Ignite Creation Date:
2024-05-06 @ 1:15 AM
Last Modification Date:
2024-10-26 @ 11:01 AM
Study NCT ID:
NCT01761318
Status:
COMPLETED
Last Update Posted:
2016-05-05
First Post:
2012-12-20
Brief Title:
Effect of Liraglutide on Cardiovascular Endpoints in Diabetes Mellitus Type 2 Patients
Sponsor:
Leiden University Medical Center
Organization:
Leiden University Medical Center
Study Overview
Official Title:
Magnetic Resonance Assessment of Victoza Efficacy in the Regression of Cardiovascular Dysfunction In Type 2 Diabetes Mellitus
Status:
COMPLETED
Status Verified Date:
2016-05
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:
MAGNA VICTORIA
Brief Summary:
The most important cause of mortality amongst DM2 patients is cardiovascular disease An early finding of cardiovascular disease in DM2 and obesity is diastolic dysfunction Diastolic dysfunction is an independent predictor of mortality and has been shown to improve in patients on a low calorie diet The improvement of diastolic function was associated with a reduction in triglyceride accumulation in the heart and liver A relatively new widely prescribed therapeutic agent for DM2 patients is Liraglutide Victoza Liraglutide is a Glucagon Like Peptide - 1 homologue that improves glucose homeostasis and reduces blood pressure and body weight Next to the induction of weight loss which is potentially beneficial for cardiac function GLP-1 therapy might have a direct advantageous effect on the cardiovascular system However the effect of Liraglutide on cardiovascular function has not been investigated yet The investigators hypothesize that treatment of DM2 patients with Liraglutide is associated with improvement of cardiovascular function and a reduction of triglyceride accumulation in end-organs
Detailed Description:
1 INTRODUCTION AND RATIONALE
Type 2 diabetes mellitus is an endemic disease associated with obesity and a sedentary lifestyle In the year 2025 the prevalence of DM2 patients worldwide is expected to be 334 million In the year 2000 there were an estimated 29 million diabetes-related deaths worldwide Especially cardiovascular disease contributes for a great deal to the high mortality rates Diabetes patients have a two-fold excess risk for a wide range of vascular diseases independently of other risk factors making cardiovascular disease the leading cause of death of diabetes patients Therefore treatment of DM2 is focused on the prevention of cardiovascular disease and other diabetes related complications such as retinopathy neuropathy and nephropathy Unfortunately despite lifestyle advises glucose lowering therapy and co-treatment of other risk factors such as hypertension and dyslipidemia complication rates remain high Classical glucose lowering treatment strategies such as sulfonylurea derivatives and insulin ultimately can not control the disease partly because they participate in the vicious cycle of increasing body weight and insulin resistance A hopeful new therapeutic agent is the Glucagon Like Peptide -1 analogue Liraglutide Next to its glucose lowering effect it reduces body weight resulting in increased insulin sensitivity The group of GLP-1 analogues are therefore widely prescribed nowadays However the effect on the cardiovascular system has not been investigated yet Since cardiovascular disease is the major threat for the DM2 patient the effect of this new drug on the cardiovascular system is a very important issue Interestingly a cardio-protective effect from Liraglutide can be expected on the basis of both the associated weight loss and because of a direct protective effect on the heart The investigators hypothesize that treatment with Liraglutide improves cardiac function in DM2 patients The pathogenesis of cardiovascular disease in DM2 is rather complex and multifactorial Ultimately most patients develop myocardial infarction and or heart failure Often DM2 patients already have subclinical signs of cardiac dysfunction before DM2 is recognized the main early sign being diastolic dysfunction Diastolic dysfunction is a strong predictor of mortality The subclinical characteristics of cardiac dysfunction are highly associated with a condition called the metabolic syndrome The metabolic syndrome consists of the existence of three out of five of the following risk factors 1 elevated waist circumference 2 elevated triglycerides 3 reduced HDL-C 4 elevated blood pressure 5 elevated fasting blood glucose including diabetic-range elevated blood glucose level With these criteria most patients with diabetes meet the criteria for the metabolic syndrome A key element in the pathogenesis of the metabolic syndrome might be ectopic fat deposition the earliest sign of the syndrome being visceral adiposity Next to visceral adiposity there is significant deposition of ectopic fat stores in the liver heart skeletal muscle and kidney Triglyceride accumulation in the cardiomyocyte is called myocardial steatosis Studies performed by our group have proven that caloric restriction results in a reduction in myocardial steatosis and improvement of diastolic function Hence myocardial steatosis and associated cardiac dysfunction seem to be reversible as is the case for hepatic steatosis The putative mechanism of steatosis resulting in cardiac dysfunction is thought to be explained by a phenomenon called lipotoxicity Altered substrate metabolism and insulin resistance of cardiomyocytes may also play an important role in the pathogenesis of cardiac dysfunction in obesity and DM2 Systemic and cardiac insulin resistance was proven to be associated with increased production of toxic lipids such as diacylglycerol and ceramide The ultimate treatment for obesity and diabetes related cardiac disease seems to be weight loss However lifestyle intervention programs have repeatedly been unsuccessful to have a sustained long term effect Liraglutide is characterized as a long-acting human GLP-1 analogue as it shows 97 homology with the amino acid sequence of human GLP-1 The phase 3a program for Liraglutide encompasses five clinical trials in which Liraglutide treatment was studied in each stage of the treatment cascade for type 2 diabetes mellitus In five studies Liraglutide was compared directly to standard treatment The phase 3a clinical development program included 3978 exposed patients with DM2 investigated the efficacy and tolerability of Liraglutide 12 or 18 mg daily n 2735 as monotherapy and in combination with various oral antidiabetic drugs The phase 3a studies showed HBA1C reductions of 1-15 and fasting plasma glucose reductions of 083 - 239 mmolL In addition weight reduction was consistent Liraglutide 18 mg as monotherapy was accompanied by a mean weight loss of 25 kg over a 52-week period A substudy of two phase 3a trials showed that the weight loss caused by Liraglutide is predominantly caused by a reduction in fat mass the visceral fat compartment was reduced by 16 from baseline during 26 weeks of Liraglutide 12 mg daily Recent experimental data suggest GLP-1 and its analogues to have direct effects on the heart In studies on rat heart the size of an infarct was diminished by more than 50 by an infusion of GLP-1 Post conditioning efficacy of GLP-1 was also demonstrated in an ex vivo rat heart Exendin-4 was shown to diminish infarct size by approximately 56 and 39 respectively in rat global and pig focal models of heart ischemia The GLP-1 receptor GLP-1R is present in the cardiomyocytes as well as in the endothelium and smooth muscle cells of myocardial vasculature The cell death effector mechanisms targeted by the GLP-1R appear to be mitochondrial permeability transition and apoptosis Animal studies have suggested myocardial contractility improvement after GLP-1 administration For instance dogs with dilated cardiomyopathy treated with GLP-1 for 48 h showed strong improvements in myocardial contractility and cardiac output GLP-1 infusion was associated with increased myocardial glucose uptake suggesting ameliorated insulin sensitivity of the cardiomyocytes In a few small clinical studies GLP-1 was infused to patients after PCI for approximately 72 h and to patients selected for elective coronary artery bypass grafting from 12 h before to 48 h after the surgery The latter group showed an improved metabolic profile but no hemodynamic change In contrast a left ventricular ejection fraction LVEF increase from 29 to 39 was found in the former study as well as in a study of 12 diabetic overweight heart failure patients New York Heart Association class IIIIV LVEF 40 given GLP-1 infusion for 5 weeks at the end of the treatment these patients showed an increased LVEF cardiac output and improved scores in a life quality questionnaire A number of laboratory studies have suggested a vasorelaxant effect of GLP-1 No pressor effect has been found associated with GLP-1 treatment in studies on diabetic patients In fact a decrease of both systolic and diastolic blood pressure values was noted in DM2 patients after an 82-week exenatide trial 33 in a manner correlated to weight loss Recent experiments unpublished data have shown that the GLP-1 analogue exendin - 4 can protect against atherosclerosis and non-alcoholic steatohepatitis NASH in APOE 3 - LeidenCETP mice on a western diet probably due to decreased hepatic CETP expression as well as reduced monocyte recruitment from the circulation to the vessel wall In addition hepatic steatosis was improved by a GLP-1 receptor agonist in mice So far no dedicated clinical studies have been performed to systematically study the effects of GLP-1 analogues on cardiovascular function Given the consistency of the results from animal experiments and clinical observations this area appears ripe for clinical studies Beneficial effects on cardiovascular endpoints will be crucial to consolidate the therapeutic profile of Liraglutide Although large scale studies on cardiovascular endpoints are underway an attractive option is to perform small scale short-term studies with advanced cardiovascular imaging techniques Thereby gaining insight in what way GLP-1 therapy affects the cardiovascular system Advanced cardiovascular magnetic resonance imaging and spectroscopy MRIS enables to assess effects of interventions in relatively small groups of patients in a limited period of time As these cardiovascular parameters are strong and clinically relevant predictors of cardiovascular events measurements of these parameters with MRIS are worthwhile Our research group has developed advanced cardiovascular MRI and MRS techniques and algorithms and gained extended experience in the field of DM2 related cardiac function and lipid metabolism
2 RECRUITMENT AND SCREENING PROCEDURE OF STUDY POPULATION
Patients will be recruited from the outpatient clinics of the Leiden University Medical Center general practitioners local hospitals and by advertisement Patients own physicists will be asked to point eligible patients to the opportunity of study participation If interested patients will be informed by the principal investigator Patients will be given oral and written explanation about the study After a consideration time of two weeks patients are asked to give written acknowledgement of informed consent to participate Then a medical screening will take place Screening will be performed after an overnight fast of at least 12 hours The screening will consist of a medical history physical examination consisting of measurement of height body weight heart rate blood pressure and examination of thorax and abdomen Furthermore laboratory tests and rest-ECG will be performed If the patient is eligible- and willing to participate in the study and has signed the informed consent the patient will be included Informed consent must be obtained before any trial related activities take place After inclusion in the study protocol the patients treating physician and general practitioner will be notified Although the patients are free to leave the study at any time it will be attempted to recruit patients who are likely to continue the study to completion
3 SAMPLE SIZE CALCULATION
