Purpose
To evaluate the efficacy and safety of 0.18% sodium hyaluronate ophthalmic solution (Rejena, Vismed) compared with its vehicle for the treatment of signs and symptoms of dry eye disease.
Design
Randomized, placebo-controlled clinical trial.
Methods
A total of 444 subjects with dry eye disease were randomized 1:1 to active study drug (n = 221) or vehicle control (n = 223) in this multicenter, double-masked trial. Subjects instilled 1 to 2 drops, 3 to 6 times daily for 14 days, with evaluations at Days 7 and 14. The study’s 2 primary efficacy endpoints were change from baseline at Day 7 in lissamine green staining scores (objective) and in global symptom frequency scores (subjective). Results were analyzed using Wilcoxon rank sum test and Student t test in the intent-to-treat (ITT) population with last observation carried forward (LOCF).
Results
At Day 7, the differences between the active and vehicle groups in change from baseline for lissamine green staining score ( P = .050, Wilcoxon; P = .029, t test) and global symptom frequency score ( P = .050, Wilcoxon; P = .017, t test) were both statistically significant. There were no clinically relevant safety findings related to the use of Rejena.
Conclusions
This study demonstrated the clinical efficacy of Rejena in the treatment of dry eye disease in both a primary objective endpoint and a primary subjective endpoint when compared to its vehicle. The study results also supported the well-known safety profile of Rejena.
Dry eye disease is a common clinical problem, with an estimated prevalence of 5% to 30% at various ages. It is a multifactorial disease resulting in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface, and it is frequently accompanied by increased osmolarity of the tear film and subsequent inflammation of the ocular surface. The tear film of the eye normally serves to nourish the ocular surface, provide lubrication between the eye surface and the lids, and act as the anterior refracting surface of the eye. It is thought to consist of an aqueous gel with mucin content decreasing in a gradient from the ocular surface to the undersurface of the outermost lipid layer. The lipid layer interacts with the underlying aqueous and mucin components, retarding evaporative loss of aqueous tears and contributing to the stability of the tear film between blinks.
Goals for treatment of patients with dry eye disease are to improve the patient’s ocular comfort and quality of life and to return the ocular surface and tear film to the normal homeostatic state. Current therapies for the management of dry eye include therapies for tear supplementation, retention, and stimulation; anti-inflammatory agents; and environmental strategies.
A patented formulation of 0.18% sodium hyaluronate ophthalmic solution is currently marketed in Europe and Asia alternatively under the brand names Vismed, Vislube, and Hylovis (TRB Chemedica AG, Haar/München, Germany), and is under development for the treatment of dry eye disease in the United States under the recently approved trade name Rejena. Hyaluronic acid occurs naturally in all vertebrates in the vitreous body of the eye, extracellular matrix of the skin, and synovial fluid. It is a biopolymer of disaccharide units composed of N-acetylglucosamine and glucuronic acid in linear chains of varying molecular weights. The sodium salt of hyaluronic acid, sodium hyaluronate (SH), is the active ingredient in this proprietary formulation of sodium hyaluronate ophthalmic solution. It is currently also used as an active ingredient in other medicinal products and medical devices, especially in ocular surgery involving the anterior or posterior segment of the eye, where it is used to maintain the shape of the globe, to cover surgical instruments, and to protect the sensitive corneal endothelium from further surgical damage. The unique viscoelastic properties of SH allow it to behave differently during and between blinks. During blinks, SH molecules align with each other, resulting in an elastic and relatively nonviscous solution that spreads easily over the surface of the cornea. Between blinks, SH molecules form a tangled meshwork, resulting in a less elastic and more viscous solution that stabilizes the precorneal tear film and maximizes the residence time of the solution on the surface, enabling it to lubricate and protect the ocular surface. Additionally, SH exhibits water entrapping and mucoadhesive properties that increase its retention time on the eye surface.
Ten clinical efficacy and safety studies have been conducted with 0.18% sodium hyaluronate ophthalmic solution in which the safety and efficacy in short- and long-term clinical use have been established. However, confirmatory efficacy and safety studies in which improvement in a sign and a symptom occur simultaneously in a single study were not available. The purpose of this Phase 3 study was to confirm, as primary endpoints of efficacy, previously reported secondary endpoints in staining and symptoms from a study by Baeyens and associates (Baeyens, unpublished poster, ARVO annual meeting 2004). The tactic applied was to compare the efficacy and safety of 0.18% sodium hyaluronate ophthalmic solution with vehicle in subjects with dry eye disease. In particular, the superiority of the drug product was studied in both a primary objective endpoint (lissamine green staining score) and a primary subjective endpoint (global symptom frequency score).
Methods
This Phase 3, multicenter, randomized, placebo-controlled, double-masked clinical trial was conducted at 15 sites in the United States. Trial design specifications, including the duration of treatment, were created with the assistance of the Food and Drug Administration (FDA) via a Special Protocol Assessment. The trial started on December 13, 2006, and was completed on May 22, 2008.
For inclusion, subjects had to be ≥18 years of age with at least a 3-month documented history of dry eye in both eyes diagnosed as dry eye syndrome, keratoconjunctivitis sicca (KCS), or dry eye due to Sjögren syndrome (immune exocrinopathy). At screening and baseline visits, subjects had to experience at least 2 symptoms of dry eye (soreness, scratchiness, dryness, grittiness, and burning) rated as ≥2 (“often”) on the symptom frequency scale and scored as ≥50 mm on the 0- to 100-mm visual analog scale (VAS) in the same eye. Additionally, subjects had to demonstrate objective parameters of dry eye at baseline and screening visits of corneal fluorescein staining total score of ≥3 and lissamine green staining total score of ≥3. Subjects were excluded if they had undergone ocular surgery (of any type, including laser surgery) or ocular trauma within the 4 months prior to screening, had punctal occlusion or diathermy within 3 months prior to screening, had abnormality of the nasolacrimal drainage apparatus, had any active inflammation of the eye not attributable to KCS (eg, iritis, scleritis, etc), or had other diseases or characteristics judged by the investigator to be incompatible with the assessments needed in the study or with reliable instillation of the study drug.
This study was double-masked; the treating physician, site personnel, and subjects were masked as to treatment assignment. The packaging of the study drug (active and vehicle) was identical, and each monodose unit was labeled with the study number and a codified lot number to avoid potential identification of the product by site personnel or subjects.
The screening visit occurred between Days -7 and -5 to allow a minimum 5-day run-in period prior to entry into the study. Subjects who met the eligibility criteria discontinued the use of all artificial tears and were given a supply of vehicle eye drops with instructions to instill 1 to 2 drops per eye at least 3 times and up to 6 times daily during the run-in period. Subjects discontinued the use of the vehicle eye drops at least 4 hours prior to the assessments performed at Day 0 (baseline). Subjects who continued to meet eligibility criteria at the baseline (Day 0) visit were randomized 1:1 to receive active study drug (0.18% sodium hyaluronate ophthalmic solution) or its vehicle (identical to active study drug except lacking sodium hyaluronate). Subjects were randomized by assigning each consecutive subject to the lowest numbered study kit provided to the study center. The kit numbers were assigned according to a block randomization list generated by an independent statistician. After randomization, subjects were given an adequate supply of their assigned study drug (active or vehicle) for the entire 14-day treatment period, with instructions to instill 1 to 2 drops per eye at least 3 times and up to 6 times daily during that time period. Subjects returned to the clinical site at Days 7 and 14 for efficacy and safety evaluations (see Table 1 , Schedule of Events), which were performed in the study eye and the fellow eye. The study eye was defined as the eye with the worse Schirmer I score at baseline; if both eyes were equal, the right eye was designated at the study eye. Follow-up safety evaluations were conducted at Day 21 via a telephone interview unless the subject experienced an adverse event (AE), in which case the subject was asked to return to the clinical site for Day-21 assessments.
| Evaluation | Screening Days -7 to -5 | Baseline Day 0 | Day 7 ± 1 | Day 14 ± 1 | Telephone Safety Follow-up: Day 21 ± 3 |
|---|---|---|---|---|---|
| Signed informed consent | X | ||||
| Inclusion/exclusion criteria | X | X | |||
| Demographics | X | ||||
| Medical history | X | X a | |||
| Ocular history | X | X a | |||
| Symptom intensity grading with VAS | X | X | X | X | |
| Symptom frequency rating | X | X | X | X | |
| Rating of impact of dry eye on daily life | X | X | X | ||
| Best-corrected visual acuity | X | X | X | X | |
| Corneal fluorescein staining b | X | X | X | X | |
| Lissamine green staining | X | X | X | X | |
| Slit-lamp examination | X | X | X | X | |
| Schirmer I test | X | X | X | ||
| Intraocular pressure c | X | X | X | ||
| Dilated fundus examination | X | X | |||
| Urine pregnancy test d | X | X | |||
| Randomization | X | ||||
| Drug administration | X | ||||
| Drug accountability | X | X | X | ||
| Adverse event assessment | X | X | X | X | |
| Prior/concomitant med assessment | X | X | X | X |
b Corneal fluorescein staining of the cornea preceded lissamine green staining. The procedures were separated by at least 15 minutes.
c Intraocular pressure was the last ophthalmic procedure to be performed except for at screening and Day 14, when it directly preceded the dilated fundus examination.
d Only female subjects of childbearing potential who are not postmenopausal (≥1 year), or are not surgically sterilized.
The study had 2 primary efficacy endpoints. The primary objective efficacy endpoint (sign) in the study eye was the change from baseline at Day 7 in lissamine green staining of the cornea, nasal conjunctiva, and temporal conjunctiva, with each graded on a 0 to 4 scale (0 = 0%; 1 = 1%-15%; 2 = 16%-30%; 3 = 31%-45%; 4 = >45%), for a maximum score of 12. Lissamine green staining was performed in both eyes using 1 drop of 1% lissamine green solution, with results observed in the low- to moderate-intensity white light of the slit lamp between 1 minute and 4 minutes following instillation. The primary subjective efficacy endpoint (symptom) was the change from baseline at Day 7 in the summed scores for global symptom frequency in both eyes (soreness, scratchiness, dryness, grittiness, and burning), with each rated on a 0 to 3 scale (0 = Never; 1 = Sometimes; 2 = Often; 3 = Constantly), for a maximum score of 15.
The primary efficacy endpoints were analyzed using Wilcoxon rank sum test as the primary statistical method and the Student t test as a supportive method. A 2-sided alpha level of .050 was used to determine statistical significance. To achieve study success, both primary endpoints were required to reach significance. The primary analysis of the endpoints for the study were conducted in the intent-to-treat (ITT) population (all randomized subjects, N = 444), using last-observation-carried-forward (LOCF) data including baseline data.
The secondary efficacy endpoints, analyzed by Student t test according to the statistical plan of the study, were the change from baseline in lissamine green staining scores at Day 14 in the study eye, the change from baseline in global symptom frequency scores at Day 14 in both eyes, the percentage change from baseline at Day 7 and Day 14 in corneal fluorescein staining in the study eye, Schirmer I testing, summed VAS symptom scores, composite index of global symptom intensity and global symptom frequency scores, and global impact of dry eye on daily life activities.
Safety assessments included slit-lamp examination, best-corrected visual acuity (BCVA), intraocular pressure (IOP), dilated fundus examination, and collection of AEs.
An interim analysis to re-estimate sample size was performed after 211 subjects (approximately 70% of the original planned sample size) completed Day-7 treatment. The masked interim analysis included the primary efficacy endpoints and was conducted by biostatisticians at The EMMES Corp (Rockville, Maryland, USA), who did not have access to the randomization code. The planned sample size of 300 subjects (150 per group) was increased to 440 subjects (220 per group) based on the greater-than-expected variability results of this masked interim analysis. All personnel connected with the trial (eg, sponsor, trial statistician, monitors, site) remained masked. The final analysis was performed after all subjects completed the 3-week study or discontinued.
Results
Subject demographics and disposition are summarized in Table 2 and Figure 1 , respectively. A total of 444 subjects were enrolled and treated (active: n = 221; vehicle: n = 223). Of these, 333 subjects (75%) were female and the mean age (± SD) of all subjects was 61.5 ± 13.7 years. The randomized groups were similar with respect to age, gender, ethnicity, and race. The majority of subjects (436/444; 98.2%) completed the study and the proportion of subjects who withdrew early from study treatment was equal for the 2 treatment groups. A total of 3 subjects (active: 2/221 [0.9%]; vehicle: 1/223 [0.4%]) withdrew because of an AE. None of the subjects’ treatment assignments were unmasked during the study.
| Active (N = 221) | Vehicle (N = 223) | Overall (N = 444) | |
|---|---|---|---|
| Disposition | |||
| Completed the study | 217 (98.2%) | 219 (98.2%) | 436 (98.2%) |
| Subjects withdrawn early | 4 (1.8%) | 4 (1.8%) | 8 (1.8%) |
| Reason for early withdrawal | |||
| Subject withdrew consent | 1 (0.5%) | 2 (0.9%) | 3 (0.7%) |
| Lost to follow-up | 1 (0.5%) | 1 (0.4%) | 2 (0.5%) |
| Adverse event | 2 (0.9%) | 1 (0.4%) | 3 (0.7%) |
| Demographics | |||
| Age (y), Mean (SD) | 60.7 (12.6) | 62.2 (14.8) | 61.5 (13.7) |
| Gender, N (%) | |||
| Male | 49 (22.2%) | 62 (27.8%) | 111 (25.0%) |
| Female | 172 (77.8%) | 161 (72.2%) | 333 (75.0%) |
| Ethnicity, N (%) | |||
| Hispanic or Latino | 17 (7.7%) | 14 (6.3%) | 31 (7.0%) |
| Not Hispanic or Latino | 204 (92.3%) | 209 (93.7%) | 413 (93.0%) |
| Race, N (%) | |||
| White | 192 (86.9%) | 188 (84.3%) | 380 (85.6%) |
| Black/African American | 20 (9.0%) | 30 (13.5%) | 50 (11.3%) |
| American Indian/Alaskan Native | 1 (0.5%) | 0 | 1 (0.2%) |
| Asian | 3 (1.4%) | 2 (0.9%) | 5 (1.1%) |
| Other | 5 (2.3%) | 3 (1.3%) | 8 (1.8%) |
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