Ignite Creation Date:
2024-05-06 @ 8:42 AM
Last Modification Date:
2024-10-26 @ 12:03 PM
Study NCT ID:
NCT02798744
Status:
COMPLETED
Last Update Posted:
2020-01-30
First Post:
2016-02-10
Brief Title:
SGLT-2 Inhibitor Empagliflozin Effects on Appetite and Weight Regulation
Sponsor:
University of Leicester
Organization:
University of Leicester
Study Overview
Official Title:
SGLT-2 Inhibitor Empagliflozin Effects on Appetite and Weight Regulation A Randomised Double-blind Placebo-controlled Trial The SEESAW Study
Status:
COMPLETED
Status Verified Date:
2020-01
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:
SEESAW
Brief Summary:
The aim of this study is to investigate the cause for the discrepancy in predicted and observed weight loss with Empagliflozin Jardiance by measuring appetite regulation
Major secondary objectives are to determine the effects of Empagliflozin Jardiance on energy expenditure and change in total body weight and body composition
The primary outcome is change in appetite hormone concentrations specifically total PYY between baseline and 24 weeks - this will be measured by sequential blood sampling during visits 1-5
Secondary outcomes which are exploratory are effect on appetite hormones ghrelin and GLP-1 appetite perceptions total body weight and fat and fat free mass energy expenditure appetite perception physical activity and blood and urine biochemical parameters after Empagliflozin Jardiance treatment for 24 weeks
The sample size for the study is 76 participants and the planned trial duration is 21 months with participants receiving approximately 24 weeks of exposure to Empagliflozin Jardiance
Major secondary objectives are to determine the effects of Empagliflozin Jardiance on energy expenditure and change in total body weight and body composition
The primary outcome is change in appetite hormone concentrations specifically total PYY between baseline and 24 weeks - this will be measured by sequential blood sampling during visits 1-5
Secondary outcomes which are exploratory are effect on appetite hormones ghrelin and GLP-1 appetite perceptions total body weight and fat and fat free mass energy expenditure appetite perception physical activity and blood and urine biochemical parameters after Empagliflozin Jardiance treatment for 24 weeks
The sample size for the study is 76 participants and the planned trial duration is 21 months with participants receiving approximately 24 weeks of exposure to Empagliflozin Jardiance
Detailed Description:
Out of a family of six sodium glucose co-transporters two have been extensively studied for therapeutic indications involving glucose reabsorption from the glomerular filtrate Sodium glucose co-transporter-1 SGLT-1 which is mainly found in both the renal tubule and enterocytes lining intestinal villi transfers glucose across a concentration gradient resulting in glucose absorption from the gut and accounting for 10 of the glucose reabsorption from the renal tubules Sodium glucose co-transporter-2 SGLT-2 which is mostly found in the kidneys is responsible for reabsorbing 90 of the glucose that is filtered by the renal tubules Compared with healthy individuals SGLT-2 is over-expressed and over-activated in those with type 2 diabetes
SGLT-2 inhibitors are a new class of glucose-lowering drugs for the management of type 2 diabetes which reduce plasma glucose levels by increasing urinary glucose excretion UGE by up to 60-80g 240-320 kilo Calories per day SGLT-1 inhibitors and combined SGLT-1 and -2 inhibitors are currently in development
Several SGLT-2 inhibitors are commercially available and licensed for use in the UK including dapagliflozin canagliflozin and Empagliflozin Jardiance They all lower glycated haemoglobin HbA1c effectively compared with placebo mean difference vs placebo -066 95 Confidence Interval -073 to -058 They also result in weight loss of approximately 18kg compared with placebo and in combination with other oral hypoglycaemic medications Some of this weight loss can be attributed to fluid loss due to osmotic diuresis from UGE Weight is lost from both subcutaneous and visceral stores of adipose tissue
Phase II studies have shown that the highly selective and potent SGLT-2 inhibitor Empagliflozin Jardiance results in significant reductions in HbA1c level after 12 weeks of therapy compared with placebo HbA1c 04-06 reduction with 5-25mg daily dose p00001 and reduction was similar to that seen with metformin Weight loss of between 181-233kg was also achieved depending on Empagliflozin Jardiance dose along with reduction in fasting plasma glucose FPG Similar improvements in HbA1c weight and FPG have been seen in phase III trials with Empagliflozin Jardiance both as monotherapy and in combination with metformin sulphonylureas or insulin
