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Trial registered on ANZCTR


Registration number
ACTRN12617000604303
Ethics application status
Approved
Date submitted
5/04/2017
Date registered
27/04/2017
Date last updated
4/03/2019
Date data sharing statement initially provided
4/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of ribose-cysteine on heart disease biomarkers
Scientific title
The effect of ribose-cysteine on antioxidant and lipid status in post-menopausal women
Secondary ID [1] 291607 0
None
Universal Trial Number (UTN)
U1111-1195-0453
Trial acronym
RCALS
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Cardiovascular 302720 0
Oxidative Stress 302721 0
Dyslipidaemia 302722 0
Condition category
Condition code
Cardiovascular 302244 302244 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study proposes an intervention with ribose-cysteine [2(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)-thiazolidine-4(R)-carboxylic acid], a dietary supplement sold in 14 countries that has been developed to boost the levels of glutathione, an important antioxidant in the body. Ribose-cysteine is listed with Australia’s Therapeutic Goods Administration as a permissible ingredient and is sold by the network marketing company, Max International. While a few animal studies have been performed on its glutathione enhancing and lipid-lowering properties, no study has been conducted to establish the potential cardio-protective effects of ribose-cysteine in humans. We propose an intervention study of healthy, non-smoking, post menopausal women between the ages of 45 and 65 that are not currently on ribose cysteine supplementation or lipid-lowering medication. Men and women have significantly different lipid levels and their results are normally analysed separately in large clinical trials where lipids are a main outcome. This is particularly important in genetic studies looking at associations with lipids as associations are often different between genders. As our trial is very small (and lipids are one of our primary outcomes) accommodating both genders would seriously underpower our study. Postmenopausal women were chosen for the study due to them having higher LDL levels and being more at risk of CVD than premenopausal women, however, the results should be generalizable to all women. As the trial is a "first in humans" trial and not a therapeutic trial, we need to recruit healthy people. The inclusion of people not suffering existing heart or liver conditions is to ensure recruitment of healthy individuals. The exclusion criteria (smoking, obesity, diabetes and excessive alcohol consumption) is also to ensure recruitment of healthy individuals. Furthermore, all of these exclusion criteria are associated with alterations in lipid levels and antioxidant status which would add unnecessary variability to our primary outcomes making it difficult to dissect real differences due to ribose-cysteine treatment. We will also exclude participants on medications that affect lipid levels i.e. statins, as this would confound any effect of ribose-cysteine on lipid levels.
The trial will be conducted in a simple randomized crossover design with participants receiving either ribose-cysteine or placebo followed by a 6 week washout period before crossover. Participants will be supplied with either a daily supplement of 500 mg ribose-cysteine for 3 months or placebo (both to be taken as oral capsules which will be supplied by Max International).They will be adviced to follow a regular diet for the duration of the trial. The trial will be double-blinded with both the study investigators and participants blinded as to which treatment arm participants are in. The Research Nurse who will dispense the capsules to the study participants at the end of each visit will hold the codes for unblinding which will be revealed after all data analysis has been completed. Participants will be instructed to return empty containers at the end of each arm of the study to monitor compliance. Blood samples (40 ml) will be collected at the beginning and the end of each treatment arm and the plasma, blood cells and genomic DNA isolated. Blood pressure, body weight and height will be measured along with the collection of diet, supplement, medication and physical activity information at each sampling. Participants will be instructed to report any noticeable side effects throughout the study. Adverse side effects will be reported. Blood samples will be measured for ribose-cysteine, glutathione (GSH), cysteine, F2-isoprostanes (an oxidative stress marker), glucose, total cholesterol, triglycerides, HDL cholesterol, apoA1, LDL cholesterol, apoB and Lp(a). The activity of the antioxidant enzyme, glutathione peroxidase and selenium levels (Se is a cofactor for glutathione peroxidase) will also be measured. Alanine transferase (ALT) will be measured to check the supplementation has no effect on liver function. Genomic DNA will be subject to genotyping of common single nucleotide polymorphisms (SNPs) in genes involved in GSH and lipid metabolism.
Intervention code [1] 297679 0
Prevention
Intervention code [2] 297680 0
Treatment: Other
Comparator / control treatment
A placebo oral capsule containing the excipients used in the ribose-cysteine capsules will be administered as the control for the study. Each placebo capsule contains microcrystalline cellulose (275mg), magnesium stearate (8 mg) and silicon dioxide syloid (3 mg).
Control group
Placebo

Outcomes
Primary outcome [1] 301660 0
Change in LDL levels which will be observed by calculation of LDL cholesterol using Friedwald's Equation at the start and end of each arm. Friedwald's Equation (LDL cholesterol = Total cholesterol - HDL cholesterol - Triglycerides)/2.2) will be calculated after measurement of total cholesterol, HDL cholesterol and triglyceride levels by enzymatic assay of serum.
Timepoint [1] 301660 0
3 months from initiation of intervention
Secondary outcome [1] 333478 0
Change in glutathione levels which will be observed by measurements of glutathione in serum by HPLC at the start and end of each arm.
Timepoint [1] 333478 0
3 months from initiation of intervention
Secondary outcome [2] 333570 0
Difference in response to ribose-cysteine supplementation due to genetic variation.
Genetic variation will be observed by sequencing of genes involved in LDL and GSH in genomic DNA extracted from whole blood samples.
Timepoint [2] 333570 0
3 months from initiation of intervention

Eligibility
Key inclusion criteria
Women who are
1.. 45-65 years of age
2. Post-menopausal
3. Not suffering from a pre-existing heart or liver condition
Minimum age
45 Years
Maximum age
65 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Women who
1. Smoke
2. Have a BMI > 35 kg/m2
3. Are Diabetic
4. Drink excessive amounts of alcohol i.e. >14 standard units per week
5. Are already taking ribose-cysteine or are on medications that can affect lipid levels i.e. statins

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealed by using sealed opaque envelopes containing a predecided computerised random allocation which was performed by a third party not involved in the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization using computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The design is a two-arm crossover intervention study. Participants will randomly be divided into two groups with one group receiving 500 mg ribose-cysteine and the other a placebo for 12 weeks. Participants will cross over to the other arm after a 6 week washout period. Based on this study design we plan to recruit 60 participants. Allowing for 20% dropouts and missing data, our power calculation requires that 60 women will be required at baseline to detect a difference between the two groups in LDL cholesterol of 0.4 mmol/L (a major outcome of the trial) with 90% power using a two-sided test, significance at 0.05, and SD for LDL of 0.48 mmol/L. A correlation between repeated measures of 0.5 is assumed. A biostatistician will help us analyse the data. Statistical analysis of the data will use linear mixed models to examine any differences in LDL cholesterol concentrations and other outcomes between interventions. Models will adjust for baseline values of each outcome. Treatment orders will be balanced, providing an unbiased estimate of the difference between the treatments in the absence of missing data. Period (first, second) will be included in the models to reduce variability attributable to any period effects and carry-over effects will be tested for to ensure that the washout period was effective. Standard model diagnostics will be performed and log-transformations investigated and retained if this improves model residual normality. Should model assumptions not be satisfied with untransformed data or by using transformations, mixed quantile regression will be used instead. Two-sided p<0.05 will be considered statistically significant. Statistical analyses will be performed using Stata 14.2 or R 3.3.1

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
12/01/2018
Actual
12/01/2018
Date of last participant enrolment
Anticipated
Actual
27/04/2018
Date of last data collection
Anticipated
28/11/2018
Actual
28/11/2018
Sample size
Target
60
Accrual to date
Final
60
Recruitment outside Australia
Country [1] 8777 0
New Zealand
State/province [1] 8777 0
Otago

Funding & Sponsors
Funding source category [1] 296096 0
Charities/Societies/Foundations
Name [1] 296096 0
The Otago Medical Research Foundation
Country [1] 296096 0
New Zealand
Funding source category [2] 296201 0
Commercial sector/Industry
Name [2] 296201 0
Max International
Country [2] 296201 0
United States of America
Primary sponsor type
Individual
Name
Prof Sally McCormick
Address
University of Otago
Department of Biochemistry
710 Cumberland Street
Dunedin 9016
Country
New Zealand
Secondary sponsor category [1] 294991 0
Commercial sector/Industry
Name [1] 294991 0
Max International
Address [1] 294991 0
c/o Scott Nagasawa, Pharm.D.
Max R&D, LLC
3868 Carson Street
Suite 212
Torrance, CA 90503
Country [1] 294991 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297353 0
HDEC
Ethics committee address [1] 297353 0
Ethics committee country [1] 297353 0
New Zealand
Date submitted for ethics approval [1] 297353 0
24/04/2017
Approval date [1] 297353 0
30/08/2017
Ethics approval number [1] 297353 0
Ethics committee name [2] 299465 0
Standing Committee on Therapeutic Trials (SCOTT)
Ethics committee address [2] 299465 0
Ethics committee country [2] 299465 0
New Zealand
Date submitted for ethics approval [2] 299465 0
03/05/2017
Approval date [2] 299465 0
23/08/2017
Ethics approval number [2] 299465 0
17/SCOTT/40

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 73782 0
Prof Sally McCormick
Address 73782 0
University of Otago
Department of Biochemistry
710 Cumberland St
Dunedin - 9016
Country 73782 0
New Zealand
Phone 73782 0
+64276316613
Fax 73782 0
+6434797866
Email 73782 0
sally.mccormick@otago.ac.nz
Contact person for public queries
Name 73783 0
Sreya Taraknath
Address 73783 0
University of Otago
Department of Biochemistry
710 Cumberland St
Dunedin - 9016
Country 73783 0
New Zealand
Phone 73783 0
+642108364955
Fax 73783 0
Email 73783 0
sresr393@student.otago.ac.nz
Contact person for scientific queries
Name 73784 0
Sally McCormick
Address 73784 0
University of Otago
Department of Biochemistry
710 Cumberland St
Dunedin - 9016
Country 73784 0
New Zealand
Phone 73784 0
+64276316613
Fax 73784 0
Email 73784 0
sally.mccormick@otago.ac.nz

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?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.