| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | In Fuchs endothelial corneal dystrophy (FECD), there is an increased rate of loss of endothelial cells, starting in the centre of Descemet’s membrane and spreading to the periphery, resulting in excrescences known as guttae, which are a marker of the condition. Guttae may coalesce and inhibit the migration of endothelial cells. Eventually the corneal endothelium ceases to function effectively, and the cornea begins to cloud, leading to blindness. | |
| E.1.1.1 | Medical condition in easily understood language | | Fuchs endothelial corneal dystrophy (FECD) | |
| 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 | PT | | E.1.2 | Classification code | 10011005 | | E.1.2 | Term | Corneal dystrophy | | E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders | |
| 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 investigate the effect of K-321 on the time to improvement in best corrected visual acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of ≥40 letters during the first 12 weeks after descemetorhexis in subjects with FECD. | |
| E.2.2 | Secondary objectives of the trial | The key secondary objective of this study is to investigate the effect of K-321 on:
• The time to improvement in BCVA by ETDRS letter score of ≥20 letters.
• The time to achievement of BCVA by ETDRS letter score of ≥70 letters.
• Central corneal ECD.
The secondary objectives (efficacy) of this study are to investigate the effect of K-321 on:
• The time to complete clearance of corneal edema in both areas (epithelial, stromal)
• The time to return of central corneal thickness to less than or equal to baseline level
• The time to failure of therapy (defined as events of rescue treatments other than keratoplasty, study drug discontinuation due to lack of efficacy, and withdrawal from the study due to lack of efficacy)
• On the time to undergo rescue therapy (keratoplasty) or rescue treatment.
The secondary objective (safety) of this study is as follows:
• To assess the safety and tolerability of K-321 in subjects with FECD after descemetorhexis. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | Pre-DSO Criteria
Each subject who is planning to undergo DSO must meet all of the following criteria to be enrolled in the study:
1. Is at least 18 years old at the screening visit (Visit 1)
2. Has a diagnosis of FECD at Visit 1
3. Has confluent central guttae in the study eye that can be removed by descemetorhexis of a circular area of 5.5 mm diameter or less (at Visit 1)
4. Study eye with BCVA of 75 letters or fewer by ETDRS testing (Snellen equivalent of 20/32 or worse) at Visit 1.
5. Can understand the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with protocol requirements before any study-specific assessments are performed.
Post-DSO Criteria
6. The study eye descemetorhexis at Visit 2 is confirmed to have excised a central area with confluent guttae and a diameter of 4.5 to 5.5 mm. | |
| E.4 | Principal exclusion criteria | Subjects meeting any of the following criteria will be excluded from the study:
1. Is a female subject of childbearing potential and any of the following is true:
a. is pregnant or lactating/breastfeeding, or
b. is not surgically sterile, not post-menopausal (no menses for the previous 12 months), or not practicing an effective method of birth control as determined by the Investigator (eg, oral contraceptives, double barrier methods, hormonal injectable or implanted contraceptives, tubal ligation, or partner with vasectomy)
[If a subject is female and of childbearing potential, she must have a negative urine pregnancy test result at Visit 2 before the descemetorhexis. Women of childbearing potential must also agree to use effective contraception throughout the study. A female of childbearing potential is defined as a woman who has experienced menarche and has not undergone successful surgical sterilization or is not post-menopausal, and a post-menopausal woman is defined as having had no menses for the previous 12 months (without a known cause)]
2. Has a study eye with confluent guttae in the periphery or confluent guttae outside the stripped area (individual guttae are allowed) after descemetorhexis
(Note that subjects may have individual or a small number of guttae remaining outside the stripped area, but there should be no areas with confluent guttae remaining after the descemetorhexis. For example, a subject who has five to ten guttae remaining in a few spots around the circumference of the descemetorhexis would not be excluded by this criterion.)
