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Therapeutic Intervention of Eriomin Associated With Metformin in the Control of Hyperglycemia in Pre-Diabetic Patients (Eriomin+Met)

Primary Purpose

Pre-diabetes

Status
Recruiting
Phase
Not Applicable
Locations
Brazil
Study Type
Interventional
Intervention
Eriomin
Washout
Placebo
Sponsored by
Thais Cesar
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pre-diabetes focused on measuring citrus flavonoids, Eriomin, oral antidiabetic biguanide (metformin), hyperglycemia, microbiota

Eligibility Criteria

35 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Glycemia of 6.1 to 7.0 mmol / L Glycated hemoglobin with values between 5.7 and 6.4% Exclusion Criteria: use of drugs, vitamins and dietary supplements, alcohol consumption (> 20 g alcohol/d), and intense physical activity (> 5 hours/week). History of cardiovascular disease, diabetes mellitus, liver, kidney or pancreatic disease

Sites / Locations

  • Centro de Estudos e Praticas em Nutrição (CEPRAN)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Eriomin/Placebo

Placebo/Eriomin

Arm Description

Group A will receive Eriomin (250 mg/day) for 12 weeks, followed by a 2-week washout period, and then placebo (250 mg/day) for 12 weeks.

Group B will receive placebo (250 mg/day) for 12 weeks, followed by a 2-week washout period, and then Eriomin (250 mg/day) for 12 weeks.

Outcomes

Primary Outcome Measures

Fasting Glycemia
Dosages of glycemia concentration (mg/dL) before and after intervention with Eriomin/placebo

Secondary Outcome Measures

Oral Glucose Tolerance Test (OGTT)
Changes in blood glucose 2 hours after the oral glucose tolerance test (mg/dL) before and after intervention with Eriomin/placebo
HbA1c
Dosages of glycated hemoglobin (%) in the blood serum/plasma before and after intervention with Eriomin/placebo
Insulin
Dosages of Insulin (µU/mL) in the blood serum/plasma before and after intervention with Eriomin/placebo
Blood Lipids profile
Dosages of cholesterol (mg/dL), HDL-cholesterol (mg/dL) and triglycerides (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo
Antioxidant Capacity
Dosages of Trolox equivalent antioxidant capacity (TEAC) (μM) in the blood serum/plasma before and after intervention with Eriomin/placebo
Lipid Peroxidation
Dosages of Malondialdehyde (MDA) (mM) the blood serum/plasma before and after intervention with Eriomin/placebo
Glucagon-like peptide-1 (GLP-1)
Dosages of GLP-1 (pmol/L) the blood serum/plasma before and after intervention with Eriomin/placebo
Inflammatory parameters
Dosages of C Reactive Protein (CRP) (mg/dL), TNF-alpha (mg/dL), IL-6 (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo
Hepatic Enzymes
dosages of alkaline phosphatase (U/L), gamma glutamyl transferase (U/L), aspartate aminotransferase (U/L), and alanine aminotransferase (U/L) in the blood serum/plasma before and after intervention with Eriomin/placebo
Kidney Blood Parameters
Dosages of urea (mg/dL) and creatinine (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo
Anthropometric Parameters
Measurements of body weight (kg), muscle mass (kg), fat mass (kg) before and after intervention with Eriomin/placebo
Microbiota composition by 16S rRNA gene sequencing
Dosages of the main bacteria groups by Operational Taxonomic Units (OTU) and % of relative abundance by group

Full Information

First Posted
March 27, 2023
Last Updated
August 21, 2023
Sponsor
Thais Cesar
Collaborators
Ingredients by Nature TM
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1. Study Identification

Unique Protocol Identification Number
NCT06005142
Brief Title
Therapeutic Intervention of Eriomin Associated With Metformin in the Control of Hyperglycemia in Pre-Diabetic Patients
Acronym
Eriomin+Met
Official Title
Therapeutic Intervention of Nutraceutical Eriomin Associated With Metformin to Improve the Control of Hyperglycemia in Patients With Prediabetes: A Double-blind, Randomized, Placebo-controlled Crossover Clinical Trial
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 15, 2023 (Actual)
Primary Completion Date
April 30, 2024 (Anticipated)
Study Completion Date
December 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Thais Cesar
Collaborators
Ingredients by Nature TM

