Efficacy and safety of sirolimus treatment for intractable lymphatic anomalies

A study protocol for an open-label, single-arm, multicenter, prospective study (SILA)

Michio Ozeki, Ryuta Asada, Akiko M. Saito, Hiroya Hashimoto, Takumi Fujimura, Tatsuo Kuroda, Shigeru Ueno, Shoji Watanabe, Shunsuke Nosaka, Mikiko Miyasaka, Akihiro Umezawa, Kentaro Matsuoka, Takanobu Maekawa, Yohei Yamada, Akihiro Fujino, Satoshi Hirakawa, Taizo Furukawa, Tatsuro Tajiri, Yoshiaki Kinoshita, Ryota Souzaki & 1 others Toshiyuki Fukao

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Introduction: Lymphatic anomalies (LAs) refer to a group of diseases involving systemic dysplasia of lymphatic vessels. These lesions are classified as cystic lymphatic malformation (macrocystic, microcystic or mixed), generalized lymphatic anomaly, and Gorham–Stout disease. LAs occur mainly in childhood, and present with various symptoms including chronic airway problems, recurrent infection, and organ disorders. Individuals with LAs often experience progressively worsening symptoms with a deteriorating quality of life. Although limited treatment options are available, their efficacy has not been validated in prospective clinical trials, and are usually based on case reports. Thus, there are no validated standards of care for these patients because of the lack of prospective clinical trials. Methods: This open-label, single-arm, multicenter, prospective study will assess the efficacy and safety of a mammalian target of the rapamycin inhibitor sirolimus in the treatment of intractable LAs. Participants will receive oral sirolimus once a day for 52 weeks. The dose is adjusted so that the nadir concentration remains within 5–15 ng/ml. The primary endpoint is the response rate of radiological volumetric change of the target lesion confirmed by central review at 52 weeks after treatment. The secondary endpoints are the response rates at 12 and 24 weeks, respiratory function, pleural effusion, ascites, blood coagulation parameters, bleeding, pain, quality of life, activities of daily living, adverse events, side effects, laboratory examinations, vital signs, and pharmacokinetic data. Results: This is among the first multicenter studies to evaluate sirolimus treatment for intractable LAs, and few studies to date have focused on the standard assessment of the efficacy for LAs treatment. Our protocol uses novel, uncomplicated methods for radiological assessment, with reference to the results of our previous retrospective survey and historical control data from the literature. Conclusions: We propose a multicenter study to investigate the efficacy and safety of sirolimus for intractable LAs (SILA study; trial registration UMIN000028905). Our results will provide pivotal data to support the approval of sirolimus for the treatment of intractable LAs.

Original languageEnglish
Pages (from-to)84-91
Number of pages8
JournalRegenerative Therapy
Volume10
DOIs
Publication statusPublished - 2019 Jun 1

Fingerprint

Sirolimus
Multicenter Studies
Labels
Prospective Studies
Safety
Pharmacokinetics
Coagulation
Blood
Therapeutics
Quality of Life
Clinical Trials
Lymphatic Vessels
Vital Signs
Blood Coagulation
Pleural Effusion
Standard of Care
Activities of Daily Living
Ascites
Hemorrhage
Pain

Keywords

  • Generalized lymphatic anomaly
  • Gorham–Stout disease
  • Lymphatic abnormalities
  • Lymphatic malformation
  • Mammalian target of rapamycin

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering
  • Developmental Biology

Cite this

Efficacy and safety of sirolimus treatment for intractable lymphatic anomalies : A study protocol for an open-label, single-arm, multicenter, prospective study (SILA). / Ozeki, Michio; Asada, Ryuta; Saito, Akiko M.; Hashimoto, Hiroya; Fujimura, Takumi; Kuroda, Tatsuo; Ueno, Shigeru; Watanabe, Shoji; Nosaka, Shunsuke; Miyasaka, Mikiko; Umezawa, Akihiro; Matsuoka, Kentaro; Maekawa, Takanobu; Yamada, Yohei; Fujino, Akihiro; Hirakawa, Satoshi; Furukawa, Taizo; Tajiri, Tatsuro; Kinoshita, Yoshiaki; Souzaki, Ryota; Fukao, Toshiyuki.

