Proof of Concept Trial of Cannabis Derivatives in Neuropathic Pain

Study Overview
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Brief Summary
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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.

Detailed Description
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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. 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.

Official Title
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Proof of Concept Trial of Cannabis Derivatives in Neuropathic Pain.

Conditions
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Diabetic Neuropathic Pain

Intervention / Treatment
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* Drug: THC (Dronabinol)
* Drug: CBD (Epidolex)
* Drug: THC + CBD (Nabiximols)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: Diabetic neuropathy is not a primary source of neuropathic pain Hypersensitivity to THC, CBD, or THC/CBD Self-report of cannabis use during screening phase confirmed by positive urine toxicology for THC-COOH as measured and resulted at visit 5 before randomization 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, or in the opinion of the investigator, prevents adherence with the protocol Need for immediate psychiatric hospitalization Enrolled in a medical marijuana program Federal employee

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind, randomized, placebo-controlled, parallel group Phase II study with 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 two-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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: THC (Dronabinol)<br>Target dose of 10mg per day. | Drug: THC (Dronabinol)<br>* Participants will receive a target dose of 10mg per day of THC (Dronabinol).<br>Drug: Placebo<br>* Placebo<br>|
| Active Comparator: CBD (Epidolex)<br>Target dose of 800 mg per day. | Drug: CBD (Epidolex)<br>* Participants will receive a target dose of 800 mg per day of CBD (Epidolex).<br>Drug: Placebo<br>* Placebo<br>|
| Active Comparator: THC + CBD (Nabiximols)<br>Target dose of 10.8 mg / 10 mg per day. | Drug: THC + CBD (Nabiximols)<br>* Participants will receive a target dose of 10.8 mg / 10 mg per day of THC + CBD (Nabiximols).<br>Drug: Placebo<br>* Placebo<br>|
| Placebo Comparator: Placebo<br>Identical in appearance to the three active comparators. | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Baseline, Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in pain quality (allodynia) as measured by the Quantitative Sensory Testing. | Allodynia measured by Quantitative Sensory Testing (QST) (0-10 scale; 0=no pain, 10=worst possible pain) | Baseline, Week 2, Week 4, Week 6, Week 8 | 
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in disability and function as measured by the Neuropathic Pain Scale. | 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). | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 | 
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in disability and function as measured by the Gait Speed Test | Distance walked (meters)/time (seconds) measured by Gait Speed Test (lower score = worse, higher score =better) | Baseline, Week 4, Week 8 | 
| 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 | Patient Global Impression of Change (PGIC) 1-7 point ordinal scale assessed (1 = worse, 7 = better) | Baseline, Week 2, Week 4, Week 6, Week 8 | 
| 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. | Patient satisfaction with intervention on visual analog scale (VAS, 0-100, 0=no satisfaction, 100 = complete satisfaction). | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 | 
| 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 | 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). | Baseline, Week 4, Week 8 | 
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in anxiety measured by the Generalized Anxiety Disorder-7. | 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) | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 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). | 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) | Baseline, Week 2, Week 4, Week 6, Week 8 | 
| 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. | 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). | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 | 
| 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. | Severity of depression is measured by Patient Health Questionnaire-9 (PHQ-9) total score (0-27; 0=none, 27=worst). | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 | 
| 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). | 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). | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 |