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Wound Healing in Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT03433820
Recruitment Status : Unknown
Verified February 2018 by prof dr J. Burggraaf, Centre for Human Drug Research, Netherlands.
Recruitment status was:  Active, not recruiting
First Posted : February 15, 2018
Last Update Posted : February 15, 2018
Sponsor:
Collaborator:
Maruho Co., Ltd.
Information provided by (Responsible Party):
prof dr J. Burggraaf, Centre for Human Drug Research, Netherlands

Brief Summary:

The skin plays a critical role in protection where it acts as a barrier from damage and pathogens between the external and internal environments. Wounds compromise its protective role by disrupting the function and the normal structure of the skin and the underlying soft tissue. As a response to injury wound healing occurs in order to rapidly restore the defect. This process involves activation of keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets and consists of multiple phases including hemostasis, inflammation, migration and cellular proliferation, and maturation and remodeling. A simplified schematic of the course of wound healing is depicted in Figure 2. Hemostasis occurs immediately after dermal injury. The inflammation phase is characterized by cellular recruitment and increased vascular permeability. The epithelization phase is achieved by proliferation of basal cells and migration of epithelial cells. The last phase is known as the maturation and remodeling phase where collagen cross-linking and remodeling, wound contraction, and repigmentation takes place. Due to the broad involvement of various cell types, extracellular matrix and many reactive molecules each phase in wound healing produces characteristic changes within the tissue. A deficiency in any part of the process can lead to delayed wound healing, abnormal scar formation or chronic wounds.

To study wound healing in healthy volunteers a challenge model with skin punch biopsies has been described in literature previously. However, the characterization of this model was not performed comprehensively since advanced analysis of biopsies were omitted. Furthermore, analyses performed in previous studies only partially described wound healing processes either by insufficient time points for characterization or scarce simultaneous evaluations of multiple wound healing modalities.

The overall aim of this study is to develop a standardized model to temporarily and locally induce a skin trauma to investigate wound healing and monitor wound closure. This clinical model will enable future application as proof-of-pharmacology and proof-of concept studies as well as drug profiling in early drug development programs. More specifically, the objective of the trial is to explore and characterize the induction of well-defined skin trauma and natural wound healing process over the course of the different phases using a battery of dermatological assessments after skin punch biopsies in healthy volunteers. Furthermore, safety and tolerability will be assessed.

Characterization and monitoring of wound healing effects following skin punch biopsies will be performed by means of biophysical, biochemical, imaging, clinical parameters and subject reported outcomes.


Condition or disease Intervention/treatment Phase
Wound Healing Other: Observation of wound healing Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Intervention Model Description: A single-arm, observational study
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: A Single-arm, Observational Study to Explore and Characterize Wound Healing After Skin Punch Biopsies in Healthy Volunteers
Actual Study Start Date : October 26, 2017
Estimated Primary Completion Date : March 23, 2018
Estimated Study Completion Date : April 30, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: randomized repeated biopsy

The study will entail 1 cohort with a randomized repeated biopsy collection time. Three skin punch biopsies (3 mm) of the lower back will be taken from each volunteer on day 0. One biopsy sample taken on day 0 will serve as a baseline measurement for the repeated samples regarding the histology, immunohistochemistry, and RNA sequencing (RNA-seq) or real-time reverse transcription polymerase chain reaction (qRT-PCR) assessments.

Repeated biopsies of the same location as on day 0 will be taken on day 7, 14 or 21 (biopsy lesion and day randomized), and day 28, 42 or 56 (biopsy lesion and day randomized) for all subjects. The observation biopsy (biopsy lesion randomized) will serve as primary biopsy and followed for all measurements.

Other: Observation of wound healing
Observation of wound healing after skin biopsy




Primary Outcome Measures :
  1. Biopsy biomarkers [ Time Frame: 3 months after end of study ]
    Histology with hematoxylin and eosin (HE) staining

  2. Local skin biomarkers [ Time Frame: 3 months after end of study ]
    Local skin biomarkers for wound healing related biomarkers (e.g. VEGF-A, TNFα, IL-8, TLSP, MMP-3, IL-4) by transdermal analysis patch (TAP)

  3. Clinical imaging [ Time Frame: 3 months after end of study ]
    2D photography

  4. Clinical evaluation [ Time Frame: 3 months after end of study ]
    Erythema grading scale. Wounds are scored on the basis of redness of the wound (from better to worse: absence, mild, moderate, or severe).

