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Trial registered on ANZCTR


Registration number
ACTRN12616000039482p
Ethics application status
Not yet submitted
Date submitted
26/12/2015
Date registered
19/01/2016
Date last updated
19/01/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Lacrimal gland botulinum toxin injection for chronic epiphora in patients with anatomical or functional nasolacrimal duct obstruction: A randomised, double-blinded, placebo-controlled, crossover trial using subjective endpoints.
Scientific title
In patients with chronic epiphora due to partial, complete, or functional nasolacrimal duct obstruction, is lacrimal gland botulinum toxin injection more effective at reducing subjective symptoms as compared to placebo?
Secondary ID [1] 286099 0
Nil
Universal Trial Number (UTN)
U1111-1176-0221
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anatomical nasolacrimal duct obstruction 295259 0
Functional nasolacrimal duct obstruction 295260 0
Chronic epiphora 297256 0
Condition category
Condition code
Eye 295505 295505 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Lacrimal gland botulinum toxin injection:

2.5U Botox (registered trademark) will be injected transconjunctivally into the lacrimal gland of the most symptomatic eye by an ophthalmologist. If the eye is still symptomatic at 1 week, a repeat injection will be given within 2 weeks of the initial injection.

The washout period between treatments will be 6 months from the initial injection.

Adherence is not an issue in this study because the drug is administered personally by the principal investigator.
Intervention code [1] 292037 0
Treatment: Drugs
Comparator / control treatment
Placebo (normal saline)

Normal saline placebo will be injected transconjunctivally into the lacrimal gland of the most symptomatic eye. If the eye is still symptomatic at 1 week, a repeat injection of normal saline will be given within 2 weeks of the initial injection.
Control group
Placebo

Outcomes
Primary outcome [1] 295243 0
Mean change in Munk Score over time

Munk Score is a subjective measure of epiphora symptoms, where participants report the number of times per day they are dabbing tears from their eyes.
Timepoint [1] 295243 0
- Baseline
- 1 week post initial treatment
- 3 weeks post initial treatment
- 3 months post initial treatment
- 6 months post initial treatment

- 1 week post crossover
- 3 weeks post crossover
- 3 months post crossover
- 6 months post crossover

Secondary outcome [1] 315171 0
Subjective change in symptoms of epiphora, as measured by a predetermined ordinal scale (designed specifically for study).
Timepoint [1] 315171 0
- Baseline
- 1 week post initial treatment
- 3 weeks post initial treatment
- 3 months post initial treatment
- 6 months post initial treatment

- 1 week post crossover
- 3 weeks post crossover
- 3 months post crossover
- 6 months post crossover
Secondary outcome [2] 315172 0
Subjective perception of the effect of epiphora on physical and mental well-being, as measured by a predetermined ordinal scale (designed specifically for study).
Timepoint [2] 315172 0
- Baseline
- 1 week post initial treatment
- 3 weeks post initial treatment
- 3 months post initial treatment
- 6 months post initial treatment

- 1 week post crossover
- 3 weeks post crossover
- 3 months post crossover
- 6 months post crossover
Secondary outcome [3] 315173 0
Complications (if any). The most common complications from lacrimal gland botulinum toxin injections are ptosis (drooping of the eyelid) and vertical diplopia (double vision in the vertical plane).

Other potential complications include:
- Allergic reaction (will be noticed at time of injection and treated as per standard clinical protocol)
- Flu-like symptoms
- Paralysis of more distant muscles (unlikely given low dose)
- Dry mouth
- Facial weakness
- Dizziness
- Paraesthesia
- Eyelid bruising/swelling

We will assess for these complications by asking if patients about them during follow-up phone consultations.
Timepoint [3] 315173 0
- Baseline (complications will be assessed at baseline in case of pre-existing ptosis/diplopia)
- 1 week post initial treatment
- 3 weeks post initial treatment
- 3 months post initial treatment
- 6 months post initial treatment

- 1 week post crossover
- 3 weeks post crossover
- 3 months post crossover
- 6 months post crossover

Eligibility
Key inclusion criteria
- Documented diagnosis of either NLDO or FNLDO (or both) as diagnosed by dye disappearance test, lacrimal lavage and Jones test;
- Pre-treatment Munk Score of 4 or 5 (moderate to severe symptoms); and
- Chronic epiphora for 6 months or more.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Age under 18 years;
- Unable to provide informed consent;
- Previous botulinum toxin treatment of any kind; or
- Any of the following conditions:

Punctal ectropion; horizontal lid laxity >8mm; tear break-up time <7 seconds; signs of superficial punctate keratopathy on slit-lamp examination with Fluorescein staining; acute or chronic conjunctivitis; acute or chronic corneal ulcer; spastic or cicatricial entropion; trichiasis; thyroid eye disease; history of allergic rhinitis with positive response to intranasal steroid; or documented dacryocystitis.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants will be formally diagnosed with NLDO or FNLDO by the principal investigator. At recruitment, informed consent will be obtained from participants and baseline details will be collected using a pre-designed questionnaire.

Participants will be randomised into one of two groups. Group A (treatment first) will have botulinum toxin treatment at the first treatment visit and placebo treatment at the second; Group B (placebo first) will have placebo treatment at the first visit and botulinum toxin treatment at the second.

We will use block randomisation with equal allocation between treatment arms. Randomisation will be performed as detailed below.An independent third party (ophthalmic technician or clinic nurse) will use the GraphPad calculator to generate a list of 50 participants, numbered 1 to 50. As participants are recruited, they will be assigned an identification number, which will correlate with the number on the randomised list. The investigators will not have access to the randomised list. If more than 50 participants are recruited, the GraphPad calculator will be used to randomly assign these participants as required.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed using the GraphPad random number calculator, available freely online (http://www.graphpad.com/quickcalcs/randomize1/). This calculator randomly assigns participants to groups. It first assigns participants non-randomly, and then swaps the assignment of each participant with the assignment of a randomly chosen participant. This process is repeated twice to ensure it is completely random.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Crossover
Other design features
Phase
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Data will be analysed on an intention-to-treat basis. Noncompliant participants as well as those who withdraw voluntarily or non-voluntarily will be included in the final analysis.

Statistical analyses will be performed using Microsoft Excel (registered trademark) and Stata (registered trademark) version 13 using standard statistical method for hypothesis testing and calculation of confidence intervals. Logistic regression methods will be used to control for the effect of confounders, if any.

Sample size was calculated using the “One Sample Using Percentage values” calculator at the following website (accessed 12/1/2016):
https://www.dssresearch.com/KnowledgeCenter/toolkitcalculators/samplesizecalculators.aspx

If we assume a 75% response in the treatment group (based on prior similar studies), a 50% response in the control group, a confidence interval of 5%, and a beta error level of 5%, the recommended sample size is 38. If we assume a 20% dropout rate, we need to recruit approximately 50 patients in total for the study


Recruitment
Recruitment status
Not yet recruiting
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] 6956 0
New Zealand
State/province [1] 6956 0
Wellington

Funding & Sponsors
Funding source category [1] 291435 0
Charities/Societies/Foundations
Name [1] 291435 0
Capital Vision Research TrustFunding yet to be confirmed
Address [1] 291435 0
Capital Vision Research Trust
PO Box 6592
Marion Square
Wellington 6011
New Zealand
Country [1] 291435 0
New Zealand
Primary sponsor type
Individual
Name
Dr Kenneth Chan
Address
Eye Department
Wellington Hospital
Private Bag 7902
Wellington 6021
Country
New Zealand
Secondary sponsor category [1] 290110 0
Individual
Name [1] 290110 0
Clark Stevenson
Address [1] 290110 0
Eye Department
Wellington Hospital
Private Bag 7902
Wellington 6021
Country [1] 290110 0
New Zealand

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 292974 0
Health and Disability Ethics Committee
Ethics committee address [1] 292974 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street
Wellington 6011
Ethics committee country [1] 292974 0
New Zealand
Date submitted for ethics approval [1] 292974 0
01/02/2016
Approval date [1] 292974 0
Ethics approval number [1] 292974 0

Summary
Brief summary
Epiphora, or excessive watering of the eye, is a distressing symptom of nasolacrimal duct obstruction. It can lead to significant reduction in quality of life and cause social embarrassment. Current treatment options, such as dacryocystorhinostomy, are surgically invasive and carry a small risk or morbidity.

Botulinum toxin injection into the lacrimal gland is a promising treatment for epiphora in patients with nasolacrimal duct obstruction who refuse, or are not fit for surgery. It can be offered in an outpatient setting and published case series suggest that this treatment is safe and effective. However, there is currently a lack of randomised, controlled trials to support its routine use in patients with nasolacrimal duct obstruction.

The proposed study will be the first of its kind to systematically evaluate botulinum toxin as a treatment for epiphora in patients with nasolacrimal duct obstruction. We propose a randomised, double-blinded, placebo-controlled, crossover trial. Patients will be randomised to receive an injection of either botulinum toxin or placebo (normal saline) initially, and 6 months later they will cross over treatments. We will perform phone follow-up interviews to assess change in subjective measures of epiphora symptoms and complication rates.

Our hypothesis is that lacrimal gland botulinum toxin injection will significantly reduce subjective symptoms of chronic epiphora in patients with nasolacrimal duct obstruction as compared to placebo.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 54626 0
Dr Kenneth Chan
Address 54626 0
Eye Department
Wellington Hospital
Private Bag 7902
Wellington 6021
Country 54626 0
New Zealand
Phone 54626 0
+64 (04) 806 2650
Fax 54626 0
Email 54626 0
kenneth.chan@ccdhb.org.nz
Contact person for public queries
Name 54627 0
Dr Clark Stevenson
Address 54627 0
c/o Dr Kenneth Chan
Eye Department
Wellington Hospital
Private Bag 7902
Wellington 6021
Country 54627 0
New Zealand
Phone 54627 0
+64 (04) 806 2650
Fax 54627 0
Email 54627 0
clark.stevenson@huttvalleydhb.org.nz
Contact person for scientific queries
Name 54628 0
Dr Clark Stevenson
Address 54628 0
c/o Dr Kenneth Chan
Eye Department
Wellington Hospital
Private Bag 7902
Wellington 6021
Country 54628 0
New Zealand
Phone 54628 0
+64 (04) 806 2650
Fax 54628 0
Email 54628 0
clark.stevenson@huttvalleydhb.org.nz

No information has been provided regarding IPD availability
Summary results
No Results