## Protocol Section
### Identification Module
**NCT ID:** NCT06419985

**Brief Title:** Ketamine HCl Prolonged Release Oral Tablets for CRPS

**Official Title:** A Phase 2 Single-arm, Open Label Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetic Profile of Ketamine HCl Prolonged Release Tablets in Participants With Complex Regional Pain Syndrome

#### Organization Study ID Info
**ID:** 23015-0001
#### Organization
**Class:** OTHER
**Full Name:** University of Southern California
### Status Module
#### Completion Date
**Date:** 2026-07

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-17

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-14

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-06

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-17
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-06
**Study First Submit QC Date:** 2024-05-14
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** University of Southern California

#### Responsible Party

**Investigator Affiliation:** University of Southern California

**Investigator Full Name:** Steven Richeimer

**Investigator Title:** Professor of Clinical Anesthesiology

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetic profile of Ketamine HCl Prolonged Release (PR) tablets in participants with pain due to complex regional pain syndrome (CRPS).

Additionally, this trial will explore the feasibility of the trial design through dosing compliance, clinical instruments, and efficacy signals.

**Detailed Description:** This study will enroll patients with history of CRPS (greater than 6 months) at a single academic medical institution in the United States. All participants will be informed about the study and potential risks and will provided written informed consents prior to undergoing any study-related procedures.

There are 3 cohorts of 3+3 participants each that are assigned escalating dose levels of oral Ketamine HCl PR (1 tablet=40mg).

The daily dose of Ketamine PR for the 3 cohort is as follows:

Cohort 1 is 80 mg/day (1 tablets of 40mg twice a day); Cohort 2 is 160 mg/day (2 tablets of 40mg twice a day); Cohort 3 is 240 mg/day (3 tablets of 40mg twice a day).

Each cohort consists of 1 sentinel participant that must complete Visit 4 before the other 2 participants are enrolled. If participants withdraw from the study before completing Cycle 1 for reasons other than a dose-limiting toxicity, additional participants will be enrolled to replace them, until at least 3 successful participants have completed Cohort 1. At this time a safety review will be conducted. If there are 2 or more DLT events observed in Cohort 1, the study will stop. If there is 1 Dose Limiting Toxicity (DLT) event observed, an additional 3 participants will be enrolled in Cohort 1. If there are 2 or more DLT events observed in the additional set of participants, the study will stop. If there is ≤ 1 DLT event observed in the additional set, enrollment will open for Cohort 2.

After at least 3 participants in Cohort 2 have completed Cycle 1, a safety review will be conducted to assess the safety and tolerability of the investigational product.

If there are 2 or more DLT events observed in Cohort 2, the Maximum Tolerated Dose (MTD) will become 80mg ketamine HCl PR per day and the study will open for general enrollment. If there is 1 Dose Limiting Toxicity (DLT) event observed, an additional 3 participants will be enrolled in Cohort 2. If there are 2 or more DLT events observed in the additional set of participants, the MTD will become 80mg ketamine HCl PR per day and the study will open for general enrollment. If there is ≤ 1 DLT event observed in the additional set, enrollment will open for Cohort 3.

After at least 3 participants in Cohort 3 have completed Cycle 1, a safety review will be conducted by the SRC to assess the safety and tolerability of the investigational product. If there are 2 or more DLT events observed in Cohort 3, the Maximum Tolerated Dose (MTD) will become 160mg ketamine HCl PR per day and the study will open for general enrollment. If there is 1 Dose Limiting Toxicity (DLT) event observed, an additional 3 participants will be enrolled in Cohort 3. If there are 2 or more DLT events observed in the additional set of participants, the MTD will become 160mg ketamine HCl PR per day and the study will open for general enrollment. If there is ≤ 1 DLT event observed in the additional set, the study will open for general enrollment where the MTD is 240mg ketamine HCl PR per day. If 0 DLT events are observed in Cohort 3, the study will open for general enrollment where the MTD is 240mg ketamine HCl PR per day.