In: Regenerative Therapy, Vol. 10, 01.06.2019, p. 84-91.

Research output: Contribution to journalArticle

Ozeki, M, Asada, R, Saito, AM, Hashimoto, H, Fujimura, T, Kuroda, T, Ueno, S, Watanabe, S, Nosaka, S, Miyasaka, M, Umezawa, A, Matsuoka, K, Maekawa, T, Yamada, Y, Fujino, A, Hirakawa, S, Furukawa, T, Tajiri, T, Kinoshita, Y, Souzaki, R & Fukao, T 2019, 'Efficacy and safety of sirolimus treatment for intractable lymphatic anomalies: A study protocol for an open-label, single-arm, multicenter, prospective study (SILA)', Regenerative Therapy, vol. 10, pp. 84-91. https://doi.org/10.1016/j.reth.2018.12.001
Ozeki, Michio ; Asada, Ryuta ; Saito, Akiko M. ; Hashimoto, Hiroya ; Fujimura, Takumi ; Kuroda, Tatsuo ; Ueno, Shigeru ; Watanabe, Shoji ; Nosaka, Shunsuke ; Miyasaka, Mikiko ; Umezawa, Akihiro ; Matsuoka, Kentaro ; Maekawa, Takanobu ; Yamada, Yohei ; Fujino, Akihiro ; Hirakawa, Satoshi ; Furukawa, Taizo ; Tajiri, Tatsuro ; Kinoshita, Yoshiaki ; Souzaki, Ryota ; Fukao, Toshiyuki. / Efficacy and safety of sirolimus treatment for intractable lymphatic anomalies : A study protocol for an open-label, single-arm, multicenter, prospective study (SILA). In: Regenerative Therapy. 2019 ; Vol. 10. pp. 84-91.
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abstract = "Introduction: Lymphatic anomalies (LAs) refer to a group of diseases involving systemic dysplasia of lymphatic vessels. These lesions are classified as cystic lymphatic malformation (macrocystic, microcystic or mixed), generalized lymphatic anomaly, and Gorham–Stout disease. LAs occur mainly in childhood, and present with various symptoms including chronic airway problems, recurrent infection, and organ disorders. Individuals with LAs often experience progressively worsening symptoms with a deteriorating quality of life. Although limited treatment options are available, their efficacy has not been validated in prospective clinical trials, and are usually based on case reports. Thus, there are no validated standards of care for these patients because of the lack of prospective clinical trials. Methods: This open-label, single-arm, multicenter, prospective study will assess the efficacy and safety of a mammalian target of the rapamycin inhibitor sirolimus in the treatment of intractable LAs. Participants will receive oral sirolimus once a day for 52 weeks. The dose is adjusted so that the nadir concentration remains within 5–15 ng/ml. The primary endpoint is the response rate of radiological volumetric change of the target lesion confirmed by central review at 52 weeks after treatment. The secondary endpoints are the response rates at 12 and 24 weeks, respiratory function, pleural effusion, ascites, blood coagulation parameters, bleeding, pain, quality of life, activities of daily living, adverse events, side effects, laboratory examinations, vital signs, and pharmacokinetic data. Results: This is among the first multicenter studies to evaluate sirolimus treatment for intractable LAs, and few studies to date have focused on the standard assessment of the efficacy for LAs treatment. Our protocol uses novel, uncomplicated methods for radiological assessment, with reference to the results of our previous retrospective survey and historical control data from the literature. Conclusions: We propose a multicenter study to investigate the efficacy and safety of sirolimus for intractable LAs (SILA study; trial registration UMIN000028905). Our results will provide pivotal data to support the approval of sirolimus for the treatment of intractable LAs.",
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T1 - Efficacy and safety of sirolimus treatment for intractable lymphatic anomalies

T2 - A study protocol for an open-label, single-arm, multicenter, prospective study (SILA)

AU - Ozeki, Michio

AU - Asada, Ryuta

AU - Saito, Akiko M.

AU - Hashimoto, Hiroya

AU - Fujimura, Takumi

AU - Kuroda, Tatsuo

AU - Ueno, Shigeru

AU - Watanabe, Shoji

AU - Nosaka, Shunsuke

AU - Miyasaka, Mikiko

AU - Umezawa, Akihiro

AU - Matsuoka, Kentaro

AU - Maekawa, Takanobu

AU - Yamada, Yohei

AU - Fujino, Akihiro

AU - Hirakawa, Satoshi

AU - Furukawa, Taizo

AU - Tajiri, Tatsuro

AU - Kinoshita, Yoshiaki

AU - Souzaki, Ryota

AU - Fukao, Toshiyuki

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Introduction: Lymphatic anomalies (LAs) refer to a group of diseases involving systemic dysplasia of lymphatic vessels. These lesions are classified as cystic lymphatic malformation (macrocystic, microcystic or mixed), generalized lymphatic anomaly, and Gorham–Stout disease. LAs occur mainly in childhood, and present with various symptoms including chronic airway problems, recurrent infection, and organ disorders. Individuals with LAs often experience progressively worsening symptoms with a deteriorating quality of life. Although limited treatment options are available, their efficacy has not been validated in prospective clinical trials, and are usually based on case reports. Thus, there are no validated standards of care for these patients because of the lack of prospective clinical trials. Methods: This open-label, single-arm, multicenter, prospective study will assess the efficacy and safety of a mammalian target of the rapamycin inhibitor sirolimus in the treatment of intractable LAs. Participants will receive oral sirolimus once a day for 52 weeks. The dose is adjusted so that the nadir concentration remains within 5–15 ng/ml. The primary endpoint is the response rate of radiological volumetric change of the target lesion confirmed by central review at 52 weeks after treatment. The secondary endpoints are the response rates at 12 and 24 weeks, respiratory function, pleural effusion, ascites, blood coagulation parameters, bleeding, pain, quality of life, activities of daily living, adverse events, side effects, laboratory examinations, vital signs, and pharmacokinetic data. Results: This is among the first multicenter studies to evaluate sirolimus treatment for intractable LAs, and few studies to date have focused on the standard assessment of the efficacy for LAs treatment. Our protocol uses novel, uncomplicated methods for radiological assessment, with reference to the results of our previous retrospective survey and historical control data from the literature. Conclusions: We propose a multicenter study to investigate the efficacy and safety of sirolimus for intractable LAs (SILA study; trial registration UMIN000028905). Our results will provide pivotal data to support the approval of sirolimus for the treatment of intractable LAs.

AB - Introduction: Lymphatic anomalies (LAs) refer to a group of diseases involving systemic dysplasia of lymphatic vessels. These lesions are classified as cystic lymphatic malformation (macrocystic, microcystic or mixed), generalized lymphatic anomaly, and Gorham–Stout disease. LAs occur mainly in childhood, and present with various symptoms including chronic airway problems, recurrent infection, and organ disorders. Individuals with LAs often experience progressively worsening symptoms with a deteriorating quality of life. Although limited treatment options are available, their efficacy has not been validated in prospective clinical trials, and are usually based on case reports. Thus, there are no validated standards of care for these patients because of the lack of prospective clinical trials. Methods: This open-label, single-arm, multicenter, prospective study will assess the efficacy and safety of a mammalian target of the rapamycin inhibitor sirolimus in the treatment of intractable LAs. Participants will receive oral sirolimus once a day for 52 weeks. The dose is adjusted so that the nadir concentration remains within 5–15 ng/ml. The primary endpoint is the response rate of radiological volumetric change of the target lesion confirmed by central review at 52 weeks after treatment. The secondary endpoints are the response rates at 12 and 24 weeks, respiratory function, pleural effusion, ascites, blood coagulation parameters, bleeding, pain, quality of life, activities of daily living, adverse events, side effects, laboratory examinations, vital signs, and pharmacokinetic data. Results: This is among the first multicenter studies to evaluate sirolimus treatment for intractable LAs, and few studies to date have focused on the standard assessment of the efficacy for LAs treatment. Our protocol uses novel, uncomplicated methods for radiological assessment, with reference to the results of our previous retrospective survey and historical control data from the literature. Conclusions: We propose a multicenter study to investigate the efficacy and safety of sirolimus for intractable LAs (SILA study; trial registration UMIN000028905). Our results will provide pivotal data to support the approval of sirolimus for the treatment of intractable LAs.

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KW - Gorham–Stout disease

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KW - Lymphatic malformation

KW - Mammalian target of rapamycin

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