Maui: Safety and Efficacy of KPI-121 in Subjects With Inflammatory Meibomian Gland Disease

• Sponsor: Kala Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02218489
• Collaborator: (none)
• Enrollment: 206
• Locations: 8
• Arms: 2
• Duration (Months): 23
• Patients Per Site: 25.8
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

The primary purpose of this study is to determine the efficacy and safety of KPI-121 ophthalmic suspension compared to vehicle (placebo) in subjects with signs and symptoms of inflammatory meibomian gland disease.

Condition or Disease	Intervention/Treatment	Phase
Blepharitis	Drug: KPI-121; Drug: Vehicle	Phase 2

Detailed Description

This is a Phase II, multicenter, double-masked, randomized, vehicle-controlled, parallel-group study designed to evaluate the efficacy and safety of KPI-121 ophthalmic suspension versus vehicle in subjects with signs and symptoms of inflammatory meibomian gland disease. The product will be studied over 28 days, with 1-2 drops instilled in each eye four times daily (QID).

Study Design

• Study Type: Interventional
• Actual Enrollment: 206 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II, Double-Masked, Randomized, Vehicle-Controlled Study to Evaluate the Effect of KPI-121 0.25% Ophthalmic Suspension on Signs and Symptoms of Inflammatory Meibomian Gland Disease
• Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Vehicle Vehicle (placebo) dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease	Drug: Vehicle; The vehicle control has the same composition as KPI-121 0.25% ophthalmic suspension except it does not contain loteprednol etabonate. The vehicle is essentially isotonic and is buffered to maintain pH 5.0 - 7.0. It is a sterile, aqueous solution supplied in the same white, low-density polyethylene plastic dropper bottle with the same white, controlled-drop polyethylene tip and white polypropylene closure as KPI-121 0.25% ophthalmic suspension.; Other Names: KPI-121 0.25% Vehicle Placebo
Active Comparator: KPI-121 0.25% Ophthalmic Suspension KPI-121 0.25% Ophthalmic Suspension dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease	Drug: KPI-121; KPI-121 drug product will be supplied in 0.25% strength as a suspension in opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, submicron suspension of loteprednol etabonate. Subjects randomized to placebo control arm will receive the same bottles containing all components at the concentrations used in the KPI-121 drug product with the exception of the active component, loteprednol etabonate.; Other Names: KPI-121 0.25% Ophthalmic Suspension Loteprednol etabonate

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Ocular Discomfort [Visit 2 (Day 1) to Visit 4 (Day 15)]

   Comparison of change from baseline in ocular discomfort between the KPI-121 0.25% ophthalmic suspension group and the vehicle group using a 0-100 visual analog grading scale where 0 was better and 100 was worse at Visit 4 (Day 15).

2. Change From Baseline in Posterior Lid Margin Hyperemia in the Subgroup of Subjects With Greater Hyperemia at Baseline [Visit 2 (Day 1) to Visit 4 (Day 15)]

   Comparison of change from baseline in posterior lid margin hyperemia between the KPI-121 0.25% ophthalmic suspension group and the vehicle group in subjects with greater baseline hyperemia at Visit 4 (Day 15). The scale for posterior lid margin hyperemia was scored on a range from 0-4 with the following description: 0=normal mild moderate severe very severe

Secondary Outcome Measures

1. Change From Baseline in Ocular Discomfort [Visit 2 (Day 1) to Visit 6 (Day 29)]

   Comparison of change from baseline in ocular discomfort between the KPI-121 0.25% ophthalmic suspension group and the vehicle group using a 0-100 visual analog grading scale where 0 was better and 100 was worse at Visit 6 (Day 29).

2. Change From Baseline in Posterior Lid Margin Hyperemia in the Subgroup of Subjects With Greater Hyperemia at Baseline [Visit 2 (Day 1) to Visit 6 (Day 29)]

   Comparison of change from baseline in posterior lid margin hyperemia between the KPI-121 0.25% ophthalmic suspension group and the vehicle group in the subgroup of subjects with greater hyperemia at baseline at Visit 6 (Day 29). The scale for posterior lid margin hyperemia was scored on a range from 0-4 with the following description: 0=normal mild moderate severe very severe

3. Change From Baseline in Posterior Lid Margin Hyperemia [Visit 2 (Day 1) to Visit 4 (Day 15)]

   Comparison of change from baseline in posterior lid margin hyperemia between the KPI-121 0.25% ophthalmic suspension group and the vehicle group at Visit 4 (Day 15). The scale for posterior lid margin hyperemia was scored on a range from 0-4 with the following description: 0=normal mild moderate severe very severe

4. Change From Baseline in Posterior Lid Margin Hyperemia [Visit 2 (Day 1) to Visit 6 (Day 29)]

   Comparison of change from baseline in posterior lid margin hyperemia between the KPI-121 0.25% ophthalmic suspension group and the vehicle group at Visit 6 (Day 29). The scale for posterior lid margin hyperemia was scored on a range from 0-4 with the following description: 0=normal mild moderate severe very severe

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Have a documented clinical diagnosis of inflammatory meibomian gland disease in both eyes.

Exclusion Criteria:

• Known hypersensitivity/contraindication to study product(s) or components.

• Be currently receiving treatment for glaucoma, have history of or current glaucoma, or an IOP (intraocular pressure) over 21mmHg at Visit 1 (Screening) or Visit 2 (Randomization).

• Be unwilling to discontinue warm compress therapy, lid expression, or lid massage 14 days prior to Day 1 and for the duration of the study.

• Diagnosis of: ongoing ocular infection; severe/serious ocular condition that in judgment of Investigator could confound study assessments or limit compliance; severe/serious systemic disease or uncontrolled medical condition that in judgment of Investigator could confound study assessments or limit compliance; or have been exposed to an investigational drug within the 30 days prior to screening.

• Have had ocular surgery in the past 90 days or require ocular surgery during the study.

• In the opinion of Investigator or study coordinator, be unwilling or unable to comply with study protocol or unable to successfully instill eye drops.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB School of Optometry	Birmingham	Alabama	United States	35294-0010
2	Sall Research Medical Center	Artesia	California	United States	90701
3	North Valley Eye Medical Group	Mission Hills	California	United States	91345
4	Wolstan & Goldberg Eye Associates	Torrance	California	United States	90505
5	Tauber Eye Center	Kansas City	Missouri	United States	64111
6	South Shore Eye Center, LLP	Wantagh	New York	United States	11793
7	Abrams Eye Center	Cleveland	Ohio	United States	44115
8	Virginia Eye Consultants	Norfolk	Virginia	United States	23502

Sponsors and Collaborators

• Kala Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Marc Abrams, MD, Abrams Eye Center
• Principal Investigator: Damien Goldberg, MD, Wolstan & Goldberg Eye Associates
• Principal Investigator: Jodi Luchs, MD, South Shore Eye Center, LLP
• Principal Investigator: Kelly Nichols, OD, PhD, UAB School of Optometry
• Principal Investigator: Steven Rauchman, MD, North Valley Eye Medical Group
• Principal Investigator: Kenneth Sall, MD, Sall Research Medical Center
• Principal Investigator: John Sheppard, MD, Virginia Eye Consultants
• Principal Investigator: Joseph Tauber, MD, Tauber Eye Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 3, 2015

More Information

Publications

None provided.

• Responsible Party: Kala Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02218489
• Other Study ID Numbers: KPI-121-C-003
• First Posted: Aug 18, 2014
• Last Update Posted: Jan 11, 2021
• Last Verified: Jan 1, 2021

• Keywords provided by Kala Pharmaceuticals, Inc.: Pain; Corticosteroid; Meibomian Gland Disease; Blepharitis; Eyelid; Ocular Discomfort
• Additional relevant MeSH terms: Blepharitis; Meibomian Gland Dysfunction; Loteprednol Etabonate

Study Results

Participant Flow

Pre-assignment Detail	206 subjects were randomized, 1 of which were not included in any analysis population as the individual did not receive randomized treatment.

Arm/Group Title	Vehicle	KPI-121 0.25% Ophthalmic Suspension
Arm/Group Description	Vehicle (placebo) dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease Vehicle: The vehicle control has the same composition as KPI-121 0.25% ophthalmic suspension except it does not contain loteprednol etabonate. The vehicle is essentially isotonic and is buffered to maintain pH 5.0 - 7.0. It is a sterile, aqueous solution supplied in the same white, low-density polyethylene plastic dropper bottle with the same white, controlled-drop polyethylene tip and white polypropylene closure as KPI-121 0.25% ophthalmic suspension.	KPI-121 0.25% Ophthalmic Suspension dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease KPI-121: KPI-121 drug product will be supplied in 0.25% strength as a suspension in opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, submicron suspension of loteprednol etabonate.
Period Title: Overall Study
STARTED	101	104
COMPLETED	96	101
NOT COMPLETED	5	3

Baseline Characteristics

Arm/Group Title	Vehicle	KPI-121 0.25% Ophthalmic Suspension	Total
Arm/Group Description	Vehicle (placebo) dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease Vehicle: The vehicle control has the same composition as KPI-121 0.25% ophthalmic suspension except it does not contain loteprednol etabonate. The vehicle is essentially isotonic and is buffered to maintain pH 5.0 - 7.0. It is a sterile, aqueous solution supplied in the same white, low-density polyethylene plastic dropper bottle with the same white, controlled-drop polyethylene tip and white polypropylene closure as KPI-121 0.25% ophthalmic suspension.	KPI-121 0.25% Ophthalmic Suspension dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease KPI-121: KPI-121 drug product will be supplied in 0.25% strength as a suspension in opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, submicron suspension of loteprednol etabonate. Subjects randomized to placebo control arm will receive the same bottles containing all components at the concentrations used in the KPI-121 drug product with the exception of the active component, loteprednol etabonate.	Total of all reporting groups
Overall Participants	101	104	205
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.6 (13.13)	60.2 (11.28)	59.4 (12.22)
Sex: Female, Male (Count of Participants)
Female	72 71.3%	62 59.6%	134 65.4%
Male	29 28.7%	42 40.4%	71 34.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	28 27.7%	35 33.7%	63 30.7%
Not Hispanic or Latino	73 72.3%	69 66.3%	142 69.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1%	0 0%	1 0.5%
Asian	6 5.9%	6 5.8%	12 5.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	13 12.9%	13 12.5%	26 12.7%
White	80 79.2%	84 80.8%	164 80%
More than one race	1 1%	1 1%	2 1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	101 100%	104 100%	205 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Ocular Discomfort
Description	Comparison of change from baseline in ocular discomfort between the KPI-121 0.25% ophthalmic suspension group and the vehicle group using a 0-100 visual analog grading scale where 0 was better and 100 was worse at Visit 4 (Day 15).
Time Frame	Visit 2 (Day 1) to Visit 4 (Day 15)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Vehicle	KPI-121 0.25% Ophthalmic Suspension
Arm/Group Description	Vehicle (placebo) dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease Vehicle: The vehicle control has the same composition as KPI-121 0.25% ophthalmic suspension except it does not contain loteprednol etabonate. The vehicle is essentially isotonic and is buffered to maintain pH 5.0 - 7.0. It is a sterile, aqueous solution supplied in the same white, low-density polyethylene plastic dropper bottle with the same white, controlled-drop polyethylene tip and white polypropylene closure as KPI-121 0.25% ophthalmic suspension.	KPI-121 0.25% Ophthalmic Suspension dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease KPI-121: KPI-121 drug product will be supplied in 0.25% strength as a suspension in opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, submicron suspension of loteprednol etabonate.
Measure Participants	101	104
Mean (Standard Deviation) [score on a scale]	-4.1 (13.8)	-2.4 (16.7)

2. Primary Outcome

Title	Change From Baseline in Posterior Lid Margin Hyperemia in the Subgroup of Subjects With Greater Hyperemia at Baseline
Description	Comparison of change from baseline in posterior lid margin hyperemia between the KPI-121 0.25% ophthalmic suspension group and the vehicle group in subjects with greater baseline hyperemia at Visit 4 (Day 15). The scale for posterior lid margin hyperemia was scored on a range from 0-4 with the following description: 0=normal mild moderate severe very severe
Time Frame	Visit 2 (Day 1) to Visit 4 (Day 15)

