Development and Evaluation of Computerized Chemosensory Based Orbitofrontal Networks Training for Treatment of Pain

NCT06218407 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: CBOTNS1257451R44NS125745-01A1
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 1

Brief Summary

The overarching goal of this study phase, Phase I component is to configure Computerized Chemosensory-Based Orbitofrontal Networks Training (CBOT) into Computerized Chemosensory-Based Orbitofrontal Networks Training for Treatment of Pain CBOT-Pain (or CBOT-P) for rapid and sustained reduction of Pain, Negative Affect (NA) and Cognitive Impairments. The investigators aimed at first establishing if stimulation parameters targeting key olfactory regions, and their associated networks, paired with tasks that synergistically activate the orbitofrontal cortex (OFC) would have significantly different acute (\< 7 days) effects in pain and NA intensity reductions. The hypothesis is that the short burst paradigm will more effectively activate the medial OFC and its functional connectivity with medial temporal affective networks, and result in greater reduction of affect and pain severity ratings after 7 days. The investigators will further examine if enhancing the odor regimen with beta-caryophyllene (BCP) content would have more dramatic effects in acute relief of pain, NA, and cognition. Aim 1.1: To optimize CBOT-P stimulation parameters and olfactory stimulants for pain, affect and cognition in CP with and without high NA. This is a 14-day prospective study, in which fMRI and rs-fMRI will be acquired at baseline and day 7 during exposure to short vs long-burst CBOT stimulations. This is followed by daily treatment with short-burst versus long-burst CBOT paradigm over 14 days, during which pain and NA measures will be recorded daily by the subjects, and assessed by train research staff at baseline, day 7 and day 14. Aim 1.2: To determine if CBOT regimen optimized with BCP content produces stronger and faster pain and affective response. This is a 14-day prospective study design, in which daily treatment of CBOT-PLUS (i.e., CBOT with BCP) will be compared against daily treatment with CBOT without BCP enhancement (CBOT). Subjects and clinicians are blinded to the assigned arms. Pain and NA measures will be recorded daily by the subjects and assessed by trained research staff at baseline and day 14.

Conditions

Chronic Pain; Low Back Pain

Keywords

Chronic Pain (CP); Pain; Negative Affect (NA); Cognitive Impairments; Attenuation of Structural Brain loss in CP with high NA; PACS outcome; Orbitofrontal cortex; Chemosensory-Based Orbitofrontal Networks Training

Outcome Measures

Primary Outcomes (12)

• Relative changes in blood oxygen level dependent (BOLD) signals from fMRI of orbitofrontal brain regions in response to short durations (i.e., short-bursts) and to long durations (i.e., long-bursts) of repetitive odor stimulations. Aim 1.1

  The blood-oxygen-level-dependent (BOLD) signal, acquired in functional Magnetic Resonance Imaging (fMRI), is a reflection of changes in deoxyhemoglobin driven by localized changes in brain blood flow and blood oxygenation, which are coupled to underlying neuronal activity by a process termed neurovascular coupling. In the context of pain disorders, fMRI has been used to study changes in brain function related to pain and to responses to interventions for pain. In the context of this study, positive BOLD signals in the brain region of interest, seen in response to odorant stimuli, represent a decrease in deoxyhemoglobin and thus an over-oxygenation of the responding region. Studies have shown that these changes in BOLD signals correlate with brain activity - with positive increase in BOLD signal reflective of increased brain activity and decreased BOLD signal reflective of reduced brain activity.

  Baseline

• Changes in the resting-state functional connectivity between midbrain and corticolimbic brain regions Aim 1.1

  Changes in the resting-state functional connectivity between midbrain and corticolimbic brain regions, defined as correlations between low-frequency oscillations in the functional magnetic resonance (fMRI) blood oxygenation level dependent signal in these brain regions of interest acquired in the absence of a cognitive task. As a correlation, this measure ranges from -1 to 1. The higher the value (above zero) between two brain regions the more positively correlated are their low-frequency oscillations of fMRI blood oxygenation level dependent signals. The lower their value (below zero) between brain regions the more negatively correlated are their low-frequency oscillations of fMRI blood oxygenation level dependent signals.

  Baseline to day 7

• Patient Reported Outcomes Measurement Information System (PROMIS) Numeric Rating Scale v1.0 - Pain Intensity Aim 1.1

  Change in 11-point score PROMIS Numeric Rating Scale v1.0 - Pain Intensity from baseline. The Numeric Rating Scale measures each consist of a single item rating pain on average over the past 7 days from 0 (no pain) to 10 (worst pain).

  Baseline to day 7

• Positive and Negative Affect Schedule (PANAS) rating scale Aim 1.1

  Change in negative affect score from the PANAS rating scale It consists of two 10-item scales to measure both positive and negative affect. Each item is rated on a 5-point scale of 1 (not at all) to 5 (very much). Positive Affect Scores can range from 10 - 50, with higher scores representing higher levels of positive affect. Negative Affect Scores can range from 10 - 50, with lower scores representing lower levels of negative affect.

  Baseline to day 7

• Relative changes in blood oxygen level dependent (BOLD) signals from fMRI of orbitofrontal brain regions in response to short durations (i.e., short-bursts) and to long durations (i.e., long-bursts) of repetitive odor stimulations. Aim 1.1

  The blood-oxygen-level-dependent (BOLD) signal, acquired in fMRI, is a reflection of changes in deoxyhemoglobin driven by localized changes in brain blood flow and blood oxygenation, which are coupled to underlying neuronal activity by a process termed neurovascular coupling. In the context of pain disorders, fMRI has been used to study changes in brain function related to pain and to responses to interventions for pain. In the context of this study, positive BOLD signals in the brain region of interest, seen in response to odorant stimuli, represent a decrease in deoxyhemoglobin and thus an over-oxygenation of the responding region. Studies have shown that these changes in BOLD signals correlate with brain activity - with positive increase in BOLD signal reflective of increased brain activity and decreased BOLD signal reflective of reduced brain activity.

  7 days after baseline

• Patient Reported Outcomes Measurement Information System (PROMIS) Numeric Rating Scale v1.0 - Pain Intensity Aim 1.2

  Change in 11-point score PROMIS Numeric Rating Scale v1.0 - Pain Intensity from baseline. The Numeric Rating Scale measures each consist of a single item rating pain on average over the past 7 days from 0 (no pain) to 10 (worst pain).

  Baseline to day 7

• Positive and Negative Affect Schedule (PANAS) rating scale Aim 1.2

  Change in negative affect score from the PANAS rating scale It consists of two 10-item scales to measure both positive and negative affect. Each item is rated on a 5-point scale of 1 (not at all) to 5 (very much). Positive Affect Scores can range from 10 - 50, with higher scores representing higher levels of positive affect. Negative Affect Scores can range from 10 - 50, with lower scores representing lower levels of negative affect.

  Baseline to day 7

• Patient Reported Outcomes Measurement Information System (PROMIS) Numeric Rating Scale v1.0 - Pain Intensity Aim 1.1

  Change in 11-point score PROMIS Numeric Rating Scale v1.0 - Pain Intensity from baseline. The Numeric Rating Scale measures each consist of a single item rating pain on average over the past 7 days from 0 (no pain) to 10 (worst pain).

  Baseline to day 14

• Positive and Negative Affect Schedule (PANAS) rating scale Aim 1.1

  Change in negative affect score from the PANAS rating scale It consists of two 10-item scales to measure both positive and negative affect. Each item is rated on a 5-point scale of 1 (not at all) to 5 (very much). Positive Affect Scores can range from 10 - 50, with higher scores representing higher levels of positive affect. Negative Affect Scores can range from 10 - 50, with lower scores representing lower levels of negative affect.

  Baseline to day 14

• Changes in the resting-state functional connectivity between midbrain and corticolimbic brain regions Aim 1.1

  Changes in the resting-state functional connectivity between midbrain and corticolimbic brain regions, defined as correlations between low-frequency oscillations in the functional magnetic resonance (fMRI) blood oxygenation level dependent signal in these brain regions of interest acquired in the absence of a cognitive task. As a correlation, this measure ranges from -1 to 1. The higher the value (above zero) between two brain regions the more positively correlated are their low-frequency oscillations of fMRI blood oxygenation level dependent signals. The lower their value (below zero) between brain regions the more negatively correlated are their low-frequency oscillations of fMRI blood oxygenation level dependent signals.

  Baseline to 14

• Patient Reported Outcomes Measurement Information System (PROMIS) Numeric Rating Scale v1.0 - Pain Intensity Aim 1.2

  Change in 11-point score PROMIS Numeric Rating Scale v1.0 - Pain Intensity from baseline. The Numeric Rating Scale measures each consist of a single item rating pain on average over the past 7 days from 0 (no pain) to 10 (worst pain).

  Baseline to day 14

• Positive and Negative Affect Schedule (PANAS) rating scale Aim 1.2

  Change in negative affect score from the PANAS rating scale It consists of two 10-item scales to measure both positive and negative affect. Each item is rated on a 5-point scale of 1 (not at all) to 5 (very much). Positive Affect Scores can range from 10 - 50, with higher scores representing higher levels of positive affect. Negative Affect Scores can range from 10 - 50, with lower scores representing lower levels of negative affect.

  Baseline to day 14

Secondary Outcomes (18)

• Patient Reported Outcomes Measurement Information System (PROMIS) Short Form v1.1 - Pain Interference scores. Aim 1.1

  Baseline to day 7

• Patient Reported Outcomes Measurement Information System (PROMIS) Short Form v1.0 - Anxiety scores Aim 1.1

  Baseline to day 7

• Patient Reported Outcomes Measurement Information System (PROMIS) Short Form v1.0 - Sleep Disturbance scores Aim 1.1

  Baseline to day 7

• Pittsburgh Sleep Quality Index (PSQI) Aim 1.1

  Baseline to day 7

• Patient Reported Outcomes Measurement Information System (PROMIS) Short Form v1.0 - Anxiety scores Aim 1.2

  Baseline to day 7

Study Arms (4)

Computerized Chemosensory-Based Orbitofrontal Cortex Training (CBOT) short-burst paradigm

EXPERIMENTAL

CBOT consists of repetitive cycles of olfactory stimulation and tasks daily for 14 days.

Combination Product: Computerized Chemosensory-Based Orbitofrontal Cortex Training (CBOT) short burst paradigm

Computerized Chemosensory-Based Orbitofrontal Cortex Training (CBOT) long-burst paradigm

EXPERIMENTAL

CBOT consists of repetitive cycles of olfactory stimulation and tasks daily for 14 days.

Combination Product: Computerized Chemosensory-Based Orbitofrontal Cortex Training (CBOT) long burst paradigm

CBOT plus (CBOT + beta caryophyllene [BCP])

EXPERIMENTAL

CBOT device enhanced with BCP

Combination Product: Computerized Chemosensory-Based Orbitofrontal Cortex Training plus beta caryophyllene (CBOT-Plus)

Computerized Chemosensory-Based Orbitofrontal Cortex Training (CBOT)

SHAM COMPARATOR

CBOT device without BCP enhancement as control for BCP

Combination Product: Computerized Chemosensory-Based Orbitofrontal Cortex Training (CBOT)

Interventions

Computerized Chemosensory-Based Orbitofrontal Cortex Training (CBOT) short burst paradigm COMBINATION_PRODUCT

The CBOT device is designed to stimulate intensive neural activity in the medial orbitofrontal regions over long periods of time.

Also known as: CBOT-Short

Computerized Chemosensory-Based Orbitofrontal Cortex Training (CBOT) short-burst paradigm

Computerized Chemosensory-Based Orbitofrontal Cortex Training (CBOT) long burst paradigm COMBINATION_PRODUCT

The CBOT device is designed to stimulate intensive neural activity in the lateral orbitofrontal regions and networks over long periods of time.

Also known as: CBOT-Long

Computerized Chemosensory-Based Orbitofrontal Cortex Training (CBOT) long-burst paradigm

Computerized Chemosensory-Based Orbitofrontal Cortex Training plus beta caryophyllene (CBOT-Plus) COMBINATION_PRODUCT

CBOT device enhanced with BCP.

Also known as: CBOT Plus

CBOT plus (CBOT + beta caryophyllene [BCP])

Computerized Chemosensory-Based Orbitofrontal Cortex Training (CBOT) COMBINATION_PRODUCT

CBOT device administering continuous olfactory stimuli (i.e., not programmed for short or long burst), and without BCP enhancement.

Also known as: CBOT

Computerized Chemosensory-Based Orbitofrontal Cortex Training (CBOT)

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ages 18-85.
• Pain duration \> 6 months.
• Must meet the minimum criteria for cognitive function using the PROMIS 2-item cognitive screener \>3.
• Average pain score of \> 5/10, with low back pain being the primary pain site.
• CLBP (chronic low back pain) meeting Quebec Task Force Classification System Categories I-III.
• Evidence of a prior lumbar spine X-ray to rule out red flags, such as infection, tumor, or fracture.
• For those taking opioids (the opioid subgroup), participants must be prescribed opioids currently for at least 3 consecutive months prior to enrollment. Such patients must be on opioids for a minimum of three months, taking them daily or intermittently during the week.
• Subject must agree that opioids cannot be increased during the study.
• No substance use disorder (SUD), except tobacco, in the past year based on substance screening surveys and frequent urine toxicology screens.
• No acute suicidality, mania, or psychosis. This will be assessed at study entry which will also include a review of history in the EHR, Structured Clinical Interview for Psychiatric Disorders (SCID-5) and Columbia Suicide Severity Rating Scale (C-SSRS) and -
• Participants must sign IRB-approved consent.

You may not qualify if:

• Back surgery within the past six months.
• Active worker's compensation or litigation claims.
• New pain and/or psychiatric treatments within 2 weeks of enrollment.
• Intent to add new or increase pain treatments during the study period, such as back surgery, nerve block procedures, or medications.
• Intent to add new psychiatric treatments during the first 3 months of the study.
• Any clinically unstable systemic illness that is judged to interfere with the trial.
• History of cardiac, nervous system, or respiratory disease that, in the investigator's judgment, precludes participation in the study because of a heightened potential for respiratory depression.
• Non-ambulatory status.
• Pregnancy or the intent to become pregnant during the study. Women of childbearing age will have urine pregnancy testing at enrollment and monthly.
• Anosmia or significant nasal disease
• Contraindications to MRI
• Stroke or TBI (traumatic brain injury).

Sponsors & Collaborators

• Evon Medics LLC: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• Howard University: collaborator
• Georgetown University: collaborator

Study Sites (1)

Howard University

Washington D.C., District of Columbia, 20060, United States

Location

MeSH Terms

Conditions

Chronic Pain; Low Back Pain; Pain; Cognitive Dysfunction

Interventions

caryophyllene

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Back Pain; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Study Officials

• Charles Nwaokobia

  Evon Medics LLC

  PRINCIPAL INVESTIGATOR

• Evaristus Nwulia, MD

  Howard University

  PRINCIPAL INVESTIGATOR

• Tanya Alim, MD

  Howar

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 8, 2024
• First Posted: January 23, 2024
• Study Start: April 27, 2023
• Primary Completion: September 15, 2023
• Study Completion: September 15, 2023
• Last Updated: January 23, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)