Relationship of Haptoglobin Phenotype to Vascular Function and Response to Vitamin E Supplementation in Patients With Diabetes Mellitus Type 2: The EVAS Trial

NCT02776397 | Unknown

• 1 other identifier: EVAS001 Version 4
• Study Type: interventional
• Target: 300
• Locations: 1 country
• Sites: 1

Brief Summary

Relationship of haptoglobin phenotype to vascular function and response to Vitamin E supplementation in Patients with Diabetes Mellitus Type 2: The EVAS Trial Specific Aims: The phenotype haptoglobin 2-2 (Hp 2-2) is associated with higher oxidative stress, inflammation, LDL peroxidation and higher cardiovascular risk in patients with diabetes. We aim to determine whether Hp 2-2 phenotype is associated with surrogate markers of cardiovascular risk, inflammation, lipids and lipoprotein profile, oxidative stress, and endothelial cell (EC) apoptosis (in vitro study) in patients with diabetes in our population and whether vitamin E supplementation mitigates this risk. Methods: Screening Phase: We will recruit 300 patients with diabetes mellitus type 2 (100 Chinese, 100 Malays and 100 Indians) and assess their Hp phenotype, surrogate markers of cardiovascular risk, inflammation, vascular biomarkers and lipids phenotype. In vitro Study: Plasma from 20 patients with Hp 2-2 phenotype and 20 patients with non Hp 2-2 phenotype will be studied in vitro using a haemodynamic lab-on-chip system to determine whether there is a difference in EC apoptosis between the two groups. Randomisation Phase 200 patients will be recruited to a pilot randomized controlled trial (RCT), stratified by Hp 2-2 phenotype status (100 Hp 2-2 and 100 non-Hp 2-2), and randomly allocated in a 1:1 ratio to either vitamin E 400 IU supplementation daily for 6 months or a placebo group. The trial will determine whether vitamin E improves the aforementioned surrogate markers in the Hp phenotype strata. Importance of proposed research to science and medicine: This study allows us to understand the possible mechanism of cardiovascular risk in patients with Hp 2-2 phenotype and to see whether vitamin E supplementation reduces this risk in a pharmacogenomic targeted manner.

Conditions

Diabetes Mellitus

Outcome Measures

Primary Outcomes (5)

• Endothelial function

  Measured as Reactive hyperemia index using RHI-EndoPAT

  6 months

• Aortic artery stiffness

  Measured as pulse wave velocity using the sphygmocor device

  6 months

• Carotid Artery Intima Media Thickness

  Measured as CIMT (average) in mm.

  6 months

• Inflammation

  Measured as hs-CRP

  6 months

• Oxidative Stress

  Measured as oxidative stress index

  6 months

Secondary Outcomes (3)

• Glycemic status

  6 months

• Retinal arteriovenous index

  6 months

• Non HDL-Cholesterol

  6 months

Study Arms (4)

Hp 2-2 Vitamin E

ACTIVE COMPARATOR

The Haptoglobin 2-2 group randomised to Vitamin E

Dietary Supplement: Vitamin E

Hp 2-2 Placebo

PLACEBO COMPARATOR

The Haptoglobin 2-2 group randomised to placebo

Other: Placebo

Non Hp 2-2 Vitamin E

ACTIVE COMPARATOR

The Non Haptoglobin 2-2 group randomised to Vitamin E

Dietary Supplement: Vitamin E

Non Hp 2-2 Placebo

PLACEBO COMPARATOR

The Non Haptoglobin 2-2 group randomised to placebo

Other: Placebo

Interventions

Vitamin E DIETARY_SUPPLEMENT

Two hundred patients will be recruited to a pilot randomized controlled trial (RCT), stratified by Hp 2-2 phenotype status (100 Hp 2-2 and 100 non-Hp 2-2), and randomly allocated in a 1:1 ratio to either vitamin E 400 IU supplementation daily for 6 months or a placebo group. The trial will determine whether vitamin E improves the aforementioned surrogate markers in the Hp phenotype strata.

Also known as: alpha tocopherol

Hp 2-2 Vitamin E; Non Hp 2-2 Vitamin E

Placebo OTHER

Placebo arm

Hp 2-2 Placebo; Non Hp 2-2 Placebo

Eligibility Criteria

• Age: 21 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Chinese, 100 Malays, 100 Indian patients with DM2
• Age 21-80 years
• Able to give informed consent
• Stable diabetes, blood pressure and hyperlipidaemia medications (a 25% dose adjustment is allowed) in the last three months
• For eligibility to be randomized: HbA1c should be 10% inclusive or below at time of randomisation
• Blood Pressure should be less than 180/120 mm Hg at time of recruitment
• Non-smokers or discontinued smoking at least 6 months ago
• No h/o previous myocardial infarction, previous cerebrovascular accident inclusive of haemorrhage and infarction, or h/o of peripheral amputation or bypass procedures

You may not qualify if:

• Inability to give informed consent
• Pregnant subjects
• Patients hospitalized for any condition less than 1 month from enrolment
• Patients having any recent infections or symptoms suggestive of any systemic infection in the last 2 weeks
• Myocardial Infarction or stroke within 6 months before enrolment
• Patients with creatinine concentrations \>200 µmol/L or eGFR\<30 µmol/L
• Patients on anticoagulants such as warfarin
• Known allergy to vitamin E
• Current smokers
• h/o previous myocardial infarction, previous cerebrovascular accident inclusive of haemorrhage and infarction, or h/o of peripheral amputation or bypass procedures
• Patients on immunosuppressive agents or corticosteroids for other conditions
• Presence of concomitant malignancies or rheumatological conditions at the time of recruitment
• Patients taking orlistat \& cholestyramine

Sponsors & Collaborators

• Tan Tock Seng Hospital: lead
• Lee Kong Chian School of Medicine, Nanyang Technological University: collaborator
• National Medical Research Council (NMRC), Singapore: collaborator

Study Sites (1)

Tan Tock Seng Hospital

Singapore, Singapore, 308433, Singapore

RECRUITING

Related Publications (5)

• Levy AP, Hochberg I, Jablonski K, Resnick HE, Lee ET, Best L, Howard BV; Strong Heart Study. Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: The Strong Heart Study. J Am Coll Cardiol. 2002 Dec 4;40(11):1984-90. doi: 10.1016/s0735-1097(02)02534-2.

  PMID: 12475459 BACKGROUND

• Milman U, Blum S, Shapira C, Aronson D, Miller-Lotan R, Anbinder Y, Alshiek J, Bennett L, Kostenko M, Landau M, Keidar S, Levy Y, Khemlin A, Radan A, Levy AP. Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial. Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):341-7. doi: 10.1161/ATVBAHA.107.153965. Epub 2007 Nov 21.

  PMID: 18032779 BACKGROUND

• Blum S, Vardi M, Levy NS, Miller-Lotan R, Levy AP. The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes. Atherosclerosis. 2010 Jul;211(1):25-7. doi: 10.1016/j.atherosclerosis.2010.02.018. Epub 2010 Feb 21. No abstract available.

  PMID: 20223458 BACKGROUND

• Levy AP, Gerstein HC, Miller-Lotan R, Ratner R, McQueen M, Lonn E, Pogue J. The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes. Diabetes Care. 2004 Nov;27(11):2767. doi: 10.2337/diacare.27.11.2767. No abstract available.

  PMID: 15505023 BACKGROUND

• Saha N, Ong YW. Distribution of haptoglobins in different dialect groups of Chinese, Malays and Indians in Singapore. Ann Acad Med Singap. 1984 Jul;13(3):498-501.

  PMID: 6517517 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus

Interventions

Vitamin E; alpha-Tocopherol

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tocopherols

Study Officials

• Rinkoo Dalan, MBBS, FRCP(Edin)

  Senior Consultant

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rinkoo Dalan, MBBS, FRCP (Edin)

CONTACT

63571000; rinkoo_dalan@ttsh.com.sg

Huiling Liew, MBBS, MRCP(UK)

CONTACT

63571000; huiling_liew@ttsh.com.sg

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 12, 2016
• First Posted: May 18, 2016
• Study Start: June 1, 2015
• Primary Completion: June 1, 2018
• Study Completion: July 1, 2018
• Last Updated: May 19, 2016

Record last verified: 2016-05

Locations

SG (1)