Topical sirolimus solution for lingual microcystic lymphatic malformations in children and adults (TOPGUN): study protocol for a multicenter, randomized, assessor-blinded, controlled, stepped-wedge clinical trial

A Marchand, A Caille, V Gissot, B Giraudeau, C Lengelle, H Bourgoin, B Largeau, S Leducq, A Maruani, A Marchand, A Caille, V Gissot, B Giraudeau, C Lengelle, H Bourgoin, B Largeau, S Leducq, A Maruani

Abstract

Background: Lingual microcystic lymphatic malformations (LMLMs) are rare congenital vascular malformations presenting as clusters of cysts filled with lymph fluid or blood. Even small well-limited lesions can be responsible for a heavy burden, inducing pain, aesthetic prejudice, or oozing, bleeding, infections. The natural history of LMLMs is progressive worsening punctuated by acute flares. Therapeutic options include surgery, laser excision, and radiofrequency ablation but all are potentially detrimental and expose to local relapse. Therefore, the management frequently relies on a "watchful waiting" approach. In complicated LMLMs, treatment with oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is often used. Topical applications of sirolimus on the buccal mucosae have been reported in other oral diseases with good tolerance and none to slight detectable blood sirolimus concentrations. We aim to evaluate the efficacy and safety of a 1 mg/mL sirolimus solution applied once daily on LMLM of any stage in children and adults after 4, 8, 12, 16, 20, and 24 weeks of treatment compared to usual care (no treatment).

Methods: This is a randomized, multicentric study using an individually randomized stepped-wedge design over 24 weeks to evaluate topical application of a 1 mg/mL sirolimus solution once daily, on LMLM, versus usual care (no treatment), the control condition. Participants begin with an observational period and later switch to the intervention at a randomized time (week 0, 4, 8, or 12). Visits occur every 4 weeks, either in the study center or by teleconsulting. The primary outcome will be the evaluation of global severity of the LMLM on monthly standardized photographs by 3 independent blinded experts using the physical global assessment (PGA) 0 to 5 scale. Secondary outcomes will include lesion size measurement and quality of life assessment, investigator, and patient-assessed global disease and specific symptoms (oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain, and global discomfort) assessment. A biological monitoring will be performed including residual blood sirolimus concentration and usual laboratory parameters.

Discussion: Given the disappointing state of current treatment options in LMLMs, topical sirolimus could become firstline therapy in treating LMLMs if its efficacy and safety were to be demonstrated.

Trial registration: ClinicalTrials.gov NCT04128722 . Registered on 24 September 2019. EudraCT: EUCTR2019-001530-33-FR Sponsor (University Hospital Center of Tours - CHRU Tours): DR190041-TOPGUN French regulatory authorities: ID RCB: 2019-001530-33.

Keywords: Lingual microcystic lymphatic malformation; Lymphangioma; Lymphatic abnormalities; Mucosa; Sirolimus; Stepped-wedge design; Topical treatment.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study diagram

References

    1. Renton JP, Smith RJH. Current treatment paradigms in the management of lymphatic malformations. Laryngoscope. 2011;121(1):56–59. doi: 10.1002/lary.20768.
    1. ISSVA Classification of Vascular Anomalies ©2018 International Society for the Study of Vascular Anomalies. Available at “”. Accessed 2 Nov 2020.
    1. Wassef M, Blei F, Adams D, et al. Vascular Anomalies Classification: recommendations from the International Society for the Study of Vascular Anomalies. Pediatrics. 2015;136(1):e203–e214. doi: 10.1542/peds.2014-3673.
    1. Wiegand S, Eivazi B, Barth PJ, et al. Pathogenesis of lymphangiomas. Virchows Arch. 2008;453(1):1–8. doi: 10.1007/s00428-008-0611-z.
    1. Elluru RG, Balakrishnan K, Padua HM. Lymphatic malformations: diagnosis and management. Semin Pediatr Surg. 2014;23(4):178–185. doi: 10.1053/j.sempedsurg.2014.07.002.
    1. Wiegand S, Eivazi B, Zimmermann AP, et al. Microcystic lymphatic malformations of the tongue: diagnosis, classification, and treatment. Arch Otolaryngol Head Neck Surg. 2009;135(10):976. doi: 10.1001/archoto.2009.131.
    1. de Serres LM, Sie KCY, Richardson MA. Lymphatic malformations of the head and neck: a proposal for staging. Arch Otolaryngology Head Neck Surg. 1995;121(5):577–582. doi: 10.1001/archotol.1995.01890050065012.
    1. Wittekindt C, Michel O, Streppel M, et al. Lymphatic malformations of the head and neck: Introduction of a disease score for children, Cologne Disease Score (CDS) Int J Pediatr Otorhinolaryngol. 2006;70(7):1205–1212. doi: 10.1016/j.ijporl.2005.12.013.
    1. Adams DM, Trenor CC, Hammill AM, et al. Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Pediatrics. 2016;137(2):e20153257. doi: 10.1542/peds.2015-3257.
    1. Perkins JA, Manning SC, Tempero RM, et al. Lymphatic malformations: review of current treatment. Otolaryngol Head Neck Surg. 2010;142(6):795–803.e1. doi: 10.1016/j.otohns.2010.02.026.
    1. Bajaj Y, Hewitt R, Ifeacho S, Hartley BEJ. Surgical excision as primary treatment modality for extensive cervicofacial lymphatic malformations in children. Intern J Pediatr Otorhinolaryngol. 2011;75(5):673–677. doi: 10.1016/j.ijporl.2011.02.009.
    1. Defnet AM, Bagrodia N, Hernandez SL, Gwilliam N, Kandel JJ. Pediatric lymphatic malformations: evolving understanding and therapeutic options. Pediatr Surg Int. 2016;32(5):425–433. doi: 10.1007/s00383-016-3867-4.
    1. Lamming DW. Inhibition of the mechanistic target of rapamycin (mTOR)–rapamycin and beyond. Cold Spring Harb Perspect Med. 2016;6(5):a025924. doi: 10.1101/cshperspect.a025924.
    1. Paghdal KV, Schwartz RA. Sirolimus (rapamycin): from the soil of Easter Island to a bright future. J Am Acad Dermatol. 2007;57(6):1046–1050. doi: 10.1016/j.jaad.2007.05.021.
    1. Kobayashi S, Kishimoto T, Kamata S, Otsuka M, Miyazaki M, Ishikura H. Rapamycin, a specific inhibitor of the mammalian target of rapamycin, suppresses lymphangiogenesis and lymphatic metastasis. Cancer Sci. 2007;98(5):726–733. doi: 10.1111/j.1349-7006.2007.00439.x.
    1. Osborn AJ, Dickie P, Neilson DE, et al. Activating PIK3CA alleles and lymphangiogenic phenotype of lymphatic endothelial cells isolated from lymphatic malformations. Human Mol Genet. 2015;24(4):926–938. doi: 10.1093/hmg/ddu505.
    1. Boscolo E, Coma S, Luks VL, et al. AKT hyper-phosphorylation associated with PI3K mutations in lymphatic endothelial cells from a patient with lymphatic malformation. Angiogenesis. 2015;18(2):151–162. doi: 10.1007/s10456-014-9453-2.
    1. Fereydooni A, Dardik A, Nassiri N. Molecular changes associated with vascular malformations. J Vasc Surg. 2019;70(1):314–326.e1. doi: 10.1016/j.jvs.2018.12.033.
    1. Marsh DJ, Trahair TN, Martin JL, et al. Rapamycin treatment for a child with germline PTEN mutation. Nat Rev Clin Oncol. 2008;5(6):357–361. doi: 10.1038/ncponc1112.
    1. Nadal M, Giraudeau B, Tavernier E, Jonville-Bera A, Lorette G, Maruani A. Efficacy and safety of mammalian target of rapamycin inhibitors in vascular anomalies: a systematic review. Acta Derm Venerol. 2016;96(4):448–452. doi: 10.2340/00015555-2300.
    1. Hammill AM, Wentzel M, Gupta A, et al. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer. 2011;57(6):1018–1024. doi: 10.1002/pbc.23124.
    1. . Accessed 2 Nov 2020.
    1. Groupe de Recherche de la Société Française de Dermatologie Pédiatrique. Maruani A, Boccara O, et al. Treatment of voluminous and complicated superficial slow-flow vascular malformations with sirolimus (PERFORMUS): protocol for a multicenter phase 2 trial with a randomized observational-phase design. Trials. 2018;19(1):340. doi: 10.1186/s13063-018-2725-1.
    1. Ormerod AD, Shah SAA, Copeland P, Omar G, Winfield A. Treatment of psoriasis with topical sirolimus: preclinical development and a randomized, double-blind trial. Br J Dermatol. 2005;152(4):758–764. doi: 10.1111/j.1365-2133.2005.06438.x.
    1. Soria A, Agbo-Godeau S, Taïeb A, Francès C. Treatment of refractory oral erosive lichen planus with topical rapamycin: 7 cases. Dermatology. 2009;218(1):22–25. doi: 10.1159/000172830.
    1. Poot AM, Jonkman MF. Topical sirolimus for oral pemphigus vulgaris: 3 unresponsive cases. J Am Acad Dermatol. 2012;67(5):e228–e229. doi: 10.1016/j.jaad.2012.04.032.
    1. Amin S, Lux A, Khan A, O’Callaghan F. Sirolimus ointment for facial angiofibromas in individuals with tuberous sclerosis complex. Int Sch Res Notices. 2017;2017:1–6. doi: 10.1155/2017/8404378.
    1. Malissen N, Vergely L, Simon M, Roubertie A, Malinge M-C, Bessis D. Long-term treatment of cutaneous manifestations of tuberous sclerosis complex with topical 1% sirolimus cream: a prospective study of 25 patients. J Am Acad Dermatol. 2017;77(3):464–472.e3. doi: 10.1016/j.jaad.2017.04.005.
    1. Leducq S, Giraudeau B, Tavernier E, Maruani A. Topical use of mammalian target of rapamycin inhibitors in dermatology: a systematic review with meta-analysis. J Am Acad Dermatol. 2019;80(3):735–742. doi: 10.1016/j.jaad.2018.10.070.
    1. Ivars M, Redondo P. Efficacy of topical sirolimus (Rapamycin) for the treatment of microcystic lymphatic malformations. JAMA Dermatol. 2017;153(1):103. doi: 10.1001/jamadermatol.2016.3697.
    1. García-Montero P, del Boz J, Sanchez-Martínez M, Escudero Santos IM, Baselga E. Microcystic lymphatic malformation successfully treated with topical rapamycin. Pediatrics. 2017;139(5):e20162105. doi: 10.1542/peds.2016-2105.
    1. Groupe de Recherche de la Société Française de Dermatologie Pédiatrique. Leducq S, Caille A, et al. Topical sirolimus 0.1% for treating cutaneous microcystic lymphatic malformations in children and adults (TOPICAL): protocol for a multicenter phase 2, within-person, randomized, double-blind, vehicle-controlled clinical trial. Trials. 2019;20(1):739. doi: 10.1186/s13063-019-3767-8.
    1. Nudelman Z, Friedman M, Barasch D, et al. Levels of sirolimus in saliva and blood following mouthwash application. Oral Dis. Published online March 2014:n/a-n/a. 10.1111/odi.12229.
    1. Cornu C, Kassai B, Fisch R, et al. Experimental designs for small randomised clinical trials: an algorithm for choice. Orphanet J Rare Dis. 2013;8(1):48. doi: 10.1186/1750-1172-8-48.
    1. Hooper R, Knowles C. Improving the efficiency of individually randomized clinical trials by staggering the introduction of the intervention. Stat Med. 2019;38(1):44–52. doi: 10.1002/sim.7959.
    1. Lewis-Jones MS, Finlay AY. The Children’s Dermatology Life Quality Index (CDLQI): initial validation and practical use. Br J Dermatol. 2010;132(6):942–949. doi: 10.1111/j.1365-2133.1995.tb16953.x.
    1. Garduno J, Bhosle MJ, Balkrishnan R, Feldman SR. Measures used in specifying psoriasis lesion(s), global disease and quality of life: a systematic review. J Dermatol Treatment. 2007;18(4):223–242. doi: 10.1080/09546630701271807.
    1. Tabolli S, Sampogna F, Pagliarello C, Paradisi A, Spagnoli A, Abeni D. Disease severity evaluation among dermatological out-patients: a comparison between the assessments of patients and physicians: patient-physician disease severity evaluation: a comparison. J Eur Acad Dermatol Venereol. 2012;26(2):213–218. doi: 10.1111/j.1468-3083.2011.04038.x.
    1. Chan A-W, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 Statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200. doi: 10.7326/0003-4819-158-3-201302050-00583.
    1. Fogel AL, Hill S, Teng JMC. Advances in the therapeutic use of mammalian target of rapamycin (mTOR) inhibitors in dermatology. J Am Acad Dermatol. 2015;72(5):879–889. doi: 10.1016/j.jaad.2015.01.014.
    1. Chalmers T. Randomize the first patient! N Engl J Med. 1977;296(2):107. doi: 10.1056/NEJM197701132960214.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner