Liraglutide in the Treatment of Type 1 Diabetes Mellitus
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 3

Summary: 
      Hypothesis 1: Treatment with Liraglutide in patients with type 1 diabetes decreases fasting,
      postprandial and the overall mean glucose concentrations.

      Aim 1.1: To compare the mean fasting, the mean weekly glucose and the standard deviation of
      weekly blood glucose concentrations as recorded by continuous glucose monitoring prior to and
      following 6 weeks and 12 weeks of treatment with 0.6, 1.2 and 1.8 mg of liraglutide daily. In
      addition, the time spent at glucose concentrations >150 and 200mg/dl and <70 and <40 mg/dl
      will also be compared.

      Aim 1.2: To compare the postprandial glucose concentrations following a test meal before and
      after 12 weeks of treatment with 0.6, 1.2 and 1.8 mg of liraglutide daily. Glucose
      concentrations will be measured as areas under the curve for the data obtained from the meal
      challenge.

      Aim 1.3: To compare HbA1c levels(glycated hemoglobin) before and after 12 weeks of treatment
      with 0.6, 1.2 and 1.8 mg of liraglutide daily Hypothesis 2: Treatment with Liraglutide in
      patients with type 1 diabetes decreases postprandial glucagon concentrations and increases
      postprandial C-peptide concentrations.

      Aim 2.1: To compare fasting and postprandial glucagon and C-peptide concentrations following
      a test meal before and after 12 weeks of treatment with 0.6, 1.2 and 1.8 mg of liraglutide
      daily.

      Hypothesis 3: Treatment with Liraglutide in patients with type 1 diabetes delays gastric
      emptying.

      Aim 3.1: To compare the gastric emptying as measured by acetaminophen absorption before and
      after 12 weeks of treatment with 0.6, 1.2 and 1.8 mg of liraglutide daily.
    

Detailed description: 
      RESEARCH DESIGN AND METHODS This investigation will be a prospective, randomized, double
      blind, placebo controlled study conducted in type 1 diabetics. The study will be conducted at
      Diabetes - Endocrinology Center of WNY at Millard Fillmore Hospital, affiliated to the State
      University of New York at Buffalo.

      Study Population: Seventy two patients with type 1 diabetes on treatment with either
      continuous subcutaneous insulin infusion (CSII; also known as insulin pump) or multiple (four
      or more) injections of insulin per day will be included in the study. They will be randomized
      into 4 groups of 18 patients each. The patients will be randomized to placebo or 0.6 mg, 1.2
      mg or 1.8 mg liraglutide daily. In view of the possibility of hypoglycemia and the side
      effect of nausea all patients will be started on 0.6 mg of liraglutide per day. The dose will
      then be titrated up to 1.2 and 1.8 mg on a weekly basis. No increases will be made once the
      target dose has been achieved in each group. Subjects will be recruited from our own
      patients, our existing database and from advertisements. The following insulin preparations
      will be used in the study: insulin detemir, glargine, aspart, glulisine and lispro. Subjects
      will continue to obtain their insulin supplies from their respective pharmacies.

      STUDY DESIGN:

      Screening Day (day -14):- Each patient will have completed the following procedures prior to
      participating in the study.

        1. Medical History;

        2. Physical Exam;

        3. Informed consent.

        4. Baseline lab draw to measure Complete blood count, comprehensive metabolic panel, Hba1c
           and lipid profile. All labs will be drawn in the fasting state in the morning before
           10am.

      Randomization Visit (day -7)

      Randomization Method: After the screening visit, subjects who meet the inclusion and
      exclusion criteria, will be assigned a number by a computerized random number generation
      program (Microsoft office - Excel) and randomized to receive subcutaneous injection daily of
      either Liraglutide 0.6mg (18 subjects), 1.2 mg (18 subjects), 1.8 mg (18 subjects) or placebo
      (18 subjects) for 12 weeks. The subjects and the study coordinators will be blinded to the
      treatment. The Liraglutide/placebo will be administered via a pen kit (obtained from Novo
      Nordisk Pharmaceuticals). The dose will be given in the morning. The sponsor is providing
      study medication in blinded form.

      All subjects will be instructed by the study staff in the dosing and administration of the
      study medication and will be seen by a Certified Diabetes Educator for instruction on
      injection technique. All subjects will also be seen by a registered dietitian who will review
      their carbohydrate counting and diet and make an assessment of their calorie and carbohydrate
      intake. The subjects will be randomized but will not start the placebo or liraglutide
      injection till study intervention visit 1.

      All subjects will be advised to monitor their capillary blood glucose by fingerstick before
      and 2 hours after each meal and to wear their CGM constantly for the duration of the study
      The subjects will be asked to keep a diary of their food intake to measure their calorie
      intake. For the entire duration of the study, the patients will maintain a diary to record
      any hypoglycemia and other untoward side effects like nausea, changes in appetite and other
      experiences. Patients will be instructed to call the Diabetes Center or an endocrinology
      fellow directly in case of any problem or untoward side effects. They will be specifically
      asked to call if they have hypoglycemia (blood sugar <70 mg/dl) or hyperglycemia (blood sugar
      >250 mg/dl) on more than one occasion.

      Study Intervention Visit 1 day 0:- Subjects will come fasting for this visit. Records of
      blood glucose concentrations monitored by fingerstick and CGM for the previous 7 days will be
      obtained to assess their glycemic control prior to liraglutide treatment. They will undergo a
      meal challenge test (described below), Liraglutide or placebo injections at a dose of 0.6 mg
      per day will then be started. No reduction will be made in the dose of pre-prandial insulin
      boluses and basal insulin if A1C is greater than or equal to 7.5%. Subjects will decrease the
      dose of pre-prandial insulin boluses by 25% and the basal by 25% if their A1C is less than or
      equal to 7%. Subjects will decrease the dose of pre-prandial insulin boluses and basal
      insulin by 10% if the A1C is between 7 and & 7.5%. This reduction is based on our experience
      (see preliminary data). Careful adjustments will be made to insulin doses at the discretion
      of the investigators on the basis of the glucose data obtained from the patients. The target
      blood glucose will be preprandial 90-120mg/dl and 2hour PP < 140mg/dl, without increasing the
      incidence of blood glucose < 70mg/dl. Patients will return to the center after 7 days

      Study Intervention Visit 2 day 7:- Blood glucose concentrations will be reviewed. Insulin
      dose will be adjusted at the discretion of the study investigator to optimize blood sugar
      control as per the targets mentioned above on day 0 visit. Patients will be advised to
      increase the Liraglutide dose to 1.2 mg a day in those whose target dose is 1.2 or 1.8 mg.
      They will return in 7 days.

      Study Intervention Visit 3 day 14:- Blood glucose concentrations will be reviewed. Insulin
      dose will be adjusted at the discretion of the study investigator to optimize blood sugar
      control as per the targets mentioned above on day 0 visit. Patients with a target dose of 1.8
      mg will be advised to increase the dose while others will continue on their previous dose.
      They will return in 7 days.

      Study Intervention Visit 4 day 21, Visit 5 day 28:

      Records of blood glucose concentrations of the last 7 days will be collected. Insulin dose
      will be adjusted at the discretion of the study investigator to optimize blood sugar control
      as per the targets mentioned above on day 0 visit.

      Study Intervention Visit 6 day 42, Visit 7 day 56, Visit 8 day 70:

      Records of blood glucose concentrations of the last 15 days will be collected. Insulin dose
      will be adjusted at the discretion of the study investigator to optimize blood sugar control
      as per the targets mentioned above on day 0 visit.

      Study Intervention Visit 9 day 84 Subjects will come fasting for this visit. Records of blood
      glucose concentrations monitored by fingerstick or CGM for the previous 7 days will be
      obtained to assess their glycemic control. They will undergo meal challenge test (described
      below). After this visit, subjects will be discharged from the study.

      Meal challenge test:- In order to assess the changes induced by liraglutide, a meal challenge
      will be carried out prior to and following liraglutide (day 0 and day 84). (910 Calorie High
      fat High carbohydrate meal as in several of our previous papers). Acetaminophen (1000 mg for
      body weight <70 kg or 1500 mg for body weight >70 kg) will be ingested at the beginning of
      the meal, and the blood levels of acetaminophen will be determined at intervals for
      assessment of the rate of gastric emptying. Bolus Insulin will be injected immediately before
      the meal based on the insulin carbohydrate ratio and correction factor for each individual
      subject. Liraglutide will be injected only on day 84 (45 min prior to the meal). Sequential
      blood samples will be obtained at 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 and 300 min.
      Samples at 15, 30, 45, 90, 150 and 210 min will be 5 ml while those at 0, 60, 120, 180, 240
      and 300 min will be 30 ml (total volume=210 ml). Blood will be collected from an indwelling
      intravenous canula in a superficial forearm vein.

      Data safety and monitoring:

      Timely, accurate, and complete reporting and analysis of safety information obtained from
      clinical trials are crucial for the protection of subjects and investigators.

      All subjects will be referred to liraglutide's labeling safety information, and will be
      provided a copy of the package insert of the medication. Discussion of the potential side
      effects and the different warning and precautions will take place at the time of signing the
      informed consent.

      The following Information from the boxed warning in the package insert regarding the risk of
      thyroid c-cell tumors will be discussed in details with all participating subjects
      "Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at
      clinically relevant exposures in both genders of rats and mice. It is unknown whether
      Liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in
      humans, as human relevance could not be ruled out by clinical or nonclinical studies.
      Liraglutide is contraindicated in patients with a personal or family history of MTC and in
      patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in
      rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical
      trials, but this may have increased the number of unnecessary thyroid surgeries. It is
      unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human
      risk of thyroid C-cell tumors."

      In addition, the following FDA text regarding the risk of developing fibrosarcomas will be
      discussed with all participating subjects "In a 2-year repeat subcutaneous dose
      carcinogenicity study of liraglutide injected once a day in CD-1 mice, a treatment-related
      increase in fibrosarcomas was seen on the dorsal skin and subcutis, the body surface used for
      drug injection, in males in the 3 mg/kg/day group. These fibrosarcomas were attributed to the
      high local concentration of drug near the injection site. The liraglutide concentration in
      the clinical formulation (6 mg/mL) is 10 times higher than the concentration in the
      formulation used to administer 3 mg/kg/day liraglutide to mice in the carcinogenicity study
      (0.6 mg/mL)".

      All Adverse events(AEs) will be reported at the time of the visit or by telephone when it
      occurs. Those meeting the definition of Serious Adverse Events(SAE's) must be reported using
      the SAE Form. Medical events that occur between the signing of the Informed Consent and the
      first intake of study drug will be documented in the medical history. Subjects should
      voluntarily report any AEs or in response to general, non-directed questioning. For each AE
      volunteered by the subject, the investigator will obtain all the information required to
      complete the AE page of the Case Report Form(CRF), in accordance with the guidelines that
      accompany it.

      All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, will
      be recorded using medical terminology in the source document and on the CRF. Whenever
      possible, diagnoses will be given when signs and symptoms are due to a common etiology (e.g.,
      cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper
      respiratory infection). Investigators will record on the CRF their opinion concerning the
      relationship of the AE to study therapy. All measures required for AE management will be
      recorded in the source document and reported according to sponsor instructions.
    

Intervention name(s): Liraglutide; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Patients randomized to 1.2 mg of liraglutide : They will start liraglutide 0.6 mg sc once daily for one week and will increase the dose to 1.2 mg sc once daily thereafter.
Patients randomized to 1.8 mg of liraglutide: They will start liraglutide 0.6 mg sc once daily for one week; will increase to 1.2 mg sc once daily for second week and will stay on 1.8 mg of liraglutide from third week onwards.; Patients randomized to 1.2 mg of placebo: They will start placebo 0.6 mg sc once daily for one week and then increase to 1.2 mg once daily thereafter.
Patients randomized to 1.8 mg of placebo: They will start placebo 0.6 mg sc once daily for one week; increase to 1.2 mg sc once daily for second week and then to 1.8 mg sc once daily from third week onwards.
Other intervention name(s): Victoza
Intervention MeSH terms: Liraglutide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Liraglutide; Glucagon; Systolic blood pressure; Weight; Carbohydrate intake; Insulin dose; HbA1c; Post-prandial glucagon