Dry Eye
Conditions
Keywords
LME636, dry eye disease, efficacy, ocular discomfort
Brief summary
The purpose of this study is to evaluate the efficacy of LME636 compared to vehicle in the reduction of ocular symptoms and to evaluate the safety and tolerability of LME636, when administered topically for up to 42 days, in subjects with severe dry eye disease.
Detailed description
This study is organized into 2 phases. Following a 2-week identification phase, eligible subjects with severe dry eye disease (DED) will be randomized into the treatment phase and will be dispensed study treatment for 10 weeks.
Interventions
BIOLOGICALLME636 ophthalmic solution
BIOLOGICALLME636 Vehicle
Inactive ingredients used as a placebo comparator
Sponsors
Novartis Institutes for BioMedical Research
Alcon, a Novartis Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must sign written informed consent. * Physician diagnosis of DED of at least 6 months prior to Visit 1. * Must use artificial tears, gels, lubricants or re-wetting drops on a regular basis. * Respond as often or constantly to the question How often do your eyes feel uncomfortable?. * Best Corrected Visual Acuity (BCVA) of 55 or greater in each eye as measured by ETDRS at Visit 1. * Other protocol-specified inclusion criteria may apply.
Exclusion criteria
* Presence of any acute infection or non-infectious ocular condition in either eye within 1 month of Visit 1. * Contact lens wearers, defined as individuals who cannot be without their contact lenses for the entire duration of the study. * Any chronic ocular degenerative condition that in the opinion of the Investigator could possibly advance during the time course of the study. * Use of biologics treatments, such as systemic biologic anti-cytokines, including anti-TNFα drugs, or immunosuppressive therapy for the treatment of severe systemic autoimmune disorders. * Diseases or conditions affecting the ocular surface that are associated with clinically significant scarring and or destruction of conjunctiva and/or cornea. * Unwilling to abstain from topical ocular non-prescription medications during the course of the study, including concomitant use of artificial tears, gels, lubricants, re-wetting drops, allergy drops, etc. after Visit 2. * Use of nasal, inhaled, systemic (including injections), or topical corticosteroids within 30 days of Visit 1. * Women of child-bearing potential unwilling to use effective contraception methods as defined in the protocol. * Other protocol-specified
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Increase in Dilated Fundus Parameter From Baseline to Any Visit | Baseline (Day 43), Day 57, Day 71, Day 85 | The dilated fundus examination was performed to evaluate the health of the vitreous, retina, macula, choroid, and optic nerve. An increase indicates worsening. Only one eye contributed to the analysis. |
| Best Corrected Visual Acuity (BCVA) | Baseline (Day 43), Day 57, Day 71, Day 85 | Visual Acuity (VA) with the subject's best spectacles or other visual corrective devices was measured using an ETDRS visual acuity chart at 3 meters (10 feet) and reported in letters read correctly. An increase (gain) in letters read indicates improvement. Both eyes contributed to the analysis. |
| Intraocular Pressure (IOP) | Baseline (Day 43), Day 57, Day 71, Day 85 | IOP (fluid pressure inside the eye) was assessed using Goldmann applanation tonometry or Tonopen and measured in millimeters of mercury (mmHg). A higher IOP can be a greater risk factor for developing glaucoma or glaucoma progression (leading to optic nerve damage). Both eyes contributed to the analysis. |
| Percentage of Subjects With Increase in Slit-Lamp Parameter From Baseline to Any Visit | Baseline (Day 43), Day 57, Day 71, Day 85 | Ocular signs (cornea, lens, and iris/anterior chamber) were assessed by slit-lamp biomicroscopy. An increase indicates worsening. Only one eye contributed to the analysis. |
| Mean Change From Baseline in Global Ocular Discomfort Score at Day 71 | Baseline (Day 43), Day 71 | Discomfort frequency and severity (each graded on a separate 100-units scale) were assessed daily using a visual analog scale (VAS) displayed on a handheld digital Pad (electronic patient-reported outcome (ePRO)). Frequency score was in response to the question 'how often your eyes felt uncomfortable during the past 24 hours' ranging from 'Rarely' to 'All the time.' Severity score was in response to the question 'how uncomfortable your eyes felt during the past 24 hours' ranging from 'Very mildly uncomfortable' to 'Very severely uncomfortable.' The Global Ocular Discomfort Score, ranging from 0 to 100, was calculated for any given day, as the square root of the product of the discomfort frequency score multiplied by the discomfort severity score. Improvement results in a reduction of the discomfort frequency or severity, or both, translating into a reduction of the resulting Global Ocular Discomfort score as compared to baseline. A negative change from baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With LME636 Serum Concentrations Below the Lower Limit of Quantification (LLOQ) | Day 15, Day 29, Day 43, Day 57, Day 71, Day 85 | Serum concentrations at each collection time point were quantitated, where possible, using a validated immunoassay method. LLOQ is defined as 0.25 ng/mL. |
| Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 15, Day 29, Day 43, Day 57, Day 71, Day 85 | Samples were collected and assessed for anti-LME636 antibodies. |
| Percentage of Subjects With More Than 20 Units Improvement in Global Ocular Discomfort Score From Baseline at Day 71 | Baseline (Day 43), Day 71 | Discomfort frequency and severity (each graded on a separate 100-units scale) were assessed daily using a VAS displayed on a handheld ePRO. Frequency score was in response to the question 'how often your eyes felt uncomfortable during the past 24 hours' ranging from 'Rarely' to 'All the time.' Severity score was in response to the question 'how uncomfortable your eyes felt during the past 24 hours' ranging from 'Very mildly uncomfortable' to 'Very severely uncomfortable.' The Global Ocular Discomfort Score, ranging from 0 to 100, was calculated for any given day, as the square root of the product of the discomfort frequency score multiplied by the discomfort severity score. Improvement results in a reduction of the discomfort frequency or severity, or both, translating into a reduction of the resulting Global Ocular Discomfort score as compared to baseline. |
Participant flow
Recruitment details
Subjects were recruited from 31 investigational sites located in the US.
Pre-assignment details
Of the 514 enrolled, 213 subjects entered the vehicle run-in period and 134 entered the randomized treatment period.
Participants by arm
| Arm | Count |
|---|---|
| LME636 All subjects randomized and treated with LME636 ophthalmic solution | 69 |
| Vehicle All subjects randomized and treated with LME636 Vehicle | 65 |
| Total | 134 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Randomized and Treated | Adverse Event | 0 | 1 | 0 |
| Randomized and Treated | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | LME636 | Vehicle | Total |
|---|---|---|---|
| Age, Continuous | 61.7 years STANDARD_DEVIATION 13.05 | 58.8 years STANDARD_DEVIATION 14.48 | 60.3 years STANDARD_DEVIATION 13.78 |
| Sex: Female, Male Female | 61 Participants | 54 Participants | 115 Participants |
| Sex: Female, Male Male | 8 Participants | 11 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 213 | 0 / 69 | 0 / 65 |
| other Total, other adverse events | 0 / 213 | 0 / 69 | 0 / 65 |
| serious Total, serious adverse events | 1 / 213 | 0 / 69 | 1 / 65 |
Outcome results
Primary
Best Corrected Visual Acuity (BCVA)
Visual Acuity (VA) with the subject's best spectacles or other visual corrective devices was measured using an ETDRS visual acuity chart at 3 meters (10 feet) and reported in letters read correctly. An increase (gain) in letters read indicates improvement. Both eyes contributed to the analysis.
Time frame: Baseline (Day 43), Day 57, Day 71, Day 85
Population: This analysis population includes all subjects that received any study drug (Safety Analysis Set). Number Analyzed is the number of subjects with data at visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LME636 | Best Corrected Visual Acuity (BCVA) | Baseline (Day 43) | 80.6 letters | Standard Deviation 6.44 |
| LME636 | Best Corrected Visual Acuity (BCVA) | Day 57 | 80.5 letters | Standard Deviation 6.82 |
| LME636 | Best Corrected Visual Acuity (BCVA) | Day 71 | 81.6 letters | Standard Deviation 5.56 |
| LME636 | Best Corrected Visual Acuity (BCVA) | Day 85 | 81.0 letters | Standard Deviation 5.73 |
| Vehicle | Best Corrected Visual Acuity (BCVA) | Day 85 | 81.6 letters | Standard Deviation 6.17 |
| Vehicle | Best Corrected Visual Acuity (BCVA) | Baseline (Day 43) | 81.5 letters | Standard Deviation 5.72 |
| Vehicle | Best Corrected Visual Acuity (BCVA) | Day 71 | 81.9 letters | Standard Deviation 5.89 |
| Vehicle | Best Corrected Visual Acuity (BCVA) | Day 57 | 81.6 letters | Standard Deviation 5.48 |
Primary
Intraocular Pressure (IOP)
IOP (fluid pressure inside the eye) was assessed using Goldmann applanation tonometry or Tonopen and measured in millimeters of mercury (mmHg). A higher IOP can be a greater risk factor for developing glaucoma or glaucoma progression (leading to optic nerve damage). Both eyes contributed to the analysis.
Time frame: Baseline (Day 43), Day 57, Day 71, Day 85
Population: Safety Analysis Set. Number Analyzed is the number of subjects with data at visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LME636 | Intraocular Pressure (IOP) | Baseline (Day 43) | 14.8 mmHg | Standard Deviation 2.71 |
| LME636 | Intraocular Pressure (IOP) | Day 57 | 14.6 mmHg | Standard Deviation 2.72 |
| LME636 | Intraocular Pressure (IOP) | Day 71 | 14.0 mmHg | Standard Deviation 3.06 |
| LME636 | Intraocular Pressure (IOP) | Day 85 | 14.4 mmHg | Standard Deviation 2.68 |
| Vehicle | Intraocular Pressure (IOP) | Day 85 | 14.6 mmHg | Standard Deviation 2.58 |
| Vehicle | Intraocular Pressure (IOP) | Baseline (Day 43) | 14.3 mmHg | Standard Deviation 2.63 |
| Vehicle | Intraocular Pressure (IOP) | Day 71 | 14.1 mmHg | Standard Deviation 2.7 |
| Vehicle | Intraocular Pressure (IOP) | Day 57 | 14.1 mmHg | Standard Deviation 2.92 |
Primary
Mean Change From Baseline in Global Ocular Discomfort Score at Day 71
Discomfort frequency and severity (each graded on a separate 100-units scale) were assessed daily using a visual analog scale (VAS) displayed on a handheld digital Pad (electronic patient-reported outcome (ePRO)). Frequency score was in response to the question 'how often your eyes felt uncomfortable during the past 24 hours' ranging from 'Rarely' to 'All the time.' Severity score was in response to the question 'how uncomfortable your eyes felt during the past 24 hours' ranging from 'Very mildly uncomfortable' to 'Very severely uncomfortable.' The Global Ocular Discomfort Score, ranging from 0 to 100, was calculated for any given day, as the square root of the product of the discomfort frequency score multiplied by the discomfort severity score. Improvement results in a reduction of the discomfort frequency or severity, or both, translating into a reduction of the resulting Global Ocular Discomfort score as compared to baseline. A negative change from baseline indicates improvement.
Time frame: Baseline (Day 43), Day 71
Population: This analysis population includes all randomized subjects with at least a post-baseline primary endpoint assessment excluding all subjects who met the critical deviation criteria (Per-Protocol Set). Number Analyzed is the number of subjects with data at visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LME636 | Mean Change From Baseline in Global Ocular Discomfort Score at Day 71 | -7.9 units on a scale | Standard Error 1.45 |
| Vehicle | Mean Change From Baseline in Global Ocular Discomfort Score at Day 71 | -3.6 units on a scale | Standard Error 1.49 |
Primary
Percentage of Subjects With Increase in Dilated Fundus Parameter From Baseline to Any Visit
The dilated fundus examination was performed to evaluate the health of the vitreous, retina, macula, choroid, and optic nerve. An increase indicates worsening. Only one eye contributed to the analysis.
Time frame: Baseline (Day 43), Day 57, Day 71, Day 85
Population: Safety Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LME636 | Percentage of Subjects With Increase in Dilated Fundus Parameter From Baseline to Any Visit | Retina | 1.4 percentage of subjects |
| LME636 | Percentage of Subjects With Increase in Dilated Fundus Parameter From Baseline to Any Visit | Choroid | 0.0 percentage of subjects |
| LME636 | Percentage of Subjects With Increase in Dilated Fundus Parameter From Baseline to Any Visit | Macula | 0.0 percentage of subjects |
| LME636 | Percentage of Subjects With Increase in Dilated Fundus Parameter From Baseline to Any Visit | Optic Nerve | 0.0 percentage of subjects |
| LME636 | Percentage of Subjects With Increase in Dilated Fundus Parameter From Baseline to Any Visit | Vitreous | 1.4 percentage of subjects |
| Vehicle | Percentage of Subjects With Increase in Dilated Fundus Parameter From Baseline to Any Visit | Optic Nerve | 0.0 percentage of subjects |
| Vehicle | Percentage of Subjects With Increase in Dilated Fundus Parameter From Baseline to Any Visit | Vitreous | 1.5 percentage of subjects |
| Vehicle | Percentage of Subjects With Increase in Dilated Fundus Parameter From Baseline to Any Visit | Retina | 0.0 percentage of subjects |
| Vehicle | Percentage of Subjects With Increase in Dilated Fundus Parameter From Baseline to Any Visit | Macula | 0.0 percentage of subjects |
| Vehicle | Percentage of Subjects With Increase in Dilated Fundus Parameter From Baseline to Any Visit | Choroid | 0.0 percentage of subjects |
Primary
Percentage of Subjects With Increase in Slit-Lamp Parameter From Baseline to Any Visit
Ocular signs (cornea, lens, and iris/anterior chamber) were assessed by slit-lamp biomicroscopy. An increase indicates worsening. Only one eye contributed to the analysis.
Time frame: Baseline (Day 43), Day 57, Day 71, Day 85
Population: Safety Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LME636 | Percentage of Subjects With Increase in Slit-Lamp Parameter From Baseline to Any Visit | Cornea | 0.0 percentage of subjects |
| LME636 | Percentage of Subjects With Increase in Slit-Lamp Parameter From Baseline to Any Visit | Lens | 0.0 percentage of subjects |
| LME636 | Percentage of Subjects With Increase in Slit-Lamp Parameter From Baseline to Any Visit | Iris | 0.0 percentage of subjects |
| LME636 | Percentage of Subjects With Increase in Slit-Lamp Parameter From Baseline to Any Visit | Anterior Chamber | 0.0 percentage of subjects |
| Vehicle | Percentage of Subjects With Increase in Slit-Lamp Parameter From Baseline to Any Visit | Anterior Chamber | 0.0 percentage of subjects |
| Vehicle | Percentage of Subjects With Increase in Slit-Lamp Parameter From Baseline to Any Visit | Cornea | 0.0 percentage of subjects |
| Vehicle | Percentage of Subjects With Increase in Slit-Lamp Parameter From Baseline to Any Visit | Iris | 0.0 percentage of subjects |
| Vehicle | Percentage of Subjects With Increase in Slit-Lamp Parameter From Baseline to Any Visit | Lens | 0.0 percentage of subjects |
Secondary
Percentage of Subjects With Anti-LME636 Antibodies by Visit
Samples were collected and assessed for anti-LME636 antibodies.
Time frame: Day 15, Day 29, Day 43, Day 57, Day 71, Day 85
Population: This analysis population includes all subjects with available immunogenicity data (Immunogenicity Analysis Set).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LME636 | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 85 (last day of dosing) | 86.8 percentage of subjects |
| LME636 | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 15 | 33.3 percentage of subjects |
| LME636 | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 29 | 37.3 percentage of subjects |
| LME636 | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 43 (prior to administration of first dose) | 31.9 percentage of subjects |
| LME636 | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 57 (Treatment Day 15) | 45.6 percentage of subjects |
| LME636 | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 71 | 79.3 percentage of subjects |
| Vehicle | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 29 | 37.7 percentage of subjects |
| Vehicle | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 85 (last day of dosing) | 40.4 percentage of subjects |
| Vehicle | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 43 (prior to administration of first dose) | 34.9 percentage of subjects |
| Vehicle | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 71 | 41.7 percentage of subjects |
| Vehicle | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 15 | 40.0 percentage of subjects |
| Vehicle | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 57 (Treatment Day 15) | 41.1 percentage of subjects |
| Run-In Only | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 43 (prior to administration of first dose) | 27.0 percentage of subjects |
| Run-In Only | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 15 | 26.9 percentage of subjects |
| Run-In Only | Percentage of Subjects With Anti-LME636 Antibodies by Visit | Day 29 | 27.0 percentage of subjects |
Secondary
Percentage of Subjects With LME636 Serum Concentrations Below the Lower Limit of Quantification (LLOQ)
Serum concentrations at each collection time point were quantitated, where possible, using a validated immunoassay method. LLOQ is defined as 0.25 ng/mL.
Time frame: Day 15, Day 29, Day 43, Day 57, Day 71, Day 85
Population: This analysis population includes all subjects with available pharmacokinetics data (Pharmacokinetics Analysis Set).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LME636 | Percentage of Subjects With LME636 Serum Concentrations Below the Lower Limit of Quantification (LLOQ) | Day 15 | 100.0 percentage of subjects |
| LME636 | Percentage of Subjects With LME636 Serum Concentrations Below the Lower Limit of Quantification (LLOQ) | Day 29 | 100.0 percentage of subjects |
| LME636 | Percentage of Subjects With LME636 Serum Concentrations Below the Lower Limit of Quantification (LLOQ) | Day 43 (prior to administration of first dose) | 98.5 percentage of subjects |
| LME636 | Percentage of Subjects With LME636 Serum Concentrations Below the Lower Limit of Quantification (LLOQ) | Day 57 | 82.1 percentage of subjects |
| LME636 | Percentage of Subjects With LME636 Serum Concentrations Below the Lower Limit of Quantification (LLOQ) | Day 71 | 71.9 percentage of subjects |
| LME636 | Percentage of Subjects With LME636 Serum Concentrations Below the Lower Limit of Quantification (LLOQ) | Day 85 (last day of dosing) | 67.9 percentage of subjects |
Secondary
Percentage of Subjects With More Than 20 Units Improvement in Global Ocular Discomfort Score From Baseline at Day 71
Discomfort frequency and severity (each graded on a separate 100-units scale) were assessed daily using a VAS displayed on a handheld ePRO. Frequency score was in response to the question 'how often your eyes felt uncomfortable during the past 24 hours' ranging from 'Rarely' to 'All the time.' Severity score was in response to the question 'how uncomfortable your eyes felt during the past 24 hours' ranging from 'Very mildly uncomfortable' to 'Very severely uncomfortable.' The Global Ocular Discomfort Score, ranging from 0 to 100, was calculated for any given day, as the square root of the product of the discomfort frequency score multiplied by the discomfort severity score. Improvement results in a reduction of the discomfort frequency or severity, or both, translating into a reduction of the resulting Global Ocular Discomfort score as compared to baseline.
Time frame: Baseline (Day 43), Day 71
Population: Per-Protocol Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LME636 | Percentage of Subjects With More Than 20 Units Improvement in Global Ocular Discomfort Score From Baseline at Day 71 | 17.9 percentage of subjects |
| Vehicle | Percentage of Subjects With More Than 20 Units Improvement in Global Ocular Discomfort Score From Baseline at Day 71 | 4.7 percentage of subjects |