Nutritional and Metabolic Diseases

Gland and Hormone Related Diseases

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Nervous System Diseases

Heart and Blood Diseases

Diabetes Mellitus

Kidney Diseases

Neuromuscular Diseases

Hypercholesterolemia

Heart Diseases

Urologic Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Hyperlipoproteinemias

Hyperlipidemias

Dyslipidemias

Metabolic Diseases

Lipid Metabolism Disorders

Teri Manolio, MD, PhD

John Harley, MD, PhD

Hakon Hakonarson, MD, PhD

Chunhua Weng, PhD

Marc Williams, MD

Elizabeth Karlson, MD

Scott Hebbring, PhD

Iftikhar Kullo, MD

Samuel Adunyah, PhD

Rex Chisholm, PhD

Gail Jarvik, MD, PhD

Dan Roden, MD

Heidi Rehm, PhD

Richard Gibbs, PhD

The Electronic Medical Records and Genomics (eMERGE) Network is in its third phase and during this time is enrolling and sequencing 25,000 individuals on a custom sequencing panel of clinically relevant, actionable genes. The genetic results will be returned to participants and outcomes tracked through the electronic health records.

The Electronic Medical Records and Genomics (eMERGE) Network is a National Human Genome Research Institute (NHGRI)-funded consortium tasked with developing methods and best practices for utilization of the electronic medical record (EMR) as a tool for genomic research. Phase III is focused on returning actionable gene variants to patients and measuring clinical outcomes. Ultimately, eMERGE hopes its efforts will result in improvements in health care, through safer and more effective prescription methodology, augmentation of primary and secondary prevention strategies, and enhanced understanding of the biology of disease.

eMERGE is composed of 10 clinical sites \[ Childrens Hospital of Pennsylvania (CHOP); Cincinnati Children's Medical Center (CCHMC); Columbia University; Geisinger; Kaiser Permanente Washington with Washington University and the Fred Hutchinson Cancer Research Center; Harvard University; Mayo Clinic; Meharry Medical College; Northwestern University; Vanderbilt University Medical center (VUMC)\], one non clinical site: Marshfield Clinic, two sequencing centers \[Baylor college of Medicine; Partners Healthcare with Broad Institute\], a Coordinating Center (VUMC), and the NHGRI. More information on the eMERGE Network can be found at www.gwas.org.

Each sites' research study is tailored to their specific interests. An eMERGE specific sequencing panel was designed and ran on participants covering 109 genes and 1551 Single Nucleotide Variants (SNVs), of which 68 genes and 14 SNVs are clinically actionable and are being returned to patients.

Blood samples are drawn from patients after consent in a CLIA certified manner. These samples are processed, DNA is extracted and sent to one of two sequencing centers (Baylor College of Medicine or Partners Healthcare with Broad Institute). DNA is then sequenced and clinical reports along with sequencing results returned to sites.

Electronic Medical Records and Genomics (eMERGE) Phase III

The network will abstract data from patient electronic health records (EHR) six months after clinically actionable results have been returned to the patients and providers. The Network will determine changes in medication or treatments after return of the sequencing results. Outcome measures on patients receiving both positive and negative results will be analyzed.

Vanderbilt University Medical Center

Associate Professor of Biomedical Informatics

Neoplasms

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Rare Diseases

Breast Neoplasms

Obesity

Oculocerebral Syndrome With Hypopigmentation

Micronutrients

All Drugs and Chemicals

Bone Density Conservation Agents

Anticoagulants

Gastrointestinal Agents

Other Dietary Supplements

Vitamins

Flavonoid

Herbal and Botanical

Ascorbic Acid

Vitamin D

Cholecalciferol

Vitamin B 6

Pyridoxal

Pyridoxine

Citric Acid

Sodium Citrate

Caseins

Vitamin B Complex

Locust bean gum

Citrate

Vitamin C

Bifidobacterium

Anthocyanidin

Vitamin D3

Calciferol

Vitamin B6

Cayenne

Phytosterol

Strawberry

The investigational food product "Cholesterol Reducing Strawberry Yogurt Drink (Tesco)" is a strawberry yogurt drink with added plant sterols. A 100g bottle (one serving) of cholesterol lowering strawberry yogurt drink contains 2g of free plant sterols. The magnitude of the effect given by this enriched food product, providing a daily intake of 1,5-2,4 g plant sterols/stanols, refers to the lowering/reducing blood cholesterol effects in the range "7 % to 10 %" within 2 to 3 weeks of treatment, as specified by Commission Regulation (EU) 384/2010 of 05/05/2010.

