E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Persistent central-involved diabetic macular edema |
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E.1.1.1 | Medical condition in easily understood language |
Diabetic macular edema is characterized by accumulation of fluid and retinal thickening within the macula and is responsible for most of the central visual loss experienced in the diabetic population |
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E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10015919 |
E.1.2 | Term | Eye disorders |
E.1.2 | System Organ Class | 10015919 - Eye disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057934 |
E.1.2 | Term | Diabetic macular edema |
E.1.2 | System Organ Class | 10015919 - Eye disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• Evaluate the safety and tolerability of OPT-302 intravitreal (IVT) injection in combination with IVT aflibercept in participants with central-involved Diabetic Macular Edema (DME) • Assess the response rate (≥ 5 letter gain in Best Corrected Visual Acuity [BCVA] from baseline to week 12according to ETDRS criteria) in participants with persistent central-involved DME receiving combination OPT-302 and aflibercept treatment |
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E.2.2 | Secondary objectives of the trial |
To assess: • the mean change from baseline in BCVA • the mean change from baseline in central subfield thickness (CST) and macular volume (by spectral domain optical coherence tomography [SD-OCT]) • the percent of eyes with ≥ 50% reduction in excess foveal thickness (SD-OCT) • the percent of eyes with CST < 300 µm on SD-OCT • the percent of participants with a ≥ 2 step improvement in ETDRS Diabetic Retinopathy Severity Score • the mean time to, and number of, retreatment injections of aflibercept anti-VEGF-A therapy during long term follow-up (week 12 to 24) • the pharmacokinetics (PK) of OPT-302 • anti-OPT-302 antibody formation
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The sub-studies listed below are part of the OPT-302-1003 protocol, Amendment 3, dated 02 Aug 2018. Evaluation of micro-vascular changes by Optical Coherence Tomography (OCT) angiography: To characterize changes in vascular morphology by evaluating scans of both the study eye and fellow eye using OCT angiography, a novel imaging modality. Pharmacokinetic (PK) Assessments sub-study: All participants will have PK serum samples collected at indicated sparse time-points throughout the study. PK samples at additional time-points will be collected in an optional sub-study from participants consenting to participation in intensive PK sampling |
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E.3 | Principal inclusion criteria |
STUDY EYE 1)Able and willing to provide written informed consent 2)Age ≥ 18 years of either gender 3)Diabetes mellitus (type 1 or type 2) 4)Edema that involves the center of the macula as confirmed by the reading center 5)Eyes with recurrent / persistent DME despite prior intravitreal anti-VEGF therapy with a suboptimal response and defined as meeting all of the following: a.Ophthalmoscopic evidence of center-involved DME b.Retinal thickness ≥ 320 µm in the central 1 mm subfield on Spectralis (Heidelberg) SD-OCT (or ≥ 305 µm on Cirrus) as confirmed by the reading center c.DME is the cause of OCT thickening despite ongoing treatment with either aflibercept or ranibizumab with ≥ 3 prior IVT injections within 5 months of study Day 1, the most recent injection being ≤ 42 days prior to study Day 1 (prior bevacizumab allowed only if therapy subsequently switched to intravitreal aflibercept or ranibizumab for ≥ 1 most recent injection(s) prior to study Day 1) 6)History of center-involved macular edema requiring treatment, including intravitreal antVEGF-A therapy, for ≤ 24 months (maximum number of intravitreal anti-VEGF-A injection cycles is ≤ 24) 7)BCVA letter score ≤ 73 and ≥ 24 (approximate Snellen equivalent 20/40 to 20/320; Snellen [metric] equivalent 6/12 to 6/96) in the study eye, inclusive 8)If female and of child-bearing potential: Pregnancy test at screening and Day 1 is negative, and agrees to use a highly effective method of contraceptive for the duration of the study and for at least 3 months following the last dose of study medication. The following are considered “highly effective methods”: i.e. hormonal contraceptive (oral, intravaginal, or implant, but excluding progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of action); intrauterine device; or documented vasectomy of partner. A participant will not be considered to be of child-bearing potential if she is postmenopausal and has not had menses for at least 12 months prior to screening (by history), or if surgically sterile 9)Only one eye will be enrolled in the study. (If both eyes meet the entry criteria the study eye chosen is the worse eye (based on investigator assessment of SD-OCT and / or VA). If both eyes are equal, the participant and investigator will select the eye for entry).
