB) will approve the Statement of Informed Consent for the study and 
provide institutional oversight of data and safety issues. The study protocol will be approved by the IRB 
prior to recruiting or obtaining consent from any participants.   
  

30 
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Each participant will sign the Informed Consent Form described above prior to participating in the 
study. To ensure participant safety, once participants are enrolled in the study, study staff will 
immediately report any adverse and serious adverse events to one of the Investigators. The Investigator 
will, per standardized procedures, report them to the IDSMB and IRB for review.   
   
13.1 Data Safety Monitoring Plan 
 
Monitoring of safety and data quality in the proposed study will be the responsibility of all personnel on 
the project, with primary responsibility and supervision by the Investigator. There will be an evaluation 
of the progress of the research study, including assessments of data quality, timelines, participant 
recruitment, accrual, and retention. The Investigator will also review the outcome and adverse event 
data to determine whether there is any change to the anticipated benefit-to-risk ratio of study 
participation and whether the study should continue as originally designed or should it be re-evaluated 
and changed.  A summary report of the data and safety monitoring meetings will be provided to the IRB 
at the time of the continuing review. 
 
Regarding monitoring of data quality and protected health information, all required personnel 
proposed for this project will have the required human subjects and confidentiality training, which 
includes information about maintaining data integrity and security. Confidentiality will be guarded 
using established procedures such as storing data in locked cabinets within locked offices or locked data 
rooms, electronic data stored behind UPMC/university firewalls and/or use of REDCap with attendant 
compliance with data safety standards, coding by study identification numbers rather than any 
personally identifying information to avoid revealing the identity of subjects, and aggregating data 
across participants. The key linking names and study identification numbers will be kept separately 
from the data sets with limited access by study personnel. Only study personnel will have access to the 
data sets on protected servers. Oversight of all aspects of data management will occur with the 
Investigator.  
 
13.2 Parameters to be Monitored 
 
The following progress will be monitored throughout the course of the research to ensure the safety of 
subjects as well as the integrity and confidentiality of their data.  
• 
An evaluation of the progress of the research study, including subject recruitment and retention, 
and an assessment of the timeliness and quality of the data.  
• 
A review of collected data (including adverse events, unanticipated problems, and subject 
withdrawals) to determine whether there is a change to the anticipated benefit-to-risk 
assessment of study participation and whether the study should continue as originally designed, 
should be changed, or should be terminated (see section 10.1).  
• 
An assessment of external factors or relevant information (e.g., pertinent scientific literature 
reports or therapeutic development, results of related studies) that may have an impact on the 
safety and study participants or the ethics of the research study.  
• 
A review of study procedures designed to protect the privacy of the research subjects and the 
confidentiality of their research data.  

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The severity of adverse changes in physical signs or symptoms were summarized in section 10.1.  
  
13.3 Frequency of Monitoring 
 
The Investigator will review subject safety data as it is generated. The Investigator and the research staff 
will meet on a weekly interval – and more frequently as necessary – to review data coding and capture, 
documentation and identification of adverse events, complaints or other issues, and subject 
confidentiality issues. There will be an evaluation of the progress of the research study, including 
assessments of data quality, timelines, participant recruitment, accrual, and retention. The PI will also 
review the outcomes and adverse event data to report to IDSMB who will subsequently decide whether 
there is any change to the anticipated benefit-to-risk ratio of study participation and whether the study 
should continue as originally designed or should it be re-evaluated and changed.  
 
An Independent Data and Safety Monitoring Board (IDSMB) will be convened prior to initiation of the 
studies and administrated by the University of Pittsburgh CTSI. The study will be reviewed a minimum 
of quarterly in the first year and twice yearly on an annual basis (or more frequently as deemed 
necessary) by the IDSMB. The IDSMB will determine the actual frequency of monitoring meetings, 
including convening of emergency meetings when necessary.  
  
13.4 Clinical Monitoring 
 
In accordance with 21 CFR 312.50 clinical site monitoring will be conducted to ensure that the rights and 
well-being of trial participants are protected, that the reported trial data are accurate, complete, and that 
the conduct of the trial is in compliance with current, approved protocol/amendment(s). 
 
13.5 Data and Safety Monitoring Board 
 
An Independent Data and Safety Monitoring Board (IDSMB) will be convened prior to initiation of the 
studies and administrated by the University of Pittsburgh CTSI. The IDSMB will include individuals in 
the specialties of Anesthesiology, Psychiatry, Neonatology, and Perinatology as such to create a 
comprehensive review of the study protocol and participants. The study will be reviewed a minimum of 
quarterly in the first year and twice yearly on an annual basis (or more frequently as deemed necessary) 
by the IDSMB. The IDSMB will determine the actual frequency of meetings and monitoring, including 
convening of emergency meetings when necessary.  
 
  
 
 

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14 Regulatory, Ethical, and Study Oversight  
 
14.1 IRB Approval  
 
The PI will obtain, from the University of Pittsburgh IRB, prospective approval of the clinical protocol 
and corresponding informed consent form(s); modifications to the clinical protocol and corresponding 
informed consent forms, and advertisements (i.e., directed at potential research subjects) for study 
recruitment.    
 
The only circumstance in which a deviation from the current IRB-approved clinical protocol/consent 
form(s) may be initiated in the absence of prospective IRB approval is to eliminate an apparent 
immediate hazard to the research subject(s).  In such circumstances, the Investigator will promptly 
notify the University of Pittsburgh IRB of the deviation.  
 
The IRB will review and approve the Informed Consent Document for the study and provide 
institutional oversight of data and safety issues. The study protocol will be approved prior to recruiting 
or obtaining consent from any participants. Moreover, the study will be reviewed at a minimum of 
annual basis (or more frequently as deemed necessary) by the IRB committee.   Each participant will 
sign the approved Informed Consent Form prior to participating in the study.  
 
The University of Pittsburgh IRB operates in compliance with FDA regulations at 21 CFR Parts 50 and 
21 CFR 56, and in conformance with applicable ICH Guidelines on GCP.  
 
14.2 Informed Consent Procedures 
 
Details of Participant Recruitment:  
Subjects approached for enrollment in this study are patients being seen during normal clinical care or 
by study personnel as part of recruitment procedures as follows. Screening will occur by prenatal clinic, 
or obstetric operating room schedule, or in the labor and delivery suite. After review, potential patients 
scheduled for elective cesarean delivery will be approached after clinical staff confirm it is appropriate 
to do so. For scheduled elective cesarean deliveries, participants will be contacted by phone or in person 
from obstetric clinic, within 0-21 days prior to the scheduled delivery, to disclose eligibility in the study 
and to assess their desire to speak to the study team to learn more about the study. The anesthesia team 
will see all patients presenting for cesarean delivery. During this visit, the anesthesia team typically 
reviews the patient’s medical history, explains the anesthetic plan, and obtains consent for anesthesia. In 
this study, for eligible participants, investigators will also use this visit to explain the availability of the 
study to the patient meeting eligibility criteria, when the anesthesiology consult occurs. Should the 
patient wish to hear more, researchers will discuss risks, benefits, and alternatives to study 
participation. Questions will be answered, and time will be afforded to patients per the Informed 
consent Procedures outlined below, minimizing risks of coercion or undue influence.  
 
Recruitment will also occur using Pitt+Me (https://pittplusme.org/) and study fliers within the OBGYN 
clinics at Magee Womens Hospital. Interested individuals will contact the study team directly. Screening 

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will take place over the phone, and eligible and interested individuals will be approached prior to their 
standard cesarean delivery care to go through the informed consent process.  
 
Informed Consent Procedures.  
The consent process will take place virtually or in person in prenatal clinics or in the preoperative 
holding area on day of surgery, in accordance with our prior study procedures. The informed consent 
process will begin when the patient has indicated interest in participating in the study. For women with 
scheduled cesarean delivery, a phone call with the investigator 0-21 days ahead of time will disclose 
eligibility and to assess their desire to speak to the study team to learn more about the study. Face-to-
face (video and audio) virtual informed consent will be permitted if acceptable to both patient and 
investigator team, and will follow existing procedures, security and protection protocols that are 
currently used in our other research protocols.   
 
