Investigating the Analgesic Potential of... — Clinical Trial Details

Investigating the Analgesic Potential of (2R,6R)-HNK in Acute Pain in Healthy Volunteers

This Phase II, randomised, double-blind, placebo-controlled crossover trial (n=92) will evaluate the analgesic potential of a single intravenous infusion of (2R,6R)-hydroxynorketamine (HNK) in healthy adults aged 18 to 60 years. The study will assess whether 0.5 mg/kg HNK reduces acute experimental pain during quantitative sensory testing (QST) and will also examine pain-related and emotion-related brain responses. Participants will receive HNK or matched placebo as a single intravenous infusion over approximately 40 minutes, with visits repeated 1 to 3 weeks apart in the treatment group. A no-treatment control arm is included to help estimate natural changes and placebo effects. Pain ratings, blood draws, and functional MRI assessments will be repeated before and after infusion, including follow-up measures immediately after treatment, at 4 to 5 hours, and one day later. The trial will also compare placebo with the no-treatment group to gauge placebo analgesia.

Detailed Description

Background:

Opioid drugs are often prescribed for acute and chronic pain. But these drugs are addictive, and they lead to more than 14,000 overdose deaths in the United States each year. Researchers want to find new drugs that relieve pain but are not addictive. This study will test whether a single dose of an experimental drug called (2R,6R)-hydroxynorketamine (HNK) can help reduce short term pain in healthy adults. HNK is related to ketamine. Studies suggest HNK might be as effective as ketamine at reducing pain but that it might have fewer side effects. In this study we will test how HNK affects pain and emotion. The results of this study may help us understand whether HNK has pain relieving effects and how it works in the brain, which could inform future pain treatments.

Objective:

To test a study drug \[(2R,6R)-hydroxynorketamine (HNK)\] for treating pain in healthy people.

Eligibility:

Healthy people aged 18 to 60 years.

Design:

Up to 92 healthy volunteers between 18 and 60 years old without chronic pain or psychiatric conditions will participate in the study. The study will take place at the NIH Clinical Center in Bethesda, Maryland. Each participant s involvement will last up to two months. The overall study is expected to last about three years (36 months).

The study has 2 parts.

In part 1, participants will have up to 2 clinic visits. They will be screened and have blood draws to make sure they're eligible for the study. They will complete sensory testsing and have MRI scans.

Sensory tests involve rating painful and nonpainful stimuli, includeincluding being touched with a hot or cold probe, brushes or pinpricks, and pinches or squeezes.

Eligible participants will have an imaging scan that shows brain activity: During the scan, they will rate heat, hear pleasant or unpleasant sounds, and view unpleasant or pleasant pictures. After completing part 1, eligible participants will be invited to part 2, which includes overnight stays at NIH.

In part 2, participants will be assigned to either a treatment group or a nontreatment group.

The treatment group will have 2 overnight visits of 2 nights each. The visits will be 1 to 3 weeks apart.

For 1 visit, participants will receive HNK. For the other, they will receive a placebo. A placebo looks just like the study drug but contains no medicine. HNK and placebo are given through a tube inserted into a vein in the arm. The sensory tests, blood draws, and MRI scans will be repeated at each visit. Participants will not be told whether they got the drug or placebo on each visit.

The nontreatment group will have 1 overnight visit. They will not receive the drug or placebo. The sensory tests, blood draws, and MRI scans will be repeated.

Participants cannot drink alcohol, use recreational drugs, or take certain other medicine or supplements during the study.

Study Arms & Interventions

(2R,6R)-HNK

experimental

Participants receive a single intravenous infusion of (2R,6R)-hydroxynorketamine (HNK) at a dose of 0.5 mg/kg over approximately 40 minutes during an inpatient research visit. Pain responses and brain activity are assessed before and after infusion using quantitative sensory testing (QST) and functional MRI (fMRI).

Interventions

Ketamine0.5 mg/kg
via IV• single intravenous infusion• 1 doses total

No Treatment<TAB>

inactive

Participants do not receive a drug or placebo infusion. They undergo baseline and follow up pain testing and imaging assessments to characterize the natural history of pain responses and isolate placebo effects.

Placebo

inactive

Participants receive a single intravenous infusion of placebo (saline) matched in volume and infusion duration (approximately 40 minutes) to the active drug. Pain and brain responses are assessed using the same procedures as the experimental condition.