Empagliflozin Jardiance is licensed in the UK for use in type 2 diabetes management In this study we will be using Empagliflozin Jardiance according to its licensed indications and dosage The commonest known side-effects include urinary tract and genital mycotic infections which are more frequent in women than men and generally mild in severity Dehydration and postural hypotension may occur due to volume depletion and modest lowering of blood pressure Increased urinary frequency may also occur Increased risk of hypoglycaemia is observed when Empagliflozin Jardiance is combined with sulphonylureas or insulin
Weight loss from increased UGE and net energy loss with SGLT-2 inhibitors is less than expected as shown by studies in patients with type 2 diabetes Endogenous glucose production is markedly increased with shifting of substrate utilisation from carbohydrate to lipid
Up to 90g of glucose are excreted per day with Empagliflozin Jardiance which equates to 360 kilo Calories per day lost by glycosuria A 90 week study of patients with type 2 diabetes treated with Empagliflozin Jardiance 25mg daily showed that average weight loss was 3242kg representing a calorie deficit of 51 kilo Calories day interquartile range 112 This was 2941 of the expected loss of 11331kg predicted by glycosuria of 206 kilo Calories per day using a validated mathematical model httpbwsimulatorniddknihgov An increase in daily calorie intake of 269 kilo Calories day Inter Quartile Range 258 and daily energy expenditure appear to be the adaptive responses due to Empagliflozin Jardiance therapy and the combination of SGLT-2 inhibitors and calorie restriction has been recommended by the authors of this study
Appetite stimulation resulting in increased energy intake may be the underlying mechanism for this weight loss deficit Furthermore glucagon response is increased by SGLT-2 inhibition using Empagliflozin Jardiance and dapagliflozin
Appetite hormones such as peptide Y-Y PYY and ghrelin are important in the control of appetite and weight regulation They are secreted from intestinal L cells which are found in the distal small intestine Ghrelin which stimulates hunger has been shown to increase with weight loss and energy restriction diets Glucagon-like peptide 1 GLP-1 is another hormone which is involved in the regulation of appetite and satiety along with other glucose homeostatic effects
There are no studies that have investigated the impact of SGLT-2 inhibitors on appetite hormones and effect on body composition It is essential to understand these mechanisms in order to maximize the weight loss achievable with these agents They may need to be combined with appropriate dietary measures such as energy restriction diets and weight-lowering or weight-neutral hypoglycaemic therapies for optimal clinical benefit The aim of our study is to explore the relationship between appetite hormones and Empagliflozin Jardiance in order to understand the underlying mechanisms for observed weight loss which does not equate with that predicted for these agents
Primary Objective
The aim of this study is to investigate the cause for the discrepancy in predicted and observed weight loss with Empagliflozin Jardiance by measuring appetite regulation
Secondary Objectives
To determine the effects of Empagliflozin Jardiance on resting energy expenditure and change in total body weight and body composition
Study End Points
The primary endpoint is effect on appetite hormones specifically total PYY with Empagliflozin Jardiance after treatment for 24 weeks
Secondary endpoints which are exploratory are effect on
i Appetite hormones ghrelin and GLP-1 and appetite perception ii Total body weight and change in body composition fat and fat free mass iii Resting energy expenditure iv Physical activity v Change in blood and urine biochemical parameters
This study is a randomised double-blind placebo-controlled trial conducted over 24 weeks in male and postmenopausal female participants with type 2 diabetes on lifestyle control or stable metformin dose only to compare the effects of Empagliflozin Jardiance on appetite and weight regulation compared with placebo and energy restriction diet
Participants will be randomised to one of four arms at baseline- i Empagliflozin Jardiance 25mg once daily ii Empagliflozin Jardiance 25mg once daily and energy restriction diet iii Placebo iv Placebo and energy restriction diet Participants will be stratified for age and BMI STUDY CONDUCT Participant Withdrawal- Each participant has the right to withdraw from the study at any time without needing to give a reason The investigator may discontinue a participant from the study at any time if considered necessary The reason for withdrawal will be recorded in the CRF and medical records If the participant is withdrawn due to an adverse event the investigator will arrange for follow-up visits or telephone calls until the adverse event has resolved or stabilised The duration of safety follow-ups will be at least five half-lives of the study medication The half-life of Empagliflozin Jardiance is 124 hours thus the duration of safety follow-ups will be rounded up to be at least 72 hours or 3 days The participant will be withdrawn from the study if they lose capacity and data collected up to that point will be used for analysis As analysis will be on an intention-to-treat basis there will be analysis of all data of participants receiving study medication eg most safety analyses and data will be admitted to the database even after the participant has withdrawn from the study
