Human Experimental Models of Pain (HEMP)

A Pilot Study for Developing a Comprehensive Signal Detection Approach for the Mechanisms of Action and Analgesic Efficacy of Two Analgesics Using Human Experimental Models of Pain (HEMP)

Study Description:

This pilot study is designed to validate the performance characteristics of HEMP. This pilot study is a single-center, randomized, double-blind, three-period, three-treatment crossover designed to investigate how well the HEMP model distinguishes the analgesic properties of two medications, one which acts centrally and the other one acts peripherally.

Up to 25 healthy adults will be enrolled in this study, which will consist of a screening phase and a treatment phase with three periods. Participants will be randomly assigned to receive either a gabapentinoid (pregabalin), a non-steroidal anti-inflammatory drug (NSAID) (naproxen), or a placebo during each period of the treatment phase (see Table 2 for the study drugs). Each dose will be separated by a wash-out period of at least 48 hours.

Assessments will be performed at baseline and over a period of 8 hours following each drug administration to establish pharmacodynamic, pharmacokinetic, and safety properties of the treatments.

Objectives:

Primary Objective:

To establish the ability of HEMP to demonstrate the analgesic efficacy of pregabalin and naproxen based on their known mechanisms of action (central vs. peripheral, respectively) as measured by the severity of experimental pain, allodynia, and hyperalgesia across three pain models.

Secondary Objectives:

To demonstrate that HEMP can determine factors that differentiate responders from non-responders to the study drugs, when evaluating their analgesic properties of these drugs in humans.

Endpoints:

Pharmacodynamics (PD) Primary Endpoint:

* Change from baseline in pain intensity (PI) visual analog scale (VAS) score for allodynia (soft brush) after first heat/capsaicin application (HCM)
* Change from baseline in PI VAS score for hyperalgesia (pin-prick) after first HCM
* Change from baseline in PI VAS score for hyperalgesia (pin-prick) ultraviolet (UVB) light exposure.
* Change from baseline in PI VAS score for heat hyperalgesia (thermal-heat pain) UVB
* Change from baseline in PI VAS score after hand removal in Cold Pressor Test (CPT), i.e., cold water immersion

Secondary Endpoints:

* Weighted mean (based on area under the curve (AUC)) VAS score for spontaneous pain over 0-60 mins following first and second HCM.
* Area of secondary hyperalgesia to pin-pick after HCM following first and second HCM
* Change from baseline in PI VAS score for thermal-heat hyperalgesia following first and second HCM
* Proportion of participant who had at least 30% reduction in PI VAS scores from baseline after a Quantitative Sensory Testing (QST) measure (soft brush, light pressure, pin-prick, thermal contact- warm, thermal contact-heat pain, cold) after first and second HCM and UVB PK parameters (e.g., AUClast, Clast, Cmax, tmax)

* INCLUSION CRITERIA:

For an individual to be eligible to participate in this study, they must meet all of the following criteria:

* Voluntarily consent to participate and provide written informed consent prior to the start of any study-specific procedures.
* Read and speak English fluently.
* State willingness to comply with all study procedures and availability for the duration of the study.
* Are not pregnant or breastfeeding.
* Are 18 or older years of age at screening.
* Have a skin type score between 2 and 5 (inclusive) on the Fitzpatrick Scale.
* Must correctly identify at least nine out of 12 temperatures (32 degrees Celsius, 38 degrees Celsius, 44 degrees Celsius, and 50 degrees Celsius, each presented three times) during the sensory discrimination test at screening.
* Provide a verbal pain rating between 4 and 9 (inclusive) during the intradermal capsaicin challenge at screening. The study team will verify tolerability, and participants will continue only after it has been confirmed.
* During the cold pressor test at screening, provide a verbal pain rating between 4 and 9 (inclusive) and keep one hand completely immersed in ice-cold water (1-4 degrees Celsius) between 1 and 4 minutes (inclusive). The study team will verify tolerability, and participants will continue only after it has been confirmed.
* Are able to learn and perform all quantitative sensory testing QST procedures (see the separate QST manual).
* Have the ability to take oral medication and be willing to adhere to the study intervention regimen.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