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E.4 | Principal exclusion criteria |
1)Eyes in which scatter PRP is needed now or within the next 3 months (e.g. eyes with high risk PDR [defined as NVD> 1/3 disc area or NVE > 1/2 disc area and presence of VH regardless of size of neovascularization] not already adequately treated with photocoagulation) 2)Macula edema is due to a cause other than DME in the study eye (e.g. clinical exam by investigator and OCT as confirmed by the reading center suggest that vitreoretinal interface abnormalities such as taut posterior hyaloid or ERM are the primary cause of macular edema) 3)Presence of any abnormality that in the opinion of the investigator would be likely to confound assessment of VA improvement in the study eye in which macular edema resolves, or improves, such as dense subfoveal hard exudates, NVG, or presence of chorioretinal / foveal atrophy involving the center of the macula 4 )Vitreoretinal traction confirmed by OCT, or seen clinically within 1 disc diameter of the center of the macula of the study eye as confirmed by the reading center 5)Any RVO involving the macula in the study eye as confirmed by the reading center 6 )Any intraocular surgery in the study eye within 4 months of study entry or within the next 3 months following dosing on Day 1 7)Previous vitrectomy or SB surgery in the study eye 8)HbA1C level ≥12% and/or recent signs of uncontrolled diabetes (3 or more episodes of severe hypoglycemia within 3 months of baseline, or hospitalization for hyperglycemia, or 2 or more episodes of ketoacidosis within 1 year of baseline, or an episode of ketoacidosis within 3 months of baseline). 9)Renal failure, dialysis, or history of renal transplant 10)Myocardial infarction, other cardiac event requiring hospitalization, stroke, TIA, or treatment for CHF within 6 months prior study Day 1. 11)Uncontrolled hypertension ≥180 mmHg systolic or ≥110 mmHg diastolic. (If blood pressure is brought below 180/110 mmHg by anti-hypertensive treatment, the individual can become eligible. Participants with a history of controlled hypertension on medication may have their blood pressure taken at a second visit to qualify based on the repeat testing). 12)Pregnant or lactating 13)Major surgery (defined as intra-abdominal or surgery requiring general anesthesia) within 28 days prior to dosing on study Day 1 or major surgery planned during the next 6 months. 14)Previous treatment with PDT or external beam radiation in the study eye 15)Subjects who have received panretinal or focal / grid photocoagulation, YAG laser, or peripheral retinal cryoablation (for retinal tears only) in the study eye within the previous 4 months 16)Parallel or prior use of systemic anti-VEGF agents 17)Parallel or prior use of intravitreal bevacizumab in the study eye, unless therapy switched to intravitreal aflibercept or ranibizumab for ≥ 1 most recent injection(s) prior to Day 1 18)Most recent intravitreal injection of aflibercept or ranibizumab less than 28 days or greater than or equal to 42 days prior to Day 1 dosing in the study eye 19)Administration of systemic steroids within 4 months prior to Day 1 20)Parallel or prior use of any intravitreal injections of steroids within 4 months prior to Day 1 in the study eye 21)Parallel or prior use of dexamethasone implant in the study eye 22)Parallel or prior use of fluocinolone implant in the study eye 23)Parallel or prior administration of experimental therapy within 30 days of screening 24)Parallel treatment for active systemic (non-ocular) infection at screening, if in the opinion of the investigator, doing so will place the participant at undue risk 25)Parallel treatment in either eye for any ocular condition with an investigational drug or device that has not received regulatory approval 26)Parallel or prior use of thiazolidinediones within 6 months prior to Day 1 dosing 27)Active or recent (within 4 weeks) intraocular inflammation (grade trace or above) in the study eye 28) Any active periocular or intraocular infection or inflammation (e.g. conjunctivitis, keratitis, scleritis, uveitis or endophthalmitis) 29)Subjects with other ocular diseases that can in the opinion of the investigator compromise the visual acuity of the study eye such as amblyopia and anterior ischemic optic neuropathy 30)History of idiopathic or autoimmune-associated uveitis in either eye. 31)Current VH at the screening assessments in the study eye as confirmed by the reading center 32)Uncontrolled glaucoma (>30 mmHg) either untreated or on anti-glaucoma medication at screening 33)Known allergy to any component of the study drug(s) 34)Prior participation in this clinical trial |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Safety: Subject incidence of adverse events, Dose Limiting Toxicities (DLTs) and clinically significant changes in vital signs, Electrocardiograms and clinical laboratory tests • Efficacy: Response rate as defined by proportion of participants receiving combination OPT-302 and aflibercept achieving at least a 5 letter gain in Best Corrected Visual Acuity (BCVA) compared to baseline at week 12 according to Early Treatment of Diabetic Retinopathy Stud (ETDRS) criteria |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Mean change in BCVA from baseline to week 12 using ETDRS criteria • Mean change from baseline to week 12 in Central Subfield Thickness (CST) and macular volume on Spectral Domain Optical Coherence Tomograph (SD-OCT) • Percent of eyes with ≥ 50% reduction in excess foveal thickness from baseline to week 12 on SD-OCT • Percent of eyes with CST < 300 µm on SD-OCT through week 12 • Percent of participants with a ≥ 2 step improvement from baseline to week 12 in ETDRS Diabetic Retinopathy Severity Score • The mean time to, and number of, retreatment injections of aflibercept anti-VEGF-A therapy based on protocol specified criteria during week 12 to week 24 follow-up • OPT-302 pharmacokinetics parameters • Incidence of anti-OPT-302 antibody formation |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary endpoints are to week 12 with the exception of the mean time and number of retreatment injections which is measured from week 12 to 24 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Intravitreal aflibercept (2 mg) + sham injection |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Israel |
Latvia |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |