GEMINI 1: Efficacy Study of Pilocarpine HCl Ophthalmic Solution (AGN-190584) in Participants With Presbyopia

• Sponsor: Allergan (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03804268
• Collaborator: (none)
• Enrollment: 323
• Locations: 36
• Arms: 2
• Actual Duration (Months): 10.3
• Patients Per Site: 9
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

A study to evaluate the efficacy, safety, and pharmacokinetics of pilocarpine hydrochloride (HCl) ophthalmic solution (AGN-190584) when administered bilaterally, once daily for 30 days in participants with presbyopia.

Condition or Disease	Intervention/Treatment	Phase
Presbyopia	Other: Vehicle; Drug: Pilocarpine HCl Ophthalmic Solution	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 323 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Double-Masked, Randomized, Vehicle-Controlled, Parallel-Group Study Evaluating the Safety and Efficacy of AGN-190584 in Participants With Presbyopia
• Actual Study Start Date: Dec 21, 2018
• Actual Primary Completion Date: Oct 31, 2019
• Actual Study Completion Date: Oct 31, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Vehicle Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Other: Vehicle; Vehicle, one drop in each eye, once daily, for up to 30 days.
Experimental: Pilocarpine HCl Ophthalmic Solution Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.	Drug: Pilocarpine HCl Ophthalmic Solution; Pilocarpine HCl ophthalmic solution 1.25%, one drop in each eye, once daily, for up to 30 days.; Other Names: AGN-190584 VUITY

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Gaining 3 Lines or More in Mesopic, High-contrast, Binocular Distance-Corrected Near Visual Acuity (DCNVA) at Day 30, Hour 3 [Baseline (Day 1) to Day 30 (Hour 3)]

   Visual acuity for near (40 centimeters (cm)) target was measured in mesopic conditions using an eye chart. Mesopic condition was defined as low lighting 3.2 to 3.5 candelas per square meter (cd/m^2) measured at the target. Percentage of participants with 3 lines or more improvement from Baseline in mesopic, high-contrast DCNVA are reported.

Secondary Outcome Measures

1. Percentage of Participants Gaining 3 Lines or More in Mesopic, High-contrast, Binocular Distance-Corrected Near Visual Acuity (DCNVA) at Day 30, Hour 6 [Baseline (Day 1) to Day 30 (Hour 6)]

   Visual acuity for near (40 cm) target was measured in mesopic conditions using an eye chart. Mesopic condition was defined as low lighting 3.2 to 3.5 candelas per square meter measured at the target. Percentage of participants with 3 lines or more improvement from Baseline in mesopic, high-contrast DCNVA are reported.

2. Percentage of Participants Gaining 3-lines or More in Mesopic, High-contrast, Binocular, DCNVA at Day 30, Hour 8 [Baseline (Day 1) to Day 30 (Hour 8)]

   Visual acuity for near (40 cm) target was measured in mesopic conditions using an eye chart. Mesopic condition was defined as low lighting 3.2 to 3.5 candelas per square meter measured at the target. Percentage of participants with 3 lines or more improvement from Baseline in mesopic, high-contrast DCNVA are reported.

3. Change From Baseline in Mesopic, High-contrast, Binocular DCNVA Letters at Day 30, Hour 0.5 [Baseline (Day 1) to Day 30 (Hour 0.5)]

   Visual acuity for near (40 cm) target was measured in mesopic conditions using an eye chart. Mesopic condition was defined as low lighting 3.2 to 3.5 cd/m^2 measured at the target. A positive change from Baseline indicates improvement in visual acuity. Mixed effect model for repeated measures (MMRM) was used for analyses.

4. Percentage of Participants Achieving 20/40 or Better in Photopic, High-contrast, Binocular, DCNVA at Day 30, Hour 1 [Day 30 (Hour 1)]

   Visual acuity for near (40 cm) target was measured in photopic conditions using an eye chart. Photopic condition was defined as high lighting ≥80 cd/m^2 measured at the target. Percentage of participants achieving 20/40 or better in photopic, high-contrast, binocular, DCNVA are reported.

