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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

Tracking Information
First Submitted Date  ICMJE March 12, 2015
First Posted Date  ICMJE March 25, 2015
Last Update Posted Date July 31, 2018
Study Start Date  ICMJE March 2015
Actual Primary Completion Date August 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 2, 2016)
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
Original Primary Outcome Measures  ICMJE
 (submitted: March 24, 2015)
Left ventricular (LV) Mass (any improvements in LV mass index and LV ejection fraction) [ Time Frame: 1 year ]
MRI will be performed to determine if there are any improvements in LV mass index and LV ejection fraction
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 2, 2016)
  • 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.
  • 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
  • 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
  • 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
  • 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
  • Cardiac and inflammatory biomarkers [ Time Frame: 1 year ]
    Brain natriuretic peptide (BNP) and other inflammatory & oxidative stress markers will be measured
  • 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
  • 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
  • Quantify amount of natriuresis [ Time Frame: 1 year ]
    Urinary analysis will be performed to quantify the amount of sodium excretion.
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 24, 2015)
  • Composite Cardiac MRI parameters (V and RV volumes, atrial volumes, and RV function) [ Time Frame: 1 year ]
    MRI will be performed to study the effects of the intervention on LV and RV volumes, atrial volumes, and RV function
  • Other Cardiac MRI parameters (effects of the intervention on LV and RV volumes, atrial volumes, and RV function) [ Time Frame: 1 year ]
    MRI will be performed to study the effects of the intervention on LV and RV volumes, atrial volumes, and RV function
  • 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
  • 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
  • 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
  • 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
  • Cardiac and inflammatory biomarkers [ Time Frame: 1 year ]
    Brain natriuretic peptide (BNP) and other inflammatory & oxidative stress markers will be measured
  • 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
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Effectiveness of SGLT-2 Inhibitors in Patients With Heart Failure and Diabetes
Official Title  ICMJE Research Into the Effect of SGLT2 Inhibition on Left Ventricular Remodeling in Patients With Heart Failure and Diabetes Mellitus
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)

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Heart Failure
  • Diabetes
Intervention  ICMJE
  • Drug: Dapagliflozin
    Sodium Glucose Linked Transporter Type 2 (SGLT-2) Inhibitor
    Other Name: Forxiga
  • Drug: Placebo
    Capsules containing microcrystalline cellulose Ph Eur overencapsulated in a hard gelatine capsule shell to match the active comparator
Study Arms  ICMJE
  • Active Comparator: Treatment
    Dapagliflozin 10mg once daily
    Intervention: Drug: Dapagliflozin
  • Placebo Comparator: Control
    Capsules containing microcrystalline cellulose Ph Eur overencapsulated in a hard gelatine capsule shell to match the active comparator
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 7, 2016)
56
Original Estimated Enrollment  ICMJE
 (submitted: March 24, 2015)
58
Actual Study Completion Date  ICMJE August 2017
Actual Primary Completion Date August 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02397421
Other Study ID Numbers  ICMJE 2014-002742-42
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jagdeep Singh Surmukh Singh, University of Dundee
Study Sponsor  ICMJE University of Dundee
Collaborators  ICMJE European Foundation for the Study of Diabetes
Investigators  ICMJE
Principal Investigator: Jagdeep Singh, MBBS University of Dundee
PRS Account University of Dundee
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP