Pharmacodynamics of Tafluprost 0.0015% Eye Drops: a Comparison Between the Preserved and Unpreserved Formulation

• Sponsor: Santen Oy (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00918346
• Collaborator: (none)
• Enrollment: 43
• Locations: 3
• Arms: 2
• Duration (Months): 7
• Patients Per Site: 14.3
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

The objective of this study is to investigate the pharmacodynamics (as expressed in intraocular pressure [IOP]) of two formulations of tafluprost 0.0015% eyedrops (preserved and unpreserved) in patients with open-angle glaucoma or ocular hypertension.

The primary aim of this study is to show that IOP reduction between the two formulations is equivalent at the end of the 4 week treatment period.

Condition or Disease	Intervention/Treatment	Phase
Open-Angle Glaucoma; Ocular Hypertension	Drug: Tafluprost 0.0015%	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Investigator)
• Primary Purpose: Treatment
• Official Title: Pharmacodynamics of Tafluprost 0.0015% Eye Drops: a Comparison Between the Preserved and Unpreserved Formulation in Patients With Open-angle Glaucoma or Ocular Hypertension
• Study Start Date: Sep 1, 2005
• Actual Primary Completion Date: Mar 1, 2006
• Actual Study Completion Date: Apr 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tafluprost 0.0015% preserved formulation	Drug: Tafluprost 0.0015%; Eye drops, 0.015 mg/ml, once daily to affected eye(s)
Experimental: Tafluprost 0.0015% unpreserved formulation	Drug: Tafluprost 0.0015%; Eye drops, 0.015 mg/ml, once daily to affected eye(s)

Outcome Measures

Primary Outcome Measures

1. Intraocular Pressures (IOPs) at Baseline [Baseline]

   IOPs at baseline: mean IOP values at four timepoints (worse eye)

2. Intraocular Pressures (IOPs) at Week 1 [Week 1]

   IOPs at week 1: mean IOP values at four timepoints (worse eye)

3. Intraocular Pressures (IOPs) at Week 4 [Week 4]

   IOPs at week 4: mean IOP values at four timepoints (worse eye)

4. Primary Pharmacodynamic Variable Intention to Treat Efficacy Dataset: Change From Baseline in the Overall Diurnal Intraocular Pressure (IOP) at Week 4 (Worse Eye) [Baseline - Week 4]

   Overall treatment difference at 4 weeks (unpreserved-preserved) evaluated using a repeated measurements analysis of covariance (RM ANCOVA) model.

5. Primary Pharmacodynamic Variable Per Protocol Efficacy Dataset: Change From Baseline in the Overall Diurnal Intraocular Pressure (IOP) at Week 4 (Worse Eye) [Baseline - Week 4]

   Overall treatment difference at 4 weeks (unpreserved-preserved) evaluated using a repeated measurments analysis of covariance (RM ANCOVA) model.

Secondary Outcome Measures

1. Overall and Time-wise Comparisons of IOP at Week 1 [Baseline - Week 1]

   The overall and time-wise, i.e. at 8:00, 12:00, 16:00 and 20:00, comparisons of IOP at week 1 (diurnal IOP and IOP value at given timepoint at 1 week minus corresponding value at baseline: unpreserved-preserved) were done using the RM ANCOVA model.

2. Change From Baseline in Time-wise IOPs at Week 4 [Baseline - Week 4]

   The time-wise, i.e. at 8:00, 12:00, 16:00 and 20:00, comparisons of IOP at week 4 (IOP value at given timepoint at 4 weeks minus corresponding value at baseline: unpreserved-preserved) were done using the RM ANCOVA model.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Age 18 years or more

• A diagnosis of open angle glaucoma or ocular hypertension

• Prior use of prostaglandin(s)

• Intra ocular pressure of 22-34 mmHg in at least one eye

Exclusion Criteria:

• Females who are pregnant, nursing or planning a pregnancy, or females of childbearing potential who are not using a reliable method of contraception

• Previous participation in any clinical trial in which tafluprost was an investigational drug or use of contact lenses at screening or during the study

• Presence of any abnormality or significant illness that could be expected to interfere with the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oulu University Hospital	Oulu		Finland	90029
2	Ulrich Richter's surgery	Regensburg		Germany	93059
3	Praxis Dr. Hamacher	Starnberg		Germany	82319

Sponsors and Collaborators

• Santen Oy

Investigators

• Principal Investigator: Juhani Airaksinen, Prof., University Hospital of Oulu

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00918346
• Other Study ID Numbers: 77550
• First Posted: Jun 11, 2009
• Last Update Posted: Dec 28, 2010
• Last Verified: Dec 1, 2010

• Keywords provided by , ,: Ocular hypertension
• Additional relevant MeSH terms: Glaucoma; Glaucoma, Open-Angle; Ocular Hypertension; Hypertension

Study Results

Participant Flow

Recruitment Details	At 2 centers in Germany, 1 center in Finland: 14 September 2005 first patient screened 08 November 2005 first patient randomized 05 April 2006 last patient completed
Pre-assignment Detail	A total of 45 patients screened and 43 patients randomized. 2 screening failure patients: 1 withdrawn consent and 1 too low IOP (inclusion criterion 4).

Arm/Group Title	Preserved Formulation First, Then Unpreserved Formulation	Unpreserved Formulation First, Then Preserved Formulation
Arm/Group Description	Tafluprost 0.0015% preserved formulation once daily for first 4 weeks, then unpreserved formulation (after washout)	Tafluprost 0.0015% unpreserved formulation once daily for first 4 weeks, then preserved formulation (after washout)
Period Title: First Treatment Period (4 Weeks)
STARTED	21	22
COMPLETED	21	21
NOT COMPLETED	0	1
Period Title: First Treatment Period (4 Weeks)
STARTED	21	21
COMPLETED	21	21
NOT COMPLETED	0	0
Period Title: First Treatment Period (4 Weeks)
STARTED	21	21
COMPLETED	21	21
NOT COMPLETED	0	0
Period Title: First Treatment Period (4 Weeks)
STARTED	21	21
COMPLETED	21	21
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes all 43 randomized patients (86 eyes)
Overall Participants	43
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.3 (10.1)
Sex: Female, Male (Count of Participants)
Female	27 62.8%
Male	16 37.2%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	43 100%
Region of Enrollment (participants) [Number]
Germany	32 74.4%
Finland	11 25.6%
Diagnosis - worse eyes (eyes) [Number]
Primary Open Angle Glaucoma	28
Capsular Glaucoma	3
Ocular Hypertension	12
Central corneal thickness (micrometer) [Mean (Standard Deviation) ]
Right eye	548.7 (42.8)
Left eye	547.0 (45.4)

Outcome Measures

1. Primary Outcome

Title	Intraocular Pressures (IOPs) at Baseline
Description	IOPs at baseline: mean IOP values at four timepoints (worse eye)
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

IOPs of all subjects who received preserved/unpreserved formulation

Arm/Group Title	Preserved Formulation	Unpreserved Formulation
Arm/Group Description	tafluprost 0.0015% preserved formulation	tafluprost 0.0015% unpreserved formulation
Measure Participants	42	43
8 o'clock	22.57 (3.04)	22.98 (3.18)
12 o'clock	20.86 (2.79)	21.78 (2.68)
16 o'clock	21.73 (3.19)	21.51 (2.49)
20 o'clock	21.77 (3.02)	21.81 (2.61)

2. Secondary Outcome

Title	Overall and Time-wise Comparisons of IOP at Week 1
Description	The overall and time-wise, i.e. at 8:00, 12:00, 16:00 and 20:00, comparisons of IOP at week 1 (diurnal IOP and IOP value at given timepoint at 1 week minus corresponding value at baseline: unpreserved-preserved) were done using the RM ANCOVA model.
Time Frame	Baseline - Week 1

Outcome Measure Data

Analysis Population Description

ITT: randomized patients who received at least one dose of study medication and had at least one pharmacodynamic (IOP) measurement available.

Arm/Group Title	RM ANCOVA: ITT Efficacy Dataset
Arm/Group Description	randomized and received study medication
Measure Participants	43
Overall	-0.27
Timepoint 8:00	-0.32
Timepoint 12:00	-0.25
Timepoint 16:00	-0.39
Timepoint 20:00	-0.13

3. Secondary Outcome

Title	Change From Baseline in Time-wise IOPs at Week 4
Description	The time-wise, i.e. at 8:00, 12:00, 16:00 and 20:00, comparisons of IOP at week 4 (IOP value at given timepoint at 4 weeks minus corresponding value at baseline: unpreserved-preserved) were done using the RM ANCOVA model.
Time Frame	Baseline - Week 4

Outcome Measure Data

Analysis Population Description

ITT: randomized patients who received at least one dose of study medication and had at least one pharmacodynamic (IOP) measurement available.

Arm/Group Title	RM ANCOVA: ITT Efficacy Dataset
Arm/Group Description	randomized and received study medication
Measure Participants	43
Timepoint 8:00	0.24
Timepoint 12:00	0.11
Timepoint 16:00	0.00
Timepoint 20:00	-0.30

4. Primary Outcome

Title	Intraocular Pressures (IOPs) at Week 1
Description	IOPs at week 1: mean IOP values at four timepoints (worse eye)
Time Frame	Week 1

Outcome Measure Data

Analysis Population Description

IOPs of all subjects who received preserved/unpreserved formulation

Arm/Group Title	Preserved Formulation	Unpreserved Formulation
Arm/Group Description	tafluprost 0.0015% preserved formulation	tafluprost 0.0015% unpreserved formulation
Measure Participants	42	43
8 o'clock	16.43 (2.11)	16.21 (2.70)
12 o'clock	15.77 (1.60)	15.72 (1.92)
16 o'clock	16.23 (1.73)	15.83 (1.99)
20 o'clock	16.26 (2.20)	16.16 (2.08)

5. Primary Outcome

Title	Intraocular Pressures (IOPs) at Week 4
Description	IOPs at week 4: mean IOP values at four timepoints (worse eye)
Time Frame	Week 4

Outcome Measure Data

Analysis Population Description

IOPs of all subjects who received preserved/unpreserved formulation

Arm/Group Title	Preserved Formulation	Unpreserved Formulation
Arm/Group Description	tafluprost 0.0015% preserved formulation	tafluprost 0.0015% unpreserved formulation
Measure Participants	42	43
8 o'clock	16.39 (2.43)	16.80 (3.00)
12 o'clock	16.30 (2.46)	16.67 (2.54)
16 o'clock	16.64 (2.37)	16.71 (2.53)
20 o'clock	17.21 (1.91)	17.01 (2.44)

6. Primary Outcome

Title	Primary Pharmacodynamic Variable Intention to Treat Efficacy Dataset: Change From Baseline in the Overall Diurnal Intraocular Pressure (IOP) at Week 4 (Worse Eye)
Description	Overall treatment difference at 4 weeks (unpreserved-preserved) evaluated using a repeated measurements analysis of covariance (RM ANCOVA) model.
Time Frame	Baseline - Week 4

Outcome Measure Data

Analysis Population Description

Intention To Treat (ITT): randomized patients who received at least one dose of study medication and had at least one pharmacodynamic (IOP) measurement available.

Arm/Group Title	RM ANCOVA: ITT Efficacy Dataset
Arm/Group Description	randomized who received at least one dose of study medication and had at least one IOP measurement
Measure Participants	43
Mean (95% Confidence Interval) [mmHg]	0.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Preserved Formulation
	Comments	H1 (the alternative hypothesis aimed to be proven): the unpreserved formulation is equivalent with the preserved formulation
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The equivalence limit was set to 1.5 mmHg. Equivalence was shown if the two-sided 95% confidence interval for the difference (unpreserved-preserved) lay entirely within the equivalence range (-1.5 mmHg, 1.5 mmHg). Target sample size was 34 evaluable patients (40 randomized), assuming a standard deviation of 3.0 mmHg change in IOP, a power of 80%, an intra-class correlation coefficient of 0.60 and a twosided type 1 error rate of 5%.
Statistical Test of Hypothesis	p-Value	0.96
	Comments
	Method	ANCOVA
	Comments	Baseline IOP a covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.01
	Confidence Interval	() 95%; -0.46 to 0.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis model used IOP measurements at four timepoints (at 8, 12, 16 and 20 o'clock) on Baseline and Week 4.

7. Primary Outcome

Title	Primary Pharmacodynamic Variable Per Protocol Efficacy Dataset: Change From Baseline in the Overall Diurnal Intraocular Pressure (IOP) at Week 4 (Worse Eye)
Description	Overall treatment difference at 4 weeks (unpreserved-preserved) evaluated using a repeated measurments analysis of covariance (RM ANCOVA) model.
Time Frame	Baseline - Week 4

Outcome Measure Data

Analysis Population Description

Per Protocol (PP): randomized patients who completed the study per protocol (i.e. excluded from PP is the discontinued patient and a patient with major protocol violation)

Arm/Group Title	RM ANCOVA: PP Efficacy Dataset
Arm/Group Description	randomized patients who completed the study per protocol (PP)
Measure Participants	41
Mean (95% Confidence Interval) [mmHg]	-0.05

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Preserved Formulation
	Comments	H1 (the alternative hypothesis aimed to be proven): the unpreserved formulation is equivalent with the preserved formulation
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The equivalence limit was set to 1.5 mmHg. Equivalence was shown if the two-sided 95% confidence interval for the difference (unpreserved-preserved) lay entirely within the equivalence range (-1.5 mmHg, 1.5 mmHg). Target sample size was 34 evaluable patients (40 randomized), assuming a standard deviation of 3.0 mmHg change in IOP, a power of 80%, an intra-class correlation coefficient of 0.60 and a twosided type I error rate of 5%.
Statistical Test of Hypothesis	p-Value	0.83
	Comments
	Method	ANCOVA
	Comments	Baseline IOP a covariate
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	() 95%; -0.52 to 0.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis model used IOP measurements at four timepoints (at 8, 12, 16 and 20 o'clock) on Baseline and Week 4

Adverse Events

Time Frame	Adverse event data was collected at Week 1 and Week 4 visits of treatment period I and II, as well as on last Post-study visit. Additionally, baseline symptoms were queried on Day 0 (=Baseline) visit of the two treatment periods.
Adverse Event Reporting Description	Patients were asked about ocular or non-ocular symptoms with a non-leading question, or they volunteered the information during a study visit. Also, any clinically significant signs observed by the investigator could be recorded as adverse events.
Arm/Group Title	Preserved Formulation		Unpreserved Formulation
Arm/Group Description	Tafluprost 0.0015% preserved formulation once daily for 4 weeks		Tafluprost 0.0015% unpreserved formulation once daily for first 4 weeks
All Cause Mortality
	Preserved Formulation		Unpreserved Formulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Preserved Formulation		Unpreserved Formulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/43 (0%)
Other (Not Including Serious) Adverse Events
	Preserved Formulation		Unpreserved Formulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/42 (16.7%)		11/43 (25.6%)
Eye disorders
Conjunctival hyperemia	2/42 (4.8%)	2	6/43 (14%)	6
Ocular hyperemia	0/42 (0%)	0	2/43 (4.7%)	2
Erythema of eyelid	1/42 (2.4%)	1	1/43 (2.3%)	1
Eye pruritus	1/42 (2.4%)	1	1/43 (2.3%)	1
Foreign body sensation	1/42 (2.4%)	1	1/43 (2.3%)	1
Anterior chamber cell	0/42 (0%)	0	1/43 (2.3%)	1
Blepharitis	0/42 (0%)	0	1/43 (2.3%)	1
Eye pain	0/42 (0%)	0	1/43 (2.3%)	1
Lacrimation increased	0/42 (0%)	0	1/43 (2.3%)	1
Punctate keratitis	0/42 (0%)	0	1/43 (2.3%)	1
Vision blurred	1/42 (2.4%)	1	0/43 (0%)	0
Asthenopia	0/42 (0%)	0	1/43 (2.3%)	1
Conjunctival haemorrhage	0/42 (0%)	0	1/43 (2.3%)	1
Dry eye	0/42 (0%)	0	1/43 (2.3%)	1
Gastrointestinal disorders
Nausea	1/42 (2.4%)	1	0/43 (0%)	0
Injury, poisoning and procedural complications
Superficial injury of eye	1/42 (2.4%)	1	0/43 (0%)	0
Musculoskeletal and connective tissue disorders
Pain in extremity	0/42 (0%)	0	1/43 (2.3%)	1
Osteoporosis	1/42 (2.4%)	1	0/43 (0%)	0
Tendonitis	1/42 (2.4%)	1	0/43 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The sponsor respects the investigators' wish to publish results of the study, and will not unnecessarily restrict the spreading of information of scientific interest. However, the study may involve confidential information affecting the company's business, such as aspects related to patent application. Therefore, the investigators agree to allow the sponsor to review any manuscripts and to negotiate timing and forum of publication.