Because of the absence of data on the effects of GLP-1 in DM2 patients without heart failure it is hard to calculate the sample size needed to detect differences between myocardial function at 26 weeks between active treatment and controls Clinically relevant differences and standard deviations of two studies were chosen to generate data for the sample size calculation The data we used to incorporate the precision of MRI assessment of cardiac function was generated by a study performed by our group with pioglitazone vs metformin on cardiac function parameters To estimate the effect of GLP-1 therapy on cardiac function we only have data of a pilot study with eight DM2 patients with heart failure Calculations for diastolic function parameters were based on the early deceleration peak and for systolic function on the basis of ejection fraction With a power of 90 and alfa 005 groups varying from 9 to 17 patients will be needed In a comparable trial the drop-out rate was 10 Taken into consideration that the population studied will have a significant better systolic function than the heart failure patients studied by Sokos et al differences may be smaller In conclusion investigators estimate to be able to detect a clinically relevant significant result with 90 power and alfa 005 with 25 patients in each group
4 USE OF CO-INTERVENTION
Patients should continue to use the oral glucose lowering medicament metformin during the study For glycaemic control after initiation of the study drug the current clinical guideline will be followed Excluded concomitant therapy thiazolidinediones other GLP-1 analogues or DPP-IV inhibitors fibrates prednisone cytostatic and antiretroviral therapy
Permitted concomitant medication any other medication required including SU derivatives insulin antihypertensive agents and incidental analgesic and antibiotic therapy Glycaemic management during study the will be performed as described in appendix 1 To avoid the potential risk of hypoglycaemia a rigorous monitoring and therapy adjustment schedule will be applied which will prevent risk of hypoglycemia to a great extent In addition patients will be instructed how to recognize and manage a hypo or hyperglycaemic episode Appropriate individualized adjustments will be made in the unlikely case of a hypo or hyperglycaemic episode Routine self-measurement of blood glucose by the study participants will be performed once a week In addition patients with insulin will be instructed to perform routine self-measurement of blood glucose more frequently when study medication and or insulin dosage is titrated see appendix 1
Furthermore patients are asked not to change their diet or level of physical activity during the study period and adequate contraception is obligatory for study participation
5 RANDOMIZATION BLINDING AND TREATMENT ALLOCATION
After the medical screening and mutual agreement of participation in the study patients will be randomized by block randomization stratified 11 for gender and insulin use A randomization schedule will be prepared by the research pharmacist who is employee at the Department of Clinical Pharmacy Coded and sealed envelopes for each participant will be kept at the department of Radiology In case of safety issues the sealed envelopes are readily available to the principal investigator and project leader In case of a serious adverse event - or a medical emergency requiring knowledge of the study medication - the randomization code will be broken In order to ensure that in medical emergencies the study participation of the patient is apparent each patient will receive a patient file in the electronic patient registry In this personal file the study number of the patient including the procedure for deblinding and notification of the investigators will be mentioned When the whole study is completed the randomization list will be provided to the principle investigator by the pharmacist
6 STUDY PROCEDURES
Withdrawal of individual subjects Patients can leave the study at any time for any reason if they wish to do so without any consequences The responsible investigator can also withdraw a subject if continuing participation is in his opinion deleterious for the subjects well being Patients can also be withdrawn in case of protocol violations and non-compliance When a subject withdraws from the study a medical examination will be performed In case of withdrawal because of a severe or serious adverse event appropriate laboratory tests or other special examinations will be performed Finally patients can be withdrawn from study participation if an incidental finding at the MRI examination - for example a malignancy - influences the ratio of justification versus risks benefits
Specific criteria for withdrawal not applicable
Replacement of individual subjects after withdrawal Patients will not be replaced after withdrawal
Follow-up of subjects withdrawn from treatment Follow-up of patients after withdrawal will be done by the treating physicist general practitioner in most cases Immediately after study withdrawal the treating physicist will be updated on the patients condition and laboratory results and whether the patient was in the control group or intervention group
Premature termination of the study In case of the incidence of three serious adverse events the study will be terminated prematurely and an independent committee will be asked to investigate the safety of the trial Furthermore the investigators will prematurely terminate the study when the number of subjects withdrawn from the study exceeds the number used for sample size calculation ie 16 individuals in total
7 ADVERSE EVENTS SERIOUS ADVERSE EVENTS and SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS
Adverse events AEs
Adverse events are defined as any undesirable experience occurring to a subject during a clinical trial whether or not considered related to the used medication or the infused drugs All adverse events reported spontaneously by the subject or observed by the investigator or hisher staff will be recorded on the adverse event data collection form The intensity of these adverse events will be graded by the investigator as follows
Mild Discomfort noted but no disruption of normal daily activity
Moderate Discomfort sufficient to reduce or affect normal daily activity
Severe Inability to work or perform daily activity All adverse events will be actively queried by asking the question Have you had any complaints since the last time we talkedmet at all visits All adverse events will be followed until they have abated or until a stable situation has been reached Depending on the event follow up may require additional tests or medical procedures as indicated
The chronicity of the event will be classified by the investigator on a three-item scale as defined below
Single occasion Single event with limited duration
Intermittent Several episodes of an event each of limited duration
Persistent Event that remains indefinitely For each adverse event the relationship to the used medication or infused drug definite probable possible unknown definitively not as judged by the investigator will be recorded as well as any actions undertaken in relation to the adverse event will be recorded The occurrence of an adverse event that is fatal life-threatening disabling or requires in-patient hospitalization or causes congenital anomaly will be described according to CHMP guidelines as suspected serious adverse events and will be notified in writing to the Medical Ethics Committee
Furthermore the investigators will copy Novo Nordisk when expediting SARs and SUSARs to competent authorities and will report all SARs related to Novo Nordisk product to Novo Nordisk The submission to Novo Nordisk must however be within day 15 from the investigator getting knowledge about a valid case no matter local timelines for reporting to the authorities All pregnancies in trial patients occurring during use of a Novo Nordisk product must be reported to Novo Nordisk
Serious Adverse Events SAEs
A serious adverse event is any untoward medical occurrence or effect that at any dose
results in death
is life threatening at the time of the event
requires hospitalization or prolongation of existing inpatients hospitalization
results in persistent or significant disability or incapacity
is a congenital anomaly or birth defect
Any other important medical event that may not result in death be life threatening or require hospitalization may be considered a serious adverse experience when based upon appropriate medical judgement the event may jeopardize the subject or may require an intervention to prevent one of the outcomes listed above
The sponsor will report the SAEs to the accredited METC that approved the protocol within 15 days after the sponsor has first knowledge of the serious adverse reactions
SAEs that result in death or are life threatening should be reported expedited The expedited reporting will occur not later than 7 days after the responsible investigator has first knowledge of the adverse reaction This is for a preliminary report with another 8 days for completion of the report
Suspected Unexpected Serious Adverse Reactions SUSARs
Unexpected adverse reactions are SUSARs if the following three conditions are met
1 the event must be serious
2 there must be a certain degree of probability that the event is a harmful and an undesirable reaction to the medicinal product under investigation regardless of the administered dose
3 the adverse reaction must be unexpected that is to say the nature and severity of the adverse reaction are not in agreement with the product information as recorded in
Summary of Product Characteristics SPC for an authorized medicinal product
Investigators Brochure for an unauthorized medicinal product The sponsor will report expedited all SUSARs to the competent authorities in other Member States according to the requirements of the Member States
The expedited reporting will occur not later than 15 days after the sponsor has first knowledge of the adverse reactions For fatal or life threatening cases the term will be maximal 7 days for a preliminary report with another 8 days for completion of the report
SAEs need to be reported till end of study within the Netherlands as defined in the protocol
8 STATISTICAL ANALYSIS
Primary and secondary study parameters
The study endpoints will be analyzed according to intention-to-treat principles All endpoint parameters are continuous variables Data will be calculated as mean SD median percentile range according to nature and distribution of the variable Within group changes from baseline will be tested with independent paired t-test or Wilcoxon signed-rank test Between group differences will be compared after 26 weeks between Liraglutide and control The endpoints will be analyzed using a linear regression model with gender age BMI and HBA1C as covariates For the covariates age BMI and HbA1c in the primary analysis the baseline value will be used The data set for the primary analysis will include data from all subjects with at least one post-baseline measurement Analysis will be performed with SPSS A 2-sided significance level of p 005 will be applied
9 REGULATION STATEMENT
The study will be conducted according to the principles of the Declaration of Helsinki as amended in Tokyo Venice and Hong Kong Somerset West and Edinburgh and in accordance with the Guideline for Good Clinical Practice CPMPICH13595 - 17th July 1996
10 ADMINISTRATIVE ASPECTS MONITORING AND PUBLICATION
Handling and storage of data and documents
Study participants are provided a study name of the letter MV followed by the number of enrollment 1-50 The study name is coupled to a randomly chosen seven - digit study number The study number will be used to register the participant in the Electronic Patient Registry of the LUMC This file will be used as the general patient record as well as collection of routine laboratory measurements needed for clinical and study treatment The MRI images will be filed under this registry so that anonymity will be safeguarded The subject identification code list will be stored by the principal investigator and will only be accessible by the principal investigator and project leader The data extracted from the study file in the Electronic Patient Registry and from the MRI images will be saved in an SPSS file From this file the true identity of the study participants can not be discovered The data will be stored for fifteen years The blood samples will be frozen and stored anonymously using the above mentioned study name and study number For ad hoc laboratory tests of inflammatory endocrine and other biomarkers blood samples will be kept for a maximum period of three years The blood samples are solely accessible by the investigator team