5. Mean Change From Baseline in Mesopic Near Vision Presbyopia Task-based Questionnaire (NVPTQ) Performance Score at Day 30, Hour 3 [Baseline (Day 1) to Day 30 (Hour 3)]

   NVPTQ had 12 questions on 4 reading tasks(reading a paragraph from book, excerpts from an article in newspaper, portion of a nutrition label, and a section from restaurant menu). Participants completed specific reading tasks under mesopic conditions without any near-vision correction and answered 3 questions for each task, rating their vision-related reading ability as 0=I could not read any text due to problems seeing up close,1=poor,2=fair,3=good,4=very good,5=excellent;impact of squinting on performance as 0=No,I did not squint, 1=Yes,squinting helped me read some/all text, 2=Yes,but I still could not read any of the text; and satisfaction as 0=very dissatisfied to 4=very satisfied. The score based on vision related ability and impact of squinting=(Book testlet+Newspaper testlet+Menu testlet+Nutrition Label testlet)/(testlets with non-missing responses), total possible score of 0-5. Higher scores=better outcomes;positive change from Baseline=improved performance(reading ability).

6. Change From Baseline in Photopic, High-contrast, Binocular Distance-corrected Intermediate Visual Acuity (DCIVA) Letters at Day 30, Hour 3 [Baseline (Day 1) to Day 30 (Hour 3)]

   Visual acuity for intermediate (66 cm) target was measured in photopic conditions using an eye chart. Photopic condition was defined as high lighting ≥80 cd/m^2 measured at the target. A positive change from Baseline indicates improvement in visual acuity. MMRM was used for analyses.

7. Percentage of Participants Gaining 3-lines or More in Mesopic, High-contrast, Binocular, DCNVA at Day 30, Hour 10 [Baseline (Day1) to Day 30 (Hour 10)]

   Visual acuity for near (40cm) target was measured in mesopic conditions using an eye chart. Mesopic condition was defined as low lighting 3.2 to 3.5 cd/m^2measured at the target. Percentage of participants with 3 lines or more improvement from Baseline in mesopic, high-contrast, binocular DCNVA are reported.

8. Change From Baseline in Mesopic, High-contrast, Binocular DCNVA Letters at Day 30, Hour 0.25 [Baseline (Day 1) to Day 30 (Hour 0.25)]

   Visual acuity for near (40 cm) target was measured in mesopic conditions. Mesopic condition was defined as low lighting 3.2 to 3.5 cd/m^2 measured at the target. A positive change from Baseline indicates improvement in visual acuity. MMRM was used for analyses.

9. Percentage of Participants Achieving 20/40 or Better in Photopic, High-contrast, Binocular, DCNVA at Day 30, Hour 3 [Day 30 (Hour 3)]

   Visual acuity for near (40 cm) target was measured in mesopic conditions using an eye chart. Photopic condition was defined as high lighting ≥80 cd/m^2 measured at the target. Percentage of participants achieving 20/40 or better in photopic, high-contrast, binocular, DCNVA are reported.

10. Mean Change From Baseline in Mesopic NVPTQ Satisfaction Score at Day 30, Hour 3 [Baseline (Day 1) to Day 30 (Hour 3)]

    NVPTQ had 12 questions on 4 reading tasks(reading a paragraph from book, excerpts from an article in newspaper, portion of a nutrition label, and a section from restaurant menu). Participants completed specific reading tasks under mesopic conditions without any near-vision correction and answered 3 questions for each task, rating their vision-related reading ability as 0=I could not read any text due to problems seeing up close to 5=excellent; impact of squinting on performance as 0=No, I did not squint, 1=Yes, squinting helped me read some/all text, 2=Yes, but I still could not read any of the text; and satisfaction as 0=very dissatisfied,1=dissatisfied,2=neither satisfied nor dissatisfied,3=satisfied, 4=very satisfied. The score based on satisfaction items=(Book testlet+Newspaper testlet+Menu testlet+Nutrition Label testlet)/(testlets with non-missing responses) for a total possible score of 0 to 4. Higher scores=better outcomes; a positive change from Baseline=higher satisfaction.

11. Mean Change From Baseline in Presbyopia Impact and Coping Questionnaire (PICQ) Coping Score at Day 30, Hour 3 [Baseline (Day 1) to Day 30 (Hour 3)]

    PICQ=20 questions about impact experienced by participants due to their problems over past 7 days.PICQ Coping domain had 8 items: 1:Normal-sized text,2:Small-sized text,3:Information on a computer,4:Information on a cell phone,5:Increase font size,6:Use glasses to read close,12:Hold reading materials farther out/closer,13:Squint to read. Each item had response categories:0=never to 4=all the time. Items 3, 4, 5, and 6 had additional response categories with values of 9/10 to indicate the question is not applicable to participant and were assigned missing values.PICQ Coping Score:(Item 1,2 Testlet+Item 3,4 Testlet+Item 5+Item 6+Item 12+Item 13)/non-missing responses to the 6 components of coping score where Items 1,2 Testlet=(Item1+Item2)/non-missing responses to Items 1,2;Items 3,4 Testlet=(Item3+Item4)/non-missing responses to Items 3, 4. Score ranges:0=to least amount of coping to 4=greatest amount of coping. Higher scores=poorer outcome; a negative change from Baseline=improvement.

12. Mean Change From Baseline in PICQ Impact Score at Day 30, Hour 3 [Baseline (Day 1) to Day 30 (Hour 3)]

    PICQ had 20 questions about impact experienced by participants due to their problems seeing up over past 7 days. PICQ Impact domain had 6 items: Item 9:Rely on others,15:rest eyes,16:Feel older,17:Feel self-conscious,19:Take longer to complete a task,20:Inconvenient. First 5 impacts items included response categories: 0=never to 4=all the time. Item 20 had response categories: 0=not at all to 4=extremely. Item 9 included an additional response category with a value of 9 to indicate question was not applicable to participant and the responses were assigned missing values. PICQ Impacts Score=[(Item9+Item15+Items16,17Testlet+Item19+Item20)/(nonmissing responses to 5 components of impacts score)] where Items 16,17 Testlet=(Item16+Item17)/non-missing responses to Items 16 and 17. PICQ Impact score ranges from 0 to 4; with 0=least amount of impacts to 4=greatest amount of impacts. Higher scores correspond to poorer outcomes. A negative change from Baseline=improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjective complaints of poor near vision that impact activities of daily living

Exclusion Criteria:

• History of cataract surgery, phakic intraocular lens surgery, corneal inlay surgery, radial keratotomy, or any intraocular surgery

• Use of any topical ophthalmic medications, including artificial tears other than the study medications during the study

• Use of temporary or permanent punctal plugs or history of punctal cautery in one or both eyes

• Corneal abnormalities (including keratoconus, corneal scar, Fuchs' endothelial dystrophy, guttata, or edema) in either eye that are likely to interfere with visual acuity

• Narrow iridocorneal angles (Shaffer grade ≤2 or lower on gonioscopy examination), history of angle-closure glaucoma, or previous iridotomy

