Mechanistic Basis of Ablative Carbon Dioxide Laser in Treating Hypertrophic Scars (SMOOTH)

A Prospective Intra-patient Single-blinded Randomised Trial to Examine the Mechanistic Basis of fractiOnal Ablative carbOn Dioxide Laser Therapy in Treating Adult Burns and/or Trauma Patients With Hypertrophic Scarring

This is an observational cohort study which will look at the biomarkers from blood and tissue sample for adult patients with hypertrophic scarring due to burns/trauma incident over 12 months from date of recruitment. The study will assess the kinetics of the response to fractionated carbon dioxide laser therapy in hypertrophic scars.

Study Overview

• Status: Recruiting
• Conditions: Burn Scar; Scar

Detailed Description

Research has identified a gap in the knowledge of how fractional ablative carbon dioxide laser works on hypertrophic (thickened) scars. At present there is no accurate measure of how effective the benefit is objectively (medically), subjectively (to the patient) and histologically (on a microscopic level). Recent systematic review has shown an improvement in scars following laser therapy, however it found the quality of the data to be poor, confounded by multiple bias, identifying the lack of evidence to prove the worth and effectiveness of lasers. It concluded the need for more robust studies.

The study plans to observe a group of patients with hypertrophic burn and/or trauma scars (over 1 year old) and see what happens to their scars using the fractionated carbon dioxide laser therapy. Two similar scars will be identified per patient volunteer and will randomly allocate to receive either fractionated carbon dioxide laser therapy or standard care. An independent assessor will be blinded to the intervention and control scar sites.

The trial will aim to identify any biological markers found in participants blood and scar tissue and if they change through the course of and following laser therapy. This will help with understanding the mechanism of how the carbon dioxide laser works on scars.

As part of the evaluation of the impact of laser treatment on patients' quality of life, a patient reported outcome measures (PROMS) validation study will be carried out. PROMs describe how the patient is functioning or feeling without input from clinical staff providing a unique perspective of patients' lived experience of the disease as not all symptoms or impacts are obvious to clinicians. In order for PROMs to be effective in clinical trials and practice, they have to capture information on domains that matter to the patient. These include: scarring, movement and function, scar sensation, psychological distress, body image and confidence, engagement in activities, treatment burden and impact on relationships.

The scars will be assessed in a number of different ways; scar assessment tools/questionnaires, clinical inspection, photography, use of ultrasound, probes with suction to test the elasticity and pliability of the scars and the colour, microscopic evaluation and the identification of biomarkers from blood samples and scar and normal tissue biopsy.

• Study Type: Observational
• Enrollment (Anticipated): 60

Contacts and Locations

Study Locations

• United Kingdom
  • Birmingham, United Kingdom
    • Recruiting
    • University Hospitals Birmingham NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Adult patient with hypertrophic scarring as a result of deep dermal or full thickness burns/trauma sustained more than 12 months prior to recruitment.

Description

Inclusion Criteria:

• Adult patients aged ≥ 16years
• Patient with hypertrophic scarring as a result of deep dermal or full thickness burns/trauma.
• Trauma or Burn sustained more than 12 months prior to recruitment.
• Treatment area to be ≥25cm2 confluent scarring with a comparable control scar on limb or trunk

General Exclusion Criteria:

• Patients under 16 years of age
• Previous laser therapy treatment to the study site
• The use of recent (within 6 months) or concurrent invasive scar treatments, including intra-lesional pharmaceuticals, micro needling or other laser modalities (e.g. Pulse-dye.)
• Known allergy or contraindication to EMLA™ 5% Cream (Lidocaine 2.5% and Prilocaine 2.5%), Dermol 500TM (Benzalkonium Chloride 0.1%; Chlorhexidine Dihydrochloride 0.1%; Liquid Paraffin 2.5%; Isopropyl Myristate 2.5%) or 50:50 ointment (White Soft Paraffin Liquid Paraffin %w/w 50 50.)
• Patients with Fitzpatrick skin type of 5-6 due to nature of the skin

