# Presentation: 066390

## Cyclosporine Ophthalmic Emulsion, 0.05%

- July 21, 1999
- William M. Boyd, M.D.
- Medical Officer

## Cyclosporine Ophthalmic Emulsion, 0.05%

- Pharmacologic Category - immunomodulator
- Proposed Indication - treatment of moderate to severe keratoconjunctivitis sicca
- Dosage Form and Route of Administration -  ophthalmic emulsion for topical administration

## Clinical Data Sources

- Two Phase 3 Protocols
- Protocol 192731-002
- Protocol 192731-003
- One Phase 2 Protocol
- Protocol 192731-001

## Protocol 192731-002

## Clinical Studies Protocol 192731-002

- Design - randomized, multicenter, parallel-group, double-masked, Phase 3 trial
- Treatment arms - cyclosporine 0.05%, cyclosporine 0.1% , common vehicle

**Notes:**
A Multicenter, Double-Masked, Randomized, Vehicle-Controlled, Parallel-Group Study of the Safety and Efficacy of Cyclosporine 0.5% and 0.1% Ophthalmic Emulsions Used Twice Daily for Up to One Year in Patients with Moderate to Severe Keratoconjunctivitis Sicca

## Protocol 192731-002

- Test drug schedule - all subjects received either cyclosporine 0.05%, 0.1% or vehicle bilaterally, BID for six months
- Total subjects - 405

## Protocol 192731-002

- Objective Signs:
- corneal staining
- conjunctival staining
- sum of corneal and interpalpebral conjunctival staining
- Schirmer Tear Test
- tear break-up time

**Notes:**
Corneal Staining
For corneal fluorescein staining, the entire cornea was evaluated using the yellow barrier filter and the slit lamp’s cobalt blue illumination.  The staining was graded using the Oxford Scheme 6-point scale of severity.  A negative change from baseline indicated improvement.
		Conjunctival Staining
Lissamine green was instilled, and interpalpebral conjunctival staining was evaluated only after 30 seconds, but before 2 minutes, had elapsed.  Using white light of moderate intensity, the interpalpebral regions of the temporal and nasal conjunctiva were graded referring to the same Oxford Scheme.  A negative change from baseline indicated improvement.
Sum of Corneal and Interpalpebral Conjunctival Staining
The sum of the temporal and nasal interpalpebral conjunctival staining was measured on an 11‐point scale of severity (grades 0 to 10).  The sum of corneal and interpalpebral (temporal and nasal) conjunctival staining was measured on a 16‐point scale of severity (grades 0 to 15).  A negative change from baseline indicated improvement.
Schirmer Tear Test
The Schirmer tear test was performed both with and without anesthesia.  Sterile strips were inserted, and the tear front marked after 5 minutes (min).  The amount of wetting was measured in millimeters (mm) using a graduated paper scale.  Schirmer values were categorized from grade 1 (< 3 mm/5 min) to grade 5 ( 15 mm/5 min).  A positive change from baseline indicated improvement.
Tear Break-up Time
Time for tear break-up was measured only up to 10 seconds with a stopwatch.  Three consecutive TBUT measurements were performed, and the actual times in seconds recorded if the first time was less than 10 seconds.

## Protocol 192731-002

- Subjective Symptoms:
- symptoms of dry eye
- Ocular Surface Disease Index Score (OSDI)
- Facial Expression Subjective Rating Scale
- Investigator’s Global Evaluation of Response to Treatment
- Treatment Success

**Notes:**
OSDI Score (Ocular Surface Disease Index)
To evaluate their functional disability from dry eye, patients completed the OSDI questionnaire.  Each of 12 questions was rated from 0 (none of the time) to 4 (all of the time).  An overall OSDI score (ranging from 0 = no disability to 1 = complete disability) was calculated as the sum of the responses for all questions answered divided by the total possible score.  A minimum entry score was required at the screening and qualification visits.  A negative change from baseline indicated improvement.
Facial Expression Subjective Rating Scale
Patients chose one of the faces from the Facial Expression Subjective Rating Scale that reflected how their eyes felt over the previous week.   The facial expressions ranged from 1 (happiest face) to 9 (unhappiest face).  Responses were categorized from grade 1 (pictures 1 and 2) to grade 5 (pictures 8 and 9).  A negative change from baseline indicated improvement.
Symptoms of Dry Eye
At the investigator's office, patients completed a questionnaire about symptoms of dry eye (ocular discomfort) in terms of stinging/burning, itching, sandiness/grittiness, blurred vision, dryness, light sensitivity, painful or sore eye, and other.  Symptoms were graded using a scale of 0 (do not have this symptom) to +4 (always notice this symptom).  A negative change from baseline indicated improvement.
Investigator’s Global Evaluation of Response to Treatment
The investigator completed a global evaluation of the overall effect of study medication relative to the qualification visit.  The 7-point scale ranged from 0 (completely cleared) to 6 (condition worsened).
Treatment Success
Treatment success was defined as a global response of approximately 90% improvement or better (almost or completely cleared).

## Protocol 192731-002

- Criteria for Effectiveness - Sponsor must show a statistically significant difference between the active treatment and the vehicle for one (1) objective sign and one (1) subjective symptom.

## Protocol 192731-002

- Safety Criteria:
- EDTRS visual acuity
- intraocular pressure
- biomicroscopy
- pharmacokinetic parameters for subsets of subjects in selected centers

**Notes:**
All patients were refracted at the qualification visit, and the best-corrected visual acuity (VA) for each eye measured using the ETDRS chart.  The investigator recorded the values in Snellen equivalents.  The illumination and test distance specified for the site’s chart were kept constant throughout the study.  

Intraocular pressure (IOP) was measured in millimeters of mercury (mm Hg) using Goldmann applanation tonometry.

Biomicroscopy was performed using slit lamp examination without pupil dilation.  The examination included evaluations of lid and lid margin erythema and swelling, conjunctiva erythema/hyperemia and chemosis, tear film debris, cornea endothelial condition, anterior chamber cells and flare.  Observations were graded on a scale of 0 (none) to +4 (very severe), with half-grade increments accepted (excluding anterior chamber cells).

Pharmacokinetic parameters were obtained for subsets of subjects in selected centers.

## Protocol 192731-002 - Objective Signs

**Notes:**
Oxford Scheme 6-point severity scale (normal 0, mild/mod 1,2, severe 3,4,5).

A negative change from baseline indicates improvement.
There are statistically significant improvements from baseline in each treatment group at each visit. 
Either concentration of cyclosporine showed greater improvement than vehicle at all time points.  
There is a statistically significant among-group difference at month 6, favoring 0.05% cyclosporine over vehicle (p = 0.008).

## Protocol 192731-002 - Objective Signs

**Notes:**
A positive change from baseline indicates improvement.
Schirmer values were categorized from grade 1 (< 3mm/5min) to grade 5 ( 15mm/5min).
There is a statistically significant improvement from baseline in the 0.05% cyclosporine group at month 6.
A statistically significant among-group difference is approached but not reached at month 6, favoring 0.05% cyclosporine over vehicle (p = 0.066).

TBUT is similar across groups at baseline.  For patients with TBUT < 10 seconds, the average baseline TBUT was approximately 3 seconds and remained so at month 6.
Statistical significance was not calculated for this variable.

Other Objective Signs
There are no statistically significant among-group differences found for 1) nasal or temporal interpalpebral conjunctival staining, 2) the sum of nasal and temporal interpalpebral conjunctival staining, 3) the sum of corneal and interpalpebral conjunctival staining, or 4) Schirmer values without anesthesia.

## Protocol 192731-002 - Subjective Symptoms

**Notes:**
A negative change from baseline indicates improvement.
There are statistically significant improvements from baseline with 0.05% cyclosporine at each visit.
There are statistically significant among-group differences at months 3 and 4, favoring 0.05% cyclosporine over vehicle (p = < 0.001 and 0.003).

## Protocol 192731-002 - Subjective Symptoms

**Notes:**
Date and time of last use of REFRESH prior to each follow-up examination were documented on the case report forms (CRFs).  Average number of times per day the patient needed to use REFRESH during the previous week and number of days patient was able to go without using any REFRESH during the previous week were recorded.

A negative change from baseline indicates improvement.
In the week prior to the month 4 visit, subjects were asked to discontinue Refresh use.  At the month 4 visit, subjects were instructed to use Refresh less than eight times a day if possible for the study duration.
There are statistically significant improvements from baseline in the 0.05% group at each visit. 
 There is a statistically significant among-group difference at month 3, favoring 0.05% cyclosporine over vehicle (p = 0.028).

## Protocol 192731-002 - Subjective Symptoms

**Notes:**
A negative change from baseline indicates improvement.
There are statistically significant among-group differences at months 4 and 6, favoring 0.05% cyclosporine over vehicle (p = 0.020 and 0.008).

## Protocol 192731-002 - Subjective Symptoms

**Notes:**
A negative change from baseline indicates improvement.
Both 0.05% and 0.1% cyclosporine showed statistically significant improvement from baseline at months 3, 4, and 6.
There are statistically significant among-group differences at months 3, 4, and 6, favoring 0.1% cyclosporine over vehicle (p = 0.005, 0.035, and 0.004).

## Protocol 192731-002 - Subjective Symptoms

**Notes:**
A negative change from baseline indicates improvement.
There are statistically significant improvements from baseline in each treatment group at each visit. 
There are statistically significant among-group differences at months 3 and 6, favoring both 0.05% and 0.1% cyclosporine over vehicle (p = 0.024, 0.008).

## Protocol 192731-002 - Subjective Symptoms

**Notes:**
A negative change from baseline indicates improvement.
There are statistically significant improvements from baseline at all visits in the 0.05% and 0.1% cyclosporine groups.
There are statistically significant among-group differences at months 3 and 4, favoring 0.05% cyclosporine over vehicle (p = 0.046, 0.045).

## Protocol 192731-002 - Subjective Symptoms

**Notes:**
A negative change from baseline indicates improvement.
There are statistically significant improvements from baseline at all visits in the 0.05% and 0.1% cyclosporine groups.
There are statistically significant among-group differences at months 3 and 6, favoring 0.1% cyclosporine over vehicle (P = 0.019, 0.044).

Other Subjective Symptoms
There are no statistically significant among-group differences found for the symptoms of 1) stinging/burning, 2) sandy or gritty feeling, 3) dryness, or 4) pain. 
There was disparity in the Investigator’s Evaluation of Global Response to Treatment.  Some investigators rated global response based on their clinical evaluations of the patients while other investigators queried their patients directly about their response to treatment.  Among-group differences in Global Response were statistically significant at month 4 for 0.1% cyclosporine (p  0.046) and month 6 for 0.05% and 0.1% (p  0.046).  Because of the disparity in how investigators recorded and rated this response, these results and the Treatment Success results generated from them are not easily interpreted.

## Protocol 192731-002Safety

- Adverse Events Monitoring
- Most Common Ocular Adverse Events
- burning
- eye pain
- pruritis
- stinging
- No increase in ocular or systemic infections

## Protocol 192731-002 - Safety

**Notes:**
Changes from baseline visual acuity were similar across the three treatment groups.

IOP
IOP (average of both eyes) was similar across the 3 treatment groups at baseline.  There were statistically significant (P  0.031) increases in IOP from baseline to month 6 in all 3 treatment groups; however, the mean increases were less than 1 mm Hg and not clinically relevant.  The among-group difference at month 6 was not statistically significant.
Biomicroscopy
Changes in biomicroscopic findings (evaluations of lid and lid margin erythema and swelling, conjunctiva erythema/hyperemia and chemosis, tear film debris, cornea endothelial condition, anterior chamber cells and flare) from baseline were similar across the 3 treatment groups.  The majority of patients in each treatment group showed no change in any parameter at any follow-up visit.

Pharmacokinetic results in review page 34.
Adverese events - Table 8, review page 35.