The dietary intervention will consist in 8 weeks consumption of PSS enriched Yogurt Drink, which provide a daily PSS intake of 3.4g/100g bottle plant sterols ester equivalent to 2g/100g bottle of free plant sterols.

The investigational food product "Low Fat Strawberry Yogurt Drinks (Morrisons)" is a strawberry flavoured yogurt drink with sweetener and sugar, vitamin C, B6 and D, British milk.

Placebo intervention consists in 8 weeks consumption of PSS non-enriched Yogurt Drinks. The placebo intervention is needed for the study design chosen (randomized double-blind placebo-controlled cross-over clinical trial). Placebo will be used in order to determine the efficacy of PSS intervention, comparing the effects of the two compounds (PSS and placebo) in the same experimental conditions and then avoiding bias.

Ingredients: Skimmed Milk, Strawberry Juice from Concentrate (5%), Plant Sterols Ester (3.4%)\*\*\*, Sugar, Maize Starch, Flavourings, Colour (Anthocyanins), Starter Culture including Bifidobacterium (Milk), Thickener (Carob Gum), Sweetener (Sucralose), Milk Proteins.

\*\*\* Equivalent to 2% Free Plant Sterols

Cholesterol Reducing Strawberry Yogurt Drink (Tesco Ltd)

Ingredients: Yogurt (Milk), Water, Sugar, Strawberry Purée (1%), Modified Maize Starch, Carrot Concentrate, Flavouring, Acidity Regulator (Citric Acid), Vitamin C, Colour (Paprika Extract), Sweetener (Sucralose), Vitamin D, Vitamin B6.

Low Fat Strawberry Yogurt Drinks (Morrisons Ltd)

James L Thorne, PhD

Giorgia, PhD

Several types of human cells convert cholesterol into other molecules, including oxysterols. Oxysterols can promote breast cancer growth and help tumours to spread. Some breast cancer types recruit other cells (host cells) able to produce oxysterols within the local cancer environment.

How these other cells help breast tumours metastasize or resist chemotherapy is not well understood, but epidemiological and clinical studies suggest elevated LDL-C is associated with worse survival, poorer response to therapy and an increased propensity for disease relapse in breast cancer patients. In this trial the investigators will test how an LDL-C lowering dietary intervention (using commercially available phytosterol added food products), alters the ability of non-cancer cells (adipocytes, fibroblasts and macrophages) collected from high LDL-C volunteers to change chemotherapy response and metastatic process in breast cancer cells.

In this trial, volunteers with high LDL-C levels will be recruited by the University of Leeds, and divided randomly into two arms that cross over. The experimental period (yogurt drink enriched with phytosterols) and placebo period (non-enriched yogurt drink) will each last for 8 weeks, alternated with a 4 weeks of wash-out period. Samples will be collected 4 times (week-0, week-8, week-12, week-20) during the study and will include blood, white blood cells (macrophages), and fat tissue cells. Measurements will include oxysterol, LDL-C and phytosterol concentrations (volunteers' serum/plasma, media from the host cells/breast cancer experimental culture) and how the host cells alter the behaviour of cancer cells in the laboratory.

Delivery of cholesterol to extra-hepatic tissues by LDL has a profound impact on different host cell types, many of which themselves have been implicated in BCa metastasis and chemoresistance.

Despite accumulating data, it is still unknown how host-cells help breast tumours metastasise or evade chemotherapy. The molecular link between cholesterol and metastasis may involve the enzymatic hydroxylation (an intermediate step in bile acid synthesis) of cholesterol. The synthesis and secretion of oxysterols into the tumour microenvironment and this is exacerbated in individuals with elevated LDL-cholesterol. This process, occurring largely in macrophages, adipocytes and fibroblasts, leads to biosynthesis and cellular export of oxysterols , which drive DNA mutations through oxidative stress, confer resistance to chemotherapy, enhance BCa growth and metastasis, and are elevated in serum of BCa patients at metastatic relapse. Our pilot data show non-cancer host-cells activate oxysterols signalling and drug resistance protein expression and confer chemotherapy resistance in adjacent cancer cells.

The investigators therefore propose to test the hypothesis that the reason epidemiological and clinical studies find elevated LDL-C and its co-morbidities associate with worse survival in BCa patients, is because the host-cells of these patients have enhanced cholesterol metabolic flux leading to increased oxysterols production and improved tolerance of chemotherapy and promotion of cancer metastatic pathways.

This trial is a multicentre cross-over double blind clinical trial in which volunteers with LDL-C ≥160mg/dL (4.1 mmol/L), recruited at the University of Leeds and/or identified through Horizon 2020 project PATHWAY-27, will be randomised into two arms of intervention, Group A (experimental arm) will be given an yoghurt drink enriched with PSS and Group B (placebo comparator) will be given yoghurt drink non-enriched with PSS. Each dietary intervention will last for 8 weeks, alternated with a 4 weeks of wash out period. This trial wants to highlight the superiority of the PSS (yoghurt drink enriched) to placebo (yoghurt drink non-enriched) intervention on the improvement of the serum/plasma and host cells (adipocytes and macrophages) LDL-C, oxysterols , PSS levels in high LDL-C levels volunteers and in respective conditioned media from the host cells/BCa cell lines co-culture, and superiority of the PSS to placebo intervention on the improvement of the cholesterol panel levels involved in BCa tolerance of chemotherapy and metastatic progression, according also to the molecular and genetical pathways.

Because of the unknown effect of PSS on the oxysterols metabolism and of its consequent chemotherapy and anti-metastatic proprieties, the trial will be divided in two phases (I and II):

I. In this pilot phase the investigators will explore the effects of PSS intervention in 10 volunteers, evaluate feasibility of study protocol (participant recruitment and retention), and changes in mean and SD in oxysterols /PSS concentrations making changes to dose and power calculations if necessary. If the intervention causes any noteworthy effect in oxysterols serum/blood levels and/or on host cell co-culture with BCa cells the study will continue to Phase II:

II. In this phase a further 40 volunteers will be enrolled in the study satisfying our power calculation prediction to observe an effect.

This randomized cross-over double blind clinical trial will be run mainly at the School of Food Science and Nutrition, of the University of Leeds (FS\&N). Each site will have a nominated principle investigator. This will be in collaboration with the NHS - Leeds Teaching Hospitals Trust (LTHT), the Leeds Institute of Biomedical \& Clinical Sciences of the Faculty of Medicine and Health of the University of Leeds (LIBACS) and the Department of Chemistry of the University of Oslo (DC).

At each step point (Day 56, day 84 and day 140), the following trial assessments and procedures will be taken:

* Weight measurement;
* Participants diary card checking;
* Adverse effects and safety;
* Blood Pressure;
* Food intervention compliance checking by asking participants to return yoghurt packages back to trial team and relative recordings;
* 24h dietary recall questionnaire interview;
* LDL-C, HDL-C, Total Cholesterol, Triglycerides, non-HDL-C blood concentration and HDL-C/LDL-C ratio measurement;
* Serum/plasma OHCs concentration measurement;
* Serum/plasma PSS concentration measurement;
* Medium LDL-C concentration measurement after host cells co-culture with breast cancer cell lines;
* Medium OHCs concentration measurement after host cells co-culture with breast cancer cell lines;
* Medium PSS concentration measurement after host cells co-culture with breast cancer cell lines;
* Adipocytes, macrophages and breast cancer cell lines cell lines OHCs content measurement;
* Migratory and chemoresistance properties of the breast cancer cell lines cell lines after host cells co-culture.

Enrolled participants will undergo 1:1 simple randomisation by the CI, to either Experimental arm or placebo arm.. Evaluations after intervention will be made at the end of the first 8 weeks of intervention (Day 56; 8th week) and at the end of the second 8 weeks intervention (Day 140; 20th week). Since a wash out period between the two food products consumption is provided, another evaluation after wash out period (Day 84; 12th week) will be performed. The wash out period consist in a 4 weeks food products free period, where will be ask to participants to maintain their usual dietary and life style habits excluding the consumption of any yoghurt drinks.

All trial investigators will be blinded to the intervention, except for the CI. The CI will keep a record of interventions administrated. All trial participants and outcome assessors will be blinded to the intervention. Each food product has the same flavour and taste, as well as the same packaging to ensure blinding in maintained throughout study.

Plant Sterol INtervention for Cancer Prevention (PINC)

Randomised Control Cross-over Trial to Test How Dietary Plant Sterols Modify Tumour Promoting Capabilities of Non-tumour Host Cells in Volunteers With Elevated LDL-C

Data will be published in scientific journals, which will depend on the outcome of data analysis. Anonymized research data will be deposited with the University of Leeds data repository.

RNA sequence will be measured with RNA-seq techniques before and after phytosterols intervention to identify the molecular effectors of the paracrine regulatory systems in the oxysterols, LDL-C and secondary BCa pattern.

Changes in interactions between proteins and DNA and using Chip/seq will be measured before and after phytosterols intervention to identify the molecular effectors of the paracrine regulatory systems in the oxysterols, LDL-C and secondary BCa pattern.

The changes of oxysterols content in serum/plasma after 8 weeks of phytosterols intervention compared to placebo. After the dietary intervention, we expect to observe a change of -20% in circulating 27-hydroxycholesterol content (marker of oxysterols systemic levels).

Concentration of oxysterols using LC-MS/MS measurement of plasma in 50 subjects after placebo and after intervention.

Concentration of oxysterols using LC-MS/MS measurement of host cells in 50 subjects after placebo and after intervention.

Effect of phytosterols enriched foods consumption compared to placebo intervention on migratory and chemoresistance properties of breast cancer cell lines (MDA.MB.231, MDA.MB.468, MCF7 and T47D) when in co-culture with the host-cells collected in each step of the trial.

Effect of phytosterols enriched foods consumption compared to placebo intervention on migratory and chemoresistance properties of breast cancer cell lines (MDA.MB.231, MDA.MB.468, MCF7 and T47D) when in co-culture with the host-cells collected in each step of the trial.

Changes in proteins expression of oxysterols target genes.

Effect of phytosterols enriched foods consumption compared to placebo intervention on migratory and chemoresistance properties of breast cancer cell lines (MDA.MB.231, MDA.MB.468, MCF7 and T47D) when in co-culture with the host-cells collected in each step of the trial.

Changes in gene expression of oxysterols target genes.

Study of the effect of phytosterols on LDL-C concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Study of the effect of phytosterols on HDL-C concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Study of the effect of phytosterols on Total Cholesterol concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Study of the effect of phytosterols on Triglycerides concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Study of the effect of phytosterols on non-HDL-C concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Phytosterols panel serum/plasma levels after phytosterols enriched food or placebo intervention during all the steps of the trial.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Electronic Medical Records and Genomics (eMERGE) Phase III	NCT03394859	Cardiac Disease Cancer Hypercholestero... Diabetes Kidney Diseases Neuromuscular D...		1 Day - 120 Years	Vanderbilt University Medical Center
Plant Sterol INtervention for Cancer Prevention (PINC)	NCT04147767	Hypercholestero... Breast Cancer Obesity	Cholesterol Red... Low Fat Strawbe...	18 Years - 65 Years	University of Leeds
Plant Sterol INtervention for Cancer Prevention (PINC)	NCT04147767	Hypercholestero... Breast Cancer Obesity	Cholesterol Red... Low Fat Strawbe...	18 Years - 65 Years	University of Leeds

Spots Global Cancer Trial Database for hypercholesterolemia