Oleanolic Acid as Therapeutic Adjuvant for Type 2 Diabetes Mellitus (OLTRAD STUDY) (OLTRAD)

• ClinicalTrials.gov Identifier: NCT06030544
• Recruitment Status: Recruiting
• First Posted: September 11, 2023
• Last Update Posted: September 11, 2023
• Sponsor: Spanish National Research Council
• Collaborators: Andalusian Health Service; Universidad Pablo de Olavide
• Information provided by (Responsible Party): José M. Castellano, PhD, Spanish National Research Council

Study Description

Brief Summary:

Oleanolic acid (OA), is a natural component of many plant food and medicinal herbs, which has shown to exert in experimental models hypoglycemic and hypolipidemic effects, and also a cytoprotective action against oxidative and chemotoxic stress underlying Type II Diabetes Mellitus (T2DM).Today it is known that OA shares mechanisms of action with metformin and other drugs of choice for the treatment of diabetes. Therefore, the OLTRAD (OLeanolic acid TReAtment for type 2 Diabetes) Study, a prospective, parallel group, randomized, double-blind, controlled trial with 100 participants, has been designed to demonstrate that the regular intake of an OA-enriched functional olive oil is effective as an adjuvant to metformin antidiabetic drug therapy. The hypothesis is that the inclusion of this functional olive oil in the diet will enhance the effects of the pharmacological treatment in diabetic patients, and may even reduce the need for prescription of such medications.

Condition or disease	Intervention/treatment	Phase
Diabetic Patients; Type II Diabetes Mellitus	Dietary Supplement: OA-enriched functional olive oil; Dietary Supplement: commercial olive oil	Phase 2

Detailed Description:

TRIAL DESIGN The OLTRAD Study is a prospective, parallel group, randomized, double-blind, controlled trial designed to demonstrate that the regular intake of an OA-enriched functional olive oil is effective as an adjunct to metformin therapy (as monotherapy or in combination with other antidiabetic drugs) in the metabolic control of T2DM patients. The effect of the OA-enriched olive oil will be compared with that of the control oil, which consists of the same commercial olive oil not fortified in the triterpene.

A total of 100 volunteers of both sex will be selected from among the T2DM patients treated at the Endocrinology and Nutrition Service of the 'Virgen del Rocío' University Hospital (Seville, SPAIN).

SAMPLE SIZE CALCULATION Serum glycosylated hemoglobin (HbA1c) is adopted as the main quantitative variable for the analysis of glycemic control. The null hypothesis stated in the trial design is that the OA-based dietary intervention will reduce the baseline serum HbA1c levels of patients by at least 7%, compared to the control group. To test this one-sided hypothesis test with a 95% confidence level (α risk = 0.05) and 95% power (β risk = 0.05), a sample size of 44 volunteers per group is required. However, due to the characteristics of the study (a long-term lifestyle intervention), participant losses of up to 15% can be assumed, resulting in an adjusted sample size of 50 individuals per group.

RANDOMIZATION Once recruited, the 100 T2DM patients will be randomly assigned to one of the two study groups. Fifty individuals will be assigned to the intervention group, which will ingest the OA-enriched functional olive oil, whereas the other 50 volunteers will be assigned to the control group, which will receive the same non-enriched olive oil. At the time of admission, the study nursing staff will request by telephone the clinical coordinator of the trial (Principal Investigator 2 of the Project) the assignment of participants to the study groups (centralized randomization). Allocation to these groups will be made using computer generated tables of random numbers. Four randomization strata will be constructed by sex and age (cuttof 50 years).

INTERVENTION Participants will be instructed to ingest 55 mL/day of the assigned oil, preferably raw and freely distributed among the three main meals. Both the OA-enriched olive oil and the control oil will be delivered labeled with alphanumeric codes, the correspondence of which will only be known by the Principal Investigator 1 of the project. This ensures blinding of the clinical researchers and participants with respect to the type of olive oil assigned.

FOLLOW-UP Participants in the clinical trial will be followed up for 12 months from enrollment, according to a plan of quarterly visits.

At the time of recruitment and every three months thereafter, participants will be measured for anthropometric, blood pressure, and heart rate measurements. They will also be asked about gastrointestinal disorders or other types of complaints, and will complete a questionnaire on lifestyle (diet, physical activity, alcohol and tobacco use), medical conditions, and medication use.

