Overview
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 (i.e. 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.
Description
BACKGROUND Intensive insulin therapy designed to near-normalize glucose levels in people with type 1 diabetes significantly reduces an individual's 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 \~1.1 million emergency department visits, 980 000 hospitalizations, and 84 000 deaths with HF as the primary cause, with an estimated cost of \~$11.3 billion (\~$11,500/per 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 3.25 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 3.1% - extrapolated to the US this would equate to 57,000 of the 1.9 million individuals with type 1 diabetes. A recent meta-analysis of all available data suggested that the incidence of HF was 3.1 times higher in individuals with type 1 diabetes compared to controls (typically the general population). Assuming a 5% incidence of HF hospitalisation/year, 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 (e.g. presentation at a younger age), the pathophysiology of HF in type 1 diabetes is similar to type 2 diabetes. Risk factors are similar (e.g. 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 (e.g., 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 ≥27kg/m2 and taking insulin doses of at least 0.5 units/kg 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 10,584 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 1,222 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 patient's 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.
Eligibility
Inclusion Criteria:
Age
• Male or female patient must be 30 to 75 years of age inclusive, at the time of signing the informed consent form (ICF).
Type of Patient and Disease Characteristics
- Diagnosis of PD between past 4 to 20 years (meet MDS 2015 clinical diagnostic criteria for PD).
- H-Y staging (Appendix III) for "OFF" episodes is 2.5-4.0.
- MDS-UPDRS-III score \> 35, and positive for the Acute levodopa challenge test (ALCT) (improvement \> 30% for MDS UPDRS-III staging from OFF episodes to ON episodes) over two screening period visits. Baseline scores will be computed as the means of two screening period visits.
- No significant change in UPDRS-III scores between the two visits during the screening period.
- Patients who take stable doing of dopamine drug for at least 4 weeks prior to receiving the study drug.
- No significant change in dose and dosing schedule of the prescribed medicines for PD during the screening period.
- Medically suitable for neurosurgery under general anesthesia.
- Acceptable laboratory test values during screening and prior to transplantation (Day 0):
- Absolute neutrophil count ≥ 2.0 × 109/L
- White blood cell count ≥ 4.0 × 109/L
- Platelet count ≥ 100 × 109/L
- Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN)
- Total bilirubin ≤ 1.5 x ULN
- Serum creatinine ≤ 1.5 x ULN
- eGFR ≥ 50 mL/min/1.73 m2
- Agree to postpone any additional neurosurgical procedures, including DBS, until completion of the 12-month follow-up study (unless recommended by a neurologist).
- Agree not to participate in any other therapeutic intervention study within 24 months after neurosurgery.
- Able to participate in all study visits and evaluations, including brain/spine MRI, CT and PET scan.
Weight • Body mass index (BMI) within the range of 18\~32 kg/m2 (inclusive) with a minimum body weight of 45 kg at screening.
Sex and Contraceptive/Barrier Requirements
• Contraceptive use by men and women for 12 months after neurosurgery should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Informed Consent
- Able to understand the rationale of the clinical trial and sign the ICF. Other Inclusion Criteria
- Agree not to receive COVID-19 vaccine within 14 days before neurosurgery, and not to receive any other vaccine within 30 days after neurosurgery
Exclusion Criteria:
Medical Conditions
- Atypical Parkinsonism (Parkinsonism-Plus syndrome, secondary parkinsonism, familial parkinsonism) Prior/Concomitant Therapy
- Patients who have had previous pallidotomy, DBS surgery, striatal or extrapyramidal surgery, brain stereotaxy, prior surgical or radiation therapy to the brain or spinal cord, or other brain surgery; as well as other surgical procedures that, in the investigator's judgment, could interfere with participation in this study.
- Patients who have a previous head CT/MRI examination showing cerebral trauma, vascular malformation, hydrocephalus, brain tumor, etc., and patients who have brain imaging abnormalities in the striatum or other brain areas leading to a significantly increased risk for surgery.
- Patients who have had previous cellular therapy.
- Patients who have used glucocorticoids for an extended period (≥14 days) and at high doses (equivalent to prednisone ≥ 20 mg/day or other glucocorticoids at equivalent doses) within 3 months prior to signing the ICF. (excluding topical treatment)
- Patients who have used immunosuppressive drugs for an extended period (≥14 days) within 3 months prior to signing the ICF.
- Patients who have used antipsychotics, such as antidepressants, antimanic drugs, etc. within 3 months prior to signing the ICF and are deemed by the investigator to potentially impact the study assessment.
- Patients who have used botulinum toxin or other drugs for dystonia or muscle spasticity within 6 months prior to signing the ICF and are deemed by the investigator to potentially impact the study assessment.
Prior/Concurrent Clinical Study Experience
- Patients who are participating in other clinical trials, or have been enrolled in other clinical studies within 3 months prior to the screening
- Patients with poor compliance based on clinical evaluation of the investigator. Diagnostic Assessments
- Patients with a history of dementia or a severe cognitive disorder; or those with obvious dementia or congnitive impairment detected during screening; MDS-UPDRS congnitive impairment score (section 1.1) \> 3 point at screening; or patinets with poor compliance, inability to accurately keep diary, and/or inability to sign ICF due to dementia.
- Severe depression as defined by HAMD ≥ 24 at screening.
- Severe anxiety as defined by HAMA ≥ 29 at screening.
- Patients with a history of psychiatric disorders that, in the investigator's opinion, make them unsuitable for participation; or patients with a history of suicidal ideation or suicide attempts within the past year or currently (including actual attempts, interrupted attempts, or failed attempts).
- Patients with abnormal coagulation (prothrombin time ≥ 1.5 ULN, activated partial thromboplastin time ≥ 1.5 ULN), or abnormal INR at screening.
- Patients cannot temporarily suspend anti-platelet agents or other anti-coagulant medications at least 5 days prior to investigational drug administration surgery.
- Patients with active disseminated intravascular coagulation and significant hemorrhagic tendency within 3 months prior to signing the ICF.
- Patients with current or history of following disease
- severe heart failure (congestive heart failure of New York Heart Association Class II or above), unstable angina pectoris, and myocardial infarction
- severe arrhythmia, including but not limited to second- or third-degree atrioventricular block, or prolonged QT interval.
- Long QT Syndrome.
- cardiovascular surgery (cardiac, vascular stent surgery, angioplasty).
- stroke or transient ischemic attack within 3 months prior to signing the ICF, as determined by the investigator to be unsuitable to participate the study.
- subarachnoid hemorrhage
- primary mitochondrial disorder, multiple sclerosis, or other neurodegenerative diseases such as Alzheimer's disease
- major vascular diseases (aortic aneurysm, aortic dissecting aneurysm, internal carotid artery stenosis), as determined by the investigator to be unsuitable to participate the study.
- previous or current malignant tumors
- immune disfunction, including autoimmune disease or immunocompromised state
- traumatic brain injury with loss of consciousness and residue neurologic symptoms
- active epilepsy or currently on anti-epileptic drugs
- Hypertensive patients with poorly controlled blood pressure (defined as blood pressure above 160/100 mmHg despite antihypertensive drugs treatment) and patients with severe postural hypotension
- Diabetic patients with poorly controlled blood glucose (glycosylated hemoglobin \> 9.0%, or fasting plasma glucose (FPG) ≥ 11.1mmol/L)
- Patients with clinically significant abnormalities in kidney or liver function at screening.
- Patient with clinically significant abnormalities in immunological tests at screening
- Patients with surgical contraindications (such as those with cochlear implant, cardiac pacemaker, cardiac defibrillator, stereotactic nucleus pallidotomy; Patients who have had unilateral or bilateral intraparenchymal implantation of cellular products, or other surgical procedures within 6 months before screening which, in the opinion of the investigator, have an impact on this trial; Patients with other neurosurgical contraindications)
- Patients with other combined severe systemic diseases, such as pulmonary heart disease, moderate to severe asthma, severe chronic obstructive pulmonary disease (COPD) (FEV1% \< 50%)
- Patients with serious infections, requiring antibiotic treatment within 2 weeks prior to signing the ICF
- Patients with any active infectious disease, including but not limited to positive for human immunodeficiency virus, SARS Covid-19 virus, syphilis antibody, quantitative HCV-RNA testing, quantitative HBV-DNA testing greater than normal range for test results, or untreated tuberculosis; any other active infection that, in the investigator's opinion, may affect the participant's ability to take part in the study or could impact study outcomes.
Other Exclusion Criteria
- Patients with alcohol or drug addiction
- Patients with contraindications or a history of allergy to any medicines used during the neurosurgical procedure.
- Patients with contraindication or a history of allergy to any medicines used during the study, such as immunosuppressants, levodopa, etc, or any of their components; Patients who are allergic to similar drugs or other macrolides.
- Female of childbearing potential who are not surgically sterilized/premenopausal/unwilling to use medically approved effective contraception during the study and lactating women; men who are not surgically sterilized/unwilling to use medically approved effective contraception during the study
- Patients who have received electric shock therapy within 30 days prior to the investigational drug administration surgery
- Patients who are participating in other clinical trials, or have been enrolled in other clinical studies within 3 months prior to the screening
- Patients with poor compliance based on clinical evaluation of the investigator
- Patients who are being treated with drugs such as neuroleptics, apomorphine, or levodopa/carbidopa infusion therapy
- Patients with severe dyskinesia in both "ON" and "OFF" drug states
- Patients who have received or will receive a live vaccine within 4 weeks prior to the study
- Patients with significant medical conditions, or with other conditions that, in the opinion of the investigator, are unsuitable to participate in the study
