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SGLT-2 Inhibition, Metabolomics and Cardiovascular/Kidney Disease

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ClinicalTrials.gov Identifier: NCT03919656
Recruitment Status : Not yet recruiting
First Posted : April 18, 2019
Last Update Posted : April 23, 2019
Sponsor:
Information provided by (Responsible Party):
Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud

Brief Summary:
This study evaluates the metabolomics changes associated with dapagliflozin treatment in patients with type 2 diabetes mellitus (T2DM). The participants in the study will be randomized to receive 10 mg dapagliflozin or placebo once daily for 12 weeks.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Drug: Dapagliflozin 10 mg Drug: Placebo Oral Tablet Phase 4

Detailed Description:

In this study, we hypothesize that metabolomics changes that occur in patients with T2DM after initiating SGLT2i (sodium-glucose cotransporter 2 inhibitors) treatment may be responsible for the beneficial cardiovascular and kidney effects observed in clinical trials with SGLT2i. Also, we propose that the study of the specific metabolome associated with the treatment with SGLT2i could help identify the possible metabolites and molecules that reduce CVD (cardiovascular disease) and renal disease in patients with T2DM.

The participants in the study will be randomized to receive 10 mg dapagliflozin or placebo once daily of for 12 weeks. Besides, all participants will be advised to engage in 150 min or more of moderate-to vigorous intensity physical activity per week, spread over at least 3 days/week, with no more than 2 consecutive days without activity and to engage in 2-3 sessions/week of resistance exercise on nonconsecutive days. Moreover, these patients will be advised to follow a lifestyle program that achieve a 500-750 kcal/day energy deficit or provide≈1,200-1,500 kcal/day for women and 1,500-1,800 kcal/day for men, adjusted for the individual's baseline body weight.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients will be randomized in a 1:1 ratio
Masking: Double (Participant, Investigator)
Masking Description: Dapagliflozin 10 mg, Green, plain, diamond shaped, film coated tablet (orally); Matching placebo for dapagliflozin Green, plain, diamond shaped, film coated tablet (orally). Does not contain active ingredient
Primary Purpose: Basic Science
Official Title: SGLT-2 Inhibition and Cardiovascular Disease. Metabolomics Study of Potential Factors Involved in Cardio- and Nephroprotection
Estimated Study Start Date : May 2019
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : April 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dapagliflozin
Dapagliflozin 10 mg daily (orally)
Drug: Dapagliflozin 10 mg
Dapagliflozin 10 mg daily in a green, plain, diamond shaped, film coated tablet (orally)
Other Name: Farxiga 10 mg

Placebo Comparator: Placebo
Matching placebo for dapagliflozin daily (orally). Does not contain active ingredient
Drug: Placebo Oral Tablet
Green, plain, diamond shaped, film coated tablet (orally). Does not contain active ingredient




Primary Outcome Measures :
  1. Metabolomics changes in blood [ Time Frame: From baseline to week 12 ]
    Targeted and quantitative analysis by ultra-high-resolution liquid chromatography coupled to triple quadrupole mass spectrometry (UHPL-QqQ/MS). Analysis of specific families of metabolites selected from hypotheses generated by previous exploratory studies: changes in acylcarnitines and other intermediates of mitochondrial β-oxidation and the urea cycle, branched-chain amino acids and biogenic amines

  2. Metabolomics changes in urine [ Time Frame: From baseline to week 12 ]
    Targeted and quantitative analysis by ultra-high-resolution liquid chromatography coupled to triple quadrupole mass spectrometry (UHPL-QqQ/MS). Analysis of specific families of metabolites selected from hypotheses generated by previous exploratory studies: changes in acylcarnitines and other intermediates of mitochondrial β-oxidation and the urea cycle, branched-chain amino acids and biogenic amines


Secondary Outcome Measures :
  1. BMI (body mass index) changes [ Time Frame: From baseline to to week 12 ]
    Measured by body composition analysis

  2. Changes in insulin resistance [ Time Frame: From baseline to to week 12 ]
    Measured as HOMA-IR (homeostatic model assessment of insulin resistance)

  3. Changes in metabolic control [ Time Frame: From baseline to to week 12 ]
    Measured as HbA1c (glycated hemoglobin)

  4. Changes in Quality of Life: 36-Item Short Form Health Survey (SF-36) questionnaire [ Time Frame: From baseline to to week 12 ]
    The SF-36 has eight scaled scores: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The scores are weighted sums of the questions in each section. Scores range from 0 - 100, lower scores indicate more disability, and higher scores indicate less disability

  5. Changes in albuminuria [ Time Frame: From baseline to to week 12 ]
    Modifications in albuminuria, measured as albumin excretion rate (AER)



Information from the National Library of Medicine

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

Inclusion Criteria:

  • Age 18-75.
  • BMI 27-39.9 kg/m2.
  • T2DM on treatment with metformin and inadequate metabolic control (defined as HbA1c≥6.5 -7%).

Exclusion Criteria:

  • Pregnancy (all women of child-bearing age, unless on treatment with contraceptive methods, will undergo a pregnancy test)
  • Breastfeeding
  • Intolerance/allergy to dapagliflozin.
  • Treatment with antidiabetic drug other than metformin.
  • Impaired kidney function: Estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 (calculated using the CKD-EPI formula).
  • Patients with established cardiovascular disease.
  • Previous or current history of cancer of any kind.
  • Uncontrolled hypertension (systolic blood pressure≥160 mmHg or diastolic blood pressure≥110 mmHg, despite adequate antihypertensive treatment).
  • History of liver tumour or acute or chronic liver disease with impaired liver function: total bilirubin levels> 2.0 mg / dl or GOT/GPT levels three times higher than normal upper limit.
  • Known HIV infection or active HBV or HCV infection.
  • Other serious underlying diseases, which could affect the patient's ability to participate in the study.
  • Reduced life expectancy (<12 months) due to advanced or terminal concomitant diseases.

In addition, female patients of child-bearing age will be advised to use contraceptive methods during the study period, given the contraindication of dapagliflozin and metformin during pregnancy as per normal clinical practice.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03919656


Contacts
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Contact: Jose Carlos Fernandez-Garcia, MD, PhD +34951034016 josecarlosfdezgarcia@hotmail.com

Locations
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Spain
Virgen de la Victoria University Hospital. Endocrinology Department Not yet recruiting
Malaga, Spain, 29010
Contact: Jose Carlos Fernández García, MD, PhD         
Sponsors and Collaborators
Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud
Investigators
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Principal Investigator: Jose Carlos Fernandez-Garcia, MD, PhD Virgen de la Victoria Hospital

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Responsible Party: Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud
ClinicalTrials.gov Identifier: NCT03919656     History of Changes
Other Study ID Numbers: FIM-DAPA-2018-01
First Posted: April 18, 2019    Key Record Dates
Last Update Posted: April 23, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud:
Metabolomics
Dapagliflozin
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs