Portable Measurement of Protoporphyrin IX in the Skin During Photodynamic Therapy

Overview

Photodynamic therapy (PDT) is increasingly used to treat superficial skin lesions, such as actinic keratosis (AK) and non-melanoma skin cancers, and has been demonstrated to be an effective and safe alternative to surgery. It is performed by applying a photosensitizing pro-drug, amino -levulinic acid (ALA) and then allowing the conversion to the metabolite Protoporphyrin IX (PpIX). While attempts to measure the concentration of this drug in the skin have been performed before, they have never been done in a clinical setting. With the development of a new handheld, smart phone-associated device to measure PpIX, this measurement is now feasible. This is a prospective single center quantitative descriptive study in which the investigators will be applying the prodrug ALA on various parts of a person's body and then taking measurements PpIX at various time points. This will then be correlated with the individuals age, skin temperature, and skin type. The investigators hypothesize that the concentration of PpIX will depend on all of these factors, including anatomical location. All data will be collected into the data collection form and then analyzed using Mat-lab. The investigators will assess for how anatomical location, skin pigmentation, skin temperature, and other factors influence PpIX concentration. PpIX levels will be measured quantitatively using our newly developed PpIX smart phone device at 0, 30, 45, and 60 min after ALA application. Skin temperature will also be measured at these time points using and infrared (IR) camera. Fitzpatrick skin type will be assessed by the provider to assess skin pigmentation. All of these factors will be correlated to the PpIX concentration in 5 anatomical locations (forehead, cheeks, forearms, hands, and bald scalp where applicable) to determine which factors most greatly influence the concentration of PpIX.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Basic Science
    • Masking: None (Open Label)
  • Study Primary Completion Date: September 2020

Detailed Description

Photodynamic Therapy (PDT) has gained popularity as an effective, non-scarring treatment for thin, non-hyperkeratotic actinic keratoses (AKs). Similar to the topical agents 5-fluorouracil and imiquimod, PDT is particularly useful when utilized as a field-directed therapy for the treatment of areas with multiple AKs and extensive sun damage. PDT consists of two steps: 1) the topical application of a photosensitizer agent aminolevulinic acid (ALA), which is preferentially converted to the photosensitive protoporphyrin IX (PpIX) in precancerous and neoplastic cells, and 2) controlled exposure to a visible wavelength light source. Current methodologies utilize a "one-size-fits-all" approach with regard to duration of incubation with photosensitizing agents and illumination. Moreover, patients frequently experience pain after long PDT prodrug incubation. Better characterization of photosensitization in PDT can help tailor incubation and overall treatment time to minimize treatment duration and discomfort while maximizing clearance of the target lesions. The direct measurement of PpIX is a promising, yet rarely performed test that may help determine the appropriate PDT treatment time, the need for re-treatment or adjuvant therapy, and potential efficacy of treatment. Point-probe measurements have shown extreme heterogeneity between PPIx levels in different patients and among different lesions in the same patient9. However, these point-probe measurements are unable to account for the variance in PpIX production in different parts of the skin because of their relatively limited field of view. The recent development of a low-cost, smart phone-based, wide-field fluorescence dosimetry imaging system to map PpIX concentration onto a 2D image allows for handheld, real-time analysis of PpIX levels in human skin. Initial unpublished clinical results have shown its utility in human subjects. However, a more extensive characterization of the factors that influence changes in PpIX during photosensitization has yet to be performed. This study intends to elaborate these inter-and intra-individual variances in photosensitization, including analysis of changes in PpIX concentrations based on anatomical location, skin temperature, pigmentation, and previous skin damage.

Interventions

  • Drug: Ameluz
    • Ameluz is a topical gel approved for use in photodynamic therapy for treatment of actinic keratoses.
  • Device: Portable Apple Smart Phone Protoporphyrin IX Spectrometer Camera
    • This is a portable device that uses a camera to non-invasively and efficiently measure the level of protoporphyrin IX in various areas skin. This camera will be used in all participants to measure the level of protoporphyrin IX in various areas of skin as detailed in the study description.
  • Device: Photodynamic Therapy Light
    • This blue light is FDA approved to work with the Ameluz gel as part of photodynamic therapy and works with the photosensitizing Ameluz gel to form reactive oxygen species that specifically target precancerous lesions, such as actinic keratoses, without damaging normal, non-cancerous skin.

Arms, Groups and Cohorts

  • Active Comparator: Ameluz (amino-levulinic acid topical gel) Only
    • Ameluz is a topical gel approved for use in photodynamic therapy for treatment of actinic keratoses, among other skin conditions. It is being applied to all participants in this study to measure the levels of PpIX in different areas of skin as detailed in study description. This arm includes those participants who have not been prescribed photodynamic therapy and thus they will not receive any light treatment during this study.
  • Active Comparator: Ameluz and Light Therapy
    • Ameluz is a topical gel approved for use in photodynamic therapy for treatment of actinic keratoses, among other skin conditions. It is being applied to all participants in this study to measure the levels of PpIX in different areas of skin as detailed in study description. For patients who have been prescribed photodynamic therapy, the investigators will perform one additional round of measurements of Protoporphyrin IX using our camera device, in addition to the other secondary outcomes including skin temperature.

Clinical Trial Outcome Measures

Primary Measures

  • Change in Protoporphyrin IX levels in the skin at baseline and at serial time points after Ameluz application (the intervention)
    • Time Frame: At baseline, immediately after intervention, 30 minutes after intervention, 45 minutes after intervention, 60 minutes after intervention, after 10-17 minutes of photodynamic therapy intervention
    • Measure change in protoporphyrin IX levels in the skin of the forehead, malar cheek, dorsal hand, and dorsal forearm patients, as well as the bald scalp in male patients

Secondary Measures

  • Effect of Skin temperature on change in protoporphyrin IX levels at baseline and at serial time points after Ameluz application (the intervention)
    • Time Frame: At baseline, immediately after intervention, 30 minutes after intervention, 45 minutes after intervention, 60 minutes after intervention, after 10-17 minutes of photodynamic therapy intervention
    • Measure the change in temperature of skin using an IR camera at the forehead, malar cheek, dorsal hand, and dorsal forearm patients, as well as the bald scalp in male patients.
  • Effect of Age on change in protoporphyrin IX levels at baseline and at serial time points after Ameluz application (the intervention)
    • Time Frame: At baseline, immediately after intervention, 30 minutes after intervention, 45 minutes after intervention, 60 minutes after intervention, after 10-17 minutes of photodynamic therapy intervention
    • Determine the relationship of participant age with change in protoporphyrin IX levels
  • Effect of Fitzpatrick skin type (skin pigmentation) on change in protoporphyrin IX levels at baseline and at serial time points after Ameluz application (the intervention)
    • Time Frame: At baseline, immediately after intervention, 30 minutes after intervention, 45 minutes after intervention, 60 minutes after intervention, after 10-17 minutes of photodynamic therapy intervention
    • Determine the relationship of participant fitzpatrick skin type (skin pigmentation) with change in protoporphyrin IX levels
  • Effect of Protoporphyrin IX levels in Development of Adverse Effects of Pain or Discomfort after receiving photodynamic therapy (the intervention)
    • Time Frame: Immediately After receiving 10-17 minutes of photodynamic light therapy intervention
    • The relationship of onset of pain or discomfort with change in protoporphyrin levels measured immediately after receiving the intervention, photodynamic therapy

Participating in This Clinical Trial

Inclusion Criteria

  • All patients appearing at the Dartmouth-Hitchcock Medical Center Heater Road Dermatology Clinic for photodynamic therapy treatment
  • All other patients at Dartmouth-Hitchcock Medical Center Heater Road Dermatology clinic without a current prescription for photodynamic therapy.

