(2R,6R)-Hydroxynorketamine for the Treatment of Neuropathic Pain

(2R,6R)-Hydroxynorketamine a Novel Therapeutic Analgesic for the Treatment of Neuropathic Pain: A Randomized Double Blind Cross-Over Trial.

The goal of this randomized double blind three way (1:1:1) cross over clinical trial is to evaluate the effectiveness and duration of analgesia of a single infusion of (2R,6R)-HNK 0.5mg/kg compared with ketamine 0.5mg/kg and saline with a 5-week interval between treatments on pain, pain qualities, physical function, pain interference, sleep disturbance and quality of life in subjects with neuropathic pain of the extremities.

The questions that this study will address are:

1. What is the analgesic efficacy of (2R,6R)-HNK on pain intensity and pain qualities in patients with chronic (>3 month) neuropathic pain (NP).
2. What will be the effective duration of a single infusion of (2R,6R)-HNK in patients with NP.
3. Will (2R,6R)-HNK reduce pain related effects including interference in daily activities of life, sleep disturbances and change the qualities of pain reported by patients.

Participants will receive each of the three study drugs in a random order at 5-week intervals over a 15 week period. The drug will be administered as a 45-minute infusion.

Participants will complete quantitative sensory and pain evaluations and complete patient reported pain outcomes prior to receiving the first study drug and at 7, 14 and 21 and 35 days following study drug administration.

Adult patients (18 to 80 years) with an established diagnosis of chronic (> 3 month) neuropathic pain (NP) of the extremities will be identified and screened for study inclusion. After informed consent is obtained, subject will be randomized into a (2R,6R)-HNK (H), ketamine (K) or saline (S) infusion groups for each of the study drug administration periods. The group sequences for the infusions will be: KSH, HSK, KHS, SKH and HKS and each group will contain 5 subjects at each sequence. Study subjects will be evaluated for at least 7 days prior to the first treatment and for 35 days following each treatment. Researchers involved in the subject's care and assessments will be blinded to group allocation. Safety will be assessed throughout the study. Baseline safety assessments will include height, body mass index (BMI), weight, temperature, medical, visual and ocular history, physical examinations, and vital signs (VS). Prior to study commencement and 28 days after each drug infusion a blood chemistry panel, liver function tests (LFT), a complete blood count (CBC) and a 12-lead electrocardiogram (ECG) will be obtained. A pretreatment quantitative pain evaluation will assess overall pain level, pain tolerance, pinprick hyperalgesia, touch, brush and cold allodynia. Patients will be maintained on their current scheduled analgesic regimen during the study and instructed to use on-demand analgesic only as needed.

Inclusion Criteria:

• Adult patients (18 to 75 years) with an established diagnosis of chronic (> 3 month) NP of the extremities.
• Presence of NP as determined at screening using the 10 item Neuropathic Pain Questionnaire (DN4), with a score of ≥4 required for study inclusion.
• Ability to read and write English sufficiently to complete study related procedures.
• A body mass index (BMI) (weight [kg]/height[m ]) between 18 and 35 kg/m (inclusive) and weighs between 50 kg and 120 kg (110 - 264 pounds).
• Blood pressure with subject is in a supine position for approximately 5 minutes between 90 and 145 mmHg systolic and no higher than 90 mmHg diastolic at baseline.
• A 12-lead ECG with no clinically significant abnormality as judged by the Investigator and QTc interval ≤ 450 milliseconds at baseline.
• Resting pulse rate between 45 and 100 beats per minute.
• Clinical laboratory findings and liver function tests within the normal range, or if outside of the normal ranges, deemed not clinically significant in the opinion of the PI.
• Agree to provide written informed consent and comply with the rules regarding consumption of alcohol, caffeinated beverages, and tobacco/nicotine products during the study.
• Patients may be taking scheduled or as needed medications for their chronic neuropathic pain and agree to continue taking the scheduled medications throughout the study period.
• If the subject experiences pain relief they may elect not to take as needed medications.

Exclusion Criteria:

• Subjects with suspected increased intracranial or intraocular pressure.
• Subjects that have previously received ketamine for the treatment of a chronic pain diagnoses.
• Previous or current participation in any clinical study with an investigational drug, device, or biologic within 30 days.
• Subjects with severe medical illness including (but not limited to) hepatic, cardiovascular, pulmonary, renal, hematologic, endocrine, gastrointestinal, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease that in the opinion of the PI would endanger the safety of the subject or the validity of the study results.
• Clinically significant acute illness in the 2 weeks prior to dosing.
• Inability to effectively communicate with research staff.
• Subjects with known liver disease.
• Widespread pain or a diagnosis of fibromyalgia.
• Current diagnosis of mental illness.
• Pregnancy.
• Allergy to ketamine or any study drug.
• Consumption of beverages or food that contain alcohol, grapefruit, poppy seeds, Brussel sprouts, pomegranate, broccoli, char-grilled meat within 2 days prior to drug administration.
• Use of tobacco or nicotine-containing products within 4 weeks prior to drug administration.
• Poor peripheral venous access.
• Subjects in the opinion of the PI should not participate in the study.