Also at the beginning of participation in the study and every three months thereafter, fasting blood samples will be drawn from the cubital vein, which will be collected in sterile plastic tubes with a vacuum system. Similarly, participants will provide aliquots of their first morning urine in sterile plastic tubes. The analytical determinations in blood and urine will be carried out in the Clinical Biochemistry and Analysis Laboratory of the 'Virgen del Rocío' University Hospital in Seville (HUVR).

In addition, aliquots of plasma will be sent to the 'Instituto de la Grasa' (IG-CSIC) for complementary biochemical determinations. Laboratory technicians from both institutions will receive the samples identified with alphanumeric ID codes and, therefore, will be blinded to the intervention groups.

In these quarterly visits, volunteers will participate in sessions of the nutritional education program and will receive 6 L of the assigned oil for free. Adherence to the dietary intervention will be assessed quarterly through the Haynes-Sackett's self-reported compliance test and the return of empty bottles presumably consumed.

The primary outcome of the trial is the improvement in glycemic control, assessed by the evolution of HbA1c. As secondary results, we will obtain data on anthropometric and clinical variables, as well as on biochemical parameters of blood and urine.

ANAMNESIS AND CLINICAL EXAMINATION OF PARTICIPANTS The medical researchers of the project have access to the electronic medical records of the participants in the platform DIRAYA of the Andalusian Health Service, and will carry out the anamnesis and physical examination of the participants, which will include vital data and general medical and surgical history, as well as the pharmacological treatments followed. Information will also be obtained on lifestyle, perception of their own body image, diet, and the type and intensity of physical activity. In addition, a general clinical examination will be carried out including general appearance and inspection of hands and arms, feet and legs, skin, face, eyes, mouth, neck, abdomen, edema, lymph nodes, and vital signs (temperature, pulse, respiratory rate and blood pressure).

ANTHROPOMETRIC STUDY AND BODY COMPOSITION The anthropometric study will include the determination of total body weight, height, body mass index (BMI), as well as waist and hip circumferences. The study and evaluation of these variables will be carried out according to the guidelines of the International Society for the Advancement of Kinanthropometry (ISAK). The study of body composition will be carried out by electrical bioimpedance. Fat mass, lean mass, muscle mass, total water, bone mass, basal metabolism, and visceral fat will be quantified with this technique, using validated prediction equations adjusted for age and sex.

ASSESSMENT OF FOOD INTAKE AND NUTRITIONAL TRAINING A nutritional education program will be implemented to assess the food intake of the participants and reinforce compliance with the dietary recommendations given. To measure food intake, we will use the food intake registration form designed by the University of Navarra (Spain) and used successfully in other trials, such as the PREvención con DIeta MEDiterránea (PREDIMED) study. This form is a validated tool that quantifies food intake in terms of food portions or food groups for adults living in Spain. On the other hand, all the participants will join workshops where they will receive specific dietary recommendations for patients with T2DM, and they will be instructed on a healthy diet, the best food options and adequate portions, limiting highly processed foods, cakes, sugar, fatty foods as well as sugary and alcoholic beverages. Additionally, patients will gain information on recipes, seasonal shopping lists, and the use of olive oil for cooking and dressing. The eating habits of the participants will be analyzed quarterly by means of a 24-hour recall questionnaire. The 'NUTRIUM' software (https://nutrium.com/; Braga; Portugal) for the nutritional evaluation of the diets will be used.

BLOOD BIOCHEMISTRY IN HUVR In ulnar blood samples, determinations related to circulating lipids [total triglycerides, total cholesterol, LDL, HDL, total apolipoprotein B and lipoprotein A]; glucose homeostasis [glycemia, insulinemia, C-peptide, HOMA-IR index, HbA1c]; oxidative stress and inflammation [uric acid, bilirubin, malondialdehyde, ultrasensitive C-reactive protein, thyroid-stimulating hormone (TSH)], as well as those associated with liver and kidney damage [lactate dehydrogenase (LDH), liver transaminases (ALT, AST, GGT ) and creatinine] will be performed.

