Table 3.

Clinical trials in morphea.

Study	Design	Intervention	Mechanism of drug	Outcomes	Phase	Status
Topical treatments
NCT03351114	pilot, proof-of-concept, open label, single arm	Crisaborole 2% ointment, applied twice per day for 12 weeks	Topical PDE4 inhibitor	Primary outcome measures Change in dermal thickness on 4 mm skin punch biopsy Secondary outcome measures • reduction in DIET (dyspigmentation, induration, erythema, telangiectasias) score • reduction in LoSCAT (Localized Scleroderma Cutaneous Assessment Tool) score • reduction in Skindex-29 score (health-related quality of life) • change in dermal thickness of sentinel plaque (using ultrasonography)	2	Completed, awaiting results (2020)
NCT02411643	open label, single group assigned trial	Calcipotriene 0.005% ointment, applied twice per day for 3 months	Vitamin D analogue – anti-proliferative, anti-inflammatory	Primary outcome measures Change of gene expression from skin biopsy Secondary outcome measure • quality of life • modified Localized Scleroderma Skin Score • change of appearance of skin biopsy	1	Terminated (2018)
NCT00147771	non-randomized, single group open-label trial	Imiquimod 5% cream, applied 3-5x/week for 24 weeks	Toll-like receptor 7 agonist	Primary outcome measures Percent improvement in the skin thickness Secondary outcome measures Frequency of side-effects	3	Completed, awaiting results (2009)
Phototherapy-based treatments
NCT04922736	non-randomized, non-blinded, open label, single group assigned trial	UVA1 phototherapy, total of 30 sessions	UV-mediated immunosuppression	Primary outcome measures Change in the Health Assessment Questionnaire Disability Index (HAQ-DI) after 30 sessions Secondary outcome measures Changes after 30 sessions in: • Hand Mobility in Scleroderma (HAMIS) score in patients with hand involvement • Localized Scleroderma Assessment Tool (LoSCAT) score durometer scores	N/A	Enrolling by invitation (2021)
NCT04954573	non-randomized, parallel assigned, open-label trial	Radiation: infrared-A Local-water filtered infrared-A irradiation	Acute and chronic wound healing and anti-inflammatory effects	Primary outcome measures Intensity of skin sclerosis determined by a high-frequency ultrasound device with a 22 MHz applicator Secondary outcome measures • assessment of modified Rodnan Skin Score (mRSS) skin score, of skin hardness determined by durometer, and of range of motions as measured by the range of motions in the presence of contractures • patient’s satisfaction determined by Patients’ Global Impression of Change (PGIC) scale	N/A	Recruiting (2021)
NCT04752397	observational, case-only, prospective trial	Extracorporeal photopheresis	UV-mediated immunosuppression	Primary outcome measures Change in Modified Rodnan Skin score in 17 areas of the body at weeks 4 ± 2, 8 ± 2, 12 ± 2, 16 ± 2, 20 ± 2, and 24 ± 2 Secondary outcome measures Change at lesional and control skin area at weeks 12 ± 2, and 24 ± 2 in: • skin thickness • transepidermal water loss (TEWL) • stratum corneum hydration (SCH) • skin firmness • skin surface sebum level Change at time point 3 (after completion of the cycle) in: • serum levels of proinflammatory factors Interleukin 4 (IL-4), Interleukin 9 (IL-9), Interleukin 33 (IL-33) and Transforming growth factor beta (TGF-beta) • serum levels of Platelet factor 4 (CXCL4) Acute change between time points 1 and 2 at weeks 8 ± 2, 16 ± 2, 24 ± 2 in: • serum levels of proinflammatory factors IL-4, IL-9, IL-33 and TGF-beta • serum levels of CXCL4 • percentage counts of Th1, Th2, Th17 and Treg cells Change between time points 1 and 3 after ECP cycle at weeks 8 ± 2, 16 ± 2, and 24 ± 2 in: • serum levels of proinflammatory factors IL-4, IL-9, IL-33 and TGF-beta • serum levels of CXCL4 • percentage counts of Th1, Th2, Th17 and Treg cells Change at time point 3 at weeks 8 ± 2, 16 ± 2, and 24 ± 2 in: • serum levels of proinflammatory factors IL-4, IL-9, IL-33 and TGF-beta • serum levels of CXCL4 • percentage counts of Th1, Th2, Th17 and Treg cells	N/S	Recruiting (2021)
NCT04875078	randomized, single-blind, cross over, parallel assigned trial	High dose (80-120 J/cm2) UVA1 phototherapy on one hand only vs. untreated hand covered with gloves, for a total of 30 sessions	UV-mediated immunosuppression	Primary outcome measures HAMIS score of treated hand compared to the untreated hand after 30 UVA1 treatments over approximately 100 days Secondary outcome measures Change from baseline to after 30 UVA-1 treatments of treated hand in: • HAMIS score • CHFDS score • skin hardness based on a durometer • skin thickness based on the modified Rodnan skin score (mRSS) • Skindex-16 score • Michigan Hand Questionnaire (MHQ) • Hand Disability in Systemic Sclerosis—Digital Ulcers (HDISS-DU) PROMIS Physical Function (PROMIS-PF)	N/A	Recruiting (2020)
NCT01799174	randomized, triple blinded, placebo controlled, parallel assignment trial	UVA1 (70 J/cm2) vs. placebo (0 J/cm2), applied 3×/week for 10 weeks	UV-mediated immunosuppression	Primary outcome measures Change in LoSSI from baseline vs. after 30 treatments Secondary outcome measures • Physician’s Global Assessment of disease Activity (PGA-A) over 3 years • Gene expression profiling over 3 years	N/A	Completed (2019)
NCT00812188	randomized, single blinded (investigator)	Fluocinonide 0.05% cream twice per day to one plaque for 12 weeks, and UVA-1 medium dose (60 J/cm2) or high dose (120 J/cm2), 3×/week for 12 weeks to another plaque	Corticosteroid-associated anti-inflammatory effects vs. UV-mediated immunosuppression	Primary outcome measures Efficacy of UVA-1 treatment versus topical steroid over a time frame of 5 years	N/A	Completed (2019)
NCT00476801	randomized, outcomes assessor, crossover assigned trial	UVA1 phototherapy, applied 5×/week for up to 14 weeks with dose increasing up to 130 J/cm2 on one side of the face vs. no treatment on opposite side, then cross-over treatment an equal length of time	UV-mediated immunosuppression	Primary outcome measures Plaque thickness and hardness, and increase in mobility at week 28 Secondary outcome measures Analysis of collagen levels and MMP induction at week 28	N/A	Completed (2004)
NCT00476697	open label, single group assigned trial	UVA1 phototherapy, applied 5×/week for up to 16 weeks with dose increasing up to 130 J/cm2	UV-mediated immunosuppression	Primary outcome measures Plaque thickness and hardness, and increase in mobility at week 16 Secondary outcome measures Analysis of collagen levels and MMP induction at week 16	N/A	Terminated (2003)
Systemic treatments
NCT03740724	open label, single group assigned, trial	FCX-013 injected intradermally 1–2 times (12 weeks apart) + veledimex initiated on the day of injection and continued for 2 weeks	FCX-013 is a genetically modified autologous fibroblast that expresses metalloproteinase-1 under the control of a RheoSwitch induced by veledimex molecule	Primary outcome measures Safety Secondary outcome measures Evaluate the antifibrotic effects of FCX-013 plus veledimex	1/2	Terminated (2022)
NCT04200755	randomized, multi-center, double-blind, placebo controlled, parallel group trial	Dupixent (dupilumab) 300 mg (30 patients) vs. placebo (15 patients), first dose 2 s.c. injections, followed by 1 s.c. injections every 2 weeks for 24 weeks	IL-4/IL-13 inhibitor	Primary outcome measures Change in LoSCAT score of target lesion (from baseline to end of treatment visit, 24 weeks) Secondary outcome measures From baseline to follow-up visit, 48 weeks • change in mLoSSI (Localized Scleroderma Skin Activity Index), LoSDI (Localized Scleroderma Skin Damage Index), DermatoLogy Quality of life Index (DLQI) • number of lesions • adverse events • clinical parameters: physical examination, body weight, blood pressure, pulse rate, body temperature, number of lesions • laboratory parameters: hematocrit, hemoglobin, blood cell count, blood enzymes, clinical chemistry, antinuclear antibodies, serum cytokine levels From baseline to follow-up visit, 24 weeks • RNAseq data • RT-Qpcr data	2	Recruiting (2020)
NCT03388255	open label, single group assigned trial	Polydeoxyribonucleotide (PLACENTEX®) 5.625 mg/3 ml, daily i.m. injections for 3 months	unknown	Primary outcome measures Localized Scleroderma Cutaneous Assessment Tool—LOSCATSecondary outcome measures Change in: • tele-thermographic profile (24 weeks) • ultrasound profile of target cutaneous lesion (24 weeks) measurement of histology improvement (12 weeks) • DLQI (24 weeks)	4	Terminated (2019)
NCT00936546	non-randomized, open label, single group assigned trial	Mabthera (rituximab) 1,000 mg injected i.v. at baseline and at 6 months	Anti-CD20	Primary outcome measures Safety at baseline, months 3, 6, 12, 15, 18, 24, 36, 48, and 60 Secondary outcome measures Efficacy at baseline, months 3, 6, 12, 15, 18, 24, 36, 48, and 60	2	Completed (2015)
NCT00479934	randomized, double blinded, placebo controlled, parallel assigned trial	Imatinib mesylate 400 mg/day per os vs. placebo for 6 months	Bcr-abl tyrosine kinase inhibitor	Primary outcome measures Percent variation of modified Rodnan score between inclusion and 6-month visits Secondary outcome measures • percent variation of modified Rodnan score between inclusion and follow-ups at 1, 3, and 12 months • skin thickness at inclusion and at 6 months using skin biopsies • quality of life using DLQI (Dermatology Quality of Life Index) and HAQ (Health Assessment Questionnaire) at 1, 3, 6, and 12 months • tolerance of treatment • effects of treatment on non-cutaneous symptoms	2	Completed (2010)
NCT00501995	open label, single site, single group assigned trial	Cyclophosphamide (50 mg/kg) i.v. daily for 4 consecutive days	DNA alkylating agent	6 patients started treatment, one patient died during the early phase. Primary outcome measures Improvement in mRSS from baseline (measured at 0, 1, 3, 6, 12, and 24 months; > 25% is considered significant): 46.75% improvement from baseline Secondary outcome measures Change in: • HAQ-DI (The Health Assessment Questionnaire-Disability Index): 79% improvement from baseline • physician global assessment (PGA) which is a visual analogue: 71% improvement from baseline	3	Completed, with results (2008)

We conducted a search on clinicaltrials.gov on October 12th 2022 with the key words ‘morphea’ and ‘localized scleroderma’. We identified a total of 36 studies. Of them, we kept only those that were updated since 2020, namely 17 studies. We excluded older studies, those that had status ‘unknown’ or ‘withdrawn’, and also the ones that focused on registries. Numbers in brackets in the Status column indicate the last year in which the study was updated on clinicaltrials.gov.