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    EudraCT Number:2018-003298-90
    Sponsor's Protocol Code Number:OPT-302-1003
    National Competent Authority:Latvia - SAM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-10-09
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedLatvia - SAM
    A.2EudraCT number2018-003298-90
    A.3Full title of the trial
    Phase 1b/2a study of OPT-302 in combination with aflibercept for persistent central-involved diabetic macular edema
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study of OPT-302 with aflibercept compared to aflibercept plus sham in patients with diabetic macular edema
    A.4.1Sponsor's protocol code numberOPT-302-1003
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03397264
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorOpthea Ltd
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportOpthea Ltd
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOpthea Ltd
    B.5.2Functional name of contact pointClinical Development
    B.5.3 Address:
    B.5.3.1Street Address650 Chapel Street
    B.5.3.2Town/ citySouth Yarra
    B.5.3.3Post codeVIC 3141
    B.5.4Telephone number61398260399
    B.5.5Fax number61398240083
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameOPT-302
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravitreal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVascular endothelial growth factor receptor-3 (VEGFR-3) derivative fused to a human immunoglobulin (IgG)1 Fc fragment (no proposed INN at this stage)
    D.3.9.2Current sponsor codeOPT-302
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Persistent central-involved diabetic macular edema
    E.1.1.1Medical 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
    E.1.1.2Therapeutic area Diseases [C] - Eye Diseases [C11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10015919
    E.1.2Term Eye disorders
    E.1.2System Organ Class 10015919 - Eye disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10057934
    E.1.2Term Diabetic macular edema
    E.1.2System Organ Class 10015919 - Eye disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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
    E.2.2Secondary 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
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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
    E.3Principal inclusion criteria
    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).

    E.4Principal 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
    E.5 End points
    E.5.1Primary 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
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    E.5.2Secondary 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
    E.5.2.1Timepoint(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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E. description
    Intravitreal aflibercept (2 mg) + sham injection
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 70
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 38
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 108
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-12-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-06-11
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