Exclusion Criteria

  • Pregnant women
  • Women who are breast-feeding
  • Adults unable to consent
  • Individuals who are not yet adults
  • Prisoners.
  • Any participants with a condition that makes them not suitable for clinical photodynamic therapy.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Dartmouth-Hitchcock Medical Center
  • Provider of Information About this Clinical Study
    • Principal Investigator: Michael S. Chapman, Principal Investigator – Dartmouth-Hitchcock Medical Center
  • Overall Official(s)
    • Michael S Chapman, MD, MBA, Principal Investigator, Dartmouth-Hitchcock Medical Center
  • Overall Contact(s)
    • Keegan O’Hern, BA, 6038313991, keegan.j.o’hern.med@dartmouth.edu

References

Landes R, Illanes A, Goeppner D, Gollnick H, Friebe M. A study of concentration changes of Protoporphyrin IX and Coproporphyrin III in mixed samples mimicking conditions inside cancer cells for Photodynamic Therapy. PLoS One. 2018 Aug 31;13(8):e0202349. doi: 10.1371/journal.pone.0202349. eCollection 2018.

Anand S, Ortel BJ, Pereira SP, Hasan T, Maytin EV. Biomodulatory approaches to photodynamic therapy for solid tumors. Cancer Lett. 2012 Dec 29;326(1):8-16. doi: 10.1016/j.canlet.2012.07.026. Epub 2012 Jul 25. Review.

Tyrrell JS, Morton C, Campbell SM, Curnow A. Comparison of protoporphyrin IX accumulation and destruction during methylaminolevulinate photodynamic therapy of skin tumours located at acral and nonacral sites. Br J Dermatol. 2011 Jun;164(6):1362-8. doi: 10.1111/j.1365-2133.2011.10265.x. Epub 2011 May 13.

Kanick SC, Davis SC, Zhao Y, Hasan T, Maytin EV, Pogue BW, Chapman MS. Dual-channel red/blue fluorescence dosimetry with broadband reflectance spectroscopic correction measures protoporphyrin IX production during photodynamic therapy of actinic keratosis. J Biomed Opt. 2014;19(7):75002. doi: 10.1117/1.JBO.19.7.075002.

Nissen CV, Heerfordt IM, Wiegell SR, Mikkelsen CS, Wulf HC. Increased protoporphyrin IX accumulation does not improve the effect of photodynamic therapy for actinic keratosis: a randomized controlled trial. Br J Dermatol. 2017 May;176(5):1241-1246. doi: 10.1111/bjd.15098. Epub 2017 Mar 8.

Kanick SC, Davis SC, Zhao Y, Sheehan KL, Hasan T, Maytin EV, Pogue BW, Chapman MS. Pre-treatment protoporphyrin IX concentration in actinic keratosis lesions may be a predictive biomarker of response to aminolevulinic-acid based photodynamic therapy. Photodiagnosis Photodyn Ther. 2015 Dec;12(4):561-6. doi: 10.1016/j.pdpdt.2015.10.006. Epub 2015 Oct 22.

Nissen CV, Philipsen PA, Wulf HC. Protoporphyrin IX formation after topical application of methyl aminolaevulinate and BF-200 aminolaevulinic acid declines with age. Br J Dermatol. 2015 Sep;173(3):760-6. doi: 10.1111/bjd.13923. Epub 2015 Aug 20.

Zhao B, He YY. Recent advances in the prevention and treatment of skin cancer using photodynamic therapy. Expert Rev Anticancer Ther. 2010 Nov;10(11):1797-809. doi: 10.1586/era.10.154. Review.

Alberto J. Ruiz, Ethan P. M. LaRochelle, M. Shane Chapman, Tayyaba Hasan, Brian Pogue. Smartphone-based fluorescence imager for PpIX-based PDT treatment planning: System design and initial results. In: Vol 10860. ; 2019. https://doi.org/10.1117/12.2510403.

Rollakanti KR, Kanick SC, Davis SC, Pogue BW, Maytin EV. Techniques for fluorescence detection of protoporphyrin IX in skin cancers associated with photodynamic therapy. Photonics Lasers Med. 2013 Nov 1;2(4):287-303.

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