Laser Treatment Exclusion Criteria

• The presence of acute infection at the proposed treatment site
• Pregnancy or lactation
• Patients with poorly controlled Diabetes mellitus HbA1C >9% or 75mmol/mol within last 3 months)
• Patients experiencing acute exacerbation of Chronic skin diseases e.g. psoriasis or eczema
• Immunosuppression (HIV, drugs with immunosuppressive effect)
• Use of Roaccutane at any time within the last 6 months
• Autoimmune disorders in active stage (for example: 1. Localised; Type 1 Diabetes Mellitus, Addison's, Grave's and Crohn's Disease, 2. Systemic; Rheumatoid Arthritis, Multiple Sclerosis, Lups and Scleroderma).
• Known history of keloid scarring

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Detect the number of senescent cells and the sub-population of fibroblasts 12 months after the last CO2 laser therapy	Measuring the proportion of senescent cells and the proportion and sub-population of fibroblasts following treatment to determine positive effect of CO2 laser therapy through histological assessment. In particular, to assess: Changes in the proportion of senescent cells (marker: p16) and types of fibroblasts (αSMA and CD90/Thy1) from baseline at 3 weeks after 1st laser treatment.; Changes in the proportion of senescent cells (marker: p16) and types of fibroblasts (αSMA and CD90/Thy1) from baseline at 3 months after 1st laser treatment.; Changes in the proportion of senescent cells (marker: p16) and types of fibroblasts (αSMA and CD90/Thy1) from baseline at 6 months after 1st laser treatment.; Changes in the protortion of senescent cells (marker: p16) and types of fibroblasts (αSMA and CD90/Thy1) from baseline at 18 months after 1st laser treatment.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vancouver Scar Scale	This scale uses a numerical assessment of four skin characteristics including: Height (range, 0-4), Pliability (range, 0-4), Vascularity (range, 0-3), and Pigmentation (range, 0-3). The assessors choose a numerical value for each of these characteristics based on a comparison with normal skin.	18 months
Patient and Observer Scar Assessment Scale (POSAS)	POSAS questionnaire seeks to measure scar quality. POSAS, version 2.0 is a subjective scar scale that consists of two parts: a Patient Scale and an Observer Scale. Both scales contain six items that are scored numerically on a ten-step scale and together they make up the 'Total Score' of the Patient and Observer Scale. The POSAS Observer scale assesses the scar in terms of vascularity, pigmentation, thickness, relief, pliability, surface area and overall opinion. The POSAS Patient scale assesses the scar in terms of pain, itching, scar colour, stiffness, thickness and irregularity, and overall opinion.	18 months
Brisbane Burn Scar Impact Profile (BBSIP)	The Brisbane Burn Scar Impact Profile (BBSIP, version 1.0) is a questionnaire that was developed to assess the health-related quality of life in people with burn scars. It consists of seven parts which measure the overall impact of burn scars; itch, pain and other sensations (and their impact on the subject); impact of the burn scars on work and daily activities; impact of the burn scars on relationships and social interactions; subjects perception of the impact of the burn scars on their appearance; their emotional reactions towards their scars; and physical symptoms caused by the burn scars.	18 months
Health status	The EQ-5D is a questionnaire used for measuring generic health status. The EQ-5D questionnaire consists of 5 questions relating to different domains of quality of life (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) for each of which there are 3 levels of response (no problems, some problems or severe problems).	18 months
Quantify scar colour	The DSM III Colormeter (Cortex Technology) combines two methods of quantifying colour: narrow-band spectrophotometry (melanin, erythema) and tristimulus reflectance colorimetry in a single measurement. It has a skin measuring area of .7mm in diameter.	18 months
Quantify scar thickness	The Dermascan C USB (Cortex Technology) is a high-frequency (20MHz) ultrasound scanner that enables the imaging of soft tissue at high resolution with a computer, and comes with software that allows automated skin thickness measurement. A medium focus transducer will be used with a 12mm wide viewing field and penetration depth of 15mm. All measurements are to be performed with an ultrasound frequency set at 1580m/s. Thickness and density (as a measure of total intensity in percentage) measurements are then generated using the dedicated software (Advance Control 6 Analysis SW package, Cortex). The thickness measured is defined as the distance between the echogenic stratum corneum and the inner surface of the dermis (in millimetres).	18 months
Quantify scar elasticity	The cutometer (MPA 580, Courage and Khazaka) is an electronic instrument that assesses skin elasticity. The probe of the device is placed over the area of measurement, and then generates a negative pressure which draws the skin into a hollow aperture in the centre of the probe and then uses a laser to estimate the amount of skin displacement. The probe with a 6-mm diameter hollow aperture was chosen for this study as previous studies have determined it to be the most efficient size to measure the visco-elasticity properties of the dermis. For this study, mode 1 was chosen. This delivers three cycles of negative air pressure (500 mbar) for 2 seconds, followed by 2 seconds of no pressure. Results are expressed as the means of the three measurement cycles.	18 months
Quantify scar volume	The Vectra H1 handheld imaging system delivers high resolution 3D images for clinical use. Three-dimensional (3D) measurement systems are used to overcome the limitation of 2D photograph, mostly used for clinical documentation. They can be utilised to measure surface area of wounds, but additionally be able to measure the volume of scars much more quickly and easily compared to traditional methods such as moulding. The study will measure the volume of scar in cubic centimetre.	18 months
Novel markers associated with scar formation, wound healing and variables of scar behaviours in response to CO2 laser therapy	The following will be assessed: The percentage expression of TGF-beta at time points on day1, 3 weeks, 3 months 6 months and 18 months.; The percentage expression of PDGF at time points on day1, 3 weeks, 3 months 6 months and 18 months.; The percentage expression of Decorin (%) at time points on day1, 3 weeks, 3 months 6 months and 18 months.	18 months

Collaborators and Investigators

• Sponsor: Naiem Moiemen
• Collaborators: University of Birmingham; The Scar Free Foundation Centre for Conflict Wound Research; Welsh Centre for Burns and Plastic Surgery, Morriston Hospital
• Investigators: Principal Investigator: Naiem Moiemen, GMC, University Hospital Birmingham NHS Foundation Trust

Publications and helpful links

General Publications

• Browne RH. On the use of a pilot sample for sample size determination. Stat Med. 1995 Sep 15;14(17):1933-40. doi: 10.1002/sim.4780141709.
• Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: recommendations for good practice. J Eval Clin Pract. 2004 May;10(2):307-12. doi: 10.1111/j..2002.384.doc.x.
• Manstein D, Herron GS, Sink RK, Tanner H, Anderson RR. Fractional photothermolysis: a new concept for cutaneous remodeling using microscopic patterns of thermal injury. Lasers Surg Med. 2004;34(5):426-38. doi: 10.1002/lsm.20048.
• Draaijers LJ, Tempelman FR, Botman YA, Tuinebreijer WE, Middelkoop E, Kreis RW, van Zuijlen PP. The patient and observer scar assessment scale: a reliable and feasible tool for scar evaluation. Plast Reconstr Surg. 2004 Jun;113(7):1960-5; discussion 1966-7. doi: 10.1097/01.prs.0000122207.28773.56.
• Gangemi EN, Gregori D, Berchialla P, Zingarelli E, Cairo M, Bollero D, Ganem J, Capocelli R, Cuccuru F, Cassano P, Risso D, Stella M. Epidemiology and risk factors for pathologic scarring after burn wounds. Arch Facial Plast Surg. 2008 Mar-Apr;10(2):93-102. doi: 10.1001/archfaci.10.2.93.
• Zuccaro J, Ziolkowski N, Fish J. A Systematic Review of the Effectiveness of Laser Therapy for Hypertrophic Burn Scars. Clin Plast Surg. 2017 Oct;44(4):767-779. doi: 10.1016/j.cps.2017.05.008. Epub 2017 Jul 10.
• Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med. 2011 Jan-Feb;17(1-2):113-25. doi: 10.2119/molmed.2009.00153. Epub 2010 Oct 5.
• Slemp AE, Kirschner RE. Keloids and scars: a review of keloids and scars, their pathogenesis, risk factors, and management. Curr Opin Pediatr. 2006 Aug;18(4):396-402. doi: 10.1097/01.mop.0000236389.41462.ef.
• Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM. Aging of the innate immune system. Curr Opin Immunol. 2010 Aug;22(4):507-13. doi: 10.1016/j.coi.2010.05.003.
• Gunin AG, Kornilova NK, Petrov VV, Vasil'eva OV. [Age-related changes in the number and proliferation of fibroblasts in the human skin]. Adv Gerontol. 2011;24(1):43-7. Russian.
• Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118. doi: 10.1146/annurev-pathol-121808-102144.
• Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dolle ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell. 2014 Dec 22;31(6):722-33. doi: 10.1016/j.devcel.2014.11.012. Epub 2014 Dec 11.
• Tyack Z, Kimble R, McPhail S, Plaza A, Simons M. Psychometric properties of the Brisbane Burn Scar Impact Profile in adults with burn scars. PLoS One. 2017 Sep 13;12(9):e0184452. doi: 10.1371/journal.pone.0184452. eCollection 2017.
• Griffiths C, Guest E, White P, Gaskin E, Rumsey N, Pleat J, Harcourt D. A Systematic Review of Patient-Reported Outcome Measures Used in Adult Burn Research. J Burn Care Res. 2017 Mar/Apr;38(2):e521-e545. doi: 10.1097/BCR.0000000000000474.
• Jones LL, Calvert M, Moiemen N, Deeks JJ, Bishop J, Kinghorn P, Mathers J; PEGASUS team. Outcomes important to burns patients during scar management and how they compare to the concepts captured in burn-specific patient reported outcome measures. Burns. 2017 Dec;43(8):1682-1692. doi: 10.1016/j.burns.2017.09.004. Epub 2017 Oct 12.
• Andrews N, Jones LL, Moiemen N, Calvert M, Kinghorn P, Litchfield I, Bishop J, Deeks JJ, Mathers J; PEGASUS Study Group. Below the surface: Parents' views on the factors that influence treatment adherence in paediatric burn scar management - A qualitative study. Burns. 2018 May;44(3):626-635. doi: 10.1016/j.burns.2017.09.003. Epub 2017 Oct 12.
• Lee KC, Dretzke J, Grover L, Logan A, Moiemen N. A systematic review of objective burn scar measurements. Burns Trauma. 2016 Apr 27;4:14. doi: 10.1186/s41038-016-0036-x. eCollection 2016.
• Brusselaers N, Pirayesh A, Hoeksema H, Verbelen J, Blot S, Monstrey S. Burn scar assessment: A systematic review of objective scar assessment tools. Burns. 2010 Dec;36(8):1157-64. doi: 10.1016/j.burns.2010.03.016. Epub 2010 May 21.
• Rothman ML, Beltran P, Cappelleri JC, Lipscomb J, Teschendorf B; Mayo/FDA Patient-Reported Outcomes Consensus Meeting Group. Patient-reported outcomes: conceptual issues. Value Health. 2007 Nov-Dec;10 Suppl 2:S66-75. doi: 10.1111/j.1524-4733.2007.00269.x.
• Patrick DL, Burke LB, Powers JH, Scott JA, Rock EP, Dawisha S, O'Neill R, Kennedy DL. Patient-reported outcomes to support medical product labeling claims: FDA perspective. Value Health. 2007 Nov-Dec;10 Suppl 2:S125-37. doi: 10.1111/j.1524-4733.2007.00275.x.
• Pallant JF, Tennant A. An introduction to the Rasch measurement model: an example using the Hospital Anxiety and Depression Scale (HADS). Br J Clin Psychol. 2007 Mar;46(Pt 1):1-18. doi: 10.1348/014466506x96931.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 9, 2019
• Primary Completion (ANTICIPATED): August 31, 2023
• Study Completion (ANTICIPATED): August 31, 2023

Study Registration Dates

• First Submitted: October 27, 2020
• First Submitted That Met QC Criteria: February 2, 2021
• First Posted (ACTUAL): February 3, 2021

Study Record Updates

• Last Update Posted (ACTUAL): November 8, 2021
• Last Update Submitted That Met QC Criteria: November 5, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Pathological Conditions, Anatomical; Fibrosis; Hypertrophy; Cicatrix
• Other Study ID Numbers: RRK6716

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No