CTRI/2022/04/041823 [Registered on: 12/04/2022] Trial Registered Prospectively
Last Modified On:
27/10/2025
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Other
Public Title of Study
Phase IIa study to evaluate the efficacy of the ISTH0036 in treatment naive and previously treated patients with Macular Degeneration and Diabetic Macular Edema
TGF-BETa 2 antisense ISTH0036 for the Treatment of diabetic macular Edema (DME) and neovascular age-related maculaR degeneration (nAMD) as Monotherapy or in combination with Aflibercept
The “BETTER†Study
The duration of study participation is 9 months preceded by an up to 40 days screening period. Screening and Baseline Visit may be combined. Last treatment is at month 6 and the Primary Endpoint will be assessed at month 7.
After termination of ISTH0036 treatment, the End of Study Visit takes place 90 days post last dosing (i.e., month 9).
Patients eligible for inclusion in this study must meet all the following 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.
ExclusionCriteria
Details
Patients meeting any of the following criteria are not eligible for inclusion in this study.
Ocular conditions
1. Any active intraocular or periocular infection or active intraocular inflammation (e.g., infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis) in either eye at Baseline.
2. Presence of amblyopia, amaurosis or ocular disorders in the fellow eye with BCVA < 35 ETDRS letters at Screening (except when due to conditions whose surgery may improve visual acuity, e.g., cataract).
Study eye nAMD
3. nAMD diagnosed for more than 9 months
4. Poor quality of SD-OCT images at Screening or Baseline.
5. Central subfield of the study eye affected by geographic atrophy assessed by OCT, color fundus photography (CFP) and fundus autofluorescence (FAF) at Screening.
6. Subretinal blood affecting the central subfield and/or ≥ 50% of the lesion of the study eye at Screening.
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 Screening 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 Baseline.
10. Uncontrolled glaucoma in the study eye defined as IOP > 25 mmHg on medication or according to the investigator’s judgment at Screening or Baseline.
11. Aphakia and/or complete absence of the posterior capsule in the study eye at Screening.
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 months
14. For VR-group: > 6 anti-VEGF injections
Study eye DME
15. Treatment requiring DME diagnosed for more than 9 months
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 Screening 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 to Baseline.
21. Uncontrolled glaucoma in the study eye defined as IOP > 25 mmHg on medication or according to the investigator’s judgment at Screening or Baseline.
22. Moderate and severe PDRP requiring PRP in study eye
23. Prior PRP treatment in study eye
24. Aphakia and/or complete absence of the posterior capsule in the study eye at Screening.
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 months after diagnosis.
27. For VR-group: > 6 anti-VEGF injections
Ocular treatments (study eye)
28. Patient has received any 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-month period prior to Baseline.
30. Previous penetrating keratoplasty or vitrectomy at any time prior to Baseline.
31. History or evidence of the following in the study eye within the 90-day period prior to Baseline:
• 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.
Systemic conditions or treatments
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-month period prior to Baseline.
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 Baseline. Note: 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-month period prior to Baseline.
37. Uncontrolled blood pressure defined as a systolic value ≥ 170 mmHg or diastolic value ≥ 110 mmHg at Screening or Baseline. (In case there is an elevated blood pressure measurement, it should be repeated after 20 minutes. If the repeat measurement is elevated, then the patient is not eligible to be enrolled into the study).
38. History of a medical condition (disease, metabolic dysfunction with exception of type 1 or 2 diabetes mellitus, physical examination finding, or clinical laboratory finding) that, in the judgment of the investigator, would preclude scheduled study visits, completion of the study, or a safe administration of investigational product.
39. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
40. History of hypersensitivity to any component of the test article, control article, or clinically relevant sensitivity to fluorescein dye, as assessed by the investigator
Other
41. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive urine pregnancy test.
42. Women of childbearing potential defined as all women less than 1 year postmenopausal or less than 6 weeks since sterilization at Baseline, unless they are using effective methods of contraception during dosing of study treatment. Effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least 6 weeks before Baseline. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment.
• Male sterilization (at least 6 months prior to Baseline). For female patients in the study, the vasectomized male partner should be the sole partner for that patient.
• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
• Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example, hormone vaginal ring or transdermal hormone contraception.
• Placement of an intrauterine device or intrauterine system.
In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of childbearing potential.
Method of Generating Random Sequence
Not Applicable
Method of Concealment
Not Applicable
Blinding/Masking
Not Applicable
Primary Outcome
Outcome
TimePoints
OCT CMT at 7 months vs. baseline. For treatment naïve patients, improvement versus BL will be analyzed, for anti-VEGF pre-treated patients, maintenance, or improvement of CMT versus BL will be assessed.
9 Months
Secondary Outcome
Outcome
TimePoints
Number and type of adverse events (AE) in all groups
Incidence and progression of cataract using LOCS III score in patients treated with ISTH0036
Change in BCVA from baseline up to month 9
Change of central macular volume up to month 9