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Proof of Concept Trial of Cannabis Derivatives in Neuropathic Pain

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ClinicalTrials.gov Identifier: NCT05351801
Recruitment Status : Not yet recruiting
First Posted : April 28, 2022
Last Update Posted : August 15, 2022
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Brief Summary:

Veterans with diabetes are more likely than diabetic civilians to develop disabling chronic diabetic neuropathic pain (CDNP). Research on frontline treatments for CDNP (enhanced glycemic control, exercise, pharmacological agents), shows inconsistent outcomes and dissatisfaction among Veterans. Veterans and clinicians have shown significant interest in cannabis derivatives (THC, CBD) for neuropathic pain control, but there are no well-controlled trials guiding expectations for benefit and adverse outcomes associated with cannabis for CDNP. Because Veterans are likely to present with pain and pain-related polymorbidity significantly differing from that of civilians, a well-structured clinical trial of cannabinoids for Veterans with CDNP is vital.

The present phase II study will offer the first evidence describing the potential benefits and adverse effects of cannabinoids for CDNP in Veterans using a four-arm, double-blind, multisite randomized trial comparing THC, CBD, THC+CBD and placebo on neuropathic pain outcomes.


Condition or disease Intervention/treatment Phase
Diabetic Neuropathic Pain Drug: THC (Dronabinol) Drug: CBD (Epidolex) Drug: THC + CBD (Nabiximols) Drug: Placebo Phase 2

Detailed Description:

Chronic pain is a significant burden to United States Veterans and is a particular concern for Veterans with diabetes. Diabetic Veterans have a higher risk of chronic diabetic neuropathic pain (CDNP) than civilians with diabetes, and CDNP is more disabling for Veterans than it is for civilians. Frontline treatment for CDNP, including enhanced glycemic control, exercise, and pharmacotherapies, show inconsistent outcomes for individuals with CDNP due to poor adherence and side effects. The ongoing opioid crisis has led to significant interest in safe and effective alternatives for pain control, and there is a significant need for research on desirable options for pain control that are likely to improve treatment adherence and outcomes. Veterans groups and Veterans Affairs clinicians have expressed significant interest in cannabis and its principal constituents (delta-9-tetrahydrocannabinol, THC; cannabidiol, CBD) for pain management, but the extant research describing the potential risks and benefits of cannabis for pain is weak. This randomized trial was developed as a proof of concept study to determine if cannabis constituents (THC, CBD, and THC+CBD) are superior to placebo in reducing pain in Veterans with CDNP. The study is to recruit a sample of 320 adult Veterans who meet diagnostic criteria for high-impact CDNP, are on stable treatment(s) for CDNP, are not current cannabis users and who do not meet diagnostic criteria for Cannabis Use Disorder. After a 2-week single-blind placebo lead-in (SBPLI) to wash out part of the placebo response, eligible Veterans will be randomly assigned to one of four study arms: 1) 10 mg THC P.O ; 2) 800 mg CBD P.O ; 3) 10.8 mg THC + 10 mg CBD P.O ; or 4) placebo P.O , with an 8-week treatment including a 2-week titration phase (to minimize side effects and improve tolerability), then 4 weeks on the target treatment dose and a subsequent 2-week down titration (to minimize cannabis withdrawal symptoms).

This randomized phase II, 4-arm clinical trial aims to determine if cannabis constituents (THC, CBD) or their combination (THC+CBD) are superior to placebo in reducing pain in Veterans with CDNP. This trial will offer the first evidence describing the potential benefits and adverse effects of cannabinoids for CDNP in Veterans.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 320 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Double-blind, randomized, placebo-controlled, parallel group Phase II study with a 2-week single-blind placebo lead-in (SBPLI) followed by randomization to one of the four treatment arms: 1) 10 mg mg THC , 2) 800 mg CBD , 3) 10.8 mg THC + 10 mg CBD , and 4) placebo. The 8-week treatment phase comprises a 2-week up-titration, 4 weeks maintenance on the target dose followed by 2 weeks down-titration, to minimize cannabis withdrawal syndrome. The 2-weeks up-titration phase is to minimize side effects and improve tolerability. Efficacy will be assessed by responses during the 4-week target dose phase.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Proof of Concept Trial of Cannabis Derivatives in Neuropathic Pain.
Estimated Study Start Date : December 1, 2022
Estimated Primary Completion Date : June 30, 2027
Estimated Study Completion Date : June 30, 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Marijuana

Arm Intervention/treatment
Active Comparator: THC (Dronabinol)
Target dose of 10mg per day.
Drug: THC (Dronabinol)
Participants will receive a target dose of 10mg per day of THC (Dronabinol).

Drug: Placebo
Placebo

Active Comparator: CBD (Epidolex)
Target dose of 800 mg per day.
Drug: CBD (Epidolex)
Participants will receive a target dose of 800 mg per day of CBD (Epidolex).

Drug: Placebo
Placebo

Active Comparator: THC + CBD (Nabiximols)
Target dose of 10.8 mg / 10 mg per day.
Drug: THC + CBD (Nabiximols)
Participants will receive a target dose of 10.8 mg / 10 mg per day of THC + CBD (Nabiximols).

Drug: Placebo
Placebo

Placebo Comparator: Placebo
Identical in appearance to the three active comparators.
Drug: Placebo
Placebo




Primary Outcome Measures :
  1. To compare the short-term efficacy of THC, CBD, or THC+CBD vs Placebo on Neuropathic Pain as measured by the Numeric Rating Scale of Pain [ Time Frame: Baseline, Week 6 ]
    The mean change in the weekly average of daily Numeric Rating Scale (NRS) pain score (0-10 scale; 0=no pain, 10=worst possible pain) from baseline to week 6.


Secondary Outcome Measures :
  1. To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in pain quality (allodynia) as measured by the Quantitative Sensory Testing. [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ]
    Allodynia measured by Quantitative Sensory Testing (QST) (0-10 scale; 0=no pain, 10=worst possible pain)

  2. To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in disability and function as measured by the Neuropathic Pain Scale. [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 ]
    Neuropathic Pain Scale (NPS) total score; 7 different questions/sensations (for each individual item 0-10 scale; 0= not present/no pain, 10= most sensation). Individual scores analyzed separately for pain quality and mean score analyzed for overall neuropathic pain).

  3. To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in disability and function as measured by the Gait Speed Test [ Time Frame: Baseline, Week 4, Week 8 ]
    Distance walked (meters)/time (seconds) measured by Gait Speed Test (lower score = worse, higher score =better)

  4. To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in mean changes in perceived improvement as measured by the Patient Global Impression of Change [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ]
    Patient Global Impression of Change (PGIC) 1-7 point ordinal scale assessed (1 = worse, 7 = better)

  5. To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in mean changes in perceived improvement as measured by the patient satisfaction visual analog scale. [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 ]
    Patient satisfaction with intervention on visual analog scale (VAS, 0-100, 0=no satisfaction, 100 = complete satisfaction).

  6. To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in mean changes in quality of life measured by the Veterans RAND 12 Item Health Survey [ Time Frame: Baseline, Week 4, Week 8 ]
    Mental Component Score (MCS) and Physical Component Score (PCS) measured by Veterans RAND 12 Item Health Survey (VR-12). VR-12 is an algorithmic score with ranges from 0-100 (0 indicates worse health-related quality of life and 100 represents better health-related quality of life).

  7. To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in anxiety measured by the Generalized Anxiety Disorder-7. [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 ]
    Generalized anxiety symptomology is measured by Generalized Anxiety Disorder-7 (GAD-7) total score. (total score ranges from 0-21; Score 0-4 = minimal anxiety, Score 5-9 = mild anxiety, Score 10-14 = moderate anxiety, Score 15-21 = severe anxiety)

  8. To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in pain quality as measured by the Short Form McGill Pain Questionnaire (SF-MPQ-2). [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8 ]
    Short Form McGill Pain Questionnaire (SF-MPQ-2) total score and four subscales (continuous pain, intermittent pain, predominantly neuropathic pain, affective). (0= no pain to 5= excruciating pain)

  9. To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in mean changes in disability and function as measured by the Brief Pain Inventory-Diabetic Peripheral Neuropathy. [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 ]
    Brief Pain Inventory-Diabetic Peripheral Neuropathy (BPI-DPN) pain intensity score (first four items 0-10; 10= pain as bad as can imagine) (remaining items 0% (no relief)-100% (complete relief)) and pain interference score (0-10, 10= completely intense).

  10. To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in emotional functioning (severity of depression) as measured by the Patient Health Questionnaire-9. [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 ]
    Severity of depression is measured by Patient Health Questionnaire-9 (PHQ-9) total score (0-27; 0=none, 27=worst).

  11. To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in emotional functioning (PTSD symptoms) as measured by the PTSD Checklist-DSM-5 (PCL-5). [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 ]
    PTSD symptoms are assessed by PTSD Checklist-DSM-5 (PCL-5) total score symptom severity score (0-80; 0= not at all to 80= worst).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Able to provide written consent
  • Veterans 21 years and older at the date of screening
  • Meet NEURODIAB criteria for painful diabetic peripheral neuropathy
  • Meet criteria for persistent, high-impact pain criteria.
  • Presence of allodynia confirmed by one of the screening dynamic brush tests

Exclusion Criteria:

  • Primary source of pain not related to diabetic neuropathy
  • Hypersensitivity to THC, CBD, or THC/CBD
  • Positive urine toxicology for THC-COOH on 2 consecutive visits before and including baseline assessment
  • Unwilling to refrain from using cannabis or cannabis-based products through the entire duration of the study
  • Diagnosis of DSM-5 Cannabis Use Disorder in the past 6 months
  • Current DSM-5 diagnosis of cannabis use disorder, substance use disorder or serious psychiatric disorders
  • Actual change or intent to change is greater than a 20% change (increase or decrease) in any other medication for pain or non-pharmacological treatment from 4 weeks before the screening appointment until completion of study (i.e., visit 13)
  • Opioid doses > 400 mg MME (morphine milligram equivalent)
  • Women who are pregnant or breastfeeding, or who intend to become pregnant in the 12 weeks from enrollment
  • Any current unstable or concerning medical condition that would place the patient at increased risk, including hepatic, respiratory, immunological, cardiovascular, endocrine, or renal disease
  • Need for immediate psychiatric hospitalization
  • Enrolled in a medical marijuana program
  • Federal employee

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05351801


Contacts
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Contact: Christina L Luddy, BS (203) 932-5711 ext 4549 christina.luddy@va.gov
Contact: Mohini Ranganathan, MD (203) 932-5711 Mohini.Ranganathan@va.gov

Locations
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United States, California
VA San Diego Healthcare System, San Diego, CA
San Diego, California, United States, 92161
Contact: Albert Leung, MD    858-642-3029    albert.leung@va.gov   
United States, Connecticut
VA Connecticut Healthcare System West Haven Campus, West Haven, CT
West Haven, Connecticut, United States, 06516
Contact: Deepak D'Souza, MD MBBS    203-932-5711 ext 2594    Deepak.DSouza@va.gov   
Principal Investigator: Deepak D'Souza, MD MBBS         
United States, Rhode Island
Providence VA Medical Center, Providence, RI
Providence, Rhode Island, United States, 02908
Contact: Jane Metrik, PhD    401-273-7100 ext 3400    jane.metrik@va.gov   
United States, Texas
South Texas Health Care System, San Antonio, TX
San Antonio, Texas, United States, 78229
Contact: Muhammad Baig, MD    210-617-5300 ext 18244    muhammad.baig@va.gov   
United States, Washington
VA Puget Sound Health Care System Seattle Division, Seattle, WA
Seattle, Washington, United States, 98108
Contact: Elaine Peskind, PhD    206-277-3965    elaine.peskind@va.gov   
Sponsors and Collaborators
VA Office of Research and Development
Investigators
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Principal Investigator: Deepak D'Souza, MD MBBS VA Connecticut Healthcare System West Haven Campus, West Haven, CT
Principal Investigator: Donald McGeary, PhD South Texas Health Care System, San Antonio, TX
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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT05351801    
Other Study ID Numbers: NURP-002-20F
First Posted: April 28, 2022    Key Record Dates
Last Update Posted: August 15, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Neuralgia
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Pain
Neurologic Manifestations
Dronabinol
Nabiximols
Hallucinogens
Physiological Effects of Drugs
Psychotropic Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Cannabinoid Receptor Agonists
Cannabinoid Receptor Modulators
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists