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Trial registered on ANZCTR


Registration number
ACTRN12617000809336
Ethics application status
Approved
Date submitted
30/05/2017
Date registered
2/06/2017
Date last updated
15/03/2019
Date data sharing statement initially provided
15/03/2019
Date results information initially provided
15/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The Effect of Vitamin B3 Supplementation in Glaucoma
Scientific title
A Prospective Study on the Effect of Nicotinamide Supplementation on Ocular Function and Structure in Glaucoma
Secondary ID [1] 292025 0
None
Universal Trial Number (UTN)
U1111-1197-0197
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Glaucoma 303415 0
Condition category
Condition code
Eye 302825 302825 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
International Nonproprietary Name (INN): nicotinamide
Intervention: daily nicotinamide supplementation for 12 weeks
Dose: accelerated dose from 1.5 grams daily for 6 weeks to 3 grams daily for 6 weeks
Mode of administration: oral tablet

Study design: 2 participant groups with cross-over study design. Participants are randomly assigned to receive either nicotinamide or placebo for 12 weeks, followed by a cross-over (i.e. those on nicotinamide first will switch to placebo and those on placebo first will switch to nicotinamide) for a further 12 weeks.
A washout period will not be utilised as the effect of nicotinamide does not have a persistent effect after intake is ceased. As participants will be seen in 6-weekly intervals, we do not expect a nicotinamide-induced effect on our measurements in the group that receives nicotinamide first and placebo second. As for those that receive placebo first, then a washout period is also unnecessary as no intervention has been given.

Adherence monitoring: remaining tablets will be counted at each visit, participants will be asked to log each time they forget a dose. To improve adherence, weekly reminders via phone, e-mail or text message will be sent, and a daily alarm set on participant's phone (if they have a smartphone). A minimum 70% compliance rate will be deemed acceptable, which approximately equates to forgetting to take the intervention twice a week.
Intervention code [1] 298152 0
Treatment: Drugs
Comparator / control treatment
Placebo control (sugar pill) will be given to participants
Control group
Placebo

Outcomes
Primary outcome [1] 302209 0
Short-term changes in retinal function after intervention, specifically visual field sensitivity assessed using perimetry (visual field machine)
Timepoint [1] 302209 0
12 weeks after commencement of intervention
Primary outcome [2] 302211 0
Short-term changes in retinal function after intervention, specifically changes to the photopic (light-adapted) electroretinogram (ERG). As nicotinamide leads to NAD+ repletion, which can drive energy repletion in the cells of the retina, the ERG can be affected in different ways. Specific parameters include amplitude and timing changes to the a-wave (photoreceptor), b-wave (bipolar cell) and photopic negative response (PhNR, retinal ganglion cell).
Timepoint [2] 302211 0
12 weeks after commencement of intervention
Secondary outcome [1] 335171 0
Short-term changes to retinal structure after intervention, specifically changes to retinal nerve fibre layer thickness measuring using optical coherence tomography (OCT)
Timepoint [1] 335171 0
6 and 12 weeks after commencement of intervention
Secondary outcome [2] 335172 0
Short-term changes in retinal function after intervention, specifically visual field sensitivity assessed using perimetry (visual field machine)
Timepoint [2] 335172 0
6 weeks after randomisation and commencement of intervention
Secondary outcome [3] 335421 0
Composite secondary outcome: change to intraocular pressure and/or ocular perfusion pressure (OPP). OPP is the balance between blood pressure and intraocular pressure.
Intraocular pressure will be measured using a rebound tonometer (iCare tonometer).
Blood pressure will be measured using a digital sphygmomanometer with inflatable arm cuff.
Timepoint [3] 335421 0
6 and 12 weeks after commencement of intervention
Secondary outcome [4] 335457 0
Short-term changes in retinal function after intervention, specifically changes to the photopic (light-adapted) electroretinogram (ERG). As nicotinamide leads to NAD+ repletion, which can drive energy repletion in the cells of the retina, the ERG can be affected in different ways. Specific parameters include amplitude and timing changes to the a-wave (photoreceptor), b-wave (bipolar cell) and photopic negative response (PhNR, retinal ganglion cell).
Timepoint [4] 335457 0
6 weeks after randomisation and commencement of intervention
Secondary outcome [5] 335458 0
Changes to the spectral characteristics of the retinal tissue assessed by hyperspectral imaging. Hyperspectral imaging provides information on the spectral characteristics of the retinal tissue, and may allow for detection of minor alterations to retinal structure, in particular, the retinal nerve fibre layer, which may not be seen using optical coherence tomography.
As hyperspectral imaging of the retina is a novel technique, images are post-processed offline in Matlab to analyse the spectral information in order to detect structural changes in the retina that may manifest after nicotinamide supplementation.
Timepoint [5] 335458 0
6 and 12 weeks after commencement of intervention

Eligibility
Key inclusion criteria
- Diagnosis of primary open angle glaucoma by an ophthalmologist
- Recent (last 6 months), reliable visual field with mean defect equal to or better than -6 dB
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- those who are currently or intending to be pregnant/breastfeeding during the study
- those unwilling to abstain from other vitamin B supplements during the study period
- history of severe allergies or allergic reaction to nicotinamide or niacin
- those diagnosed with cancer in the last 5 years (except treated basal or squamous cell carcinoma)
- those with a history of liver disease
- those who cannot commit to the follow-up visits which occur at 6-weekly intervals over 24 weeks
- those who cannot provide informed consent
- eyes with a history of intraocular surgery in the past 6 months (uncomplicated cataract surgery within the last 3 months)
- systemic/ocular disease that are known to affect retinal function (e.g. age-related macular degeneration, demyelinating diseases, diabetic retinopathy)

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 randomly assigned to a numbered container which will contain either placebo or nicotinamide tablets.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly assigned to receive either placebo or nicotinamide first by simple randomisation, using Microsoft Excel for random number generation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Sample size calculation: Based on pilot data using the electroretinogram to detect functional changes in eyes after glaucoma surgery, an effect size of 0.56 was derived. A power calculation estimates that 48 eyes are required (power 80%, alpha = 0.05). To account for an attrition rate of 20%, we see to recruit 60 eyes all together with early glaucoma to effectively characterise the functional changes associated with NAD+ repletion with nicotinamide.

Statistics: Two-way repeated measures analysis of variance (RM-ANOVA) will be used to assess changes in the electroretinogram with nicotinamide, and the interaction nested within stimulus intensity. Two-way RM-ANOVA will also be used to assess the effect of nicotinamide on the electroretinogram, and the interaction nested within treatment change. Dunnett’s multiple comparisons tests will be used for post-hoc analysis to compare changes should they arise, between follow-up visits and baseline. One-way RM-ANOVA will be used to assess changes in individual locations on the 24-2 visual field. Correlations between the change in intraocular pressure and visual function will also be made in both nicotinamide and placebo groups.

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 in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 8211 0
The Royal Victorian Eye and Ear Hospital - East Melbourne
Recruitment hospital [2] 8290 0
Melbourne Eye Specialists - Fitzroy
Recruitment postcode(s) [1] 16270 0
3002 - East Melbourne
Recruitment postcode(s) [2] 16355 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 296555 0
Other
Name [1] 296555 0
Centre for Eye Research Australia
Address [1] 296555 0
32 Gisborne Street, East Melbourne, Victoria 3002
Country [1] 296555 0
Australia
Primary sponsor type
Other
Name
Centre for Eye Research Australia
Address
32 Gisborne Street, East Melbourne, Victoria 3002
Country
Australia
Secondary sponsor category [1] 295505 0
None
Name [1] 295505 0
Address [1] 295505 0
Country [1] 295505 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297769 0
Royal Victorian Eye and Ear Hospital Human Research Ethics Committee
Ethics committee address [1] 297769 0
32 Gisborne Street, East Melbourne, Victoria 3002
Ethics committee country [1] 297769 0
Australia
Date submitted for ethics approval [1] 297769 0
29/05/2017
Approval date [1] 297769 0
29/06/2017
Ethics approval number [1] 297769 0
17/1339H

Summary
Brief summary
This project aims to translate into the clinic a recently published study, demonstrating the protective role of vitamin B3 supplements (nicotinamide) in a mouse model of glaucoma. Glaucoma causes progressive loss of nerve tissue in the eye, and irreversible vision loss. This study investigates the short-term effect of taking nicotinamide supplements on the eye’s structure and function compared to placebo.
Primary aims of this study include: 1) determining whether nicotinamide supplements in participants with glaucoma leads to short-term improvement in visual function measured using visual fields and the electroretinogram (ERG) and 2) determining whether nicotinamide leads to structural changes to the nerve tissue, imaged using hyperspectral imaging and optical coherence tomography.
Participants diagnosed with glaucoma by an ophthalmologist will be invited to undertake the 24-week study with crossover design. They will be randomly assigned to take nicotinamide or placebo daily for 12 weeks. The ERG, visual fields and imaging are performed at baseline, 6 and 12-weeks post-intervention. Participants then crossover to take placebo or nicotinamide for another 12 weeks and the same measurements are repeated at 6 and 12-weeks post-intervention.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75062 0
Prof Jonathan Crowston
Address 75062 0
Centre for Eye Research Australia
Level 7, Peter Howson Wing
32 Gisborne Street, East Melbourne, Victoria 3002
Country 75062 0
Australia
Phone 75062 0
+61 3 9929 8429
Fax 75062 0
Email 75062 0
crowston@unimelb.edu.au
Contact person for public queries
Name 75063 0
Dr Flora Hui
Address 75063 0
Centre for Eye Research Australia
Level 7, Peter Howson Wing
32 Gisborne Street, East Melbourne, Victoria 3002
Country 75063 0
Australia
Phone 75063 0
+61 3 99298114
Fax 75063 0
Email 75063 0
f.hui@unimelb.edu.au
Contact person for scientific queries
Name 75064 0
Prof Jonathan Crowston
Address 75064 0
Centre for Eye Research Australia
Level 7, Peter Howson Wing
32 Gisborne Street, East Melbourne, Victoria 3002
Country 75064 0
Australia
Phone 75064 0
+61 3 9929 8429
Fax 75064 0
Email 75064 0
crowston@unimelb.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary