UVA-1 for Treatment of Skin Tightening and Improvement of Hand Function in Scleroderma

Systemic sclerosis (SSc), also called scleroderma, is a rare chronic autoimmune disease that can have a wide range of cutaneous, joint, and internal organ involvement. In the skin, SSc is characterized by enhanced fibroblast activity leading to hypertrophic dermal collagen that results in thickened, less flexible skin. (Hassani, 2016) SSc is often divided into two types based on extent of cutaneous involvement: diffuse SSc and limited SSc. The hand is a frequent area of involvement in both subtypes of SSc. Hand disability in SSc leads to a high burden on quality of life for patients as it limits both work and activities of daily living. Treatment for hand sclerosis remains limited with generally progressive disease despite aggressive treatment with anti-fibrotic medications, immunosuppressive agents, and topical approaches. Specific hand therapies include physiotherapy and injections of autologous adipose-derived stromal vascular fraction into the fingers with some success. (Guillaume-Jugnot, 2016; Liem, 2019)

Ultraviolet therapy has been used in dermatology for several decades. UVA-1 is a form of phototherapy that utilizes the longest wavelengths in the UV spectrum from 340-400 nm. It is able to penetrate deeper in the skin than other types of phototherapy and target different types of cells including fibroblasts. In sclerosing skin conditions UVA-1 appears to be superior to other forms of UV light. Medium to high dose UVA-1 also appears to be superior to low dose UVA-1 for sclerosing conditions. (Kreuter 2006).

UVA-1 has been reported to be beneficial to skin changes in SSc in several case reports and a few small studies. (Jacobe 2020) Interpretation of these reports has been difficult based on the small numbers of subjects involved and the non-blinded non-randomized nature of the reports. In a single controlled study with half-side comparison of 9 patients, the investigators could not demonstrate improvement with UVA-1 in the treated hand. (Thomas 2007) This study was limited by a small number of patients and the long disease duration prior to treatment (mean of 13 years). A more recent report of a patient with SSc for 2.5 years and severe acrosclerosis that responded to 21 sessions of UVA-1 with improved mobility and functionality renews interest in this treatment modality. (Cuenca-Barrales 2019)

If UVA1 therapy can significantly improve hand involvement in SSc with regards to functionality and disability, it may be a cost-effective and beneficial treatment for this patient segment with debilitating disease.

Purpose and Objectives:

1. To assess the efficacy of 30 sessions of ultraviolet-1 (UVA1) therapy in treating hand involvement of SSc in a prospective, randomized, investigator-blinded, intra-patient, UV-blocking glove-controlled, crossover clinical trial.

1. To compare improvement in hand function as measured by the Hand Mobility in Scleroderma (HAMIS) test, in the UVA1-treated hand compared to control hand (gloved). 2. To compare the improvement in hand function as measured by the Cochin hand functional disability scale (CHFDS) in the UVA1-treated hand compared to control hand (gloved). 3. To compare the improvement in skin hardening based on durometer measurements in the UVA1-treated hand compared to control hand (gloved). 4. To measure improvement in the physician measure of skin thickness on hands and fingers (0-3) scale after completion of 30 UVA1 sessions. 5. To assess the duration of response after a complete 30-treatment course at 3 and12 months post treatment using the HAMIS, CHFDS, durometer, and physician skin thickness assessment. 2. Assess patient-reported outcomes before, during and after treatment using Skindex-16, Michigan Hand Questionnaire (MHQ), PROMIS-Physical Function (PROMIS-PF), Hand Disability in Systemic Sclerosis - Digital Ulcers(HDISS-DU) and Visual Analog Scale (VAS).

Study Design:

This study will use a single-blind, prospective, randomized (dominant/non-dominant hand) comparator design to assess the effect of high dose (80-120 J/cm2) UVA1 therapy on hand function in scleroderma in a paired t-test design. This study will be placebo-controlled (with a UV-blocking gloved hand), cross-over, randomized clinical trial. Following the initial treatment period (30 treatments), patients will have the option to undergo the same high dose UVA1 treatment protocol on the untreated control hand. A follow up period of 12 months following completion of UVA1 therapy will prospectively follow patients to monitor for relapse of their disease to assess the durability of the clinical response to UVA1 therapy on hand scleroderma.

Inclusion criteria:

* Must be able to understand and provide written informed consent * Scleroderma skin involvement affecting both hands approximately equally * Age of at least 18-years-old * Male or female * Ability to engage in twice weekly UVA1 sessions * No changes in systemic therapy during the first 100 days of the study period

Exclusion criteria:

* On photosensitizing medication * Inability to complete study visits * UV light therapy in the 4 weeks prior to entering the study * Commercial tanning or excessive sun exposure in the 4 weeks prior to entering the study * Current pregnancy or planned pregnancy during the study period * Use of topical therapies other than emollients (suprapotent corticosteroids) in the 2 weeks prior to entering the study * History of intolerance to ultraviolet light * Any other condition that will disqualify the patient from the study in the opinion of the investigator

Procedures:

This is a single-blinded, randomized, UV-blocking glove controlled, dominant/non-dominant hand, cross-over study to determine the efficacy of UVA1 in the treatment of hand scleroderma. Each participant will have at least one hand treated with UVA1 during the active treatment period of the study. The study will be performed at the University of Utah Dermatology Department using both the University of Utah E12 Clinic space as well as the Midvalley Clinic space. UVA1 lights boxes are located at both E12 and Midvalley locations. Personnel involved in the study will include the PI, the co-investigators, and the study coordinators. Approximately 27 patients will be enrolled to account for a 25% drop-out rate. The number needed to treat to show a difference in the treatment vs. control hands is 21. The study timeline is summarized in Table 1.

Screening:

For screening, subjects with qualifying scleroderma involving both hands will be asked to read and sign the informed consent document. They will be reminded that they are to take their time and, if necessary, take it home for further consideration. Questions will be answered. Those meeting inclusion / exclusion criteria who have signed informed consent will be enrolled.

After answering questions and prior to the first treatment the Principal Investigator (PI) will examine the entire patient and assess for the diagnosis of systemic sclerosis with bilateral hand involvement and perform the following assessments: HAMIS, CHFDS, durometer measurements, and mRSS. (Please see efficacy assessment section for details of HAMIS, CHFDS, durometer, and mRSS). Photographs of the hands and other affected areas will be taken. The patient will be asked to identify their dominant (writing) hand and their answer will be noted. Using a random number generator, the patient will be randomized to undergo UVA1 treatment vs UV-blocking glove (control) on the dominant hand. The non-dominant hand will receive the other modality. A study coordinator will perform the randomization on the day of first treatment and the PI will be blinded to the treatment assignment.

UVA1 Treatments:

Blinding:

A UV-blocking glove will be placed on the control hand as determined by the randomization process. Subjects will wear eyewear that occludes external light.

Evaluations for adverse effects will be carried out by the UVA1 operator (a nurse not involved in any assessments) and the blinded investigator at prescribed intervals. Evaluation of UVA1 efficacy on hand scleroderma will be assessed by a trained and experienced evaluator who is blinded as to the UVA1-treated side (covered / not covered). The efficacy evaluations will be carried out prior to treatments on days both evaluations and treatments are completed. After participants have been evaluated at the 3-month post-treatment study visit the blinded evaluator will become unblinded to the UVA1-treated side for the purpose of allowing participants to receive standard of care therapy. Therefore, participants will be allowed to receive additional UVA-1 treatments to one or both hands in addition to any other necessary standard of care treatments after the 3-month post-treatment visit.

Dosing Schedule:

Prior studies with UVA1 have shown that high and medium dose protocols (\>40-120 J/cm2) are more effective than low dose (20-40 J/cm2) to treat sclerosing skin conditions. (Hassani, 2016) Thus, we will set the initiation dose at 50 J. The hands will be positioned approximately 9 inches from the bulbs. The palmar surface of the hand will be exposed for half the treatment and the dorsal surface for half the treatment. If tolerating well after three treatments, the dose will be increased to 60 J for three treatments and then 70 J for the remaining treatments.

Patients will return to clinic two-to-three times per week for 30 treatments over a 100-day period to receive UVA1 treatments. If the patient experiences redness, burning, pain, or blistering at the treatment site, treatment will be held if active symptoms persist at the time of the next scheduled treatment. If the symptoms have resolved and the patient has healed by the next scheduled treatment, the UVA1 energy will be reduced by 10 J of the previously delivered dose. Dose escalation will then proceed by increasing the UVA1 energy after three well tolerated treatments.

Evaluations:

1\. Efficacy evaluations will be performed at baseline, after 15 UVA1 treatment sessions, after 30 UVA1 treatment sessions, and at 3 and 12 months after completion of all UVA1 treatments. For each evaluation prior to the 12-month evaluation, one of the sub-Investigators who is blinded to the treatment assignments will generate and record the HAMIS, CHFDS, Durometer, and mRSS. Hands will be photographed. Patients will complete all PROM including using Skindex-16, Michigan Hand Questionnaire (MHQ), PROMIS-Physical Function (PROMIS-PF), Hand Disability in Systemic Sclerosis - Digital Ulcers(HDISS-DU), and Visual Analog Scale (VAS).

The blinded evaluator will also perform safety evaluation and document study-related adverse events.

1. Primary Efficacy Measure:

The efficacy will be measured using the HAMIS test score to assess for improvement over time and as compared to the untreated hand. The primary endpoint will be assessed after 30 UVA1 treatments. The primary endpoint is improvement in HAMIS score as compared to the untreated hand after 30 UVA1 treatment sessions. 2. Secondary Efficacy Measures:

Secondary efficacy measures include HAMIS test score improvement from baseline in treated and untreated hands after 30 UVA1 treatment sessions, as well as changes in CHFDS, Durometer measures, mRSS, Skindex-16, MHQ, PROMIS-PF, and VAS scores between baseline and after 30 UVA1 treatment sessions and (when applicable) between treated and untreated hands. Other secondary efficacy measures include change in HAMIS test scores CHFDS, Durometer measures, Physician assessment, Skindex-16, MHQ, PROMIS-PF, HDISS-DU, and VAS scores between completion of 30 UVA1 treatments and 3 and 12 months post-treatment in both hands as compared to baseline and after 30 UVA1 treatment sessions in each hand. Secondary endpoint measures also include time to disease worsening after treatment as defined by a 3-point (\~10%) increase in HAMIS scores post-treatment.

Endpoint measure descriptions:

HAMIS is a hand function test develop

• Change in HAMIS score from baseline to after 30 UVA-1 treatments of treated hand. [Срок оценки: Approximately 100 days]
• Change in CHFDS score from baseline to after 30 UVA-1 treatments of treated hand. [Срок оценки: Approximately 100 days]
• Change in skin hardness from baseline to after 30 UVA-1 treatments of treated hand. [Срок оценки: Approximately 100 days]
• Change in skin thickness from baseline to after 30 UVA-1 treatments of treated hand. [Срок оценки: Approximately 100 days]
• Change in Skindex-16 score from baseline to after 30 UVA-1 treatments of treated hand. [Срок оценки: Approximately 100 days]
• Change in MHQ scores from baseline to after 30 UVA-1 treatments of treated hand. [Срок оценки: Approximately 100 days]
• Change in HDISS-DU from baseline to after 30 UVA-1 treatments of treated hand. [Срок оценки: Approximately 100 days]
• Change in PROMIS-PF scores from baseline to after 30 UVA-1 treatments of treated hand. [Срок оценки: Approximately 100 days]