Health status assessments including physical exams, blood work, urinalysis, EKG and questionnaires to assess quality of life and pain scale measurement will be conducted at the clinic visits. The participants will also keep a daily diary to record pain levels and any additional pain medication needed.

There will be a screening visit (day -28 to -7), clinic visits at day 1, week 2, week 4, week 8, and at the end of study (EOS) visit. There will be additional telemedicine visits at week 1, week 3 and at the safety followup visit approximately 4 weeks after the EOS visit.

Definition of Dose Limiting Toxicities (DLT):

Any of the following symptoms, if they interfere with the daily life of the participant, will be considered DLTs:

* General - sedation, impaired consciousness
* Head, Ear, Eyes, Nose, Throat - horizontal, vertical or rotary nystagmus, mydriasis, excessive salivation
* Cardiovascular - hypertension, tachycardia, palpitations, arrhythmias, chest pain
* Abdominal - abdominal pain, abdominal tenderness, nausea, vomiting
* Neurological - altered mental status (disorientation), paranoia, dysphoria, anxiety, confusion, slurred speech, dizziness, ataxia, dysarthria, trismus, muscular rigidity, psychomotor, psychomimetic, or acute dystonic reactions
* Genitourinary - lower urinary tract symptoms
* Trauma - a thorough examination for evidence of trauma is needed as injuries secondary to ketamine intoxication can occur due to the diminished perception of pain.

Any of the following symptoms will always be considered DLTs:

* Respiratory - respiratory depression, apnea, laryngospasm
* Cardiovascular - hypotension, bradycardia, myocardial infarction
* Neurological - seizure, stupor, coma

### Conditions Module

**Conditions:**

- Complex Regional Pain Syndromes

**Keywords:**

- CRPS

### Design Module

#### Design Info

**Allocation:** NON_RANDOMIZED

**Intervention Model:** SEQUENTIAL

**Intervention Model Description:** 3 Cohorts of 3+3

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 50

**Type:** ESTIMATED

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** One 40mg tablet of Ketamine HCl PR twice a day

**Intervention Names:**

- Drug: 80mg Ketamine HCl Prolonged Release

**Label:** 80mg Ketamine HCl PR

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Two 40mg tablets of Ketamine HCl PR twice a day

**Intervention Names:**

- Drug: 160mg Ketamine HCl Prolonged Release

**Label:** 160mg Ketamine HCl PR

**Type:** EXPERIMENTAL

#### Arm Group 3

**Description:** Three 40mg tablets of Ketamine HCl PR twice a day

**Intervention Names:**

- Drug: Administration of Ketamine HCl Prolonged Release - 240mg

**Label:** 240mg Ketamine HCl PR

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- 80mg Ketamine HCl PR

**Description:** Administration of Ketamine HCl Prolonged Release - 80mg

**Name:** 80mg Ketamine HCl Prolonged Release

**Other Names:**

- 80mg Ketamine PR

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- 160mg Ketamine HCl PR

**Description:** Administration of Ketamine HCl Prolonged Release - 160mg

**Name:** 160mg Ketamine HCl Prolonged Release

**Other Names:**

- 160mg Ketamine PR

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- 240mg Ketamine HCl PR

**Description:** Administration of Ketamine HCl Prolonged Release - 240mg

**Name:** Administration of Ketamine HCl Prolonged Release - 240mg

**Other Names:**

- 240mg Ketamine PR

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** Number of participants with AEs, with abnormal vital signs, abnormal physical examination parameters; abnormal Electrocardiogram (EKG) parameters; abnormal laboratory parameters

**Measure:** Safety of Ketamine HCl PR oral tablets

**Time Frame:** Day 1 to 18 weeks

**Description:** Maximum Plasma concentration \[Cmax\] is the maximum concentration of the drug, Ketamine, in the body, measured in grams/Liter. Blood samples are obtained at Day 2, 4, and 7.