* Have a history or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the participant or the validity of the study results.
* Have alcohol or drug dependence (excluding nicotine and caffeine) within the past 2 years, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM IV-TR) and/or participants who have ever been in a substance or alcohol rehabilitation program to treat their substance dependence are currently seeking such treatment.
* Have a clinically significant abnormal finding on the physical exam, medical history, or clinical laboratory results at screening.
* Have a history of psychotic reactions, a non-psychotic emotional disorder, or another mental illness that, in the opinion of the investigator, may affect the ability of the participant to participate in the study.
* Have recent history of suicidal ideation or suicidal behavior within the past 6 months, as assessed by the Columbia- Suicide Severity Rating Scale (C-SSRS) at screening (baseline version) or at check-in ( Since Last Visit version).
* Have a history of allergy or hypersensitivity to pregabalin or other gabapentinoids, naproxen or other NSAIDs, or another ingredient in the study drugs, or anything else that, in the opinion of the Investigator, could put the participant at risk.
* Have participated in another clinical trial (randomized participants only) within 30 days prior to the first dose of study medication.
* Use any prescription medication, except hormonal contraceptive or hormonal replacement therapy, from 14 days prior to the first dose of study medication until study participation has ended without evaluation and approval by the Investigator.
* Donate blood or plasma within 30 days prior to the first dose of study medication until the end of study participation. It is recommended that participants not donate blood or plasma until at least 30 days after their study participation has ended.
* Female participants who are currently pregnant or breastfeeding, or who are planning to become pregnant during the study or within 30 days after the last study drug administration.
* Show a positive urine alcohol test at screening.
* Have smoked or used tobacco- or nicotine-containing products within 30 days prior to the first dose of study treatment until the end of the study.
* Have an allergy to capsaicin or another capsaicinoid.
* Have a tattoo, excessive scarring or discoloration, keloid formation, or, at the Investigator s discretion, otherwise unhealthy skin (e.g., eczema, psoriasis, burn, and cut) at a QST site.
* Have a significant history of nerve injury or damage at a QST site, at the Investigator s discretion.
* Participants who report any stimulus as intolerable at any point during the screening procedures will be excluded from participation.

Over-encapsulated matching placebo administered as a single oral dose in one treatment period of this randomized, double-blind, 3-period crossover study. The placebo is made to look identical to active study drug capsules to maintain blinding. Each participant receives placebo once, with at least 48 hours washout between treatment periods.

Over-encapsulated oral naproxen, 550 mg, administered as a single dose in one treatment period of this randomized, double-blind, 3-period crossover study. Each participant receives naproxen once, with at least 48 hours washout between treatment periods.

Over-encapsulated oral pregabalin, 300 mg, administered as a single dose in one treatment period of this randomized, double-blind, 3-period crossover study. Each participant receives pregabalin once, with at least 48 hours washout between treatment periods.

Participants assigned to this sequence will receive single-dose oral pregabalin 300 mg in Period 1, naproxen 550 mg in Period 2, and matching placebo in Period 3. Treatment periods are separated by at least 48 hours.

Participants assigned to this sequence will receive single-dose oral pregabalin 300 mg in Period 1, matching placebo in Period 2, and naproxen 550 mg in Period 3. Treatment periods are separated by at least 48 hours.

Participants assigned to this sequence will receive single-dose oral naproxen 550 mg in Period 1, pregabalin 300 mg in Period 2, and matching placebo in Period 3. Treatment periods are separated by at least 48 hours.

Participants assigned to this sequence will receive single-dose oral naproxen 550 mg in Period 1, matching placebo in Period 2, and pregabalin 300 mg in Period 3. Treatment periods are separated by at least 48 hours.

Participants assigned to this sequence will receive matching placebo in Period 1, pregabalin 300 mg in Period 2, and naproxen 550 mg in Period 3. Treatment periods are separated by at least 48 hours.

Participants assigned to this sequence will receive matching placebo in Period 1, naproxen 550 mg in Period 2, and pregabalin 300 mg in Period 3. Treatment periods are separated by at least 48 hours.