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Citrus bioflavonoids, such as eriocitrin, hesperidin and naringin, have been shown improved hyperglycemia, insulin resistance and systemic inflammation, related to the development of type 2 diabetes. The nutraceutical Eriomin, a lemon flavonoid extract composed mainly by eriocitrin (70%) and other flavonoids (30%), improved the control of moderate hyperglycemia in pre-diabetic and diabetic patients without drug therapy. However, most patients with pre-diabetes are on oral biguanide (metformin) therapy, despite its limited efficacy (30-40%) on glycemic control and its undesirable gastrointestinal effects. Therefore, in the current study, Eriomin will be administered at a dose of 250 mg/d to adults diagnosed with pre-diabetes and being treated with metformin (1,000 mg/d). This clinical trial was designed as a placebo-control, double-blind, two-arm, crossover design. Clinical characteristics, body composition, food consumption, metabolic and inflammatory biomarkers and the microbiota of all patients will be evaluated before, during and at the end of the 12-week period (arm). Biochemical and metabolic parameters associated with prediabetes are expected to improve or return to normal with Eriomin in combination with metformin. At the same time, an increase in beneficial intestinal bacteria is expected, reducing pre-diabetic dysbiosis, and perhaps a noticeable improvement in body composition.
Detailed Description
Recent evidence shows that bioflavonoids from citrus fruits and herbs can reduce hyperglycemia, dyslipidemia, insulin resistance and the systemic inflammatory process related to type 2 diabetes (T2D). Although they can be found in fruits and herbs, bioflavonoid supplements and nutraceuticals can provide sufficient and safe amounts of bioactive compounds to prevent the development of metabolic disorders, such as metabolic syndrome, diabetes, obesity and others. Eriocitrin flavanone, present in lemons, limes and oranges, has demonstrated anti-inflammatory, anti-hyperglycemic and antioxidant properties and is an integral part of lemon bioflavonoid supplements that have been widely marketed. Eriocitrin metabolism, similar to hesperidin, is resistant to pancreatic enzymes and are mostly deglycosylated by intestinal bacteria (Bacteroides distasonis or Bacteroides uniformis) to eriodictyol before absorption. A minimal amount can be absorbed as glycosylated in the upper intestine. Eriodictyol, the aglycon of eriocitrin, can be metabolized by intestinal bacteria (with 3,4-dihydroxycinnamic acid formation) to homoeriodictyol and hesperetin through methoxylation. In the liver, eriodictyol is metabolized into glucuronides and conjugated sulfates of eriodictyol, homoeriodictyol, and hesperitin, through sulfation, glucuronidation and methylation, and later released into the circulation to exert biological activity. Eriocitrin can increase the total antioxidant capacity, leading to a decrease in inflammatory markers (IL-6, MCP-1 and us-CRP) in the blood and organs of mice supplemented with the flavonoid. Eriocitrin also increased catalase and glutathione enzymes in the liver of diabetic rats, and decreased lipid peroxidation in blood, liver and kidney. Furthermore, oral administration of eriodictyol to diabetic rats improved glucose metabolism in the blood, liver and kidney, and suppressed diabetes by upregulating PPARγ29 mRNA expression. Based on this experimental evidence, the nutraceutical Eriomin, composed of lemon bioflavonoids, was tested as a dietary supplement to control mild to moderate hyperglycemia in pre-diabetic and diabetic patients. After three months of therapy, there was a decrease in hyperglycemia, improvement in insulin resistance and a decrease in HbA1c. Thus, the hypothesis of the current study is to use the nutraceutical Eriomin as a co-adjuvant to oral biguanide (metformin) therapy, improving control of hyperglycemia and insulin resistance, while increasing efficacy with a low dosage (250 mg/d) of the nutraceutical. It is expected to improve the quality of the microbiota, the glucose metabolism and body composition, in addition to reducing the side effects associated with the continuous use of metformin. Therefore, the main objective of this study is to evaluate the effects of Eriomin (250mg/day) associated with metformin on glycemic control, insulin resistance and other metabolic, inflammatory and clinical parameters. Furthermore, it will evaluate changes in the microbiota of pre-diabetic patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pre-diabetes
Keywords
citrus flavonoids, Eriomin, oral antidiabetic biguanide (metformin), hyperglycemia, microbiota

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Model Description
A crossover, randomized, placebo-controlled, double-blind clinical trial will be conducted for 12 weeks, with a two-week washout interval, followed by another 12 weeks, totaling 26 weeks. All participants must be under oral biguanide (metformin) (1000 mg/day) regimen by at least two weeks before the intervention, and they will be measure for glycemia, HbA1c and OGTT, and an interview with an MD and Nutritionist in order to confirm eligibility, according to the inclusion/exclusion criteria. The selected individuals will be randomly distributed into 2 groups, and they will receive alternately Eriomin (or placebo), followed by 2-weeks of washout, and placebo (or Eriomin) for 12 weeks. At the beginning of the first, 12th, 14th, and 26th weeks, all subjects will be evaluated for the following: Glycemia, OGTT, HbA1c, Insulin, Lipids, TEAC, MDA, GLP-1, inflammatory, hepatic, kidney, and anthropometric parameters, and microbiota composition.
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
All subjects and the principal investigator will remain blinded to treatment until data analysis is complete. Eriomin (lemon flavonoids extract) and Placebo (composed of microcrystalline corn starch) were encapsulated in tablets of the same size, shape, and color, by a registered pharmacist.
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Eriomin/Placebo
Arm Type
Active Comparator
Arm Description
Group A will receive Eriomin (250 mg/day) for 12 weeks, followed by a 2-week washout period, and then placebo (250 mg/day) for 12 weeks.
Arm Title
Placebo/Eriomin
Arm Type
Placebo Comparator
Arm Description
Group B will receive placebo (250 mg/day) for 12 weeks, followed by a 2-week washout period, and then Eriomin (250 mg/day) for 12 weeks.
Intervention Type
Dietary Supplement
Intervention Name(s)
Eriomin
Intervention Description
Pre-diabetic patients on oral biguanide (metformin) (1000 mg/day) will receive a 250 mg/day capsule of Eriomin for 12 weeks.
Intervention Type
Dietary Supplement
Intervention Name(s)
Washout
Intervention Description
After 12 weeks of treatment with the active component (Eriomin) or placebo, the participants will follow a washout for 2 weeks.
Intervention Type
Dietary Supplement
Intervention Name(s)
Placebo
Intervention Description
Pre-diabetic patients on oral biguanide (metformin) (1000 mg/day) will receive a 250 mg/day placebo capsule for 12 weeks.
Primary Outcome Measure Information:
Title
Fasting Glycemia
Description
Dosages of glycemia concentration (mg/dL) before and after intervention with Eriomin/placebo
Time Frame
0-12-18-26 week
Secondary Outcome Measure Information:
Title
Oral Glucose Tolerance Test (OGTT)
Description
Changes in blood glucose 2 hours after the oral glucose tolerance test (mg/dL) before and after intervention with Eriomin/placebo
Time Frame
0-12-18-26 week
Title
HbA1c
Description
Dosages of glycated hemoglobin (%) in the blood serum/plasma before and after intervention with Eriomin/placebo
Time Frame
0-12-18-26 week
Title
Insulin
Description
Dosages of Insulin (µU/mL) in the blood serum/plasma before and after intervention with Eriomin/placebo
Time Frame
0-12-18-26 week
Title
Blood Lipids profile
Description
Dosages of cholesterol (mg/dL), HDL-cholesterol (mg/dL) and triglycerides (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo
Time Frame
0-12-18-26 week
Title
Antioxidant Capacity
Description
Dosages of Trolox equivalent antioxidant capacity (TEAC) (μM) in the blood serum/plasma before and after intervention with Eriomin/placebo
Time Frame
0-12-18-26 week
Title
Lipid Peroxidation
Description
Dosages of Malondialdehyde (MDA) (mM) the blood serum/plasma before and after intervention with Eriomin/placebo
Time Frame
0-12-18-26 week
Title
Glucagon-like peptide-1 (GLP-1)
Description
Dosages of GLP-1 (pmol/L) the blood serum/plasma before and after intervention with Eriomin/placebo
Time Frame
0-12-18-26 week
Title
Inflammatory parameters
Description
Dosages of C Reactive Protein (CRP) (mg/dL), TNF-alpha (mg/dL), IL-6 (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo
Time Frame
0-12-18-26 week
Title
Hepatic Enzymes
Description
dosages of alkaline phosphatase (U/L), gamma glutamyl transferase (U/L), aspartate aminotransferase (U/L), and alanine aminotransferase (U/L) in the blood serum/plasma before and after intervention with Eriomin/placebo
Time Frame
0-12-18-26 week
Title
Kidney Blood Parameters
Description
Dosages of urea (mg/dL) and creatinine (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo
Time Frame
0-12-18-26 week
Title
Anthropometric Parameters
Description
Measurements of body weight (kg), muscle mass (kg), fat mass (kg) before and after intervention with Eriomin/placebo
Time Frame
0-12-18-26 week
Title
Microbiota composition by 16S rRNA gene sequencing
Description
Dosages of the main bacteria groups by Operational Taxonomic Units (OTU) and % of relative abundance by group
Time Frame
0-12-18-26 week

10. Eligibility

Sex
All
Minimum Age & Unit of Time
35 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Glycemia of 6.1 to 7.0 mmol / L Glycated hemoglobin with values between 5.7 and 6.4% Exclusion Criteria: use of drugs, vitamins and dietary supplements, alcohol consumption (> 20 g alcohol/d), and intense physical activity (> 5 hours/week). History of cardiovascular disease, diabetes mellitus, liver, kidney or pancreatic disease
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Thais B Cesar, PhD
Phone
+1 (352) 978-7557
Email
thais.cesar@unesp.br
First Name & Middle Initial & Last Name or Official Title & Degree
Maria Rita M De Oliveira, PhD
Email
maria-rita.oliveira@unesp.br
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Thais B Cesar, PhD
Organizational Affiliation
Sao Paulo State University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Maria Rita M De Oliveira, PhD
Organizational Affiliation
Sao Paulo State University
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Valeria Cristina Samdrim, PhD
Organizational Affiliation
Sao Paulo State University
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Katia Sivieri, PhD
Organizational Affiliation
Sao Paulo State University
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Adriana Lucia Mendes, PhD
Organizational Affiliation
Sao Paulo State University
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Gabriela A Meira, Nutrition
Organizational Affiliation
Sao Paulo State University
Official's Role
Study Chair
Facility Information:
Facility Name
Centro de Estudos e Praticas em Nutrição (CEPRAN)
City
Botucatú
State/Province
SP
ZIP/Postal Code
18618-689
Country
Brazil
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maria Rita M de Oliveira, PhD
Phone
(14) 98154-1509
Email
maria-rita.oliveira@unesp.br
First Name & Middle Initial & Last Name & Degree
Valeria Cristina Sandrim, PhD
Phone
(14) 98154-1509
Email
valeria.sandrim@unesp.br
First Name & Middle Initial & Last Name & Degree
Thais B Cesar, PhD

12. IPD Sharing Statement

Citations:
PubMed Identifier
27213445
Citation
Testa R, Bonfigli AR, Genovese S, De Nigris V, Ceriello A. The Possible Role of Flavonoids in the Prevention of Diabetic Complications. Nutrients. 2016 May 20;8(5):310. doi: 10.3390/nu8050310.
Results Reference
background
PubMed Identifier
26705405
Citation
Vinayagam R, Xu B. Antidiabetic properties of dietary flavonoids: a cellular mechanism review. Nutr Metab (Lond). 2015 Dec 23;12:60. doi: 10.1186/s12986-015-0057-7. eCollection 2015.
Results Reference
background
PubMed Identifier
12551749
Citation
Minato K, Miyake Y, Fukumoto S, Yamamoto K, Kato Y, Shimomura Y, Osawa T. Lemon flavonoid, eriocitrin, suppresses exercise-induced oxidative damage in rat liver. Life Sci. 2003 Feb 21;72(14):1609-16. doi: 10.1016/s0024-3205(02)02443-8.
Results Reference
background
PubMed Identifier
24424211
Citation
Hiramitsu M, Shimada Y, Kuroyanagi J, Inoue T, Katagiri T, Zang L, Nishimura Y, Nishimura N, Tanaka T. Eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis. Sci Rep. 2014 Jan 15;4:3708. doi: 10.1038/srep03708.
Results Reference
background
PubMed Identifier
10956094
Citation
Miyake Y, Shimoi K, Kumazawa S, Yamamoto K, Kinae N, Osawa T. Identification and antioxidant activity of flavonoid metabolites in plasma and urine of eriocitrin-treated rats. J Agric Food Chem. 2000 Aug;48(8):3217-24. doi: 10.1021/jf990994g.
Results Reference
background
PubMed Identifier
27182608
Citation
Ferreira PS, Spolidorio LC, Manthey JA, Cesar TB. Citrus flavanones prevent systemic inflammation and ameliorate oxidative stress in C57BL/6J mice fed high-fat diet. Food Funct. 2016 Jun 15;7(6):2675-81. doi: 10.1039/c5fo01541c. Epub 2016 May 16.
Results Reference
background
PubMed Identifier
31183921
Citation
Ribeiro CB, Ramos FM, Manthey JA, Cesar TB. Effectiveness of Eriomin(R) in managing hyperglycemia and reversal of prediabetes condition: A double-blind, randomized, controlled study. Phytother Res. 2019 Jul;33(7):1921-1933. doi: 10.1002/ptr.6386. Epub 2019 Jun 11.
Results Reference
background
PubMed Identifier
35796695
Citation
Cesar TB, Ramos FMM, Ribeiro CB. Nutraceutical Eriocitrin (Eriomin) Reduces Hyperglycemia by Increasing Glucagon-Like Peptide 1 and Downregulates Systemic Inflammation: A Crossover-Randomized Clinical Trial. J Med Food. 2022 Nov;25(11):1050-1058. doi: 10.1089/jmf.2021.0181. Epub 2022 Jul 7.
Results Reference
background
PubMed Identifier
31009043
Citation
Flory J, Lipska K. Metformin in 2019. JAMA. 2019 May 21;321(19):1926-1927. doi: 10.1001/jama.2019.3805.
Results Reference
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Therapeutic Intervention of Eriomin Associated With Metformin in the Control of Hyperglycemia in Pre-Diabetic Patients

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