Interventions

Placebo
via IV• single infusion• 1 doses total

Participants

Ages

18 – 60

Sexes

Male & Female

BMI

Psychosis History

Inclusion Criteria

In order to be eligible to participate in this study, an individual must meet all of the following criteria:
1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Aged 18-60
4. In good general health as evidenced by medical history
5. Ability to take intravenous medication and be willing to adhere to the (2R,6R)-HNK regimen
6. For females of reproductive potential: Use of highly effective contraception starting at the time of enrollment and agreement to use such a method during study participation and for an additional four weeks after the end of participation
7. For males of reproductive potential: Use of condoms or other effective contraceptive methods from the time of enrollment, and for an additional 90 days after the end of participation
8. Agreement to adhere to Lifestyle Considerations throughout study duration
9. Ability of participant to understand and the willingness to sign a written informed consent document

Exclusion Criteria

An individual who meets any of the following criteria will be excluded from participation in this study:00
1. Current use of disallowed concomitant medications.
2. Presence of ferromagnetic devices or any devices that could pose a risk relating to the safety of the fMRI procedure, including implanted cardiac pacemaker or auto-defibrillator, insulin pump, ferromagnetic metal in the cranial cavity or eye (e.g. aneurysm clip, implanted neural stimulator, cochlear implant, ocular foreign body), and irremovable body piercings.
3. Pregnancy or lactation.
4. Has a clinically important acute or active chronic disease
5. Has a history of any clinically important cardiovascular findings
6. Has a history of serious medical illness, including but not limited to the following body systems and organs or those that in the judgment of the Principal Investigator and Medical Advisory Investigator pose a risk to the participant s ability to safely participate in the study:
1. Hepatic diseases (e.g. active viral hepatitis infection or cirrhosis of the liver)
2. Cardiovascular disease (including ischemic heart disease, coronary artery disease, congestive heart failure, poorly controlled hypertension due to risk of further blood pressure elevation and increase in demand on cardiac function from study drug)
3. Renal/urologic (e.g chronic kidney disease or acute kidney injury, history of bladder dysfunction due to theoretical risk of ketamine-induced cystitis)
4. Endocrinologic (including diabetes due to association with progressive abnormality of the microvasculature and nervous system)
5. Central nervous system disorder, neuromuscular disease, or other neurologic disorder (e.g. stroke, brain damage, elevated intraocular pressure or history of or presence of diseases that are associated with elevated intracranial pressure).
6. Pulmonary disease (e.g., asthma, emphysema, chronic bronchitis)
7. Has a clinically important vital sign, ECG, or clinical laboratory finding.
8. Has a major medical condition or medical history that in a clinician's assessment could affect heat sensitivity, pain thresholds, or somatosensation (e.g., Raynaud s disease, peripheral neuropathy, or circulatory disorder)
9. Has a significant current psychiatric condition (including mood disorders, anxiety disorders, or substance use disorders) or has a history of psychosis, hospitalization for a mental health condition, or recurrent psychiatric episodes.
10. Has a current chronic pain condition or has had chronic pain in the past (painful condition lasting more than six months).
11. Has a dermatological condition that might influence cutaneous sensibility such as scars or burns, or has a tattoo in the testing region
12. Unable to comply with study procedures or follow-up visits.
13. Those with an abnormality on a structural MRI.
14. Individuals who are left-handed (based on self-report or score on handedness questionnaire).
15. Participants who are currently using drugs (except for caffeine, nicotine, or cannabis) must not have used illicit substances or known drugs of abuse in the two weeks prior to screen and must have a negative drug urine test at baseline and on each research visit prior to infusion. Cannabis use is exclusionary if the use is daily, or if participants are unable to abstain during the study, or if function of daily life is impaired by use as determined by a clinician.
16. Participants with a history of head injury that resulted in loss of consciousness exceeding five minutes.
17. Participants with unstable clinical hyperthyroidism or hypothyroidism.
18. Participants with one or more seizures without a clear and resolved etiology.
19. Clinically significant abnormal laboratory tests specifically defined by:
1. Alkaline phosphatase (Alk Phos) \> 150 U/L
2. Alanine aminotransferase (ALT) \>55 U/L
3. Aspartate aminotransferase (AST) \> 34 U/L
4. Total bilirubin (TB) \> 1.2 mg/dL
5. Direct bilirubin (DB) \> 0.5 mg/dL
6. 25-hydroxyvitamin D \< 20 ng/mL
7. Folate \< 2ng/mL
8. Vitamin B12 \< 200 pg/mL
20. Positive Human Immunodeficiency Virus (HIV) test.
21. Participants with Coronavirus Disease 2019 (COVID-19) or suspected COVID-19.
22. NIH employee who is a subordinate/relative/co-worker of any investigator on the protocol.
23. Inability to read and understand English. Non-English speakers will not be eligible as most of the required monitoring and rating instruments are not validated in languages other than English.
24. Participants may not use any prescription or nonprescription drugs including OTC, herbal medicine, or dietary supplements within 14 days or 5 half-lives, whichever is longer, prior to drug administration.

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Investigating the Analgesic Potential of (2R,6R)-HNK in Acute Pain in Healthy Volunteers

Detailed Description

Locations

Study Arms & Interventions

(2R,6R)-HNK

Interventions

No Treatment<TAB>

Placebo

Interventions

Participants

Inclusion Criteria

Exclusion Criteria

Study Details

Study Team

Sponsors & Collaborators