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Trial registered on ANZCTR


Registration number
ACTRN12616000404426
Ethics application status
Approved
Date submitted
22/03/2016
Date registered
30/03/2016
Date last updated
2/03/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy of the tissue press method for reducing systemic side effects of eye drops compared to nasolacrimal occlusion
Scientific title
A new technique to reduce possible systemic side effects of eye drops: the difference in plasma concentration of Timolol after dry tissue pressure compared to nasolacrimal occlusion following ocular application
Secondary ID [1] 288825 0
Nil known
Universal Trial Number (UTN)
U1111-1179-6872
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Adverse systemic effects of eye drops 298101 0
Condition category
Condition code
Eye 298268 298268 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participation of subjects includes applying Timolol 0.5% eye drops, one drop in each eye (one drop consists of 33 - 64 microliter), immediately followed either by an action, which is thought to reduce systemic uptake or followed by no action at all. The first action (arm 1) is the tissue press method (after applying 1 drop of Timolol 0.5% in each eye, a clean facial tissue is balled-up. It is firmly pressed on one eye, then on the other eye, simultaneously wiping excess medication, which takes around 2-3 seconds to perform), the second action (arm 2) is nasolacrimal occlusion (after applying 1 drop of Timolol 0.5% in each eye one finger per eye is pressed on the area nasally to the medial canthus for 5 minutes), and no action (arm 3; Timolol 0.5% is applied in each eye. No additional action must be performed then) represents the control. One hour after application a blood sample is taken to detect Timolol plasma levels. Patients are planned to undergo both, two different procedures, which are thought to reduce systemic substance uptake and drop application without any following action. The washout period between each treatment is at least 7 days. Administration of the eye drops is conducted by a member of the staff and the following action is supervised by the the same person to ensure that administration and action are both performed correctly.
Intervention code [1] 294280 0
Behaviour
Intervention code [2] 294293 0
Prevention
Comparator / control treatment
Patients are planned to undergo both, two different procedures, which are thought to reduce systemic substance uptake and drop application without any following action. The Timolol application with no following action will be used as the control treatment. Therefore participants form their own control group.
Control group
Active

Outcomes
Primary outcome [1] 297753 0
The primary objective is to assess the difference in plasma Timolol following the tissue press method compared to no action. Timolol plasma concentration is assessed by LC-MS/MS (Liquid chromatography-tandem mass spectrometry).
Timepoint [1] 297753 0
Blood samples are taken one hour after Timolol administration for each treatment arm
Secondary outcome [1] 322131 0
The secondary objective is to assess the difference in plasma Timolol following the tissue press method compared to nasolacrimal occlusion. Timolol plasma concentration is assessed by LC-MS/MS (Liquid chromatography-tandem mass spectrometry).
Timepoint [1] 322131 0
Blood samples are taken one hour after Timolol administration for each treatment arm

Eligibility
Key inclusion criteria
Participants must be 18 years old or more and be able to understand the purpose of this study and perform the interventions following Timolol application. Otherwise, all people, not fulfilling any of the exclusion criteria may be included. Informed consent has to be obtained.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Health conditions that increase the probability of side effects of Timolol
- Hypersensitivity to Timolol or one of the additives
- Systemic Beta blocker intake
- Inability to understand and perform the instructions
- Pregnancy or ongoing breast feeding

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Statistical evaluation of the difference between the tested methods. The sample size was determined by a power analysis, assuming the tissue press method is about as effective as nasolacrimal occlusion and therefore able to reduce Timolol plasma levels to the same amount, compared to no intervention after drop application. This calculation based on results from previous studies comparing nasolacrimal occlusion (which showed 0.41 ng/ml (+/- 0.07) Timolol plasma concentration) to no intervention after drop application (which showed 1.28 ng/ml (+/- 0.19) Timolol plasma concentration). Power calculation included a power of 0.8 and a alpha significance criterion of 0.05. To find a difference between the tissue press method and nasolacrimal occlusion, an infinit sample size would be appropriate (assuming there is no difference). As this is not possible we based the power analysis on an assumed difference of 20% - 25% in plasma levels (corresponds 0.492 ng/ml and 0.512 ng/ml respectively) after those two interventions, which results in a sample size of 14 - 22 participants.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 7728 0
New Zealand
State/province [1] 7728 0
Wellington

Funding & Sponsors
Funding source category [1] 293187 0
Charities/Societies/Foundations
Name [1] 293187 0
Capital Vision Research Trust
Address [1] 293187 0
148 Cuba Street, Level 2
Te Aro
Wellington 6011
Country [1] 293187 0
New Zealand
Primary sponsor type
Individual
Name
Luzia Mueller
Address
Capital Eye Specialists
148 Cuba Street, Level 2
Te Aro
Wellington 6011
Country
New Zealand
Secondary sponsor category [1] 291980 0
Charities/Societies/Foundations
Name [1] 291980 0
Capital Vision Research Trust
Address [1] 291980 0
148 Cuba Street, Level 2
Te Aro
Wellington 6011
Country [1] 291980 0
New Zealand
Secondary sponsor category [2] 291982 0
Other
Name [2] 291982 0
Capital Eye Specialists
Address [2] 291982 0
148 Cuba Street, Level 2
Te Aro
Wellington 6011
Country [2] 291982 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294674 0
Health and Disability Ethics Committees (HDECs)
Ethics committee address [1] 294674 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street
Wellington 6011
Ethics committee country [1] 294674 0
New Zealand
Date submitted for ethics approval [1] 294674 0
26/02/2016
Approval date [1] 294674 0
11/03/2016
Ethics approval number [1] 294674 0
16/CEN/26

Summary
Brief summary
The absorption of eyedrop medications into the systemic circulation is an uncommon but well known cause of morbidity in glaucoma patients. As a result of Timolol drop application, adverse cardiac and respiratory events in vulnerable individuals are described among other consequences of circulating beta-blockers. Other drops which may be used regularly can also cause adverse effects via systemic absorption. Minimising the amount of drugs that reach the bloodstream is an advice dispensed on every eyedrop drug information and taught worldwide: pressing on the nasolacrimal ducts adjacent to the nose for several minutes (nasolacrimal occlusion). The aim is to stop medications in the tear film draining into the the nose to be absorbed. In papers describing clinical study situations, nasolacrimal occlusion has been shown to decrease blood levels of absorbed beta-blocker drops compared to no action. But in reality it is difficult, may be uncomfortable, and is usually performed poorly for an inadequate amount of time. We suspect that a simpler technique, pressing firmly a dry tissue on the closed eyelid after drop application, will be as effective and much easier to do consistently in the daily life. This study is planned to be a prospective controlled trial. Participation includes applying Timolol 0.5% drops in each eye, followed either by an action, which is thought to reduce systemic uptake or followed by no action. One hour after application a blood sample is taken to detect Timolol plasma levels. Patients are planned to undergo 2 procedures, which are thought to reduce systemic substance uptake and drop application without any following action. Between each procedure will be an interval of at least 1 week to avoid any remaining effects. Therefore participants form their own control group. Participants with risk factors for adverse effects are excluded. The aim is to show the effectiveness of a new procedure in reducing systemic uptake after eye drop application
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64610 0
Dr Luzia Mueller
Address 64610 0
Augenklinik Luzern
Spitalstrasse
CH - 6004 Luzern
Country 64610 0
Switzerland
Phone 64610 0
+41412053337
Fax 64610 0
Email 64610 0
luzia.mueller@luks.ch
Contact person for public queries
Name 64611 0
Dr Luzia Mueller
Address 64611 0
Augenklinik Luzern
Spitalstrasse
CH - 6004 Luzern
Country 64611 0
Switzerland
Phone 64611 0
+41412053337
Fax 64611 0
Email 64611 0
luzia.mueller@luks.ch
Contact person for scientific queries
Name 64612 0
Dr Luzia Mueller
Address 64612 0
Augenklinik Luzern
Spitalstrasse
CH - 6004 Luzern
Country 64612 0
Switzerland
Phone 64612 0
+41412053337
Fax 64612 0
Email 64612 0
luzia.mueller@luks.ch

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary