ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12619000436178

Ethics application status

Approved

Date submitted

12/03/2019

Date registered

18/03/2019

Date last updated

22/04/2020

Date data sharing statement initially provided

18/03/2019

Date results information initially provided

18/03/2019

Type of registration

Retrospectively registered

Titles & IDs

Public title

Impact of Ubiquinol Supplementation on Endothelial Function in Subjects at Risk of Cardiovascular Disease Development

Scientific title

Impact of Ubiquinol Supplementation on Endothelial Function in Subjects at Risk of Cardiovascular Disease Development: a Double Blind, Randomized, Placebo–controlled, Parallel Groups, Spontaneous Clinical Study

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1229-8941

Trial acronym

QHHC-FMD-PILOT

Linked study record

Health condition

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

Dyslipidemia

Endothelial Dysfunction

Condition category

Condition code

Cardiovascular

Diseases of the vasculature and circulation including the lymphatic system

Metabolic and Endocrine

Metabolic disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The study aims to evaluate the impact of a supplementation with ubiquinol (reduced form of ubiquinone or reduced CoQ10) on endothelial function and oxidative stress in patients with mild to moderate dyslipidemia.
During Screening Visit the eligibility criteria will be verified and, if fulfilled, each subject will be randomized to one of the 3 study groups after signing the Informed Consent Form.
At Screening Visit and at Week 4, subjects will receive the assigned test product, according to randomization, for consumption at home during the coming 4 weeks and leave the facility.
The study products include test treatment (ubiquinol, two dosages, 100 and 200 mg daily) and placebo; details on these study products are given in the study products dossiers. Each product (ubiquinol or placebo), have to be taken daily at breakfast and dinner (total two pills: 1 before breakfast and 1 before dinner).
The active study products, Ubiquinol-QH 100 mg, will be provided in the form of softgel capsules. Each active softgel capsule contains ubiquinol (Kaneka QH™ active antioxidant form of coenzyme Q10) 100 mg. The product contains also soy and other ingredients: medium chain triglycerides, gelatin, glycerin, ascorbyl palmitate, purified water, beeswax, soy lecithin, annatto extract.
Placebo will consist of softgel capsules too, matching the active study products but without any active principle.

The subjects will consume 2 softgel capsules per day according to the following scheme:
- Group A - Ubiquinol 200mg/day: 2 Ubiquinol-QH 100 mg soft capsules/day
- Group B - Ubiquinol 100mg/day: 1 Ubiquinol-QH 100 mg soft capsule and 1 Placebo capsule /day
- Group C – Matched placebo: 2 Placebo capsules/day

The study products, provided as softgel capsules, will be consumed at home by the subjects, one capsule in the morning and one capsule in the evening, with a meal. Subjects will be instructed to complete a daily diary, in order to evaluate the compliance to both treatment and dietary restrictions. Diary and unopened and empty study products packs will be returned on each follow-up visit and checked by the study personnel as an assessment of compliance.

During each visit a short physical examination will be performed and a blood sample (approximately 10 ml) will be collected from the vein in the left arm to evaluate CoQ10 levels and the secondary endpoints. After acclimatisation and rest for at least 30 minutes blood pressure (triplicate, first discarded) and flow-mediated dilation (FMD) (baseline or Week 4 and 8 measurement) will be measured.

Intervention code [1]

Treatment: Other

Comparator / control treatment

Placebo capsules, equal in colour, shape and weight to study products capsules (softgel capsules) but without active ingredients.

Control group

Placebo

Outcomes

Primary outcome [1]

Change in endothelium-dependent vasodilation at week 8, assessed through non-invasive ultrasound measurement of the flow-mediated dilation (FMD) of the brachial artery. Measures will be conducted by a trained sonographer using a dedicated ultrasound machine and analysed through an edge-detection and wall-tracking software developed by Quipu (Pisa, Italy).

Timepoint [1]

Visit 2 (8 weeks)

Secondary outcome [1]

Change in endothelium-dependent vasodilation at week 4, assessed through non-invasive ultrasound measurement of the flow-mediated dilation (FMD) of the brachial artery. Measures will be conducted by a trained sonographer using a dedicated ultrasound machine and analysed through an edge-detection and wall-tracking software developed by Quipu (Pisa, Italy).

Timepoint [1]

Visit 1 (4 weeks)

Secondary outcome [2]

Change in the ratio between oxidized and total Coenzyme Q10 (CoQ10) plasma levels (composite outcome). Oxidized and total CoQ10 levels will be measured by high-pressure liquid chromatography (HPLC) using a direct extraction method.

Timepoint [2]

Visit 1 (4 weeks), Visit 2 (8 weeks)

Secondary outcome [3]

Evaluation of plasma levels of nitric oxide quantified in terms of its stable reaction product (nitrites and nitrates) through the Griess reaction.