Plasma level of vitamin B12 will be also assessed. In addition, the possible appearance of liver fibrosis will be evaluated through the Hepamet Fibrosis Score, a non-invasive method that calculates a score taking into account factors such as age, sex, presence of diabetes, glucose levels, insulin, albumin, platelets, and AST. This tool, designed by the Seville Institute of Biomedicine (IBiS), is indicated to assess suspected fibrosis in patients with obesity, diabetes, metabolic syndrome, hepatic steatosis, and/or abnormal liver function markers. The method offers diagnostic reliability and a cost/benefit ratio that is superior to other methods, such as the FIB-4 and the NAFLD Fibrosis Score.

CONTINUOUS BLOOD GLUCOSE MONITORING Plasma glucose will be continuously monitored using the 'FreeStyle Libre' subcutaneous system (ABBOTT Diagnostics; Chicago, IL.; USA). The sensors will be attached to the participants at two times throughout the trial: at baseline and after 12 months of follow-up, and will collect data for 48 hours. With this system, different glycemic parameters will be determined, such as the area under the curve (AUC), the mean amplitude of the glycemic excursion (MAGE), the mean glycemia, as well as the standard deviation (SD) and the coefficient of variation (CV).

PLASMA BIOCHEMISTRY IN IG-CSIC The investigators of the IG-CSIC will perform a number of complementary determinations in plasma samples, such as the plasmatic concentrations of OA, the glutathione (GSH and GSSG) levels, the fatty acid composition, serum adipokines (ceruloplasmin, adiponectin, leptin, resistin, and ghrelin). Serum Antioxidant enzymes (superoxide dismutase, catalase) and proinflammatory cytokines (TNF-α, IL-1β, IL-6) will also be determined.

On the other hand, the VLDL fraction of plasma lipoproteins will be isolated by ultracentrifugation (230,000 × g for 18 h at 4 °C). In these particles, the total content of fatty acids, triglycerides, diglycerides, phospholipids and total Apolipoprotein B will be measured.

URINE ANALYSIS The first morning urine samples will be analyzed for the usual physical, chemical, and microscopic determinations (pH, density, glycosuria, ketones, nitrites, urobilinogen, bilirubin, sediment, leukocytes, microalbuminuria/g creatinine). The determination of these parameters will also be carried out in the facilities of the Clinical Biochemistry and Analysis Laboratory of the 'Virgen del Rocío' University Hospitals in Seville.

STATISTICAL ANALYSIS The trial will be conducted according to the intention-to-treat (ITT) principle. Qualitative variables will be expressed by their absolute and relative frequencies, whereas the quantitative ones with normal distribution will be expressed by the mean and standard deviation and those with non-normal distribution by the median and interquartile range (IQR). Comparisons between study groups for qualitative variables will be performed with the Chi-square and McNemar's tests, whereas comparisons for quantitative variables will be executed with the Student's t-test and ANOVA. The homogeneity of the populations included in the allocation groups will be evaluated using theMann-Whitney-Wilcoxon U-test. All P-values will be two-tailed at α = 0.05. Statistical analysis will be performed with SPSS 27 (IBM SPSS Statistics, NY, USA) software

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: prospective, parallel group, randomized, double-blind, controlled trial
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Both the OA-enriched olive oil and the control oil will be delivered labeled with alphanumeric codes, the correspondence of which will only be known by the Dr. Jose M. Castellano (Principal Investigator 1). This ensures blinding of the other researchers and trial participants with respect to the type of olive oil assigned.
• Primary Purpose: Treatment
• Official Title: Oleanolic Acid as Therapeutic Adjuvant for Type 2 Diabetes Mellitus (OLTRAD STUDY)
• Actual Study Start Date: February 25, 2022
• Estimated Primary Completion Date: December 30, 2024
• Estimated Study Completion Date: June 30, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: OA-enriched functional olive oil; Functional olive oil elaborated enriching the control olive oil with high purity (> 95 %) Oleanolic acid from olive leaf up to 600 mg OA/kg oil.	Dietary Supplement: OA-enriched functional olive oil; Dietary intervention in diabetic patients. Oral intake of 55 mL/day of a functional olive oil enriched in Oleanolic acid (equivalent dose 30 mg/day OA) Oleanolic acid (CAS no. 598-02-1; PubChem CID 10494).; Other Name: Functional olive oil enriched in Oleanolic acid
Active Comparator: Control olive oil; Commercial olive oil (blend of virgin and refined olive oils) chosen by its very low content of bioactive minor components.	Dietary Supplement: commercial olive oil; Dietary intervention in diabetic patients. Oral intake of 55 mL/day of a commercial olive oil (blend of virgin and refined olive oils) chosen by its very low content of bioactive minor components.; Other Name: control olive oil

