Ketamine HCl Prolonged Release Oral Tablets for CRPS

The purpose of this study is to evaluate the efficacy 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 for safety and quality of life measurements, and pharmacokinetic profile.

This study will enroll patients (age 18 to 64 years old) with history of CRPS (diagnosis greater than 6 months prior) 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.

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 throughout the study to record pain levels, daily blood pressure and any additional pain medication needed.

There will be a total of 10 visits: a screening visit (day -28 to -7), clinic visits at day 1 (Baseline), week 2, week 4, week 8, and at the end of study (EOS) visit at 12 weeks. There will be additional telemedicine visits at week 1, week 3, week 5 and at the safety followup visit approximately 4 weeks after the EOS visit. There will also be followup phone call throughout the study to check on compliance and any adverse events.

All subjects will start with 40mg BID of Ketamine PR (80 mg/day) on the Baseline visit. The subjects are required to be observed in person for 6 hours following the first dose for any side effects using the Ketamine Side Effects Tools (KSET) - Baseline and Acute Treatment forms \[From: Brooke Short et al. "Development of ketamine side effect tool (KSET) as a reference: J Affect Disord. 2020 April 01; 266: 615-620. doi:10.1016/j.jad.2020.01.120\].

At an in person clinic visit 4 weeks after the Baseline visit, the dose may be increased to 80 mg BID (160 mg/day), using the same observation period as described at the Baseline visit. The study drug dosage will only be increased at this visit if the subject has not experienced adequate pain relief and has not experienced any adverse events.

Administration of the study drug will stop at the EOS visit (at 12 weeks after the Baseline visit).

Hemodynamic measurements, laboratory results, KSET - Followup form results and examination by the PI/Co-PI will be used throughout the study to assess possible adverse events (AEs). If the subject experiences any Grade 2 AEs, the PI/Co-PI will use clinical expertise and best judgement after determining the subject's level of distress and or discomfort to decide whether the subject will remain at the current dose, decrease the dose or discontinue study drug. If the subject experiences any Grade 3 Adverse Events (AEs), the study drug will be discontinued.

Eligibility Criteria:
Inclusion Criteria:

1. Male and female participants between 18 and 64 years of age, inclusive, at Screening Visit.
2. Participants with a documented history of CRPS of at least 6 months at Visit 1.
3. 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, 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 prior to 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 (females: barrier (condom, diaphragm, sponge, cervical cap) and/or oral, implantable rod, or intrauterine device birth control; males: barrier (condom)) 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.

Exclusion Criteria:

1. Known or suspected cardiovascular disease, arrythmias, and/or respiratory issues.
2. Abnormal EKG results, abnormal blood pressure (SBP \<90 or ≥ 140; DBP \<50 or ≥ 90) and/or heart rates (\<50 or \>110).
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 current or past substance use disorder within the last 5 years for any psychoactive substances other than nicotine or caffeine.
12. Known hepatic dysfunction or serious liver disease, including presence of aspartate aminotransferase (AST) levels ≥ 2 X upper limit of normal and/or alanine aminotransferase (ALT) levels ≥ 2 X upper limit of normal and/or total bilirubin ≥ 1.5 X upper limit of normal
13. Abnormal urinalysis, urine culture or abnormal creatinine
14. Evidence of moderate or severe renal impairment (CRCL \<60 ml/min) or participants with renal failure who are on any form of dialysis.
15. Current or previous history of seizures.
16. A positive pregnancy test/confirmed pregnancy test at the screening or baseline visit.
17. If Ask Suicide-Screening Questionnaire (ASQ) is positive at Grade 2 (moderate), subject will be excluded.
18. 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.
19. Previous enrollment in this trial or participation in any other clinical trial within the past 30 days prior to enrollment.