Timepoint [3]

Visit 1 (4 weeks), Visit 2 (8 weeks)

Secondary outcome [4]

Evaluation of plasma levels of peroxinitrite (evaluation of oxidative inactivation of NO to peroxinitrite using fluorescent probes).

Timepoint [4]

Visit 1 (4 weeks), Visit 2 (8 weeks)

Secondary outcome [5]

Evaluation of susceptibility to oxidation of plasma lipoprotein quantified as kinetic of conjugate dienes formation following copper exposure.

Timepoint [5]

Visit 1 (4 weeks), Visit 2 (8 weeks)

Eligibility

Key inclusion criteria

This study will include male and post-menopausal female subjects.
- Male aged 35 - 65 years (35 and 65 included).
- Post-menopausal female (without a period for more than 1 year), until 65 years (65 included).
- Subjects enrolled for primary prevention but never treated (only life style modification suggested, according guidelines).
- FMD level measured between 2,5% and 6% (at Screening Visit).
- Body mass index (BMI) between 18.5 and 29.9 kg/m2.
- LDL Cholesterol levels between 130 and 200 mg/dl (based on previous evaluation, performed within 1 month from the Screening Visit).

Minimum age

35 Years

Maximum age

65 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

A subject will not be eligible for inclusion in this study if any of the following apply:
- Use of any cardiovascular disease related drugs prior to Screening Visit.
- Participation in any clinical trial while participating in this trial.
- Greater than 5% change in body weight within 1 month of Screening Visit.
- Subjects playing competitive physical activity.
- Subject taking lipid-altering drug therapy within four weeks prior to Screening Visit. Also excluded are supplements known to have significant lipid altering effects, such as niacin (>100 mg per day), garlic (> 600 mg per day), omega-3 fatty acids (> 1 g omega-3 fatty acids per day), red yeast rice extract, phytostanols / phytosterols (> 0.5 g per day), soluble fiber (>1 g per day), chitosan (> 1 g per day) and conjugated linoleic acid (CLA; > 3 g per day).
- Subject taking any concomitant treatment with phosphodiesterase inhibitors (e.g. sildenafil citrate, tadalafil, vardenafil) and donors of NO (nitric oxide), like other long-acting derivatives of GTN (glyceryl trinitrate), such as isosorbide dinitrate and amyl or butyl nitrite.
- Excluded concurrent medications are: systemic corticosteroids (nasal and inhaled corticosteroids are permitted), orlistat, bile acid resins, no more than 1 g of prescription omega-3 fatty acids, cyclical or non-continuous hormone therapy (estrogen or testosterone).
- No more than 2 alcoholic units per day. Units are defined as 12 grams of ethanol, e.g. a small glass (125 ml) of medium gradation wine, a can of beer (330 ml) of average gradation or 40 ml dose of liquors.
- Consumption of flavonoids-enriched products.
- Consumption of vitamin C-enriched products or supplements containing vitamin C.
- Has a diagnosis of type 1 or type 2 diabetes mellitus, hepatic or renal impairment or diseases, thyroid disorders.
- Known cardiovascular disease or stroke, except for conditions that are deemed clinically insignificant by Principle Investigator or Sub-investigator, or study site physician (e.g. clinically insignificant atherosclerotic lesions observed by imaging studies).
- History of significant gastrointestinal disease such as severe constipation, diarrhea, malabsorptive disease, inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis).
- History of severe psychiatric illness which in the opinion of the investigator would interfere with the optimal participation in the study.
- History if cancer within 5 years of Screening Visit (except for successfully treated basal and squamous cell carcinoma of the skin).
- Known HIV seropositivity.
- History of bariatric surgery.
- Allergic to the test products or placebo.
- Smokers > 10 cigarettes/day.
- Individuals who in the opinion of the principal investigator have a risk of non-compliance to the study procedures or who are otherwise not appropriate to include in this clinical trial.

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 is concealed. Subjects fulfilling inclusion criteria will be randomly allocated to one of the 3 study groups; treatments will be randomised to subject numbers (1-51).
A Pharmacy designate independent of the study will conduct the product dispensing procedure. Each subject will receive two bottles containing either Ubiquinol 100 mg or Placebo. The product is dispensed according to a 3-digit code previously assigned by a 3rd party to each bottle. The link between the treatment code and the treatment will not be available to the personnel involved in the collection, revision, or evaluation of adverse events, to the clinical laboratory, or to personnel who could have an impact on the outcome of the study, until after the end of the study (when all adverse events have been finalized).

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

A simple randomization technique, i.e. a randomization based on a single sequence of random assignments, will be used. A computer-generated random numbers list will be used and subjects will be assigned a number according to their order of inclusion in the study.

