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Treatment of Chronic Itch in Atopic Dermatitis With Topical Naltrexone

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ClinicalTrials.gov Identifier: NCT04154033
Recruitment Status : Not yet recruiting
First Posted : November 6, 2019
Last Update Posted : September 4, 2020
Sponsor:
Information provided by (Responsible Party):
University of Minnesota

Tracking Information
First Submitted Date  ICMJE November 4, 2019
First Posted Date  ICMJE November 6, 2019
Last Update Posted Date September 4, 2020
Estimated Study Start Date  ICMJE October 1, 2020
Estimated Primary Completion Date March 31, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 4, 2019)
  • Visual Analog Scale for Itching: Circadian 2 Hours AW [ Time Frame: 7 days ]
    To assess the effects of circadian rhythm on pruritus, participants will record itch intensity using a visual analog scale (VAS) at the following time points after waking (AW): AW+2h for 7 days. VAS ranges from 0mm (no itch) to 100mm (unbearable itch). The mean (in millimeters) of 7 daily measurements will be reported.
  • Visual Analog Scale for Itching: Circadian 4 Hours AW [ Time Frame: 7 days ]
    To assess the effects of circadian rhythm on pruritus, participants will record itch intensity using a visual analog scale (VAS) at the following time points after waking (AW): AW+4h for 7 days. VAS ranges from 0mm (no itch) to 100mm (unbearable itch). The mean (in millimeters) of 7 daily measurements will be reported.
  • Visual Analog Scale for Itching: Circadian 6 Hours AW [ Time Frame: 7 days ]
    To assess the effects of circadian rhythm on pruritus, participants will record itch intensity using a visual analog scale (VAS) at the following time points after waking (AW): AW+6h for 7 days. VAS ranges from 0mm (no itch) to 100mm (unbearable itch). The mean (in millimeters) of 7 daily measurements will be reported.
  • Visual Analog Scale for Itching: Circadian 8 Hours AW [ Time Frame: 7 days ]
    To assess the effects of circadian rhythm on pruritus, participants will record itch intensity using a visual analog scale (VAS) at the following time points after waking (AW): AW+8h for 7 days. VAS ranges from 0mm (no itch) to 100mm (unbearable itch). The mean (in millimeters) of 7 daily measurements will be reported.
  • Visual Analog Scale for Itching: Circadian 10 Hours AW [ Time Frame: 7 days ]
    To assess the effects of circadian rhythm on pruritus, participants will record itch intensity using a visual analog scale (VAS) at the following time points after waking (AW): AW+10h for 7 days. VAS ranges from 0mm (no itch) to 100mm (unbearable itch). The mean (in millimeters) of 7 daily measurements will be reported.
  • Visual Analog Scale for Itching: Circadian 12 Hours AW [ Time Frame: 7 days ]
    To assess the effects of circadian rhythm on pruritus, participants will record itch intensity using a visual analog scale (VAS) at the following time points after waking (AW): AW+12h for 7 days. VAS ranges from 0mm (no itch) to 100mm (unbearable itch). The mean (in millimeters) of 7 daily measurements will be reported.
  • Visual Analog Scale for Itching: Treatment 0 min [ Time Frame: 0 minutes after applying topical cream ]
    To assess the effects of naltrexone 1% or placebo cream on pruritus, participants will record itch intensity using a visual analog scale (VAS) at 0 minutes after applying cream for 3 pruritis attacks in 1 week. VAS ranges from 0mm (no itch) to 100mm (unbearable itch). The mean (in millimeters) over 3 pruritis attacks will be reported.
  • Visual Analog Scale for Itching: Treatment 20 min [ Time Frame: 20 minutes after applying topical cream ]
    To assess the effects of naltrexone 1% or placebo cream on pruritus, participants will record itch intensity using a visual analog scale (VAS) at 20 minutes after applying cream for 3 pruritis attacks in 1 week. VAS ranges from 0mm (no itch) to 100mm (unbearable itch). The mean (in millimeters) over 3 pruritis attacks will be reported.
  • Visual Analog Scale for Itching: Treatment 40 min [ Time Frame: 40 minutes after applying topical cream ]
    To assess the effects of naltrexone 1% or placebo cream on pruritus, participants will record itch intensity using a visual analog scale (VAS) at 40 minutes after applying cream for 3 pruritis attacks in 1 week. VAS ranges from 0mm (no itch) to 100mm (unbearable itch). The mean (in millimeters) over 3 pruritis attacks will be reported.
  • Visual Analog Scale for Itching: Treatment 1 Hour [ Time Frame: 1 hour after applying topical cream ]
    To assess the effects of naltrexone 1% or placebo cream on pruritus, participants will record itch intensity using a visual analog scale (VAS) at 1 hour after applying cream for 3 pruritis attacks in 1 week. VAS ranges from 0mm (no itch) to 100mm (unbearable itch). The mean (in millimeters) over 3 pruritis attacks will be reported.
  • Visual Analog Scale for Itching: Treatment 2 Hours [ Time Frame: 2 hours after applying topical cream ]
    To assess the effects of naltrexone 1% or placebo cream on pruritus, participants will record itch intensity using a visual analog scale (VAS) at 2 hours after applying cream for 3 pruritis attacks in 1 week. VAS ranges from 0mm (no itch) to 100mm (unbearable itch). The mean (in millimeters) over 3 pruritis attacks will be reported.
  • Visual Analog Scale for Itching: Treatment 3 Hours [ Time Frame: 3 hours after applying topical cream ]
    To assess the effects of naltrexone 1% or placebo cream on pruritus, participants will record itch intensity using a visual analog scale (VAS) at 3 hours after applying cream for 3 pruritis attacks in 1 week. VAS ranges from 0mm (no itch) to 100mm (unbearable itch). The mean (in millimeters) over 3 pruritis attacks will be reported.
  • Visual Analog Scale for Itching: Treatment 4 Hours [ Time Frame: 4 hours after applying topical cream ]
    To assess the effects of naltrexone 1% or placebo cream on pruritus, participants will record itch intensity using a visual analog scale (VAS) at 4 hours after applying cream for 3 pruritis attacks in 1 week. VAS ranges from 0mm (no itch) to 100mm (unbearable itch). The mean (in millimeters) over 3 pruritis attacks will be reported.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2019)
  • Time to Itching Intensity Decrease by 50% [ Time Frame: 4 hours ]
    Time to itching intensity decrease by 50% using visual analog scale (VAS) after applying topical cream (either naltrexone or placebo) for 3 pruritis attacks in 1 week. VAS ranges from 0mm (no itch) to 100mm (unbearable itch). VAS will be recorded at 6 time points after application (AA) of cream: 0minAA, 20minAA, 40minAA, 60minAA, 120minAA, 180minAA, and 240minAA. The mean value (in min AA) across 3 pruritis attacks in 1 week will be reported.
  • Total Reduction in Itch Intensity [ Time Frame: 4 hours ]
    The total reduction of itch intensity as measured by visual analog scale (VAS) after applying topical cream (either naltrexone or placebo). VAS ranges from 0mm (no itch) to 100mm (unbearable itch). Participants will measure itching via VAS at 0min after cream application and 4hr after cream application. Total reduction in itch will be measured in millimeters on VAS. The mean value (across 3 pruritis attacks in 1 week) will be reported.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment of Chronic Itch in Atopic Dermatitis With Topical Naltrexone
Official Title  ICMJE Treatment of Chronic Itch in Atopic Dermatitis With Topical Naltrexone as Well as the Influence of Circadian Rhythm
Brief Summary To study the etiology and the epigenetic pathways leading to and regulating chronic itch. Similarly, to examine the mechanisms underlying skin changes, including epigenetic alterations while also testing the efficacy of medications, especially topical intervention. In this study, the investigators aim to examine chronic sensory disorder mechanisms related to chronic itch.
Detailed Description

Itch was recently identified as one of the top three priority topics in dermatology at a Research Agenda Conference sponsored by the American Academy of Dermatology in 2012. Chronic itch is a complex phenomenon, involving the skin, immune and nervous systems to various degrees. Therefore, focusing on a particular pruritic disease will enable us to work out the underlying pathophysiological mechanisms that occur between the skin and the brain to establish a rational treatment approach.

Atopic Dermatitis (AD) is defined as a chronic inflammatory dermatological disease characterized by immunological and neurological cutaneous hyperreactivity with ongoing itch and inflammation. It is linked to an atopic predisposition with skin barrier abnormalities, recurrent delayed-type inflammations; frequently the development of IgE-mediated inhalant and gastrointestinal-related immediate type reactions. It is estimated that the prevalence for AD is at least 17% of the population lifetime worldwide with some reports of increasing prevalence in the last decades. It is also increasingly being observed in the aging population with dry, itchy skin.

Various topical and systemic therapies are available and choices are based on disease extent, presence of acute flare, and age of the patient. Unfortunately, itch in AD can be challenging to control; although multiple topical and systemic treatments are available, to date no universally accepted treatment exists.

The investigators have previously shown that opioid receptors play an important role in pruritus. Therefore, the investigators plan on expanding on previous and ongoing experiences with opioid antagonists and study the epigenetic and molecular mechanisms behind. Moreover, the investigators have recently discovered that the endogenous opioid ligand Met-Enkephalin influences circadian rhythm by binding directly to CLOCK gene promoters in the nucleus, which then change the amplitude and phase-shift these genes in keratinocytes.

Ultimately, the investigators would like to evaluate the effectiveness of topical application of Naltrexone in an effort to potentially help to treat chronic, untreatable itch and learn more about peripheral disorders of sensation (itch and pain).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Atopic Dermatitis
  • Pruritus
  • Dermatitis
Intervention  ICMJE
  • Drug: Naltrexone
    Topical naltrexone cream (1%)
  • Other: Placebo Cream
    Topical placebo cream
Study Arms  ICMJE
  • No Intervention: Arm A: Circadian Rhythm of Itch
    For the study arm A, to evaluate circadian rhythm of itching, patients will record for 7 days 6 times daily in a booklet the itch intensity on a visual analog scale (VAS) scale. These time points for itch intensity recording will be hours after time of awakening (AW), so they will be AW+2h, AW+4h, AW+6h, AW+8h, AW+10h, AW+12h. Patients are to document all their pruritus attacks at these time points. On day 8 the investigators will collect suction blisters (4-5 10mm blisters) at these 6 time points from unaffected skin on the trunk. For this purpose, the investigators will use the commercially available 47mm orifice plate (Electronic Diversities, Finksburg MD, USA) with 4-5 x10mm openings for each time point and use the 4-5 1mm blister roofs for harvesting.
  • Experimental: Arm B: Topical Naltrexone Cream
    Patients will start with placebo in week 2 and move on to naltrexone treatment in week 3. There will be a wash-in phase during week 1. Following week 2 and week 3, at visits 3 and 4, patients will be asked for the area where they are experiencing most intense itch and the investigators will take suction blisters from that area before any treatment. They will be told to bring the medication they have been using and they will apply this topically. After an hour, another suction blister will be taken from the same area. This will ensure the study is still blinded as neither the physician or the participant will know whether the medication was a placebo or not. Participants may apply their topical treatment as often as he wishes.
    Intervention: Drug: Naltrexone
  • Placebo Comparator: Arm C: Placebo Cream
    Patients will start with naltrexone treatment in week 2 and move on to placebo treatment in week 3. Other than this, all procedures will be the same as in study arm B.
    Intervention: Other: Placebo Cream
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: November 4, 2019)
56
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 31, 2024
Estimated Primary Completion Date March 31, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of AD via simplified UK Working Group Criteria and a baseline PSGA score of 2 or greater
  • Subjects taking hormone-containing medications must be on a stable dose for 6 months prior to study start to avoid any confounding influence on sensory and pain perception

Exclusion Criteria:

  • Use of topical or oral anti-inflammatory medications for 2 weeks prior to the study start
  • Use of topical or oral anti-histamines for 2 weeks prior to the study start
  • Use of topical or oral anti-pruritic agents for 2 weeks prior to the study start
  • Use of oral neuromodulatory agents for 2 months prior to study start
  • Current use of chronic pain medications (including opioids, antidepressants and anti-epileptic drugs)
  • Use of nicotine-containing products for the past 6 months prior to study start
  • History of radiation or chemotherapy
  • History of traumatic injury on prospective test sites
  • Unstable thyroid function within the past 6 months prior to study start to exclude thyroid-related neuropathy (Duyff et al, 2000)
  • Known history of central or peripheral nervous system dysfunction
  • History of acute hepatitis, chronic liver disease or end stage liver disease
  • History of human immunodeficiency virus (HIV) or acquired immune deficiency syndrome
  • History of neuropathy associated with chronic obstructive pulmonary disease, diabetes mellitus, documented exposure to organophosphates or heavy metals or polychlorinated biphenyls
  • Known nutritional deficiency (vitamin B12, vitamin D, iron or zinc) within 3 months prior to the study start
  • Use of illicit drugs within the past 6 months prior to study start
  • History of daily use of power tools
  • Lyme disease, porphyria, rheumatoid arthritis, Hansen's disease (leprosy) or use of antineoplastic chemotherapeutic agents
  • Subject has any medical condition that, in the judgment of the Investigator, would jeopardize the subject's safety following exposure to the administered medications
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Paul Bigliardi, MD 612-625-6118 pbigliar@umn.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04154033
Other Study ID Numbers  ICMJE DERM-2019-27870
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Minnesota
Study Sponsor  ICMJE University of Minnesota
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Paul Bigliardi, MD University of Minenesota
PRS Account University of Minnesota
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP