Safety and Efficacy of Difluprednate 0.05% for the Treatment of Anterior Uveitis

• ClinicalTrials.gov Identifier: NCT01201798
• Recruitment Status: Completed
• First Posted: September 15, 2010
• Results First Posted: November 15, 2012
• Last Update Posted: November 15, 2012
• Sponsor: Alcon Research
• Information provided by (Responsible Party): Alcon Research

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Endogenous Anterior Uveitis
• Interventions: Drug: Difluprednate 0.05% ophthalmic emulsion; Drug: Prednisolone acetate 1.0% ophthalmic suspension
• Enrollment: 111

Participant Flow

Recruitment Details	Subjects were recruited from 21 US study sites.
Pre-assignment Details	This reporting group includes all randomized subjects: 110. One subject was enrolled but discontinued prior to receiving study medication, with treatment randomization unknown.

Arm/Group Title	Durezol	Pred Forte
Arm/Group Description	Difluprednate 0.05% ophthalmic emulsion, 1 drop in study eye, 4 times a day for 14 days, followed by a 14-day tapering period	Prednisolone acetate 1.0% ophthalmic suspension, 1 drop in study eye, 8 times a day for 14 days, followed by a 14-day tapering period
Period Title: Overall Study
Started	56	54
Completed	47	39
Not Completed	9	15
Reason Not Completed
Adverse Event	2	0
Lost to Follow-up	3	5
Decision Unrelated to an Adverse Event	1	1
Noncompliance	1	0
Protocol Violation	1	1
Treatment Failure	1	8

Baseline Characteristics

Arm/Group Title		Durezol	Pred Forte	Total
Arm/Group Description		Difluprednate 0.05% ophthalmic emulsion, 1 drop in study eye, 4 times a day for 14 days, followed by a 14-day tapering period	Prednisolone acetate 1.0% ophthalmic suspension, 1 drop in study eye, 8 times a day for 14 days, followed by a 14-day tapering period	Total of all reporting groups
Overall Number of Baseline Participants		56	54	110
Baseline Analysis Population Description		[Not Specified]
Age Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	56 participants	54 participants	110 participants
		49.8 (15.20)	45.5 (18.29)	47.7 (16.85)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	56 participants	54 participants	110 participants
	Female	31 55.4%	29 53.7%	60 54.5%
	Male	25 44.6%	25 46.3%	50 45.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline (Day 0) in Anterior Chamber Cell Grade at Day 14
Description	Inflammatory cells in the anterior chamber were assessed by the investigator during slit lamp examination and graded on a 5-point scale, with 0 = ≤ 1 cell count; 1 = 2 to 10 cell count; 2 = 11 to 20 cell count; 3 = 21 to 50 cell count; and 4 = > 50 cell count.
Time Frame	Baseline (Day 0), Day 14

Outcome Measure Data

Analysis Population Description

Per Protocol: All randomized patients who received at least one dose of the allocated study medication and had no major protocol deviations, including violation of entry criteria, poor compliance, and use of prohibited medications. Last observation carried forward (LOCF) was performed for missing data.

Arm/Group Title	Durezol	Pred Forte
Arm/Group Description:	Difluprednate 0.05% ophthalmic emulsion, 1 drop in study eye, 4 times a day for 14 days, followed by a 14-day tapering period	Prednisolone acetate 1.0% ophthalmic suspension, 1 drop in study eye, 8 times a day for 14 days, followed by a 14-day tapering period
Overall Number of Participants Analyzed	46	47
Mean (Standard Deviation); Unit of Measure: Units on a scale
Baseline (Day 0)	2.6 (0.68)	2.6 (0.68)
Day 14	-2.2 (0.96)	-2.0 (1.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Durezol, Pred Forte
	Comments	A two-tailed 95% confidence interval was calculated for the difference in change from baseline in anterior chamber cell grade at Day 14 (difluprednate minus prednisolone). The confidence interval was derived from an analysis of covariance (ANCOVA), with investigative site included as a fixed effect to match the stratification used in the randomization process. Treatment and baseline anterior chamber cell grade were also included as fixed effects.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The noninferiority margin was 0.5 units, meaning that the upper limit of the two-tailed 95% confidence interval must have been less than 0.5 to establish noninferiority.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.53 to 0.09
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Change From Baseline (Day 0) in Anterior Chamber Cell Grade at All Time Points Other Than Day 14
Description	Inflammatory cells in the anterior chamber were assessed by the investigator during slit lamp examination and graded on a 5-point scale, with 0 = ≤ 1 cell count; 1 = 2 to 10 cell count; 2 = 11 to 20 cell count; 3 = 21 to 50 cell count; and 4 = > 50 cell count.
Time Frame	Baseline (Day 0), Day 3, Day 7, Day 21, Day 28, Day 35, Day 42

Outcome Measure Data

Analysis Population Description

Per Protocol: All randomized patients who received at least one dose of the allocated study medication and had no major protocol deviations, including violation of entry criteria, poor compliance, and use of prohibited medications. Last observation carried forward (LOCF) was performed for missing data.

Arm/Group Title	Durezol	Pred Forte
Arm/Group Description:	Difluprednate 0.05% ophthalmic emulsion, 1 drop in study eye, 4 times a day for 14 days, followed by a 14-day tapering period	Prednisolone acetate 1.0% ophthalmic suspension, 1 drop in study eye, 8 times a day for 14 days, followed by a 14-day tapering period
Overall Number of Participants Analyzed	46	47
Mean (Standard Deviation); Unit of Measure: Units on a scale
Baseline (Day 0)	2.6 (0.68)	2.6 (0.68)
Day 3	-1.1 (0.95)	-1.0 (0.86)
Day 7	-1.8 (0.77)	-1.6 (0.85)
Day 21	-2.4 (0.98)	-2.1 (0.80)
Day 28	-2.3 (0.95)	-2.1 (0.95)
Day 35	-2.3 (0.94)	-2.1 (1.04)
Day 42	-2.3 (1.00)	-2.1 (1.01)

3. Secondary Outcome

Title	Change From Baseline (Day 0) in Anterior Chamber Flare Grade at All Time Points
Description	Anterior chamber flare (protein escaping from dialated vessels) was assessed by the investigator during slit lamp examination and graded on a 5-point scale, with 0 = none; 1 = mild (trace to clearly noticeable, visible); 2 = moderate; 3 = marked; and 4 = severe.
Time Frame	Baseline (Day 0), Day 3, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42

Outcome Measure Data

Analysis Population Description

Per Protocol: All randomized patients who received at least one dose of the allocated study medication and had no major protocol deviations, including violation of entry criteria, poor compliance, and use of prohibited medications. Last observation carried forward (LOCF) was performed for missing data.

Arm/Group Title	Durezol	Pred Forte
Arm/Group Description:	Difluprednate 0.05% ophthalmic emulsion, 1 drop in study eye, 4 times a day for 14 days, followed by a 14-day tapering period	Prednisolone acetate 1.0% ophthalmic suspension, 1 drop in study eye, 8 times a day for 14 days, followed by a 14-day tapering period
Overall Number of Participants Analyzed	46	47
Mean (Standard Deviation); Unit of Measure: Units on a scale
Baseline (Day 0)	2.2 (0.48)	2.3 (0.54)
Day 3	-1.1 (0.83)	-1.2 (1.07)
Day 7	-1.6 (0.77)	-1.6 (0.95)
Day 14	-2.0 (0.75)	-1.9 (0.91)
Day 21	-2.0 (0.77)	-2.0 (0.78)
Day 28	-2.0 (0.76)	-2.0 (0.79)
Day 35	-2.0 (0.77)	-2.0 (0.83)
Day 42	-2.0 (0.77)	-2.0 (0.82)

4. Secondary Outcome

Title	Proportion of Subjects With Anterior Chamber Cell Grade of 0
Description	Inflammatory cells in the anterior chamber were assessed by the investigator during slit lamp examination and graded on a 5-point scale, with 0 = ≤ 1 cell count; 1 = 2 to 10 cell count; 2 = 11 to 20 cell count; 3 = 21 to 50 cell count; and 4 = > 50 cell count. Proportion is reported as percentage of subjects.
Time Frame	Day 3, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42

Outcome Measure Data

Analysis Population Description

Per Protocol: All randomized patients who received at least one dose of the allocated study medication and had no major protocol deviations, including violation of entry criteria, poor compliance, and use of prohibited medications. Last observation carried forward (LOCF) was performed for missing data.

