Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000414718
Ethics application status
Approved
Date submitted
4/03/2022
Date registered
10/03/2022
Date last updated
27/10/2023
Date data sharing statement initially provided
10/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
The Vitamin B3 in Glaucoma Study (VBIGS)
Scientific title
The Vitamin B3 in Glaucoma Study (VBIGS): A 2-year Multi-centre, Double-masked, Randomised, Placebo-controlled Trial of Nicotinamide (Vitamin B3) Supplementation in Glaucoma
Secondary ID [1] 306977 0
NCT05275738
Universal Trial Number (UTN)
U1111-1269-9944
Trial acronym
VBIGS
Linked study record
This is a follow-up study from ACTRN12617000809336. In the earlier study, we showed the short-term effects (12 weeks) of nicotinamide supplementation in people with glaucoma.

Health condition
Health condition(s) or problem(s) studied:
Glaucoma 325480 0
Condition category
Condition code
Eye 322864 322864 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 24 months
Dose: accelerated dose from 1.5 grams daily for 6 weeks to 3 grams daily (1.5 grams, twice a day) for the remaining period
Mode of administration: oral tablet, to be taken with food

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 may be sent, and a daily alarm set on participant's phone (if required). A minimum 70% compliance rate will be deemed acceptable, which approximately equates to forgetting to take the intervention twice a week.
Intervention code [1] 323013 0
Treatment: Drugs
Comparator / control treatment
Placebo comparator: Microcrystalline cellulose (matching tablets containing no active ingredients)
Control group
Placebo

Outcomes
Primary outcome [1] 330650 0
Changes to rate of visual field progression, specifically visual field sensitivity assessed using perimetry (visual field machine)
Timepoint [1] 330650 0
Baseline and 24 months after commencement of intervention
Secondary outcome [1] 407083 0
Changes to retinal structure after intervention, specifically changes to retinal nerve fibre layer thickness measuring using optical coherence tomography (OCT)
Timepoint [1] 407083 0
Baseline and 24 months after commencement of intervention
Secondary outcome [2] 407084 0
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] 407084 0
Baseline, 4, 12 and 24 months after commencement of intervention
Secondary outcome [3] 407085 0
Quality of life as measured using the GAL-9 questionnaire
Timepoint [3] 407085 0
Baseline, 12 and 24 months after commencement of intervention

Eligibility
Key inclusion criteria
• Adults with definitive, treated primary open angle glaucoma (POAG), normal tension glaucoma (NTG) or pseudoexfoliative glaucoma (PXFG) in both eyes
• Best-corrected visual acuity of at least 6/18 in each eye
• Severity of visual field (VF) loss, mean deviation (MD) between -3 and -18 dB. This range includes people with moderate disease which optimises detection of progression.
• Patients must have prior 2-3 x 24-2 VF tests in the past which meet VF reliability criteria.
• Previous selective laser trabeculoplasty is acceptable (IOP-lowering laser treatment) if more than 3 months prior, and normal liver function tests.
• Those taking nicotinamide (NAM) already will undergo a 1-month washout period before commencing the study.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Adults with a history of hepatic disease, visually significant cataracts, other conditions that can affect visual field results, glaucoma filtration surgery in last 6 months, cataract surgery in the last 3 months

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)
Centrally randomised on cloud-based software, REDCap
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
1:1 randomisation stratified by trial site and glaucoma subtype
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size calculation:
Simulation studies were performed to estimate power based on a two-year study with four-monthly visit intervals and repeated VF testing at each visit. Estimates of variance and between-visit correlation were based on existing literature and unpublished research data.28,29 Under the assumption of an average decline in VF MD of 0.4 dB/year among the placebo group and the minimum clinically meaningful effect size worth detecting of 30% (for which there is evidence of a significant benefit to QoL, the mean difference in rate of change between intervention groups would be 0.12 dB/year. Assumed standard deviations of 3.4 dB for the intercept, 0.3 dB/year for the rate of change, and 1 dB for within visit were incorporated in the 1000 simulated datasets per scenario.31 The intraclass correlation between eyes was assumed to be 0.5.

Under these assumptions, where 60% of participants enrol one eye only, and a type I error of 0.05, 80% power would be achieved with 180 participants per group. Complete dropout of 15% of participants would require an additional 32 per group, resulting in a target of 424 participants.

Statistical Methods:
The statistical analysis plan (SAP) will be finalised before the database lock. It will describe methodology for summary and statistical analyses of the primary and secondary outcomes, provide definitions of analysis sets, and detail approaches for handling missing data. A summary of primary and secondary analysis methods is presented below. Any major modifications to the primary outcome definition or analysis will be reflected in a protocol amendment.

Primary efficacy analysis: The primary analysis will be conducted among the modified intention-to-treat (mITT) set. The unit of analysis will be the eye. Linear mixed-effects models (LMM) will be used to estimate the mean difference in the rate of VF MD change between intervention and placebo groups over two years with two-sided 95% CIs. Potential baseline predictors of the outcome and stratification variables will included as model covariates. Model parameters and covariates will be specified in the statistical analysis plan. The primary analysis will be assessed using a two-sided significance level of 0.05. Assuming VF data will be missing at random, the LMM will produce an unbiased estimate of the estimand. Imputation for missing data may be considered under conditions specified in the SAP.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
25/04/2022
Actual
31/01/2023
Date of last participant enrolment
Anticipated
31/07/2024
Actual
Date of last data collection
Anticipated
31/07/2026
Actual
Sample size
Target
424
Accrual to date
5
Final
Recruitment in Australia
Recruitment state(s)
SA,VIC

Funding & Sponsors
Funding source category [1] 310916 0
Charities/Societies/Foundations
Name [1] 310916 0
Glaucoma Australia
Country [1] 310916 0
Australia
Funding source category [2] 310917 0
Other
Name [2] 310917 0
Centre for Eye Research Australia
Country [2] 310917 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] 312203 0
None
Name [1] 312203 0
Address [1] 312203 0
Country [1] 312203 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310476 0
St Vincent's Hospital Melbourne Human Research Ethics Committee
Ethics committee address [1] 310476 0
Ethics committee country [1] 310476 0
Australia
Date submitted for ethics approval [1] 310476 0
14/01/2022
Approval date [1] 310476 0
29/03/2022
Ethics approval number [1] 310476 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117802 0
Prof Keith Martin
Address 117802 0
Centre for Eye Research Australia
Level 7, Peter Howson Wing
32 Gisborne Street, East Melbourne, Victoria 3002
Country 117802 0
Australia
Phone 117802 0
+61 3 9929 8429
Fax 117802 0
Email 117802 0
[email protected]
Contact person for public queries
Name 117803 0
Maria Hamidi
Address 117803 0
Centre for Eye Research Australia
Level 7, Peter Howson Wing
32 Gisborne Street, East Melbourne, Victoria 3002
Country 117803 0
Australia
Phone 117803 0
+61 3 9929 8748
Fax 117803 0
Email 117803 0
[email protected]
Contact person for scientific queries
Name 117804 0
Flora Hui
Address 117804 0
Centre for Eye Research Australia
Level 7, Peter Howson Wing
32 Gisborne Street, East Melbourne, Victoria 3002
Country 117804 0
Australia
Phone 117804 0
+61 3 9929 8114
Fax 117804 0
Email 117804 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified participant data underlying published results
When will data be available (start and end dates)?
Data will be available following publication.
No end date
Available to whom?
Researchers who provide a methodologically sound proposal
The trial database may by uploaded to the Health Studies National Data Asset program (HeSANDA) following completion
Available for what types of analyses?
To achieve the aims in the proposal
How or where can data be obtained?
Access subject to approvals by Principal Investigators, Prof Keith Martin and Dr Flora Hui
[email protected]


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.