## Protocol 192731-002Summary

- Statistically Significant Objective Signs
- Corneal Staining

**Notes:**
Reviewer’s Summary of Efficacy and Safety:
There are statistically significant among-group differences favoring cyclosporine over vehicle in at least one objective sign and at least one subjective symptom.  This satisfies protocol criteria for efficacy.
Adverse experiences appear mostly limited to mild to moderate ocular events.  There were no increases in the occurrence of systemic or ocular infections.

## Protocol 192731-002Summary

- Statistically Significant Subjective Symptoms
- Blurred Vision, Refresh Use, Sensitivity to Light, Itching, Composite Score, OSDI, Facial Expression Subjective Scale

## Protocol 192731-003

## Clinical Studies Protocol 192731-003

- Design - randomized, multicenter, parallel-group, double-masked, Phase 3 trial
- Treatment arms - cyclosporine 0.05%, cyclosporine 0.1% , common vehicle

**Notes:**
A Multicenter, Double-Masked, Randomized, Vehicle-Controlled,Parallel-Group Study of the Safety and Efficacy of Cyclosporine 0.5% and 0.1% Ophthalmic Emulsions Used Twice Daily for Up to One Year in Patients with Moderate to Severe Keratoconjunctivitis Sicca

## Protocol 192731-003

- Test drug schedule - all subjects received either cyclosporine 0.05%, 0.1% or vehicle bilaterally, BID for six months
- Total subjects - 472

## Protocol 192731-003

- Objective Signs:
- corneal staining
- conjunctival staining
- sum of corneal and interpalpebral conjunctival staining
- Schirmer Tear Test
- tear break-up time

**Notes:**
Identical to first protocol (002).

## Protocol 192731-003

- Subjective Symptoms:
- symptoms of dry eye
- Ocular Surface Disease Index Score (OSDI)
- Facial Expression Subjective Rating Scale
- Investigator’s Global Evaluation of Response to Treatment
- Treatment Success

**Notes:**
Identical to first protocol (002).

## Protocol 192731-003

- Safety Criteria:
- EDTRS visual acuity
- intraocular pressure
- biomicroscopy

**Notes:**
Identical to first protocol (002) except pharmacokinetic parameters not drawn.

## Protocol 192731-003 - Objective Signs

**Notes:**
A negative change from baseline indicates improvement.
Baseline mean corneal staining scores are significantly higher in the 0.05% and 0.1% cyclosporine groups than in the vehicle group (respectively, 2.72, 2.70, and 2.52; p = 0.036).
There are statistically significant improvements from baseline in each treatment group at each visit.
There are no statistically significant among-group differences.

## Protocol 192731-003 - Objective Signs

**Notes:**
A positive change from baseline indicates improvement.
There are statistically significant improvements from baseline in the 0.05% and 0.1% cyclosporine groups at month 6. 
There are statistically significant among-group differences favoring both 0.05% and 0.1% cyclosporine over vehicle (p  0.001).

TBUT is similar across groups at baseline.  For patients with TBUT < 10 seconds, the average baseline TBUT was approximately 3.5 seconds and remained so at month 6.

Other Objective Signs
There are no statistically significant among-group differences found for 1) nasal or temporal interpalpebral conjunctival staining, 2) the sum of nasal and temporal interpalpebral conjunctival staining, 3) the sum of corneal and interpalpebral conjunctival staining, or 4) categorized Schirmer values without anesthesia.
Statistically significant improvement from baseline (p  0.05) was seen for all treatment groups at most follow-up visits for 1) nasal or temporal interpalpebral conjunctival staining, 2) the sum of nasal and temporal interpalpebral conjunctival staining, 3) the sum of corneal and interpalpebral conjunctival staining, or 4) categorized Schirmer values without anesthesia.

## Protocol 192731-003 - Subjective Symptoms

**Notes:**
A negative change from baseline indicates improvement.
There are statistically significant improvements from baseline with both 0.05% and 0.1% cyclosporine at 6 months.
There are no statistically significant among-group differences

## Protocol 192731-003 - Subjective Symptoms

**Notes:**
A negative change from baseline indicates improvement.
In the week prior to the month 4 visit, subjects were asked to discontinue Refresh use.  At the month 4 visit, subjects were instructed to use Refresh less than eight times a day if possible for the study duration.
There are statistically significant improvements from baseline with 0.05% and 0.01% cyclosporine at months 4 and 6.
A statistically significant among-group difference is approached but not reached at month 6, favoring 0.05% cyclosporine over vehicle (p = 0.087).

## Protocol 192731-003 - Subjective Symptoms

**Notes:**
Among-group differences are statistically significant at month 3 (p = 0.031).  Pairwise comparisons show statistically significant greater responses for the 0.1% cyclosporine group than for the 0.05% cyclosporine and vehicle group;

There was disparity in the Investigator’s Evaluation of Global Response to Treatment.  Some investigators rated global response based on their clinical evaluations of the patients while other investigators queried their patients directly about their response to treatment.

Because of the disparity in how investigators recorded and rated this response, these results and the Treatment Success results generated from them are not easily interpreted.

Other Subjective Symptoms
There were no statistically significant differences among the treatment groups at baseline for any of the symptoms except burning/stinging, where the mean for the 0.05% cyclosporine group was significantly higher than for vehicle (respectively, 2,32 and 2.01; p = 0.050).

There are no statistically significant among-group differences found for the symptoms of 1) sensitivity to light, 2) dryness, 3) sandy or gritty feeling, 4) stinging/burning, 5) pain, 
6) itching, or 7) composite symptom score.

Statistically significant improvement from baseline (p  0.05) is seen for all treatment groups at most follow-up visits for 1) sensitivity to light, 2) dryness, 3) sandy or gritty feeling, and 4) itching.

There are no statistically significant among-group differences in the Ocular Surface Disease Index or Facial Expression Subjective Scale at any time point.

## Protocol 192731-003Safety

- Adverse Events Monitoring
- Most Common Ocular Adverse Events
- burning
- conjunctival hyperemia
- photophobia
- stinging
- No increase in ocular or systemic infections

## Protocol 192731-003 - Safety

**Notes:**
Changes from baseline visual acuity were similar across the three treatment groups.

IOP
IOP (average of both eyes) was similar across the 3 treatment groups at baseline.  There was no statistically significant difference in the mean IOP at month 6 among the treatment groups, and no statistically significant changes from baseline within any of the 3 treatment groups.

Changes in biomicroscopic findings (evaluations of lid and lid margin erythema and swelling, conjunctiva erythema/hyperemia and chemosis, tear film debris, cornea endothelial condition, anterior chamber cells and flare) from baseline were similar across the 3 treatment groups.  The majority of the patients in each treatment group showed no change in any parameter at any follow-up visit, with the exception of tear film debris where almost one-half the patients had improved from baseline to month 6.

## Protocol 192731-003Summary

- Statistically Significant Objective Signs
- Categorized Schirmer w/ Anesthesia

**Notes:**
There are statistically significant among-group differences favoring cyclosporine over vehicle in at least one objective sign and at least one subjective symptom.  The subjective symptom that demonstrates statistical significance (Global Response to Treatment) appears to have been evaluated differently by different investigators.  Some investigators rated global response based on their clinical evaluations of the patients while other investigators queried their patients directly about their response to treatment. The protocol does not clearly state which of these evaluations was originally intended.

## Protocol 192731-003Summary

- Statistically Significant Subjective Symptoms
- Global Response to Treatment

## Protocol 192731-003Summary

- Global Response to Treatment
- Some investigators rated Global Response based on their clinical evaluations of their subjects while other investigators queried subjects directly about their response to treatment.

## Protocol 192731-003 - Variables Approaching Significance*favoring cyclosporine 0.05% over vehicle

## Protocol 192731-001

## Clinical Studies Protocol 192731-001

- Design - randomized, multicenter, parallel-group, double masked, Phase 2 trial
- Treatment arms - cyclosporine 0.05%, 0.1%, 0.2%, and 0.4% and vehicle of cyclosporine 0.2%

**Notes:**
A Dose-Ranging Study Evaluating the Safety, Tolerability, and Efficacy of Cyclosporine (0.05%, 0.1%, 0.2%, 0.4%) and Vehicle Ophthalmic Emulsions in the Treatment of Moderate to Severe Keratoconjunctivitis Sicca (KCS)

There was a washout phase of –16 to –12 days from baseline day 0 (screening visit) prior to beginning the treatment phase, and a 4-week post-treatment phase.

## Protocol 192731-001

- Test drug schedule - all subjects received either cyclosporine 0.05%, 0.1%, 0.2%, 0.4% or vehicle bilaterally, BID for 12 weeks
- Total subjects - 162

## Protocol 192731-001

- Primary Efficacy Measures:
- Schirmer Tear Test w/o Anesthesia
- Corneal Staining (SPK)
- symptoms of dry eye (from diaries and CRF queries)

**Notes:**
Schirmer readings obtained, and strip marked at tear front and taped to Case Report Form.

SPK evaluated in 5 corneal areas and graded on a scale of 0 to 3 (0=none, 3=severe).  Total score each eye of 15.

	Patient symptoms evaluated by CRF query and self-		administered diaries.  Graded on a scale of 0 to 4 (0=no 		discomfort, 4=interferes with ADLs).

## Protocol 192731-001

- Secondary Efficacy Measures:
- tear film debris
- rose bengal staining
- tear break-up time
- brush cytology
- tear meniscus
- meibomian gland health

**Notes:**
Tear film debris evaluated at SLE and graded on a scale of 0 to 4 (0=none, 4=severe).

Rose Bengal Staining evaluated at SLE with six conjunctival exposure zones and graded 0 to 3 (0=none, 3=severe).  Average of zones 1,2,3 analyzed together as “nasal”; average of zones 4,5,6 analyzed together as “temporal.”

Tear Breakup Time evaluated with SLE.  Three consecutive TBUTs recorded if time less than 10 seconds.

Brush cytology evaluated at centralized lab with harvested cells mounted on glass slides and Papanicolau stained.  Number of inflammatory cells expressed as % of total cells.	

Tear Meniscus at SLE with 0=absent, +1=present.

Meibomian Gland Health assessed at SLE with categorization as normal or plugged.

## Protocol 192731-001

- Secondary Efficacy Measures cont’d:
- tear proteins
- Facial Expression Subjective Rating Scale
- Ocular Surface Disease Index Score (OSDI)
- Refresh use
- Investigator’s Global Evaluation of Response to Treatment

**Notes:**
Tear Proteins collected from a randomized eye and analyzed at a central laboratory.

Facial Expression Subjective Rating Scale recorded in subject diary with 1=happiest face and 9=unhappiest face.

Ocular Surface Disease Index assessed via questionnaire.

Artificial tear use evaluated by unused inventory of samples and subject diary.

Global evaluation scored 0 to 6 with 0=condition worsened, 6=condition cleared

## Protocol 192731-001

- Safety Criteria:
- vital signs
- ETDRS visual acuity
- intraocular pressure
- biomicroscopy
- conjunctival microbiology
- CBC, blood chemistry, whole blood cyclosporine concentration

**Notes:**
Micro at 4 selected centers.

## Protocol 192731-001 - Primary Efficacy Measures

**Notes:**
Weeks 14 and 16 constitute the 4-week post-treatment phase.

A negative change from baseline indicates improvement.
There are statistically significant improvements from baseline in each treatment group at each visit.
There are no statistically significant among-group differences.

## Protocol 192731-001 - Primary Efficacy Measures

**Notes:**
A positive change from baseline indicates improvement.
There are statistically significant improvements from baseline at weeks 4 and 8 for the 0.1% cyclosporine treatment group.
There are no statistically significant among-group differences.

Nasal Rose Bengal Staining
A negative change from baseline indicates improvement.
There are statistically significant improvements from baseline in the 0.05%, and 0.2% cyclosporine groups at weeks 4, 8, and 12.
There are no statistically significant among-group differences.

Temporal Rose Bengal Staining
A negative change from baseline indicates improvement.
There are statistically significant improvements from baseline in the 0.05% and 0.1 % cyclosporine groups at weeks 8 and 12.
There are no statistically significant among-group differences.

## Protocol 192731-001 - Primary Efficacy Measures

**Notes:**
A negative change from baseline indicates improvement.
There are statistically significant improvements from baseline in the vehicle, 0.05%, 0.1%, and 0.2% cyclosporine groups at weeks 4,8, and 12.
There is a statistically significant among-group difference at week 12, favoring 0. 2% cyclosporine over 0.05% cyclosporine (p = 0.046) and at week 16, favoring vehicle over 0.05% and 0.4% cyclosporine (p = 0.049).

Other Symptoms of Ocular Discomfort
There are no other statistically significant among-group differences in the scheduled queries or diaries for dryness, burning/stinging, sandiness/grittiness, pain, itching, photophobia, blurred vision, tearing, or discharge.

Secondary Efficacy Measures
TBUT is similar across groups at baseline, and shows very slight improvement in most treatment groups (including vehicle) at Week 16.  Statistical significance was not reported for this variable.
There are no statistically significant among-group differences found in 1) tear film debris, 2) rose bengal staining, 3) brush cytology, 4) tear meniscus, 5) meibomian gland plugging or 6) the Ocular Surface Disease Index.

The Treatment Success efficacy variable cannot be evaluated easily because only five out of nine investigators performed this evaluation correctly 

Tear protein data is not reliably interpretable because of problems with shipping delays and variations in collection techniques.

## Protocol 1921731-001Safety

- No clinically significant changes in visual acuity, IOP, biomicroscopy
- Comparable changes in microbial flora across all treatment groups (including vehicle)
- No adverse events related to blood chemistry or hematology

## Protocol 192731-001Summary

- Statistically Significant Primary Efficacy Variables
- Foreign Body Sensation (Scheduled Visit Query)

**Notes:**
This dose ranging study in a limited number of subjects demonstrates that the efficacy of cyclosporine is not dose related.  No additional benefit in efficacy is evident with 0.2% and 0.4% cyclosporine concentrations.  There are statistically significant improvements from baseline in the treatment groups (intent-to-treat population) favoring cyclosporine over vehicle in the selected efficacy measures.

Adverse experiences appear mostly limited to mild or moderate ocular events.  There are no clinically significant differences in the safety variables recorded.

## Overview of Efficacy

## Overview of EfficacyProtocol 192731-002

- Objective Signs Reaching Statistical Significance
- Corneal Staining

- Subjective Symptoms Reaching Statistical Significance
- Blurred Vision, Sensitivity to Light, and Itching
- Refresh Use
- Composite Symptom Score
- Facial Expression Subjective Scale
- OSDI
- Global Response to Treatment

## Overview of EfficacyProtocol 192731-003

- Objective Signs Reaching Statistical Significance
- Categorized Schirmer w/ Anesthesia

- Subjective Symptoms Reaching Statistical Significance
- Global Response to Treatment

## Overview of EfficacyProtocol 192731-001

- Primary Efficacy Variables Reaching Statistical Significance
- Foreign Body Sensation (Scheduled Visit Query)

## Overview of EfficacyCyclosporine Ophthalmic Emulsion, 0.05%

- Both Phase 3 Studies technically satisfy the criteria for efficacy as set forth in their study reports (statistically significant differences in one objective sign and one subjective symptom)

## Overview of EfficacyCyclosporine Ophthalmic Emulsion, 0.05%

- However, it is apparent the two Phase 3 Studies are not replicative.

## Overview of Safety

## Overview of SafetyCyclosporine Ophthalmic Emulsion, 0.05%

- There are no increases in ocular or systemic infections in the cyclosporine treatment groups.
- Adverse experiences are predominantly mild-to-moderate ocular events in all 3 studies.

## Cyclosporine Ophthalmic Emulsion, 0.05%

- July 21, 1999
- William M. Boyd, M.D.
- Medical Officer