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

Primary Purpose

Heart Failure, Diabetes

Status
Completed
Phase
Phase 4
Locations
United Kingdom
Study Type
Interventional
Intervention
Dapagliflozin
Placebo
Sponsored by
University of Dundee
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring Heart failure, Diabetes, Left ventricular remodelling, SGLT-2 inhibitors

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Ninewells Hospital and Medical School

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Treatment

Control

Arm Description

Dapagliflozin 10mg once daily

Capsules containing microcrystalline cellulose Ph Eur overencapsulated in a hard gelatine capsule shell to match the active comparator

Outcomes

Primary Outcome Measures

Change in LV end systolic volume (absolute value and indexed for BSA) or LV end diastolic volume (absolute value and indexed for BSA)
Cardiac MRI will be performed to determine the change in end systolic and diastolic volumes between both groups of patients

Secondary Outcome Measures

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)
MRI will be performed to study the effects of the intervention on various other cardiac parameters.
Fluid status (Bioelectrical Impedence Analysis (BIA)
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)
6 Minute Walk Test (6MWT) will be performed to objectively determine the functional capacity of participants
Exercise capacity (Cardio-pulmonary Exercise Testing (CPET)
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)
will be conducted to determine the impact of the intervention on subjective quality of life
Cardiac and inflammatory biomarkers
Brain natriuretic peptide (BNP) and other inflammatory & oxidative stress markers will be measured
Diuretic requirement (total diuretic requirement to maintain euvolemia)
The total diuretic requirement to maintain euvolemia will be compared between the beginning and end of the trial
Change in degree of microalbuminuria
Urinary analysis will be performed to determine if there has been any change in the severity of microalbuminuria
Quantify amount of natriuresis
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

Full Information

First Posted
March 12, 2015
Last Updated
July 29, 2018
Sponsor
University of Dundee
Collaborators
European Foundation for the Study of Diabetes
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1. Study Identification

Unique Protocol Identification Number
NCT02397421
Brief Title
Safety and Effectiveness of SGLT-2 Inhibitors in Patients With Heart Failure and Diabetes
Acronym
REFORM
Official Title
Research Into the Effect of SGLT2 Inhibition on Left Ventricular Remodeling in Patients With Heart Failure and Diabetes Mellitus
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
March 2015 (undefined)
Primary Completion Date
August 2017 (Actual)
Study Completion Date
August 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Dundee
Collaborators
European Foundation for the Study of Diabetes

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure, Diabetes
Keywords
Heart failure, Diabetes, Left ventricular remodelling, SGLT-2 inhibitors

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
56 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment
Arm Type
Active Comparator
Arm Description
Dapagliflozin 10mg once daily
Arm Title
Control
Arm Type
Placebo Comparator
Arm Description
Capsules containing microcrystalline cellulose Ph Eur overencapsulated in a hard gelatine capsule shell to match the active comparator
Intervention Type
Drug
Intervention Name(s)
Dapagliflozin
Other Intervention Name(s)
Forxiga
Intervention Description
Sodium Glucose Linked Transporter Type 2 (SGLT-2) Inhibitor
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Capsules containing microcrystalline cellulose Ph Eur overencapsulated in a hard gelatine capsule shell to match the active comparator
Primary Outcome Measure Information:
Title
Change in LV end systolic volume (absolute value and indexed for BSA) or LV end diastolic volume (absolute value and indexed for BSA)
Description
Cardiac MRI will be performed to determine the change in end systolic and diastolic volumes between both groups of patients
Time Frame
1 year
Secondary Outcome Measure Information:
Title
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)
Description
MRI will be performed to study the effects of the intervention on various other cardiac parameters.
Time Frame
1 year
Title
Fluid status (Bioelectrical Impedence Analysis (BIA)
Description
Bioelectrical Impedence Analysis (BIA) will be conducted to determine the effect of the study dug on overall fluid balance
Time Frame
1 year
Title
Objective functional capacity (6 Minute Walk Test (6MWT)
Description
6 Minute Walk Test (6MWT) will be performed to objectively determine the functional capacity of participants
Time Frame
1 year
Title
Exercise capacity (Cardio-pulmonary Exercise Testing (CPET)
Description
Cardio-pulmonary Exercise Testing (CPET) will be performed to determine the exercise capacity of participants
Time Frame
1 year
Title
Quality of life (Minnesota Living with Heart Failure and SF-36 questionnaire)
Description
will be conducted to determine the impact of the intervention on subjective quality of life
Time Frame
1 year
Title
Cardiac and inflammatory biomarkers
Description
Brain natriuretic peptide (BNP) and other inflammatory & oxidative stress markers will be measured
Time Frame
1 year
Title
Diuretic requirement (total diuretic requirement to maintain euvolemia)
Description
The total diuretic requirement to maintain euvolemia will be compared between the beginning and end of the trial
Time Frame
1 year
Title
Change in degree of microalbuminuria
Description
Urinary analysis will be performed to determine if there has been any change in the severity of microalbuminuria
Time Frame
1 year
Title
Quantify amount of natriuresis
Description
Urinary analysis will be performed to quantify the amount of sodium excretion.
Time Frame
1 year
Title
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jagdeep Singh, MBBS
Organizational Affiliation
University of Dundee
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ninewells Hospital and Medical School
City
Dundee
State/Province
Angus
ZIP/Postal Code
DD1 9SY
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
34693515
Citation
Kanie T, Mizuno A, Takaoka Y, Suzuki T, Yoneoka D, Nishikawa Y, Tam WWS, Morze J, Rynkiewicz A, Xin Y, Wu O, Providencia R, Kwong JS. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. Cochrane Database Syst Rev. 2021 Oct 25;10(10):CD013650. doi: 10.1002/14651858.CD013650.pub2.
Results Reference
derived
PubMed Identifier
32245746
Citation
Singh JSS, Mordi IR, Vickneson K, Fathi A, Donnan PT, Mohan M, Choy AMJ, Gandy S, George J, Khan F, Pearson ER, Houston JG, Struthers AD, Lang CC. Dapagliflozin Versus Placebo on Left Ventricular Remodeling in Patients With Diabetes and Heart Failure: The REFORM Trial. Diabetes Care. 2020 Jun;43(6):1356-1359. doi: 10.2337/dc19-2187. Epub 2020 Apr 3.
Results Reference
derived
PubMed Identifier
27422625
Citation
Singh JS, Fathi A, Vickneson K, Mordi I, Mohan M, Houston JG, Pearson ER, Struthers AD, Lang CC. Research into the effect Of SGLT2 inhibition on left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM) trial rationale and design. Cardiovasc Diabetol. 2016 Jul 15;15:97. doi: 10.1186/s12933-016-0419-0.
Results Reference
derived

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

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