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Participants will receive 0.5mg/kg of Ketamine orally with an equivalent quantity of placebo via an intramuscular injection on Day 0/Visit 4 and receive Meaning and Purpose (MaP) therapy 4 times, twice before ketamine administration (Day 0), and twice afterward. The duration of treatment for ketamine plus MaP (K-MaP) therapy is approximately up to 28 days. Participants will be followed up to 35 days (+/-2 days) after ketamine administration.

Participants will receive 0.5mg/kg of Ketamine IM with a placebo oral solution on Day 0/Visit 4 and receive Meaning and Purpose (MaP) therapy 4 times, twice before ketamine administration (Day 0), and twice afterward. The duration of treatment for ketamine plus MaP (K-MaP) therapy is approximately up to 28 days. Participants will be followed up to 35 days (+/-2 days) after ketamine administration.

Ketamine Injectable Product

Meaning and Purpose therapy

Placebo

Zoe Lopez-Meraz

Brian T Anderson, MD

Andrea Rosati, MD, PhD

Nicky Mehtani, MD, MPH

This clinical trial evaluates whether it is possible to use a single dose of ketamine in combination with talk therapy to treat moderate to severe demoralization in patients with pancreatic ductal adenocarcinoma (PDAC) who take opioids for cancer-related pain. PDAC patients often suffer from high rates of psychosocial distress and pain. Symptoms of anxiety are highly prevalent among PDAC patients. While opioid analgesia (pain reliever) succeeds in managing some symptoms, chronic opioid therapy is associated with significant adverse effects, underscoring a need to identify alternative interventions in the treatment of PDAC-associated pain. PDAC patients frequently suffer from existential distress. Demoralization is a form of existential distress that is common among people with serious medical illnesses; it is characterized by poor coping with stressful events, and a loss of meaning and purpose in life. Talk therapy is a form of psychological treatment during which patients discuss problems, thoughts, and feelings. Ketamine has demonstrated efficacy for the treatment of depression, suicidality, and pain in non-cancer patients. This study may help researchers learn whether both ketamine and talk therapy may improve psychosocial distress and pain, as well as decreases in opioid analgesic use in patients with PDAC who take opioids for cancer-related pain.

PRIMARY OUTCOMES:

I. To assess the feasibility of Meaning and Purpose therapy combined with oral ketamine (K-MaP) in demoralized participants.

SECONDARY OUTCOMES:

I. To characterize the preliminary safety and tolerability of K-MaP in demoralized participants with pancreatic ductal adenocarcinoma.

II. To assess the magnitude and durability of improvement from randomization in psychosocial distress.

III. To assess the magnitude and durability of improvement from randomization in pain.

IV. To assess the magnitude of change from randomization in opioid analgesic use.

V. To assess the magnitude and durability of change from randomization in interoceptive awareness

EXPLORATORY OBJECTIVES:

I. To assess how the participant's subjective experiences with ketamine may be related to clinical outcomes.

II. To assess how participants' stage of PDAC may be related to clinical outcomes.

III. To assess how the participants' changes in measures of cardiac interoception following receipt of ketamine may be related to subjective experiences with ketamine and clinical outcomes.

OUTLINE:

Adult pancreatic ductal adenocarcinoma (PDAC) participants receiving care at the Helen Diller Family Comprehensive Cancer Center (HDFCCC) will be randomized in a 1:1 ratio to one of two double-blinded conditions consisting of a single drug treatment and several therapy sessions, for up to 7 weeks. Participants will be followed up to 35 days (+/-2 days) after ketamine administration.

The study is double-blinded, meaning neither the study participants nor the study investigators will know which ketamine administration each participant is receiving.

Ketamine-assisted Therapy for Patients With Pancreatic Ductal Adenocarcinoma

Pilot Study of Ketamine-assisted Talk Therapy for Demoralization in Patients With Pancreatic Ductal Adenocarcinoma and Pain

The rate of recruitment is defined as the proportion of eligible participants who participate compared to the number of total participants who were screened or signed consent but did not meet eligibility criteria will be reported.

Proportion of enrolled participants completing K-MaP intervention and all Demoralization Scale II (DS-II) assessments will be reported.

The participants will provide qualitative feedback on the acceptability of the intervention via a 20-minute interview with the study team upon study termination. Frequency of responses will be categorized and reported by arm.

The percentage of participants in each arm reporting treatment-related adverse events will be reported. Pre-determined criteria for assessment of tolerability to K-MaP include zero treatment-related serious adverse events, and all other adverse events will be assessed using Common Terminology Criteria for Adverse Events version 5.0.

At time of ketamine administration, participants blood pressure will be monitored for any clinically significant changes. The percentage of participants with a clinically significant change in blood pressure from pre-medication administration to end of study visit will be reported.

At time of ketamine administration, participants heart rate will be monitored for any clinically significant changes. The percentage of participants with a clinically significant change in heart rate from pre-medication administration to end of study visit will be reported.