Source Data- Source documents are original documents data and records from which participants CRF data will be obtained These include but are not limited to hospital records from which medical history and previous and concurrent medication will be summarised into the CRF clinical and office charts laboratory and pharmacy records diaries microfiches radiographs and correspondence On all study-specific documents other than the signed consent the participant will be referred to by the study participant numbercode only and not by name
Drug Management- The licensed product Empagliflozin Jardiance will be handled according to the University Hospitals of Leicester pharmacy in-house protocols
Compliance with Study Treatment- The participants will be instructed to return all unused or part-used medication and packaging from used medication at each visit The Investigator may withdraw the participants if they consider dose compliance is unsatisfactory
Concomitant Medication- Throughout the study Investigators will be able to prescribe any concomitant medications or treatments deemed necessary to provide adequate supportive care except for those listed in the exclusion criteria If these are required the participant will be withdrawn Any medication other than the study medication taken during the study will be recorded in the CRF Contraindicated medications during the study will include any other glucose-lowering therapies apart from metformin Loop diuretic therapy will also be contraindicated As study drug Empagliflozin Jardiance placebo and metformin do not cause hypoglycaemia participants will not be expected to perform home blood glucose monitoring during the study
SAFETY REPORTING Expected Serious Adverse EventsReactions SAE- The most common adverse events seen with Empagliflozin Jardiance are urinary tract and mycotic fungal infections eg balanitis and volume depletion leading to dehydration postural hypotension and dizziness If these events lead to hospitalisation of the participant they will require immediate reporting to the study team Otherwise they will be treated as an AE and need reporting to the study team within 2 working days
Abnormalities of renal and liver function will also be closely monitored as part of the usual study visits and any significant clinical deterioration in renal andor liver function will be reported as an SAE A serious deterioration in renal function to be classified as an SAE will be a reduction in eGFR to less than 30mlmin173m2 A serious deterioration in liver function will be classified as an SAE if ALT Alanine aminotransferase or AST Aspartate aminotransferase is 3 x greater than the upper limit of normal
Ketoacidosis and Diabetic Ketoacidosis DKA have recently been reported as a possible serious SAE occurring with SGLT-2 inhibitor use by the US Food and Drugs Administration Participants will be closely monitored for the development of this SAE and will be advised to seek medical attention immediately if they experience symptoms such as difficulty breathing nausea vomiting abdominal pain confusion unusual fatigue or sleepiness anorexia excessive thirst dehydration low food intake weight loss infection poor control of diabetes andor only moderately increased glucose levels
In patients where DKA is suspected or diagnosed treatment with SGLT-2 inhibitors will be discontinued immediately Restarting SGLT-2 inhibitor treatment in patients with previous DKA while on SGLT-2 inhibitor treatment is not recommended unless another clear precipitating factor is identified and resolved Treatment will also be interrupted in patients who are hospitalised for major surgical procedures or acute medical illnesses In both cases treatment with SGLT-2 inhibitors may be restarted once the patients condition has stabilised and only once the necessary safety assessments have been performed The decision to stop or interrupt and subsequently re-start the study treatment Empagliflozin Jardiance will be documented in the participants medical notes Any decisions regarding the withdrawal of participants from the study will be made by the study clinician and Principal Investigator
Suspected Unexpected Serious Adverse Reactions SUSAR A serious adverse reaction the nature or severity of which is not consistent with the Summary of Product Characteristics for Empagliflozin Jardiance will be reported as a SUSAR
Adverse Events of Special Interests AESI Adverse Events of Special Interests AESI
Decreased renal function creatinine value shows a 2 fold increase from baseline and is above ULN
Hepatic injury defined by the following alterations of liver parameters after randomization at visit 1-
Elevation of AST andor ALT3 fold ULN combined with an elevation of total bilirubin2 fold ULN measured in the same blood draw sample
Isolated elevation of AST andor ALT5 fold ULN irrespective of any bilirubin elevation
Diabetic Ketoacidosis DKA o DKA is defined by the diagnostic criteria in the table below and as defined by the American Diabetes Association ADA
Investigators should note that not all criteria in Table 2 below need to apply for the diagnosis of DKA and clinical judgment should also be taken into consideration Due to its mechanism of action Empagliflozin Jardiance may potentially modify the clinical presentation of DKA which may occur at lower plasma glucose levels
If any AESIs occur they will be reported to the Sponsor and Boehringer Ingelheim using the same procedure as reporting Serious Adverse Events SAEs
Reporting Procedures for Serious Adverse Events- All SAEs will be reported internally to the Sponsor within one working day 24 hours of discovery or notification of the event The SAE will be reported using appropriate forms and the immediate report will be made in writing and shall be followed by a detailed written report of the event Additional information can be provided if requested to the Sponsor and main Research Ethics Committee REC eg in the event of a death The Principal Investigator or another delegated physician is responsible for the review and sign off of the SAE or in their absence another member of the team in order to avoid a delay
The Sponsor will perform an initial check of the information and ensure that it is reviewed at the next RD management meeting All SAE information must be recorded on an SAE form and sent to the Sponsor Additional information received for a case follow-up or corrections to the original case needs to be detailed on a new SAE form and sent to the Sponsor
The Sponsor will report all SUSARs to the MHRA and the REC concerned Fatal or life-threatening SUSARs must be reported within 7 days and all other SUSARs within 15 days The Chief Investigator will inform all investigators concerned of relevant information about SUSARs that could adversely affect the safety of participants The Sponsor will use the Summary of Product Characteristics SmPC as the Reference Safety Information RSI when determining the expectedness of any untoward medical occurrences and thus SAESUSAR reporting
In addition to the expedited reporting above the Chief Investigator will submit once a year throughout the clinical study or on request a Developmental Safety Update Report DSUR to the MHRA and REC The PI will inform all investigators concerned of relevant information about SUSARs that could adversely affect the safety of participants
STATISTICS Description of Statistical Methods- Participants recruited to the study will be compared within and by treatment group For the latter each active treatment arm whether medication medication and energy restriction diet or placebo and energy restriction diet will be compared against the placebo only arm Baseline variables will be presented by arm using N for categorical variables and mean standard deviation or median interquartile range as appropriate for continuous variables
The primary outcome is change in appetite hormones from baseline to week 24 within and between treatment groups AUC values for appetite hormone measurements at baseline and 24 weeks will be calculated using the trapezoidal rule Paired t-tests or equivalent non-parametric tests will be used to analyse the change in appetite hormones within individual treatment groups One way analysis of variance will be used to calculate mean changes in AUC from baseline to 24 weeks by treatment group Adjusted treatment effects will be calculated via linear regression analysis or similarly appropriate methods to compare each treatment against placebo Models will include a categorical treatment variable and will be adjusted for stratification factors age and BMI as well as baseline AUC value Changes in appetite hormones from baseline to weeks 2 6 and 12 will also be analysed using the same methods however will represent hypothesis generating analyses only Similarly overall changes in appetite hormones over time will be analysed using multilevel models adjusted for stratification factors
The analysis for the primary outcome will be repeated for secondary endpoints changes in resting energy expenditure weight and body composition physical activity and biochemical parameters from baseline
All analyses of outcome data will be carried out on a complete case basis so only those patients with complete data will be included in the analysis Intention to treat and per protocol analyses will be carried out as sensitivity analyses using multiple imputation and including only those who remain on their treatment regimen for the duration of the study respectively
The Number of Participants- The power calculation is based on the primary outcome of change in appetite hormones and a standard deviation of area under the curve of 962pgml of total PYY based on a study looking at the influence of resistance and aerobic exercise on hunger and circulating levels of total PYY in healthy males To detect a minimum clinically significant difference of 120pgml in area under the curve of total PYY between groups we will require 15 participants in each of the four arms with 80 power and 2-sided alpha of 17 This will allow three comparisons between arms To account for up to 20 dropout 19 participants will be required in each arm therefore 76 participants will be recruited in total