Patients will be offered additional time to consider the study and their desire to participate - the amount 
of time for them to consider will be determined by the patient herself and individualized to her level of 
comfort. They will be informed that they do not need to make any decisions in that encounter and will 
be encouraged to take time to consider and discuss the study with their support persons without the 
presence of study personnel. Blank informed consent documents and study brochures will be made 
available to the subjects and their support people, to support their deliberations.    
 
Individuals will be provided with full explanation of study-related goals and procedures. Questions will 
be answered for the patient as well as their support people. Patients will be given as much time as they 
desire to read the consent form and materials and ask questions. If desired, patients can take materials 
home for review and will be consented to participate via videoconferencing software and electronic 
consent via REDCap. 
 
Informed consent procedures will be followed and written informed consent will be obtained. No 
elements of informed consent will be waived.  
 
14.3  Protocol Deviations 
 
Clinical research investigators and staff will be familiarized with the study protocol, GCPs, and 
applicable federal regulations to ensure that the study protocol procedures are followed. When a 
deviation is perceived to have occurred, the procedure completed will be verified against the study 
protocol, applicable regulations and relevant GCP principles. Deviations in the study protocol will be 
identified verbally and in writing to the PI and/or study coordinator as they occur. In addition to 
deviations noticed during completion of study protocol procedures, deviations may be identified 
through routine monitoring visits or audits of the clinical research records, as the research team will 
meet weekly to review the study recruitment, procedures, and retention. All deviations will be verified 
and presented to the PI for timely assessment and IRB reporting, if warranted. Any deviation, regardless 
of severity, will be recorded in the Non-compliance/deviation log by the PI or research staff member as 
they occur. Protocol deviations that do not meet the definition of IRB reporting requirements will be 
subject to yearly review and evaluation during the continuing review period.  

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Deviations determined to be reportable to the IRB include Unanticipated Problems involving risk to 
participants, Serious Non-compliance with study protocol, and/or Continuing Non-compliance of study 
protocol. The PI will submit all Unanticipated Problems Involving Risks to Human Subjects or Others 
and incidents of Reportable Non-compliance within 10 working days of the Investigator becoming 
aware of the Reportable New Information.  Unanticipated Problems involving risk to participants include 
adverse medical occurrences that are: 
• 
Unexpected in terms of nature, severity, or frequency; AND 
• 
Related, or possibly related, to a subject’s participation in the research; AND 
• 
Places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
Any protocol deviation that results in an Adverse Events which are unexpected, fatal, or life-
threatening, and related or possibly Related to the Research Intervention will be immediately reported 
to the PI, Clinical Research Coordinator, and reported to the IRB within 24 hours of learning of the 
event. (All other internal Adverse Events that meet the definition of an Unanticipated Problem 
Involving Risk to Human Subjects or Others will be reported to the IRB within 10 working days of the 
investigator learning of the event. If an unexpected adverse event occurs, the investigators will reassess 
the risk to benefit ratio of the study and will submit any modifications necessary to the IRB. At the time 
of IRB renewal, the PI will submit information about the frequency of monitoring, any relevant 
information that may influence the safety or ethical conduct of the study, and any conclusions or 
changes to the study necessary for continuation, modification, or termination of the study. 
Reportable incidence of Non-compliance includes any protocol deviation that: 
• 
Significantly adversely affects the safety, rights, or welfare of the research participants; OR 
• 
Significantly compromises the quality or integrity of the research data (i.e., negatively impacts 
the ability to draw conclusions from the study data); OR 
• 
Represents Continuing Non-compliance (i.e., has been previously reported or represents a 
pattern of ongoing non-compliance). 
Incidents of Non-compliance that do not meet the IRB reporting requirements will be documented in 
a Non-compliance/deviation log and managed as part of the Data and Safety Monitoring Plan. The Non-
compliance/deviation log will be kept throughout the study and the documentation will be made 
available upon request.  
 
 
 

35 
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48 
 
 
Appendix 1 – Surveys Measures 
 
Item 
Description, Rationale and Evidence 
Demographic information 
Age, gravidity, parity, estimated gestational age at delivery, weight (kg), height (cm), BMI (kg/m2) 
Estimated blood volume on day of surgery (calculated by investigator team):  
     EBV = 65ml x weight (kg)     non-obese 
     EBV = 50ml x weight (kg)     obese BMI ≥30 
Smoking status (yes/no), number of prior cesarean deliveries, race/ethnicity, highest level of education, and 
household income will be self-reported by subjects. These items relate to social correlates of health that are not 
otherwise obtainable by surveys. If differences in these characteristics are observed between groups, a regression 
model will control for these factors (see statistical analysis plan). 
Edinburgh Postnatal 
Depression Scale 
(EPDS) 
The EPDS is self-completed, 10-item scale specifically for women in the perinatal period. It has been shown to be 
an effective means of identifying patients at risk for depression138,139. 
PROMIS Inventories 
PROMIS inventories assess core aspects of pain. PROMIS-PI: Pain interference with activities measures external 
manifestations of pain including social role participation and pain interference (i.e., pain behavior). They are 
valid and reliable for the constructs that they assess (143-145). 
Pain intensity 
(numeric rating scale) 
This question assesses the somatic pain experience. 
 
Question: Over the last 24 hours, how intense has your pain been? Please rate on the scale below. 
0-10 numeric rating scale where 0 is “no intensity at all” and 10 is “the most intense pain I can imagine” 
Pain unpleasantness 
(numeric rating scale) 
This question assesses the emotional pain experience, the emotional valence of pain. 
 
Question: Over the last 24 hours, how unpleasant has your pain been? Please rate on the scale below 
0-10 numeric rating scale where 0 is “not unpleasant at all” and 10 is “the most unpleasant pain I can imagine” 
McGill Pain 
Questionnaire, Short 
Form (SF-MPQ) 
The McGill Pain Questionnaire Short Form measures multiple dimensions of pain experience including sensory 
and affective aspects140,141. The instrument is psychometrically sound, valid, reliable, and has good 
discriminative capacity142. These measures are necessary to better understand the role that these factors play in 
pain intensity, quality, and duration. 
Perceived Stress 
Scale (PSS) 
Psychological stress/distress affects pain, post-operative recovery, and depression. It will be measured in these 
populations using the validated Perceived Stress Scale.  
Daily opioid use 
Estimated weekly, daily average (avg) and maximum (max) pill use counts 
“Over the last week, how many opioid pills have you used every day on average?” 
“Over the last week, what was the highest number of opioid pills you have needed for pain?”  
Opioid use (milligram 
morphine equivalent, 
MME) 
We will measure oxycodone, hydromorphone and morphine (mg) totals in hospital. These medications will be 
converted to a single variable, milligram morphine equivalent (MME), per information from the Center for 
Disease Control 
 

49 
 
 
 
Appendix 2 – Schedule of Perinatal, Surgical, and Infusion-Specific Research Activities 
 
 
 
 
Study Visit# 1; Day 0—Delivery/Cesarean Surgery -24 hours post-surgery 
Procedures 
Prenatal Screening 
& Baseline 
Measures 
Presurgical Intake 
T-1 hour 
If not completed at 
baseline 
Cesarean Surgery 
Ketamine Infusion 
15-45 minutes Post 
12-hour Ketamine Infusion 
12-hour post-infusion 
15 
Minutes 
30 
Minutes 
Hour 1 
Hour 4 
Hour 6 
Hour 8 
10Hour  
Hour 12 
Hour 16 
Hour 20 
Hour 24 
Informed consent 
X 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
Demographics and Medical 
History (inc. Opioid use in 
hospital) 
X 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
Concomitant medication review 
X 
X 
 
 
  
  
  
  
  
  
  
  
  
  
  
Administer study intervention 
  
 
 
X 
  
  
  
  
  
  
  
  
  
  
  
Maternal Plasma Samples a 
  
 
 
  
  
  
X 
  
X 
  
X 
X 
  
  
  
Adverse event review b 
  
 
 
X-------------------------------------------------------------------------------------------------------------------------------------------------X 
Surgical operative survey 
  
 
 
X 
  
  
  
  
  
  
  
  
  
  
  
Pain Intensity 
 X 
X 
 
 
  
  
  
  
  
  
  
  
  
  
  
Pain Unpleasantness 
 X 
X 
 
 
  
  
  
  
  
  
  
  
  
  
  
PROMIS-PI 
 X 
X 
 
 
  
  
  
  
  
  
  
  
  
  
  
EPDS 
 X 
X 
 
 
  
  
  
  
  
  
  
  
  
  
  
PSS 
 X 
X 
 
 
  
  
  
  
  
  
  
  
  
  
  
SF-MPQ 
 X 
X 
 
 
  
  
  
  
  
  
  
  
  
  
  
RASS b 
  
 
 
  
X 
X 
X 
X 
  
X 
X 
X 
X 
X 
X 
Patient Vitals b 
  
X 
 
 X 
X 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
LSD Short b 
  
 
 
  
X 
 X 
X 
X 
  
X 
X 
X 
X 
X 
X 
Side Effect Diary and Patient 
Acceptability b 
  
 
 
  
 X 
X  
X 
X 
  
X 
X 
X 
X 
X 
X 
a Maternal Plasma Sampling includes analysis of Ketamine, ketamine metabolites (Nor-Ketamine & DKNK), Ketamine R- & S-isomers, cortisol, prolactin, and CYP3A and 
CYP2B6 enzymes 
b Adverse Events will result in collection of RASS, LSD short form, Patient vitals, Patient Acceptability ratings, and Maternal plasma sampling at any point between infusion start 
 (t = 0) to 24-hours post-infusion start. LSD score of >8 will trigger a notification to staff and investigator to prompt bedside evaluation. 
 
 

50 
 
 
Appendix 3 – Schedule of Postpartum Research Activities 
 
Procedures 
All procedures within +/-3 days 
Study 
Visit 2 
Study 
Visit 3 
Study 
Visit 4 
Study 
Visit 5 
Study 
Visit 6 
Study 
Visit 7 
Study 
Visit 8 
Study 
Visit 9 
Study 
Visit 10 
Study 
Visit 11 
Study  
Visit 12 
Study  
Visit 13 
Day 7 
Day 14 
Day 21 
Day 28 
Day 35 
Day 42 
Day 49 
Day 56 
Day 63 
Day 70 
Day 77 
Day 84 
Pain Intensity 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pain Unpleasantness 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PROMIS-PI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EPDS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-MPQ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily opioid use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 

51 
 
 
Appendix 4. Participant Payment per Task 
 
PREPARE 1 Payment 
 
Patient 
Tasks 
Timing 
Payment 
 
Patient 
Tasks 
Timing 
Payment 
Baseline Surveys 
Postpartum Surveys 
Prior to delivery 
$60  
Week 1 
$25  
 
 
 
Week 2 
$25  
Infusion Payments 
 
Week 3 
$25  
Plasma Samples (12 ml of blood) 
Week 4 
$25  
Infusion 
T 1 hour 
$62.50  
Week 5 
$25  
T 6 hour 
$62.50  
Week 6 
$25  
T 10 hour 
$62.50  
Week 7 
$25  
T 12 hour 
$62.50  
Week 8 
$25  
Total 
$250.00  
Week 9 
$25  
 
 
 
 
 
Week 10 
$25  
Side Effect Diaries 
Week 11 
$25  
Infusion 
T 1 hour 
$50.00  
Week 12 
$25  
T 6 hour 
$50.00  
 
 
 
T 10 hour 
$50.00  
Total 
$300  
T 12 hour 
$50.00  
 
 
Post-
Infusion 
T 16 hour 
$50.00  
T 20 hour 
$50.00  
T 24 hour 
$50.00  
T 12 hour 
$50.00  
GRAND TOTAL 
$1,050  
Total 
$400.00  
 
 
 
 
 
 
 
Vital Signs 
Infusion 
T 1 hour 
$5.00  
T 6 hour 
$5.00  
T 10 hour 
$5.00  
T 12 hour 
$5.00  
Post-
Infusion 
T 16 hour 
$5.00  
T 20 hour 
$5.00  
T 24 hour 
$5.00  
T 12 hour 
$5.00  
Total 
$40.00