In order to ensure that in medical emergencies the study participation of the patient is apparent each patient will receive a patient file in the electronic patient registry In this personal file the investigator will mention the study number of the patient including the procedure for de-blinding and notification of the investigators In this file the signed Informed Consent form of the patient will be stored
Public disclosure and publication policy The data analysis will be performed by the investigators Novo Nordisk has no role in data analysis and or publication of the results of the trial in peer reviewed papers The results of the study will be submitted to peer reviewed papers also in case the hypothesis has not been proven
Type 2 diabetes mellitus is an endemic disease associated with obesity and a sedentary lifestyle In the year 2025 the prevalence of DM2 patients worldwide is expected to be 334 million In the year 2000 there were an estimated 29 million diabetes-related deaths worldwide Especially cardiovascular disease contributes for a great deal to the high mortality rates Diabetes patients have a two-fold excess risk for a wide range of vascular diseases independently of other risk factors making cardiovascular disease the leading cause of death of diabetes patients Therefore treatment of DM2 is focused on the prevention of cardiovascular disease and other diabetes related complications such as retinopathy neuropathy and nephropathy Unfortunately despite lifestyle advises glucose lowering therapy and co-treatment of other risk factors such as hypertension and dyslipidemia complication rates remain high Classical glucose lowering treatment strategies such as sulfonylurea derivatives and insulin ultimately can not control the disease partly because they participate in the vicious cycle of increasing body weight and insulin resistance A hopeful new therapeutic agent is the Glucagon Like Peptide -1 analogue Liraglutide Next to its glucose lowering effect it reduces body weight resulting in increased insulin sensitivity The group of GLP-1 analogues are therefore widely prescribed nowadays However the effect on the cardiovascular system has not been investigated yet Since cardiovascular disease is the major threat for the DM2 patient the effect of this new drug on the cardiovascular system is a very important issue Interestingly a cardio-protective effect from Liraglutide can be expected on the basis of both the associated weight loss and because of a direct protective effect on the heart The investigators hypothesize that treatment with Liraglutide improves cardiac function in DM2 patients The pathogenesis of cardiovascular disease in DM2 is rather complex and multifactorial Ultimately most patients develop myocardial infarction and or heart failure Often DM2 patients already have subclinical signs of cardiac dysfunction before DM2 is recognized the main early sign being diastolic dysfunction Diastolic dysfunction is a strong predictor of mortality The subclinical characteristics of cardiac dysfunction are highly associated with a condition called the metabolic syndrome The metabolic syndrome consists of the existence of three out of five of the following risk factors 1 elevated waist circumference 2 elevated triglycerides 3 reduced HDL-C 4 elevated blood pressure 5 elevated fasting blood glucose including diabetic-range elevated blood glucose level With these criteria most patients with diabetes meet the criteria for the metabolic syndrome A key element in the pathogenesis of the metabolic syndrome might be ectopic fat deposition the earliest sign of the syndrome being visceral adiposity Next to visceral adiposity there is significant deposition of ectopic fat stores in the liver heart skeletal muscle and kidney Triglyceride accumulation in the cardiomyocyte is called myocardial steatosis Studies performed by our group have proven that caloric restriction results in a reduction in myocardial steatosis and improvement of diastolic function Hence myocardial steatosis and associated cardiac dysfunction seem to be reversible as is the case for hepatic steatosis The putative mechanism of steatosis resulting in cardiac dysfunction is thought to be explained by a phenomenon called lipotoxicity Altered substrate metabolism and insulin resistance of cardiomyocytes may also play an important role in the pathogenesis of cardiac dysfunction in obesity and DM2 Systemic and cardiac insulin resistance was proven to be associated with increased production of toxic lipids such as diacylglycerol and ceramide The ultimate treatment for obesity and diabetes related cardiac disease seems to be weight loss However lifestyle intervention programs have repeatedly been unsuccessful to have a sustained long term effect Liraglutide is characterized as a long-acting human GLP-1 analogue as it shows 97 homology with the amino acid sequence of human GLP-1 The phase 3a program for Liraglutide encompasses five clinical trials in which Liraglutide treatment was studied in each stage of the treatment cascade for type 2 diabetes mellitus In five studies Liraglutide was compared directly to standard treatment The phase 3a clinical development program included 3978 exposed patients with DM2 investigated the efficacy and tolerability of Liraglutide 12 or 18 mg daily n 2735 as monotherapy and in combination with various oral antidiabetic drugs The phase 3a studies showed HBA1C reductions of 1-15 and fasting plasma glucose reductions of 083 - 239 mmolL In addition weight reduction was consistent Liraglutide 18 mg as monotherapy was accompanied by a mean weight loss of 25 kg over a 52-week period A substudy of two phase 3a trials showed that the weight loss caused by Liraglutide is predominantly caused by a reduction in fat mass the visceral fat compartment was reduced by 16 from baseline during 26 weeks of Liraglutide 12 mg daily Recent experimental data suggest GLP-1 and its analogues to have direct effects on the heart In studies on rat heart the size of an infarct was diminished by more than 50 by an infusion of GLP-1 Post conditioning efficacy of GLP-1 was also demonstrated in an ex vivo rat heart Exendin-4 was shown to diminish infarct size by approximately 56 and 39 respectively in rat global and pig focal models of heart ischemia The GLP-1 receptor GLP-1R is present in the cardiomyocytes as well as in the endothelium and smooth muscle cells of myocardial vasculature The cell death effector mechanisms targeted by the GLP-1R appear to be mitochondrial permeability transition and apoptosis Animal studies have suggested myocardial contractility improvement after GLP-1 administration For instance dogs with dilated cardiomyopathy treated with GLP-1 for 48 h showed strong improvements in myocardial contractility and cardiac output GLP-1 infusion was associated with increased myocardial glucose uptake suggesting ameliorated insulin sensitivity of the cardiomyocytes In a few small clinical studies GLP-1 was infused to patients after PCI for approximately 72 h and to patients selected for elective coronary artery bypass grafting from 12 h before to 48 h after the surgery The latter group showed an improved metabolic profile but no hemodynamic change In contrast a left ventricular ejection fraction LVEF increase from 29 to 39 was found in the former study as well as in a study of 12 diabetic overweight heart failure patients New York Heart Association class IIIIV LVEF 40 given GLP-1 infusion for 5 weeks at the end of the treatment these patients showed an increased LVEF cardiac output and improved scores in a life quality questionnaire A number of laboratory studies have suggested a vasorelaxant effect of GLP-1 No pressor effect has been found associated with GLP-1 treatment in studies on diabetic patients In fact a decrease of both systolic and diastolic blood pressure values was noted in DM2 patients after an 82-week exenatide trial 33 in a manner correlated to weight loss Recent experiments unpublished data have shown that the GLP-1 analogue exendin - 4 can protect against atherosclerosis and non-alcoholic steatohepatitis NASH in APOE 3 - LeidenCETP mice on a western diet probably due to decreased hepatic CETP expression as well as reduced monocyte recruitment from the circulation to the vessel wall In addition hepatic steatosis was improved by a GLP-1 receptor agonist in mice So far no dedicated clinical studies have been performed to systematically study the effects of GLP-1 analogues on cardiovascular function Given the consistency of the results from animal experiments and clinical observations this area appears ripe for clinical studies Beneficial effects on cardiovascular endpoints will be crucial to consolidate the therapeutic profile of Liraglutide Although large scale studies on cardiovascular endpoints are underway an attractive option is to perform small scale short-term studies with advanced cardiovascular imaging techniques Thereby gaining insight in what way GLP-1 therapy affects the cardiovascular system Advanced cardiovascular magnetic resonance imaging and spectroscopy MRIS enables to assess effects of interventions in relatively small groups of patients in a limited period of time As these cardiovascular parameters are strong and clinically relevant predictors of cardiovascular events measurements of these parameters with MRIS are worthwhile Our research group has developed advanced cardiovascular MRI and MRS techniques and algorithms and gained extended experience in the field of DM2 related cardiac function and lipid metabolism
2 RECRUITMENT AND SCREENING PROCEDURE OF STUDY POPULATION
Patients will be recruited from the outpatient clinics of the Leiden University Medical Center general practitioners local hospitals and by advertisement Patients own physicists will be asked to point eligible patients to the opportunity of study participation If interested patients will be informed by the principal investigator Patients will be given oral and written explanation about the study After a consideration time of two weeks patients are asked to give written acknowledgement of informed consent to participate Then a medical screening will take place Screening will be performed after an overnight fast of at least 12 hours The screening will consist of a medical history physical examination consisting of measurement of height body weight heart rate blood pressure and examination of thorax and abdomen Furthermore laboratory tests and rest-ECG will be performed If the patient is eligible- and willing to participate in the study and has signed the informed consent the patient will be included Informed consent must be obtained before any trial related activities take place After inclusion in the study protocol the patients treating physician and general practitioner will be notified Although the patients are free to leave the study at any time it will be attempted to recruit patients who are likely to continue the study to completion
3 SAMPLE SIZE CALCULATION
Because of the absence of data on the effects of GLP-1 in DM2 patients without heart failure it is hard to calculate the sample size needed to detect differences between myocardial function at 26 weeks between active treatment and controls Clinically relevant differences and standard deviations of two studies were chosen to generate data for the sample size calculation The data we used to incorporate the precision of MRI assessment of cardiac function was generated by a study performed by our group with pioglitazone vs metformin on cardiac function parameters To estimate the effect of GLP-1 therapy on cardiac function we only have data of a pilot study with eight DM2 patients with heart failure Calculations for diastolic function parameters were based on the early deceleration peak and for systolic function on the basis of ejection fraction With a power of 90 and alfa 005 groups varying from 9 to 17 patients will be needed In a comparable trial the drop-out rate was 10 Taken into consideration that the population studied will have a significant better systolic function than the heart failure patients studied by Sokos et al differences may be smaller In conclusion investigators estimate to be able to detect a clinically relevant significant result with 90 power and alfa 005 with 25 patients in each group
4 USE OF CO-INTERVENTION
Patients should continue to use the oral glucose lowering medicament metformin during the study For glycaemic control after initiation of the study drug the current clinical guideline will be followed Excluded concomitant therapy thiazolidinediones other GLP-1 analogues or DPP-IV inhibitors fibrates prednisone cytostatic and antiretroviral therapy
Permitted concomitant medication any other medication required including SU derivatives insulin antihypertensive agents and incidental analgesic and antibiotic therapy Glycaemic management during study the will be performed as described in appendix 1 To avoid the potential risk of hypoglycaemia a rigorous monitoring and therapy adjustment schedule will be applied which will prevent risk of hypoglycemia to a great extent In addition patients will be instructed how to recognize and manage a hypo or hyperglycaemic episode Appropriate individualized adjustments will be made in the unlikely case of a hypo or hyperglycaemic episode Routine self-measurement of blood glucose by the study participants will be performed once a week In addition patients with insulin will be instructed to perform routine self-measurement of blood glucose more frequently when study medication and or insulin dosage is titrated see appendix 1
Furthermore patients are asked not to change their diet or level of physical activity during the study period and adequate contraception is obligatory for study participation
5 RANDOMIZATION BLINDING AND TREATMENT ALLOCATION
After the medical screening and mutual agreement of participation in the study patients will be randomized by block randomization stratified 11 for gender and insulin use A randomization schedule will be prepared by the research pharmacist who is employee at the Department of Clinical Pharmacy Coded and sealed envelopes for each participant will be kept at the department of Radiology In case of safety issues the sealed envelopes are readily available to the principal investigator and project leader In case of a serious adverse event - or a medical emergency requiring knowledge of the study medication - the randomization code will be broken In order to ensure that in medical emergencies the study participation of the patient is apparent each patient will receive a patient file in the electronic patient registry In this personal file the study number of the patient including the procedure for deblinding and notification of the investigators will be mentioned When the whole study is completed the randomization list will be provided to the principle investigator by the pharmacist
6 STUDY PROCEDURES
Withdrawal of individual subjects Patients can leave the study at any time for any reason if they wish to do so without any consequences The responsible investigator can also withdraw a subject if continuing participation is in his opinion deleterious for the subjects well being Patients can also be withdrawn in case of protocol violations and non-compliance When a subject withdraws from the study a medical examination will be performed In case of withdrawal because of a severe or serious adverse event appropriate laboratory tests or other special examinations will be performed Finally patients can be withdrawn from study participation if an incidental finding at the MRI examination - for example a malignancy - influences the ratio of justification versus risks benefits
Specific criteria for withdrawal not applicable
Replacement of individual subjects after withdrawal Patients will not be replaced after withdrawal
Follow-up of subjects withdrawn from treatment Follow-up of patients after withdrawal will be done by the treating physicist general practitioner in most cases Immediately after study withdrawal the treating physicist will be updated on the patients condition and laboratory results and whether the patient was in the control group or intervention group
Premature termination of the study In case of the incidence of three serious adverse events the study will be terminated prematurely and an independent committee will be asked to investigate the safety of the trial Furthermore the investigators will prematurely terminate the study when the number of subjects withdrawn from the study exceeds the number used for sample size calculation ie 16 individuals in total
7 ADVERSE EVENTS SERIOUS ADVERSE EVENTS and SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS
Adverse events AEs
Adverse events are defined as any undesirable experience occurring to a subject during a clinical trial whether or not considered related to the used medication or the infused drugs All adverse events reported spontaneously by the subject or observed by the investigator or hisher staff will be recorded on the adverse event data collection form The intensity of these adverse events will be graded by the investigator as follows
Mild Discomfort noted but no disruption of normal daily activity
Moderate Discomfort sufficient to reduce or affect normal daily activity
Severe Inability to work or perform daily activity All adverse events will be actively queried by asking the question Have you had any complaints since the last time we talkedmet at all visits All adverse events will be followed until they have abated or until a stable situation has been reached Depending on the event follow up may require additional tests or medical procedures as indicated
The chronicity of the event will be classified by the investigator on a three-item scale as defined below
Single occasion Single event with limited duration
Intermittent Several episodes of an event each of limited duration
Persistent Event that remains indefinitely For each adverse event the relationship to the used medication or infused drug definite probable possible unknown definitively not as judged by the investigator will be recorded as well as any actions undertaken in relation to the adverse event will be recorded The occurrence of an adverse event that is fatal life-threatening disabling or requires in-patient hospitalization or causes congenital anomaly will be described according to CHMP guidelines as suspected serious adverse events and will be notified in writing to the Medical Ethics Committee