Arm/Group Title	Durezol	Pred Forte
Arm/Group Description:	Difluprednate 0.05% ophthalmic emulsion, 1 drop in study eye, 4 times a day for 14 days, followed by a 14-day tapering period	Prednisolone acetate 1.0% ophthalmic suspension, 1 drop in study eye, 8 times a day for 14 days, followed by a 14-day tapering period
Overall Number of Participants Analyzed	46	47
Measure Type: Number; Unit of Measure: Percentage of subjects
Day 3	15.2	6.4
Day 7	34.8	25.5
Day 14	65.2	55.3
Day 21	84.8	63.8
Day 28	80.4	70.2
Day 35	78.3	70.2
Day 42	76.1	74.5

5. Secondary Outcome

Title	Proportion of Subjects With Anterior Chamber Cell Count of 0
Description	Inflammatory cells in the anterior chamber were assessed by the investigator during slit lamp examination and recorded based on actual cell count. Proportion is reported as a percentage of subjects.
Time Frame	Day 3, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42

Outcome Measure Data

Analysis Population Description

Per Protocol: All randomized patients who received at least one dose of the allocated study medication and had no major protocol deviations, including violation of entry criteria, poor compliance, and use of prohibited medications. Last observation carried forward (LOCF) was performed for missing data.

Arm/Group Title	Durezol	Pred Forte
Arm/Group Description:	Difluprednate 0.05% ophthalmic emulsion, 1 drop in study eye, 4 times a day for 14 days, followed by a 14-day tapering period	Prednisolone acetate 1.0% ophthalmic suspension, 1 drop in study eye, 8 times a day for 14 days, followed by a 14-day tapering period
Overall Number of Participants Analyzed	46	47
Measure Type: Number; Unit of Measure: Percentage of subjects
Day 3	13.0	2.1
Day 7	21.7	21.3
Day 14	52.2	38.3
Day 21	73.9	48.9
Day 28	73.9	63.8
Day 35	69.6	63.8
Day 42	69.6	68.1

6. Secondary Outcome

Title	Proportion of Subjects With Anterior Chamber Cell Count ≤5 and Flare Grade of 0
Description	Inflammatory cells in the anterior chamber were assessed by the investigator during slit lamp examination and recorded based on actual cell count. Anterior chamber flare (protein escaping from dialated vessels) was assessed by the investigator during slit lamp examination and graded on a 5-point scale, with 0 = none; 1 = mild (trace to clearly noticeable, visible); 2 = moderate; 3 = marked; and 4 = severe. Proportion is reported as percentage of subjects.
Time Frame	Day 3, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42

Outcome Measure Data

Analysis Population Description

Per Protocol: All randomized patients who received at least one dose of the allocated study medication and had no major protocol deviations, including violation of entry criteria, poor compliance, and use of prohibited medications. Last observation carried forward (LOCF) was performed for missing data.

Arm/Group Title	Durezol	Pred Forte
Arm/Group Description:	Difluprednate 0.05% ophthalmic emulsion, 1 drop in study eye, 4 times a day for 14 days, followed by a 14-day tapering period	Prednisolone acetate 1.0% ophthalmic suspension, 1 drop in study eye, 8 times a day for 14 days, followed by a 14-day tapering period
Overall Number of Participants Analyzed	46	47
Measure Type: Number; Unit of Measure: Percentage of subjects
Day 3	13.0	14.9
Day 7	41.3	40.4
Day 14	78.3	61.7
Day 21	82.6	76.6
Day 28	80.4	76.6
Day 35	82.6	76.6
Day 42	80.4	78.7

7. Secondary Outcome

Title	Proportion of Subjects With Anterior Chamber Cell Grade ≤1
Description	As assessed by the investigator during slit lamp examination. Anterior chamber cell grade was graded on a 5-point scale, with 0 = no cells; 1 = 1 to 10 cells; 2 = 11 to 20 cells; 3 = 21 to 50 cells; and 4 = more than 50 cells. Proportion is reported as percentage of subjects.
Time Frame	Day 3, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42

Outcome Measure Data

Analysis Population Description

Per Protocol: All randomized patients who received at least one dose of the allocated study medication and had no major protocol deviations, including violation of entry criteria, poor compliance, and use of prohibited medications. Last observation carried forward (LOCF) was performed for missing data.

Arm/Group Title	Durezol	Pred Forte
Arm/Group Description:	Difluprednate 0.05% ophthalmic emulsion, 1 drop in study eye, 4 times a day for 14 days, followed by a 14-day tapering period	Prednisolone acetate 1.0% ophthalmic suspension, 1 drop in study eye, 8 times a day for 14 days, followed by a 14-day tapering period
Overall Number of Participants Analyzed	46	47
Measure Type: Number; Unit of Measure: Percentage of subjects
Day 3	50.0	57.4
Day 7	87.0	80.9
Day 14	93.5	85.1
Day 21	93.5	89.4
Day 28	93.5	87.2
Day 35	93.5	85.1
Day 42	91.3	85.1

8. Secondary Outcome

Title	Proportion of Subjects Who Discontinued Due to Lack of Efficacy
Description	Lack of efficacy was defined as those subjects who discontinued study participation either due to treatment failure or an adverse event with a preferred term of iridocyclitis, iritis, uveitis, or vitritis. Proportion is reported as percentage of subjects.
Time Frame	Time to Event

Outcome Measure Data

Analysis Population Description

Per Protocol: All randomized patients who received at least one dose of the allocated study medication and had no major protocol deviations, including violation of entry criteria, poor compliance, and use of prohibited medications.

Arm/Group Title	Durezol	Pred Forte
Arm/Group Description:	Difluprednate 0.05% ophthalmic emulsion, 1 drop in study eye, 4 times a day for 14 days, followed by a 14-day tapering period	Prednisolone acetate 1.0% ophthalmic suspension, 1 drop in study eye, 8 times a day for 14 days, followed by a 14-day tapering period
Overall Number of Participants Analyzed	46	47
Measure Type: Number; Unit of Measure: Percentage of subjects
	0	14.9

9. Secondary Outcome

Title	Change From Baseline (Day 0) in Visual Analog Scale (VAS) Total Symptom Score at All Time Points
Description	The following symptoms were each graded by the subject according to a 0-100 visual analog scale (VAS) using a mark on a 100 mm line (0 = absent, 100 = maximal): eye pain, photophobia, blurred vision, and lacrimation. The total symptom score was calculated as the sum of the 4 individual symptom scores.
Time Frame	Baseline (Day 0), Day 3, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42

Outcome Measure Data

Analysis Population Description

Per Protocol: All randomized patients who received at least one dose of the allocated study medication and had no major protocol deviations, including violation of entry criteria, poor compliance, and use of prohibited medications. Last observation carried forward (LOCF) was performed for missing data.

Arm/Group Title	Durezol	Pred Forte
Arm/Group Description:	Difluprednate 0.05% ophthalmic emulsion, 1 drop in study eye, 4 times a day for 14 days, followed by a 14-day tapering period	Prednisolone acetate 1.0% ophthalmic suspension, 1 drop in study eye, 8 times a day for 14 days, followed by a 14-day tapering period
Overall Number of Participants Analyzed	46	47
Mean (Standard Deviation); Unit of Measure: Units on a scale
Baseline (Day 0)	186.7 (112.6)	203.2 (110.8)
Day 3	-88.4 (92.55)	-88.4 (92.71)
Day 7	-108.2 (114.2)	-123.8 (100.4)
Day 14	-133.3 (109.3)	-137.4 (108.8)
Day 21	-138.8 (112.7)	-149.5 (108.0)
Day 28	-140.1 (111.4)	-152.4 (115.9)
Day 35	-143.9 (111.0)	-147.3 (111.3)
Day 42	-146.2 (111.7)	-155.5 (112.1)

10. Secondary Outcome

Title	Change From Baseline (Day 0) in Slit-Lamp Total Sign Score at All Visits
Description	The following signs were each graded on a 0 - 3 scale (0 = absent; 1 = mild; 2 = moderate; 3 = severe): posterior synechia, hypopyon, limbal injection, and keratic precipitates. Peripheral synechia was graded by the combined number of clock hours affected (0 = absent; 1 = < 3 hrs; 2 = 3-6 hours; 3 = > 6 hours). The total sign score was calculated as the sum of the 5 individual sign scores, the anterior chamber cell grade and the anterior chamber flare grade. The minimum/best total sign score was 0, and the maximum/worst total sign score was 23.
Time Frame	Baseline (Day 0), Day 3, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42

Outcome Measure Data

Analysis Population Description

Per Protocol: All randomized patients who received at least one dose of the allocated study medication and had no major protocol deviations, including violation of entry criteria, poor compliance, and use of prohibited medications. Last observation carried forward (LOCF) was performed for missing data.

Arm/Group Title	Durezol	Pred Forte
Arm/Group Description:	Difluprednate 0.05% ophthalmic emulsion, 1 drop in study eye, 4 times a day for 14 days, followed by a 14-day tapering period	Prednisolone acetate 1.0% ophthalmic suspension, 1 drop in study eye, 8 times a day for 14 days, followed by a 14-day tapering period
Overall Number of Participants Analyzed	46	47
Mean (Standard Deviation); Unit of Measure: Units on a scale
Baseline (Day 0)	7.1 (2.71)	7.3 (2.87)
Day 3	-3.5 (2.71)	-3.6 (2.95)
Day 7	-5.2 (2.31)	-5.0 (3.05)
Day 14	-6.1 (2.81)	-5.8 (3.34)
Day 21	-6.5 (3.07)	-6.2 (3.04)
Day 28	-6.4 (2.96)	-6.2 (3.18)
Day 35	-6.3 (2.98)	-6.2 (3.34)
Day 42	-6.2 (3.21)	-6.3 (3.27)

Adverse Events

Time Frame	Adverse events were collected for the duration of the study: 9 months, 3 weeks. The safety population consisted of all randomized subjects who received at least 1 dose of the allocated study medication.
Adverse Event Reporting Description	Adverse events were obtained as solicited comments from study subjects and observations by study investigator as outlined in study protocol. An adverse event was defined as any untoward medical occurrence in a subject administered a study treatment regardless of causal relationship.
Arm/Group Title	Durezol	Pred Forte
Arm/Group Description	Difluprednate 0.05% ophthalmic emulsion, 1 drop in study eye, 4 times a day for 14 days, followed by a 14-day tapering period	Prednisolone acetate 1.0% ophthalmic suspension, 1 drop in study eye, 8 times a day for 14 days, followed by a 14-day tapering period
All-Cause Mortality
	Durezol	Pred Forte
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Durezol	Pred Forte
	Affected / at Risk (%)	Affected / at Risk (%)
Total	2/56 (3.57%)	0/54 (0.00%)
Eye disorders
Necrotising retinitis † 1 [1]	1/56 (1.79%)	0/54 (0.00%)
Vascular disorders
Hypertension † 1 [2]	1/56 (1.79%)	0/54 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 13.0; [1] Non-related; [2] Not related
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Durezol	Pred Forte
	Affected / at Risk (%)	Affected / at Risk (%)
Total	14/56 (25.00%)	8/54 (14.81%)
Eye disorders
Iridocyclitis † 1	3/56 (5.36%)	2/54 (3.70%)
Punctate keratitis † 1	3/56 (5.36%)	0/54 (0.00%)
Investigations
Intraocular Pressure Increased † 1	5/56 (8.93%)	2/54 (3.70%)
Nervous system disorders
Headache † 1	3/56 (5.36%)	4/54 (7.41%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 13.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Alcon reserves the right of prior review of any publication or presentation of information related to the study.

Results Point of Contact

• Name/Title: Head, Alcon Clinical
• Organization: Alcon Research, Ltd.
• Phone: 1-888-451-3937
• EMail: medinfo@alconlabs.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Sheppard JD, Toyos MM, Kempen JH, Kaur P, Foster CS. Difluprednate 0.05% versus prednisolone acetate 1% for endogenous anterior uveitis: a phase III, multicenter, randomized study. Invest Ophthalmol Vis Sci. 2014 May 6;55(5):2993-3002. doi: 10.1167/iovs.13-12660.

• Responsible Party: Alcon Research
• ClinicalTrials.gov Identifier: NCT01201798
• Other Study ID Numbers: C-10-034
• First Submitted: September 13, 2010
• First Posted: September 15, 2010
• Results First Submitted: August 31, 2012
• Results First Posted: November 15, 2012
• Last Update Posted: November 15, 2012