The CEQ is a 26-item, self-reported measure of challenging experiences with psychedelics. The CEQ assesses seven factors: grief (5 items), fear (6 items), subjective experience of death (2 items), insanity (3 items), isolation (3 items), physical distress (5 items), and paranoia (2 items). Each of the 26 items is scored on a 5-point Likert scale (0 = "None; not at all" to 5 = "Extreme \[more than ever before in my life\]"). Participants are asked to rate each item based on the degree to which each item was experienced. A higher total CEQ score indicates greater psychologically adverse reactions to psilocybin.

The CGI is a 3-item clinician-administered measure developed by the National Institute of Mental Health to assess clinical change in participants in psychopharmacology trials. This study will be using the Global Impression of Severity item ("Considering your total clinical experience with participants with demoralization, how would you rate this participant's level of demoralization at this time?"), on the scale from "1 = Normal, not at all demoralized" to "7 = Among the most extremely demoralized participants" to assess change in demoralization.

The DI is a clinician-rated measure of demoralization which consists of 14-items designed from items of the Demoralization Scale II. The items measure events that occurred over the past 2 weeks, which are scored on a 3-point scale ranging from 0 to 2. Scores are calculated by adding each item score, for a total score range of 0 to 28. Higher scores indicate a greater degree of demoralization.

The 6-item Hamilton Depression Rating Scale (HAMD-6) is a validated, brief, clinician-rated measure of the core symptoms of major depression. With permission from authors (the International Society for Central Nervous System Drug Development (ISCDD)) a modified, 6-items version of the HAMD-6 in the GRID-HAMD format to will be used by clinicians to create a brief, responsive and reliable measure of core depression symptoms of participants. Responses on the items will range from 0=absent; 1=mild; 2=moderate; 3=severe; 4=incapacitating and scores will be summed to create a total score. The higher the total score the more severe the depression symptoms of the participant.

The DCPR is a structured, clinician-administered, interview regarding various psychosomatic conditions and will be administered to participants over the course of the study. Clinicians will record the rates of demoralization as present or not per participant

The DS-II is a measure of demoralization which consists of 16-items designed from items of the Demoralization Scale II. The items measure events that occurred over the past 2 weeks, which are scored on a 3-point scale ranging from 0 to 2. Scores are calculated by adding each item score, for a total score range of 0 to 32. Higher scores indicate a greater degree of demoralization.

The Patient Health Questionnaire-9 (PHQ-9) is used to measure depression symptoms. The total Patient Health Questionnaire-9 (PHQ-9) score is calculated by combining the responses of the participant on questions addressing how bothered the participant has been by various problems over the past 2 weeks. Each of the 9 items is scored on a scale of 0 ("Not bothered at all") to 4 ("Nearly every day"). A total score of 5-9='Mild Depression Symptoms", 10-14="Minor Depression, Major Depression (mild), or Dysthymia", 15-19="Major Depression, moderately severe", and \>20="Major Depression".

The GAD-7 is a seven-item instrument that is used to measure or assess the severity of generalized anxiety disorder. The GAD-7 score is calculated by assigning scores of 0, 1, 2, and 3, to the response categories of "not at all," "several days," "more than half the days," and "nearly every day," respectively, and then adding together the scores for the seven questions. Scores of 5, 10, and 15 represent cut-points for mild, moderate, and severe anxiety, respectively. When used as a screening tool, further evaluation is recommended when the score is 10 or greater.

The FACIT-Pal-14 is a 14-item, self-report measure of quality of life in palliative care participants. The measure has a 7-day recall period with responses to items which fall on a 5-point Likert scale, with scores ranging from 0 = "Not at all" to 4 = "Very much". Scores are summed to create a total score of 0 to 56, with higher scores indicating a greater quality of life.

The BPI-SF is a 9-item questionnaire used to assess the severity of pain and the impact of pain on activities of daily living over a recall period of 24 hours. Pain severity is assessed across four sub-scales; 'worst pain', 'least pain', 'average pain' and 'current pain'. A pain score for each subscale is presented separately. Scales are rated on a scale of 0 to 10 (0 = no pain; 10 = pain as bad as one can imagine). A composite score for pain severity is calculated as the mean of the four severity items. Question 9 comprises a 7-item interference scale. Questions assess the level to which pain interferes with general activity, walking, work, mood, enjoyment of life, relations with others and sleep on a scale of 0 to 10 (0 = does not interfere; 10 = completely interferes). Mean interference score will be calculated as an average of the seven subparts of question 9 where at least four of the seven items are completed.

Using the Morphine Milligram Equivalents (MME) calculation, participants cumulative daily dose of opioids will be calculated for the past 24 hours at each study visit. The proportion of participants with any reported opioid use at any of the study visits will be reported.

The MAIA-2 is a validated a widely used questionnaire to measure interoceptive awareness. This measure consists of 37-items using a 6-point Likert scale (0 = "Never" to 5 = "Always"). The MAIA-2 has demonstrated good internal consistency and reliability for the evaluation of clinical mind-body interventions, with higher scores indicating increased awareness.

Spots Global Cancer Trial Database for meaning and purpose therapy