Furthermore the investigators will copy Novo Nordisk when expediting SARs and SUSARs to competent authorities and will report all SARs related to Novo Nordisk product to Novo Nordisk The submission to Novo Nordisk must however be within day 15 from the investigator getting knowledge about a valid case no matter local timelines for reporting to the authorities All pregnancies in trial patients occurring during use of a Novo Nordisk product must be reported to Novo Nordisk
Serious Adverse Events SAEs
A serious adverse event is any untoward medical occurrence or effect that at any dose
results in death
is life threatening at the time of the event
requires hospitalization or prolongation of existing inpatients hospitalization
results in persistent or significant disability or incapacity
is a congenital anomaly or birth defect
Any other important medical event that may not result in death be life threatening or require hospitalization may be considered a serious adverse experience when based upon appropriate medical judgement the event may jeopardize the subject or may require an intervention to prevent one of the outcomes listed above
The sponsor will report the SAEs to the accredited METC that approved the protocol within 15 days after the sponsor has first knowledge of the serious adverse reactions
SAEs that result in death or are life threatening should be reported expedited The expedited reporting will occur not later than 7 days after the responsible investigator has first knowledge of the adverse reaction This is for a preliminary report with another 8 days for completion of the report
Suspected Unexpected Serious Adverse Reactions SUSARs
Unexpected adverse reactions are SUSARs if the following three conditions are met
1 the event must be serious
2 there must be a certain degree of probability that the event is a harmful and an undesirable reaction to the medicinal product under investigation regardless of the administered dose
3 the adverse reaction must be unexpected that is to say the nature and severity of the adverse reaction are not in agreement with the product information as recorded in
Summary of Product Characteristics SPC for an authorized medicinal product
Investigators Brochure for an unauthorized medicinal product The sponsor will report expedited all SUSARs to the competent authorities in other Member States according to the requirements of the Member States
The expedited reporting will occur not later than 15 days after the sponsor has first knowledge of the adverse reactions For fatal or life threatening cases the term will be maximal 7 days for a preliminary report with another 8 days for completion of the report
SAEs need to be reported till end of study within the Netherlands as defined in the protocol
8 STATISTICAL ANALYSIS
Primary and secondary study parameters
The study endpoints will be analyzed according to intention-to-treat principles All endpoint parameters are continuous variables Data will be calculated as mean SD median percentile range according to nature and distribution of the variable Within group changes from baseline will be tested with independent paired t-test or Wilcoxon signed-rank test Between group differences will be compared after 26 weeks between Liraglutide and control The endpoints will be analyzed using a linear regression model with gender age BMI and HBA1C as covariates For the covariates age BMI and HbA1c in the primary analysis the baseline value will be used The data set for the primary analysis will include data from all subjects with at least one post-baseline measurement Analysis will be performed with SPSS A 2-sided significance level of p 005 will be applied
9 REGULATION STATEMENT
The study will be conducted according to the principles of the Declaration of Helsinki as amended in Tokyo Venice and Hong Kong Somerset West and Edinburgh and in accordance with the Guideline for Good Clinical Practice CPMPICH13595 - 17th July 1996
10 ADMINISTRATIVE ASPECTS MONITORING AND PUBLICATION
Handling and storage of data and documents
Study participants are provided a study name of the letter MV followed by the number of enrollment 1-50 The study name is coupled to a randomly chosen seven - digit study number The study number will be used to register the participant in the Electronic Patient Registry of the LUMC This file will be used as the general patient record as well as collection of routine laboratory measurements needed for clinical and study treatment The MRI images will be filed under this registry so that anonymity will be safeguarded The subject identification code list will be stored by the principal investigator and will only be accessible by the principal investigator and project leader The data extracted from the study file in the Electronic Patient Registry and from the MRI images will be saved in an SPSS file From this file the true identity of the study participants can not be discovered The data will be stored for fifteen years The blood samples will be frozen and stored anonymously using the above mentioned study name and study number For ad hoc laboratory tests of inflammatory endocrine and other biomarkers blood samples will be kept for a maximum period of three years The blood samples are solely accessible by the investigator team
In order to ensure that in medical emergencies the study participation of the patient is apparent each patient will receive a patient file in the electronic patient registry In this personal file the investigator will mention the study number of the patient including the procedure for de-blinding and notification of the investigators In this file the signed Informed Consent form of the patient will be stored
Public disclosure and publication policy The data analysis will be performed by the investigators Novo Nordisk has no role in data analysis and or publication of the results of the trial in peer reviewed papers The results of the study will be submitted to peer reviewed papers also in case the hypothesis has not been proven
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
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2012-001623-12 | EUDRACT_NUMBER | None | None |