Heart FailurePhase 4REFORMNCT02397421
Safety and Effectiveness of SGLT-2 Inhibitors in Patients With Heart Failure and Diabetes
A Phase 4 study testing Dapagliflozin in people with Heart Failure and Diabetes, run by University of Dundee at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Heart Failure, Diabetes
- What is being tested?
- Dapagliflozin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 56 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Mar 2015to Aug 2017
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
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- 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.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Ninewells Hospital and Medical School
Dundee, Angus, DD1 9SY
About this study
Official title: Research Into the Effect of SGLT2 Inhibition on Left Ventricular Remodeling in Patients With Heart Failure and Diabetes Mellitus
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.
Read more
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)
Read the 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.
- Conditions
- Heart Failure, Diabetes
- Being tested
- Dapagliflozin, Placebo
- Keywords
- Heart failure, Diabetes, Left ventricular remodelling, SGLT-2 inhibitors
- Medical subject headings
- Heart Failure, Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DapagliflozinDrug
Also called Forxiga
Sodium Glucose Linked Transporter Type 2 (SGLT-2) Inhibitor
PlaceboDrug
Capsules containing microcrystalline cellulose Ph Eur overencapsulated in a hard gelatine capsule shell to match the active comparator
| Study group | Role | What they receive |
|---|---|---|
| Treatment | Active comparator | Dapagliflozin 10mg once daily Receives: Drug: Dapagliflozin |
| Control | Placebo comparator | Capsules containing microcrystalline cellulose Ph Eur overencapsulated in a hard gelatine capsule shell to match the active comparator Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 1 year
Secondary outcomes (10)
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.
Measured: 1 year
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
Measured: 1 year
Objective functional capacity (6 Minute Walk Test (6MWT)
6 Minute Walk Test (6MWT) will be performed to objectively determine the functional capacity of participants
Measured: 1 year
Exercise capacity (Cardio-pulmonary Exercise Testing (CPET)
Cardio-pulmonary Exercise Testing (CPET) will be performed to determine the exercise capacity of participants
Measured: 1 year
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
Measured: 1 year
Cardiac and inflammatory biomarkers
Brain natriuretic peptide (BNP) and other inflammatory \& oxidative stress markers will be measured
Measured: 1 year
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
Measured: 1 year
Change in degree of microalbuminuria
Urinary analysis will be performed to determine if there has been any change in the severity of microalbuminuria
Measured: 1 year
Quantify amount of natriuresis
Urinary analysis will be performed to quantify the amount of sodium excretion.
Measured: 1 year
The safety of dapagliflozin use in diabetic, heart failure patients with regard to worsening HF, hospitalization and death will be evaluated
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Mar 2015 (estimated)
- Study startMar 2015
- Primary completionAug 2017
- Study completionAug 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 56 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Dundee
- Sponsor type
- University, hospital or other
- Collaborators
- European Foundation for the Study of Diabetes
- Responsible party
- Principal investigator, Jagdeep Singh Surmukh Singh, University of Dundee
- Investigators
- Jagdeep Singh, MBBS, Principal investigator, University of Dundee
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02397421
- Sponsor's protocol ID
- 2014-002742-42
- Other IDs
- 2014
- Acronym
- REFORM
- Status last verified
- Jul 2018
- First submitted
- 12 Mar 2015
- Last updated
- 31 Jul 2018
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 34693515Singh 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.
PubMed 32245746Singh 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.
PubMed 27422625
Study at a glance
From the registry record, last updated by the sponsor on 31 Jul 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Research Into the Effect of SGLT2 Inhibition on Left Ventricular Remodeling in Patients With Heart Failure and Diabetes Mellitus
- ClinicalTrials.gov ID
- NCT02397421
- Acronym / sponsor ID
- REFORM / 2014-002742-42
- Conditions
- Heart Failure, Diabetes
- Keywords
- Heart failure, Diabetes, Left ventricular remodelling, SGLT-2 inhibitors
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 56 participants (actual)
- Lead sponsor
- University of DundeeUniversity, hospital or other
- Collaborators
- European Foundation for the Study of Diabetes
- Study start
- Mar 2015
- Primary completion
- Aug 2017 (actual)
- Study completion
- Aug 2017 (actual)
- First posted
- 25 Mar 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Treatment | Active comparator | Drug: DapagliflozinDapagliflozin 10mg once daily |
| Control | Placebo comparator | Drug: PlaceboCapsules containing microcrystalline cellulose Ph Eur overencapsulated in a hard gelatine capsule shell to match the active comparator |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DapagliflozinAlso: ForxigaSodium Glucose Linked Transporter Type 2 (SGLT-2) Inhibitor | Drug | Treatment |
| PlaceboCapsules containing microcrystalline cellulose Ph Eur overencapsulated in a hard gelatine capsule shell to match the active comparator | Drug | Control |
Primary outcome
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
10 secondary outcomes
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
Fluid status (Bioelectrical Impedence Analysis (BIA)
Time frame: 1 year
Objective functional capacity (6 Minute Walk Test (6MWT)
Time frame: 1 year
Exercise capacity (Cardio-pulmonary Exercise Testing (CPET)
Time frame: 1 year
Quality of life (Minnesota Living with Heart Failure and SF-36 questionnaire)
Time frame: 1 year
Cardiac and inflammatory biomarkers
Time frame: 1 year
Diuretic requirement (total diuretic requirement to maintain euvolemia)
Time frame: 1 year
Change in degree of microalbuminuria
Time frame: 1 year
Quantify amount of natriuresis
Time frame: 1 year
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Jul 2018.
- Derived from this study: PubMed 34693515Kanie 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.
- Derived from this study: PubMed 32245746Singh 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.
- Derived from this study: PubMed 27422625Singh 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jagdeep Singh, MBBS principal investigator
University of Dundee
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Dapagliflozin in people with Heart Failure and Diabetes, run by University of Dundee at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Jul 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02397421, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jul 2018.