Rocket-1: Double-masked Study of AR-13324 Ophthalmic Solution in Patients With Glaucoma or Ocular Hypertension

• Sponsor: Aerie Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02207491
• Collaborator: (none)
• Enrollment: 411
• Location: 1
• Arms: 2
• Duration (Months): 8
• Patients Per Site Per Month: 51.5

Study Details

Study Description

Brief Summary

To evaluate the ocular hypotensive efficacy and ocular and systemic safety of AR-13324 Ophthalmic Solution, 0.02% compared to the active comparator Timolol maleate Ophthalmic Solution, 0.5%

Condition or Disease	Intervention/Treatment	Phase
Ocular Hypertension; Open-angle Glaucoma	Drug: Timolol maleate Ophthalmic Solution 0.5% BID; Drug: AR-13324 Ophthalmic Solution 0.02%; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 411 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-masked, Randomized, Multi-center, Active-controlled, Parallel, 3-month Study Assessing the Safety and Ocular Hypotensive Efficacy of AR-13324 Ophthalmic Solution, 0.02% Compared to Timolol Maleate Ophthalmic Solution, 0.5% in Patients With Elevated Intraocular Pressure
• Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AR-13324 Ophthalmic Solution 0.02% & Placebo 1 drop AR-13324 in the evening (PM) & 1 drop placebo in the morning (AM) in both eyes (OU)	Drug: AR-13324 Ophthalmic Solution 0.02%; 1 drop once daily (QD), PM, OU; Other Names: Netarsudil ; Other: Placebo; 1 drop QD, AM, OU
Active Comparator: Timolol maleate Ophthalmic Solution 0.5% BID 1 drop Timolol maleate twice daily (BID) in the morning (AM) & evening (PM) in both eyes (OU)	Drug: Timolol maleate Ophthalmic Solution 0.5% BID; 1 drop BID, AM/PM, OU

Outcome Measures

Primary Outcome Measures

1. Intraocular Pressure (IOP) [3 months]

   The primary efficacy outcome is mean IOP

Secondary Outcome Measures

1. Extent of Exposure [3 months]

   Exposure to study medication in days for all treatment groups.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Subject Inclusion criteria:

1. 0-2 years of age and 18 years or greater.

2. Diagnosis of open angle glaucoma or ocular hypertension

3. Unmedicated (post-washout) IOP (Intraocular Pressure) >20 mm Hg and < 27 mm Hg in the study eye at 2 qualification visits.

4. Corrected visual acuity in each eye equivalent to 20/200.

5. Able and willing to give signed informed consent (parent or guardian consent for pediatric patient) and follow study instructions.

Subject exclusion criteria

Ophthalmic:

1. Glaucoma: pseudoexfoliation or pigment dispersion component, history of angle closure, or narrow angles. Note: Previous laser peripheral iridotomy is NOT acceptable.

2. Intraocular pressure ≥27 mm Hg (unmedicated) in both eyes (individuals who are excluded for this criterion are not allowed to attempt requalification), or use of more than two ocular hypotensive medications within 30 days of screening. Note: fixed dose combinations count as two medications.

3. Known hypersensitivity to any component of the formulations to be used (benzalkonium chloride, etc.), to topical anesthetics or beta adrenoceptor antagonists.

4. Previous glaucoma intraocular surgery or glaucoma laser procedures in either eye

5. Refractive surgery in either eye.

6. Ocular trauma in either eye within the six months prior to screening, or ocular surgery or non-refractive laser treatment within the three months prior to screening.

7. Recent or current evidence of ocular infection or inflammation in either eye. Current evidence of clinically significant blepharitis, conjunctivitis, or a history of herpes simplex or zoster keratitis at screening in either eye.

8. Ocular medication in either eye of any kind within 30 days of screening.

9. Clinically significant ocular disease in either eye (e.g., corneal edema, uveitis, severe keratoconjunctivitis sicca) which might interfere with the study, including glaucomatous damage so severe that washout of ocular hypotensive medications for one month is not judged safe.

10. Central corneal thickness in either eye greater than 600 µm at screening.

11. Any abnormality in either eye preventing reliable applanation tonometry of either eye.

Systemic:

1. Clinically relevant abnormalities (as determined by the investigator) in laboratory tests at screening which may impact the study.

2. Known hypersensitivity or contraindication to beta-adrenoceptor antagonists (e.g., chronic obstructive pulmonary disease or bronchial asthma; abnormally low blood pressure or heart rate; second or third degree heart block or congestive heart failure; severe diabetes).

3. Clinically significant systemic disease (e.g., uncontrolled diabetes, myasthenia gravis, hepatic, renal, endocrine or cardiovascular disorders) which might interfere with the study.

4. Participation in any investigational study within 30 days prior to screening.

5. Changes of systemic medication that could have an effect on intraocular pressure within 30 days prior to screening, or anticipated during the study.

6. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not using a medically acceptable form of birth control. An adult woman is considered to be of childbearing potential unless she is one year post-menopausal or three months post-surgical sterilization. All females of childbearing potential must have a negative urine pregnancy test result at the screening examination and must not intend to become pregnant during the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Aerie Pharmaceuticals	Bedminster	New Jersey	United States	07921

Sponsors and Collaborators

• Aerie Pharmaceuticals

Investigators

• Study Director: Theresa Heah, MD, Aerie Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Aerie Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02207491
• Other Study ID Numbers: AR-13324-CS301
• First Posted: Aug 4, 2014
• Last Update Posted: Apr 13, 2018
• Last Verified: Jan 1, 2018

• Keywords provided by Aerie Pharmaceuticals: Glaucoma
• Additional relevant MeSH terms: Glaucoma; Glaucoma, Open-Angle; Ocular Hypertension; Hypertension; Timolol; Pharmaceutical Solutions; Ophthalmic Solutions

Study Results

Participant Flow

Recruitment Details	Participants were recruited at 35 clinical trial sites starting in June of 2014. The first participant was enrolled in July of 2014 and the last participant was enrolled in December of 2014.
Pre-assignment Detail	Prior to enrollment, adult participants were to have a Screening Visit and 2 Qualification Visits to allow for washout of ocular hypotensive medication if needed. The Randomized Population includes all subjects who were randomized to treatment. Baseline variables and demographic characteristics were summarized for this population.

Arm/Group Title	AR-13324 Ophthalmic Solution 0.02% & Placebo	Timolol Maleate Ophthalmic Solution 0.5% BID
Arm/Group Description	1 drop AR-13324 in the evening (PM) & 1 drop placebo in the morning (AM) in both eyes (OU)	1 drop Timolol maleate twice daily (BID) in the morning (AM) and evening (PM) in both eyes (OU)
Period Title: Overall Study
STARTED	202	209
COMPLETED	171	196
NOT COMPLETED	31	13

Baseline Characteristics

Arm/Group Title	AR-13324 Ophthalmic Solution 0.02% & Placebo	Timolol Maleate Ophthalmic Solution 0.5% BID	Total
Arm/Group Description	1 drop AR-13324 in the evening (PM) & 1 drop placebo in the morning (AM) in both eyes (OU)	1 drop Timolol maleate twice daily (BID) in the morning (AM) and evening (PM) in both eyes (OU)	Total of all reporting groups
Overall Participants	202	209	411
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.8 (11.65)	64.2 (11.34)	65.0 (11.5)
Sex: Female, Male (Count of Participants)
Female	114 56.4%	136 65.1%	250 60.8%
Male	88 43.6%	73 34.9%	161 39.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	27 13.4%	28 13.4%	55 13.4%
Not Hispanic or Latino	175 86.6%	181 86.6%	356 86.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 1%	4 1.9%	6 1.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	43 21.3%	51 24.4%	94 22.9%
White	157 77.7%	153 73.2%	310 75.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 0.5%	1 0.2%

Outcome Measures

1. Primary Outcome

Title	Intraocular Pressure (IOP)
Description	The primary efficacy outcome is mean IOP
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Per-Protocol (PP) Population. The PP population includes subjects who did not have major protocol violations likely to seriously affect the primary outcome of the study. The PP population summarizes subjects as treated for purpose of analysis.

Arm/Group Title	AR-13324 Ophthalmic Solution 0.02% & Placebo	Timolol Maleate Ophthalmic Solution 0.5% BID
Arm/Group Description	1 drop AR-13324 in the evening (PM) & 1 drop placebo in the morning (AM) in both eyes (OU)	1 drop Timolol maleate twice daily (BID) in the morning (AM) and evening (PM) in both eyes (OU)
Measure Participants	182	188
Day 1, 0800 hours	23.42 (1.756)	23.37 (1.658)
Day 1, 1000 hours	22.28 (2.128)	21.92 (2.053)
Day 1, 1600 hours	21.78 (2.385)	21.45 (2.365)
Day 15, 0800 hours	18.68 (3.342)	18.33 (2.566)
Day 15, 1000 hours	17.29 (3.303)	17.55 (2.570)
Day 15, 1600 hours	17.24 (3.294)	17.70 (2.661)
Day 43, 0800 hours	19.35 (3.629)	18.24 (2.924)
Day 43, 1000 hours	18.14 (3.502)	17.44 (2.725)
Day 43, 1600 hours	17.86 (3.580)	17.71 (2.820)
Day 90 (month 3), 0800 hours	19.81 (3.647)	18.47 (2.711)
Day 90 (month 3), 1000 hours	18.92 (3.702)	17.96 (2.674)
Day 90 (month 3), 1600 hours	18.48 (3.595)	17.74 (2.546)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AR-13324 Ophthalmic Solution 0.02% & Placebo, Timolol Maleate Ophthalmic Solution 0.5% BID
	Comments	Assuming zero difference between AR-13324 and timolol, a 2-tailed alpha of 0.05 at each of 9 time points, a common SD of 3.0 mmHg, and a correlation between time points of 0.60 or less, 170 PP subjects per arm were necessary to have 90% power to show clinical noninferiority of AR-13324 to timolol in mean IOP.
	Type of Statistical Test	Non-Inferiority
	Comments	Clinical noninferiority was to be concluded if the upper limit of the 95% CIs around the difference (AR-13324 - timolol) was within 1.5 mmHg at all time points and was within 1.0 mmHg at a majority of the time points.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Calculated p-value
	Method	ANCOVA
	Comments	Statistical analysis applies at all 3 timepoints on Day 15, Day 43, and Day 90

2. Secondary Outcome

Title	Extent of Exposure
Description	Exposure to study medication in days for all treatment groups.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Safety Population: all randomized subjects who received at least 1 dose of study medication. The safety population summarizes subjects as treated for purpose of analysis. Three (3) subjects received incorrect study medication from that to which they were randomized, shown in the Participant Flow.

Arm/Group Title	AR-13324 Ophthalmic Solution 0.02% & Placebo	Timolol Maleate Ophthalmic Solution 0.5% BID
Arm/Group Description	1 drop AR-13324 in the evening (PM) & 1 drop placebo in the morning (AM) in both eyes (OU)	1 drop Timolol maleate twice daily (BID) in the morning (AM) and evening (PM) in both eyes (OU)
Measure Participants	203	208
Mean (Standard Deviation) [days]	82.8 (21.44)	87.4 (15.53)

Adverse Events

Time Frame	Adverse event data was collected during the course of the 90-day treatment period.
Adverse Event Reporting Description	The Safety Population included all randomized subjects who received at least 1 dose of study medication and was used to summarize safety variables. Three (3) subjects received incorrect study medication from that to which they were randomized, shown in the Participant Flow.
Arm/Group Title	AR-13324 Ophthalmic Solution 0.02% & Placebo		Timolol Maleate Ophthalmic Solution 0.5% BID
Arm/Group Description	1 drop AR-13324 in the evening (PM) & 1 drop placebo in the morning (AM) in both eyes (OU)		1 drop Timolol maleate twice daily (BID) in the morning (AM) and evening (PM) in both eyes (OU)
All Cause Mortality
	AR-13324 Ophthalmic Solution 0.02% & Placebo		Timolol Maleate Ophthalmic Solution 0.5% BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/203 (0%)		0/208 (0%)
Serious Adverse Events
	AR-13324 Ophthalmic Solution 0.02% & Placebo		Timolol Maleate Ophthalmic Solution 0.5% BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/203 (1.5%)		4/208 (1.9%)
Cardiac disorders
Congestive Heart Failure	0/203 (0%)	0	1/208 (0.5%)	1
Exacerbation of Coronary Artery Disease	1/203 (0.5%)	1	0/208 (0%)	0
Infections and infestations
Pneumonia	0/203 (0%)	0	1/208 (0.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate Cancer	1/203 (0.5%)	1	0/208 (0%)	0
Nervous system disorders
Left Upper Extremity Numbness	0/203 (0%)	0	1/208 (0.5%)	1
Stroke (CVA)	0/203 (0%)	0	1/208 (0.5%)	1
Reproductive system and breast disorders
Worsening of Adenomyosis	0/203 (0%)	0	1/208 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	0/203 (0%)	0	1/208 (0.5%)	1
Vascular disorders
Hypertension	1/203 (0.5%)	1	0/208 (0%)	0
Other (Not Including Serious) Adverse Events
	AR-13324 Ophthalmic Solution 0.02% & Placebo		Timolol Maleate Ophthalmic Solution 0.5% BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	145/203 (71.4%)		75/208 (36.1%)
Eye disorders
Conjunctival hyperemia	108/203 (53.2%)		17/208 (8.2%)
Conjunctival Haemmorrhage	32/203 (15.8%)		2/208 (1%)
Cornea Verticillata	12/203 (5.9%)		0/208 (0%)
Erythema of Eyelid	12/203 (5.9%)		0/208 (0%)
Vision Blurred	11/203 (5.4%)		1/208 (0.5%)
General disorders
Instillation Site Pain	30/203 (14.8%)		42/208 (20.2%)
Instillation Site Erythema	24/203 (11.8%)		4/208 (1.9%)
Investigations
Vital Dye Staining Cornea Present	17/203 (8.4%)		19/208 (9.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.