The Level of Statistical Significance- Statistical significance will be taken at the level of p005 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES The study will be conducted in accordance with the current approved protocol International Conference on Harmonisation Good Clinical Practice relevant regulations and standard operating procedures SOPs
Regular monitoring will be performed according to International Conference on Harmonisation Good Clinical Practice Data will be evaluated for compliance with the protocol and accuracy in relation to source documents Following written standard operating procedures the monitors will verify that the clinical trial is conducted and data are generated documented and reported in compliance with the protocol Good Clinical Practice and the applicable regulatory requirements
STUDY GOVERNANCE The study will be conducted in accordance with the Research Governance Framework for Health and Social Care ICH GCP and the Data Protection Act The Sponsor responsible for checking research governance arrangements will be the University of Leicester A Trial Steering Committee TSC Data Safety Monitoring Committee DSMC and Project Management Committee PMC will be set up to support the running of the study
SGLT-2 inhibitors are a new class of glucose-lowering drugs for the management of type 2 diabetes which reduce plasma glucose levels by increasing urinary glucose excretion UGE by up to 60-80g 240-320 kilo Calories per day SGLT-1 inhibitors and combined SGLT-1 and -2 inhibitors are currently in development
Several SGLT-2 inhibitors are commercially available and licensed for use in the UK including dapagliflozin canagliflozin and Empagliflozin Jardiance They all lower glycated haemoglobin HbA1c effectively compared with placebo mean difference vs placebo -066 95 Confidence Interval -073 to -058 They also result in weight loss of approximately 18kg compared with placebo and in combination with other oral hypoglycaemic medications Some of this weight loss can be attributed to fluid loss due to osmotic diuresis from UGE Weight is lost from both subcutaneous and visceral stores of adipose tissue
Phase II studies have shown that the highly selective and potent SGLT-2 inhibitor Empagliflozin Jardiance results in significant reductions in HbA1c level after 12 weeks of therapy compared with placebo HbA1c 04-06 reduction with 5-25mg daily dose p00001 and reduction was similar to that seen with metformin Weight loss of between 181-233kg was also achieved depending on Empagliflozin Jardiance dose along with reduction in fasting plasma glucose FPG Similar improvements in HbA1c weight and FPG have been seen in phase III trials with Empagliflozin Jardiance both as monotherapy and in combination with metformin sulphonylureas or insulin
Empagliflozin Jardiance is licensed in the UK for use in type 2 diabetes management In this study we will be using Empagliflozin Jardiance according to its licensed indications and dosage The commonest known side-effects include urinary tract and genital mycotic infections which are more frequent in women than men and generally mild in severity Dehydration and postural hypotension may occur due to volume depletion and modest lowering of blood pressure Increased urinary frequency may also occur Increased risk of hypoglycaemia is observed when Empagliflozin Jardiance is combined with sulphonylureas or insulin
Weight loss from increased UGE and net energy loss with SGLT-2 inhibitors is less than expected as shown by studies in patients with type 2 diabetes Endogenous glucose production is markedly increased with shifting of substrate utilisation from carbohydrate to lipid
Up to 90g of glucose are excreted per day with Empagliflozin Jardiance which equates to 360 kilo Calories per day lost by glycosuria A 90 week study of patients with type 2 diabetes treated with Empagliflozin Jardiance 25mg daily showed that average weight loss was 3242kg representing a calorie deficit of 51 kilo Calories day interquartile range 112 This was 2941 of the expected loss of 11331kg predicted by glycosuria of 206 kilo Calories per day using a validated mathematical model httpbwsimulatorniddknihgov An increase in daily calorie intake of 269 kilo Calories day Inter Quartile Range 258 and daily energy expenditure appear to be the adaptive responses due to Empagliflozin Jardiance therapy and the combination of SGLT-2 inhibitors and calorie restriction has been recommended by the authors of this study
Appetite stimulation resulting in increased energy intake may be the underlying mechanism for this weight loss deficit Furthermore glucagon response is increased by SGLT-2 inhibition using Empagliflozin Jardiance and dapagliflozin
Appetite hormones such as peptide Y-Y PYY and ghrelin are important in the control of appetite and weight regulation They are secreted from intestinal L cells which are found in the distal small intestine Ghrelin which stimulates hunger has been shown to increase with weight loss and energy restriction diets Glucagon-like peptide 1 GLP-1 is another hormone which is involved in the regulation of appetite and satiety along with other glucose homeostatic effects
There are no studies that have investigated the impact of SGLT-2 inhibitors on appetite hormones and effect on body composition It is essential to understand these mechanisms in order to maximize the weight loss achievable with these agents They may need to be combined with appropriate dietary measures such as energy restriction diets and weight-lowering or weight-neutral hypoglycaemic therapies for optimal clinical benefit The aim of our study is to explore the relationship between appetite hormones and Empagliflozin Jardiance in order to understand the underlying mechanisms for observed weight loss which does not equate with that predicted for these agents
Primary Objective
The aim of this study is to investigate the cause for the discrepancy in predicted and observed weight loss with Empagliflozin Jardiance by measuring appetite regulation
Secondary Objectives
To determine the effects of Empagliflozin Jardiance on resting energy expenditure and change in total body weight and body composition
Study End Points
The primary endpoint is effect on appetite hormones specifically total PYY with Empagliflozin Jardiance after treatment for 24 weeks
Secondary endpoints which are exploratory are effect on
i Appetite hormones ghrelin and GLP-1 and appetite perception ii Total body weight and change in body composition fat and fat free mass iii Resting energy expenditure iv Physical activity v Change in blood and urine biochemical parameters
This study is a randomised double-blind placebo-controlled trial conducted over 24 weeks in male and postmenopausal female participants with type 2 diabetes on lifestyle control or stable metformin dose only to compare the effects of Empagliflozin Jardiance on appetite and weight regulation compared with placebo and energy restriction diet
Participants will be randomised to one of four arms at baseline- i Empagliflozin Jardiance 25mg once daily ii Empagliflozin Jardiance 25mg once daily and energy restriction diet iii Placebo iv Placebo and energy restriction diet Participants will be stratified for age and BMI STUDY CONDUCT Participant Withdrawal- Each participant has the right to withdraw from the study at any time without needing to give a reason The investigator may discontinue a participant from the study at any time if considered necessary The reason for withdrawal will be recorded in the CRF and medical records If the participant is withdrawn due to an adverse event the investigator will arrange for follow-up visits or telephone calls until the adverse event has resolved or stabilised The duration of safety follow-ups will be at least five half-lives of the study medication The half-life of Empagliflozin Jardiance is 124 hours thus the duration of safety follow-ups will be rounded up to be at least 72 hours or 3 days The participant will be withdrawn from the study if they lose capacity and data collected up to that point will be used for analysis As analysis will be on an intention-to-treat basis there will be analysis of all data of participants receiving study medication eg most safety analyses and data will be admitted to the database even after the participant has withdrawn from the study
Source Data- Source documents are original documents data and records from which participants CRF data will be obtained These include but are not limited to hospital records from which medical history and previous and concurrent medication will be summarised into the CRF clinical and office charts laboratory and pharmacy records diaries microfiches radiographs and correspondence On all study-specific documents other than the signed consent the participant will be referred to by the study participant numbercode only and not by name
Drug Management- The licensed product Empagliflozin Jardiance will be handled according to the University Hospitals of Leicester pharmacy in-house protocols
Compliance with Study Treatment- The participants will be instructed to return all unused or part-used medication and packaging from used medication at each visit The Investigator may withdraw the participants if they consider dose compliance is unsatisfactory
Concomitant Medication- Throughout the study Investigators will be able to prescribe any concomitant medications or treatments deemed necessary to provide adequate supportive care except for those listed in the exclusion criteria If these are required the participant will be withdrawn Any medication other than the study medication taken during the study will be recorded in the CRF Contraindicated medications during the study will include any other glucose-lowering therapies apart from metformin Loop diuretic therapy will also be contraindicated As study drug Empagliflozin Jardiance placebo and metformin do not cause hypoglycaemia participants will not be expected to perform home blood glucose monitoring during the study
SAFETY REPORTING Expected Serious Adverse EventsReactions SAE- The most common adverse events seen with Empagliflozin Jardiance are urinary tract and mycotic fungal infections eg balanitis and volume depletion leading to dehydration postural hypotension and dizziness If these events lead to hospitalisation of the participant they will require immediate reporting to the study team Otherwise they will be treated as an AE and need reporting to the study team within 2 working days
Abnormalities of renal and liver function will also be closely monitored as part of the usual study visits and any significant clinical deterioration in renal andor liver function will be reported as an SAE A serious deterioration in renal function to be classified as an SAE will be a reduction in eGFR to less than 30mlmin173m2 A serious deterioration in liver function will be classified as an SAE if ALT Alanine aminotransferase or AST Aspartate aminotransferase is 3 x greater than the upper limit of normal
Ketoacidosis and Diabetic Ketoacidosis DKA have recently been reported as a possible serious SAE occurring with SGLT-2 inhibitor use by the US Food and Drugs Administration Participants will be closely monitored for the development of this SAE and will be advised to seek medical attention immediately if they experience symptoms such as difficulty breathing nausea vomiting abdominal pain confusion unusual fatigue or sleepiness anorexia excessive thirst dehydration low food intake weight loss infection poor control of diabetes andor only moderately increased glucose levels
In patients where DKA is suspected or diagnosed treatment with SGLT-2 inhibitors will be discontinued immediately Restarting SGLT-2 inhibitor treatment in patients with previous DKA while on SGLT-2 inhibitor treatment is not recommended unless another clear precipitating factor is identified and resolved Treatment will also be interrupted in patients who are hospitalised for major surgical procedures or acute medical illnesses In both cases treatment with SGLT-2 inhibitors may be restarted once the patients condition has stabilised and only once the necessary safety assessments have been performed The decision to stop or interrupt and subsequently re-start the study treatment Empagliflozin Jardiance will be documented in the participants medical notes Any decisions regarding the withdrawal of participants from the study will be made by the study clinician and Principal Investigator
Suspected Unexpected Serious Adverse Reactions SUSAR A serious adverse reaction the nature or severity of which is not consistent with the Summary of Product Characteristics for Empagliflozin Jardiance will be reported as a SUSAR
Adverse Events of Special Interests AESI Adverse Events of Special Interests AESI
Decreased renal function creatinine value shows a 2 fold increase from baseline and is above ULN
Hepatic injury defined by the following alterations of liver parameters after randomization at visit 1-
Elevation of AST andor ALT3 fold ULN combined with an elevation of total bilirubin2 fold ULN measured in the same blood draw sample
Isolated elevation of AST andor ALT5 fold ULN irrespective of any bilirubin elevation
Diabetic Ketoacidosis DKA o DKA is defined by the diagnostic criteria in the table below and as defined by the American Diabetes Association ADA
Investigators should note that not all criteria in Table 2 below need to apply for the diagnosis of DKA and clinical judgment should also be taken into consideration Due to its mechanism of action Empagliflozin Jardiance may potentially modify the clinical presentation of DKA which may occur at lower plasma glucose levels
If any AESIs occur they will be reported to the Sponsor and Boehringer Ingelheim using the same procedure as reporting Serious Adverse Events SAEs
Reporting Procedures for Serious Adverse Events- All SAEs will be reported internally to the Sponsor within one working day 24 hours of discovery or notification of the event The SAE will be reported using appropriate forms and the immediate report will be made in writing and shall be followed by a detailed written report of the event Additional information can be provided if requested to the Sponsor and main Research Ethics Committee REC eg in the event of a death The Principal Investigator or another delegated physician is responsible for the review and sign off of the SAE or in their absence another member of the team in order to avoid a delay
The Sponsor will perform an initial check of the information and ensure that it is reviewed at the next RD management meeting All SAE information must be recorded on an SAE form and sent to the Sponsor Additional information received for a case follow-up or corrections to the original case needs to be detailed on a new SAE form and sent to the Sponsor
The Sponsor will report all SUSARs to the MHRA and the REC concerned Fatal or life-threatening SUSARs must be reported within 7 days and all other SUSARs within 15 days The Chief Investigator will inform all investigators concerned of relevant information about SUSARs that could adversely affect the safety of participants The Sponsor will use the Summary of Product Characteristics SmPC as the Reference Safety Information RSI when determining the expectedness of any untoward medical occurrences and thus SAESUSAR reporting
In addition to the expedited reporting above the Chief Investigator will submit once a year throughout the clinical study or on request a Developmental Safety Update Report DSUR to the MHRA and REC The PI will inform all investigators concerned of relevant information about SUSARs that could adversely affect the safety of participants
STATISTICS Description of Statistical Methods- Participants recruited to the study will be compared within and by treatment group For the latter each active treatment arm whether medication medication and energy restriction diet or placebo and energy restriction diet will be compared against the placebo only arm Baseline variables will be presented by arm using N for categorical variables and mean standard deviation or median interquartile range as appropriate for continuous variables
The primary outcome is change in appetite hormones from baseline to week 24 within and between treatment groups AUC values for appetite hormone measurements at baseline and 24 weeks will be calculated using the trapezoidal rule Paired t-tests or equivalent non-parametric tests will be used to analyse the change in appetite hormones within individual treatment groups One way analysis of variance will be used to calculate mean changes in AUC from baseline to 24 weeks by treatment group Adjusted treatment effects will be calculated via linear regression analysis or similarly appropriate methods to compare each treatment against placebo Models will include a categorical treatment variable and will be adjusted for stratification factors age and BMI as well as baseline AUC value Changes in appetite hormones from baseline to weeks 2 6 and 12 will also be analysed using the same methods however will represent hypothesis generating analyses only Similarly overall changes in appetite hormones over time will be analysed using multilevel models adjusted for stratification factors
The analysis for the primary outcome will be repeated for secondary endpoints changes in resting energy expenditure weight and body composition physical activity and biochemical parameters from baseline
All analyses of outcome data will be carried out on a complete case basis so only those patients with complete data will be included in the analysis Intention to treat and per protocol analyses will be carried out as sensitivity analyses using multiple imputation and including only those who remain on their treatment regimen for the duration of the study respectively
The Number of Participants- The power calculation is based on the primary outcome of change in appetite hormones and a standard deviation of area under the curve of 962pgml of total PYY based on a study looking at the influence of resistance and aerobic exercise on hunger and circulating levels of total PYY in healthy males To detect a minimum clinically significant difference of 120pgml in area under the curve of total PYY between groups we will require 15 participants in each of the four arms with 80 power and 2-sided alpha of 17 This will allow three comparisons between arms To account for up to 20 dropout 19 participants will be required in each arm therefore 76 participants will be recruited in total
The Level of Statistical Significance- Statistical significance will be taken at the level of p005 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES The study will be conducted in accordance with the current approved protocol International Conference on Harmonisation Good Clinical Practice relevant regulations and standard operating procedures SOPs
Regular monitoring will be performed according to International Conference on Harmonisation Good Clinical Practice Data will be evaluated for compliance with the protocol and accuracy in relation to source documents Following written standard operating procedures the monitors will verify that the clinical trial is conducted and data are generated documented and reported in compliance with the protocol Good Clinical Practice and the applicable regulatory requirements
STUDY GOVERNANCE The study will be conducted in accordance with the Research Governance Framework for Health and Social Care ICH GCP and the Data Protection Act The Sponsor responsible for checking research governance arrangements will be the University of Leicester A Trial Steering Committee TSC Data Safety Monitoring Committee DSMC and Project Management Committee PMC will be set up to support the running of the study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None