Ignite Creation Date:
2024-06-16 @ 11:49 AM
Last Modification Date:
2024-10-26 @ 3:30 PM
Study NCT ID:
NCT06435156
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-05-30
First Post:
2024-05-16
Brief Title:
Sotagliflozin in Patients With Heart Failure Symptoms and Type 1 Diabetes
Sponsor:
University of Dundee
Organization:
University of Dundee
Study Overview
Official Title:
A Phase 2 Double-blind Randomised Controlled Trial Studying the Effect of Sotagliflozin Versus Placebo in Individuals With Heart Failure and Type 1 Diabetes
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
SOPHIST
Brief Summary:
People with type 1 diabetes sometimes develop heart failure which can cause symptoms like breathlessness tiredness or ankle swelling reduced quality of life and lead to being admitted to hospital or suffering potential fatal consequences This trial is investigating if a tablet called sotagliflozin can improve quality of life in people with type 1 diabetes and heart failure In addition this trial will also assess the safety and tolerability of sotagliflozin in this population
In previous trials that included people with type 2 diabetes and heart failure sotagliflozin was shown to improve patients symptoms of heart failure quality of life and reduce the chance of people with heart failure being admitted to hospital or dying However people with type 1 diabetes and heart failure were not included in these trials meaning that it is not known if these benefits also apply to this population
This trial aims to recruit 320 people with type 1 diabetes and heart failure symptoms in multiple sites in the United Kingdom UK This trial will compare the health and quality of life of participants who take sotagliflozin tablets with participants who take placebo tablets which is a dummy tablet that looks the same as sotagliflozin Participants will be randomly allocated to one of two groups ie one taking sotagliflozin and the other the placebo and both the medical team and participants will not know in which group each participant is until the end of the study Participants will be in the trial for approximately 6 months and will be given sotagliflozin or placebo tablets to take 1 per day for 4 months The trial is expected to run for a total of 26 months
In previous trials that included people with type 2 diabetes and heart failure sotagliflozin was shown to improve patients symptoms of heart failure quality of life and reduce the chance of people with heart failure being admitted to hospital or dying However people with type 1 diabetes and heart failure were not included in these trials meaning that it is not known if these benefits also apply to this population
This trial aims to recruit 320 people with type 1 diabetes and heart failure symptoms in multiple sites in the United Kingdom UK This trial will compare the health and quality of life of participants who take sotagliflozin tablets with participants who take placebo tablets which is a dummy tablet that looks the same as sotagliflozin Participants will be randomly allocated to one of two groups ie one taking sotagliflozin and the other the placebo and both the medical team and participants will not know in which group each participant is until the end of the study Participants will be in the trial for approximately 6 months and will be given sotagliflozin or placebo tablets to take 1 per day for 4 months The trial is expected to run for a total of 26 months
Detailed Description:
BACKGROUND Intensive insulin therapy designed to near-normalize glucose levels in people with type 1 diabetes significantly reduces an individuals risk of long-term micro- and macrovascular complications Unfortunately glycaemic targets are not achieved by the majority of people with type 1 diabetes and as such overall life expectancy remains reduced compared to those without type 1 diabetes Cardiovascular disease remains a major cause of morbidity and mortality in type 1 diabetes There is growing recognition that heart failure HF is an increasing problem in type 1 diabetes Diabetes itself is an independent risk factor for HF causing structural and functional cardiac changes that predispose to HF known as diabetic cardiomyopathy HF is the end result of many cardiovascular diseases such as hypertension and myocardial infarction and improved treatments for these conditions and changing demographic trends mean that many more people are surviving longer and developing HF
HF has a substantial healthcare burden In the United States US and Europe the prevalence of HF in the general population is around 1-2 - around 6 million adults in the US are estimated to be living with HF currently In 2014 in the US there were 11 million emergency department visits 980 000 hospitalizations and 84 000 deaths with HF as the primary cause with an estimated cost of 113 billion 11500per patient for each hospitalisation Despite advances in management of HF over the past 30 years the incidence of mortality and HF hospitalisation in recent HF clinical trials remained high at 20-30 over 2 years
The burden of HF in type 1 diabetes is less well characterised compared to HF in those with type 2 diabetes and individuals without diabetes however the data still indicate the substantial nature of this growing problem One of the largest epidemiological studies was a Scottish national data study of 325 million individuals 30 years old where the crude incidence of HF hospitalisation was over twice that of the population without diabetes While the crude incidence was less than in type 2 diabetes type 1 diabetes patients were on average 20 years younger Despite their younger age 30-day mortality following HF hospitalisation was higher in individuals with type 1 diabetes after adjustment for age sex and socioeconomic status indicating that outcomes are worse in HF patients with type 1 diabetes compared to those with either type 2 diabetes or without diabetes Data from Scandinavia supports this finding and suggests that the risk of both incident HF and cardiovascular mortality was higher for individuals with type 1 diabetes compared to type 2 diabetes after adjustment for age The overall prevalence of HF in this study at baseline was 31 - extrapolated to the US this would equate to 57000 of the 19 million individuals with type 1 diabetes A recent meta-analysis of all available data suggested that the incidence of HF was 31 times higher in individuals with type 1 diabetes compared to controls typically the general population Assuming a 5 incidence of HF hospitalisationyear HF hospitalizations cost the US healthcare system 29 million per year In summary these data suggest that not only is HF a significant problem in individuals with type 1 diabetes but there is evidence of an outcome disparity compared to individuals with type 2 diabetes or those without diabetes
Although there are some differences eg presentation at a younger age the pathophysiology of HF in type 1 diabetes is similar to type 2 diabetes Risk factors are similar eg glycaemic control coronary artery disease and hypertension leading to inflammation endothelial dysfunction fibrosis and subsequent diastolic and systolic dysfunction Given the pathophysiological similarities there is little to suggest that HF therapies that have shown benefit in individuals with type 2 diabetes or individuals without diabetes would not also be efficacious in type 1 diabetes In all current HF guidelines mainstay HF treatments renin-angiotensin system blockers beta-blockers and mineralocorticoid receptor antagonists are recommended for all patients with HF regardless of diabetes status
Sodium-glucose co-transporter inhibitors SGLTi were initially developed as oral add-on treatments for glycaemic control in type 2 diabetes A consistent finding in large cardiovascular outcome trials was a significant 30 risk reduction in hospitalisation for HF as well as overall reductions in cardiovascular mortality Subsequently SGLTi in addition to guideline-directed HF therapy have been studied in HF patients either with type 2 diabetes or without diabetes and have again shown a consistent benefit compared to placebo with significant reductions in mortality and HF hospitalisation irrespective of cardiac function left ventricular ejection fraction LVEF at baseline without any concerning safety signals SGLTi also improve HF-related quality of life QoL and renal outcomes This has led to the inclusion of SGLTi in the most recent HF treatment guidelines as a cornerstone of therapy in addition to established pharmacological agents eg renin-angiotensin system inhibitors beta-blockers and mineralocorticoid receptor antagonists However there is one key issue - individuals with type 1 diabetes have been excluded from these HF trials in part due to concerns around safety At present there is no evidence to support the use of these life-saving therapies in this population that already has worse outcomes than other groups with HF
In adult type 1 diabetes Phase III trials with dapagliflozin empagliflozin and sotagliflozin have been completed collectively showing modest benefits of SGLT inhibition in terms of Haemoglobin A1c HbA1c reduction increased time in range reduced body weight and total insulin dose However SGLTi use in type 1 diabetes was also associated with an increased risk of diabetic ketoacidosis DKA which has limited their more widespread use in type 1 diabetes