Outcome Measures

Primary Outcome Measures :

1. HbA1c [ Time Frame: 1 year ]
   The primary outcome of the trial is the evaluation of the glycemic control, assessed through the evolution of the plasma glycosylated hemoglobin (HbA1c) level, expressed in %

Secondary Outcome Measures :

1. Body weight [ Time Frame: 1 year ]
   Body weight (expressed in kilograms, kg) wil be determined using a TANITA® model BC-418MA body composition analyzer.
2. Body height [ Time Frame: 1 year ]
   The body height (expressed in meters, m) will be determined by using an approved column stadiometer
3. Body mass index (BMI) [ Time Frame: 1 year ]
   body weight and height will be combined to report BMI in kg/m^2, according to the equation BMI = body mass/(height)^2
4. Waist circumference [ Time Frame: 1 year ]
   Waist circumference (expressed in centimeters, cm) will be measured with a measuring tape
5. Hip circumference [ Time Frame: 1 year ]
   Hip circumference (expressed in centimeters, cm) will be measured with a measuring tape
6. Body composition - fat mass [ Time Frame: 1 year ]
   Fat mass (expressed in kilograms, kg) will be measured using a TANITA® (model BC-418MA) body composition analyzer. Quantification will be made using validated prediction equations adjusted for age and sex.
7. Body composition - visceral fat mass [ Time Frame: 1 year ]
   Visceral fat mass (expressed in kilograms, kg) will be measured using a TANITA® (model BC-418MA) body composition analyzer. Quantification will be made using validated prediction equations adjusted for age and sex.
8. Body composition - lean mass [ Time Frame: 1 year ]
   Lean mass (expressed in kilograms, kg) will be measured using a TANITA® (model BC-418MA) body composition analyzer. Quantification will be made using validated prediction equations adjusted for age and sex.
9. Body composition - muscle mass [ Time Frame: 1 year ]
   Muscle mass (expressed in kilograms, kg) will be measured using a TANITA® (model BC-418MA) body composition analyzer. Quantification will be made using validated prediction equations adjusted for age and sex.
10. Body composition - bone mass [ Time Frame: 1 year ]
    Bone mass (expressed in kilograms, kg) will be measured using a TANITA® (model BC-418MA) body composition analyzer. Quantification will be made using validated prediction equations adjusted for age and sex.
11. Body composition - total water composition [ Time Frame: 1 year ]
    Total water composition (expressed in litre, L) will be measured using a TANITA® (model BC-418MA) body composition analyzer. Quantification will be made using validated prediction equations adjusted for age and sex.
12. Basal metabolism [ Time Frame: 1 year ]
    Basal metabolism (expressed in kilojoule, kJ) will be measured using a TANITA® (model BC-418MA) body composition analyzer. Quantification will be made using validated prediction equations adjusted for age and sex.
13. Diastolic blood pressure (DBP) [ Time Frame: 1 year ]
    DBP (expressed in milimeters of mercury) using a calibrated automatic sphygmomanometer
14. Systolic blood pressure (SBP) [ Time Frame: 1 year ]
    SBP (expressed in milimeters of mercury) using a calibrated automatic sphygmomanometer
15. Pulse [ Time Frame: 1 year ]
    heart rate measured with a calibrated automatic sphygmomanometer
16. Serum glucose [ Time Frame: 1 year ]
    Determined by enzymatic method and expressed in miligrams/decilitre (mg/dL)
17. Serum insulin [ Time Frame: 1 year ]
    determined by commercial ELISA kit and expressed in international microunits per millilitre (µIU/mL)
18. HOMA-IR index [ Time Frame: 1 year ]
    serum glucose (expressed in millimole/litre) and serum insulin (expressed in µIU/mL) are combined to report the homeostatic model assessment for insulin resistance (HOMA-IR), according to the equation HOMA-IR = (glucose x insulin)/22.5 HOMA-IR= [serum insulin (μU/ml) × blood glucose (mmol/l)]/22.5}.
19. Serum C-peptide [ Time Frame: 1 year ]
    measured by commercial ELISA kit and expressed as nanogram/millilitre (ng/mL)
20. Plasma triglycerides (TG) [ Time Frame: 1 year ]
    plasma concentrations of total triglycerides is determined by an automated colorimetric enzymatic method (GPO-PAP, Roche Diagnostics, Mannheim, Germany) and expressed as milligrams/decilitre (mg/dL)
21. Plasma total cholesterol (CT) [ Time Frame: 1 year ]
    plasma concentrations of total cholesterol is determined by an automated colorimetric enzymatic method (CHOD-PAP, Roche Diagnostics, Mannheim, Germany) and expressed as milligrams/decilitre (mg/dL)
22. Plasma high density lipoproteins (HDL) [ Time Frame: 1 year ]
    plasma concentrations of HDL is determined by an automated direct enzymatic method (HDL-C-plus 2nd generation, Roche Diagnostics, Mannheim, Germany) and expressed as milligrams/decilitre (mg/dL)
23. Plasma low density lipoproteins (LDL) [ Time Frame: 1 year ]

    Triglycerides, total cholesterol and high densitity lipoproteins are combined to report LDL, according to the Friedewald formula:

    LDL = CT - (TG/ 5) - HDL

24. Plasma lipoprotein A [ Time Frame: 1 year ]
    the plasma content of lipoprotein A is quantified by ELISA and the values are expressed as milligram/decilitre (mg/dL)
25. Plasma total lipoprotein B [ Time Frame: 1 year ]
    the plasma content of total lipoprotein B (Apo B48 + Apo B100) is quantified by an immunoturbidimetric assay (Tinaquant; Roche Diagnostics, Mannheim, Germany), The values are expressed as milligram/decilitre (mg/dL)
26. Plasma creatinine [ Time Frame: 1 year ]
    standard spectrophotometric assay. Values expressed as milligrams per decilitre (mg/dL)
27. Plasma uric acid [ Time Frame: 1 year ]
    Evaluated by an enzymatic procedure, with results expressed in milligrams per decilitre (mg/dL)
28. Plasma alanine aminotransferase (ALT) [ Time Frame: 1 year ]
    use of a diagnose kit with values expressed as units per litre (U/L)
29. Plasma aspartate aminotransferase (AST) [ Time Frame: 1 year ]
    use of a diagnose kit with values expressed as units per litre (U/L)
30. Plasma gamma-glutamyl transferase (GGT) [ Time Frame: 1 year ]
    use of a diagnose kit with values expressed as units per litre (U/L)
31. Plasma lactate dehydrogenase (LDH) [ Time Frame: 1 year ]
    L-Lactic Dehydrogenase kit. Results expressed as units per litre (U/L)
32. Plasma bilirubin [ Time Frame: 1 year ]
    Spectrofotometric assay. Results expressed as milligrams per decilitre (mg/dL)
33. Plasma levels of glutathion (GSH and GSSG) [ Time Frame: 1 year ]
    Glutathione Reductase (GR) Assay Kit. Values expressed as milliunits per millilitre (mU/mL)
34. Plasma malondialdehyde [ Time Frame: 1 year ]
    Thiobarbituric acid (TBA) assay and HPLC determination. Results expressed as µmole per litre (µmol/L)
35. Plasma ultra-sensitive C-reactive protein [ Time Frame: 1 year ]
    Immunoturbidimetric method. Results expressed as milligrams per litre (mg/L)
36. Plasma vitamin B12 [ Time Frame: 1 year ]
    chemiluminescence immunoassay (CLIA). Results expressed as picograms per millilitre (pg/mL)
37. Plasma thyroid-stimulating hormone (TSH) [ Time Frame: 1 year ]
    ELISA kit. Values expressed as international micro-units per millilitre (µlU/ml)
38. Plasma levels of Oleanolic acid [ Time Frame: 1 year ]
    Liquid/liquid extraction and quantification by gas chromatography con flame ionization detection (GC-FID). Values expressed as nanograms per millilitre (ng/mL)
39. Serum fatty acids composition [ Time Frame: 1 year ]
    Liquid/liquid extraction and quantification by gas chromatography con flame ionization detection (GC-FID). Values expressed as percentage of the total of fatty acids (%)
40. Plasma adiponectin [ Time Frame: 1 year ]
    ELISA kit. values expressed as picograms per millilitre (pg/mL)
41. Plasma ceruloplasmin [ Time Frame: 1 year ]
    ELISA kit. values expressed as milligrams per decilitre (mg/dL)
42. Plasma leptin [ Time Frame: 1 year (measures at the time of recruitment and every three months thereafter) ]
    ELISA kit. values expressed as picograms per millilitre (pg/mL)
43. Plasma resistin [ Time Frame: 1 year ]
    ELISA kit. values expressed as picograms per millilitre (pg/mL)
44. Plasma ghrelin [ Time Frame: 1 year ]
    ELISA kit. values expressed as picograms per millilitre (pg/mL)
45. Plasma catalase [ Time Frame: 1 year ]
    ELISA kit. values expressed as micromole per milligrams of protein (µmol/mg protein)
46. Plasma superoxide dismutase [ Time Frame: 1 year ]
    ELISA kit. values expressed as units per millilitre (U/mL)
47. Plasma tumor necrosis factor-alpha (TNF-alpha) [ Time Frame: 1 year ]
    ELISA kit. values expressed as picograms per millilitre (pg/mL)
48. Plasma interleukine 1-beta [ Time Frame: 1 year ]
    ELISA kit. values expressed as picograms per millilitre (pg/mL)
49. Plasma interleukine 6 [ Time Frame: 1 year ]
    ELISA kit. values expressed as picograms per millilitre (pg/mL)
50. Triglycerides in VLDL [ Time Frame: 1 year ]
    the VLDL fraction of plasma lipoproteins will be isolated by ultracentrifugation (230,000 × g for 18 h at 4 0C). Lipds will be extracted by a modification of the Folch's method. Triglycerides are determined by HPLC, and results expressed as milligrams per milligram of protein (mg/mg protein)
51. Diglycerides in VLDL [ Time Frame: 1 year ]
    the VLDL fraction of plasma lipoproteins will be isolated by ultracentrifugation (230,000 × g for 18 h at 4 0C). Lipds will be extracted by a modification of the Folch's method. Diglycerides are determined by HPLC, and results expressed as milligrams per milligram of protein (mg/mg protein)
52. Phospholipids in VLDL [ Time Frame: 1 year ]
    the VLDL fraction of plasma lipoproteins will be isolated by ultracentrifugation (230,000 × g for 18 h at 4 0C). Lipds will be extracted by a modification of the Folch's method. Phospholipids are determined by HPLC, and results expressed as milligrams per milligram of protein (mg/mg protein)
53. Fatty acids composition of VLDL [ Time Frame: 1 year ]
    the VLDL fraction of plasma lipoproteins will be isolated by ultracentrifugation (230,000 × g for 18 h at 4 0C). Lipds will be extracted by a modification of the Folch's method. Fatty acids are derivatized to their methyl esters and analyzed by gas chromatography. The results are expressed as percentage of the total of fatty acids (%)
54. Apo B in VLDL [ Time Frame: 1 year ]
    Determined by immunoturbidimetry using a commercial kit. Values expressed as micrograms per milligram of protein (µg/mg protein)
55. Continuous blood glucose monitoring [ Time Frame: 1 year ]
    FreeStyle Libre subcutaneous system (ABBOTT Diagnostics). Values expressed as milligrams per decilitre (mg/dL)
56. Blood Count - hematocrit [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as percentage (%)
57. Blood Count - red blood cells [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as cell count x 10^6 per microlitre (count x 10^6/µL)
58. Blood Count - hemoglobin [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as gram per decilitre (g/dL)
59. Blood Count - mean corpuscular volume [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as femtolitre (fL)
60. Blood Count - mean corpuscular hemoglobin [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as picograms (pg)
61. Blood Count - leukocytes [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as count x 10^3 per microlitre (count x 10^3 /µL)
62. Blood Count - neutrophils [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as count x 10^3 per microlitre (count x 10^3 /µL)
63. Blood Count - lymphocytes [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as count x 10^3 per microlitre (count x 10^3 /µL)
64. Blood Count - monocytes [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as count x 10^3 per microlitre (count x 10^3 /µL)
65. Blood Count - eosinophils [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as count x 10^3 per microlitre (count x 10^3 /µL)
66. Blood Count - basophils [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as count x 10^3 per microlitre (count x 10^3 /µL)
67. Blood Count - platelets [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as count x 10^3 per microlitre (count x 10^3 /µL)
68. Blood Count - partial thromboplastin time [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as seconds (s)
69. Blood Count - prothrombin time [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as seconds (s)
70. Blood Count - coagulative fibrinogen [ Time Frame: 1 year ]
    Automated blood analyzer. Results expressed as milligrams per decilitre (mg/dL)
71. Urine pH [ Time Frame: 1 year ]
    Urine pH
72. Urine density [ Time Frame: 1 year ]
    Automated urine analyzer. Results expressed as milligrams per millilitre (mg/mL)
73. Glycosuria [ Time Frame: 1 year ]
    Automated urine analyzer. Results expressed as milligrams per decilitre (mg/dL)
74. Ketone bodies in urine [ Time Frame: 1 year ]
    Automated urine analyzer. Results expressed as millimole per litre (mmol/L)
75. Presence of nitrite in urine [ Time Frame: 1 year ]
    Automated urine analyzer. Results expressed as negative or positive
76. Urobilinogen [ Time Frame: 1 year ]
    Automated urine analyzer. Results expressed as milligrams per decilitre (mg/dL)
77. Urine bilirubin [ Time Frame: 1 year ]
    Automated urine analyzer. Results expressed as milligrams per decilitre (mg/dL)
78. Urine creatinine [ Time Frame: 1 year ]
    Automated urine analyzer. Results expressed as milligrams per decilitre (mg/dL)
79. Urine albumin/creatinine ratio (UACR) [ Time Frame: 1 year ]
    Automated urine analyzer. Results expressed as milligrams of albumin per gram of creatinine
80. Leukocytes in urine [ Time Frame: 1 year ]
    Automated urine analyzer. Results expressed as count x 1 per microlitre (count x 1 /µL)
81. Presence of sediment in urine [ Time Frame: 1 year ]
    Automated urine analyzer. Results expressed as negative or positive

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. community-residing men and women aged.
2. Body Mass Index (BMI) between 25 and 39.9 kg/m2.
3. diagnosed with T2DM [Following the American Diabetes Association (ADA) 2019 criteria] at least six months before being included in this trial.
4. be treated with metformin (stable dose >= 850 mg/day at least three months before recruitment) as monotherapy, or in combination with other hypoglycemic agents (administration of insulin exclusively in a single basal dose), except pioglitazone and sulphonylureas.
5. HbA1c below 9% at baseline, with a variation compared with a prior HbA1c from at least three months before inclusion in this trial of less than +/- 0.5 %.
6. be able to give voluntary informed consent and willing to comply with all study procedures.

Exclusion Criteria:

1. suffering from Type 1 Diabetes Mellitus or latent autoimmune diabetes in adults.
2. suffering from chronic kidney disease (estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m2).
3. suffering from acute or chronic hepatitis, signs and symptoms of any liver disease other than non-alcoholic fatty liver disease (NAFLD), or ALT/AST ratio >3 times the upper limit of the reference range.
4. To present, at the time of recruitment, allergies and intolerances associated with food consumption.
5. pregnant and lactating women.
6. lack of willingness to use a highly effective contraceptive method (in women of childbearing potential).
7. fasting triglyceridemia > 600 mg/dL despite adequate treatment.
8. grade 3 hypertension (systolic blood pressure ≥ 180 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg) according to the 2018 guidelines of the European Society of Hypertension.
9. use of pioglitazone or sulfonylureas.
10. being treated with medications that promote weight loss (eg, Saxenda® [liraglutide 3.0 mg], Xenical® [orlistat], or similar over-the-counter [OTC] medications) within six months prior to the start of the trial.
11. Being on chronic (>14 days) therapy with systemic glucocorticoids (excluding topical, intraocular, intranasal, intra-articular, or inhaled preparations) within six months prior to enrollment.
12. Presenting any of the following cardiovascular conditions within 6 months prior to study entry: acute myocardial infarction, unstable angina, New York Heart Association (NYHA) class III or class IV heart failure, or cerebrovascular accident.
13. Evidence, in the investigators' opinion, of significant uncontrolled endocrine abnormality (e.g., thyrotoxicosis, adrenal crisis) at baseline.
14. History of active or untreated malignancy, or being in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer, cervical carcinoma in situ, or prostate cancer in situ) during the last 5 years before the study entry.
15. Participation in the last 30 days in a clinical trial with an investigational product [if the previous investigational product has a long half-life, 3 months or 5 half-lives (whichever is longer) should have passed].