  5. Skin microbiome [ Time Frame: 3 months after end of study ]
    Skin microbiome (healthy and biopsy lesions). Collection of skin culture samples is a non-invasive procedure where a sterile polyester flock tip per site is passed along the surface of the 3 different areas. The target areas are i) regions surrounding one of the biopsy lesions on the lower back, ii) a control site of healthy, unaffected skin in proximity of a biopsy lesion and iii) a control area on the lower back with a minimum distance of 10cm from a biopsy site. The skin swab will be placed in a 2 ml lysis tube containing DNA/RNA shield to stabilize and preserve the DNA. The DNA extraction will be performed using adapted DNA extraction method based on the Zymo Research fecal DNA extraction methodology. After DNA extraction, the variable regions 3 and 4 of the 16S rRNA gene are amplified giving an amplicon of around 450 base pairs. This amplicon is analyzed by capillary systems using standard protocols.

  6. Biopsy biomarkers [ Time Frame: 3 months after end of study ]
    Immunohistochemistry with wound healing related biomarkers (e.g. CD31, collagen I, collagen III, aSMA, fibronectin)

  7. Biopsy biomarkers [ Time Frame: 3 months after end of study ]
    RNA-seq or qRT-PCR for wound healing related biomarkers (e.g. VEGFα, TGFβ1, TGFβ2, TGFβ3, PDGF, CTGF, TNF, IL-1B, IL-4, GM-CSF, IL-6, IL-10, MMP1, MMP3, OSM, LOX)

  8. Clinical imaging [ Time Frame: 3 months after end of study ]
    3D photography

  9. Clinical imaging [ Time Frame: 3 months after end of study ]
    Thermography

  10. Clinical imaging [ Time Frame: 3 months after end of study ]
    Laser speckle contrast imaging (LSCI)

  11. Clinical imaging [ Time Frame: 3 months after end of study ]
    Trans epidermal water loss (TEWL)

  12. Clinical imaging [ Time Frame: 3 months after end of study ]
    Colorimetry

  13. Clinical evaluation [ Time Frame: 3 months after end of study ]
    Red-Yellow-Black (RYB) wound assessment scale. Wounds are scored based on the color of the wound bed (from healthy to least healthy: red, yellow, or black). The least healthy color is chosen in multi-color wounds. Furthermore, a humidity subscale (dry, humid, or wet) is added to further classify the health status of the wounds.

  14. Clinical evaluation [ Time Frame: 3 months after end of study ]

    POSAS. The observer scale of the POSAS consists of six items (vascularity, pigmentation, thickness, relief, pliability and surface area). All items are scored on a scale ranging from 1 ('like normal skin') to 10 ('worst scar imaginable'). The sum of the six items results in a total score of the POSAS observer scale. Categories boxes are added for each item:

    • Vascularity category: pale, pink, red, purple, mix
    • Pigmentation category: hypo, hyper, mix
    • Thickness category: thicker, thinner
    • Relief category: more, less, mix
    • Surface area category: expansion, contraction, mix Furthermore, an overall opinion is scored on a scale ranging from 1 to 10. All parameters are preferably compared to normal skin on a comparable anatomic location.


Secondary Outcome Measures :
  1. Adverse events (AEs) [ Time Frame: 3 months after end of study ]
    Adverse events

  2. Local tolerance [ Time Frame: 3 months after end of study ]
    Erythema grading scale. Wounds are scored on the basis of redness of the wound (from better to worse: absence, mild, moderate, or severe).

  3. Local tolerance [ Time Frame: 3 months after end of study ]
    Red-Yellow-Black (RYB) wound assessment scale. Wounds are scored based on the color of the wound bed (from healthy to least healthy: red, yellow, or black). The least healthy color is chosen in multi-color wounds. Furthermore, a humidity subscale (dry, humid, or wet) is added to further classify the health status of the wounds.

  4. Local tolerance [ Time Frame: 3 months after end of study ]

    POSAS. The observer scale of the POSAS consists of six items (vascularity, pigmentation, thickness, relief, pliability and surface area). All items are scored on a scale ranging from 1 ('like normal skin') to 10 ('worst scar imaginable'). The sum of the six items results in a total score of the POSAS observer scale. Categories boxes are added for each item:

    • Vascularity category: pale, pink, red, purple, mix
    • Pigmentation category: hypo, hyper, mix
    • Thickness category: thicker, thinner
    • Relief category: more, less, mix
    • Surface area category: expansion, contraction, mix Furthermore, an overall opinion is scored on a scale ranging from 1 to 10. All parameters are preferably compared to normal skin on a comparable anatomic location.

  5. Local tolerance [ Time Frame: 3 months after end of study ]
    NRS pruritus and pain. The pruritus and pain NRS are single-question assessment tools that are used to assess the subject's worst itch and pain in the previous time interval. Subjects will be asked the following question; "on a scale of 0 - 100, with 0 being no itch, and 100 being the worst itch imaginable, how would you rate your average degree of itch of all biopsy sites combined experienced during the previous time interval?" and "on a scale of 0 - 100, with 0 being no pain, and 100 being the worst pain imaginable, how would you rate your average degree of pain of all biopsy sites combined experienced during the previous time interval?"



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 30 Years   (Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Gender Eligibility Description:   18 to 30 years of age (inclusive)
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion criteria

Eligible subjects must meet all of the following inclusion criteria at screening:

  1. Healthy subjects, 18 to 30 years of age (inclusive). The health status is verified by absence of evidence of any clinical significant active or uncontrolled chronic disease following a detailed medical history, a complete physical examination including vital signs, blood sampling of hematology, chemistry, and virology, urinalysis, urine drug and cotinine testing, and alcohol breath testing. In the case of uncertain or questionable results, tests performed during screening may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant for healthy subjects.
  2. Body mass index (BMI) between 18 and 30 kg/m2, inclusive
  3. Fitzpatrick Skin type I-II (Caucasian type).
  4. Eligible lower back to perform biopsies (no excessive hair growth, no local skin disorder)
  5. Willing to give written informed consent and willing and able to comply with the study protocol.

Exclusion criteria

Eligible subjects must meet none of the following exclusion criteria at screening:

  1. History of pathological scar formation (keloid, hypertrophic scars)
  2. Any form of body modification of the lower back hindering biopsy collection of unaltered skin (e.g. tattoos, piercings, implants)
  3. Any disease associated with immune system impairment, including auto-immune diseases, HIV and transplantation patients.
  4. Requirement of immunosuppressive or immunomodulatory medication, including glucocorticoids, non-steroid anti-inflammatory drugs (NSAIDs), and chemotherapeutic drugs within 30 days prior to enrollment or planned to use during the course of the study.
  5. Have any current and/or recurrent pathologically, clinical significant relevant skin condition.
  6. Use of topical medication (prescription or over-the-counter (OTC)) within 30 days of the start of the study.in local treatment area.
  7. Pregnant, a positive pregnancy test, intending to become pregnant, or breastfeeding.
  8. Current smoker and/or regular user of other nicotine-containing products (e.g., patches).
  9. Average consumption of more than 14 units of alcohol per week
  10. Tanning due to sunbathing, excessive sun exposure or a tanning booth within 3 weeks of enrollment or planned to do so during the course of the study
  11. Participation in an investigational drug or device study within 3 months prior to screening or more than 4 times a year.
  12. Loss or donation of blood over 500 mL within three months prior to screening.
  13. Any (medical) condition that would, in the opinion of the investigator, potentially compromise the safety or compliance of the subject or may preclude the subjects' successful completion of the clinical trial.

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): NCT03433820


Locations
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Netherlands
Centre for Human Drug Research
Leiden, Netherlands, 2333 CL
Sponsors and Collaborators
Centre for Human Drug Research, Netherlands
Maruho Co., Ltd.
Investigators
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Principal Investigator: Robert Rissmann, PhD CHDR
  Study Documents (Full-Text)

Documents provided by prof dr J. Burggraaf, Centre for Human Drug Research, Netherlands:

Additional Information:
Publications:

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Responsible Party: prof dr J. Burggraaf, Research Director, Centre for Human Drug Research, Netherlands
ClinicalTrials.gov Identifier: NCT03433820    
Other Study ID Numbers: CHDR1736
First Posted: February 15, 2018    Key Record Dates
Last Update Posted: February 15, 2018
Last Verified: February 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Wounds and Injuries