Sotagliflozin is a dual SGLT1 and 2 inhibitor that is currently approved in the United Kingdom for use in individuals with type 1 diabetes with a body mass index BMI of 27kgm2 and taking insulin doses of at least 05 unitskg of body weight in patients with inadequate glycaemic control As with selective SGLT2i sotagliflozin also improves HF-related outcomes The key evidence for this comes from two clinical trials In the Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease SCORED trial including 10584 patients with type 2 diabetes chronic kidney disease and cardiovascular risk factors sotagliflozin caused a 26 relative risk reduction in the primary endpoint of cardiovascular death HF hospitalisation or urgent HF visit compared to placebo There was also a 33 relative risk reduction in HF hospitalisation or urgent HF visits figures consistent with other SGLT2i trials
The second key trial was the Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure SOLOIST-WHF trial In this trial 1222 patients with type 2 diabetes and a recent HF hospitalisation were randomised to sotagliflozin 200mg once daily with uptitration to 400mg once daily or placebo Patients were included regardless of left ventricular ejection fraction LVEF at baseline The median follow-up duration was 9 months
Sotagliflozin caused a 33 relative risk reduction in the primary outcome of cardiovascular death HF hospitalisation or urgent HF visit with a 36 reduction in HF hospitalisation or urgent HF visits that met statistical significance Sotagliflozin also significantly improved QoL at 4 months measured using the Kansas City Cardiomyopathy Questionnaire KCCQ Rates of serious adverse events SAEs leading to study drug withdrawal were similar in both sotagliflozin and placebo groups though severe hypoglycaemia was more common with sotagliflozin than placebo 9 individuals vs 2 There was no significant increase in incidence of DKA with sotagliflozin compared to placebo 2 vs 4 Taken together these two trials confirm the benefit of sotagliflozin on HF related outcomes consistent with selective SGLT2i Again individuals with type 1 diabetes were excluded from both of these trials
In summary there is significant HF related morbidity and mortality in type 1 diabetes and outcomes are worse than in HF patients with type 2 diabetes or without diabetes Oral sotagliflozin 200mg daily is licensed for improving glycaemic control in type 1 diabetes in the UK Although sotagliflozin improves HF related outcomes and QoL in patients with type 2 diabetes and patients with HF who do not have diabetes studies are needed to determine whether these benefits might extend to patients with type 1 diabetes and heart failure
RATIONALE As outlined above HF is a significant problem in type 1 diabetes with an estimated prevalence of 3-5 Outcomes for individuals with type 1 diabetes and HF are worse than in those with type 2 diabetes or without diabetes with increased mortality and hospitalisation rates Critically patients with type 1 diabetes have been excluded from pivotal trials of the latest advance in HF treatment SGLT2i potentially exacerbating these outcome disparities further
The proposed trial will be the first to provide data on the efficacy and safety of sotagliflozin in patients with type 1 diabetes and HF regardless of LVEF If a beneficial signal is found this would provide strong support for extending the use of sotagliflozin in this group of patients with type 1 diabetes and adoption into clinical guidelines A multi-centre double-blind randomised controlled trial to provide the strongest level of evidence for previous findings of the researchers will be conducted Importantly by choosing QoL measured using the KCCQ as the primary endpoint an outcome that not only correlates strongly with mortality and hospitalisation but is also accepted by the US Food and Drug Administration FDA as a valid endpoint for regulatory approval has been selected The KCCQ is a 23- item self-administered questionnaire that measures the patients perception of their health status including HF symptoms impact on physical and social function and how their HF impacts their QOL within the preceding 2 weeks Improvements in KCCQ score map very well to reductions in mortality and hospitalisation and SGLT2i have consistently improved KCCQ scores A 5-point increase in KCCQ score is traditionally considered clinically meaningful and is associated with a 7 reduction in mortality and HF hospitalisation Given the prohibitive size of trial that would be required to demonstrate an improvement in mortality or HF hospitalizations with sotagliflozin in type 1 diabetes the KCCQ represents an ideal endpoint for the trial The proposed trial has the potential to be a high-impact practice-changing trial
HF has a substantial healthcare burden In the United States US and Europe the prevalence of HF in the general population is around 1-2 - around 6 million adults in the US are estimated to be living with HF currently In 2014 in the US there were 11 million emergency department visits 980 000 hospitalizations and 84 000 deaths with HF as the primary cause with an estimated cost of 113 billion 11500per patient for each hospitalisation Despite advances in management of HF over the past 30 years the incidence of mortality and HF hospitalisation in recent HF clinical trials remained high at 20-30 over 2 years
The burden of HF in type 1 diabetes is less well characterised compared to HF in those with type 2 diabetes and individuals without diabetes however the data still indicate the substantial nature of this growing problem One of the largest epidemiological studies was a Scottish national data study of 325 million individuals 30 years old where the crude incidence of HF hospitalisation was over twice that of the population without diabetes While the crude incidence was less than in type 2 diabetes type 1 diabetes patients were on average 20 years younger Despite their younger age 30-day mortality following HF hospitalisation was higher in individuals with type 1 diabetes after adjustment for age sex and socioeconomic status indicating that outcomes are worse in HF patients with type 1 diabetes compared to those with either type 2 diabetes or without diabetes Data from Scandinavia supports this finding and suggests that the risk of both incident HF and cardiovascular mortality was higher for individuals with type 1 diabetes compared to type 2 diabetes after adjustment for age The overall prevalence of HF in this study at baseline was 31 - extrapolated to the US this would equate to 57000 of the 19 million individuals with type 1 diabetes A recent meta-analysis of all available data suggested that the incidence of HF was 31 times higher in individuals with type 1 diabetes compared to controls typically the general population Assuming a 5 incidence of HF hospitalisationyear HF hospitalizations cost the US healthcare system 29 million per year In summary these data suggest that not only is HF a significant problem in individuals with type 1 diabetes but there is evidence of an outcome disparity compared to individuals with type 2 diabetes or those without diabetes
Although there are some differences eg presentation at a younger age the pathophysiology of HF in type 1 diabetes is similar to type 2 diabetes Risk factors are similar eg glycaemic control coronary artery disease and hypertension leading to inflammation endothelial dysfunction fibrosis and subsequent diastolic and systolic dysfunction Given the pathophysiological similarities there is little to suggest that HF therapies that have shown benefit in individuals with type 2 diabetes or individuals without diabetes would not also be efficacious in type 1 diabetes In all current HF guidelines mainstay HF treatments renin-angiotensin system blockers beta-blockers and mineralocorticoid receptor antagonists are recommended for all patients with HF regardless of diabetes status
Sodium-glucose co-transporter inhibitors SGLTi were initially developed as oral add-on treatments for glycaemic control in type 2 diabetes A consistent finding in large cardiovascular outcome trials was a significant 30 risk reduction in hospitalisation for HF as well as overall reductions in cardiovascular mortality Subsequently SGLTi in addition to guideline-directed HF therapy have been studied in HF patients either with type 2 diabetes or without diabetes and have again shown a consistent benefit compared to placebo with significant reductions in mortality and HF hospitalisation irrespective of cardiac function left ventricular ejection fraction LVEF at baseline without any concerning safety signals SGLTi also improve HF-related quality of life QoL and renal outcomes This has led to the inclusion of SGLTi in the most recent HF treatment guidelines as a cornerstone of therapy in addition to established pharmacological agents eg renin-angiotensin system inhibitors beta-blockers and mineralocorticoid receptor antagonists However there is one key issue - individuals with type 1 diabetes have been excluded from these HF trials in part due to concerns around safety At present there is no evidence to support the use of these life-saving therapies in this population that already has worse outcomes than other groups with HF
In adult type 1 diabetes Phase III trials with dapagliflozin empagliflozin and sotagliflozin have been completed collectively showing modest benefits of SGLT inhibition in terms of Haemoglobin A1c HbA1c reduction increased time in range reduced body weight and total insulin dose However SGLTi use in type 1 diabetes was also associated with an increased risk of diabetic ketoacidosis DKA which has limited their more widespread use in type 1 diabetes
Sotagliflozin is a dual SGLT1 and 2 inhibitor that is currently approved in the United Kingdom for use in individuals with type 1 diabetes with a body mass index BMI of 27kgm2 and taking insulin doses of at least 05 unitskg of body weight in patients with inadequate glycaemic control As with selective SGLT2i sotagliflozin also improves HF-related outcomes The key evidence for this comes from two clinical trials In the Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease SCORED trial including 10584 patients with type 2 diabetes chronic kidney disease and cardiovascular risk factors sotagliflozin caused a 26 relative risk reduction in the primary endpoint of cardiovascular death HF hospitalisation or urgent HF visit compared to placebo There was also a 33 relative risk reduction in HF hospitalisation or urgent HF visits figures consistent with other SGLT2i trials
The second key trial was the Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure SOLOIST-WHF trial In this trial 1222 patients with type 2 diabetes and a recent HF hospitalisation were randomised to sotagliflozin 200mg once daily with uptitration to 400mg once daily or placebo Patients were included regardless of left ventricular ejection fraction LVEF at baseline The median follow-up duration was 9 months
Sotagliflozin caused a 33 relative risk reduction in the primary outcome of cardiovascular death HF hospitalisation or urgent HF visit with a 36 reduction in HF hospitalisation or urgent HF visits that met statistical significance Sotagliflozin also significantly improved QoL at 4 months measured using the Kansas City Cardiomyopathy Questionnaire KCCQ Rates of serious adverse events SAEs leading to study drug withdrawal were similar in both sotagliflozin and placebo groups though severe hypoglycaemia was more common with sotagliflozin than placebo 9 individuals vs 2 There was no significant increase in incidence of DKA with sotagliflozin compared to placebo 2 vs 4 Taken together these two trials confirm the benefit of sotagliflozin on HF related outcomes consistent with selective SGLT2i Again individuals with type 1 diabetes were excluded from both of these trials
In summary there is significant HF related morbidity and mortality in type 1 diabetes and outcomes are worse than in HF patients with type 2 diabetes or without diabetes Oral sotagliflozin 200mg daily is licensed for improving glycaemic control in type 1 diabetes in the UK Although sotagliflozin improves HF related outcomes and QoL in patients with type 2 diabetes and patients with HF who do not have diabetes studies are needed to determine whether these benefits might extend to patients with type 1 diabetes and heart failure
RATIONALE As outlined above HF is a significant problem in type 1 diabetes with an estimated prevalence of 3-5 Outcomes for individuals with type 1 diabetes and HF are worse than in those with type 2 diabetes or without diabetes with increased mortality and hospitalisation rates Critically patients with type 1 diabetes have been excluded from pivotal trials of the latest advance in HF treatment SGLT2i potentially exacerbating these outcome disparities further
The proposed trial will be the first to provide data on the efficacy and safety of sotagliflozin in patients with type 1 diabetes and HF regardless of LVEF If a beneficial signal is found this would provide strong support for extending the use of sotagliflozin in this group of patients with type 1 diabetes and adoption into clinical guidelines A multi-centre double-blind randomised controlled trial to provide the strongest level of evidence for previous findings of the researchers will be conducted Importantly by choosing QoL measured using the KCCQ as the primary endpoint an outcome that not only correlates strongly with mortality and hospitalisation but is also accepted by the US Food and Drug Administration FDA as a valid endpoint for regulatory approval has been selected The KCCQ is a 23- item self-administered questionnaire that measures the patients perception of their health status including HF symptoms impact on physical and social function and how their HF impacts their QOL within the preceding 2 weeks Improvements in KCCQ score map very well to reductions in mortality and hospitalisation and SGLT2i have consistently improved KCCQ scores A 5-point increase in KCCQ score is traditionally considered clinically meaningful and is associated with a 7 reduction in mortality and HF hospitalisation Given the prohibitive size of trial that would be required to demonstrate an improvement in mortality or HF hospitalizations with sotagliflozin in type 1 diabetes the KCCQ represents an ideal endpoint for the trial The proposed trial has the potential to be a high-impact practice-changing trial
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 3-SRA-2023-1376-M-B | OTHER_GRANT | None | None |
| 1007807 | OTHER | IRAS | None |