3. Has a study eye with baseline (pre-DSO) peripheral ECD ungradable for any area (nasal, temporal, superior, and inferior) due to any reason other than a medical reason (eg, guttae, corneal edema, or striae)
4. Has a study eye with a history of cataract surgery within 90 days of Visit 1
5. Has a study eye with a history of any previous intraocular surgery other than for cataract prior to Visit 1
6. Has a non-study eye with a history of any previous intraocular surgery within 30 days of Visit 1
7. Plans to receive any surgical treatment on the study eye, other than the study descemetorhexis, during the duration of the study
8. Plans to receive any surgical treatment for FECD or cataract on the non-study eye during either the screening or treatment period
9. Has advanced corneal stromal edema, which is defined as the presence of widespread haze or bullae on slit lamp examination at Visits 1 and 2
10. Has a study eye with central corneal thickness ≥ 670 μm at Visits 1 and 2
11. Has known severe comorbidities that may interfere with descemetorhexis (including but not limited to a bacterial, viral, or fungal ophthalmic infection)
12. Has any clinically significant ocular condition, other than FECD, cataract, primary open-angle glaucoma* or dry eye in the study eye that requires medication or ocular surgery
(* Only primary open-angle glaucoma is allowed, NOT angle closure or any secondary glaucomas. Use of a single glaucoma medication, except for any carbonic anhydrase inhibitor [CAI] or ROCK inhibitor, is acceptable. Prior YAG-laser surgery is acceptable, but incisional surgery and micro invasive glaucoma surgery are not allowed.)
13. Has diabetes with poor blood sugar control, defined as hemoglobin A1c (HbA1c) value > 8.5% at Visit 1
14. Has used either collagen shield or contact lenses in either one eye or both eyes within 7 days of Visit 1
15. Is unwilling to stop use of either collagen shield or contact lenses for the duration of the study
16. Has hypersensitivity to any ophthalmic medication used for diagnosis or treatment, including eye drops containing antibiotic(s) or glucocorticoid(s)
17. Has known hypersensitivity to any component of the study drugs
18. Has previously used ripasudil
19. Has used netarsudil or eye drops and ointments containing ≥ 2% sodium chloride within 14 days prior to Visit 1
20. Has used any investigational medications within 30 days of Visit 1
21. Has a positive urine test result for drugs of abuse (opiates, methadone, cocaine, amphetamines, barbiturates, or benzodiazepines) or alcohol at screening; however, drugs prescribed to treat current medical conditions are allowed
22. Is a member or a family member of the professional or ancillary personnel working at the study site or the Sponsor involved in the study
23. Has a concomitant medical or psychological condition that could interfere with study participation or is otherwise not suitable for entry into the study in the opinion of the Investigator.
24. Is using any prohibited prescription or over-the-counter (OTC) medications or devices and is unwilling or unable to discontinue these medications or devices for the required time period before entry into the study | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | The primary efficacy endpoint is the Time to ≥40 ETDRS letter improvement in BCVA during the first 12 weeks after descemetorhexis. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | The secondary efficacy endpoints are:
• Time to ≥20 ETDRS letter improvement during the first 12 weeks after descemetorhexis.
• Time to achievement of ≥70 ETDRS letters during the first 12 weeks after descemetorhexis.
• Central corneal ECD change from baseline at Week 12.
• Time to complete clearance of corneal edema in both areas (epithelial, stromal) during the first 12 weeks and during the 52-week period after descemetorhexis.
• Time to return of central corneal thickness to less than or equal to baseline level during the first 12 weeks and during the 52-week period after descemetorhexis.
• Time to failure of therapy (defined as events of rescue keratoplasty, rescue treatments other than keratoplasty, study drug discontinuation due to lack of efficacy, and withdrawal from the study due to lack of efficacy) during the 52-week period after descemetorhexis.
• Time to undergo rescue therapy (keratoplasty) or rescue treatment during the 52-week period after descemetorhexis.
| |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | | Canada | | United States | | Denmark | | Germany | | Spain | | United Kingdom | |
| 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 | | LVLS. Although Kowa Research Institute, Inc. has every intention of completing the study, Kowa Research Institute, Inc. reserves the right to discontinue the study at any time for clinical or administrative reasons. | |
| 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 | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
