Effect of Liraglutide on Cardiovascular Endpoints in Diabetes Mellitus Type 2 Patients of South Asian Descent

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. 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 patient's treating physician and general practitioner will be notified.

SAMPLE SIZE CALCULATION

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. With a power of 90% and alfa = 0.05, 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 = 0.05 with 25 patients in each group.

USE OF CO-INTERVENTION

Patients should continue to use the oral glucose lowering medicaments during the study. For glycaemic control after initiation of the study drug, the current clinical guideline will be followed.

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.

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.

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 1:1 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.

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 subject's wellbeing. 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, after the first dose of study medication. However, patients may be replaced when withdrawal took place between randomization and administration of the first dose of study medication (for example withdrawal on the first study day due to claustrophobia).

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 patient's 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, i.e. 16 individuals in total.

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 his/her 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 talked/met?" 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;
• Investigator's 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

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. Analysis will be performed with SPSS. A 2-sided significance level of p < 0.05 will be applied.

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 (CPMP/ICH/135/95 - 17th July 1996).

ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION

Handling and storage of data and documents:

Study participants are provided a study name of the letter "MAVI" followed by the number of enrolment (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.