GEMINI 2: A Phase 3 Efficacy Study of Pilocarpine HCl Ophthalmic Solution (AGN-190584) in Participants With Presbyopia

• Sponsor: Allergan (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03857542
• Collaborator: (none)
• Enrollment: 427
• Locations: 35
• Arms: 2
• Actual Duration (Months): 18.4
• Patients Per Site: 12.2
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

This clinical study will evaluate pilocarpine hydrogen chloride (HCl) ophthalmic solution (AGN-190584) in an expanded participant population to establish efficacy, safety, and tolerability versus the vehicle-control when administered, over a 30-day study intervention period, once daily bilaterally in participants with presbyopia.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 427 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: Mar 1, 2019
• Actual Primary Completion Date: Sep 10, 2020
• Actual Study Completion Date: Sep 10, 2020

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 DCNVA, Without Losing More Than 5 Letters of Mesopic, High-Contrast, Binocular CDVA With the Same Refractive Correction at Day 30, Hour 3 [Baseline (Day 1) to Day 30 (Hour 3)]

   Visual acuity for near (40 centimeter (cm)) and distance (4 meter (m)) targets were measured in mesopic conditions using an eye chart. High contrast corrected distance visual acuity (CDVA) was assessed binocularly (in each eye) using the provided visual acuity charts for distance vision in a room with mesopic lighting conditions measured at the target. Forced choice letter by-letter scoring was used for each test and the total number of correct letters or the highest value (number) of the grid identified (as applicable) were recorded. Mesopic condition was defined as low lighting 3.2 to 3.5 candelas per square meter (cd/m^2) measured at the target. DCNVA= distance-corrected near visual acuity.

Secondary Outcome Measures

1. Percentage of Participants Gaining 3 Lines or More in Mesopic, High-contrast, Binocular 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 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.

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) 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. Baseline for efficacy was defined as the last non-missing efficacy assessment before the first dose of study intervention. 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 lighting 3.2 to 3.5 cd/m^2 measured at the target. Mixed effect model for repeated measures (MMRM) was used for the analysis.

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.

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 a newspaper article, 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, rated 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 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. MMRM was used for the analysis.

7. Percentage of Participants Gaining 3 Lines or More in Mesopic, High-contrast, Binocular, DCNVA at Day 30, Hour 10 [Baseline (Day 1) to Day 30 (Hour 10)]

   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^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 using an eye chart. Mesopic condition was defined as low lighting 3.2 to 3.5 cd/m^2 measured at the target. MMRM was used for the analysis.

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) targets was measured in photopic conditions using an eye chart. Photopic condition was defined as high lighting ≥80 cd/m^2 measured at the target.

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 a newspaper article, 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, related 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 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. NVPTQ Satisfaction Score=(Book testlet+Newspaper testlet+Menu testlet+Nutrition Label testlet)/(testlets with non-missing responses)based on satisfaction items for a total possible score of 0 to 4. Higher scores=better outcomes; a positive change from Baseline indicates higher satisfaction.

11. Mean Change From Baseline in Presbyopia 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. Impact domain of PICQ has 6 items:Item9:Rely on others,Item15:rest eyes,Item16:Feel older,Item17:Feel self-conscious,Item19:Take longer to complete task,Item20:Inconvenient.First 5 impacts items include response ranges from 0=never to 4=all of time. Item20 ranged from 0=Not at all,to 4=Extremely. Item9 included an additional response category, labeled with value of 9 to indicate question is not applicable because participant did not have opportunity to experience impact responses are assigned missing values. PICQ Impacts Score=[(Items 9+15+16&17 Testlet+Item19+Item20)/(nonmissing responses to 5 components of impacts score)] where Items 16&17 Testlet=(Items16+17)/non-missing responses to Items16 and 17. PICQ Impact score ranged 0-4, 0=least amount of impacts,4=greatest amount of impacts. Higher scores correspond to poorer outcomes; 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

Uncontrolled systemic disease

Any clinical condition or previous surgery that might affect the absorption, distribution, biotransformation, or excretion of AGN-190584. History of cataract surgery, phakic intraocular lens surgery, corneal inlay surgery, radial keratotomy, or any intraocular surgery. However, participants with history of photorefractive keratectomy (PRK) or laser-assisted in situ keratomileusis (LASIK) with corrected distance visual acuity (CDVA) meeting inclusion criteria will be allowed to enroll.

Known allergy or sensitivity to the study intervention or its components or other cholinergic agonist medications

Concurrent use of any topical ophthalmic medications, including artificial tears, other than the study intervention during the course of the study

Concurrent use of temporary or permanent punctal plugs or history of punctal cautery in one or both eyes

Current enrollment in an investigational drug or device study or participation in such a study within 30 days of entry into this study

Participation in a blood or plasma donation program within 30 days prior to study intervention administration

Severe dry eye disease (defined as total corneal staining ≥ grade 3 on the 5-point Oxford scale and an ocular surface disease index (OSDI) score of > 33) at the screening visit

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

History of iris trauma, Adie's tonic pupil, abnormal pupil shape in either eye, or anisocoria > 1 mm between pupils under mesopic conditions at the screening visit

Lens opacity in either eye that is determined to cause significant disturbance of the central visual axis on screening biomicroscopy

Diagnosis of any type of glaucoma or ocular hypertension

Bifocal or multifocal spectacles or contact lenses for habitual correction. Participants willing to wear study-provided monofocal correction (either spectacles or contact lenses) during the study can be enrolled

Abnormal and clinically significant results according to the investigator or designee, on physical/ophthalmic examination or medical history

Females who are pregnant, nursing, or planning a pregnancy during the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Eye Center South	Dothan	Alabama	United States	36301
2	M&M Eye Institute	Prescott	Arizona	United States	86301
3	Walman Eye Center	Sun City	Arizona	United States	85351
4	Milton M. Hom, OD, FAAO	Azusa	California	United States	91702
5	Global Research Management	Glendale	California	United States	91204
6	Advanced Vision Care	Los Angeles	California	United States	90067
7	North Valley Eye Medical Group, Inc.	Mission Hills	California	United States	91345
8	Eye Research Foundation	Newport Beach	California	United States	92663
9	Corneal Consultants of Colorado	Littleton	Colorado	United States	80120
10	Benjamin Knox Lambright, MD	Crystal River	Florida	United States	34429
11	South Florida Vision Center	Fort Lauderdale	Florida	United States	33309
12	Bowden Eye Associates	Jacksonville	Florida	United States	32256
13	Mid Florida Eye Center	Mount Dora	Florida	United States	32757
14	Newsom Eye & Laser Center	Sebring	Florida	United States	33870
15	Clayton Eye Center	Morrow	Georgia	United States	30260
16	The Midwest Center for Sight	Des Plaines	Illinois	United States	60016
17	Jacksoneye	Lake Villa	Illinois	United States	60046
18	Kannarr Eye Care	Pittsburg	Kansas	United States	66762
19	Heart of America Eyecare	Shawnee Mission	Kansas	United States	66204
20	Cincinnati Eye Institute	Edgewood	Kentucky	United States	41017
21	Chu Laser Eye Institute	Bloomington	Minnesota	United States	55420
22	Silverstein Eye Centers	Kansas City	Missouri	United States	64133
23	Moyes Eye Center	Kansas City	Missouri	United States	64154
24	Tekwani Vision Center	Saint Louis	Missouri	United States	63128
25	Amel Youssef, OD	Las Vegas	Nevada	United States	89117
26	Debry Medical Services PC	Las Vegas	Nevada	United States	89128
27	Bucci Laser Vision	Wilkes-Barre	Pennsylvania	United States	18702
28	Waring Vision Institute	Mount Pleasant	South Carolina	United States	29464
29	University Eye Surgeons	Maryville	Tennessee	United States	37803
30	Total Eye Care, PA	Memphis	Tennessee	United States	38119
31	Keystone Research ltd. at Texan Eye	Austin	Texas	United States	78731
32	The Cataract and Glaucoma Center	El Paso	Texas	United States	79902
33	Texas Eye & Laser Ctr	Hurst	Texas	United States	76054
34	Benjamin Travis Dastrup, MD	Ogden	Utah	United States	84403
35	Vision Consultants and Surgeons	Falls Church	Virginia	United States	22046

Sponsors and Collaborators

• Allergan

Investigators

• Study Director: Eleonora Safyan, Allergan

Study Documents (Full-Text)

• Study Protocol - Mar 6, 2020
• Statistical Analysis Plan - Aug 20, 2020

More Information

Publications

None provided.

• Responsible Party: Allergan
• ClinicalTrials.gov Identifier: NCT03857542
• Other Study ID Numbers: 1883-302-013
• First Posted: Feb 28, 2019
• Last Update Posted: Dec 29, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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

Pre-assignment Detail	Distance-corrected near visual acuity (DCNVA) measurements at 1 site were not conducted correctly at the screening and baseline visits; all participants from this site were excluded from efficacy 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 hydrochloride (HCl) ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.
Period Title: Overall Study
STARTED	215	212
COMPLETED	209	207
NOT COMPLETED	6	5

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	215	212	427
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.9 (3.48)	49.6 (3.71)	49.8 (3.60)
Sex: Female, Male (Count of Participants)
Female	162 75.3%	138 65.1%	300 70.3%
Male	53 24.7%	74 34.9%	127 29.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	41 19.1%	37 17.5%	78 18.3%
Not Hispanic or Latino	174 80.9%	175 82.5%	349 81.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 0.9%	1 0.5%	3 0.7%
Asian	8 3.7%	5 2.4%	13 3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	29 13.5%	35 16.5%	64 15%
White	176 81.9%	171 80.7%	347 81.3%
More than one race	0 0%	0 0%	0 0%
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 DCNVA, Without Losing More Than 5 Letters of Mesopic, High-Contrast, Binocular CDVA With the Same Refractive Correction at Day 30, Hour 3
Description	Visual acuity for near (40 centimeter (cm)) and distance (4 meter (m)) targets were measured in mesopic conditions using an eye chart. High contrast corrected distance visual acuity (CDVA) was assessed binocularly (in each eye) using the provided visual acuity charts for distance vision in a room with mesopic lighting conditions measured at the target. Forced choice letter by-letter scoring was used for each test and the total number of correct letters or the highest value (number) of the grid identified (as applicable) were recorded. Mesopic condition was defined as low lighting 3.2 to 3.5 candelas per square meter (cd/m^2) measured at the target. DCNVA= distance-corrected near visual acuity.
Time Frame	Baseline (Day 1) to Day 30 (Hour 3)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Missing data was imputed as non-responders; excluding data from 1 site.

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	203	196
Number [percentage of participants]	10.8 5%	26.0 12.3%

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	<.0001
	Comments	P-value was adjusted for multiplicity control.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	15.2
	Confidence Interval	(2-Sided) 95%; 7.7 to 22.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was done using Chi-square test. The 95% confidence intervals for the proportion differences were 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 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 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 6)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Missing data was imputed as non-responders; excluding data from 1 site.

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	203	196
Number [percentage of participants]	9.9 4.6%	16.3 7.7%

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	0.0548
	Comments	P-value was adjusted for multiplicity control.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	6.5
	Confidence Interval	(2-Sided) 95%; -0.1 to 13.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was done using Chi-square test. The 95% confidence intervals for the proportion difference 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) 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. Baseline for efficacy was defined as the last non-missing efficacy assessment before the first dose of study intervention. 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 of participants analyzed is the number of participants with data available for analysis at Baseline and timepoint; excluding data from 1 site.

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	197	193
Number [percentage of participants]	8.6 4%	14.5 6.8%

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	0.0693
	Comments	P-value was adjusted for multiplicity control.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	5.9
	Confidence Interval	(2-Sided) 95%; -0.5 to 12.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was done using Chi-square test. The 95% confidence intervals for the proportion difference 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 lighting 3.2 to 3.5 cd/m^2 measured at the target. Mixed effect model for repeated measures (MMRM) was used for the analysis.
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 of participants analyzed is the number of participants with data available for analysis; excluding data from 1 site.

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	197	193
Least Squares Mean (Standard Error) [letters read correctly]	4.7 (0.44)	8.8 (0.44)

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	<.0001
	Comments	MMRM with study intervention group, visit, visit by study intervention group interaction, age group, Baseline binocular DCNVA severity, iris color, emmetrope/non-emmetrope, Baseline value; Baseline value by visit interaction as fixed effects.
	Method	MMRM
	Comments	P-value was adjusted for multiplicity control.
Method of Estimation	Estimation Parameter	Least Squares (LS) Mean Difference
	Estimated Value	4.1
	Confidence Interval	(2-Sided) 95%; 2.9 to 5.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.59
	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.
Time Frame	Day 30 (Hour 1)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number of participants analyzed is the number of participants with data available for analysis; excluding data for 1 site.

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	198	193
Number [percentage of participants]	82.8 38.5%	92.7 43.7%

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	0.0141
	Comments	P-value was adjusted for multiplicity control.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	9.9
	Confidence Interval	(2-Sided) 95%; 3.5 to 16.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was done using chi-square test. The 95% confidence intervals 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 a newspaper article, 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, rated 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 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 of participants analyzed is the number of participants with data available for analysis; excluding data for 1 site. ANCOVA was used for the 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	197	192
Least Squares Mean (Standard Error) [score on a scale]	0.5 (0.09)	1.3 (0.09)

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	<.0001
	Comments	Analysis of covariance (ANCOVA) 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 1.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	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. MMRM was used for the analysis.
Time Frame	Baseline (Day 1) to Day 30 (Hour 3)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number of participants analyzed is the number of participants with data available for analysis; excluding data from 1 site.

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	198	193
Least Squares Mean (Standard Error) [number of letters read correctly]	2.9 (0.38)	6.4 (0.39)

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	<.0001
	Comments	MMRM with 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 as fixed effects.
	Method	MMRM
	Comments	P-value was adjusted for multiplicity control.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	3.4
	Confidence Interval	(2-Sided) 95%; 2.4 to 4.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.52
	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 (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^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 (Day 1) to Day 30 (Hour 10)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number of participants analyzed is the number of participants with data available for analysis at Baseline and timepoint; excluding data from 1 site.

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	195	191
Number [percentage of participants]	8.7 4%	12.6 5.9%

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	0.2200
	Comments	P-value was adjusted for multiplicity control.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	3.8
	Confidence Interval	(2-Sided) 95%; -2.3 to 10.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was done using chi-square test. The 95% confidence intervals for the proportion differences were 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 using an eye chart. Mesopic condition was defined as low lighting 3.2 to 3.5 cd/m^2 measured at the target. MMRM was used for the analysis.
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 of participants analyzed is the number of participants with data available for analysis; excluding data from 1 site.

Arm/Group Title	Vehicle	Pilocarpine HCl Ophthalmic Solution 1.25%
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	196	193
Least Squares Mean (Standard Error) [letters read correctly]	3.9 (0.41)	6.5 (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	<.0001
	Comments	MMRM with 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 as fixed effects.
	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%; 1.5 to 3.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.55
	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) targets was measured in photopic conditions using an eye chart. Photopic condition was defined as high lighting ≥80 cd/m^2 measured at the target.
Time Frame	Day 30 (Hour 3)

Outcome Measure Data

Analysis Population Description

ITT Population included all randomized participants. Overall number of participants analyzed is the number of participants with data available 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	198	193
Number [percentage of participants]	77.8 36.2%	90.2 42.5%

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	0.0141
	Comments	P-value was adjusted for multiplicity control.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	12.4
	Confidence Interval	(2-Sided) 95%; 5.2 to 19.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was done using chi-square test. The 95% confidence intervals was calculated based on 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 a newspaper article, 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, related 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 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. NVPTQ Satisfaction Score=(Book testlet+Newspaper testlet+Menu testlet+Nutrition Label testlet)/(testlets with non-missing responses)based on satisfaction items for a total possible score of 0 to 4. Higher scores=better outcomes; a positive change from Baseline indicates 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 of participants analyzed is the number of participants with data available for analysis. ANCOVA is used for the 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	197	192
Least Squares Mean (Standard Error) [score on a scale]	0.5 (0.08)	1.2 (0.08)

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	<.0001
	Comments	ANCOVA 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	0.7
	Confidence Interval	(2-Sided) 95%; 0.5 to 1.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

12. Secondary Outcome

Title	Mean Change From Baseline in Presbyopia 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 of participants analyzed is the number of participants with data available for analysis. ANCOVA was used for the 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	197	193
Least Squares Mean (Standard Error) [score on a scale]	-0.5 (0.06)	-0.9 (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	0.0002
	Comments	ANCOVA 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	-0.4
	Confidence Interval	(2-Sided) 95%; -0.5 to -0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.08
	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. Impact domain of PICQ has 6 items:Item9:Rely on others,Item15:rest eyes,Item16:Feel older,Item17:Feel self-conscious,Item19:Take longer to complete task,Item20:Inconvenient.First 5 impacts items include response ranges from 0=never to 4=all of time. Item20 ranged from 0=Not at all,to 4=Extremely. Item9 included an additional response category, labeled with value of 9 to indicate question is not applicable because participant did not have opportunity to experience impact responses are assigned missing values. PICQ Impacts Score=[(Items 9+15+16&17 Testlet+Item19+Item20)/(nonmissing responses to 5 components of impacts score)] where Items 16&17 Testlet=(Items16+17)/non-missing responses to Items16 and 17. PICQ Impact score ranged 0-4, 0=least amount of impacts,4=greatest amount of impacts. Higher scores correspond to poorer outcomes; 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 of participants analyzed is the number of participants with data available for analysis. ANCOVA was used for the 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	197	193
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	0.0002
	Comments	ANCOVA 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 -0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments

Adverse Events

Time Frame	First dose of study drug intervention to within 30 days after last dose (Up to 60 days)
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	0/215 (0%)		0/212 (0%)
Serious Adverse Events
	Vehicle		Pilocarpine HCl Ophthalmic Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/215 (0.9%)		0/212 (0%)
Gastrointestinal disorders
Dysphagia	1/215 (0.5%)		0/212 (0%)
Nervous system disorders
Guillain-Barre syndrome	1/215 (0.5%)		0/212 (0%)
Other (Not Including Serious) Adverse Events
	Vehicle		Pilocarpine HCl Ophthalmic Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/215 (11.6%)		58/212 (27.4%)
Eye disorders
Conjunctival hyperaemia	11/215 (5.1%)		15/212 (7.1%)
Vision blurred	1/215 (0.5%)		13/212 (6.1%)
Eye pain	3/215 (1.4%)		12/212 (5.7%)
Nervous system disorders
Headache	11/215 (5.1%)		33/212 (15.6%)

Limitations/Caveats

DCNVA measurements at 1 site were not conducted correctly at the screening and baseline visits; all participants from this site were excluded from efficacy analyses.

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.