The Safety and Efficacy of Intravitreal Topotecan for the Treatment of Proliferative Vitreoretinopathy

Обзор

The goal of this clinical trial is to evaluate the safety and efficacy of intravitreal topotecan for the treatment of patients with rhegmatogenous retinal detachment due to proliferative vitreoretinopathy (PVR) or resulting from an open globe injury, and compare the outcomes to those who do no receive intravitreal topotecan. The main objectives it aims to achieve are: * to study the safety profile of intravitreal topotecan in the treatment of PVR * to evaluate the efficacy of intravitreal topotecan in treating PVR. Post-consent, participants will: * undergo vitrectomy (with or without scleral buckle) as part of standard treatment for retinal detachment. * receive intravitreal topotecan at the time of surgery, post-operative day 7 and post-operative day 28 (if randomized to receive the medication) * come in at post-operative day 1, 7, 28, 56, 84, 126 and 168 to undergo a complete ophthalmic exam along with a fundus photography and optical coherence tomography of the macula, have their intraocular pressure and visual acuity measured and their adverse events monitored, if any. Researchers will compare participants who receive intravitreal topotecan for PVR to those who do not to see if there is a significant variability in recurrence of retinal detachment, rate of retinal reattachment and PVR grade 6 months after surgery.

Подробное описание

Rhegmatogenous retinal detachment (RRD) is an acute, sight-threatening condition that occurs after separation of the neurosensory retina from the underlying retinal pigment epithelium (RPE) due to the presence of a retinal break. Proliferative vitreoretinopathy (PVR) represents growth of ectopic fibrocellular growth on the surface of, within and underneath the retina. PVR is hypothesized to occur secondary to the migration of RPE cells to the peri-retina, leading to a mesenchymal transition into contractile myofibroblasts. PVR affects 5-10% of RRDs and is the most common cause of surgical failure in RRD.

Given that PVR involves a pro-inflammatory and pro-fibrotic cellular response, adjuvants such as corticosteroids and antimetabolites such as 5-fluorouracil have been attempted in the treatment of this condition. Overall, the efficacy results of these treatments have been mixed, and no standard of care adjuvant therapy has emerged.

Topotecan is a chemotherapeutic agent that acts as a topoisomerase inhibitor. It is most commonly administered intravitreally for patients with refractory or recurrent vitreous seeds from retinoblastoma, and shows high efficacy in this setting. At the same time, intravitreal topotecan administered at doses of 5-30µg has been associated with no ocular or systemic complications or adverse electroretinogram changes. To the best of available knowledge, topotecan has not been administered for the treatment of proliferative vitreoretinopathy. Topotecan has anti-inflammatory, anti-proliferative and anti-fibrotic activity that is hypothesized to exhibit high efficacy for the treatment of PVR. In this study, the efficacy and safety of intravitreal topotecan for the treatment of PVR will be investigated.

Вмешательства

• Препарат Topotecan
  20 micrograms of intravitreal topotecan given in a 1 cc tuberculin syringe at a concentration of 20 mcg/20mcL.

Первичные конечные точки

• Recurrence of rhegmatogenous retinal detachment secondary to PVR [Срок оценки: 6 months after initial surgery, or last follow-up visit available]

Вторичные конечные точки (5)

• Best corrected visual acuity (BCVA) [Срок оценки: at the pre-operative assessment, and post-operative day1, 7, 28, 56, 84, 126, 168]
• Variation of PVR grade [Срок оценки: at the pre-operative assessment, and post-operative day1, 7, 28, 56, 84, 126, 168]
• Retinal reattachment rate at month 6 or last follow up [Срок оценки: at post-operative day 168 (or last follow-up visit available if the participant did not show up at post-operative day 168)]
• Recurrence of rhegmatogenous retinal detachment due to any cause [Срок оценки: at the pre-operative assessment, and post-operative day1, 7, 28, 56, 84, 126, 168]
• Number of participants and type of intraoperative or postoperative complications [Срок оценки: at time of surgery, and each follow up visit (post-operative day1, 7, 28, 56, 84, 126, 168)]

Критерии участия

Критерии включения

• Patients > 18 years old
• Patients presenting with retinal detachment due with PVR (grade C or higher) or retinal detachment associated with open globe trauma
• Patients undergoing vitrectomy or vitrectomy with scleral buckle as part of standard care.

Критерии исключения

• Patient unable to give consent
• Patient unable to follow-up
• Females of childbearing age who are pregnant at the time of recruitment. A pregnancy test will be done to all women of ages 18-55 prior to surgery to ensure they are not pregnant at the time of recruitment.
• Patients with a history of tractional or exudative retinal detachment.
• Patients with other planned ocular surgery following PPV
• Active or chronic or recurrent uncontrolled ocular or systemic disease
• Active or history of chronic or recurrent inflammatory eye disease
• Diagnosis of severe nonproliferative or proliferative diabetic retinopathy or vasoproliferative disease in the operative eye
• Signs of ocular infection at presentation in either eye
• Known or suspected sensitivity or allergy to any of the medications used in the operation or postoperatively
• No Light Perception vision in the operative eye
• Failure to achieve intraoperative reattachment
• Patient with silicone oil instilled in the operative eye at time of presentation

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

• Ohman T, Gawriyski L, Miettinen S, Varjosalo M, Loukovaara S. Molecular pathogenesis of rhegmatogenous retinal detachment. Sci Rep. 2021 Jan 13;11(1):966. doi: 10.1038/s41598-020-80005-w. PMID 33441730
• Mysore Y, Del Amo EM, Loukovaara S, Hagstrom M, Urtti A, Kauppinen A. Statins for the prevention of proliferative vitreoretinopathy: cellular responses in cultured cells and clinical statin concentrations in the vitreous. Sci Rep. 2021 Jan 13;11(1):980. doi: 10.1038/s41598-020-80127-1. PMID 33441813
• Claes C, Lafeta AP. Proliferative vitreoretinopathy. Dev Ophthalmol. 2014;54:188-95. doi: 10.1159/000360466. Epub 2014 Aug 26. PMID 25196769
• Pastor JC, de la Rua ER, Martin F. Proliferative vitreoretinopathy: risk factors and pathobiology. Prog Retin Eye Res. 2002 Jan;21(1):127-44. doi: 10.1016/s1350-9462(01)00023-4. PMID 11906814
• Sadaka A, Giuliari GP. Proliferative vitreoretinopathy: current and emerging treatments. Clin Ophthalmol. 2012;6:1325-33. doi: 10.2147/OPTH.S27896. Epub 2012 Aug 14. PMID 22942638
• Rao R, Honavar SG, Sharma V, Reddy VAP. Intravitreal topotecan in the management of refractory and recurrent vitreous seeds in retinoblastoma. Br J Ophthalmol. 2018 Apr;102(4):490-495. doi: 10.1136/bjophthalmol-2017-310641. Epub 2017 Aug 26. PMID 28844050
• Bogan CM, Kaczmarek JV, Pierce JM, Chen SC, Boyd KL, Calcutt MW, Bridges TM, Lindsley CW, Nadelmann JB, Liao A, Hsieh T, Abramson DH, Francis JH, Friedman DL, Richmond A, Daniels AB. Evaluation of intravitreal topotecan dose levels, toxicity and efficacy for retinoblastoma vitreous seeds: a preclinical and clinical study. Br J Ophthalmol. 2022 Feb;106(2):288-296. doi: 10.1136/bjophthalmol-2020-318 PMID 33972235
• Nadelmann J, Francis JH, Brodie SE, Muca E, Abramson DH. Is intravitreal topotecan toxic to retinal function? Br J Ophthalmol. 2021 Jul;105(7):1016-1018. doi: 10.1136/bjophthalmol-2020-316588. Epub 2020 Jul 14. PMID 32665221

Идентификаторы

NCT: NCT06425419 · 2023P002259

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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