Neurotrophic Keratitis
Conditions
Brief summary
A phase 2 study, aiming to evaluate the efficacy, safety and pharmacokinetics of REC 0/0559 in treatment of Neurotrophic Keratitis in Adult Patient in Europe and United States of America.
Detailed description
This was a Phase 2, international, multicentre, dose-ranging, double-masked, randomised, parallel-group, vehicle-controlled study designed to evaluate 3 different doses of REC 0/0559 vs vehicle in patients with Stage 2 and Stage 3 neurotrophic keratitis (NK).
Interventions
DRUGUdonitrectag
Eye drop solution in single dose unit.
OTHERVehicle
Eye drop solution with no active substance in single dose unit.
Sponsors
Syneos Health
RECORDATI GROUP
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-masked: dose and nature of the product
Intervention model description
The study will have an initial period of dose escalation followed by a parallel recruitment period. Randomisation in the first 24 patients will be sequential and after, patients will be randomised to all 4 treatment arms.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Have read, understood, and signed the informed consent form (ICF). 2. Be a male or female aged ≥18 years at the time of ICF signature. 3. Have stage 2 moderate (PED) or stage 3 severe (corneal ulcer) NK involving only 1 eye (study eye) and of at least 2 weeks duration. Patients with Stage 1 NK in the fellow eye can be enrolled. for the study eye 4. Have no objective clinical evidence of improvement in the PED or corneal ulceration within the 2 weeks before the screening visit despite use of conventional non-surgical treatment (eg, nonpreserved ocular lubricants, nonpreserved topical antibiotics, oral doxycycline, patching, serum tears, and/or therapeutic contact lenses) as determined by the investigator's or referring physician's medical record. 5. Have decreased corneal sensitivity (≤ 4 cm using the Cochet-Bonnet aesthesiometer) within the area of the PED or corneal ulcer and outside of the area of the defect in at least one corneal quadrant. 6. Have a BCDVA score ≤ 75 ETDRS letters in the study eye, due to NK.
Exclusion criteria
1. Have participated in any clinical trial with an investigational drug/device within 2 months before the Screening Visit and throughout the study duration. 2. Have a known hypersensitivity to one of the components of the study drug or procedural medications (eg, fluorescein), including to a compound chemically related to MT8 3. Have a presence or history of any ocular or systemic disorder or condition that might hinder the efficacy of the study treatment or its evaluation, could possibly interfere with the interpretation of study results, or could be judged by the investigator to be incompatible with the study visit schedule or conduct (eg, progressive or degenerative corneal or retinal conditions, lagophthalmos, uveitis, optic neuritis, poorly controlled diabetes, autoimmune disease, systemic infection, neoplastic diseases), or that may compromise the safety of the patient. 4. Have a significant history of alcohol abuse or drug/solvent abuse 5. Be unwilling to comply with any study assessments or procedures. 6. Be a woman who is pregnant, nursing or planning a pregnancy. 7. Be a woman of childbearing potential not using a highly effective method of birth control. 8. Be a male patient who is not permanently sterile and who is not willing to use condoms during the study and for 4 weeks after the end of study treatment. For the study eye: 9. Have any active ocular infection (bacterial, viral, fungal or protozoal) or active inflammation not related to NK in the study eye. 10. Have any other ocular disease requiring topical ocular treatment in the study eye during the course of the study treatment period, except for glaucoma if treated by preservative-free eye drop (single-agent treatment, once daily, stable regimen 4 weeks before screening and during the study), 11. Receive topical ophthalmological treatments other than the study drug provided by the study Sponsor and the treatments allowed by the study protocol (eg, preservative-free artificial tears; preservative-free eye drop (single-agent treatment, once daily, stable regimen 4 weeks before screening and during the study) for glaucoma; topical antibiotics; other than tetracycline). 12. Have severe blepharitis and/or severe meibomian gland disease in the study eye. 13. Have severe vision loss in the study eye with no potential for visual improvement in the opinion of the investigator as a result of the study treatment. 14. Have evidence of corneal ulceration/melting involving the posterior third of the corneal stroma, or perforation in the study eye. 15. Have a history of any ocular surgery (including laser or refractive surgical procedures) within 3 months before the Screening Visit in the study eye. An exception to the preceding statement will be allowed if the ocular surgery is considered to be the cause of the Stage 2 or 3 NK. 16. Have a history of corneal transplantation in the study eye, except if performed to treat NK and at least 6 months prior screening. 17. Have had prior surgical procedures for the treatment of NK (eg, tarsorrhaphy, conjunctival flap, etc.) except AMT, if at least 2 wks after the membrane has disappeared within the area of the PED or corneal ulcer (and at least 6 weeks after the procedure) in the study eye. 18. Use therapeutic contact lenses or wear contact lenses for refractive correction during the study treatment periods in the eye(s) with NK. 19. Have an anticipated need for punctal occlusion during the study treatment period. Patients with punctal occlusion or punctal plugs inserted before the study are eligible for enrolment provided that the punctal occlusion is maintained during the study. 20. Have an uncontrolled glaucoma at the Screening Visit. (Patients suffering from glaucoma requiring ophthalmic drops for topical treatment at the Screening Visit or during the study are not eligible, except if the ophthalmic drops is a preservative-free treatment administered maximum once daily as a single-agent treatment and at a stable regimen 4 weeks before screening and at the same dose during the study. Patients treated with oral intraocular pressure-lowering drugs at the Screening Visit and during the study may be enrolled if their glaucoma status is assessed as stable and controlled. For the fellow eye 21. Have Stage 2 or 3 NK or perforation. For any eye: 22. Have a history of ocular cancer. 23. Have had prior treatment with Oxervate™
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Corneal Healing | At week 8 | The primary endpoint of this study is the percentage of patients achieving complete corneal healing of PED or corneal ulcer at Week 8, defined as no corneal fluorescein staining in the area of the PED or corneal ulcer as assessed by an independent central reading centre. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Visual Acuity | At week 8 | Percentage of patients who achieve a 5-, 10-, and 15-letter mean improvement in best corrected distance visual acuity (BCDVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) chart at Week 8 compared to baseline (in all patients and in patients with a central location of the PED or corneal ulcer, respectively). |
Countries
France, Germany, Hungary, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
Overall, 108 patients were randomised, and all of them received at least one dose of study drug. A total of 83 patients (76.9%) completed the 8-week treatment period and 88 patients (81.5%) completed the study regardless of the study treatment duration. The drug was instilled in 1 study eye per participant.
Participants by arm
| Arm | Count |
|---|---|
| Dose 1 - 0.5 µg/Day Dose of study drug per day: 0.5 µg/day Study drug concentration: 5 µg/mL MT8 given 1 drop QID
Udonitrectag: Eye drop solution in single dose unit.
Vehicle: Eye drop solution with no active substance in single dose unit. | 27 |
| Dose 2 - 2.5 µg/Day Dose of study drug per day: 2.5 µg/day Study drug concentration: 25 µg/mL MT8 given 1 drop QID
Udonitrectag: Eye drop solution in single dose unit.
Vehicle: Eye drop solution with no active substance in single dose unit. | 26 |
| Dose 3 - 5 µg/Day Dose of study drug per day: 5 µg/day Study drug concentration: 50 µg/mL MT8 given 1 drop QID
Udonitrectag: Eye drop solution in single dose unit.
Vehicle: Eye drop solution with no active substance in single dose unit. | 26 |
| Vehicle Dose of study drug per day: 0 µg/day Study drug concentration: Vehicle given 1 drop QID
Vehicle: Eye drop solution with no active substance in single dose unit. | 29 |
| Total | 108 |
Baseline characteristics
| Characteristic | Vehicle | Total | Dose 3 - 5 µg/Day | Dose 1 - 0.5 µg/Day | Dose 2 - 2.5 µg/Day |
|---|---|---|---|---|---|
| Age, Continuous | 67.0 years STANDARD_DEVIATION 16.76 | 65.7 years STANDARD_DEVIATION 16.12 | 65.6 years STANDARD_DEVIATION 17.14 | 70.3 years STANDARD_DEVIATION 14.05 | 59.6 years STANDARD_DEVIATION 15.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 16 Participants | 4 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 23 Participants | 91 Participants | 22 Participants | 24 Participants | 22 Participants |
| Height | 167.662 cm STANDARD_DEVIATION 14.8453 | 168.748 cm STANDARD_DEVIATION 11.7409 | 169.598 cm STANDARD_DEVIATION 12.1409 | 166.694 cm STANDARD_DEVIATION 9.5229 | 171.99 cm STANDARD_DEVIATION 9.5848 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 11 Participants | 4 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) White | 27 Participants | 93 Participants | 19 Participants | 26 Participants | 21 Participants |
| Region of Enrollment France | 2 participants | 6 participants | 2 participants | 1 participants | 1 participants |
| Region of Enrollment Germany | 4 participants | 29 participants | 9 participants | 6 participants | 10 participants |
| Region of Enrollment Hungary | 3 participants | 5 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Italy | 7 participants | 32 participants | 6 participants | 13 participants | 6 participants |
| Region of Enrollment Spain | 4 participants | 9 participants | 2 participants | 1 participants | 2 participants |
| Region of Enrollment United Kingdom | 3 participants | 10 participants | 3 participants | 2 participants | 2 participants |
| Region of Enrollment United States | 6 participants | 17 participants | 4 participants | 3 participants | 4 participants |
| Sex: Female, Male Female | 14 Participants | 52 Participants | 14 Participants | 13 Participants | 11 Participants |
| Sex: Female, Male Male | 15 Participants | 56 Participants | 12 Participants | 14 Participants | 15 Participants |
| Weight | 74.718 kg STANDARD_DEVIATION 19.6181 | 75.889 kg STANDARD_DEVIATION 19.0756 | 72.377 kg STANDARD_DEVIATION 14.5292 | 79.051 kg STANDARD_DEVIATION 19.1023 | 77.379 kg STANDARD_DEVIATION 22.5637 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 1 / 26 | 0 / 26 | 0 / 29 |
| other Total, other adverse events | 18 / 27 | 17 / 26 | 18 / 26 | 11 / 29 |
| serious Total, serious adverse events | 4 / 27 | 3 / 26 | 7 / 26 | 4 / 29 |
Outcome results
Primary
Corneal Healing
The primary endpoint of this study is the percentage of patients achieving complete corneal healing of PED or corneal ulcer at Week 8, defined as no corneal fluorescein staining in the area of the PED or corneal ulcer as assessed by an independent central reading centre.
Time frame: At week 8
Population: The total patients were divided in subgroups according to disease stage (moderate or severe) and Region (EU or NA)
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Dose 1 - 0.5 µg/Day | Corneal Healing | Disease stage 2 (moderate) NA | Healed | 2 Participants |
| Dose 1 - 0.5 µg/Day | Corneal Healing | Disease stage 3 (Severe) EU | Healed | 3 Participants |
| Dose 1 - 0.5 µg/Day | Corneal Healing | Disease stage 3 (Severe) NA | Not healed | 1 Participants |
| Dose 1 - 0.5 µg/Day | Corneal Healing | Disease stage 3 (Severe) EU | Not healed | 11 Participants |
| Dose 1 - 0.5 µg/Day | Corneal Healing | Disease stage 3 (Severe) NA | Healed | 0 Participants |
| Dose 1 - 0.5 µg/Day | Corneal Healing | Disease stage 2 (moderate) EU | Not healed | 6 Participants |
| Dose 1 - 0.5 µg/Day | Corneal Healing | Disease stage 2 (moderate) EU | Healed | 4 Participants |
| Dose 1 - 0.5 µg/Day | Corneal Healing | Disease stage 2 (moderate) NA | Not healed | 0 Participants |
| Dose 2 - 2.5 µg/Day | Corneal Healing | Disease stage 3 (Severe) EU | Not healed | 9 Participants |
| Dose 2 - 2.5 µg/Day | Corneal Healing | Disease stage 2 (moderate) EU | Healed | 2 Participants |
| Dose 2 - 2.5 µg/Day | Corneal Healing | Disease stage 2 (moderate) EU | Not healed | 9 Participants |
| Dose 2 - 2.5 µg/Day | Corneal Healing | Disease stage 3 (Severe) EU | Healed | 2 Participants |
| Dose 2 - 2.5 µg/Day | Corneal Healing | Disease stage 2 (moderate) NA | Healed | 0 Participants |
| Dose 2 - 2.5 µg/Day | Corneal Healing | Disease stage 2 (moderate) NA | Not healed | 2 Participants |
| Dose 2 - 2.5 µg/Day | Corneal Healing | Disease stage 3 (Severe) NA | Healed | 1 Participants |
| Dose 2 - 2.5 µg/Day | Corneal Healing | Disease stage 3 (Severe) NA | Not healed | 1 Participants |
| Dose 3 - 5 µg/Day | Corneal Healing | Disease stage 2 (moderate) EU | Not healed | 9 Participants |
| Dose 3 - 5 µg/Day | Corneal Healing | Disease stage 3 (Severe) NA | Not healed | 1 Participants |
| Dose 3 - 5 µg/Day | Corneal Healing | Disease stage 3 (Severe) NA | Healed | 1 Participants |
| Dose 3 - 5 µg/Day | Corneal Healing | Disease stage 2 (moderate) NA | Healed | 0 Participants |
| Dose 3 - 5 µg/Day | Corneal Healing | Disease stage 2 (moderate) NA | Not healed | 2 Participants |
| Dose 3 - 5 µg/Day | Corneal Healing | Disease stage 3 (Severe) EU | Not healed | 9 Participants |
| Dose 3 - 5 µg/Day | Corneal Healing | Disease stage 2 (moderate) EU | Healed | 1 Participants |
| Dose 3 - 5 µg/Day | Corneal Healing | Disease stage 3 (Severe) EU | Healed | 3 Participants |
| Vehicle | Corneal Healing | Disease stage 2 (moderate) EU | Healed | 2 Participants |
| Vehicle | Corneal Healing | Disease stage 2 (moderate) NA | Healed | 0 Participants |
| Vehicle | Corneal Healing | Disease stage 3 (Severe) NA | Not healed | 0 Participants |
| Vehicle | Corneal Healing | Disease stage 2 (moderate) NA | Not healed | 3 Participants |
| Vehicle | Corneal Healing | Disease stage 2 (moderate) EU | Not healed | 9 Participants |
| Vehicle | Corneal Healing | Disease stage 3 (Severe) NA | Healed | 3 Participants |
| Vehicle | Corneal Healing | Disease stage 3 (Severe) EU | Healed | 5 Participants |
| Vehicle | Corneal Healing | Disease stage 3 (Severe) EU | Not healed | 7 Participants |
Secondary
Visual Acuity
Percentage of patients who achieve a 5-, 10-, and 15-letter mean improvement in best corrected distance visual acuity (BCDVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) chart at Week 8 compared to baseline (in all patients and in patients with a central location of the PED or corneal ulcer, respectively).
Time frame: At week 8
Population: The population was analysed in subgroups according to the location of the PED or corneal ulcer (central versus all locations).
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Dose 1 - 0.5 µg/Day | Visual Acuity | Improvement ≥ 10 letters (central PED or central corneal ulcer) | Not improved | 18 Participants |
| Dose 1 - 0.5 µg/Day | Visual Acuity | Improvement ≥ 15 letters (central PED or central corneal ulcer) | Not improved | 18 Participants |
| Dose 1 - 0.5 µg/Day | Visual Acuity | Improvement ≥ 5 letters (central PED or central corneal ulcer) | Not improved | 17 Participants |
| Dose 1 - 0.5 µg/Day | Visual Acuity | Improvement ≥ 5 letters (all locations) | Improved | 9 Participants |
| Dose 1 - 0.5 µg/Day | Visual Acuity | Improvement ≥ 10 letters (central PED or central corneal ulcer) | Improved | 3 Participants |
| Dose 1 - 0.5 µg/Day | Visual Acuity | Improvement ≥ 10 letters (all locations) | Improved | 7 Participants |
| Dose 1 - 0.5 µg/Day | Visual Acuity | Improvement ≥ 10 letters (all locations) | Not improved | 20 Participants |
| Dose 1 - 0.5 µg/Day | Visual Acuity | Improvement ≥ 5 letters (all locations) | Not improved | 18 Participants |
| Dose 1 - 0.5 µg/Day | Visual Acuity | Improvement ≥ 15 letters (central PED or central corneal ulcer) | Improved | 3 Participants |
| Dose 1 - 0.5 µg/Day | Visual Acuity | Improvement ≥ 15 letters (all locations) | Improved | 7 Participants |
| Dose 1 - 0.5 µg/Day | Visual Acuity | Improvement ≥ 15 letters (all locations) | Not improved | 20 Participants |
| Dose 1 - 0.5 µg/Day | Visual Acuity | Improvement ≥ 5 letters (central PED or central corneal ulcer) | Improved | 4 Participants |
| Dose 2 - 2.5 µg/Day | Visual Acuity | Improvement ≥ 5 letters (all locations) | Not improved | 15 Participants |
| Dose 2 - 2.5 µg/Day | Visual Acuity | Improvement ≥ 5 letters (central PED or central corneal ulcer) | Improved | 10 Participants |
| Dose 2 - 2.5 µg/Day | Visual Acuity | Improvement ≥ 10 letters (all locations) | Not improved | 17 Participants |
| Dose 2 - 2.5 µg/Day | Visual Acuity | Improvement ≥ 10 letters (central PED or central corneal ulcer) | Improved | 8 Participants |
| Dose 2 - 2.5 µg/Day | Visual Acuity | Improvement ≥ 10 letters (central PED or central corneal ulcer) | Not improved | 16 Participants |
| Dose 2 - 2.5 µg/Day | Visual Acuity | Improvement ≥ 5 letters (central PED or central corneal ulcer) | Not improved | 14 Participants |
| Dose 2 - 2.5 µg/Day | Visual Acuity | Improvement ≥ 5 letters (all locations) | Improved | 11 Participants |
| Dose 2 - 2.5 µg/Day | Visual Acuity | Improvement ≥ 15 letters (all locations) | Not improved | 21 Participants |
| Dose 2 - 2.5 µg/Day | Visual Acuity | Improvement ≥ 15 letters (all locations) | Improved | 5 Participants |
| Dose 2 - 2.5 µg/Day | Visual Acuity | Improvement ≥ 10 letters (all locations) | Improved | 9 Participants |
| Dose 2 - 2.5 µg/Day | Visual Acuity | Improvement ≥ 15 letters (central PED or central corneal ulcer) | Not improved | 19 Participants |
| Dose 2 - 2.5 µg/Day | Visual Acuity | Improvement ≥ 15 letters (central PED or central corneal ulcer) | Improved | 5 Participants |
| Dose 3 - 5 µg/Day | Visual Acuity | Improvement ≥ 5 letters (central PED or central corneal ulcer) | Not improved | 12 Participants |
| Dose 3 - 5 µg/Day | Visual Acuity | Improvement ≥ 5 letters (all locations) | Improved | 10 Participants |
| Dose 3 - 5 µg/Day | Visual Acuity | Improvement ≥ 5 letters (all locations) | Not improved | 16 Participants |
| Dose 3 - 5 µg/Day | Visual Acuity | Improvement ≥ 10 letters (all locations) | Improved | 6 Participants |
| Dose 3 - 5 µg/Day | Visual Acuity | Improvement ≥ 10 letters (all locations) | Not improved | 20 Participants |
| Dose 3 - 5 µg/Day | Visual Acuity | Improvement ≥ 15 letters (all locations) | Improved | 5 Participants |
| Dose 3 - 5 µg/Day | Visual Acuity | Improvement ≥ 15 letters (all locations) | Not improved | 21 Participants |
| Dose 3 - 5 µg/Day | Visual Acuity | Improvement ≥ 5 letters (central PED or central corneal ulcer) | Improved | 7 Participants |
| Dose 3 - 5 µg/Day | Visual Acuity | Improvement ≥ 10 letters (central PED or central corneal ulcer) | Improved | 5 Participants |
| Dose 3 - 5 µg/Day | Visual Acuity | Improvement ≥ 10 letters (central PED or central corneal ulcer) | Not improved | 14 Participants |
| Dose 3 - 5 µg/Day | Visual Acuity | Improvement ≥ 15 letters (central PED or central corneal ulcer) | Improved | 4 Participants |
| Dose 3 - 5 µg/Day | Visual Acuity | Improvement ≥ 15 letters (central PED or central corneal ulcer) | Not improved | 15 Participants |
| Vehicle | Visual Acuity | Improvement ≥ 15 letters (all locations) | Not improved | 23 Participants |
| Vehicle | Visual Acuity | Improvement ≥ 15 letters (all locations) | Improved | 6 Participants |
| Vehicle | Visual Acuity | Improvement ≥ 5 letters (all locations) | Improved | 7 Participants |
| Vehicle | Visual Acuity | Improvement ≥ 10 letters (central PED or central corneal ulcer) | Not improved | 15 Participants |
| Vehicle | Visual Acuity | Improvement ≥ 10 letters (all locations) | Not improved | 23 Participants |
| Vehicle | Visual Acuity | Improvement ≥ 10 letters (all locations) | Improved | 6 Participants |
| Vehicle | Visual Acuity | Improvement ≥ 15 letters (central PED or central corneal ulcer) | Not improved | 15 Participants |
| Vehicle | Visual Acuity | Improvement ≥ 15 letters (central PED or central corneal ulcer) | Improved | 4 Participants |
| Vehicle | Visual Acuity | Improvement ≥ 5 letters (central PED or central corneal ulcer) | Not improved | 14 Participants |
| Vehicle | Visual Acuity | Improvement ≥ 5 letters (central PED or central corneal ulcer) | Improved | 5 Participants |
| Vehicle | Visual Acuity | Improvement ≥ 5 letters (all locations) | Not improved | 22 Participants |
| Vehicle | Visual Acuity | Improvement ≥ 10 letters (central PED or central corneal ulcer) | Improved | 4 Participants |