| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Neovascular age-related macular degeneration (nAMD)
Diabetic Macular edema (DME) |
|
| E.1.1.1 | Medical condition in easily understood language |
age-related disease of the macula due to the formation of abnormal blood vessels in the eye
Macular edema caused by diabetes
|
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057934 |
| E.1.2 | Term | Diabetic macular edema |
| E.1.2 | System Organ Class | 100000004853 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10075568 |
| E.1.2 | Term | Wet age-related macular degeneration |
| E.1.2 | System Organ Class | 100000004853 |
|
| 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 |
| To demonstrate preliminary efficacy of ISTH0036 administered with intravitreal injections on central macular thickness (CMT) in patients with nAMD and DME that are treatment naïve or that are pretreated with aflibercept. Two different patient populations with nAMD and DME will be enrolled: Newly diagnosed, treatment naïve patients and patients that were diagnosed not more than 9 months ago and which received up to 6 initial anti-VEGF injections. In nAMD an additional group of patients who is initially primed with 1 single aflibercept injection will be assessed |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of ISTH0036 monotherapy or in combination with aflibercept rescue treatment
• To evaluate the effects of ISTH0036 in monotherapy or in combination with aflibercept rescue treatment on best corrected visual acuity (BCVA)
• To evaluate the effects of ISTH0036 in monotherapy or with aflibercept rescue treatment on central macular volume
• To evaluate the effects of ISTH0036 in monotherapy or with aflibercept rescue treatment on the extent of fibrosis and subretinal hyperreflective material visualized on OCT and multicolor images
• To evaluate the effects of ISTH0036 in monotherapy or with aflibercept rescue treatment on the regression of DRP severity and ischemia. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Patients must provide written informed consent before any study related procedures are performed
2.Patients must be ≥18 yrs in the DME cohort and ≥ 50 in the nAMD cohort at Screening
Study eye nAMD:
3. Active CNV lesions secondary to nAMD (including retinal angiomatous proliferation lesions with a CNV component) in the study eye at Screening in treatment naïve nAMD arm.
4. About 50% of the patients in the AMD treatment naïve group should have classic or predominantly classic CNV / Type II CNV or hemorrhage
5. Pretreated CNV lesions secondary to nAMD (including retinal angiomatous proliferation lesions with a CNV component) in the study eye at Screening in pretreated nAMD. About 50% of the patients should be included with SHRM present on OCT despite anti-VEGF therapy or hemorrhage present at initial diagnosis/ therapy start
6. Intra- and/or subretinal fluid affecting the central subfield of the study eye at Screening with CMT ≥305 µm in women, and ≥320µm in men or with a center point thickness of >260 in women and >270 micrometer in men as measured by SD-OCT in treatment naïve nAMD arm
7. For treatment naïve patients, BCVA between 83 and 23 letters, inclusive, in the study eye at Screening and Baseline using early treatment diabetic retinopathy study (ETDRS) testing.
8. For Treatment naïve and VEGF primed group: Treatment naïve nAMD in study eye
9. For VR-group: Dry or ≤50 micrometer SRF in vertical extension after receiving 1-6 anti-VEGF injections. Diagnosis no longer than 9 months before Baseline
Study eye DME:
10. Active CME secondary to diabetes in the study eye at Screening in treatment naïve DME.
11. Intra- and/or subretinal fluid affecting the central subfield of the study eye at Screening with CMT ≥305 µm in women, and ≥320µm in men or with a center point thickness of >260 in women and >270 micrometer in men as measured by SD-OCT in treatment naïve DME arm.
12. For treatment naïve patients, BCVA between 83 and 23 letters, inclusive, in the study eye at Screening and Baseline using early treatment diabetic retinopathy study (ETDRS) testing.
13. Moderate to severe NPDRP assessed via ETDRS severity scale and mild PDRP (with 1 NVE) in study eye (diabetic retinopathy severity scale DRSS 43-61)
14. Absence of prior PRP treatment
15. For Treatment naïve group: Treatment naïve DME in study eye
16. For VR-group: History of CME secondary to diabetes in the study eye with complete resolution of IRF and/or SRF or a ≥20% reduction in CMT secondary to diabetes after receiving 1-6 monthly anti-VEGF injections over the last 9 months |
|
| E.4 | Principal exclusion criteria |
1.Any active intraocular or periocular infection or active intraocular inflammation (e.g., infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis) in either eye at BL
2.Presence of amblyopia, amaurosis or ocular disorders in the fellow eye with BCVA < 35 ETDRS letters at Scr (except when due to conditions whose surgery may improve visual acuity, e.g., cataract)
3.nAMD diagnosed for more than 9 mon
4.Poor quality of SD-OCT images at Scr or BL
5.Central subfield of the study eye affected by geographic atrophy assessed by OCT, color fundus photography (CFP) and fundus autofluorescence (FAF) at Scr
6.Subretinal blood affecting the central subfield and/or ≥ 50% of the lesion of the study eye at Scr
7.Concomitant conditions or ocular disorders in the study eye, including retinal diseases other than nAMD, that, in the judgment of the investigator, could require medical or surgical intervention during the study to prevent or treat visual loss that might result from that condition, or that limits the potential to gain visual acuity upon treatment with the investigational product
8.Structural damage within 0.5-disc diameter of the center of the macula in the study eye, e.g., vitreomacular traction, epiretinal membrane, retinal pigment epithelium (RPE) rip/tear scar, laser burn, at the time of Scr that in the investigator’s opinion could preclude visual function improvement with treatment
9.Current vitreous hemorrhage or history of vitreous hemorrhage in the study eye within 4 weeks prior to BL
10.Uncontrolled glaucoma in the study eye defined as IOP > 25 mmHg on medication or according to the investigator’s judgment at Scr or BL
11.Aphakia and/or complete of the posterior capsule in the study eye at Scr
12.For Treatment naïve and VEGF primed group:Any prior treatment for nAMD in study eye
13.For VR-group: > 50 micrometer SRF in vertical extension after receiving 1-6 anti-VEGF injections over the last 9 mon
14.For VR-group: > 6 anti-VEGF injections
15.Treatment requiring DME diagnosed for more than 9 mon
16.Poor quality of SD-OCT images
17.Focal laser scars within the central 1 mm ETDRS subfield
18.Concomitant conditions or ocular disorders in the study eye, including retinal diseases other than DME, that, in the judgment of the investigator, could require medical or surgical intervention during the study to prevent or treat visual loss that might result from that condition, or that limits the potential to gain visual acuity upon treatment with the investigational product
19.Structural damage within 0.5-disc diameter of the center of the macula in the study eye, e.g., vitreomacular traction, epiretinal membrane, retinal pigment epithelium (RPE) rip/tear scar, laser burn, at the time of Scr that in the investigator’s opinion could preclude visual function improvement with treatment
20.Current vitreous hemorrhage or history of vitreous hemorrhage in the study eye within 4 weeks prior BL
21.Uncontrolled glaucoma in the study eye defined as IOP > 25 mmHg on medication or according to the investigator’s judgment at Scr or BL
22.Moderate and severe PDRP requiring PRP in study eye
23.Prior PRP treatment in study eye
24.Aphakia and/or complete of the posterior capsule in the study eye at Scr
25.For Treatment naïve group: Any prior treatment for DME in study eye
26.For VR-group: <20% reduction in CMT after receiving 1-6 monthly anti-VEGF injections over the last 9 mon after diagnosis.
27.For VR-group: > 6 anti-VEGF injections
28.Patient has received any approved or investigational treatment for nAMD or DME (other than vitamin supplements) in the study eye at any time
29.Intraocular or periocular use of corticosteroids in the study eye during the 6-mon period prior to BL
30.Previous penetrating keratoplasty or vitrectomy at any time prior to BL
31.History or evidence of the following in the study eye within the 90-day period prior to BL
•Intraocular or refractive surgery.
•Previous submacular surgery, other surgical intervention, or laser treatment for nAMD or DME including photodynamic therapy (PDT) and focal laser treatment
32.End stage renal disease requiring dialysis or renal transplant
33.Systemic medications known to be toxic to the lens, retina, or optic nerve (e.g., deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines and ethambutol) used during the 6-mon period prior to BL
34.Participation in an investigational drug, biologic, or device study within 30 days or the duration of 5 half-lives of the investigational product (whichever is longer) prior to BL (observational clinical studies solely involving over-the-counter vitamins, supplements, or diets are not exclusionary)
35.Systemic anti-VEGF therapy at any time
36.Stroke or myocardial infarction in the 6-mon period prior BL
Further exclusion criteria please see clinical protocol page 31ff |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • OCT CMT at 7 months vs. baseline |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Number and type of adverse events (AE) in all groups
• Incidence and progression of cataract using LOCS score in patients treated with ISTH0036
• Change in BCVA from baseline up to month 9
• Change of macular volume up to month 9
• Percentage of patients with IRF and/or SRF from Baseline to Month 7.
• Change in OCT-A features assessed by qualitative criteria from baseline to Month 7
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 2 |
| 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 |
|
| 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
|
|
| 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 | 4 |
| 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 | 4 |
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