16. Being, at the time of recruitment, enrolled in any other clinical trial involving an investigational product or any other type of medical research that is not considered scientifically or medically compatible with this study.
17. Presence of any hematologic condition that may interfere with HbA1c measurement (eg, hemolytic anemias, sickle cell anemia).
18. History of any other condition (eg, known drug or alcohol abuse or psychiatric disorder, or any other physical or intellectual limitations), which, in the opinion of the investigator, may prevent the patient from following and completing the protocols.

Contacts and Locations

Contacts

Contact: Pedro Pablo García-Luna, MD; +34 955013551; garcialunapp@yahoo.es

Contact: José María Castellano, PhD; +34 954611550 ext 431088; jmcas@ig.csic.es

Locations

Spain

Virgen del Rocío University Hospital; Recruiting

Sevilla, Andalicía, Spain, 41013

Contact: Pedro Pablo García-Luna, MD +34 955013551 garcialunapp@yahoo.es

Sponsors and Collaborators

Spanish National Research Council

Andalusian Health Service

Universidad Pablo de Olavide

Investigators

• Principal Investigator: José María Castellano, PhD; Spanish National Research Council (CSIC)
• Principal Investigator: Pedro Pablo García-Luna, MD; Virgen del Rocío University Hospital

More Information

Additional Information:

website of the OLTRAD Project (BIO-OLTRAD and OLTRAD trials 

Publications:

Castellano JM, Ramos-Romero S, Perona JS. Oleanolic Acid: Extraction, Characterization and Biological Activity. Nutrients. 2022 Jan 31;14(3):623. doi: 10.3390/nu14030623.

Fernandez-Aparicio A, Schmidt-RioValle J, Perona JS, Correa-Rodriguez M, Castellano JM, Gonzalez-Jimenez E. Potential Protective Effect of Oleanolic Acid on the Components of Metabolic Syndrome: A Systematic Review. J Clin Med. 2019 Aug 23;8(9):1294. doi: 10.3390/jcm8091294.

Castellano JM, Guinda A, Delgado T, Rada M, Cayuela JA. Biochemical basis of the antidiabetic activity of oleanolic acid and related pentacyclic triterpenes. Diabetes. 2013 Jun;62(6):1791-9. doi: 10.2337/db12-1215.

Santos-Lozano JM, Rada M, Lapetra J, Guinda A, Jimenez-Rodriguez MC, Cayuela JA, Angel-Lugo A, Vilches-Arenas A, Gomez-Martin AM, Ortega-Calvo M, Castellano JM. Prevention of type 2 diabetes in prediabetic patients by using functional olive oil enriched in oleanolic acid: The PREDIABOLE study, a randomized controlled trial. Diabetes Obes Metab. 2019 Nov;21(11):2526-2534. doi: 10.1111/dom.13838. Epub 2019 Aug 28.

• Responsible Party: José M. Castellano, PhD, Principal Investigator, Spanish National Research Council
• ClinicalTrials.gov Identifier: NCT06030544
• Other Study ID Numbers: PID2019-107837RB-I00
• First Posted: September 11, 2023
• Last Update Posted: September 11, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by José M. Castellano, PhD, Spanish National Research Council:

Oleanolic acid; T2DM treatment; randomized controlled trial; parallel groups design; dietary intervention; functional olive oil

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases