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Incretin and Treatment With Inhibition of Sodium-glucose Cotransporter-2 Combination Insights Into Mechanisms Implicated in Congestive Heart Failure: "NATRIURETIC" Trial (NATRIURETIC)

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ClinicalTrials.gov Identifier: NCT04535960
Recruitment Status : Recruiting
First Posted : September 2, 2020
Last Update Posted : September 2, 2020
Sponsor:
Information provided by (Responsible Party):
David Z.I. Cherney, University Health Network, Toronto

Brief Summary:
This study aims to provide essential mechanistic insights into natriuretic and hemodynamic effects of SGLT2i and GLP-1RA agents in T2D patients. Ultimately, by obtaining physiological data in T2D patients without HF, our aims are to gain insight into how the use of this combined therapy may be used in T2D with HF in future work.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Drug: Empagliflozin 25 MG + Liraglutide 1.8 MG Drug: Liraglutide 1.8 MG + Empagliflozin 25 MG Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Patients will be randomized to initial therapy with empagliflozin 25mg PO daily or liraglutide 1.8 mg SC daily, for 6 weeks. After that, patients in the empagliflozin group will also receive liraglutide 1.8mg SC daily for additional 6 weeks and patients in the liraglutide group will also receive empagliflozin 25mg PO daily for 6 weeks (combination therapy).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Incretin and Treatment With Inhibition of Sodium-glucose Cotransporter-2 Combination Insights Into Mechanisms Implicated in Congestive Heart Failure: "NATRIURETIC" Trial
Actual Study Start Date : January 24, 2019
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Experimental: Liraglutide
Liraglutide Subcutaneous Total Dose 1.8mg daily for 6 weeks
Drug: Empagliflozin 25 MG + Liraglutide 1.8 MG
Patients will be randomized to initial therapy with empagliflozin 25mg PO daily for 6 weeks. After that, patients in the empagliflozin group will also receive liraglutide 1.8mg SC daily for additional 6 weeks.
Other Name: Generic names are above, listed

Drug: Liraglutide 1.8 MG + Empagliflozin 25 MG
Patients will be randomized to initial therapy with liraglutide 1.8 mg SC daily, for 6 weeks. After that, patients will also receive empagliflozin 25mg PO daily for 6 weeks.
Other Name: Generic names are above, listed

Experimental: Empagliflozin
Empagliflozin Tablets Total Dose 25mg daily for 6 weeks
Drug: Empagliflozin 25 MG + Liraglutide 1.8 MG
Patients will be randomized to initial therapy with empagliflozin 25mg PO daily for 6 weeks. After that, patients in the empagliflozin group will also receive liraglutide 1.8mg SC daily for additional 6 weeks.
Other Name: Generic names are above, listed

Drug: Liraglutide 1.8 MG + Empagliflozin 25 MG
Patients will be randomized to initial therapy with liraglutide 1.8 mg SC daily, for 6 weeks. After that, patients will also receive empagliflozin 25mg PO daily for 6 weeks.
Other Name: Generic names are above, listed




Primary Outcome Measures :
  1. Proximal tubular natriuresis [ Time Frame: up to 12 weeks ]
    Measured by fractional excretion of sodium


Secondary Outcome Measures :
  1. Glomerular Filtration Rate [ Time Frame: Glomerular Filtration Rate (GFR, based on plasma iohexol clearance) will be measured at 2 time points: monotherapy (6 weeks) and combination therapy (12 weeks) ]
    GFR

  2. Systolic blood pressure [ Time Frame: Systolic blood pressure (SBP) will be measured at 2 time points: monotherapy (6 weeks) and combination therapy (12 weeks) ]
    SBP

  3. Body weight [ Time Frame: Body weight will be measured at 2 time points: monotherapy (6 weeks) and combination therapy (12 weeks) ]
    Kilograms

  4. Arterial stiffness [ Time Frame: Arterial stiffness will be measured at 2 time points: monotherapy (6 weeks) and combination therapy (12 weeks) ]
    Measured using a Sphygmocor device

  5. Systemic vascular resistance [ Time Frame: Systemic vascular resistance will be measured at 2 time points: monotherapy (6 weeks) and combination therapy (12 weeks) ]
    Measured using non-invasive cardiac output monitor (NICOM)

  6. Urinary concentration of the renin-angiotensin aldosterone system (RAAS) markers [ Time Frame: Outcome will be measured at 2 time points: monotherapy (6 weeks) and combination therapy (12 weeks) ]
    Measured using ELISA

  7. Urinary EGF,FGF2,Eotaxin,TGFa,G-CSF,Flt-3L,GM-CSF,Fractalkine,IFNa2,IFNy,GRO,IL10,MCP-3,IL-12P40,MDC,IL-12P70,PDGF-AA,IL-13,PDGF-BB,IL-15,sCD40L,IL-17A,IL-1RA,IL1a,IL9,IL1B,IL2,IL3,IL4,IL5,IL6,IL7,IL8,IL10,MCP-1,MIP-1a,MIP-1B,RANTES,TNFalpha,TNFB,VEGF [ Time Frame: Outcome will be measured at 2 time points: monotherapy (6 weeks) and combination therapy (12 weeks) ]
    41-plex chemo/chemokine profile assay: urinary



Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Men and women diagnosed with T2D ≥6 months prior to informed consent;
  2. eGFR ≥30 mL/min/1.73m2;
  3. Age >18 years;
  4. HbA1c 7.0%-12.0%;
  5. Body Mass Index (BMI) 18.5-40.0 kg/m2;
  6. Stable HbA1c, measured 2-12 months prior to screening, within 5% of baseline value;
  7. Blood pressure ≤160/100 mmHg at screening, >90/60 mmHg;
  8. Stable on dose of ACE inhibitor, angiotensin receptor blocker or renin inhibitor for at least 2 weeks.

Exclusion Criteria:

  1. Type 1 Diabetes;
  2. Leukocyte and/or nitrite positive urinalysis that is untreated;
  3. Severe hypoglycaemia within 2 months prior to screening;
  4. History of hypoglycaemia unawareness based on investigator judgement;
  5. Unstable coronary artery disease with acute coronary syndrome, percutaneous intervention or bypass surgery within 3 months;
  6. Clinically significant valvular disease subject to PI/Sub PI's discretion;
  7. Congestive heart failure subject to PI/Sub PI's discretion;
  8. Bariatric surgery or other surgeries that induce chronic malabsorption within one year;
  9. Anti-obesity drugs or diet regimen and unstable body weight three months prior to screening;
  10. Treatment with systemic corticosteroids;
  11. Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells;
  12. Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control;
  13. Participation in another trial with an investigational drug within 30 days of informed consent;
  14. Alcohol or drug abuse within three months prior to informed consent that would interfere with trial participation or any ongoing clinical condition that would jeopardize subject safety or study compliance based on investigator judgement;
  15. Liver disease, defined by serum levels of alanine transaminase, aspartate transaminase, or alkaline phosphatase >3 x upper limit of normal as determined during screening;
  16. Medical history of cancer or treatment for cancer in the last five years prior to screening;
  17. History of pancreatitis;
  18. Personal of family history of medullary thyroid cancer or MEN2B;
  19. Tachycardia, HR >100;
  20. Use of SGLT2i, GLP-1RA or DPP-4i within the past 1 month (1-month minimum washout is allowed);
  21. History of gastroparesis;
  22. Known intolerance to SGLT2i or GLP-1RA;
  23. Allergy to iodine-based substances if receiving iohexol for GFR measures.

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): NCT04535960


Contacts
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Contact: Vesta Lai, RN 416-340-4800 ext 8508 vesta.lai@uhn.ca
Contact: Yuliya Lytvyn, PhD julia.lytvyn@mail.utoronto.ca

Locations
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Canada, Ontario
Renal Physiology Laboratory Recruiting
Toronto, Ontario, Canada
Contact: Vesta Lai, RN    416-340-4800 ext 8508    vesta.lai@uhn.ca   
Contact: Yuliya Lytvyn, PhD       julia.lytvyn@mail.utoronto.ca   
Principal Investigator: David Cherney, MD, PhD         
Sponsors and Collaborators
University Health Network, Toronto
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Responsible Party: David Z.I. Cherney, Associate Professor of Medicine, Clinician Scientist, University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT04535960    
Other Study ID Numbers: NATRIURETIC (18-5058)
First Posted: September 2, 2020    Key Record Dates
Last Update Posted: September 2, 2020
Last Verified: September 2020
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
Keywords provided by David Z.I. Cherney, University Health Network, Toronto:
SGLT2 inhibition
GLP-1 receptor agonist
type 2 diabetes mellitus
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Heart Failure
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Heart Diseases
Cardiovascular Diseases
Liraglutide
Empagliflozin
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action