A Randomised, Double-Masked Vehicle-Controlled, Multiple Dose, Dose Escalation Study To Evaluate The Safety and Tolerability of EXN407 in Subjects With Centre Involved Diabetic Macular Oedema Secondary to Diabetes Mellitus
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 48
- 试验地点
- 11
- 主要终点
- The Primary Objective of the Study is to Evaluate the Ocular Safety and Tolerability (by Incidence of Ocular Adverse Events) of EXN407 Ophthalmic Solution in Dose Escalation Phase.
研究概览
简要总结
This first in human (FIH), Phase Ib/II study of EXN407 is a randomised, double-masked, vehicle-controlled, multiple dose, dose-escalating study to evaluate the safety and tolerability of EXN407 in subjects with centre involved Diabetic Macular Oedema (DMO), with Centre-subfield macular thickness (CMT) between 280-420 µm and Best corrected visual acuity (BCVA) better than or equal to 69 ETDRS score (approximate Snellen equivalent 20/40 (6/12 letters) in the study eye, which is considered secondary to diabetes mellitus.
This study will provide a basis for further clinical development of EXN407 ophthalmic solution.
详细描述
EXN407 or vehicle-control solution administered unilaterally to the study eye only. To select the study eye the Investigator examines the subjects and identifies which eye exhibits centre involved DMO with a CMT between 280-420 μm (as determined by SD-OCT). Further, all other inclusion/exclusion criteria required to be met.
Dose Escalation Cohorts The study assesses the safety and tolerability of EXN407 in eligible subjects with center involved Diabetic Macular Oedema (DMO) at up to 3 escalating dose (concentration) levels and placebo (vehicle) consisting of an excipient formulation adjusted for osmolality. EXN407 or vehicle-control administered as a single 30 μL drop by unilateral eye drop administration to the study eye only, and the drops dosed BID for 7 days. Subjects assessed throughout the treatment period for safety, tolerability, and efficacy at Follow-up visits. Each of the ascending dose subject cohorts consists of 4 subjects (3 subjects randomised to receive EXN407 and 1 subject randomised to receive placebo).
Dose Expansion Cohort The highest well tolerated dose of EXN407 (as recommended by the DEC) is evaluated in a subject expansion cohort in eligible subjects with center involved Diabetic Macular Oedema (DMO) which consists of up to a maximum of 40 subjects (randomised to receive EXN407 at the selected dose or vehicle at a 2:1 drug: placebo ratio). Each eligible subject in the expansion cohort to receive study drug for up to 84 days, resulting in a total of 168 doses (168 single drops of 30 μL volume) of EXN407 or vehicle.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject is at least 18 years of age inclusive, at the time of signing the informed consent.
- •BCVA better than or equal to 69 ETDRS score (approximate Snellen equivalent 20/40 or 6/12) in the study eye using the ETDRS visual acuity scale at Screening or BCVA less than 69 ETDRS score (approximate Snellen equivalent 20/50 or 6/15) but who, in the Investigator's opinion, is unsuitable for treatment with anti-VEGF by intravitreal injection or refuses it. Subjects should have no more than a 7-letter difference in BCVA at Screening and baseline visit.
- •Ocular media is consistent with SD-OCT imaging and cataracts are not expected in the subject for the duration of the study.
- •The subject has no other retinal disease.
- •Subject or the subject's partner successfully demonstrates their ability to self-administer/administer eye drops at Screening, with multiple attempts allowed at the discretion of the Investigator.
排除标准
- •Any other retinal disease in the study eye, other than centre involved DMO or diabetic retinopathy.
- •Poor vision (VA 6/60 or worse) in the contralateral eye.
- •Intraocular inflammation (including trace or greater) in the study eye. History of idiopathic or autoimmune uveitis in either eye.
- •Use of intravitreal anti-VEGF drugs including ranibizumab, bevacizumab, aflibercept in the study eye within 6 months of the Screening Visit, or in the fellow (non study) eye within 3 months of the Screening Visit. Use of topical corticosteroids or topical non-steroidal anti-inflammatory agents in the study eye within 28 days of the Screening Visit. Use of intravitreal corticosteroids in either eye or systemic steroids within 12 months of the Screening Visit. Prior use of Iluvien (without time limitation).
- •Within 180 days prior to the Screening visit, use of medications known to be toxic to the retina, lens or optic nerve (e.g. desferoximine, chloroquine/hydrochloroquine, chlorpromazine, phenothiazines, tamoxifen, and ethambutol).
- •History of (within 90 days of Screening date) cerebral vascular accident (stroke) or MI.
- •Significant renal impairment including subjects on chronic renal dialysis and subjects with a history of nephrectomy or kidney transplant (regardless of renal function).
- •History of anaphylaxis, anaphylactoid (resembling anaphylaxis) reactions, or severe allergic responses.
- •Positive pregnancy test (all female subjects of childbearing potential must have a urine β-human chorionic gonadotropin [hCG] pregnancy test performed at Screening and within 7 days prior to randomisation) or is known to be pregnant or lactating.
- •Known to have, or history of a positive test result for, hepatitis B or C, HIV, syphilis, tuberculosis, or COVID-19.
研究组 & 干预措施
Dose Escalation Cohort 1
Each subject will receive a low-dose 0.5 mg/mL (0.05%) of EXN407 or placebo twice a day in 14 doses over a 7 day period.
干预措施: EXN407 (Drug)
Dose Escalation Cohort 2
Each subject will receive a mid-dose 1 mg/mL (0.1%) of EXN407 or placebo twice a day in 14 doses over a 7 day period.
干预措施: EXN407 (Drug)
Dose Escalation Cohort 3
Each subject will receive a high-dose 1.5 mg/mL (0.15%) of EXN407 or placebo twice a day in 14 doses over a 7 day period.
干预措施: EXN407 (Drug)
Dose Expansion Cohort
The highest well-tolerated dose of EXN407 will be evaluated where subjects will receive EXN407 at the selected dose or placebo twice a day for up to 84 days resulting in a total of 168 doses
干预措施: EXN407 (Drug)
结局指标
主要结局
The Primary Objective of the Study is to Evaluate the Ocular Safety and Tolerability (by Incidence of Ocular Adverse Events) of EXN407 Ophthalmic Solution in Dose Escalation Phase.
时间窗: Assessed starting from Day 1 of treatment to Day 36 in Dose Escalation.
Number of Participants with Ocular Treatment Emergent Adverse Events (TEAEs)
The Primary Objective of the Study is to Evaluate the Ocular Safety and Tolerability (by Incidence of Ocular Adverse Events) of EXN407 Ophthalmic Solution in Dose Expansion Phase.
时间窗: Assessed starting from Day 1 of treatment to Day 113 in Dose Expansion phase.
Number of Participants with Ocular Treatment Emergent Adverse Events (TEAEs)
次要结局
- To Evaluate the Systemic Pharmacokinetics of EXN407 Ophthalmic Solution in Subjects With DMO Secondary to Diabetes Mellitus by Tmax.(Blood draws for PK will be collected only on Day 3(Dose Escalation) and Day 8(Dose Expansion) at the following timepoints: pre-dose and 15 mins, 30 mins, 1, 2, 3,and 4 hours post-dose.)
- To Evaluate the Systemic Pharmacokinetics of EXN407 Ophthalmic Solution in Subjects With DMO Secondary to Diabetes Mellitus by Cmax(Blood draws for PK will be collected only on Day 3(Dose Escalation) and Day 8(Dose Expansion) at the following timepoints: pre-dose and 15 mins, 30 mins, 1, 2, 3,and 4 hours post-dose.)
- To Evaluate the Systemic Pharmacokinetics of EXN407 Ophthalmic Solution in Subjects With DMO Secondary to Diabetes Mellitus by AUC.(Blood draws for PK will be collected only on Day 3(Dose Escalation) and Day 8(Dose Expansion) at the following timepoints: pre-dose and 15 mins, 30 mins, 1, 2, 3,and 4 hours post-dose.)
- To Evaluate the Systemic Pharmacokinetics of EXN407 Ophthalmic Solution in Subjects With DMO Secondary to Diabetes Mellitus by t½.(Blood draws for PK will be collected only on Day 3(Dose Escalation) and Day 8(Dose Expansion) at the following timepoints: pre-dose and 15 mins, 30 mins, 1, 2, 3,and 4 hours post-dose.)
- To Evaluate Changes in Ocular Functional Measures as Assessed Using Ophthalmoscopy.(From Day 1 of Treatment to End of Treatment i.e. assessed upto 36 Days/EOS in Dose Escalation and upto 4 months(113 days/EOS) in Dose Expansion.)
- To Evaluate Changes in Ocular Structural Measures as Assessed Using Ophthalmoscopy.(From Day 1 of Treatment to End of Treatment i.e. assessed upto 36 Days/EOS in Dose Escalation and up to 4 months(113 days) in Dose Expansion.)