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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]

Nil known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Diabetes Mellitus

Diabetic Nephropathy

Diabetic Retinopathy

Diabetic Neuropathy

Condition category

Condition code

Metabolic and Endocrine

Diabetes

Renal and Urogenital

Other renal and urogenital disorders

Eye

Diseases / disorders of the eye

Neurological

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]

Treatment: Drugs

Intervention code [2]

Prevention

Comparator / control treatment

This clinical trial is placebo controlled. Each placebo capsule contains pure palm oil.

Control group

Placebo

Outcomes

Primary outcome [1]

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]

48 weeks

Primary outcome [2]

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]

48 weeks

Primary outcome [3]

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]

48 weeks

Secondary outcome [1]

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]

48 weeks

Secondary outcome [2]

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]

48 weeks

Secondary outcome [3]

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]

48 weeks

Secondary outcome [4]

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]

48 weeks

Secondary outcome [5]

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]

48 weeks

Secondary outcome [6]

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]

48 weeks

Secondary outcome [7]

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]

48 weeks

Secondary outcome [8]

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]

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?

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

Final

Recruitment outside Australia

Country [1]

Malaysia

State/province [1]

Bandar Sunway, Selangor

Country [2]

Malaysia

State/province [2]

Johor Bahru, Johor

Funding & Sponsors

Funding source category [1]

University

Name [1]

Monash University Malaysia

Address [1]

Jalan Lagoon Selatan,
Bandar Sunway,
47500 Subang Jaya,
Selangor

Country [1]

Malaysia

Funding source category [2]

Government body

Name [2]

Fundamental Research Grant Scheme (FRGS)

Address [2]

Ministry of Education Malaysia
Higher Education
No. 2, Tower 2,
Jalan P5/6, Precinct 5,
62200 Putrajaya, Malaysia

Country [2]

Malaysia

Funding source category [3]

Commercial sector/Industry

Name [3]

HOVID Berhad

Address [3]

121, Jalan Tunku Abdul Rahman
30010 Ipoh,
Perak

Country [3]

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]

Commercial sector/Industry

Name [1]

HOVID Berhad

Address [1]

121, Jalan Tunku Abdul Rahman
30010 Ipoh,
Perak

Country [1]

Malaysia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash University Human Research Ethics Committee (MUHREC)

Ethics committee address [1]

Monash Research Office,
26 Sports Walk,
Monash University,
Wellington Road,
Clayton VIC 3800

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

08/02/2018

Approval date [1]

12/02/2018

Ethics approval number [1]

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

Prof Khalid Abdul Kadir

Address

Monash University Malaysia Clinical Research Centre
No. 20 & 22, Jalan PJS 11/5,
Bandar Sunway,
46150 Petaling Jaya,
Selangor Darul Ehsan.

Country

Malaysia

Phone

+60355159779

Fax

khalid.kadir@monash.edu

Contact person for public queries

Name

Khalid Abdul Kadir

Address

Monash University Malaysia Clinical Research Centre
No. 20 & 22, Jalan PJS 11/5,
Bandar Sunway,
46150 Petaling Jaya,
Selangor Darul Ehsan.

Country

Malaysia

Phone

+60355159779

Fax

khalid.kadir@monash.edu

Contact person for scientific queries

Name

Khalid Abdul Kadir

Address

Monash University Malaysia Clinical Research Centre
No. 20 & 22, Jalan PJS 11/5,
Bandar Sunway,
46150 Petaling Jaya,
Selangor Darul Ehsan.

Country

Malaysia

Phone

+60355159779

Fax

khalid.kadir@monash.edu

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?

Doc. No.	Type	Other Details	Attachment
3659	Study protocol		378026-(Uploaded-07-08-2019-13-42-04)-Study-related document.pdf
3660	Ethical approval		378026-(Uploaded-07-08-2019-13-50-34)-Study-related document.pdf
3661	Informed consent form		378026-(Uploaded-07-08-2019-13-54-14)-Study-related document.pdf
3662	Other	Explanatory statement	378026-(Uploaded-07-08-2019-13-56-13)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually

Type	Is Peer Reviewed?	Citations or Other Details	Attachment
Plain language summary	No	(i) Vitamin E supplementation of 200 mg daily for ... [More Details]
Study results article	Yes	The Effects of Tocotrienol-Rich Vitamin E (Tocovid... [More Details]	378026-(Uploaded-20-10-2020-13-55-02)-Journal results publication.pdf
Study results article	Yes	Tocotrienol-rich vitamin E improves diabetic nephr... [More Details]	378026-(Uploaded-20-10-2020-14-01-35)-Journal results publication.pdf

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Tocotrienol-rich vitamin E improves diabetic nephropathy and persists 6-9 months after washout: a phase IIa randomized controlled trial.	2019	https://dx.doi.org/10.1177/2042018819895462
Embase	The effects of tocotrienol-rich vitamin E (Tocovid) on diabetic neuropathy: A phase II randomized controlled trial.	2020	https://dx.doi.org/10.3390/nu12051522
Embase	A phase iib randomized controlled trial investigating the effects of tocotrienol-rich vitamin e on diabetic kidney disease.	2021	https://dx.doi.org/10.3390/nu13010258

N.B. These documents automatically identified may not have been verified by the study sponsor.

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Documents added manually

Documents added automatically