• Diagnosis of any type of glaucoma or ocular hypertension

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Eye Center	Chandler	Arizona	United States	85224
2	Schwartz Laser Eye Center	Scottsdale	Arizona	United States	85260
3	Assil Eye Institute	Beverly Hills	California	United States	90210
4	American Institute of Research	Los Angeles	California	United States	90017
5	Eye Research Foundation	Newport Beach	California	United States	92663
6	Martel Eye Medical Group	Rancho Cordova	California	United States	95670
7	Grutzmacher & Lewis, A Medical Corporation DBA Sacramento Eye Consultants	Sacramento	California	United States	95815
8	Haas Vision Center	Colorado Springs	Colorado	United States	80919
9	Danbury Eye Physicians and Surgeons P.C.	Danbury	Connecticut	United States	06810
10	The Eye Associates	Bradenton	Florida	United States	34209
11	Bruce Segal, MD	Delray Beach	Florida	United States	33484
12	Direct Helpers Research Center	Hialeah	Florida	United States	33012
13	Research Centers of America	Hollywood	Florida	United States	33024
14	Florida Eye Associates	Melbourne	Florida	United States	32901
15	USF Eye Institute	Tampa	Florida	United States	33612
16	Price Vision Group	Indianapolis	Indiana	United States	46260
17	Sabates Eye Centers	Leawood	Kansas	United States	66211
18	The Eye Care Institute	Louisville	Kentucky	United States	40206
19	Seidenberg Protzko Eye Associates	Havre De Grace	Maryland	United States	21078
20	Tauber Eye Center	Kansas City	Missouri	United States	64111
21	Alterman, Modi & Wolter	Poughkeepsie	New York	United States	12603
22	Rochester Ophthalmological Group, PC	Rochester	New York	United States	14618
23	Mundorf Eye Center	Charlotte	North Carolina	United States	28204
24	The Ohio State University	Columbus	Ohio	United States	43212
25	EyeCare Professionals DWA Insight Research Clinic, LLC	Powell	Ohio	United States	43065
26	Devers Eye Institute	Portland	Oregon	United States	97210
27	Scott & Christie and Associates, PC	Cranberry Township	Pennsylvania	United States	16066
28	Black Hills Regional Eye Institute	Rapid City	South Dakota	United States	57701
29	Vance Thompson Vision	Sioux Falls	South Dakota	United States	57108
30	Southern College of Optometry	Memphis	Tennessee	United States	38104
31	Nashville Vision Associates	Nashville	Tennessee	United States	37205
32	Hill Country Eye Center	Cedar Park	Texas	United States	78613
33	Key-Whitman Eye Center	Dallas	Texas	United States	75243
34	PNV Clinical Research LLC	San Antonio	Texas	United States	78229
35	R and R Eye Research, LLC	San Antonio	Texas	United States	78229
36	Hoopes, Durrie, Rivera Research	Draper	Utah	United States	84020

Sponsors and Collaborators

• Allergan

Investigators

• Study Director: Eleonora Safyan, Allergan

Study Documents (Full-Text)

• Study Protocol - Dec 5, 2018
• Statistical Analysis Plan - Jan 30, 2020

More Information

Publications

None provided.

• Responsible Party: Allergan
• ClinicalTrials.gov Identifier: NCT03804268
• Other Study ID Numbers: 1883-301-013
• First Posted: Jan 15, 2019
• Last Update Posted: Dec 28, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Presbyopia; Ophthalmic Solutions; Pilocarpine

Study Results

Participant Flow

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine hydrochloride (HCl) ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Period Title: Overall Study
STARTED	160	163
COMPLETED	153	161
NOT COMPLETED	7	2

Baseline Characteristics

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution	Total
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.	Total of all reporting groups
Overall Participants	160	163	323
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.7 (3.23)	49.5 (3.81)	49.6 (3.53)
Sex: Female, Male (Count of Participants)
Female	122 76.3%	113 69.3%	235 72.8%
Male	38 23.8%	50 30.7%	88 27.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	26 16.3%	31 19%	57 17.6%
Not Hispanic or Latino	134 83.8%	132 81%	266 82.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 1.3%	0 0%	2 0.6%
Asian	1 0.6%	2 1.2%	3 0.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	12 7.5%	13 8%	25 7.7%
White	144 90%	148 90.8%	292 90.4%
More than one race	1 0.6%	0 0%	1 0.3%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Gaining 3 Lines or More in Mesopic, High-contrast, Binocular Distance-Corrected Near Visual Acuity (DCNVA) at Day 30, Hour 3
Description	Visual acuity for near (40 centimeters (cm)) target was measured in mesopic conditions using an eye chart. Mesopic condition was defined as low lighting 3.2 to 3.5 candelas per square meter (cd/m^2) measured at the target. Percentage of participants with 3 lines or more improvement from Baseline in mesopic, high-contrast DCNVA are reported.
Time Frame	Baseline (Day 1) to Day 30 (Hour 3)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) Population included all randomized participants. Missing data was imputed as non-responders.

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Measure Participants	160	163
Number [percentage of participants]	8.1 5.1%	30.7 18.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vehicle, Pilocarpine HCl Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value was adjusted for multiplicity control.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	22.5
	Confidence Interval	(2-Sided) 95%; 14.3 to 30.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was done using Chi-square test. 95% confidence interval for the percentage differences was calculated based on the normal approximation based on pooled variance without continuity correction.

2. Secondary Outcome

Title	Percentage of Participants Gaining 3 Lines or More in Mesopic, High-contrast, Binocular Distance-Corrected Near Visual Acuity (DCNVA) at Day 30, Hour 6
Description	Visual acuity for near (40 cm) target was measured in mesopic conditions using an eye chart. Mesopic condition was defined as low lighting 3.2 to 3.5 candelas per square meter measured at the target. Percentage of participants with 3 lines or more improvement from Baseline in mesopic, high-contrast DCNVA are reported.
Time Frame	Baseline (Day 1) to Day 30 (Hour 6)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Missing data was imputed as non-responders.

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine HCl ophthalmic solution1.25% in each eye, once daily, for up to 30 days.
Measure Participants	160	163
Number [percentage of participants]	8.8 5.5%	18.4 11.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vehicle, Pilocarpine HCl Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0114
	Comments	P-value was adjusted for multiplicity control.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	9.7
	Confidence Interval	(2-Sided) 95%; 2.3 to 17.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was done using Chi-square test. 95% confidence interval for the percentage differences was calculated based on the normal approximation based on pooled variance without continuity correction.

3. Secondary Outcome

Title	Percentage of Participants Gaining 3-lines or More in Mesopic, High-contrast, Binocular, DCNVA at Day 30, Hour 8
Description	Visual acuity for near (40 cm) target was measured in mesopic conditions using an eye chart. Mesopic condition was defined as low lighting 3.2 to 3.5 candelas per square meter measured at the target. Percentage of participants with 3 lines or more improvement from Baseline in mesopic, high-contrast DCNVA are reported.
Time Frame	Baseline (Day 1) to Day 30 (Hour 8)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number analyzed is the number of participants with data available for analyses at Baseline and the timepoint.

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Measure Participants	153	161
Number [percentage of participants]	8.5 5.3%	10.6 6.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vehicle, Pilocarpine HCl Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0000
	Comments	P-value was adjusted for multiplicity control.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	2.1
	Confidence Interval	(2-Sided) 95%; -4.4 to 8.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was done using Chi-square test. 95% confidence interval for the percentage differences was calculated based on the normal approximation based on pooled variance without continuity correction.

4. Secondary Outcome

Title	Change From Baseline in Mesopic, High-contrast, Binocular DCNVA Letters at Day 30, Hour 0.5
Description	Visual acuity for near (40 cm) target was measured in mesopic conditions using an eye chart. Mesopic condition was defined as low lighting 3.2 to 3.5 cd/m^2 measured at the target. A positive change from Baseline indicates improvement in visual acuity. Mixed effect model for repeated measures (MMRM) was used for analyses.
Time Frame	Baseline (Day 1) to Day 30 (Hour 0.5)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number analyzed is the number of participants with data available for analyses.

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Measure Participants	153	158
Least Squares Mean (Standard Error) [letters read correctly]	4.2 (0.55)	9.3 (0.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vehicle, Pilocarpine HCl Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0114
	Comments	MMRM with fixed effects: study intervention group,visit,visit by study intervention group interaction,age group,Baseline binocular DCNVA severity,iris color,emmetrope/non-emmetrope, Baseline value, and Baseline value by visit interaction was used.
	Method	MMRM
	Comments	P-value was adjusted for multiplicity control.
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	5.1
	Confidence Interval	(2-Sided) 95%; 3.7 to 6.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.72
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants Achieving 20/40 or Better in Photopic, High-contrast, Binocular, DCNVA at Day 30, Hour 1
Description	Visual acuity for near (40 cm) target was measured in photopic conditions using an eye chart. Photopic condition was defined as high lighting ≥80 cd/m^2 measured at the target. Percentage of participants achieving 20/40 or better in photopic, high-contrast, binocular, DCNVA are reported.
Time Frame	Day 30 (Hour 1)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number analyzed is the number of participants with data available for analyses at Baseline and the timepoint.

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Measure Participants	153	161
Number [percentage of participants]	73.9 46.2%	92.5 56.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vehicle, Pilocarpine HCl Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0114
	Comments	P-value was adjusted for multiplicity control.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	18.7
	Confidence Interval	(2-Sided) 95%; 10.6 to 26.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was done using Chi-square test. 95% confidence interval was calculated based on normal approximation based on pooled variance without continuity correction.

6. Secondary Outcome

Title	Mean Change From Baseline in Mesopic Near Vision Presbyopia Task-based Questionnaire (NVPTQ) Performance Score at Day 30, Hour 3
Description	NVPTQ had 12 questions on 4 reading tasks(reading a paragraph from book, excerpts from an article in newspaper, portion of a nutrition label, and a section from restaurant menu). Participants completed specific reading tasks under mesopic conditions without any near-vision correction and answered 3 questions for each task, rating their vision-related reading ability as 0=I could not read any text due to problems seeing up close,1=poor,2=fair,3=good,4=very good,5=excellent;impact of squinting on performance as 0=No,I did not squint, 1=Yes,squinting helped me read some/all text, 2=Yes,but I still could not read any of the text; and satisfaction as 0=very dissatisfied to 4=very satisfied. The score based on vision related ability and impact of squinting=(Book testlet+Newspaper testlet+Menu testlet+Nutrition Label testlet)/(testlets with non-missing responses), total possible score of 0-5. Higher scores=better outcomes;positive change from Baseline=improved performance(reading ability).
Time Frame	Baseline (Day 1) to Day 30 (Hour 3)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number analyzed is the number of participants with data available for analyses. Analysis of Covariance (ANCOVA) was used for analysis.

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Measure Participants	148	154
Least Squares Mean (Standard Error) [score on a scale]	0.6 (0.11)	1.4 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vehicle, Pilocarpine HCl Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0114
	Comments	Analysis of covariance (ANCOVA) was used with study intervention group, age group, Baseline binocular DCNVA severity, iris color (brown/non-brown), emmetrope/non-emmetrope, and Baseline domain score as fixed effects.
	Method	ANCOVA
	Comments	P-value was adjusted for multiplicity control.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; 0.6 to 1.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Photopic, High-contrast, Binocular Distance-corrected Intermediate Visual Acuity (DCIVA) Letters at Day 30, Hour 3
Description	Visual acuity for intermediate (66 cm) target was measured in photopic conditions using an eye chart. Photopic condition was defined as high lighting ≥80 cd/m^2 measured at the target. A positive change from Baseline indicates improvement in visual acuity. MMRM was used for analyses.
Time Frame	Baseline (Day 1) to Day 30 (Hour 3)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number analyzed is the number of participants with data available for analyses.

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Measure Participants	153	161
Least Squares Mean (Standard Error) [letters read correctly]	3.1 (0.42)	6.6 (0.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vehicle, Pilocarpine HCl Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0114
	Comments	MMRM with fixed effects: study intervention group,visit,visit by study intervention group interaction,age group,Baseline binocular DCNVA severity,iris color,emmetrope/non-emmetrope, Baseline value, and Baseline value by visit interaction was used.
	Method	MMRM
	Comments	P-value was adjusted for multiplicity control.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	3.5
	Confidence Interval	(2-Sided) 95%; 2.4 to 4.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.55
	Estimation Comments

8. Secondary Outcome

Title	Percentage of Participants Gaining 3-lines or More in Mesopic, High-contrast, Binocular, DCNVA at Day 30, Hour 10
Description	Visual acuity for near (40cm) target was measured in mesopic conditions using an eye chart. Mesopic condition was defined as low lighting 3.2 to 3.5 cd/m^2measured at the target. Percentage of participants with 3 lines or more improvement from Baseline in mesopic, high-contrast, binocular DCNVA are reported.
Time Frame	Baseline (Day1) to Day 30 (Hour 10)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number analyzed is the number of participants with data available for analyses at Baseline and the timepoint.

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Measure Participants	152	160
Number [percentage of participants]	8.6 5.4%	7.5 4.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vehicle, Pilocarpine HCl Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0000
	Comments	P-value was adjusted for multiplicity control.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -7.1 to 5.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was done using Chi-square test. 95% confidence interval for the percentage differences was calculated based on the normal approximation based on pooled variance without continuity correction.

9. Secondary Outcome

Title	Change From Baseline in Mesopic, High-contrast, Binocular DCNVA Letters at Day 30, Hour 0.25
Description	Visual acuity for near (40 cm) target was measured in mesopic conditions. Mesopic condition was defined as low lighting 3.2 to 3.5 cd/m^2 measured at the target. A positive change from Baseline indicates improvement in visual acuity. MMRM was used for analyses.
Time Frame	Baseline (Day 1) to Day 30 (Hour 0.25)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number analyzed is the number of participants with data available for analyses.

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Measure Participants	153	158
Least Squares Mean (Standard Error) [letters correctly read]	3.7 (0.50)	6.3 (0.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vehicle, Pilocarpine HCl Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0114
	Comments	MMRM with fixed effects: study intervention group,visit,visit by study intervention group interaction,age group,Baseline binocular DCNVA severity,iris color,emmetrope/non-emmetrope, Baseline value, and Baseline value by visit interaction was used.
	Method	MMRM
	Comments	P-value was adjusted for multiplicity control.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.6
	Confidence Interval	(2-Sided) 95%; 1.3 to 3.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.66
	Estimation Comments

10. Secondary Outcome

Title	Percentage of Participants Achieving 20/40 or Better in Photopic, High-contrast, Binocular, DCNVA at Day 30, Hour 3
Description	Visual acuity for near (40 cm) target was measured in mesopic conditions using an eye chart. Photopic condition was defined as high lighting ≥80 cd/m^2 measured at the target. Percentage of participants achieving 20/40 or better in photopic, high-contrast, binocular, DCNVA are reported.
Time Frame	Day 30 (Hour 3)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number analyzed is the number of participants with data available for analyses at Baseline and the timepoint.

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Measure Participants	153	161
Number [percentage of participants]	71.9 44.9%	84.5 51.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vehicle, Pilocarpine HCl Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0171
	Comments	P-value was adjusted for multiplicity control.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	12.6
	Confidence Interval	(2-Sided) 95%; 3.5 to 21.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was done using Chi-square test. 95% confidence interval for the percentage differences was calculated based on the normal approximation based on pooled variance without continuity correction.

11. Secondary Outcome

Title	Mean Change From Baseline in Mesopic NVPTQ Satisfaction Score at Day 30, Hour 3
Description	NVPTQ had 12 questions on 4 reading tasks(reading a paragraph from book, excerpts from an article in newspaper, portion of a nutrition label, and a section from restaurant menu). Participants completed specific reading tasks under mesopic conditions without any near-vision correction and answered 3 questions for each task, rating their vision-related reading ability as 0=I could not read any text due to problems seeing up close to 5=excellent; impact of squinting on performance as 0=No, I did not squint, 1=Yes, squinting helped me read some/all text, 2=Yes, but I still could not read any of the text; and satisfaction as 0=very dissatisfied,1=dissatisfied,2=neither satisfied nor dissatisfied,3=satisfied, 4=very satisfied. The score based on satisfaction items=(Book testlet+Newspaper testlet+Menu testlet+Nutrition Label testlet)/(testlets with non-missing responses) for a total possible score of 0 to 4. Higher scores=better outcomes; a positive change from Baseline=higher satisfaction.
Time Frame	Baseline (Day 1) to Day 30 (Hour 3)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number analyzed is the number of participants with data available for analyses. ANCOVA was used for analysis.

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Measure Participants	148	154
Least Squares Mean (Standard Error) [score on a scale]	0.6 (0.11)	1.4 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vehicle, Pilocarpine HCl Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0114
	Comments	ANCOVA was used with study intervention group, age group, baseline binocular DCNVA severity, iris color (brown/non-brown), emmetrope/non-emmetrope, and baseline domain score as fixed effects.
	Method	ANCOVA
	Comments	P-value was adjusted for multiplicity control.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; 0.5 to 1.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

12. Secondary Outcome

Title	Mean Change From Baseline in Presbyopia Impact and Coping Questionnaire (PICQ) Coping Score at Day 30, Hour 3
Description	PICQ=20 questions about impact experienced by participants due to their problems over past 7 days.PICQ Coping domain had 8 items: 1:Normal-sized text,2:Small-sized text,3:Information on a computer,4:Information on a cell phone,5:Increase font size,6:Use glasses to read close,12:Hold reading materials farther out/closer,13:Squint to read. Each item had response categories:0=never to 4=all the time. Items 3, 4, 5, and 6 had additional response categories with values of 9/10 to indicate the question is not applicable to participant and were assigned missing values.PICQ Coping Score:(Item 1,2 Testlet+Item 3,4 Testlet+Item 5+Item 6+Item 12+Item 13)/non-missing responses to the 6 components of coping score where Items 1,2 Testlet=(Item1+Item2)/non-missing responses to Items 1,2;Items 3,4 Testlet=(Item3+Item4)/non-missing responses to Items 3, 4. Score ranges:0=to least amount of coping to 4=greatest amount of coping. Higher scores=poorer outcome; a negative change from Baseline=improvement.
Time Frame	Baseline (Day 1) to Day 30 (Hour 3)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number analyzed is the number of participants with data available for analyses. ANCOVA was used for analysis.

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Measure Participants	148	159
Least Squares Mean (Standard Error) [score on a scale]	-0.5 (0.07)	-1.0 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vehicle, Pilocarpine HCl Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0114
	Comments	ANCOVA was used with study intervention group, age group, Baseline binocular DCNVA severity, iris color (brown/non-brown), emmetrope/non-emmetrope, and Baseline domain score as fixed effects.
	Method	ANCOVA
	Comments	P-value was adjusted for multiplicity control.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -0.6 to -0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

13. Secondary Outcome

Title	Mean Change From Baseline in PICQ Impact Score at Day 30, Hour 3
Description	PICQ had 20 questions about impact experienced by participants due to their problems seeing up over past 7 days. PICQ Impact domain had 6 items: Item 9:Rely on others,15:rest eyes,16:Feel older,17:Feel self-conscious,19:Take longer to complete a task,20:Inconvenient. First 5 impacts items included response categories: 0=never to 4=all the time. Item 20 had response categories: 0=not at all to 4=extremely. Item 9 included an additional response category with a value of 9 to indicate question was not applicable to participant and the responses were assigned missing values. PICQ Impacts Score=[(Item9+Item15+Items16,17Testlet+Item19+Item20)/(nonmissing responses to 5 components of impacts score)] where Items 16,17 Testlet=(Item16+Item17)/non-missing responses to Items 16 and 17. PICQ Impact score ranges from 0 to 4; with 0=least amount of impacts to 4=greatest amount of impacts. Higher scores correspond to poorer outcomes. A negative change from Baseline=improvement.
Time Frame	Baseline (Day 1) to Day 30 (Hour 3)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number analyzed is the number of participants with data available for analyses. ANCOVA was used for analysis.

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.	Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Measure Participants	148	159
Least Squares Mean (Standard Error) [score on a scale]	-0.4 (0.06)	-0.7 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vehicle, Pilocarpine HCl Ophthalmic Solution
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0114
	Comments	ANCOVA was used with study intervention group, age group, Baseline binocular DCNVA severity, iris color (brown/non-brown), emmetrope/non-emmetrope, and Baseline domain score as fixed effects.
	Method	ANCOVA
	Comments	P-value was adjusted for multiplicity control.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.4 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.08
	Estimation Comments

Adverse Events

Time Frame	First dose of study drug intervention to within 30 days after last dose (Up to 60 days)
Adverse Event Reporting Description	All-cause Mortality: All enrolled participants. Serious Adverse Events and Other (non-serious) Adverse Events: Safety Population included all participants who received at least 1 administration of study intervention.
Arm/Group Title	Vehicle		Pilocarpine HCl Ophthalmic Solution
Arm/Group Description	Participants received one drop of vehicle in each eye, once daily, for up to 30 days.		Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
All Cause Mortality
	Vehicle		Pilocarpine HCl Ophthalmic Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/160 (0%)		0/163 (0%)
Serious Adverse Events
	Vehicle		Pilocarpine HCl Ophthalmic Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/159 (0%)		0/163 (0%)
Other (Not Including Serious) Adverse Events
	Vehicle		Pilocarpine HCl Ophthalmic Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/159 (9.4%)		23/163 (14.1%)
Nervous system disorders
Headache	15/159 (9.4%)		23/163 (14.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

A disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 90 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.