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Safety and Effectiveness of SGLT-2 Inhibitors in Patients With Heart Failure and Diabetes (REFORM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02397421
Recruitment Status : Completed
First Posted : March 25, 2015
Last Update Posted : July 31, 2018
Sponsor:
Collaborator:
European Foundation for the Study of Diabetes
Information provided by (Responsible Party):
Jagdeep Singh Surmukh Singh, University of Dundee

Brief Summary:

Patients with diabetes are at increased risk of developing heart failure (HF) which can lead to increased shortness of breath, reduced ability to exercise and in some cases premature death as the heart becomes less efficient at pumping blood around the body. However the treatment options for such patients remain limited.

This study will test the safety and benefits of using a new class of drug, the SGLT2 Inhibitor (Dapagliflozin), in treating HF and diabetes.

Participants will have a Magnetic Resonance Imaging (MRI) scan of the heart, to measure the efficiency and the extent of thickening of the heart muscle before they start on treatment of dapagliflozin, or placebo for one year. They will also do exercise testing on an exercise bike (if capable) and a walking test plus fill in some questionnaires on how their heart failure affects their quality of life. Participants will then continue as normal with currently prescribed medication for their diabetes and heart failure. After a year the tests will be repeated to determine if patients receiving Dapagliflozin benefited more than those who weren't on the drug.

This study is funded by the European Foundation for the Study of Diabetes (EFSD)


Condition or disease Intervention/treatment Phase
Heart Failure Diabetes Drug: Dapagliflozin Drug: Placebo Phase 4

Detailed Description:

Men and women with diabetes have a 2-5-fold increased risk of heart failure (HF). The prevalence and incidence of HF is increasing in diabetes and mortality rates remain alarmingly high. This highlights the need for novel therapies in diabetes that will reduce HF risk and /or delay disease progression.

Drug options are currently limited as some diabetic therapies such as thiazolidinediones are contra-indicated in HF. SGLT2 inhibitors, the newest class of anti-diabetic drugs, are an exciting new approach to diabetes management that may have additional beneficial effects in diabetes and HF. SGLT2 inhibitors may have beneficial effects on adverse left ventricular (LV) remodelling that occurs in patients with diabetes and heart failure by reducing the load on the heart through its diuretic and blood pressure lowering actions.

Exercise intolerance is a cardinal symptom of patients with HF and improving insulin sensitivity has been shown to improve exercise capacity. SGLT2 inhibition has been shown to improve insulin sensitivity and to reduce weight and therefore has the potential to improve exercise capacity in HF.

This study will assess the potential beneficial effects of the oral SGLT2 inhibitor, dapagliflozin, on LV remodelling and exercise capacity in patients with diabetes and HF. The findings of this study may help to establish the utility of SGLT2 inhibitors in diabetic patients with HF and provide important clinical data on the impact of SGLT2 inhibition on LV remodelling.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 56 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Research Into the Effect of SGLT2 Inhibition on Left Ventricular Remodeling in Patients With Heart Failure and Diabetes Mellitus
Study Start Date : March 2015
Actual Primary Completion Date : August 2017
Actual Study Completion Date : August 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Active Comparator: Treatment
Dapagliflozin 10mg once daily
Drug: Dapagliflozin
Sodium Glucose Linked Transporter Type 2 (SGLT-2) Inhibitor
Other Name: Forxiga

Placebo Comparator: Control
Capsules containing microcrystalline cellulose Ph Eur overencapsulated in a hard gelatine capsule shell to match the active comparator
Drug: Placebo
Capsules containing microcrystalline cellulose Ph Eur overencapsulated in a hard gelatine capsule shell to match the active comparator




Primary Outcome Measures :
  1. Change in LV end systolic volume (absolute value and indexed for BSA) or LV end diastolic volume (absolute value and indexed for BSA) [ Time Frame: 1 year ]
    Cardiac MRI will be performed to determine the change in end systolic and diastolic volumes between both groups of patients


Secondary Outcome Measures :
  1. Change in LV mass, LV ejection fraction, RV end diastolic volume, RV end systolic volume, RV ejection fraction, atrial dimensions and volumes, and LV remodelling index (LV mass / LVEDV) [ Time Frame: 1 year ]
    MRI will be performed to study the effects of the intervention on various other cardiac parameters.

  2. Fluid status (Bioelectrical Impedence Analysis (BIA) [ Time Frame: 1 year ]
    Bioelectrical Impedence Analysis (BIA) will be conducted to determine the effect of the study dug on overall fluid balance

  3. Objective functional capacity (6 Minute Walk Test (6MWT) [ Time Frame: 1 year ]
    6 Minute Walk Test (6MWT) will be performed to objectively determine the functional capacity of participants

  4. Exercise capacity (Cardio-pulmonary Exercise Testing (CPET) [ Time Frame: 1 year ]
    Cardio-pulmonary Exercise Testing (CPET) will be performed to determine the exercise capacity of participants

  5. Quality of life (Minnesota Living with Heart Failure and SF-36 questionnaire) [ Time Frame: 1 year ]
    will be conducted to determine the impact of the intervention on subjective quality of life

  6. Cardiac and inflammatory biomarkers [ Time Frame: 1 year ]
    Brain natriuretic peptide (BNP) and other inflammatory & oxidative stress markers will be measured

  7. Diuretic requirement (total diuretic requirement to maintain euvolemia) [ Time Frame: 1 year ]
    The total diuretic requirement to maintain euvolemia will be compared between the beginning and end of the trial

  8. Change in degree of microalbuminuria [ Time Frame: 1 year ]
    Urinary analysis will be performed to determine if there has been any change in the severity of microalbuminuria

  9. Quantify amount of natriuresis [ Time Frame: 1 year ]
    Urinary analysis will be performed to quantify the amount of sodium excretion.

  10. The safety of dapagliflozin use in diabetic, heart failure patients with regard to worsening HF, hospitalization and death will be evaluated [ Time Frame: 1 year ]


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:

  • were previously diagnosed with Type 2 Diabetes
  • are diagnosed with NYHA functional class I-III HF with prior echocardiographic evidence of Left Ventricular Systolic Dysfunction (LVSD) (At least mild LV systolic dysfunction on sonographer assessment or ejection fraction at 45% or less)
  • on furosemide 80mg daily or less, or equivalent loop diuretic
  • have stable HF symptoms for at least three months prior to consent
  • on stable therapy for HF for at least three months prior to consent
  • have not been hospitalised for HF for at least three months prior to consent

Exclusion Criteria:

  • severe hepatic disease
  • renal disease defined as Chronic Kidney Disease (CKD) class 3b or worse (i.e. estimated glomerular filtration rate (eGFR) / creatinine clearance CrCl <45ml/min)
  • systolic BP <95mmHg at screening visit
  • screening HbA1c <6.0%
  • unable to walk to perform cardio pulmonary exercise testing or 6MWT
  • malignancy (receiving active treatment) or other life threatening diseases
  • pregnant or lactating women
  • any contraindication to MRI (e.g. claustrophobia, metal implants, penetrative eye injury or exposure to metal fragments in eye requiring medical attention)
  • patients who have participated in any other clinical trial of an investigational medicinal product within the previous 30 days
  • patients who are unable to give informed consent
  • any other reason considered by a study physician to be inappropriate for inclusion.

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): NCT02397421


Locations
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United Kingdom
Ninewells Hospital and Medical School
Dundee, Angus, United Kingdom, DD1 9SY
Sponsors and Collaborators
University of Dundee
European Foundation for the Study of Diabetes
Investigators
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Principal Investigator: Jagdeep Singh, MBBS University of Dundee
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Jagdeep Singh Surmukh Singh, Dr, University of Dundee
ClinicalTrials.gov Identifier: NCT02397421    
Other Study ID Numbers: 2014-002742-42
First Posted: March 25, 2015    Key Record Dates
Last Update Posted: July 31, 2018
Last Verified: July 2018
Keywords provided by Jagdeep Singh Surmukh Singh, University of Dundee:
Heart failure
Diabetes
Left ventricular remodelling
SGLT-2 inhibitors
Additional relevant MeSH terms:
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Heart Failure
Diabetes Mellitus
Ventricular Remodeling
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Heart Diseases
Cardiovascular Diseases
Pathological Conditions, Anatomical
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