Outcome Measure Data

Analysis Population Description

m1ITT- a subset of the ITT population with greater baseline hyperemia

Arm/Group Title	Vehicle	KPI-121 0.25% Ophthalmic Suspension
Arm/Group Description	Vehicle (placebo) dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease Vehicle: The vehicle control has the same composition as KPI-121 0.25% ophthalmic suspension except it does not contain loteprednol etabonate. The vehicle is essentially isotonic and is buffered to maintain pH 5.0 - 7.0. It is a sterile, aqueous solution supplied in the same white, low-density polyethylene plastic dropper bottle with the same white, controlled-drop polyethylene tip and white polypropylene closure as KPI-121 0.25% ophthalmic suspension.	KPI-121 0.25% Ophthalmic Suspension dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease KPI-121: KPI-121 drug product will be supplied in 0.25% strength as a suspension in opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, submicron suspension of loteprednol etabonate. Subjects randomized to placebo control arm will receive the same bottles containing all components at the concentrations used in the KPI-121 drug product with the exception of the active component, loteprednol etabonate.
Measure Participants	77	79
Mean (Standard Deviation) [score on a scale]	-0.5 (0.7)	-04 (0.7)

3. Secondary Outcome

Title	Change From Baseline in Ocular Discomfort
Description	Comparison of change from baseline in ocular discomfort between the KPI-121 0.25% ophthalmic suspension group and the vehicle group using a 0-100 visual analog grading scale where 0 was better and 100 was worse at Visit 6 (Day 29).
Time Frame	Visit 2 (Day 1) to Visit 6 (Day 29)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Vehicle	KPI-121 0.25% Ophthalmic Suspension
Arm/Group Description	Vehicle (placebo) dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease Vehicle: The vehicle control has the same composition as KPI-121 0.25% ophthalmic suspension except it does not contain loteprednol etabonate. The vehicle is essentially isotonic and is buffered to maintain pH 5.0 - 7.0. It is a sterile, aqueous solution supplied in the same white, low-density polyethylene plastic dropper bottle with the same white, controlled-drop polyethylene tip and white polypropylene closure as KPI-121 0.25% ophthalmic suspension.	KPI-121 0.25% Ophthalmic Suspension dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease KPI-121: KPI-121 drug product will be supplied in 0.25% strength as a suspension in opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, submicron suspension of loteprednol etabonate.
Measure Participants	101	104
Mean (Standard Deviation) [score on a scale]	-8.2 (17.1)	-5.0 (15.8)

4. Secondary Outcome

Title	Change From Baseline in Posterior Lid Margin Hyperemia in the Subgroup of Subjects With Greater Hyperemia at Baseline
Description	Comparison of change from baseline in posterior lid margin hyperemia between the KPI-121 0.25% ophthalmic suspension group and the vehicle group in the subgroup of subjects with greater hyperemia at baseline at Visit 6 (Day 29). The scale for posterior lid margin hyperemia was scored on a range from 0-4 with the following description: 0=normal mild moderate severe very severe
Time Frame	Visit 2 (Day 1) to Visit 6 (Day 29)

Outcome Measure Data

Analysis Population Description

m1ITT- a subset of the ITT population with greater baseline hyperemia. m1ITT population minus subjects in each treatment group that discontinued the study by this time point or otherwise did not have this assessment completed.

Arm/Group Title	Vehicle	KPI-121 0.25% Ophthalmic Suspension
Arm/Group Description	Vehicle (placebo) dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease Vehicle: The vehicle control has the same composition as KPI-121 0.25% ophthalmic suspension except it does not contain loteprednol etabonate. The vehicle is essentially isotonic and is buffered to maintain pH 5.0 - 7.0. It is a sterile, aqueous solution supplied in the same white, low-density polyethylene plastic dropper bottle with the same white, controlled-drop polyethylene tip and white polypropylene closure as KPI-121 0.25% ophthalmic suspension.	KPI-121 0.25% Ophthalmic Suspension dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease KPI-121: KPI-121 drug product will be supplied in 0.25% strength as a suspension in opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, submicron suspension of loteprednol etabonate.
Measure Participants	76	79
Mean (Standard Deviation) [score on a scale]	-0.4 (0.7)	-0.6 (0.7)

5. Secondary Outcome

Title	Change From Baseline in Posterior Lid Margin Hyperemia
Description	Comparison of change from baseline in posterior lid margin hyperemia between the KPI-121 0.25% ophthalmic suspension group and the vehicle group at Visit 4 (Day 15). The scale for posterior lid margin hyperemia was scored on a range from 0-4 with the following description: 0=normal mild moderate severe very severe
Time Frame	Visit 2 (Day 1) to Visit 4 (Day 15)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Vehicle	KPI-121 0.25% Ophthalmic Suspension
Arm/Group Description	Vehicle (placebo) dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease Vehicle: The vehicle control has the same composition as KPI-121 0.25% ophthalmic suspension except it does not contain loteprednol etabonate. The vehicle is essentially isotonic and is buffered to maintain pH 5.0 - 7.0. It is a sterile, aqueous solution supplied in the same white, low-density polyethylene plastic dropper bottle with the same white, controlled-drop polyethylene tip and white polypropylene closure as KPI-121 0.25% ophthalmic suspension.	KPI-121 0.25% Ophthalmic Suspension dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease KPI-121: KPI-121 drug product will be supplied in 0.25% strength as a suspension in opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, submicron suspension of loteprednol etabonate.
Measure Participants	101	104
Mean (Standard Deviation) [score on a scale]	-0.56 (0.72)	-0.55 (0.64)

6. Secondary Outcome

Title	Change From Baseline in Posterior Lid Margin Hyperemia
Description	Comparison of change from baseline in posterior lid margin hyperemia between the KPI-121 0.25% ophthalmic suspension group and the vehicle group at Visit 6 (Day 29). The scale for posterior lid margin hyperemia was scored on a range from 0-4 with the following description: 0=normal mild moderate severe very severe
Time Frame	Visit 2 (Day 1) to Visit 6 (Day 29)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Vehicle	KPI-121 0.25% Ophthalmic Suspension
Arm/Group Description	Vehicle (placebo) dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease Vehicle: The vehicle control has the same composition as KPI-121 0.25% ophthalmic suspension except it does not contain loteprednol etabonate. The vehicle is essentially isotonic and is buffered to maintain pH 5.0 - 7.0. It is a sterile, aqueous solution supplied in the same white, low-density polyethylene plastic dropper bottle with the same white, controlled-drop polyethylene tip and white polypropylene closure as KPI-121 0.25% ophthalmic suspension.	KPI-121 0.25% Ophthalmic Suspension dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease KPI-121: KPI-121 drug product will be supplied in 0.25% strength as a suspension in opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, submicron suspension of loteprednol etabonate.
Measure Participants	101	104
Mean (Standard Deviation) [score on a scale]	-0.63 (0.76)	-0.65 (0.8)

Adverse Events

Time Frame	Adverse events were collected from the time a subject signed the informed consent at Visit 1 until they exited the study at Visit 6.
Arm/Group Title	Vehicle		KPI-121 0.25% Ophthalmic Suspension
Arm/Group Description	Vehicle (placebo) dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease Vehicle: The vehicle control has the same composition as KPI-121 0.25% ophthalmic suspension except it does not contain loteprednol etabonate. The vehicle is essentially isotonic and is buffered to maintain pH 5.0 - 7.0. It is a sterile, aqueous solution supplied in the same white, low-density polyethylene plastic dropper bottle with the same white, controlled-drop polyethylene tip and white polypropylene closure as KPI-121 0.25% ophthalmic suspension.		KPI-121 0.25% Ophthalmic Suspension dosed QID for up to 30 days in subjects with inflammatory meibomian gland disease KPI-121: KPI-121 drug product will be supplied in 0.25% strength as a suspension in opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, submicron suspension of loteprednol etabonate.
All Cause Mortality
	Vehicle		KPI-121 0.25% Ophthalmic Suspension
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/101 (0%)		0/104 (0%)
Serious Adverse Events
	Vehicle		KPI-121 0.25% Ophthalmic Suspension
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/101 (0%)		0/104 (0%)
Other (Not Including Serious) Adverse Events
	Vehicle		KPI-121 0.25% Ophthalmic Suspension
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/101 (7.9%)		8/104 (7.7%)
General disorders
Instillation site pain	8/101 (7.9%)	8	8/104 (7.7%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The agreement between the Principal Investigator and the Sponsor restricts the PI's rights to discuss or publish trial results until after the first to occur of the following: (a) publication of such multi-center clinical trial results; (b) notification by sponsor that such a multi-center clinical trial submission is no longer planned; or ( c) the eighteen ( 18) month anniversary of the completion, abandonment or termination of such multi-center clinical trial.