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Trial registered on ANZCTR


Registration number
ACTRN12621001268831
Ethics application status
Approved
Date submitted
23/10/2020
Date registered
20/09/2021
Date last updated
23/09/2022
Date data sharing statement initially provided
20/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of tocotrienol-rich vitamin E (Tocovid Suprabio) compared to tocopherol on diabetic microvascular complications: A double-blinded placebo controlled, multicentre clinical trial
Scientific title
The Effect of Lower-dose 100mg and 200mg Tocotrienol-rich Vitamin E (Tocovid Suprabio®) and 200IU Alpha-Tocopherol on Diabetic Microvascular Complications in Patients with Diabetes
Secondary ID [1] 302579 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetes Mellitus 319457 0
Diabetic Nephropathy 319464 0
Diabetic Retinopathy 319465 0
Diabetic Neuropathy 319466 0
Condition category
Condition code
Metabolic and Endocrine 317430 317430 0 0
Diabetes
Renal and Urogenital 317431 317431 0 0
Other renal and urogenital disorders
Eye 317432 317432 0 0
Diseases / disorders of the eye
Neurological 317433 317433 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: 100mg tocotrienol-rich Vitamin E from palm oil
Dose: 100mg once daily
Duration: 24 weeks
Mode of administration: Oral capsule
Active ingredients:
1) d-Alpha Tocotrienol 30.76mg
2) d-Gamma-Tocotrienol 56.40mg
3) d-Delta-Tocotrienol 12.84mg
4) d-Alpha-Tocopherol 45.80IU
5) Plant Squalene 25.64mg
6) Phytosterol Complex 10.24mg
7) Phytocarotenoid Complex 180.00ug

Arm 2: 200mg tocotrienol-rich Vitamin E from palm oil
Dose: 200mg once daily
Duration: 24 weeks
Mode of administration: Oral capsule
Active ingredients:
1) d-Alpha-Tocotrienol 61.52mg
2) d-Gamma-Tocotrienol 112.80mg
3) d-Delta-Tocotrienol 25.68mg
4) d-Alpha-Tocopherol 91.60IU
5) Plant Squalene 51.28mg
6) Phytosterol Complex 20.48mg
7) Phytocarotenoid Complex 360.00ug

Arm 3: Alpha-tocopherol
Dose: 200IU once daily
Duration: 24 weeks
Mode of administration: Oral capsule
Active ingredients: d-Alpha-Tocopherol 200IU

Adherence will be assessed by counting the remaining capsules brought back by the participants during the follow-up visits. In addition, the plasma Vitamin E levels will be measured to assess adherence of the participants.
Intervention code [1] 318866 0
Treatment: Drugs
Intervention code [2] 318869 0
Prevention
Comparator / control treatment
This is a placebo controlled clinical trial. Each placebo capsule is made up of pure palm oil.
Control group
Placebo

Outcomes
Primary outcome [1] 325468 0
Changes in nerve conduction parameters as assessed by nerve conduction study
Timepoint [1] 325468 0
Baseline, and 2, 4, 8, 12, and 24 (primary endpoint) weeks post-intervention commencement
Primary outcome [2] 327606 0
Change in kidney function as assessed by serum creatine level
Timepoint [2] 327606 0
Baseline, and 2, 4, 8, 12, and 24 (primary endpoint) weeks post-intervention commencement
Primary outcome [3] 327607 0
Change in kidney function as assessed by eGFR
Timepoint [3] 327607 0
Baseline, and 2, 4, 8, 12, and 24 (primary endpoint) weeks post-intervention commencement
Secondary outcome [1] 388056 0
This is a primary outcome:
Changes in retinal microhaemorrhages by means of fundal photography
Timepoint [1] 388056 0
Baseline, and 2, 4, 8, 12, and 24 (primary endpoint) weeks post-intervention commencement
Secondary outcome [2] 388057 0
This is a primary outcome:
Changes in macular edema by means of fundal photography
Timepoint [2] 388057 0
Baseline, and 2, 4, 8, 12, and 24 (primary endpoint) weeks post-intervention commencement
Secondary outcome [3] 395936 0
Levels of vitamin E measured using high-performance liquid chromatograph (HPLC)
Timepoint [3] 395936 0
Baseline, and 2, 4, 8, 12, and 24 (primary endpoint) weeks post-intervention commencement

Eligibility
Key inclusion criteria
1) Subject, or legal representative, has voluntarily signed and dated an Informed Consent Form.
2) Subject is 30-75 years of age at the initial Screening visit.
3) Subject has type 2 diabetes mellitus (T2DM) with stable glucose control (not more than 10% change in HbA1c levels over the last 2 months) and the HbA1c range should be within 6-9%.
4) If a subject has hypertension, he/she must have a stable blood pressure control for the past 2 months with not more than 10% change and the blood pressure (BP) range should be less than 145/90 mmHg.
5) Subject has at least one of the following symptoms of diabetic peripheral neuropathy:
(a) Reduction in nerve conduction velocity (defined by baseline conduction velocity less than 40m/s)
(b) Reduction in negative to peak (NP) and peak to peak (PP) amplitude
(c) Abnormality found in clinical assessment (Eg: pain, light, touch, temperature, position sense, vibration and reflexes)
6) Subject has either one of the following or both:
(a) Inactive diabetic retinopathy as assessed by retinal photography
(b) Mild to moderate nephropathy which is defined by urine albumin-to-creatinine ratio (UACR) of greater than 20 mg/g or eGFR between 30 to 60 ml/min/bsa (Stage 3 chronic kidney disease (CKD))
Minimum age
30 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 greater than150 g/L during screening
3) Subject has current urinary tract infection during screening (symptomatic or definitively
on urine dipstick: presence of pyuria, nitrites and red blood cells)
4) Subject has known non-diabetic kidney disease, such as kidney stones, etc.
5) Subject has a corrected visual acuity of less than 20/200
6) Subject with eye diseases such as media opacity, amblyopic and glaucoma
7) Subject on anti-epileptic or sedative medications
8) Subject has acute or severe chronic illness such as acute coronary syndrome, active
tuberculosis, and previous or current history of cancer, liver or inflammatory disease,
etc.
9) Subject is taking other water-soluble antioxidants for the past 2 weeks or fat-soluble
antioxidants for the past 1 month
10) Subject is a heavy smoker (equal to 20 sticks/day) or has stopped smoking for less than 1 month
11) Subject has elevated liver enzymes (serum ALT and/or serum AST greater than 3x the upper limit of normal)
12) Subject with severely deranged renal profile. (Stage 5 CKD; eGFR less than or equal to 15 ml/min/bsa)

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 will be concealed by numbered containers.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified allocation will be employed in the study. The participants will be stratified according to their gender, duration of diabetes mellitus and glycemic control as assessed by HbA1c levels. Allocation of subjects will be done by simple randomisation using a randomisation table created by computer software (i.e. computerised sequence).
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
Not yet recruiting
Date of first participant enrolment
Anticipated
1/11/2022
Actual
Date of last participant enrolment
Anticipated
31/08/2023
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
200
Accrual to date
Final
Recruitment outside Australia
Country [1] 23067 0
Malaysia
State/province [1] 23067 0
Thomson Hospital, Kota Damansara, Selangor
Country [2] 23068 0
Malaysia
State/province [2] 23068 0
Johor Bahru, Johor

Funding & Sponsors
Funding source category [1] 307011 0
University
Name [1] 307011 0
Monash University Malaysia
Country [1] 307011 0
Malaysia
Funding source category [2] 307028 0
Commercial sector/Industry
Name [2] 307028 0
HOVID Berhad
Country [2] 307028 0
Malaysia
Funding source category [3] 308663 0
Government body
Name [3] 308663 0
Malaysian Palm Oil Board (MPOB)
Country [3] 308663 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] 307579 0
Commercial sector/Industry
Name [1] 307579 0
HOVID Berhad
Address [1] 307579 0
121, Jalan Tunku Abdul Rahman,
30010 Ipoh,
Perak
Country [1] 307579 0
Malaysia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307142 0
Monash University Human Research Ethics Committee (MUHREC)
Ethics committee address [1] 307142 0
Monash Research Office,
26 Sports Walk,
Monash University,
Wellington Road,
Clayton VIC 3800
Ethics committee country [1] 307142 0
Australia
Date submitted for ethics approval [1] 307142 0
03/01/2018
Approval date [1] 307142 0
12/02/2018
Ethics approval number [1] 307142 0
12090

Summary
Brief summary
The overarching aim of the research is to establish the potential mechanisms of action(s) of increasing doses tocotrienol-rich Vitamin E on diabetes and its diabetes microvascular complications, namely nephropathy, retinopathy and neuropathy.

In this study, we aim to establish the potential renal-, retinal- and/or neuro-protective role(s) of increasing doses of tocotrienol-rich Vitamin E by measuring the renal, retinal and nerve parameters respectively. In addition, we focus on investigating the mechanisms by which tocotrienol-rich Vitamin E improves nerve function, protects the retina and gives renal protection. We will also look into the superiority of tocotrienol-rich Vitamin E to natural alpha-tocopherol (200IU) in showing beneficial effects on the diabetic complications.

This is a prospective, multi-centered, randomized, double-blinded, placebo-controlled study involving patients with type 2 diabetes mellitus with reasonable glycaemic control (HbA1c between 6.0 - 9.0%) and diabetic neuropathy as assessed by nerve conduction study. Subjects in interventional groups will receive one of the following treatments: 100mg of tocotrienol-rich Vitamin E, 200mg of tocotrienol-rich Vitamin E or 200IU of alpha-tocopherol once per day for 24 weeks. The control arm will receive matching placebo once per day for 24 weeks. All study subjects will be followed up at 2, 4, 8, 12, and 24 weeks throughout the double-blinded treatment period. Study subjects will be asked to return 3 months after treatment cessation to monitor for adverse events. The detail timeline of the study will be provided in the relevant section below.

The improvement of the microvascular complications will be assessed by respective parameters as follows:
(i) Nephropathy: UACR & eGFR
(ii) Retinopathy: Intraretinal hemorrhages & macular edema by means of fundal photography
(iii) Peripheral Neuropathy: Nerve conduction study parameters
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106182 0
Prof Khalid Abdul Kadir
Address 106182 0
Monash University Malaysia Clinical Research Centre
No. 20 & 22, Jalan PJS 11/5,
Bandar Sunway,
46150 Petaling Jaya,
Selangor
Country 106182 0
Malaysia
Phone 106182 0
+6035519779
Fax 106182 0
Email 106182 0
[email protected]
Contact person for public queries
Name 106183 0
Prof Khalid Abdul Kadir
Address 106183 0
Monash University Malaysia Clinical Research Centre
No. 20 & 22, Jalan PJS 11/5,
Bandar Sunway,
46150 Petaling Jaya,
Selangor
Country 106183 0
Malaysia
Phone 106183 0
+6035519779
Fax 106183 0
Email 106183 0
[email protected]
Contact person for scientific queries
Name 106184 0
Prof Khalid Abdul Kadir
Address 106184 0
Monash University Malaysia Clinical Research Centre
No. 20 & 22, Jalan PJS 11/5,
Bandar Sunway,
46150 Petaling Jaya,
Selangor
Country 106184 0
Malaysia
Phone 106184 0
+6035519779
Fax 106184 0
Email 106184 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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
9511Study protocol    380781-(Uploaded-22-10-2020-20-40-24)-Study-related document.pdf
9512Informed consent form    380781-(Uploaded-22-10-2020-14-08-43)-Study-related document.pdf
9513Ethical approval    The ethics approval has been obtained on the 26th ... [More Details] 380781-(Uploaded-15-09-2021-14-20-40)-Study-related document.pdf
9514Other    Explanatory Statement 380781-(Uploaded-22-10-2020-14-09-02)-Study-related document.pdf
13216Other    Please find the revised English Explanatory Statem... [More Details] 380781-(Uploaded-15-09-2021-14-28-13)-Study-related document.pdf
13217Other    Please find the revised Malay Explanatory Statemen... [More Details] 380781-(Uploaded-15-09-2021-14-33-09)-Study-related document.pdf
13218Other    The amended study protocol which was approved by M... [More Details] 380781-(Uploaded-15-09-2021-14-40-40)-Study-related document.pdf



Results publications and other study-related documents

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