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Trial registered on ANZCTR


Registration number
ACTRN12619001568101
Ethics application status
Approved
Date submitted
7/08/2019
Date registered
13/11/2019
Date last updated
13/11/2019
Date data sharing statement initially provided
13/11/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
The Effects of Tocotrienol-Rich Vitamin E (Tocovid) on Diabetes and Diabetic Microvascular Complications: Kidney Disease (Nephropathy), Eye Disease (Retinopathy) and (Nerve Impariment (Neuropathy)
Scientific title
The Effects of Tocotrienol-Rich Vitamin E (Tocovid) on Diabetes and Diabetic Microvascular Complications: Nephropathy, Retinopathy and Neuropathy
Secondary ID [1] 298811 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetes Mellitus 313863 0
Diabetic Nephropathy 313864 0
Diabetic Retinopathy 313865 0
Diabetic Neuropathy 313866 0
Condition category
Condition code
Metabolic and Endocrine 312275 312275 0 0
Diabetes
Renal and Urogenital 312490 312490 0 0
Other renal and urogenital disorders
Eye 312491 312491 0 0
Diseases / disorders of the eye
Neurological 312492 312492 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Tocotrienol-Rich Vitamin E from palm oil. Details are as follows:
Contents:
1. d-Alpha-Tocotrienol 15.38 mg
2. d-Gamma-Tocotrienol 28.20 mg
3. d-Delta-Tocotrienol 6.42 mg
4. d-Alpha-Tocopherol 22.90 IU
5. Plant Squalene 12.82 mg
6. Phytosterol Complex 5.12 mg
7. Phytocarotenoid Complex 90.00 ug
Dose: 200mg twice daily
Duration: 48 weeks
Mode of administration: oral capsule

Adherence will be assessed by calculating the number of remaining capsules in the bottles containing investigation products given to the participants during the follow-up visits. Besides, the serum Vitamin E levels will be measured to assess adherence of the participants.
Intervention code [1] 315165 0
Treatment: Drugs
Intervention code [2] 315166 0
Prevention
Comparator / control treatment
This clinical trial is placebo controlled. Each placebo capsule contains pure palm oil.
Control group
Placebo

Outcomes
Primary outcome [1] 320914 0
To determine any changes in early diabetic nephropathy as assessed by microalbuminuria (urine albumin-creatinine ratio) in patients given tocotrienol-rich vitamin E from palm oil (Tocovid)
Timepoint [1] 320914 0
48 weeks
Primary outcome [2] 320915 0
To determine any changes in early diabetic retinopathy as assessed by changes in intraretinal microhaemorrhage by means of fundal photography in patients given tocotrienol-rich vitamin E from palm oil (Tocovid)
Timepoint [2] 320915 0
48 weeks
Primary outcome [3] 320916 0
To determine any changes in diabetic peripheral neuropathy as assessed by nerve conduction study in patients given tocotrienol-rich vitamin E from palm oil (Tocovid)
Timepoint [3] 320916 0
48 weeks
Secondary outcome [1] 373322 0
This is a primary outcome, the objective is stated as follows:
To determine any changes in early diabetic nephropathy as assessed by serum creatinine (eGFR) in patients given tocotrienol-rich vitamin E from palm oil (Tocovid)
Timepoint [1] 373322 0
48 weeks
Secondary outcome [2] 373324 0
This is a primary outcome, the objective is stated as follows:
To determine any changes in early diabetic retinopathy as assessed by changes in macular edema by means of fundal photography in patients given tocotrienol-rich vitamin E from palm oil (Tocovid)
Timepoint [2] 373324 0
48 weeks
Secondary outcome [3] 374099 0
To determine the changes in oxidative stress biomarkers (as assessed by the levels of serum AGEs) in patients with early diabetic microvascular complications (i.e. nephropathy, retinopathy and neuropathy) given tocotrienol-rich vitamin E from palm oil (Tocovid)
Timepoint [3] 374099 0
48 weeks
Secondary outcome [4] 375224 0
To determine the changes in oxidative stress biomarkers (as assessed by the levels of serum MDA) in patients with early diabetic microvascular complications (i.e. nephropathy, retinopathy and neuropathy) given tocotrienol-rich vitamin E from palm oil (Tocovid)
Timepoint [4] 375224 0
48 weeks
Secondary outcome [5] 375225 0
To determine the changes in inflammatory biomarkers (as assessed by the levels of serum TNFR-1) in patients with early diabetic microvascular complications (i.e. nephropathy, retinopathy and neuropathy) given tocotrienol-rich vitamin E from palm oil (Tocovid)
Timepoint [5] 375225 0
48 weeks
Secondary outcome [6] 375226 0
To determine the changes in inflammatory biomarkers (as assessed by the levels of serum VCAM-1) in patients with early diabetic microvascular complications (i.e. nephropathy, retinopathy and neuropathy) given tocotrienol-rich vitamin E from palm oil (Tocovid)
Timepoint [6] 375226 0
48 weeks
Secondary outcome [7] 375227 0
To determine the effects of platelet aggregation (as assessed by the levels of serum Thromboxane B2) in patients with early diabetic microvascular complications (i.e. nephropathy, retinopathy and neuropathy) given tocotrienol-rich vitamin E from palm oil (Tocovid)
Timepoint [7] 375227 0
48 weeks
Secondary outcome [8] 375228 0
To determine the effects of neuroregeneration markers (as assessed by the levels of serum NGF) in patients with early diabetic microvascular complications (i.e. nephropathy, retinopathy and neuropathy) given tocotrienol-rich vitamin E from palm oil (Tocovid)
Timepoint [8] 375228 0
48 weeks

Eligibility
Key inclusion criteria
1. Subject, or legal representative, has voluntarily signed and dated an Informed Consent Form.
2. Subject is 35-75 years of age at screening date
3. Subject has T2DM with stable glucose control (not more than 10% change in HbA1c levels over the last 2 months) AND HbA1c range should be within 6-9%
4. Subject has eGFR of 30-89 AND has microalbuminuria as assessed by UACR of 20-200mg/mmol, or
5. Mild/moderate retinopathy as defined by: Mild: At least one microaneurysm Moderate: Hemorrhage/microaneurysm, cotton wool spots, venous beading, and intraretinal
microvascular abnormalities
6. If subject has hypertension, he/she must have stable blood pressure control for the past 2 months with not more than 10% change and BP range should be <145/90mmHg
Minimum age
35 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Subject is pregnant during screening, OR planning to be pregnant, OR not on contraception
2. Subject has urine protein >1.5g/L during screening
3. Subject has current urinary tract infection during screening (symptomatic or definitively on urine FEME: pyuria, nitrites and red blood cells)
4. Subject has acute or severe chronic illness such as acute coronary syndrome, active tuberculosis, current history of cancer, liver or inflammatory disease etc.
5. Subject with unstable eye diseases such as media opacity and glaucoma
6. Subject has known non-diabetic kidney disease, such as kidney stones etc
7. Patient has severe chronic kidney disease (Stage 4/5 CKD, eGFR <30ml/min/1.73m2)
8. Subject is taking other water-soluble antioxidants for the past 2 weeks or fat-soluble antioxidants for the past 1 month
9. Subject is a heavy smoker (>20 sticks/day) that is currently smoking or has stopped smoking for <1 month

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)
Allocation was concealed by numbered containers
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified allocation was employed in the study. The participants were stratified by gender, duration of diabetes mellitus and glycemic control as assessed by HbA1c levels. The sequence generation used was simple randomisation by a randomisation table created by computer software (i.e. computerised sequence generation).
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
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
6/03/2019
Date of last participant enrolment
Anticipated
30/06/2020
Actual
Date of last data collection
Anticipated
30/06/2021
Actual
Sample size
Target
116
Accrual to date
80
Final
Recruitment outside Australia
Country [1] 21734 0
Malaysia
State/province [1] 21734 0
Bandar Sunway, Selangor
Country [2] 21735 0
Malaysia
State/province [2] 21735 0
Johor Bahru, Johor

Funding & Sponsors
Funding source category [1] 303365 0
University
Name [1] 303365 0
Monash University Malaysia
Country [1] 303365 0
Malaysia
Funding source category [2] 303435 0
Government body
Name [2] 303435 0
Fundamental Research Grant Scheme (FRGS)
Country [2] 303435 0
Malaysia
Funding source category [3] 303436 0
Commercial sector/Industry
Name [3] 303436 0
HOVID Berhad
Country [3] 303436 0
Malaysia
Primary sponsor type
University
Name
Monash University Malaysia
Address
Jalan Lagoon Selatan,
Bandar Sunway,
47500 Subang Jaya,
Selangor
Country
Malaysia
Secondary sponsor category [1] 303396 0
Commercial sector/Industry
Name [1] 303396 0
HOVID Berhad
Address [1] 303396 0
121, Jalan Tunku Abdul Rahman
30010 Ipoh,
Perak
Country [1] 303396 0
Malaysia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303895 0
Monash University Human Research Ethics Committee (MUHREC)
Ethics committee address [1] 303895 0
Monash Research Office,
26 Sports Walk,
Monash University,
Wellington Road,
Clayton VIC 3800
Ethics committee country [1] 303895 0
Australia
Date submitted for ethics approval [1] 303895 0
08/02/2018
Approval date [1] 303895 0
12/02/2018
Ethics approval number [1] 303895 0
12090

Summary
Brief summary
The overarching aim of the research is to establish the potential mechanisms of action(s) of Vitamin E on diabetes and its diabetes microvascular complications, namely nephropathy, retinopathy and neuropathy.
In this study, we aim to demonstrate the various mechanisms of actions(s) of Vitamin E; namely its anti-oxidant, anti-inflammatory, anti-thrombotic effects as well as establishing Vitamin E potential renal-, retinal- and/or neuro-protective role(s) by measuring its renal, retinal and nerve parameters respectively. We will also be measuring circulating levels of anti-oxidants and anti-inflammatory markers and determine any correlation with the severity of diabetes microvascular complications (i.e. nephropathy, retinopathy and neuropathy). We will also establish the levels of Vitamin E sub-types found both in extracellular fluid and erythrocytes.
This is a prospective, randomized, double-blinded, placebo-controlled study. The study will take 12 months to complete. Patients (n=116) will be randomized into intervention and control groups. The interventional (INT) group will receive active treatment (200 mg Tocovid BD) and the control group will receive placebo (200 mg placebo BD) for 6 months. These patients will be followed up for 12 months and attend a total 8 visits. The detail timeline of the study will be provided in the relevant section below. The improvement of the microvascular complications will be assessed by (i) UACR & eGFR for renal parameters (ii) Intraretinal hemorrhages for retinal parameters and (iii) nerve conduction study for peripheral neuropathy. In addition, we will be measuring circulating inflammatory markers such as AGEs, MDA, TNFR1, VCAM-1, Thromboxane B2 and NGF in these patients.
Trial website
Trial related presentations / publications
Public notes
The ethical approval was obtained on 12/02/2018 for the clinical trial titled "Tocotrienol-rich Vitamin E from Palm oil (Tocovid) and its effects in Diabetes and Diabetic Nephropathy". However, the aforementioned study was extended to further investigate on diabetic microvascular complications (i.e. nephropathy, retinopathy and neuropathy). The proposal was amended, and an extended approval for the clinical trial extension was granted on 10/01/2019. The extended approval is available here (link): https://drive.google.com/open?id=0B_Ls_LduHueaMHhxSHMwcnUtM2pYanBQMVItd2FzTHJoUjhN

Contacts
Principal investigator
Name 95162 0
Prof Khalid Abdul Kadir
Address 95162 0
Monash University Malaysia Clinical Research Centre
No. 20 & 22, Jalan PJS 11/5,
Bandar Sunway,
46150 Petaling Jaya,
Selangor Darul Ehsan.
Country 95162 0
Malaysia
Phone 95162 0
+60355159779
Fax 95162 0
Email 95162 0
[email protected]
Contact person for public queries
Name 95163 0
Khalid Abdul Kadir
Address 95163 0
Monash University Malaysia Clinical Research Centre
No. 20 & 22, Jalan PJS 11/5,
Bandar Sunway,
46150 Petaling Jaya,
Selangor Darul Ehsan.
Country 95163 0
Malaysia
Phone 95163 0
+60355159779
Fax 95163 0
Email 95163 0
[email protected]
Contact person for scientific queries
Name 95164 0
Khalid Abdul Kadir
Address 95164 0
Monash University Malaysia Clinical Research Centre
No. 20 & 22, Jalan PJS 11/5,
Bandar Sunway,
46150 Petaling Jaya,
Selangor Darul Ehsan.
Country 95164 0
Malaysia
Phone 95164 0
+60355159779
Fax 95164 0
Email 95164 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?




Results publications and other study-related documents

Documents added manually

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseTocotrienol-rich vitamin E improves diabetic nephropathy and persists 6-9 months after washout: a phase IIa randomized controlled trial.2019https://dx.doi.org/10.1177/2042018819895462
EmbaseThe effects of tocotrienol-rich vitamin E (Tocovid) on diabetic neuropathy: A phase II randomized controlled trial.2020https://dx.doi.org/10.3390/nu12051522
EmbaseA phase iib randomized controlled trial investigating the effects of tocotrienol-rich vitamin e on diabetic kidney disease.2021https://dx.doi.org/10.3390/nu13010258
N.B. These documents automatically identified may not have been verified by the study sponsor.