Sickle Cell Pain: Intervention With Capsaicin Exposure

Study Overview
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Brief Summary
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This study evaluates the safety and feasibility of using high dose topical capsaicin patches for the treatment of neuropathic pain in pediatric patients with sickle cell disease, as well as the feasibility of using a number of tests for the evaluation and monitoring of neuropathic pain. The hypothesis, based on evidence obtained from studies in adults with neuropathic pain related to other diseases as well as a single previously published study of capsaicin in pediatric patients, is that capsaicin will be well tolerated in this population. Additionally, it is hypothesized that it is feasible to monitor changes in neuropathic pain via the testing listed below.

Detailed Description
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Patients with sickle cell disease suffer debilitating painful episodes, as well as chronic, often daily, pain that are commonly treated with non-steroidal anti-inflammatory drugs, opioids, and other non-pharmacologic supportive measures. Neuropathic pain has been shown to be present in these patients, with frequency increasing with age. It is believed, based on knowledge of neuropathic pain related to other conditions and from the small number of studies in sickle cell patients, to result from repeated vaso-occlusive pain episodes that prime central and peripheral pain sensing pathways in a maladaptive manner, leading to hyper-sensitization. Very few studies to date have evaluated therapies specifically targeting this aspect of the pain experienced by patients with sickle cell disease. This is a pilot study for a future longitudinal study of neuropathic pain in pediatric patients with sickle cell disease. The first aim of this pilot study is to establish the safety of treating participants with sickle cell disease aged fourteen to twenty-one with eight percent topical capsaicin patches on an every three-month dosing schedule as recommended by the manufacturer. This will be a single-arm safety study. Presence of neuropathic pain will be determined by day zero evaluation via the testing shown in the outcome measures below. Topical medication will be administered over one hour, every three months, for six months (total of three applications), to sites of recurrent vaso-occlusive pain, according to the package insert administration guidelines. Subjective and objective evaluations of pain and inflammation including questionnaires, blood tests, and quantitative sensory testing will be carried out every six weeks throughout the study period until twelve weeks after the final capsaicin application. Additionally, participants will record daily pain and medication use in a mobile app. Safety will be established by there being no grade three or four adverse events according to CTCAE definitions. Grade two adverse events will be evaluated on a case by case basis throughout the duration of the study. Feasibility of monitoring neuropathic pain with the aforementioned studies will be established by participant compliance with greater than eighty percent of all study activities.

Official Title
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Safety and Feasibility of High-Dose Topical Capsaicin for the Treatment of Neuropathic Pain in Pediatric Sickle Cell Disease

Conditions
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Neuropathic Pain, Sickle Cell Disease

Intervention / Treatment
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* Drug: Eight Percent Topical Capsaicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of either Sickle Cell Disease with genotype SS or S Beta-zero, or SC disease. Must have recurrent sites of pain, where majority of acute pain episodes are localized Subjects are willing and able to comply with scheduled visits, treatment plan, laboratory tests, pain assessments, and other study procedures. Subjects who are being treated with hydroxyurea (HU) must have been on a stable dose for at least 8 weeks prior to Visit 1 (Day 0), with the intent of remaining on the same dose of hydroxyurea throughout the clinical trial including the protocol-specified follow-up period unless adjustments are medically necessary due to bone marrow suppression. At least 80% compliance (defined as logging pain at least once daily) with mobile application use during 14-day lead in period from time of enrollment to time of first capsaicin application. Exclusion Criteria: Age less than 14 or greater than 21 History of major surgery within the past 3 months. Patients receiving scheduled chronic partial exchange transfusions as part of their sickle cell disease management protocol. Concurrently taking another medication used in the treatment of neuropathic pain or with the potential to affect the peripheral nervous system (e.g. gabapentin, anti-epileptics, antidepressants, systemic alpha or beta adrenergic receptor blockers) Use of another topical analgesic at home in the treatment of pain episodes such as topical lidocaine, diclofenac, or menthol (must discontinue use at the time of enrollment). Recurrent pain secondary to an underlying condition other than vaso-occlusive pain (avascular necrosis, scoliosis, fracture, etc.) Patients lacking the mental capacity to assent to the study Patients with another chronic inflammatory/immune disorder that could skew the inflammatory markers listed above. Pregnant females Expectation that the subject will not be able to be followed for the duration of the study Active use of illicit drugs and/or alcohol dependence, as determined by the investigator. Opioid use beyond the amount necessary for pain related to the underlying sickle cell disease as determined by the investigator. Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator.

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum 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
Intervention Model: Single Group Assignment
Interventional Model Description: Single arm, safety and feasibility trial assessing the suitability of an FDA approved medication for use in children with an off-label condition.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Capsaicin Arm<br>Single arm to receive eight percent topical capsaicin applied to up to 4 sites of recurrent pain over one hour on an every three month schedule. Participants in this arm will receive pretreatment with topical five percent lidocaine. | Drug: Eight Percent Topical Capsaicin<br>* See arm description<br>* Other names: Qutenza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE Criteria | Safety will be established by there being no treatment-related adverse events greater than grade 2 using CTCAE definitions of adverse events. Grade 2 CTCAE events will be evaluated on a case by case basis to determine safety of continuing the study. Grade 3 events will result in immediate suspension of study activities until a full analysis of the event in question is completed. | At the end of the 9 month study period all participant information will be reviewed and adverse events assessed. | 
| Compliance with Serum Substance P Levels | Feasibility will be established by participants having greater than 80 percent compliance with all study investigations, including serum substance P levels. | At the end of the 9 month study period all participant information will be reviewed and compliance with testing assessed. | 
| Compliance with Subjective Neuropathic Pain Questionnaire | Feasibility will be established by participants having greater than 80 percent compliance with all study investigations, including completion of PainDETECT Questionnaire during study visits. The questionnaire is a validated assessment of neuropathic pain. It consists of a series of questions regarding the experience of pain for which the participant will provide an answer ranging from never (0 points) to very strongly (5 points). Points are added to provide a total score from 0 to 38. A score from 0 to 12 indicates a neuropathic pain component is unlikely, a score of 12 to 18 is equivocal, and a score greater than 18 indicates a neuropathic component is likely. | At the end of the 9 month study period all participant information will be reviewed and compliance with testing assessed. | 
| Compliance with Quantitative Sensory Testing | Feasibility will be established by participants having greater than 80 percent compliance with all study investigations, including quantitative sensory testing using electronic von frey machine. | At the end of the 9 month study period all participant information will be reviewed and compliance with testing assessed. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compliance with Mobile App Record Keeping | Feasibility, as above, will be established by greater than 80 percent compliance with daily mobile app recordings of pain and home medication use. | Duration of study period (9 months). Mobile app recordings can be reviewed in real time and will be recorded on a weekly basis. | 
| Compliance with Blood Draws for Hyperspectral Imaging Analysis for Determining Presence and Improvement of Chronic Neuropathic Pain | Feasibility will be established by the successful processing of greater than 80 percent of target number of blood samples to be sent for hyperspectral analysis, a novel test capable of detecting chronic pain states, but not yet used in the sickle cell population. | Duration of study period (9 months). Will be drawn and processed at 6 week intervals throughout the study period. | 
| Morphine Equivalents Utilized | Will assess changes in pain medication required during the course of the study period based on electronic medical record, participant report, and controlled substance monitoring database. | Duration of study period (9 months). Will be evaluated at 6 week intervals throughout the study period. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Capsaicin, Topical Analgesia, Quantitative Sensory Testing, Pain