**Measure:** Maximum Plasma concentration [Cmax] of Ketamine

**Time Frame:** Day 1 to Day 7

**Description:** Time to Maximum Plasma concentration \[Tmax\] is the time it takes for the drug Ketamine, to reach maximum concentration (Cmax), measured in minutes. Blood samples are obtained at Day 2, 4, and 7.

**Measure:** Time to Maximum Plasma concentration [Tmax] of Ketamine

**Time Frame:** Day 1 to Day 7

**Description:** MTD is determined by testing increasing doses from 80mg to 160mg to 240mg on dose escalation cohorts 1, 2, 3 with 3 to 6 participants each. MTD reflects the highest dose of drug that did not cause \>1 Dose Limiting Toxicity (DLT) event.

**Measure:** Maximum Tolerated Dose (MTD) of Ketamine HCl PR oral tablets

**Time Frame:** Up to 4 weeks for each dosing cohort

#### Secondary Outcomes

**Description:** Average Daily Pain Numerical Rating Scale is a validated, self-reported instrument used to assess average pain intensity level over the past 24 hours. It uses an 11-point (0-10) scale, with 0 being "no pain" and 10 being "worst pain imaginable."

**Measure:** Average Daily Pain Numerical Rating Scale (ADP NRS)

**Time Frame:** Day 1 to week 12

**Description:** The PROMIS-29 Profile v2.1 is a validated, self-reported instrument to measure functioning and well-being in 7 categories: physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social roles and activities and pain interference. There are 4 questions in each of the 7 categories. Each question has five responses with a score from 1 to 5 (1 being best and 5 being worst). For each of these 7 categories, the lowest score is 4; the highest is 20.

**Measure:** Patient-Reported Outcomes Measurement Information System-2 (PROMIS-29 Profile v2.1)

**Time Frame:** Day 1 to week 12

**Description:** The CSS Questionnaire assesses changes in Complex Regional Pain Syndrome (CRPS) severity by asking for the presence or absence (score of 1 or 0) of 16 clinically assessed signs and symptoms of CRPS. A higher score is worse, indicate greater CRPS severity (range 0-16).

**Measure:** Complex Regional Pain Syndrome Severity Scale (CSS)

**Time Frame:** Day 1 to week 12

**Description:** Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2) is a validated, self-reported tool used to measure the quality and the intensity of both neuropathic and non-neuropathic pain. It consists of 22 different descriptors of pain and each item is rated based on a 0-10 scale (with 0 being 'none' and 10 being 'worst possible'). The total score is calculated by summing the 22 individual scores. The higher the score, the greater the pain level.

**Measure:** Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2)

**Time Frame:** Day 1 to week 12

**Description:** Patient Global Impression of Change is a validated, self-reported instrument consisting of a 7-point scale (1 through 7) depicting a patient's rating of overall improvement since a certain point in time. The higher PGIC scores, the greater improvement. We will compare the scores at the end of Cycle 1 (1-4 weeks), 2 (4-8 weeks), and 3 (8-12 weeks).

**Measure:** Patient Global Impression of Change (PGIC)

**Time Frame:** Day 1 to week 12

**Description:** Participants will record any change in the amount (expressed as MME) and frequency of opioid medications used for treating CRPS pain.

**Measure:** Opioid sparing

**Time Frame:** Day 1 to week 12

**Description:** Participants will record daily use of rescue medication (expressed in mg and number of tablets) for treating CRPS pain. Acetaminophen (up to 3000mg/day) will be offered as rescue medication for breakthrough pain.

**Measure:** Medication sparing

**Time Frame:** Day 1 to week 12

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

1. Male and female participants between 18 and 70 years of age, inclusive, at Screening Visit.
2. Participants with a documented history of CRPS of at least 6 months at Visit 1.
3. Documented history of at least one sign in two of the categories of The Budapest Criteria for CRPS to support the diagnosis of CRPS.
4. Stable individual regular standard treatment regimen for CRPS pain, i.e., no change in drug and non-drug treatments for at least 4 weeks prior to Screening Visit and anticipated to remain stable throughout the study.
5. No surgery within one month, denervation procedures or neural blockade within 1 month of Screening Visit.
6. Participants on ketamine therapy at Screening Visit must agree to discontinue use for at least 14 days prior to the Baseline Observation Period.
7. Agree to discontinue any prohibited medications within 14 days of the Baseline Observation Period and for the duration of the study.
8. Average daily CRPS pain intensity score in the affected limb of ≥5 and ≤9 on an 11-point (0-10) NRS averaged over 7 days prior to Baseline Visit (Visit 1). This will be based on completion of at least 5 daily pain diary entries during the week prior to Visit 1, with no more than one 24-hour pain intensity score of zero or more than one 24-hour pain intensity score of 10.
9. Participants willing and able (e.g., mental and physical condition) to participate in all aspects of the trial, including use of medication, completion of subjective evaluations, attending scheduled clinic visits, completing telephone contacts, and compliance with protocol requirements as evidenced by providing signed written informed consent at Screening Visit.
10. For persons of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 6 weeks after the end of study intervention administration.
11. Previous enrollment in this trial or participation in any other clinical trial within the past 30 days prior to enrollment.

Exclusion Criteria:

1. Known or suspected cardiovascular disease, arrythmias, and/or respiratory issues.
2. Abnormal EKG results, abnormal blood pressure and/or heart rates.
3. Known or suspected psychotic illness or neurologic disease.
4. Known or suspected elevated intraocular and/or intracranial pressure.
5. Known or suspected renal or urologic conditions or symptoms (i.e., bladder pain syndrome, interstitial cystitis), and/or abnormal baseline urinalysis results.
6. Known or suspected hyperthyroidism.
7. Allergy, hypersensitivity, or intolerance to ketamine or any of the investigational product excipients.
8. Participants receiving opioids ≥30 mg/day morphine milligram equivalents (MME), whether as part of their individual standard treatment regimen for CRPS pain or in context with any other indication, within the last two weeks prior to Visit 1.
9. Positive urine screen for any of the following: cocaine, amphetamine, methamphetamine, PCP, opioids, THC (other than medication used for individual standard treatment of pain) at Visit 1.
10. Known or suspected acute or chronic alcoholism, delirium tremens, or toxic psychosis.
11. Meet DSM-5 criteria for or current or past substance use disorder within the last 5 years for any psychoactive substances other than nicotine or caffeine.
12. Presence of aspartate aminotransferase (AST) levels ≥ 3 X upper limit of normal and/or alanine aminotransferase (ALT) levels ≥ 3 X upper limit of normal and/or total bilirubin ≥ 1.5 X upper limit of normal and/or creatinine ≥ 1.5 X upper limit of normal.
13. Evidence of moderate or severe renal impairment (CRCL \<60 ml/min) or participants with renal failure who are on any form of dialysis.
14. Any other condition of the patient that in the opinion of the investigator may compromise evaluation of the trial treatment or may jeopardize participant's safety, compliance or adherence to protocol requirements.
15. Previous enrollment in this trial or participation in any other clinical trial within the past 30 days prior to enrollment.

**Maximum Age:** 70 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** dmcintee99@gmail.com

**Name:** Diane McIntee, MS

**Phone:** 626-372-0075

**Role:** CONTACT

**Contact 2:**

**Email:** faye.weinstein@med.usc.edu

**Name:** Faye Weinstein, PhD

**Phone:** 323-442-6202

**Phone Ext:** 1

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Los Angeles

**Contacts:**

***Contact 1:***

- **Email:** steven.richeimer@med.usc.edu

- **Name:** Steven Richeimer, MD

- **Phone:** 323-442-6202

- **Role:** CONTACT

***Contact 2:***

- **Email:** faye.weinstein@med.usc.edu

- **Name:** Faye Weinstein, PhD

- **Phone:** 323-442-6202

- **Phone Ext:** 1

- **Role:** CONTACT

***Contact 3:***

- **Name:** Steven Richeimer, MD

- **Role:** PRINCIPAL_INVESTIGATOR

***Contact 4:***

- **Name:** Ashley Balentine, MD

- **Role:** SUB_INVESTIGATOR

**Country:** United States

**Facility:** Pain Center, Keck Medical Center of University of Southern California

**State:** California

**Zip:** 90033

#### Overall Officials

**Official 1:**

**Affiliation:** Keck Medical Center of USC

**Name:** Steven Richeimer, MD

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000004194

- Term: Disease

- ID: D000010335

- Term: Pathologic Processes

- ID: D000001342

- Term: Autonomic Nervous System Diseases

- ID: D000009422

- Term: Nervous System Diseases

- ID: D000010523

- Term: Peripheral Nervous System Diseases

- ID: D000009468

- Term: Neuromuscular Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC10

- Name: Nervous System Diseases

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M16355

- Name: Syndrome

- Relevance: HIGH

- As Found: Syndrome

- ID: M13066

- Name: Pain

- Relevance: LOW

- As Found: Unknown

- ID: M22653

- Name: Complex Regional Pain Syndromes

- Relevance: HIGH

- As Found: Complex Regional Pain Syndrome

- ID: M14861

- Name: Reflex Sympathetic Dystrophy

- Relevance: HIGH

- As Found: Complex Regional Pain Syndrome

- ID: M4643

- Name: Autonomic Nervous System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M27979

- Name: Primary Dysautonomias

- Relevance: LOW

- As Found: Unknown

- ID: M13432

- Name: Peripheral Nervous System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M12411

- Name: Neuromuscular Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T1440

- Name: Complex Regional Pain Syndrome

- Relevance: HIGH

- As Found: Complex Regional Pain Syndrome

### Condition Browse Module - Meshes

- ID: D000020918

- Term: Complex Regional Pain Syndromes

- ID: D000012019

- Term: Reflex Sympathetic Dystrophy

- ID: D000013577

- Term: Syndrome

### Intervention Browse Module - Ancestors

- ID: D000000700

- Term: Analgesics

- ID: D000018689

- Term: Sensory System Agents

- ID: D000018373

- Term: Peripheral Nervous System Agents

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000000778

- Term: Anesthetics, Dissociative

- ID: D000018686

- Term: Anesthetics, Intravenous

- ID: D000018681

- Term: Anesthetics, General

- ID: D000000777

- Term: Anesthetics

- ID: D000002492

- Term: Central Nervous System Depressants

- ID: D000018691

- Term: Excitatory Amino Acid Antagonists

- ID: D000018683

- Term: Excitatory Amino Acid Agents

- ID: D000018377

- Term: Neurotransmitter Agents

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

### Intervention Browse Module - Browse Branches

- Abbrev: Analg

- Name: Analgesics

- Abbrev: CNSDep

- Name: Central Nervous System Depressants

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M10674

- Name: Ketamine

- Relevance: HIGH

- As Found: Provided

- ID: M4032

- Name: Analgesics

- Relevance: LOW

- As Found: Unknown

- ID: M4107

- Name: Anesthetics

- Relevance: LOW

- As Found: Unknown

- ID: M4108

- Name: Anesthetics, Dissociative

- Relevance: LOW

- As Found: Unknown

- ID: M20766

- Name: Anesthetics, Intravenous

- Relevance: LOW

- As Found: Unknown

- ID: M20761

- Name: Anesthetics, General

- Relevance: LOW

- As Found: Unknown

- ID: M20771

- Name: Excitatory Amino Acid Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M20504

- Name: Neurotransmitter Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000007649

- Term: Ketamine

### Misc Info Module

- Version Holder: 2024-05-31
