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Trial registered on ANZCTR


Registration number
ACTRN12618000705280
Ethics application status
Approved
Date submitted
23/04/2018
Date registered
30/04/2018
Date last updated
11/07/2019
Date data sharing statement initially provided
11/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Omega-3 supplements for improving peripheral nerve health in type-1 diabetes
Scientific title
A proof-of-concept, placebo-controlled trial to evaluate the effects of omega-3 fatty acid supplementation on peripheral nerve health in type-1 diabetes
Secondary ID [1] 294668 0
Nil
Universal Trial Number (UTN)
U1111-1212-5858
Trial acronym
nPROOFS-1 (Investigating the NeuroPRotective effect of Oral Omega-3 Fatty acid Supplementation in type1 diabetes)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type-1 diabetes 307526 0
Condition category
Condition code
Metabolic and Endocrine 306600 306600 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1 (Treatment 1): trigylceride long-chain omega-3 oral supplement, twice daily oral capsule, for six months

Adherence to treatment will be monitored by the analysis of systemic fatty acid profiles at the end of the study, and counting of the return of unused capsules at follow-up visits by an independent researcher.
Intervention code [1] 300969 0
Treatment: Drugs
Comparator / control treatment
Arm 2 (Placebo): olive oil oral supplement for six months
Control group
Placebo

Outcomes
Primary outcome [1] 305603 0
Central Corneal Nerve Fibre Length (CNFL) (measured in mm/mm2 using a Heidelberg Rostock Tomographer III with corneal module, quantified using a fully-automated method (ACCMetrics))
Timepoint [1] 305603 0
Change in CNFL from Day 1 at Days 90 +/- 7, 180 +/- 14 [primary timepoint]
Secondary outcome [1] 345854 0
Central Corneal Nerve Fibre Density (CNFD) (measured in mm/mm2 using a Heidelberg Rostock Tomographer III with corneal module, quantified using a fully-automated method (ACCMetrics))
Timepoint [1] 345854 0
Change in CNFD from Day 1 at 90 +/- 7, 180 +/- 14
Secondary outcome [2] 345855 0
Central Corneal Nerve Branch Density (CNBD) (measured in mm/mm2 using a Heidelberg Rostock Tomographer III with corneal module, quantified using a fully-automated method (ACCMetrics))
Timepoint [2] 345855 0
Change in CNBD from Day 1 at Days 90 +/- 7, 180 +/- 14
Secondary outcome [3] 345856 0
Central corneal dendritic cell count (CDC) (measured in mm/mm2 using a Heidelberg Rostock Tomographer III with corneal module)
Timepoint [3] 345856 0
Change in CDC count from Day 1 at Days 90 +/- 7, 180 +/- 14
Secondary outcome [4] 345857 0
Peripheral Corneal Nerve Fibre Length (CNFL) (measured in mm/mm2 using a Heidelberg Rostock Tomographer III with corneal module, quantified using a fully-automated method (ACCMetrics))
Timepoint [4] 345857 0
Change in CNFL from Day 1 at Days 90 +/- 7, 180 +/- 14
Secondary outcome [5] 345858 0
Peripheral Corneal Nerve Fibre Density (CNFD) (measured in mm/mm2 using a Heidelberg Rostock Tomographer III with corneal module, quantified using a fully-automated method (ACCMetrics))
Timepoint [5] 345858 0
Change in CNFD from Day 1 at Days 90 +/- 7, 180 +/- 14
Secondary outcome [6] 345859 0
Peripheral Corneal Nerve Branch Density (CNBD) (measured in mm/mm2 using a Heidelberg Rostock Tomographer III with corneal module, quantified using a fully-automated method (ACCMetrics))
Timepoint [6] 345859 0
Change in CNBD from Day 1 at Days 90 +/- 7, 180 +/- 14
Secondary outcome [7] 345860 0
Peripheral corneal dendritic cell count (CDC) (measured in mm/mm2 using a Heidelberg Rostock Tomographer III with corneal module)
Timepoint [7] 345860 0
Change in CDC count from Day 1 at Days 90 +/- 7, 180 +/- 14
Secondary outcome [8] 345861 0
Central corneal thresholds to a room-temperature air stimulus (measured in mBar using a non-contact corneal aesthesiometer)
Timepoint [8] 345861 0
Change from Day 1 at Days 90 +/- 7, 180 +/- 14
Secondary outcome [9] 345862 0
Peripheral corneal thresholds to a room-temperature air stimulus (measured in mBar using a non-contact corneal aesthesiometer)
Timepoint [9] 345862 0
Change from Day 1 at Days 90 +/- 7, 180 +/- 14
Secondary outcome [10] 345863 0
Central corneal thresholds to a cold air stimulus (measured in mBar using a non-contact corneal aesthesiometer)
Timepoint [10] 345863 0
Change from Day 1 at Days 90 +/- 7, 180 +/- 14
Secondary outcome [11] 345864 0
Peripheral corneal thresholds to a cold air stimulus (measured in mBar using a non-contact corneal aesthesiometer)
Timepoint [11] 345864 0
Change from Day 1 at Days 90 +/- 7, 180 +/- 14
Secondary outcome [12] 345865 0
Dry eye symptoms (measured using the validated Ocular Surface Disease Index (OSDI) questionnaire)
Timepoint [12] 345865 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [13] 345866 0
Tear osmolarity: electrolyte concentration of the tears (measured in mOsm/L using the TearLab system (TearLab Corporation Pty Ltd)
Timepoint [13] 345866 0
Change from Day 1 at Days 180 +/- 14
Secondary outcome [14] 345868 0
Tear stability: standard clinical measure of TBUT using sodium fluorescein dye.
Timepoint [14] 345868 0
Change from Day 1 at 90 +/- 7, 180 +/- 14
Secondary outcome [15] 345869 0
Michigan Diabetic Neuropathy Score (MDNS) (measured through clinical examination)
Timepoint [15] 345869 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [16] 345870 0
Routine nerve conduction studies (NCS) – ulnar sensory nerve (measured using Dantec Keypoint G4 Workstation)
Timepoint [16] 345870 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [17] 345871 0
Nerve excitability composite profile (measured with QTRAC software using TROND protocol)
Timepoint [17] 345871 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [18] 345872 0
Quantitative sudomotor axonal reflex testing (QSART), measured in sweat volume in nL using the QSWEAT system.
Timepoint [18] 345872 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [19] 345873 0
Cutaneous silent period testing: upper limb (measuring silent period onset latency and duration), using an electromyographic (EMG) device (Dantec Keypoint G4 Workstation)
Timepoint [19] 345873 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [20] 345932 0
Safety outcome: Change in best corrected visual acuity (BCVA) measured using a standard eye chart
Timepoint [20] 345932 0
Change from Day 1 at Days 30 +/- 7, 90 +/- 7, 180 +/- 14
Secondary outcome [21] 345933 0
Safety outcome: Change in intraocular pressure (IOP) measured using a Goldmann tonometer
Timepoint [21] 345933 0
Change from Day 1 at Days 30 +/- 7, 90 +/- 7, 180 +/- 14
Secondary outcome [22] 345936 0
Safety outcome: Diabetic retinopathy graded using the Wisconsin Scale grading system
Timepoint [22] 345936 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [23] 345937 0
Safety outcome: Standard blood pathology (fasting glucose, lipid profiles, FBC, ESR, CRP, Vitamin B-12, Folate, TSH, UEC, HbA1C, liver function, electrolytes)
Timepoint [23] 345937 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [24] 345938 0
Safety outcome: Incidence of adverse events (AEs). Common AEs, such as gastrointestinal discomfort (e.g., loose stools, constipation, heartburn, nausea, bloating) and rare AEs, such as minor bleeding (e.g., nose bleeds) will be assessed as the number of participants reporting AEs at each follow-up visit.
Timepoint [24] 345938 0
Change from Day 1 at Days 30 +/- 7, 90 +/- 7, 180 +/- 14
Secondary outcome [25] 345979 0
Routine nerve conduction studies (NCS) – median sensory nerve (measured using Dantec Keypoint G4 Workstation)
Timepoint [25] 345979 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [26] 345980 0
Routine nerve conduction studies (NCS) – sural sensory nerve (measured using Dantec Keypoint G4 Workstation)
Timepoint [26] 345980 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [27] 345981 0
Routine nerve conduction studies (NCS) – median motor nerve (measured using Dantec Keypoint G4 Workstation)
Timepoint [27] 345981 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [28] 345982 0
Routine nerve conduction studies (NCS) – peroneal motor nerve (measured using Dantec Keypoint G4 Workstation)
Timepoint [28] 345982 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [29] 345983 0
Routine nerve conduction studies (NCS) – tibial motor nerve (measured using Dantec Keypoint G4 Workstation)
Timepoint [29] 345983 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [30] 345984 0
Cutaneous silent period testing: lower limb (measuring silent period onset latency and duration) using an electromyographic (EMG) device (Dantec Keypoint G4 Workstation)
Timepoint [30] 345984 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [31] 345989 0
Quantitative sensory testing (measuring cold detection thresholds at the foot), using a NerveCheck Master, pending instrumentation availability
Timepoint [31] 345989 0
Change from Day 1 at Day 180 +/- 14
Secondary outcome [32] 349041 0
Change in health state (as measured using the EQ-5D-5L questionnaire).
Timepoint [32] 349041 0
Change from Day 1 at Days 30 +/- 7, 90 +/- 7, 180 +/- 14

Eligibility
Key inclusion criteria
Provision of written informed consent to participate
Confirmed diagnosis of type-1 diabetes for at least five years
Ability to understand and follow study instructions, and intent to complete all study visits
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Uncontrolled systemic disease (other than sub-optimally controlled diabetes mellitus)
Confirmed neuropathy secondary to causes other than diabetes
Co-morbid ocular pathology (e.g., ocular infection, intra-ocular inflammation) or presence of corneal abnormalities that could distrupt normal corneal nerve morphology
Known allergy to or previous reaction to any ocular agents used in the study (i.e., ocular anaesthetics, sodium fluorescein, ocular mydriatics)
Scheduled or planned ocular surgery or procedure over the course of the study
Any history of hard (rigid) contact lens wear
Use of autologous serum eye drops within three (3) months of enrolment, or anticipated use during the course of the study;
Known or suspected allergy to fish/seafood, nuts, oil or gelatin
Current or previous regular consumption of any omega-3 oral supplements (>3 times/week) in the three months preceding Visit 1
A systemic medical condition where omega-3 supplements are contraindicated (e.g., bleeding disorders, diabetes, atrial fibrillation, familial immunocompromise, adenomatous polyposis, liver disease.)

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 must satisfy all eligibility criteria and provide written informed consent to participate.
Eligible participants will be enrolled and assigned in sequential order to one of the two treatment groups (omega-3 or placebo treatment) using a participant/randomisation number sequence generated in advance that randomly assigns subjects to one of the two groups. This randomisation schedule will be generated by an independent data manager and provided to a separate independent entity responsible for labelling the investigational product.
To preserve masking, the oral supplements will be packaged in identical containers. Investigators collecting and analysing data will not be involved in the reconciliation of returned study product, The treatment allocation for which will not be known to the study personnel who was involved in enrolment (i.e., the study investigator) or the participant.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A randomised allocation sequence will be generated, in advance, by the independent data manager, using Microsoft Excel, to assign equal numbers of participants to the treatment and placebo groups. The code will be kept by the independent data manager and made available for labelling of the investigational product by sequential participant number.
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Given a two-arm parallel design, with the pre-specified primary outcome of CNFL (taken as a continuous measure), for 80% power at a confidence level of 95%, using an estimated true difference between intervention arms, the required sample size is 22 participants per group. To allow for 10% participant attrition, the sample size within each group will be increased by this amount, giving a need to recruit a total of 25 participants in each interventions arm (n=50 for the trial).

Recruitment
Recruitment status
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 in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 10770 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 22498 0
3065 - Fitzroy
Recruitment postcode(s) [2] 22499 0
3053 - Carlton

Funding & Sponsors
Funding source category [1] 299280 0
University
Name [1] 299280 0
Melbourne Neuroscience Institute (MNI) InterDisciplinary Seed Funding
Address [1] 299280 0
The University of Melbourne
Parkville
Victoria, Australia 3010
Country [1] 299280 0
Australia
Primary sponsor type
University
Name
The University of Melbourne
Address
The University of Melbourne
Parkville
Victoria, Australia 3010
Country
Australia
Secondary sponsor category [1] 298550 0
None
Name [1] 298550 0
Address [1] 298550 0
Country [1] 298550 0
Other collaborator category [1] 280080 0
Hospital
Name [1] 280080 0
St Vincent's Hospital
Address [1] 280080 0
St Vincent's Hospital Melbourne
41 Victoria Parade
Fitzroy
VIC 3065
Country [1] 280080 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300192 0
St Vincent's Hospital Melbourne Human Research Ethics Committee (HREC)
Ethics committee address [1] 300192 0
St Vincent's Hospital
41 Victoria Parade
Fitzroy
VIC 3065
Ethics committee country [1] 300192 0
Australia
Date submitted for ethics approval [1] 300192 0
17/11/2017
Approval date [1] 300192 0
09/02/2018
Ethics approval number [1] 300192 0

Summary
Brief summary
Diabetic neuropathy is the most common complication of diabetes mellitus, affecting >50% of individuals with the condition. The Diabetes Control and Complications Trial demonstrated that intensive blood glucose control could reduce the incidence of neuropathy and potentially slow progressive nerve damage; however, there are currently no clinical therapies for attenuating the onset or progression of neuropathy.

Omega-3 supplements have potential general health benefits, however their effect on peripheral nerves is currently unknown. There is growing scientific evidence that dietary supplementation with omega-3 essential fatty acids, may be of benefit in improving peripheral nerve integrity.

This randomised, double-masked, placebo-controlled clinical trial to assess the effects of a six-month period of supplementation with omega-3 PUFAs on small nerve fibre structure and function, measured both in the eye and the extremities of the body, in individuals with type-1 diabetes. The effects omega-3 supplements will be compared with a control group, who will consume an olive oil supplement. If shown to be effective, omega-3 supplements could be an adjuvant therapy (additional to achieving optimal glucose control), for treating diabetic neuropathy, for which there are currently no other treatments.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82862 0
Dr Laura Downie
Address 82862 0
Senior Lecturer and Research Leader - Anterior Eye, Clinical Trials and Research Translation Unit
Department of Optometry and Vision Sciences
Level 4 – Alice Hoy Building (Bldg 162), Monash Road
The University of Melbourne
Parkville, Victoria, Australia 3010.
Country 82862 0
Australia
Phone 82862 0
+61 3 9035 3043
Fax 82862 0
Email 82862 0
ldownie@unimelb.edu.au
Contact person for public queries
Name 82863 0
Dr Laura Downie
Address 82863 0
Senior Lecturer and Research Leader - Anterior Eye, Clinical Trials and Research Translation Unit
Department of Optometry and Vision Sciences
Level 4 – Alice Hoy Building (Bldg 162), Monash Road
The University of Melbourne
Parkville, Victoria, Australia 3010.
Country 82863 0
Australia
Phone 82863 0
+61 3 9035 3043
Fax 82863 0
Email 82863 0
ldownie@unimelb.edu.au
Contact person for scientific queries
Name 82864 0
Dr Laura Downie
Address 82864 0
Senior Lecturer and Research Leader - Anterior Eye, Clinical Trials and Research Translation Unit
Department of Optometry and Vision Sciences
Level 4 – Alice Hoy Building (Bldg 162), Monash Road
The University of Melbourne
Parkville, Victoria, Australia 3010.
Country 82864 0
Australia
Phone 82864 0
+61 3 9035 3043
Fax 82864 0
Email 82864 0
ldownie@unimelb.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Clinical demographics and primary outcome data.
When will data be available (start and end dates)?
Start date: following publication of the study findings (dates to be advised).
End date: No end date determined as yet.
Available to whom?
Researchers seeking to undertake IPD meta-analyses.
Available for what types of analyses?
IPD meta-analyses.
How or where can data be obtained?
By contacting the Principal Investigator.
What supporting documents are/will be available?
No other documents available
Summary results
No Results