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

Not Applicable

Type of endpoint/s

Efficacy

Statistical methods / analysis

Sample size calculation was carried out with using G*power Software.
The parameters used to compute sample size for this study were retrieved from the paper by Gao et al., 2012 (DOI: 10.1016/j.atherosclerosis.2011.10.027), who performed a meta-analysis of 5 randomized controlled trials.
Mean and SD from the article by Watts GF et al., 2002 (DOI: 10.1007/s00125-001-0760-y), one of the randomized controlled trials mentioned in the reference article (see Fig. 2 in Gao et al.), were considered as appropriate values to be taken into account: considering group one FMD mean (SD) as 1.6 (1.16) and second group FMD mean (SD) as -0.4 (2.24), with 80% power and 5% two-sided significance level, 14 subjects per group are required.
In this study, considering a 20% dropout rate, a total of 52.5 subjects should have been enrolled; a sample size equal to 51 subjects was deemed as appropriate.
It is to be noted that in this study the minimum increment of FMD reached with the number of patients provided for each group is to be considered as equal to 1.6% (according to Figure 2 shown in Gao et al., in particular by referring to the study of Watts, which provides a sample size similar to ours).

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

Actual

19/12/2016

Date of last participant enrolment

Anticipated

Actual

25/04/2017

Date of last data collection

Anticipated

Actual

26/06/2017

Sample size

Target

Accrual to date

Final

Recruitment outside Australia

Country [1]

Italy

State/province [1]

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

I.N.R.C.A. (Italian National Research Centre on Aging)-IRCCS

Address [1]

Via della Montagnola, 81
60127 Ancona (AN)
Italy

Country [1]

Italy

Primary sponsor type

Hospital

Name

I.N.R.C.A. (Italian National Research Centre on Aging)-IRCCS

Address

Via della Montagnola, 81
60127 Ancona (AN)
Italy

Country

Italy

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Comitato Etico Regione Marche - Ethics Committee of the Marche Region

Ethics committee address [1]

Comitato Etico Regione Marche
Azienda Ospedaliero Universitaria "Ospedali Riuniti Umberto I, G.M. Lancisi, G. Salesi"
Via Conca 71
60126 Ancona
Italy

Ethics committee country [1]

Italy

Date submitted for ethics approval [1]

19/07/2016

Approval date [1]

15/12/2016

Ethics approval number [1]

2016-0614 IN

Summary

Brief summary

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality. The importance of CVDs prevention remains undisputed and should be aimed at reducing increased levels of cardiovascular risk factors, such as increased blood lipids, hypertension and endothelial dysfunction.
The QHHC-FMD-PILOT study is a double blind, placebo-controlled, Randomized Controlled Trial, aimed to evaluate the impact of a supplementation with Ubiquinol (reduced form of Coenzyme Q10, 200 mg or 100 mg/day) on endothelial function, assessed through a non-invasive ultrasound technique, and oxidative stress in patients with mild-to-moderate dyslipidemia. Given the beneficial antioxidant properties of Coenzyme Q10, we expect that a 8-week supplementation with Ubiquinol could significantly ameliorate endothelial dysfunction and improve selected blood markers of oxidative stress.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Roberto Antonicelli

Address

Department of Cardiology
I.N.R.C.A. (Italian National Research Centre on Aging)-IRCCS
Via della Montagnola, 81
60127 Ancona (AN)
Italy

Country

Italy

Phone

+390718003450

Fax

[email protected]

Contact person for public queries

Name

Dr Jacopo Sabbatinelli

Address

Department of Clinical and Molecular Sciences
Università Politecnica delle Marche
Via Tronto, 10/A
60126 Ancona (AN)
Italy

Country

Italy

Phone

+390712205243

Fax

[email protected]

Contact person for scientific queries

Name

Prof Luca Tiano

Address

Department of Environmental and Life Sciences
Università Politecnica delle Marche
Via Ranieri, 65
60131 Ancona (AN)
Italy

Country

Italy

Phone

+390712204394

Fax

[email protected]

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	Attachment
1575	Informed consent form	377173-(Uploaded-12-03-2019-02-14-54)-Study-related document.pdf
1610	Ethical approval	377173-(Uploaded-12-03-2019-20-50-03)-Study-related document.pdf
4025	Study protocol	377173-(Uploaded-09-08-2019-23-53-07)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Study results article	Yes		Sabbatinelli, J.; Orlando, P.; Galeazzi, R.; Silve... [More Details]	377173-(Uploaded-16-04-2020-03-53-23)-Journal results publication.pdf

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Ubiquinol ameliorates endothelial dysfunction in subjects with mild-to-moderate dyslipidemia: A randomized clinical trial.	2020	https://dx.doi.org/10.3390/nu12041098

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

Trial Review

Documents added manually

Documents added automatically